MXPA00001586A - Process for the creation of an optical plane that generates a three-dimensional vision. - Google Patents

Abstract

The invention refers to the creation of an optical plane (A-A1) that generates a three-dimensional vision by means of a window (2) or hole that is incorporated into sports instruments such as a golf club (3) or other objects such as tennis rackets, baseball bats, hockey sticks, skateboards and sports shoes. The optical perspective created by means of the window (2) incorporated produces information from the exterior, creating a response of increased hold, grip, equilibrium, coordination and control, thus improving the handling of the sport instrument.

Description

NEW IDINA DERIVATIVES Field of the Invention This invention relates to new amidine derivatives, to processes for their preparation, to compositions containing them and to their use in therapy.

Background of the Invention Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes - constitutive NOS (cNOS) and inducible NOS (iNOS). In the present, two constitutive NOSs have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and regulation of blood pressure and blood flow, while the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of several biological functions such as cerebral ischemia. The inducible NOS have been implicated in the pathogenesis of inflammatory diseases Ref. 031842. The specific regulation of these enzymes must therefore offer considerable potential in the treatment of a wide variety of disease states. Compounds of various structures have been described as NOS inhibitors and their use in therapy has been claimed. See, for example, WO 95/09619 (The Wellcome Foundation) and WO 95/11231 (G.D. Searle). The Applicant has previously described in WO 95/05363 and WO 96/01817 amidine derivatives which are inhibitors of NOS that exhibit some selectivity for the inhibition of the neuronal enzyme, ncNOS. A group of amidines which are within the generic scope of WO 96/01817 are now described, but which are not specifically exemplified in WO 96/01817. These compounds exhibit surprisingly advantageous properties and are the subject of the present application.

Description of the invention According to the invention there is provided a compound of the formula (I) wherein: R1 represents a 2-thienyl or 3-thienyl ring; and R2 represents alkyl with 1 to 4 carbons; and the optical isomers and racemates thereof and pharmaceutically acceptable salts thereof. Preferably R1 represents 2-thienyl. Particularly preferred compounds of the invention include: N- (2-methyl-1,2,3-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2-isopropyl-1,2,4,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2-propyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; N- (2-methyl-1,2,4,4-tetrahydroisoquinolin-7-yl) -3-thiophenecarboximidamide; and pharmaceutically acceptable salts thereof.

A more preferred preferred compound of the invention is: N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; and pharmaceutically acceptable salts thereof. Unless otherwise indicated, the term "1-4 carbon alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. The present invention includes the compounds of the formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable, although salts of the pharmaceutically unacceptable acids may be useful in the preparation and purification of the compound in question. Accordingly, the preferred salts include those formed of hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulfonic and benzenesulfonic acids.

In accordance with the invention, there is further provided a process for the preparation of the compounds of the formula (I), and the optical isomers and racemates thereof and the pharmaceutically acceptable salts thereof, which comprises: preparing a compound of the formula (I) by ionating a corresponding compound of the formula wherein 2 is as defined above, with a compound of the formula (III) or an acid addition salt thereof wherein R1 is as defined above and L is a separation group; b) preparing a compound of the formula (I) by reacting a corresponding compound of the formula (IV) wherein 2 is as defined above and HA is an acid, with a compound of the formula (V) R1 = N (V) wherein R1 is as defined above; (c) preparing a compound of the formula (I) by reacting a compound of the formula (VI) wherein R is as defined above, with a compound of the formula (VII) R2 L (VII) wherein R2 represents alkyl with 1 to 4 carbons and L is a separation group, or (d) preparing a compound of the formula (I) in which R 2 represents methyl, by reacting a compound of the formula (VI) with formaldehyde and formic acid; and wherein it is desirable or necessary to convert the resulting compound of the formula (I), or other salt thereof, into a pharmaceutically acceptable salt thereof, or vice versa, and where desired, convert the resulting compound of the formula ( I) in an optical isomer thereof. In process (a), the reaction will be carried out by stirring a mixture of the reactants in a suitable solvent, for example, N-methyl-2-pyrrolidinone or a lower alkanol such as ethanol, isopropanol or tertiary butanol, at a temperature between the ambient temperature and the reflux temperature of the solvent. The reaction time will depend inter alia on the solvent and on the nature of the separation group, and can be up to 48 hours; however, it will typically be from 1 to 24 hours. Suitable spacing groups that L may represent include thioalkyl, sulfonyl, trifluoromethyl sulfonyl, halide, alkyl alcohols, aryl and tosyl alcohols; others are described in 'Advanced Organic Chemistry', J. March (1985) 3 / a. Edition, on page 315 and are well known in the art. In process (b), the reaction is preferably carried out by refluxing a mixture of the two compounds for several hours in the presence of a suitable solvent whereby the reaction temperature is sufficiently high so that the condensation is carried out quickly, 'but not so high that the amidine formed is decomposed. The temperature of the reaction can be varied from room temperature to about 250 ° C, although it is preferable to carry out the reaction at temperatures from about 100 ° C to 200 ° C. It was found that o-dichlorobenzene is a particularly suitable solvent. It was also found that it is often useful to add 4-dimethylaminopyridine as a catalyst. During cooling, two layers are formed, the solvent can be decanted, and the reaction worked by the addition of an aqueous base. Alternatively, where the reactants are soluble in the solvent, the solvent can be removed by evaporation under vacuum and the reaction mixture worked by the addition of water. The acid HA can be an organic or inorganic acid, for example, hydrochloric, hydrobromic, iohydric, sulfuric, nitric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic or methanesulfonic acid. It is preferred that the HA is a hydrohalic acid. In process (c) the reaction will be carried out under standard conditions, for example by reacting the two compounds in an inert solvent such as DMF under basic conditions at a suitable temperature, typically room temperature, for a period of up to 72 minutes. hours or until the reaction is complete. It has been found desirable to treat the amine with NaH before reacting it with the compound of the formula (VII). Suitable groups of separation L are mentioned above. It is preferred that L represents halide, particularly bromide. In process (d), the reaction will typically be carried out by refluxing the reaction mixture for up to 4 hours or until the reaction is complete. The salts of the compounds of the formula (I) can be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction can be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by the subsequent removal of the solvent in vacuo or by spray dehydration. Suitable solvents include, for example, water, dioxane, ethanol, isopropanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction can be a metathetic process or it can be carried out on an ion exchange resin. The compounds of the formula '(II) can be prepared by the reduction of a corresponding compound of the formula (VIII) wherein R2 is as defined above. The reduction reaction can be carried out under various conditions, for example those described in J. March "Advanced Organic Chemistry" on pages 1103-1104. These include catalytic hydrogenation, the use of a metal of Zn, Sn or Fe, AIH3-AICI3, sulfides and others. It is preferred to carry out the reaction by hydrogenation at atmospheric pressure in the presence of a palladium and carbon catalyst until the reaction is complete, typically 3 to 6 hours, or by reduction using the zinc metal in acetic acid and methanol. The compounds of the formula (VIII) can be prepared by the nitration of a compound of the formula (IX) wherein R2 is as defined above. The nitration reaction will be carried out under conditions well known to a person skilled in the art, for example, during treatment with nitric acid and sulfuric acid or potassium nitrate and sulfuric acid, optionally in an inert organic solvent. It may also be convenient to prepare compounds of the formula (VIII) by nitration of a carbonyl or dicarbonyl derivative of a compound of the formula (IX); such a nitro carbonyl or dicarbonyl derivative can be reduced to the desired compound of the formula (VIII) using, for example, diborane. The compounds of the formula (VIII) and (IX), as well as certain carbonyl and dicarbonyl derivatives of the aforementioned compounds of the formula (IX), can also be prepared by one of the numerous methods for the preparation of the heterocyclic compounds bicycles. Accordingly, a compound of the formula (X) can be prepared by the ring expansion of a cyclic ketone (XI) by treatment with sodium azide in acid (Grunewald and Dahanukar, J. Heterociclyc Chem., 1994, 31, 1609-1617). It will be apparent to a person skilled in the art that the compounds of the formula (X) can also be desirably prepared in the nitrated form. Nitration can be achieved by the treatment of the non-nitrated analogue with nitric acid and sulfuric acid or potassium nitrate and sulfuric acid under standard conditions. The intermediate compounds can be prepared as such or in the protected form. In particular, the amine groups can be protected. Suitable protective groups are described in the standard text "Protective Grpups in Organic Synthesis", 2 / a. Edition (1991) by Greene and Wuts. Amine protecting groups which may be mentioned include alkyloxycarbonyl such as t-butyloxycarbonyl # phenylalkyloxycarbonyl such as benzyloxycarbonyl, or trifluoroacetate. The deprotection can be carried out normally during the treatment with an aqueous base or aqueous acid. The compounds of the formula (VIII) and (IX) in which R 2 represent alkyl with 1 to 4 carbon atoms can also. be prepared by the alkylation of the corresponding N-H compound following the process (c) above. The compounds of the formula (IV) can be prepared by processes analogous to those described for the preparation of the compounds of the formula (II). The compounds of the formula (IV) can be converted into the corresponding compounds of the formula (II) by the treatment with a base. The compounds of the formula (II) can be converted into the corresponding compounds of the formula. (IV) by treatment with an HA of protic acid, for example, one of those listed above. The compounds of the formula (III) are either known or can be prepared by the known methods. For example, the compounds of the formula (III) in which L represents thioalkyl can be prepared by the treatment of the corresponding thioamide of the formula (XII) wherein it is as defined above, with an alkyl halide under conditions well known to a person skilled in the art. Alternatively, the acid addition salts of the compounds of the formula (III) wherein L is thioalkyl can be prepared by the reaction of a nitrile of the formula (V) with an alkyl thiol and acid, for example hydrochloric acid, in a solvent such as dichloromethane or diethyl ether.

The compounds of the formula (V), (VII), (X), (XI) and (XII) are either known or can be prepared by conventional methods known per se. It will be apparent to a person skilled in the art that it may be desirable to protect an amine or other reactive group in an intermediate compound using a protecting group as described in the standard text "Protective Groups in 'Organic Synthesis", 2 / a. Edition (1991) by Greene and Wuts. Suitable amine protecting groups are mentioned above. The compounds of the invention and the intermediates can be isolated from their reaction mixtures, and if necessary further purified, using standard techniques. The compounds of the formula (I) may exist in the tautomeric, enantiomeric or diastereomeric forms, all of which are included within the scope of the invention. The various optical isomers may be isolated by the separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallization or HPLC. Alternatively, the individual enantiomers can be made by reacting the appropriate optically active starting materials under reaction conditions which do not cause racemization. Intermediates can also exist in the enantiomeric forms and can be used as enantiomers, diastereoisomers, racemates or purified mixtures. The compounds of the general formula (I) possess a useful nitric oxide synthase inhibitory activity, and in particular, they exhibit good selectivity for the inhibition of the neuronal isoform of nitric oxide synthase. They are therefore useful in the treatment or prophylaxis of human conditions or diseases or the conditions in which the synthesis or oversynthesis of nitric oxide by nitric oxide synthase forms a contributing part. Examples of such diseases or conditions include hypoxia, such as in cases of cardiac arrest, attacks and neonatal hypoxia, neurodegenerative conditions that include nerve degeneration and / or necrosis of the nerves in disorders such as ischemia, hypoxia. , hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injuries), hyperbaric oxygen seizures and toxicity, dementia, eg, pre-senile dementia, Alzheimer's disease and AIDS-related dementia , Sydenham's chorea, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, orsakoff's disease, imbecility related to a cerebral vessel disorder, sleep disorders, schizophrenia, anxiety, depression, seasonal affective illness, depression by aircraft delays, depression or other symptoms associated with Premenstrual Syndrome (???), anxiety and shock I know optical The compounds of formula (I) are also useful in the treatment and relief of acute or persistent neuropathic or inflammatory pain, or pain of central origin, and in the treatment or prophylaxis of inflammation. The compounds of the formula (I) are also predicted to show activity in the prevention and reversal of tolerance to opiate substances and diazepines, the treatment of drug addiction and the treatment of migraine and other vascular headaches. The compounds of the present invention may also show useful immunosuppressive activity, and be useful in the treatment of gastrointestinal motility disorders, and in the induction of labor. The compounds may also be useful in the treatment of cancers that express nitric oxide synthase.

The compounds of the formula (I) are predicted to be particularly useful in the treatment or prophylaxis of hypoxia or attacks or ischemia or neurodegenerative conditions or schizophrenia or migraine or for the prevention and reversal of tolerance to opiate substances and diazepines or for the treatment of drug addiction or for the treatment of pain and especially in the treatment or prophylaxis of hypoxia or attacks or ischemia or neurodegenerative disorders or schizophrenia or pain. Applicants are particularly interested in the selected conditions of the group consisting of hypoxia, ischemia, attacks, pain, schizophrenia, Parkinson's disease, Hungtington's disease and Amyotrophic Lateral Sclerosis. For the treatment of Parkinson's disease, the compounds of the formula (I) are expected to be particularly useful either alone, or in combination with other agents such as L-Dopa.- For the treatment of pain, the compounds of Formula (I) is expected to be particularly useful either alone, or in combination with other agents such as opiate substances, particularly morphine.

Prophylaxis is expected to be particularly relevant to the treatment of people who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. People at risk of developing a particular disease or condition generally include those who have a family history of the disease or condition, or those who have been identified by the particular test or selection so that they are particularly susceptible to developing the disease or condition. Accordingly, according to a further aspect of the invention there is provided a compound of the formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament. According to another characteristic of the invention, there is provided the use of a compound of the formula (I) or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of the aforementioned diseases or conditions, and a method of treatment or prophylaxis of one of the diseases or conditions mentioned above, which comprises administering a therapeutically effective amount of a compound of the formula (I), or an optical isomer or racemate of the same or a pharmaceutically acceptable salt thereof, to a person suffering from or who is susceptible to such disease or condition. For the therapeutic indications mentioned above, the dosage administered, of course, will vary with the compound employed, the mode of administration and the desired treatment. However, satisfactory results are generally obtained when the compounds are administered to a human being at a daily dose of between 0.5 mg and 2000 mg (measured as the active ingredient) per day, particularly at a daily dose of between 2 mg and 500 mg. mg. The compounds of the formula (I), and the optical isomers and racemates thereof and the pharmaceutically acceptable salts thereof, may be used by themselves, or in the form of appropriate medicinal formulations. The administration may be, but is not limited to, the enteral route (including oral, sublingual or rectal), intranasal, or topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988. In accordance with the invention, a pharmaceutical formulation is provided which preferably comprises less than 95% by weight and more preferably less than 50% by weight of a compound of the formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, mixed with a diluent. or pharmaceutically acceptable carrier. The formulation may also optionally contain a second pharmacologically active ingredient such as L-Dopa, or an analgesic of opiate substance such as morphine. A method of preparing such a pharmaceutical formulation is also provided, which comprises mixing the ingredients. Examples of such diluents and carriers are: for tablets and dragees: lactose, starch, talc, stearic acid; for the capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: oils or natural or hardened waxes. Compositions in a form suitable for oral, ie esophageal, administration include: tablets, capsules and lozenges, sustained release compositions include those in which the active ingredient is bound to an ion exchange resin which is optionally coated with an diffusion barrier to modify the release properties of the resin. The enzyme nitric oxide synthase has a number of isoforms and compounds of the formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, may be selected to verify the nitric oxide synthase inhibitory activity following the procedures based on those of Bredt and Snyder in Proc. Nati Acad. Sci. , 1990, 87, 682-685. Nitric oxide synthase converts 3H-L-arginine to 3H-L-citrulline which can be separated by cation exchange chromatography and quantified by scintillation counting.

Selection for the inhibitory activity of neuronal nitric oxide synthase The enzyme is isolated from the hippocampus or cerebellum of the rat. The hippocampus or cerebellum of a male Sprague-Dawley rat (250-275 g) is removed following anesthesia with CO2 from the animal and decapitation. The supernatant of the cerebellum or hippocampus is prepared by homogenization in 50 mM Tris-HCl with 1 mM EDTA buffer (pH 7.2 at 25 ° C) and centrifugation for 15 minutes at 20,000 g. The residual L-arginine is removed from the supernatant by chromatography through sodium and hydrogen columns Dowex AG-50W-X8 successively, and further centrifugation at 1000 g for 30 seconds. For the test, · 25 μ are added? of the final supernatant to each of the 96 cavities (of a 96-well filter plate) containing either 25 μ? of a test buffer solution (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, pH 7.) or 25 μ? of the test compound in the buffer at 22 ° C and 25 μ? of the complete buffer solution (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, 1 mM DTT, 100 μMADPH, 10 μg / ml calmodulin, pH 7.4). Following a 10-minute equilibrium period, 25 μ? of a solution of L-arginine (with a concentration of 18 μl 1 H-L-arginine, 96 nM of 3 H-L-arginine) to each cavity to initiate the reaction. The reaction is stopped after 10 minutes by the addition of 200 μ? of a suspension of • the termination buffer (20 mM HEPES, 2 mM EDTA, pH 5.5) and Dowex AG-50W-X8 200-400 mesh. The labeled L-citrulline is separated from the L-arginine labeled by the filtration of each filter plate and 75 μ? of each completed reaction are added to 3 ml of the cocktail of scintillations. The L-citrulline is then quantified by scintillation counting. In a typical experiment using the cerebellar supernatant, the basal activity is increased by 20,000 dpm / ml of the sample above a layer of the reagent which has an activity of 7,000 dpm / ml. A reference standard, N-nitro-L-arginine, which provides 80% inhibition of nitric oxide synthase at a concentration of 1 Jim, is tested in the assay to verify the procedure.

Selection for the inhibitory activity of nitric oxide, endothelial synthase The enzyme is isolated from endothelial cells of the human umbilical vein (HUVECs) by a procedure based on that of Pollock et al in Proc. Nati Acad. Sci., 1991, 88, 10480-10484. The HUVECs were purchased from Clonetics Corp (San Diego, CA, USA) and cultivated until confluence. The cells can be maintained to go from 35-40 without significant loss of nitric oxide synthase production. When the cells reach confluence, they are resuspended again in a saline solution buffered with Dulbecco's phosphate, centrifuged at 800 rpm for 10 minutes, and the microsphere of the cells is then homogenized in ice-cold 50 mM Tris-HCl, 10% glycerol, 1 mM phenylmethylsulfonyl fluoride, 2 μ? of leupeptin at pH 4.2. Following centrifugation at 34,000 rpm for 60 minutes, the microsphere is solubilized in the homogenization buffer which also contains 20 mM CHAPS. After a 30 minute incubation on ice, the suspension is centrifuged at 34,000 rpm for 30 minutes. The resulting supernatant is stored at -80 ° C until use. For under test, 25 μ? of the final supernatant are added to each of the 12 sample tubes containing 25 μ? of the solution of L-arginine (concentration of 12 μ? 1H-L-arginine, 64 nM 3H-L-arginine) and either 25 μ? of a test buffer solution (50 mM HEPES, 1 mM EDTA, 1.5 mM EDTA, 1.5 mM CaCl2, pH 7.4.) or 25 μm of the test compound in the buffer at 22 ° C. 25 μl of the complete assay buffer is added (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl2, 1 mM DTT, 100 μm NADPH, '10 g ml of calmodulin, 12 μ? of tetrahydrobiopterin, pH 7.4) to start the reaction and the reaction is stopped after 10 minutes by the addition of 2 ml of a buffer buffer (20 mM HEPES, 2 mM EDTA, pH 5.5). The labeled L-citrulline is separated from the L-arginine labeled by chromatography on a 200-400 mesh Dowex AG-50W-X8 column. A 1 ml portion of each finished reaction mixture is added to a 1 ml single column and the eluent combined with that of two 1 ml and 16 ml distilled water washes from the scintillation cocktail. The L-citrulline is then quantified by counting the scintillations. In a typical experiment, the basal activity is increased by 5,000 dpm / ml of the sample above a layer of reagent which has an activity of 1500 dpm / ml. A standard, reference N-nitro-L-arginine, which provides 70-90% of the inhibition of nitric oxide synthetase at a concentration of 1 μ ?, is tested in the assay to verify the procedure. In the selections to verify nitric oxide synthase inhibition activity, the activity of the compound is expressed as the IC50 (the concentration of the drug substance which provides 50% inhibition of the enzyme in the assay). The IC 50 values for the test compounds were initially estimated from the inhibitory activity of 1, 10 and 100 μ? of the solutions of the compounds. The compounds that inhibited the enzyme by at least 50% at 10 μ? they were retested using more appropriate concentrations so that an IC50 could be determined. When tested in the above selections, the compounds of Examples 1 to 6 below show IC 50 values for the inhibition of neuronal nitric oxide synthase of less than 10 μ? and a good selectivity for the inhibition of the neuronal isoform of the enzyme, indicating that they are predicted to show a particularly useful therapeutic activity. When compared to other compounds, the compounds of the formula (I), and the optical isomers and racemates thereof and the pharmaceutically acceptable salts thereof, have the advantage that they can be less toxic, more effective, longer acting, which have a broader range of activity, more potent, more selective for the neuronal isoform of the nitric oxide synthase enzyme, which produce fewer side effects, which are more readily absorbed or which have other useful pharmacological properties. The invention is illustrated by the following examples.

Example 1 N- (2-Methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide dihydrochloride a) 2-Methyl-7-nitro-l, 2, 3, 4-tetrahydroisoquiline hydrochloride The 7-nitro-1, 2, 3, 4-tetrahydroisoquinoline (20 g, 93.2 mmol), formaldehyde (37% solution in water, 50 ml) and formic acid (90 ml) is heated at reflux for 1 hour, cool and pour on ice. The reaction mixture is basified with concentrated ammonium hydroxide. The precipitated solid is collected, dissolved in hot ethanol (200 ml), acidified with a mixture of 95% ethanol-conc HCl, and the product is allowed to crystallize. The title compound was obtained as a white solid (18.71 g, 87.8%), m.p. 256-257 ° C. b) 2-Methyl-l, 2, 3, 4-tetrahydroisoquinolin-7-ylamine hydrochloride 2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride is dissolved in methanol and hydrogenated at 3.52 kg / cm2 (50 psi) in the presence of a catalytic amount of 10% Pd-C . After 1 hour the mixture is filtered through the glass and evaporated to give 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine hydrochloride, m.p. 137-138 ° C. c) 2-thiophenecarboximidothioic acid ethyl ester hydrochloride To a stirred solution of ethantiol (2.8.4 g, 0.45 moles) in. Methylene chloride (500 ml) at 10 ° C under nitrogen is added 2-thiophenecarbonitrile (50.0 g, 0.45 mol). This solution is treated with a slow gas stream of HC1 for 6 hours. The reaction mixture is then allowed to warm to room temperature for 18 hours. The ether (200 ml) is added and a white solid crystallizes. The ethyl ester hydrochloride of 2-thiophenecarboximidothioic acid is collected by filtration and dried with air (65.8 g), m.p. 196-197 ° C. d) N- (2-methyl-1,2,3-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide dihydrochloride 2-Methyl-1,2,3-tetrahydroisoquinolin-7-ylamine hydrochloride (34.66 g) in 95% ethanol (600 ml) is heated to 65 ° C to dissolve most of the solids, and the mixture Allow it to cool then with agitation. The next day, the fine suspension of the solids is treated with 2-thiophenecarboxyimidothioic acid ethyl ester hydrochloride (41 g) and stirred at 23 ° C. All solids dissolved at 2 hours, and at 4 hours new solids were precipitated. The mixture is treated with concentrated hydrochloric acid (2 ml). The mixture is cooled to 0 ° C and stirred for 30 minutes. The solids are removed by filtration, washed with ethanol (2 x 50 mL), and air dried to provide the N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) dihydrochloride. 2-thiophenecarboximidamide, p. f. 142-146 ° C; MS m / z 272 [M + H] +.

Example 2 N- (2-Isopropyl-1,2,4,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide To a stirred solution of N- (1,2,4,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide (7.0 g, 21 mmol) in dimethylformamide (100 ml) is added potassium carbonate (14.6 g, 100 g). mmoles). To this mixture is added 2-bromopropane (5.1 g, 42 mmol), and the mixture is then heated at 40 ° C for 72 hours. The.

The reaction mixture is poured into water (500 ml) and extracted with ethyl acetate (3 x 100 ml). The combined ethyl acetate extracts are washed with water (200 ml) and dried over magnesium sulfate. Evaporation of the solvent produced a crude oil, which was then dissolved in hot cyclohexane (250 ml) and ethyl acetate (10 ml). After standing the title compound was crystallized and collected by filtration (3.2 g), m.p. 110-111 ° C.

Example 3 N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide hydrochloride a) 2-ethyl-7-nitro-l, 2, 3,4-tetrahydroisoquinoline hydrochloride To the 7-nitro-1,2,3,4-tetrahydroisoquinoline (5 g, 30 mmol) in acetonitrile (100 mL) is added ethyl methanesulfonate (6.38 g, 60 mmol) and potassium carbonate (5 g). The mixture is heated at 40 ° C for 18 hours. The mixture is filtered and concentrated to an oil. The oil is dissolved in methanol and treated with isopropanol-HCl. The hydrochloride salt is collected by filtration (4.89 g, 67%), m.p. 259-260 ° C. b) 2-Ethyl-l, 2, 3, 4-tetrahydroisoquinolin-7-ylamine hydrochloride The hydrochloride of 2-ethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (4.89 g) is dissolved in methanol (250 ml) and hydrogenated at 3.52 kg / cm2 (50 psi) in the presence of a catalytic amount of 5% Pd-C. After 1 h the mixture is filtered through the glass and evaporated to an oil which was used immediately in the next step. c) N- (2-ethyl-l 2,3, 4- tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide hydrochloride To the hydrochloride. from 2-ethyl-l, 2, 3, 4-tetrahydroisoquinolin-7-ylamine (2.48 g, 10 mmol) in isopropanol (25 mL) is added the 2-thiophenecarboximidothioic acid methyl ester hydroiodide (5.68 g, 20 mmol) ). The mixture is heated at 50 ° C for 24 hours. The mixture is poured into water (50 ml), then into basic water (150 ml). The mixture is extracted with ethyl acetate (3 x 100 mL). The extracts are washed with water, dried with magnesium sulfate, filtered, and concentrated to an oil which crystallizes during rest. The solids are dissolved in ether and treated with isopropanol-HC1. The solids were collected by filtration (1.41 g, 49%), m.p. 122-126 ° C.

Example 4 N- (2-propyl-l, 2, 3,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide dihydrochloride d) Hydrochloride of 7-nitro-2-propyl-l, 2, 3, 4-tetrahydroisoquinoline The title compound was prepared from 7-nitro-1,2,3,4-tetrahydroisoquinoline (5 g, 30 mmol) and 1-bromopropane (7.36 g, 60 mmol) by a procedure analogous to that of Example 3 (a). This produced the hydrochloride salt (3.29 g, 43%), MS m / z 221 [M + H] +. b) 2-propyl-l, 2, 3, 4-tetrahydroisoquinolin-7-ylamine hydrochloride The hydrochloride of 7-nitro-2-propyl-1,2,3,4-tetrahydroisoquinoline (Example 4 (a), 3.29 g, 13 mmol) is hydrogenated using the process described in Example 3 (b). The hydrochloride salt of the title compound thus obtained (3.07 g, 100%) was used immediately in the next step. . c) N- (2-Propyl-l, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide dihydrochloride The hydrochloride of 2-propyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine (3.07 g, 13 mmol) in DMF (30 mL) is treated with 2-thiophenecarboximidothioic acid methyl ester hydroiodide (2.84 g, 10 mmol) according to the method of Example 3 (c). The solids were recrystallized from the ether (1.28 g, 43%), MS m / z 300 [M + H] +. The salt of the dihydrochloride was made by dissolving these solids in ethanol-HCl, and triturating them with ethyl acetate (0.86 g, 73%), m.p. 241-243 ° C.

Example 5 N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -3-thiophenecarboximidamide di-hydrochloride a) 3-thiophenecarboximidothioic acid methyl ester hydroiodide The title compound was prepared from 3-thiophenecarbothioamide and methyl iodide by an analogous procedure to that described in Example 1 (d) of WO 95/05363. b) N- (2-methyl-1,2,3-tetrahydroisoquinolin-7-yl) -3-thiophenecarboximidamide dihydrochloride A mixture of 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine hydrochloride (1.5 g, 7.55 mmol) and acid methyl ester hydroiodide. 3-thiophenecarboximidothioic acid (2.69 g, 9.44 mmol) in N-methyl-2-pyrrolidinone (10 mL) is heated at 50 ° C for 5 hours. The resulting solid mass is treated with isopropanol (50 ml), dissolved in water, basified with concentrated ammonium hydroxide, and extracted twice with chloroform. The combined extracts are dried over magnesium sulfate, the solvent is evaporated and the residue is treated with ethanol-HCl to give the title compound (1.37 g, 52%), ?? · m / z 272 [M + H] + .

Example 6 N- (2-Butyl-1,2,4,4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide N- (1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide (3.0 g, 9 mmol) and 1-chlorobutane (1.67 g, 18 mmol) were reacted together according to the method of Example 2 except that 95% ethanol was used as the solvent. The crude oil thus obtained was subjected to chromatography on silica gel eluting with 10% methanol-chloroform to give an oil which was crystallized from hot hexane (1.12 g, 40%), m.p. 95-96 ° C.

It is noted that in relation to this date the best method known by 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 above, property is claimed as contained in the following

Claims (1)

1. CLAIMS 1. A compound of the formula ( characterized because: R ^^ represents a 2-tieryl or 3-thienyl ring; and R- represents alkyl / with 1 to 4 carbon atoms; and the isomers and racemates thereof and the pharmaceutically acceptable salts thereof. 3 A compound of the formula (I), according to claim 1, characterized in that R ^ represents methyl. Rx ^ represents the 2-tievi'c and R2 ^ represents core. A compound of the formula (I), characterized in that it is: thiophenecarboximidamide; thiophenecarboximidamide; N- (2-ethyl-1,2,3-tetrahydroquinoline-7-yl) -2-thiophenecarboximidamide; ^? ^ S- G? ?? - ?, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; ^ r '(' 2-methyl-1,2,4,4-tetrahydroisoquinolin-7-yl) -3-thiophenecarboximidamide; , N ^ 2-butyl-l, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2-thiophenecarboximidamide; or an optical isomer or racemate of any of them or a salt of any of them pharmaceutically acceptable. > ./ A compound of the formula (I), according to any of claims 1 characterized in that it is used as a meditiate. pharmaceutical formulation, characterized in that it comprises a compound of the formula (I), as defined in any of claims 1 to 5, or - an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, optionally mixed with a pharmaceutically acceptable carrier or diluent. .d'G A pharmaceutical formulation, characterized in that it comprises a compound of the formula (I) / as defined in any of claims 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in combination with L-jDopa, or with "an analgesic treatment of an opiate substance, particularly the morphine, optionally mixed with a pharmaceutically acceptable diluent or carrier. J V9. A method of treating, or reducing the risk of, a human disease or condition in which the inhibition of the activity of nitric oxide synthase is beneficial, characterized in that it comprises administering to a person suffering from or who is susceptible to such a disease or condition, a therapeutically effective amount of a compound of the formula (I), as defined in any one of claims 1 to 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof. 10. A method of treatment according to claim 9, characterized in that it is predominantly the neuronal isoform of the oxide or reduction of risk of, hypoxia or attacks or ischemia or neurodegenerative conditions. or schizophrenia or pain or migraine, or for the prevention and reversal of tolerance to opiate substances and diazepines, or for the treatment of drug addiction, characterized in that it comprises administering to a person suffering from, or which is susceptible to, such a disease or condition, a therapeutically effective amount of a compound of the formula (I), as defined in any one of claims 1 to 5, or an optical isomer or racemate thereof or a salt thereof acceptable pharmaceutically 1 ^ 12. A method of treatment according to claim 11, characterized in that the condition to be treated is selected from the group consisting of hypoxia, ischemia, attacks, Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, schizophrenia and pain. ' and 13. A method of treatment according to claim 12, characterized in that the condition to be treated is the attacks. % 14. A method according to claim 12, characterized in that the condition to be treated is Amyotrophic Lateral Sclerosis. v. 15. A method of treatment according to claim 12, characterized in that the condition to be treated is pain. \ > ^ 16. A method of treatment according to claim 12, characterized in that the condition that is to be treated is Huntington's disease. > V '17. A method of treatment according to claim 12, characterized in that the condition to be treated is the disease of Parkinson. '| · * '. · Vf 18. A method of treatment according to claim 12, characterized in that the condition to be treated is schizophrenia. 19. A method for the treatment, or reduction of the risk of suffering from pain, characterized in that it comprises administering to a person suffering from or at risk of suffering, a pain, a therapeutically effective amount of a compound of the formula (I), as defined in any one of claims 1 to 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in combination with an analgesic agent of an opiate substance, particularly morphine. A method of treating Parkinson's disease, characterized in that it comprises administering to a person suffering from, or at an increased risk of suffering from, a Parkinson's disease, a therapeutically effective amount of a compound of the formula (I) , as defined in any one of claims 1 to 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in combination "with the L-Dopa. 2)/. The use of a . compound of the formula (I) as defined in any of claims 1 to 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or the conditions in which the inhibition of nitric oxide synthase activity is beneficial. 2,2 '. The use according to claim 21, wherein it is predominantly the neuronal isoform of nitric oxide synthase that is inhibited. 23. The use of a compound of the formula (I) as defined in any one of claims 1 to 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of hypoxia or attacks or ischemia or neurodegenerative conditions or schizophrenia or pain or migraine or for the prevention and reversal of tolerance to opiate substances and diazepines or for the treatment of 1-a "addiction to drugs. 24. The use according to claim 23, wherein the condition is selected from the group consisting of hypoxia, ischemia, attacks, Amyotrophic Lateral Sclerosis, Huntington's disease, schizophrenia and pain. according to claim 24, wherein the condition is attacks. use according to claim 24, wherein the condition is Amyotrophic Lateral Sclerosis ^ T according to claim 24, wherein the condition is pain. : The use according to claim 24, wherein the condition is Huntington's disease. use according to claim 24, wherein the condition is Parkinson's disease. use according to claim 24, wherein the condition is schizophrenia. 3 . The use of a compound of the formula (I) as defined in any one of claims 1 to 5, or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in combination with an analgesic agent of an opiate substance, particularly morphine, in the manufacture of a medicament for the treatment or prophylaxis of pain. pQ .. The use of a compound of the formula (I) according to any one of claims 1 to 5, or a racemate or optical isomer thereof or a pharmaceutically acceptable salt thereof, in combination with the L-Dopa, in the manufacture of a medicament for the treatment or prophylaxis of Parkinson's disease. 33. A process for the preparation of a compound of the formula (I), as defined in any of claims 1 to 5, and the optical isomers and racemates thereof and the pharmaceutically acceptable salts thereof, characterized in that it comprises: compound of the formula (I) by reacting a corresponding compound of the formula (II) in step 1, with a compound of the formula (III) or an acid addition salt thereof wherein R is as defined in claim 1 and L is a separation group; ii > ) preparing a compound of the formula (I) by reacting a corresponding compound of the formula (IV) / wherein R2 is as defined in the claim HA is an acid, with a compound of the formula (V) wherein "R1" is as defined in claim 1; (c) preparing a compound, of the formula (I) by reacting a compound of the formula (VI) wherein R-1"is as defined in claim 1, / with a compound of the formula (VII) wherein it is desired or necessary to convert the resulting compound of the formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof, or vice versa, and where it is desired to convert the resulting compound of the formula (I) ) in an optical isomer thereof. RESUME OF THE. INVENTION The present invention provides novel compounds of the formula (I) wherein R 1 represents a 2-thienyl or 3-thienyl ring and R 2 represents an alkyl with 1 to 4 carbon atoms and the optical isomers and racemates thereof and the pharmaceutically acceptable salts thereof; along with processes for its preparation, compositions that contain them and their use in therapy. The compounds are selective inhibitors of the neuronal isoform of nitric oxide synthase.