MXPA98008153A - Derivatives of aminoisoquinolinas and aminotienopiridinas and their use as agents antiinflamator - Google Patents

Abstract

The compounds of formula (I) wherein R represents (i) phenyl, benzothiazolyl or a 6-membered heterocyclic aromatic ring containing from 1 to 3 hydrogen atoms, which phenyl, benzothiazolyl benzo ring or heterocyclic aromatic ring are substituted optionally by C1 to 6 alkyl, C1 to 6 alkoxy, halogen, hydroxy, C1 to 6 thioalkyl, benzyloxy, or a group -Q (CH2) pNR4R5; or (ii) C1 to 8 alkyl, C3 to 8 cycloalkyl, C2 alkynyl to 8, piperidyl, phenylalkyl C7 to 14, which alkyl, cycloalkyl, alkynyl, or piperidyl are optionally substituted by a group - (CH2) pNR4R5, phenylalkyl is optionally substituted by a group - (CH2) pNR4R5, C1 alkyl at 6, C1 to 6 alkoxy, halogen or nitro, or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from O, NOS, optionally substituted by C1 to 6 alkyl, C7 to 14 phenylalkyl halogen, or (iv) hydrogen or phenylalkynyl C7 to 14; O, NR6 a bond, R1 represents hydrogen, C1 to 6 alkyl, C1 to 6 alkoxy, trimethylsilyl or halogen, R2 represents hydrogen, C1 to 6 alkyl or phenyl optionally substituted by C1 to 6 alkyl, C1 to 6 alkoxy, halogen or hydroxy, R3 represents a hydrogen or halogen, R4, R5 and R6 independently represent a hydrogen or C1 to 6 alkyl, or -NR4R5 together represent piperidyl, pyrrolidinyl or morpholinyl, P represents a number 1 to 5, A represents a ring thieno or benzo, provided that A represents a benzo ring and Q represents O, P does not represent 1, or pharmaceutically acceptable salts, enantiomers or tautomers thereof, has been found to be useful as a pharmaceutical, especially for the treatment of inflammatory disease

Description

DERIVATIVES OF AMINOISOQUINOLINES AND AMINOTIENOPIRIDINAS AND THEIR USE AS AOTIINFLAMMATORY AGENTS FIELD OF THE INVENTION The present invention relates to new compounds which are the aminopyridine derivatives. The invention also relates to aspects that include processes for the preparation of compounds, compositions containing them and their use as pharmaceuticals. Useful chemical intermediates are also provided for the production of the compounds. US-A-4127720 discloses the l-amino-3,4-dihydroisoquinolines of the following formula: REF: 02846-7. wherein R represents a hydrogen, Cl to 6 alkyl, or phenyl; R1 represents a hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy or halogen; and R2 represents a hydrogen, Cl to 6 alkyl or an unsubstituted phenyl. US-A-4127720 discloses the use of these compounds as input materials for the synthesis of other compounds. There is no discovery of pharmaceutical use. Especially mentioned are compounds such as: l-amino-3, 4-dihydro-7-methoxyisoquinoline, l-amino-3,4-dihydro-6-methoxyisoquinoline and (+ -) - l-amino-4-ethyl-3, 4-dihydroisoquinoline, "Synthesis and antihypertensive activity of l-amino-3,4-dihydroisoquinolines", GD Diana et al. J Med. Chem., Vol 20, No. 3, March 1977, page 449 to 452 discloses that the hydroiodic salt of 1-amino-3,4-dihydroisoquinoline has antihypertensive activity. WO 95/11231 discloses a decahydroisoquinoline as an inhibitor of nitric oxide synthesis (NOS). The synthesis of heterocyclic combinations using nitric salts. XIII. l-amino-3,4-dihydroisoquinoline derivatives ", V. Gómez-Parra et al, An. Quim., vol 70, No. 12, 1974, page 980 to 985 discloses the derivatives of l-amino-3, 4 -dihydroisoquinoline which the amino group is substituted for. "The reaction of Bischler-Napierals and N (3,4-dimethoxyphenylethyl) urea", T Yamazaki et al, Yakugaku Zasshi, vol 82, 1962, page 352 to 355 reveals the 1 -amino-6,7-dimethoxy-3,4-dihydroisoquinoline.

BACKGROUND OF THE INVENTION According to the invention, a compound of formula I is provided R2 R3 NH, wherein: R represents (i) phenyl, benzothiazolyl or a 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen atoms, which phenyl, benzo ring of benzothiazolyl or a heterocyclic aromatic ring is optionally substituted by alkyl Cl to 6, C1 to 6 alkoxy, halogen, hydroxy, Cl to 6 thioalkyl, benzyloxy, or a group -Q (CH2) PNR4R5; or (ii) Cl to 8 alkyl, C3 to 8 cycloalkyl, C2 to 8 alkynyl, piperidyl, phenyl to C7 to C14 alkyl, which alkyl, cycloalkyl, alkynyl, or piperidyl is optionally substituted by a group - (CH2) PNR4R5, the phenylalkyl is optionally substituted by a group - (CH 2) PNR 4 R 5, alkyl Cl 6, alkoxy Cl 6, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms is selected from O, N or S, optionally substituted by C1 to 6 alkyl, C7 to 14 phenylalkyl or halogen; or (iv) hydrogen or phenylalkynyl C7 to 14; Q represents O, NR6 or a bond; R1 represents a hydrogen, Cl to 6 alkyl, Cl-alkoxy to 6, trimethylsilyl or halogen; R 2 represents a hydrogen, Cl to 6 alkyl or phenyl optionally substituted by Cl to 6 alkyl, alkoxy Cl to 6, halogen or hydroxy; R represents hydrogen or halogen; R4, R5 and R6 independently represents a hydrogen or C1 to 6 alkyl, or -NRR5 together represent piperidyl, pyrrolidinyl or morpholinyl; p represents a number from 1 to 5; and A represents a thieno or benzo ring; provided that when A represents a benzo ring and Q represents 0, p does not represent 1; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof; provided that when A represents a benzo ring, the compounds of the formula I in which R represents a hydrogen, Cl to 6 alkyl or phenyl, R1 represents a hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy or halogen, R2 represents a hydrogen, Cl to 6 alkyl or an unsubstituted phenyl and R3 represents an excluded hydrogen.

DESCRIPTION OF THE INVENTION The invention further provides a process for the preparation of these compounds or pharmaceutically acceptable salts, enantiomers or tautomers thereof. According to the invention, there is also provided a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, for use as a pharmaceutical, provided that the iodohydric salt of the compound of formula I which A represents a benzo ring and each R, R1, R2, and R3 represent a hydrogen, for use as an excluded pharmacist. Another aspect of the invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease. According to the invention, there is also provided a method of treatment, or reduction of risk of inflammatory diseases in a patient with pain of, or risk of, said disease, wherein the method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof. Preferably, when A represents a thieno ring, the compound is a thieno [2, 3-c] pyridine or a thieno [3,2-c] pyridine of the compound of formula I. One embodiment, R represents 2-benzothiazolyl, ethinyl, cyclopropyl, fluorophenyl (e.g., 2-, 3- or 4-fluorophenyl), benzyloxyphenyl (e.g., 4-benzyloxyphenyl), thiomethylphenyl (e.g., 4-thiomethyl), methylphenyl (e.g. 2-, 3-, 4- methylphenyl), methoxyphenyl (for example, 4-methoxyphenyl), chlorophenyl (for example, 2-, 3- or 4-chlorophenyl), furyl (for example 2- or 3-furyl), thienyl (for example, 2- or 3-thienyl), pyridyl (for example, 3- or 4-pyridyl), phenylethynyl, aminopropyloxyphenyl (for example, 4-. {3-aminopropyloxy) phenyl), aminoethylphenyl (for example, 3- (2-aminoethyl) phenyl) or 4- (2-aminoethyl) phenyl), aminopropylphenyl (for example 3- (3-aminopropyl) phenyl), thiazolyl (for example, 2-thiazolyl), imidazolyl (for example, 2-imidazolyl), methyl, ((dimethylamino) ) methyl) phenyl (for example or, 2- or 3- ((dimethylamino) methyl) phenyl), propynyl (for example, 1-propynyl), butynyl (for example, tert-butynyl), phenylethynyl, benzylpyrrolyl (for example, l-benzyl-2-pyrrolyl) ), methylpyrrolyl (e.g., l-methyl-2-pyrrolyl), ethyl, cyclobutyl, hydroxyphenyl (e.g., 4-hydroxyphenyl) or propyl. The process mentioned above, for the preparation of the compounds of the invention, or pharmaceutically acceptable salts, enantiomers, tautomers thereof comprise: (a) hydrolysis and / or deprotection of a compound of formula II or a protected derivative thereof, or hydrolysis and / or deprotection of a pharmaceutically acceptable salt, enantiomers or tautomers of a compound of formula II or said protected derivative, wherein formula II is A, R, R1, R2 and R3 is as defined above, P represents a protective group and M represents an alkali metal; or (b) the preservation of a compound of formula Illa or 11Ib or of a pharmaceutically acceptable salt, enantiomer, or tautomer thereof wherein R, R1 and R2 is as defined above and P represents a protecting group; or (c) treatment of a compound of formula IV or a pharmaceutically acceptable salt, enantiomer or tautomer thereof with ammonia, wherein formula IV is wherein A, R, R1, R2 and R3 is as defined above and L is an output group; or (d) preparation of a compound of formula I which R represents ethynyl, or a pharmaceutically acceptable salt, enantiomers or tautomers of such a compound, by hydrolysis of a corresponding compound, which R represents trimethylsilylethynyl; or (e) reaction of a compound of formula V or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formula V is wherein A, R, R1, R2 and R3 is as defined above and M represents an alkali metal, with a compound of formula VI or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formula VI is NH where R is as defined above; or (f) preparation of a compound or pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the compound is of formula I in which R represents an alkyl Cl to 8 substituted by a group - (CH2) PNRR5 and one or both of R4 and R5 represent an alkyl Cl to 6, by alkylation of a corresponding compound in which one or more of R4 and R5 represent a hydrogen; or (g) preparation of a compound or pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the compound is of formula I in which R represents a phenyl or a 6-membered heterocyclic aromatic ring, the phenyl or the aromatic ring heterocyclic is substituted by a group - Q (CH2) PNR4R5 and one or both of R4 and R5 represent an alkyl Cl to 6,, by alkylation of a corresponding compound in which one or more of R4 and R5 represent a hydrogen; or (h) deprotection of a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in which one or both nitrogen atoms and / or other protected atoms; or (i) preparation of a compound or pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the compound is of formula I in which R represents a phenyl or a 6-membered heterocyclic aromatic ring substituted by a -Q group ( CH2) pNH2, by the reduction of the corresponding azido; or (j) preparation of a compound or pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the compound is of formula I in which R represents a piperidyl, by reduction of a corresponding compound in which R represents pyridyl. In process (a), the step of hydrolysis can be carried out by methods well known in the art.

For example, the compound of formula II can be treated with aqueous acid, for example, dilute hydrochloric acid. The alkali metals M include lithium, magnesium, sodium and potassium. In processes (a) and (b), suitable protecting P groups include alkyl, aralkyl, acyl, acyl sulfonyl, aryl sulfonyl and trialkylsilyl. It is preferred that P represents a trialkylsilyl, especially trimethylsilyl. When P represents a trialkylsilyl, the protecting group can be removed by hydrolysis, for example, with tetra-n-butylammonium fluoride. When P represents an alkyl, aralkyl, acyl, acyl sulfonyl or aryl sulfonyl, the protecting group can be removed by reduction for example, using zinc in acetic acid. More details of the processes for the removal of these protective groups can be found by reference in the standard text "Protecting groups in Organic Synthesis", 2nd Edition (1991) by Greene and Wuts. In process (c), the reaction can be carried out by combining the reactants in a polar protic solvent, for example, methanol, ethanol or propanol at a temperature between room temperature and boiling temperature of the solvent for a period of 1 to 12 hours. , or under full reaction. It is preferred, although not required, that the reaction may be carried out in the presence of an ammonium salt, for example, ammonium iodide. More details of this process can be obtained by reference in Gómez-Parra et al. (1974) An. Quim. 70, 980-985. Suitable leaving groups L include thioalkyl, sulfonic acid, trifluorocarbon sulfonic acid, halide, alkyl and aryl alcohols and tosyl groups; others are cited in Advanced Organic Chemistry, J. Marzo (1985) 3rd Edition. McGraw-Hill on page 315 and is well known in the art. In process (d), the hydrolysis is preferably carried out in the presence of a base, in a polar protic solvent, typically in a period of up to 120 hours. In the process (e), the reaction can be carried out in an inert solvent, for example THF, at a lower temperature, typically between -78 C and room temperature. It is preferred, although not required, to carry out the reaction in the presence of at least one equivalent of a polar additive such as hexamethylphosphoric triamide (HMPA) or, 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (also known as dimethylpropyleneurea, DMPU). In processes (f) and (g), the alkylation reaction can be carried out by the process well known in the art. For example, the amine may react with the alkyl halide, especially the bromine or iodine. In process (h), the protecting groups for the amines are described in process (a) above. The alcohol groups can be protected, for example, by treatment with an enol ether for example, dihydropyran, which the protecting group is removed by the subsequent treatment with the dilute acid. Other protective groups and more details of the processes for their elimination can be found by reference in the standard text "Protecting groups in Organic Synthesis", 2nd Edition (1991) by Greene and Wuts. It is preferred to protect the reactive positions of the heterocyclics with a trimethylsilyl protecting group, which group can typically be removed by treatment with tetra-n-butylammonium fluoride. In process (i), the reduction can be carried out by treatment with tin (II) chloride. The corresponding azido derivatives can be prepared by analogous processes for that use in the preparation of compounds of formula I. In process (j), the reduction reaction can be carried out by hydrogenation of the corresponding pyridyl derivative in platinum oxide or Pd / C. The salts of the compounds of formula I can be formed by reaction of the free base or a salt, enantiomer, tautomer or protective 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, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which it can be eliminated in vacuum or by dehydration by freezing. The reaction may be a meta-tetical process or it may be carried out on an ion exchange resin. The compounds of formula II can be prepared by cyclization of a compound of formula VII VII where A, R, R1, R2, R3, M and P is as defined above. The cyclization reaction will generally be carried out by heating the compound of formula VII in an inert solvent for up to 4 hours. It has been found that the temperature and duration of the reaction depends freely on the natural of the protective group P and in the same case, the reaction can continue between -78C and room temperature with less or no heating if something is required. The reaction can be accelerated, or lower temperatures that can be used, by eliminating the reaction in the presence of the acid. The compounds of formula VII can be prepared by reaction of the compounds of formula V and VI. However, the compounds of formula VII can not be isolated and closed from the ring that can take place to produce a compound of formula II directly. The compounds of formula Illa or 11Ib can be prepared by processes analogous to that described above by the preparation of the compounds of formula I. The compounds of formula IV can be prepared by generally known methods, for example by reference to Lora-Tamayo et al. (1996) Tetrahedron 8 (Suppl.), 305-312; Gitttos et al. (1976) J. Chem. Soc. Perkin Trans. 1, 33-38 and Diana et al. (1977) J. Med. Chem. 3, 449-451. These methods include the formation of the thioalkyls derivatives of formula IV by cyclization of an isothiocyanate and the formation of an iminoester derivative of formula IV by treatment of the corresponding cyclic amide with the Meerwein reagent (triethyloxonium tetrafluoroborate). These isothiocyanate and iminoester precursors can be freely prepared by methods also disclosed in these papers, or in references thereto, or by conventional methods known per se. Alternatively, compounds of formula IV in which L represents a thioalkyl can be prepared by treatment of a compound of formula VIII.

Where A, R, R1, R1 and RJ is as defined above, with an alkylating agent such as alkyl tosylate, methosulfonate, mesylate, fluorosulfonate, or halide, especially alkyl iodide. The solvent suitable for the alkylation reaction including ethers, preferably diethyl ether, tetrahydrofuran, dioxane, lower ketones, for example acetone or 2-butanone, halohydrocarbons for example, dichloromethane and lower alkanols, for example, methanol, methyl iodide as the particularly suitable acetone alkylating agent. Generally, equimolar to a broad excess of the alkylating agent that is used, an amount that depends inter alia on the reactivity of the compound of formula VIII and the solubility of the reactants in the solvent employed. The alkylation reaction can be carried out at various temperatures from room temperature to reflux, or in a suitably sealed container at high temperatures. The compounds of formula VIII can be prepared by ring closure in a corresponding compound of formula IX.

IX Where A, R, R1, R2 and R3 is as defined above. This reaction can be carried out using the conditions analogous to this, described for the phenyl analogs in paper Gittos et al. (1976) as mentioned above. The compounds of formula VIII can also be prepared from the compound of formula X wherein A, R, R1, R2 and R3 is as defined above, by treatment with P2Ss or the Lawesson's reagent. The conditions for this reaction, and the details of the reactants containing alternative sulfur can be obtained by reference in the paper Smith et al. (1994) J. Org. Chem., 59, 348-354. Other compounds of formula IV are both known or can be prepared by known methods.

The compounds of formula V in which M represents Li can be prepared by the treatment of the corresponding compound of formula V in which M represents a hydrogen with a compound of formula XI XI • N- Li wherein R7 represents an alkyl or trialkylsilyl.

The compounds of formula V in which M represents a metal other than Li which can be prepared by analogous methods. This reaction can be removed in an inert solvent, for example THF, at a lower temperature, typically below -50C. The compounds of formula V in which M represents a hydrogen are both known or can be prepared by conventional methods known per se. The compounds of formula VI can be prepared by treatment of a compound of formula XII R-CHO XII wherein R is as defined above, with ammonia under standard conditions well known in the art.

The protective derivative of a compound of formula VI is obtained by treatment of a compound of formula XII, as defined above, with a compound of formula XIII P-NH, Xlil wherein P is as defined above or a compound of formula XIV P2N- M XIV where P and M is as defined above. The reaction of the compound of formula XII with a compound of formula XIII can be carried out by combining two reactants in a polar protic solvent at a temperature between room temperature and the boiling temperature of the solvent and is well known in the art.

The reaction of a compound of formula XII with a compound of formula XIV which can be performed by combining two reactants in an aprotic solvent for example THF at a lower temperature, typically between -10 C and room temperature, and is well known in the art. The compounds of formula IX, X, XI, XII, XIII, and XIV are both known or can be prepared by conventional methods known per se. It is obvious 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 process (f) above.

The following chemical intermediates are useful for the compounds produced of the invention, or pharmaceutically acceptable salts, enantiomers or tautomers thereof; 3-methoxy-2-methylbenzonitrile; or 3-fluoro-2-methylbenzonitrile; or 2-fluoro-6-methylbenzonitrile; or 3,6-difluoro-2-methylbenzonitrile; or 4-fluoro-2-methylbenzonitrile; or 3-fluoro-6-methy1-2-trimethylsilylbenzonitrile; or 4- (3-azidopropyloxy) benzaldehyde; or 3- (2-aziethyl) benzaldehyde; or 3- (3-azidopropyl) enzaldehyde; or 4- (2-aziethyl) benzaldehyde; or 2- (N, N-dimethyl) aminomethylbenzaldehyde; or 3- (N, N-dimethyl) aminomethylbenzaldehyde; or 4-tert-butyldiphenylsilyloxybenzaldehyde; or 2-cyano-3-methyl-5-trimethylsilylthiophene; or 3-cyano-2-methyl-5-trimethylsilylthiophene; or 5- (trimethylsilyl) thiazole-2-carboxaldehyde; or l-amino-3- (4- (3-azidopropyloxy) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (2-azidoethyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (2-aminoethyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (3-azidopropyl) phenyl) -3,4-dihydroisoquinoline; or 4-methylthio-6,7-dihydrothieno [3,2-c] pyridine.

The compounds of formula I can exist in enantiomeric forms. In addition, all enantiomers, diastereomers, racemates and mixtures thereof are included in the summary of the invention. Various optical isomers can be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example fractional crystallization, or HPLC. Alternatively, the individual enantiomers can be manufactured by reaction of the optionally suitable starting active materials under reaction conditions which do not cause racemization. The compounds of formula II, III, IV, V, VI, VII, VIII, IX, X and XII and other intermediates which also exist in enantiomer forms and can be used as purified enantiomers, diastereomers, racemates or mixtures.

The compounds of formula I can exist in the form IA tauto erica alternative wherein A, R, R1, R2 and R3 is as defined above. The compounds of formula I can be provided in tautomeric form or as a mixture thereof. The compounds of formula Illa and IIIb may also exist in the form Illa 'alternative tautomeric or Illb' respectively.

Illa ' Where A, R, R1 and R2 is as defined above. "alkyl", includes for example "thioalkyl" and "phenylalkyl", which includes straight or branched chain alkyl groups. "alkoxy" and "alkynyl" are to be interpreted similarly. The compounds of formula I, and the pharmaceutically acceptable salts, enantiomers and tautomers thereof, are useful because they possess pharmaceutical activity in animals. In particular, the compounds are activated as inhibitors of the inducible isoform of nitric oxide (NOS) enzyme synthesis present in macrophages and as such is supposed to be useful as therapy, for example as anti-inflammatory agents. The compounds and their pharmaceutically acceptable salts, enantiomers and tautomers are indicated for use in the treatment or prophylaxis diseases or conditions in which the synthesis or synthesis of the nitric oxide synthesis forms of a contributing part. In particular, the compounds are indicated for use in the treatment of inflammatory conditions in mammals including man. The conditions that can be especially mentioned are: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other conditions of arthritis, inflamed joints; eczema, psoriasis, dermatitis or other inflamed skin conditions such as burns; conditions of the inflamed eye including uveitis and conjunctivitis; disorders of the lung in which the inflammation is involved, for example, asthma, bronchitis, dreamy pigeon disease, cultivated lung, acute respiratory distress syndrome, bacteraemia, endotoxaemia (septic shock) and pancreatitis; conditions of the gastrointestinal tract including foot ulcers, gingivitis, Crohn's disease (a minimal condition and also sometimes the large intestine), atrophic gastritis and gastritis varialoforma (stomach conditions), ulcerative colitis (a minimal condition and also sometimes the small intestine), celiac disease (a condition of the small intestine), regional ileitis (a condition of the inflamed region of the terminal ileum), peptic ulceration (a condition of the stomach and duodenum) and irritated bowel syndrome; pyrosis; pain; damage to the gastrointestinal tract resulting from infections for example, by Helicobacter pylori, or treatments with non-steroidal anti-inflammatory drugs, and other conditions associated with inflammation. The compounds of formula I may also be useful in the treatment of diseases or conditions in addition to those mentioned above. For example, the compounds of formula I may be useful in the treatment of hypotension associated with toxic and / or septic shocks, in the treatment of immune system dysfunction, as an adjunct to immunosuppression of short-term operation in organ transplant therapy. , in the treatment of vascular complications associated with diabetes and in co-therapy with cytokines, for example, THF or interleukins. The compounds of formula I may also show inhibitory activity against the neuronal isoform of nitric oxide synthesis. Thus this may also be useful in the treatment of hypoxia, for example in cases of cardiac arrest and stroke, neurodegerative disorders including nerve degeneration and / or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and an external wound ( such as the spine and head injury), hyperbaric oxygen seizures and toxicity, dementia, for example pre-senile dementia, Alzheimer's disease and dementia related to AIDS, Syndenham's chorea, Parkinson's disease, Tourette syndrome. s, Huntington's disease, amyotrophic lateral sclerosis, orsakoff's disease, imbecility related to a disorder in the brain vessel, sleep disorders, schizophrenia, depression, autism, temporary affective disorder, jet-lag, depression or other symptoms associated with Premestrual syndrome (PMS), septic shock and anxiety. The compounds of formula I can also be presumed to show activity in the prevention and tolerance reserve for narcotics and diazepines, drug addition treatment, pain relief and treatment of migraine and other vascular headaches, neurogenic inflammation, in the treatment of disorders of gastrointestinal mobility, cancer and in the induction of labor.

For the therapeutic indications mentioned above, the dose administered will be of course, and varies with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a daily dose of the solid form between 1 and 2000 mg per day. The compounds of formula I, and the pharmaceutically acceptable derivatives thereof, may be used in their own, or as a pharmaceutical composition in which the compound or derivative is a mixture with a pharmaceutically acceptable auxiliary, diluent or carrier. For example in a form suitable for parenteral or enteral administration. The pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of the compound or derivative.

Suitable auxiliary examples, diluents and carriers are well known to one skilled in the art.

The compounds of formula I and their pharmaceutically acceptable salts, enantiomers and tautomers have the advantage that they are less toxic, more effective, have more action, have a broad range of activity, are more potent, are more selective, produce fewer side effects , are more easily absorbed or have other useful pharmaceutical properties, than compounds of similar structure. The invention illustrates, but is not limited to, the following examples. The preparation of intermediates for the production of the examples is as follows.

PREPARATION OF THE INTERMEDIATES EXAMPLE A 3-methoxy-2-methylbenzonitrile The hydroxylamine hydrochloride (0.75 g, 11 mmol) is added to 3-methoxy-2-methylbenzaldehyde (1.25 g, 8.32 mmol) in formic acid (89-91%) (10 mL), and the mixture is heated to reflux by 40 minutes, cool, dilute with ice water, basify with a 10% aqueous sodium hydroxide solution and extract with diethyl ether. The organic extract is washed with saturated aqueous sodium chloride (50 ml), dried over magnesium sulfate and evaporated. The residue is purified by flash chromatography on silica gel eluting with 5% diethyl ether in hexane to give the product as a white solid (0.98 g). M + 147; 360 MHz XH n.m.r (CDC13) 7.26.7.17 (2H, m), 7.02 (1H, d, J 7.9 Hz), 3.86 (3H, s), 2.41 (3H, s).

EXAMPLE B Following the method of Example A, the following compound is prepared: 3-fluoro-2-methylbenzonitrile, M + 135; 360 MHz XH n.m.r (CDCl 3), 7.49-7.39 (1H, m), 7.28-7.17 (2H, m), 2.47 (3H, s).

EXAMPLE C 2-FLUORO-6-METILBENZONITRILO N-Butyllithium (1.45M, 44.0 mmol, 30.3 ml) is added dropwise to a stirred solution of tetramethylenediamine (48 mmol, 6.2 ml) in tetrahydrofuran (THF) at -22C. After 15 minutes, a portion of n-butyllithium (120 mmol, 82.8 ml) is added dropwise, and after about 15 minutes 2-fluorobenzaldehyde (40.0 mmol, 4.21 ml) in THF is added dropwise ( 16 ml). The mixture is stirred at -22 C for 16 hours, methyl iodide (12.5 ml) is added dropwise and the mixture is washed at room temperature for 30 minutes, poured into 2N hydrochloric acid and cooled, extracted twice with diethyl ether, dried over magnesium sulphate and evaporated to give a brown oil. This is dissolved in formic acid (50 ml) and treated with hydroxylamine hydrochloride (52 mmol, 3.6 g). The mixture is refluxed for 16 hours, cooled to room temperature and poured into cold water, basified with 10% aqueous sodium hydroxide, extracted twice with diethyl ether, dried over magnesium sulfate and evaporated. . The residue is purified by flash chromatography on silica gel, eluting with dichloromethane, to give a yellow solid (2.50 g). Further this was purified by flash chromatography, eluting with 5% diethyl ether / hexane, to give the title compound as a yellow solid and white (1.95 g). M + 135; 360 MHz XH nmr (CDCl3), 7.45 (1H, dt, J5.9, 8.1 Hz), 7.11 (1H, d, J7.8Hz), 7.03 (1H, t, J 8.6 Hz), 2.56 (3H, s) . EXAMPLE D 3,6-DIFLUORO-2-METHYLENEBENZONITRILE This is prepared from the 2,5-difluorobenzaldehyde by the method of Example C, with slight modifications for the first step; addition of the aldehyde, the mixture is stirred for 15 minutes, cooled to -45 ° C, stirred for 3 hours, methyl iodide is added and the reaction works as before. The reaction subsequently gives the title compound as a yellow oil. M + 153; 360 MHz H n.m.r (CDC13), 7.25 (1H, dt J 8.8, 4.6 Hz), 7.02 (1H, dt, J8.6, 3.9 Hz), 2.48 (3H, d, J 2.3 Hz).

EXAMPLE E 4-FLUORO-2-METILBENZONITRILO This is prepared from 4-fluorobenzaldehyde by the method of Example C, with slight modifications for the first step; the reaction is brought to -78C under the second addition of n-butyllithium is complete. The reaction is then warmed to -20 C and stirred for 2 hours, cooled to -45 C and quenched with methyl iodide as before. The subsequent reaction gives the title compound as a yellow solid. M + 135; 360 MHz XH n.m.r (d6-DMS0), 7.61 (1H, dd, J 5.5, 8.5 Hz), 7.05-6.96 (2H, m), 2.56 (3Hf s).

EXAMPLE F 3-FLU0R0-6-METHYL-2-TRIMETILSILILBENZ0NITRIL0 N-Butyllithium (1.40M in hexanes, 11.8 mmol, 8.44 ml) is added dropwise to a stirred solution of diisopropylamine (1.84 ml) in THF (5 ml) to OC. After 30 minutes, the solution is cooled to -78 C and 3-fluoro-6-methylbenzonitrile (1.60 g, 11.8 mmol) in THF (5 ml) is added dropwise. The pale purple anion is stirred for 20 minutes., Trimethylsilyl chloride (3.0 ml, 24 mmol) is added and the mixture is warmed to room temperature for 1 hour, evaporated, the residue is taken in a small amount of diethyl ether and filtered. Evaporation of the filtrate gives a white crystalline solid (2.3 g), m.p. 71-73C.

EXAMPLE G 4- (3-AZID0PR0PIL0XI) BENZALDEHIDO a) 4- (3-bromopropyloxy) enzaldehyde A solution of 4-hydroxybenzaldehyde (3.7 g, 30 mmol) in DMF (10 mL) is cautiously added to a stirred solution of sodium hydride (60% in oil, 1.44 g) in DMF (80 ml). After 30 minutes of adding 1, 3-dibromopropane (9.2 ml, 90 mmol) in DMF (10 ml) dropwise, the mixture is stirred for 16 hours, poured into water, extracted twice with ethyl acetate, and the combined extracts are washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% diethylether in hexane, to give 4- (4-bromopropyloxy) benzaldehyde (3.85 g), M + 205; 360 MHz H nmr (CDCl3), 7.85 (2H, d, J7.0 Hz), 7.01 (2H, d, J7.0Hz), 4.20 (2H, t, J5.8 Hz), 3.62 (2H, t, J6 .4 Hz), 2.36 (2H, pentet, J6.1 Hz). (b) 4- (3-azidopropyloxy) benzaldehyde A mixture of 4- (3-bromopropyloxy) benzaldehyde (3.5 g, 14.5 mmol) and sodium azide (29 mmol, 1.9 g) in DMSO (70 mL) is stirred for 16 hours , it is poured into water (100 ml) and extracted twice with diethyl ether. The extracts are washed with water (50 ml) and saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to give a colorless oil M + 205; 360 MHz XH n.m. r (CDC13), 7.84 (2H, d, J 11 Hz), 7.02 (2H, d, J 11 Hz), 4.14 (2H, t, J 5.9 Hz), 3.55 (2H, t, J 6.5 Hz), 2.09 (2H, app. Pentet, J 6.2 Hz).

EXAMPLE H 3- (2-AZIDOETHYL) BENZALDEHIDO a) 3-bromobenzenetanol The borane-dimethylsulfide complex (2.0 M in THF, 49 ml) is added dropwise to a stirred solution of 3-bromostyrene (10 g, 55 mmol) in THF (130 ml) at 0 C and the solution stir for 3 hours at room temperature. 10% aqueous sodium hydroxide is added slowly, followed by hydrogen peroxide (30% weight solution in water, 6 ml) dropwise. After 16 hours, the mixture is diluted with water, extracted twice with ethyl acetate, the combined extracts are washed with the saturated sodium bisulfite solution and the saturated sodium chloride solution, dried in sodium sulfate and evaporate to give a colorless oil, purification by flash chromatography, elute with hexane and 30% diethyl ether to give a colorless oil, [derived from M + Si (CH3)] + 272. b) 3-bromobenzenetanol 4-methylbenzene sulphonate A prudent portion of 4-methylbenzensulfonyl chloride (4.38 g) is added to a solution of 3-bromobenzenetanol [Example H (a)] (2.30 g, 11.4 mmol) in pyridine (30 ml ) to OC, and the mixture is maintained at -20C for 16 hours. The mixture is diluted with water, extracted with diethyl ether, the combined extracts are washed twice with aqueous 4N hydrochloric acid and once with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give an oil. pale yellow (3.98 g), [M-0ts] + 182; 360 MHz XH nmr (CDC13), 7.66 (2H, d, J 8.3 Hz), 7.34 (1H, dm, J 7.9 Hz), 7.30-7.26 (2H, m), 7.20 (1H, d, J 1.5Hz), 7.12 (1H, t, J 7.7Hz), 7.05.1H, d, J 7.7Hz), 4.20 (2H, t, J 6.8 Hz), 2.91 (2H, t, J 6.8 Hz), 2.44 (2H, s) . c) l-azido-2- (3-bromophenyl) ethane A mixture of 4-methylbenzensulfonate of 3-bromobenzenetanol [Example H (b)] (3.96 g, 11.2 mmol) and sodium azide (22.4 mmol, 1.46 g) in DMSO (50 ml) is stirred at room temperature for 16 hours, diluted with water (200 ml), extracted with diethyl ether (2 x 40 ml), the combined extracts are washed with saturated aqueous sodium chloride (40 ml) , dried over sodium sulfate and evaporated, to give the product as a pale yellow oil (2.46 g). M + 227; 360 MHz XH nmr (CDC13), 7.52 (1H, s), 7.45-7.42 (lH, m), 7.31-7.25 (2H, m), 3.58 (2H, t, J 7.0Hz), 2.85 (2H, t, J 7.0Hz). d) 3-82-azidoethyl) benzaldehyde n-Butyllithium (1.50M in hexane, 10.8 mmol, 7.23 ml) is added dropwise at -78 C to a solution of 1-azido-2- (3-bromophenyl) ethane [Example H (c)} (2.45 g, 10.8 mmol) in THF (80 ml). The light yellow solution is stirred for 20 hours, N-formylmorpholine (2.4 ml) in THF (10 ml) is added dropwise, the solution is stirred for more than 30 minutes, and then it is heated at room temperature for 1 hour. hour. The solution is diluted with diethyl ether, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The residue is purified by flash chromatography, eluting with hexane and 10% diethyl ether, to give the product as a pale yellow oil (750 mg). [M-N2] + 146; 360 MHz XH nmr (CDCl3), 10.02 (1H, s), 7.79-7.76 (2H, m), 7.52-7.50 (2H, m), 3.57 (2H, t, J 7.0Hz), 2.98 (2H, t, J 7.0Hz).

EXAMPLE I 3- (3-azidopropyl) enzaldehyde a) Methyl bromocyanamate Trimethylsilyl chloride (5.6 ml) is added dropwise to a stirred solution of m-bromocinic acid. { 5.0 g, 22 mmol) in methanol (110 ml).

After 4 hours, the mixture is evaporated to give the product as a white solid, M + 242; 360 MHz XH nmr (CDCl3), 7.67 (1H, s), 7.60 (lH, d, J 16Hz), 7.50 (1H, d, J 7.9 Hz), 7.43 (1H, d, J 7.9 Hz), 7.26 (1H , d, J 15.6 Hz), 6.43 (1H, d, J 16.1 Hz), 3.81 (3H, s). b) 3-bromobenzenprop-2-enol Diisobutylaluminum chloride (1.5M in toluene, 85 mmol, 57 ml) is added dropwise to a stirred solution of methyl m-bromocyanamate [Example I (a)} (5.10 g, 21.2 mmol) in toluene (100 mL) at OC. The mixture is stirred for 16 hours at room temperature, cautiously cooled with 4N hydrochloric acid (100 ml), extracted three times with diethyl ether, the combined extracts are dried over sodium sulphate and evaporated to give a viscous oil of Yellow color? Alid (4.40 g). M + 286; 360 MHz XH nmr (CDC13), 7.58 (1H, s), 7.36 (1H, d, J 7.8Hz), 7.28 (1H, t, J 7.8 Hz), 7.18 (1H, t, J 7.8 Hz), 6.54 ( 1H, d, J 15.9 Hz), 6.35 (1H, dt, J 15.9, 4 Hz), 4.33 (2H, d, J 4.1 Hz), 2.35 (1H, br.s). c) 3-bromobenzenpropanol A solution of 3-bromobenzenprop-2-enol [Example I (b)] (4.40 g, 20.8 mmol) in ethanol (100 ml) is stirred for 3 hours under 3 atmospheres of hydrogen with 10% palladium. on carbon (5 mol%, 1 g, 1.0 mmol). The mixture is then filtered through celite and the filtrate is evaporated. The residue is purified by flash chromatography on silica gel eluting with hexane and 20% ethyl acetate to give the title compound as a colorless oil (2.10 g), M + 216. d) 3-bromobenzenepropanol 4-methylbenzene sulphonate This is prepared by the method of Example H (b) using 3-bromobenzenepropanol [Example I (c)],. { M-Ots] + 198; 360 MHz XH nmr (CDCl3), 7.79 (lH, d, J 8.2 Hz), 7.37-6.99 (7H, m), 4.02 (2H, t, J 6.1 Hz), 2.62 (2H, t, J 7.5 Hz), 2.46 (3H, s), 1.98-1.90 (2H, m). e) l-azido-3- (3-bromophenyl) propane This is prepared by the method of Example H (c) using 4-methylbenzensulfonate of 3-bromobenzenpropanol [Example I (d)], [M-N2] + 213; 360 MHz H nmr (d6-DMS0), 7.44 (1H, s), 7.39 (1H, d, J 7.1 Hz), 7.29-7.22 (2H,), 3.33 (2H, t, J 4.5 Hz), 2.64 (2H , t, J 7.8 Hz), 1.87-1.78 (2H, m). f) 3- (3-azidopropyl) benzaldehyde This is prepared by the method of Example H (d) using l-azido-3- (3-bromophenyl) propane [Example I (e)], [M-N2] + 161; 360 MHz XH n.m. r (CDC13), 10.01 (1H, s), 7.75-7.72 (2H, m), 7.51-7.47 (2H, m), 3.32 (2H, t, J 6.7 Hz), 2.80 (2H, t, J 7.5 Hz ), 1.95 (2H, pentet, J 7 Hz).

EXAMPLE J 4- (2-AZIDOETHYL) BENZALDEHIDO a) 4-bromobenzenetanol 4-methylbenzene sulphonate This is prepared by the method of Example H (b) using 4-bromobenzenetanol [M-Ots] + 184/182. b) l-azido-2- (4-bromophenyl) ethane This is prepared by the method of Example H (c) using 4-methylbenzensulfonate of 4-bromobenzenetanol [example J (a) j, M + 227; 360 MHz XH n.m.r (CDCl3), 7.50 (2H, d, J 8.2 Hz), 7.25 (2H, d, J 8.2 Hz), 3.56 (2H, t, J 7.0 Hz), 2.83 (2H, t, J 7.0 Hz). c) 4- (2-azidoethyl) benzaldehyde This is prepared by the method of Example H (d) using l-azido-2- (4-bromophenyl) ethane [example J (b)], [M-N2] + 147; 360 MHz XH n.m. r (CDC13), 10.03 (1H, s), 7.90 (2H, d, J 8.0 Hz), 7.56 (2H, d, J 8.0 Hz), 3.68 (2H, t, J 6.9 Hz), 3.00 (2H, t , J 6.9 Hz).

EXAMPLE K 2- (N, N-DIMETHYL) AMINOMETILBENZALDEHIDO a) 2-bromo- (N, N-dimethyl) -enzylamine Dimethylamine (33% by weight in metal) (25 ml) is added to 2-bromobenzylbromide (7.5 g, 30 mmol) to OC in methanol (35 ml), and the solution is stirred for 30 minutes, evaporated, diluted with water and extracted twice with diethyl ether. The combined extracts are dried over sodium sulfate and evaporated to give the product as a yellow oil (6.0 g). M + 215/213; 360 MHz XH nmr (CDCl3), 7.54 (1H, dd, _ J 1.2, 8.0 Hz), 7.42 (1H, dd, J 1.6, 7.6 Hz), 7.30-7.26 (1H, m), 7.11 (1H, dt, J 1.7.7.7 Hz), 3.52 (2H, s), 2.30 (6H, s). b) 2- (N, N-dimethyl) aminomethylbenzaldehyde It is prepared with the intermediate of Example K (a) using the method of Example H (c); 360 MHz XH nmr (CDC13), 10.41 (1H, s), 7.87 (1H, d, J 6.3 Hz), 7.52 (lH, t, J 7.5 Hz), 7.44-7.15 (2H, m), 3.8-3.7 ( 3H, s), 2.24 (3H, s).

EXAMPLE L 3- (N, N-DIMETHYL) AMINOMETILBENZALDEHIDO a) 3-cyano- (N, N-dimethyl) benzylamine Prepared using the method of example k (a); M + 160; 360 MHz XH n.m. r (CDC13), 7.63 (1H, s), 7.55 (2H, m), 7.43 (1H, t, J 7.7 Hz), 3.44 (2H, s), 2.24 (6H, s). b) 3- (N, N-dimethyl) aminomethylbenzaldehyde Diisobutylaluminum hydride (l.OM solution in toluene, 20 ml, 20 mmol) is added dropwise to a solution of 3-cyano- (N, N-dimethyl) -enzylamine. [Example K (a)] (3.20 g, 20 mmol) in toluene (50 ml). The mixture is stirred at room temperature for 2 hours. Methanol (30 ml) is cautiously added, followed by methanol / water (1: 1, 40 ml) and 10% aqueous sodium hydroxide (100 ml). The mixture is extracted twice with diethyl ether, washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give a yellow oil (3.0 g). M + 163; 360 MHz XH n.m. r (CDC13), 10.02 (1H, s), 7.83 (lH, s), 7.79 (1H, d, J 7.6 Hz), 7.60 (1H, d, J 7.5 Hz), 7.49 (1H, t, J 7.5 Hz ), 3.50 (2H, s), 2.26 (6H, s).

EXAMPLE M 4-TER-BUTILDIFENILSILILOXIBENZALDEHIDO Tert-butyldiphenylsilyl chloride (13.3 mmol, 2.5 ml) is added to a stirred solution of 4-hydroxybenzaldehyde (12 mmol, 1.5 g) and DBU (14 mmol, 2.2 ml) in dichloromethane (25 ml). After 5 minutes, the solution is washed with water, the aqueous layer is further extracted with dichloromethane and the combined organic extracts are washed with 0.5 N hydrochloric acid and the saturated sodium bicarbonate solution, dried in sodium sulfate and dried. evaporates The residue is purified by flash chromatography on silica gel eluting with 15% hexane / diethyl ether to give a white solid (4.0 g). M + 360; 360 MHz XH n.m.r (CDC13), 7.73-7.63 (6H, m), 7.47-7.36 (6H, m), 6.85 (2H, d, J 6.5 Hz), 1.1K9H, s), 9.80 (1H, s).

EXAMPLE N 2-CYANO-3-METHYL-5-TRIMETILSILYLTHOFEN N-butyllithium (1.45M in hexanes, 51.9 ml) is added dropwise to a solution of diisopropylamine (11.7 ml, 83.0 mmol) in dry THF (150 ml) at -5C. and the solution is stirred for 30 minutes. 1,3-Dimethyl-3,4,5,6-tetrahydro-2 (lH) -pyrimidinone (DMPU) (13.6 ml, 0.11 mmol) is added, the mixture is cooled to -78 C and a solution is added dropwise. of 2-cyano-3-methylthiophene (9.27 g, 75.4 mmol) in THF (20 ml), followed by trimethylsilyl chloride (19.1 ml) after 30 seconds. The mixture is warmed to room temperature for 30 minutes, evaporated, taken up in diethyl ether, the solids are filtered and the filtrate is evaporated to give a yellow oil. This is purified by flash chromatography on untreated neutral alumina, eluting with 1% diethyl ether in hexane, to give 2-cyano-3-methyl-5-trimethylsilylthiophene as a clear oil (6.52 g). M + 195; 360 MHz XH n.m.r (CDC13), 7.02 (1H, s), 2.43 (3H, s), 0.33 (9H, s).

EXAMPLE 3-CYANO-2-METHYL-5-TRIMETHYLSYLTHYLOPHENE N-Butyllithium (1.4M in hexanes, 1.3 ml, 1.8 mmol) is added dropwise to a stirred solution of diisopropylamine (0.25 ml) in dry THF (16 ml) at - 5-0C and the solution is stirred for 30 minutes. The mixture is cooled to -78 C and a solution of 3-cyanothiophene (0.20 g, 1.8 mmol) in THF (4 mL) is added dropwise, followed by methyl iodide (0.23 mL, 0.35 g, 2.5 mmol) after 1 minute. The mixture is stirred for 20 minutes, warmed to room temperature for 30 minutes, and evaporated. Meanwhile, n-butyllithium (0.25 ml) in dry THF (16 ml) is added dropwise at -5 ° C and the solution is stirred for 30 minutes. The mixture is cooled to -78 C and crude 3-cyano-2-methylthiophene is added dropwise as above is prepared in THF (4 ml), followed by trimethylsilyl chloride (0.43 ml) after 1 minute. The mixture is stirred for 20 minutes, heated at room temperature for 30 minutes and evaporated to give a yellow oil. Purification by flash chromatography on untreated neutral alumina, eluting with 5% diethyl ether in hexane, to give 3-cyano-2-methyl-5-trimethylsilylthiophene as a clear oil (0.20 g). M + 195; 360 MHz XH n.m. r (CDC13), 7.19 (1H, s), 2.66 (3H, s), 0.3K9H, s).

EXAMPLE P - (TRIMETILSILIL) TIAZOLA-2-CARBOXALDEHYDE n-Butyllithium (1.50M in hexane, 39 mmol, 22 ml) is added dropwise at -78 C to a solution of 5- (trimethylsilyl) thiazole (A. Dondoni et al. J. Org. Chem, 1998, 53, 1748) (5.2 g, 33 mmol) in THF (40 ml). After 30 minutes a solution of N-formylmorpholine (4.57 g) in TH (40 ml) is added dropwise over 15 minutes. The resulting red solution is stirred for 30 minutes and then left to warm to room temperature, diluted with 4N hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give a brown oil (5.5 g). M + 185; 360 MHz XH n.m.r (CDC13), 9.89 (1H, S), 7.95 (1H, s), 0.24 (9H, s).

PREPARATION OF THE PRODUCTS EXAMPLE 1 CHLORHYDRATE OF L-AMINO-3- (2-FLUOROFENIL) -3,4-DIHYDROISOQUINOLINE Lithium hexamethyldisilyl azide (l.OM in THF, 5.0 ml, 5.0 mmol) is added dropwise to a stirred solution of 2-fluorobenzaldehyde (0.53) ml, 5.0 mmol) in THF (5 ml) at -10 C, and the imine solution is allowed to warm to OC for a period of 2 hours. Meanwhile, n-butyllithium (1.45M in hexanes, 5.0 mmol, 3.5 ml) is added dropwise to a stirred solution of diisopropylamine (5.5 mmol, 0.78 ml) in dry THF (8 ml) at -5-OC and the Solution is stirred for 30 minutes. DMPU (0.91 ml, 5.0 mmol) is added, the mixture is cooled to -78 C and a solution of 2-methylbenzonitrile (5.0 mmol, 0.59 ml) in THF (4 ml) is added dropwise. The dark red anion is stirred for 30 minutes, and a freshly prepared solution is added dropwise. After 40 minutes, the mixture is heated to 0 C for 30 minutes, cooled with 6N aqueous hydrochloric acid., three times are extracted with dichloromethane and the combined extracts are dried with sodium sulfate and evaporated to give a yellow oil. This is purified by flash chromatography on untreated neutral alumina, eluted with 5% methanol in dichloromethane, the gradient is increased to 10% methanol in dichloromethane to give a pale yellow foam (0.49 g). This is recrystallized from dichloromethane / hexane to give pale yellow crystals of l-amino-3- (2-fluorophenyl) -3,4-dihydroisoquinoline hydrochloride (0.35 g), m.p. 204-206C.

The compounds of Example 2-47 are prepared using the method of Example 1 using the appropriate nitriles and aldehydes.

EXAMPLE 2 CHLORHYDRATE OF 1-AMINO-3-PHENYL-3, 4-DIHYDROISOQUINOLINE methylbenzonitrile and benzaldehyde; p.f. 204-206C.

EXAMPLE 3 CHLORHYDRATE OF L-AMINO-3- (4- (BENZYLOXY) PHENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-benzyloxybenzaldehyde; p.f. 248-250C.

EXAMPLE 4 CHLORHYDRATE OF L-AMINO-3- (4- (MEYLTHYL) PHENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-methylthiobenzaldehyde; colorless glass M + 268, Calculated for C? 6H1N2ClS; C 63.0, H 5.6, N 9.2, Cl 11.6, S 10.5%. Found; C 63.0, H 5.9, N 9.3, Cl 12.0, S 10.2%.

EXAMPLE 5 CHLORHYDRATE OF L-AMINO-3- (4- (METHYL) PHENYL) -3, 4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-methylthiobenzaldehyde; colorless glass M + 236, Calculated for C? 6H? 7N2Cl; C 70.45, H 6.3, N 10.3, Cl 13.0%. Found; C 70.6, H 6.6, N 10.35, Cl 13.0%.

EXAMPLE 6 CHLORHYDRATE OF 1-AMIN0-3- (3- (METHYL) PHENYL) -3,4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 3-methylthiobenzaldehyde; colorless foam. M + 236, Calculated for d6H? 7N2Cl + 0.8 mol H20; C 66.95, H 6.5, N 9.8, Cl 12.35%. Found; C 66.6, H 6.5, N 9.7, Cl 11.8%.

EXAMPLE 7 CHLORHYDRATE OF l-AMINQ-3- (4- (METHYL) PHENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-methoxybenzaldehyde; colorless glass M + 252, Calculated for C 16 H 17 N 2 C 1; C 66.55, H 5.9, N 9.7, Cl 12.3%. Found; C 66.2, H 6.3, N 9.8, Cl 12.3%. EXAMPLE 8 CHLORHYDRATE OF] 1-AMINQ-5-MET0XI-3-PHENYL-3, 4- DIHYDROISOQUINQLINE Prepared using 3-methoxy-2-methylbenzonitrile and benzaldehyde; p.f. 252-254C.

EXAMPLE 9 l-AMINO-3- (2- (CHLORINE) PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 2-chlorobenzaldehyde, mp 166-168C.

EXAMPLE 10 CHLORHYDRATE OF L-AMINO-3- (3- (CHLORINE) PHENYL) -3, 4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 3-chlorobenzaldehyde; p.f. 179-182C.

EXAMPLE 11 CHLORHYDRATE OF L-AMINO-3- (4- (CHLORINE) PHENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-chlorobenzaldehyde; p.f. 279-299C.

EXAMPLE 12 CHLORHYDRATE OF 1-AMINO-5-CHLORO-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 3-chloro-2-methylbenzonitrile and benzaldehyde; colorless foam. M + 256, Calculated for C? 5H? N2Cl2; C 61.5, H 4.8, N 9.6, Cl 24.2%. Found; C 61.2, H 5.1, N 9.7, Cl 24.1%.

EXAMPLE 13 CHLORHYDRATE OF 1-AMINO-8-CHLORO-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2-chloro-6-methylbenzonitrile and benzaldehyde; p.f. 247-249C EXAMPLE 14 CHLORHYDRATE OF; l-AMINO-3- (4- (FLUORO) PHENYL) -3,4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-fluorobenzaldehyde; p.f. 246-247C.

EXAMPLE 15 CHLORHYDRATE OF L-AMINO-3- (3- (FLUORO) PHENYL) -3, 4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 3-fluorobenzaldehyde; colorless foam. (M + H) + 240, Calculated for C? 5H? 4N2ClF + 0.30 mol H20; C 63.9, H 5.0, N 9.9%. Found; C 63.9, H 5.2, N 9.9%.

EXAMPLE 16 1-AMINO-5-FLUORO-3-PHENYL-3, 4 HYDROCHLORINOLINE HYDROCHLORIDE Prepared using 3-fluoro-2-methylbenzonitrile and benzaldehyde; p.f. 181-184C.

EXAMPLE 17 CHLORHYDRATE OF 1-AMINO-8-FLUORO-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2-fluoro-6-methylbenzonitrile and benzaldehyde; foam pale yellow. (M + H) + 241, Calculated for C? 5H14N2Cl; C 65. 1, H 5. 1, N 10. 1%. Found; C 64 9, H 5. 4, N 9. 9%.

EXAMPLE 18 CHLORHYDRATE OE 1-AMINO-6-BROMO-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 4-bromo-2-methylbenzonitrile and benzaldehyde; p.f. 224-225C.

EXAMPLE 19 O-CHLORHYDRATE O-AMINQ-3- (2- (METHYL) PHENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 2-methylbenzaldehyde; colorless foam. M + 236.

Calculated for C? 6H17N2Cl + 0.2 mol H20; C 69.5, H 6.35, N 10.1, Cl 12.8%. Found; C 69.4, H 6.5, N 10.3, Cl 12.3%.

EXAMPLE 20 CHLORHYDRATE OF 1-AMINO-7-METHYL-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2,5-dimethylbenzonitrile and benzaldehyde; colorless foam. M + 236.

Calculated for C? 6H? 7N2Cl; C 70.45, H 6.3, N 10.3%. Found; C 70.6, H 6.3, N 10.4%.

EXAMPLE 21 CHLORHYDRATE OF 1-AMINO-5-METHYL-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2,3-dimethylbenzonitrile and benzaldehyde; p.f. 211-212C.

EXAMPLE 22 CHLORHYDRATE D l-AMINO-3- (2-FURYL) -3, 4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 2-furaldehyde; p.f. 208-211C.

EXAMPLE 23 CHLORHYDRATE OF l-AMINQ-3- (3-FURYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 3-furaldehyde; p.f. 188-190C. EXAMPLE 24 CHLORHYDRATE OE l-AMINQ-3- (2-THIENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 2-thiophene carboxaldehyde; p.f. 200-202C.

EXAMPLE 25 CHLORHYDRATE OF L-AMINO-3- (3-THIENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and carboxaldehyde of 3-thiophene; p.f. 101-103C.

EXAMPLE 26 CHLORHYDRATE OF 1-AMINO-8-CHLORO-3- (2-FURYL) -3, 4-DIHYDROISOQUINOLINE Prepared using 2-chloro-6-methylbenzonitrile and carboxaldehyde of 3-thiophene; p.f. 229-231C.

EXAMPLE 27 L-AMINO-3- (3-PYRIDYL) -3,4-HYDROCHLORINOLINE HYDROCHLORIDE It is prepared using 2-methylbenzonitrile and 3-pyridine carboxaldehyde; foam pale yellow. M + 223.

Calculated for C 4 H 14 N 3 Cl; C 64.7, H 5.4, N 16.2%. Found; C 64.9, H 5.8, N 15.9%.

EXAMPLE 28 CHLORHYDRATE OE l-AMINO-3- (4-PIRIDYL) -3, 4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 4-pyridine carboxaldehyde; p.f. 238-241C.

EXAMPLE 29 CHLORHYDRATE OF 1-AMINO-3-CICLOPROPIL-3, 4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and cyclopropyl carboxaldehyde; p.f. 200-202C.

EXAMPLE 30 CHLORHYDRATE OF L-AMINO-3- (2- (DIMETHYLAMINE) METHYL) PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and the intermediate of example (b); p.f. 117-119C.

EXAMPLE 31 CHLORHYDRATE OF L-AMINO-3- (3- (DIMETHYLAMINE) METHYL) PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and the intermediate of example L (b); oxalate p.f. 170-171C.

EXAMPLE 32 CHLORHYDRATE OF L-AMINO-3- (2-BENZOTIZAZOL) -3, 4- DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and 2-benzothiazole carboxaldehyde; p.f. 258-260C. EXAMPLE 33 CHLORHYDRATE OF 1-AMINQ-8-CHLORO-3- (4-FLUOROFENIL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-chloro-6-methylbenzonitrile and 4-fluorobenzaldehyde; p.f. 176-178C.

EXAMPLE 34 CHLORHYDRATE OF L-AMINO-3- (4-FENILETINYL) -3,4-DIHYDROISOQUINOLINE Prepared using 2-methylbenzonitrile and propinal phenyl; p.f. 235-236C.

EXAMPLE 35 CHLORHYDRATE OF 1-AMINO-8-METHYL-3-PHENYL-3, 4-DIHYDROISOQUINOLINE Prepared using 2,6-dimethylbenzonitrile and benzaldehyde; p.f. 145-147C.

EXAMPLE 36 1-AMINO-5-FLUORO-3- (4-FLUOROFENYL) -3,4-DIHYDROISOQUINOLINE CHLORHYDRATE Prepared using the intermediate of Example B (a) and 4-fluorobenzaldehyde; p.f. 235-237C.

EXAMPLE 37 CHLORHYDRATE OF 1-AMINO-8-FLUORO-3- (4-FLUOROFENYL) -3,4-DIHYDROISOQUINOLINE Prepared using the intermediate of Example C and 4-fluorobenzaldehyde; M + 258; 360 MHz XH nmr (d6-DMSO), 7.48 (1H, m), 7.39 (2H, m), 7.08 (4H, m), 4.69 (1H, dd, J 11.7, 4.7 Hz), 3.04 (2H, ddd, 15.8, 11.7, 4.7 Hz).

EXAMPLE 38 CHLORHYDRATE OF L-AMINO-5, 8-DIFLUORO-3- (4-FLUOROFENYL) -3,4-DIHYDROISOQUINOLINE Prepared using the intermediate of Example D and 4-fluorobenzaldehyde; p.f. 221-223C.

EXAMPLE 39 CHLORHYDRATE OF 1-AMINO-6-FLUORO-3- (4-FLUORO-PHENYL) -3,4-DIHYDROISOQUINOLINE Prepared using 4-fluoro-2-methylbenzonitrile and 4-fluorobenzaldehyde; p.f. 227-228C.

EXAMPLE 40 CHLORHYDRATE OF 1-AMINO-7-FLUORO-3- (4-FLUOROFENIL) -3,4-DIHYDROISOQUINOLINE This is prepared by the method of Example 1 using 3-fluoro-6-methyl-2-trimethylsilylbenzonitrile (Example F), give a 9: 1 mixture of the title compound and the corresponding substituted 8-trimethylsilyl compound. This is purified by the following procedure: the contaminated product (570 mg) in THF (8 ml) is treated with butylammonium fluoride (1.OM in THF, 2.0 ml) and stirred at room temperature for 16 hours. The mixture is evaporated and purified by flash chromatography on untreated neutral alumina, eluted with 2% methanol in dichloromethane, increasing the gradient to 100% methanol to give a pale yellow oil which is triturated with dichloromethane to give fine white powder (270 mg), M + 258; 360 MHz * H nmr (d6-DMS0), 9.29 (1H, br.s), 8.11 (1H, dd, J 2.3, 9.7 Hz), 7.62-7.43 (4H, m), 7.26-7.21 (2H, m) , 5.05UH, dd, J 5.6, 8.5 Hz), 3.34-3.22 (2H, m).

EXAMPLE 41 CHLORHYDRATE OF 1-AMIN0-3-ETINYL-3, 4-DIHYDROISQUINOLINE a) l-amino-3- (trimethylsilylethynyl) -3,4-dihydroisoquinoline hydrochloride, is prepared by the method of example 1 using 2-methylbenzonitrile and trimethylsilylacetylene carboxaldehyde; p.f. 230-232C. b) l-amino-3-ethylsilylethynyl) -3,4-dihydroisoquinoline hydrochloride, a mixture l-amino-3- (trimethylsilylethynyl) -3,4-dihydroisoquinoline hydrochloride, the intermediate of example 41 (a), and carbonate of potassium (100 mg) in methanol (60 ml) is stirred at room temperature by 74 hours Add more potassium carbonate (630 mg), stir continuously for 16 hours, concentrate the solution in vacuo and purify by flash chromatography in untreated neutral alumina, elute with 5% methanol in dichloromethane, increasing the gradient of 10% methanol in dichloromethane to give a yellow / tan solid (0.75 g). This is recrystallized from methanol / dichloromethane to give the hydrochloride of 1-amino-3-ethynyl-3,4-dihydroisoquinoline as yellow crystals, m.p. 226-227C.

EXAMPLE 42 CHLORHYDRATE OF L-AMINO-3- (4- (AMINOPROPYLLOXY) PHENYL) -3, 4- DIHYDROISOQUINOLINE a) l-amino-3- (4- (3-azidopropyloxy) phenyl) -3,4-dihydroisoquinoline hydrochloride, is prepared by the method of example 1 using 2-methylbenzonitrile and the intermediate of example G (b); pale yellow oil. (M + H) + 322; 360 MHz XH nmr (d6-DMSO) 10.26 (1H, br.s), 9.57 (1H, br.s), 9.02 (1H, br.s), 8.13.1H, d, J 7.9 Hz), 7.69 (1H , t, J 7.5 Hz), 7. 52 (1H, t, J 7.7 Hz), 7.45 (1H, d, J 7.7 Hz), 7.31 (2H, d, J 8.0 Hz), 6.96 (1H, d, J 6.8 Hz), 4.95 (1H, t, J 6.8 Hz), 4.14-4.0K2H, m), 3.79-3.76 (1H, m), 3.51-3.48 (1H, m), 3.28 (2H, d, J 7 Hz), 2.16-2.13 (1H, m) , 1.98-1.94 (1H, m). b) l-amino-3- (4- (3-aminopropyloxy) phenyl) -3,4-dihydroisoquinoline hydrochloride A mixture of l-amino-3- (4- (3-azidopropyloxy) phenyl) -3 hydrochloride, 4-dihydroisoquinoline (360 mg, 1.01 mmol) [example 42 (a) and tin (II) chloride (330 mg, 1.51 mmol) is stirred at room temperature for 30 minutes. The solvent is evaporated, taken up in a mixture of water / methanol / trifluoroacetic acid (85: 15: 0.5), the precipitate is filtered through cotton wool, evaporated and purified by RP-HPLC to give hydrochloride dihydrochloride. -amino-3- (4- (3-azidopropyloxy) phenyl) -3,4-dihydroisoquinoline (195 mg) as a white solid, mp 180-182C.

The compounds of Example 43-44 are prepared by the method of Example 42 using the appropriate isoquinoline.

EXAMPLE 43 DICHLORHYDRATE OF L-AMINO-3- (3- (2- (AMINOETHYL) PHENYL) -3,4-DIHYDROISOQUINOLINE a) l-amino-3- (3- (2-azidoethyl) phenyl) -3,4-dihydroisoquinoline hydrochloride, prepared by the method of example 1 using 2-methylbenzonitrile and the intermediate of example H (d); colorless foam, (M + H) + 292. b) l-amino-3- (3- (2-aminoethyl) phenyl) -3,4-dihydroisoquinoline dihydrochloride, p.f.97-100C.

EXAMPLE 44 l-amino-3- (4- (2-aminoethyl) phenyl) -3,4-dihydroisoquinoline hydrochloride a) l-amino-3- (4- (2-azidoethyl) phenyl) -3,4-dihydroisoquinoline hydrochloride Prepared by the method of example 1 using 2-methylbenzonitrile and the intermediate of example J (c); foam yellow, (M + H) + 292. b) l-amino-3- (4- (2-aminoethyl) phenyl) -3,4-dihydroisoquinoline hydrochloride, m.p. 206-209C.

EXAMPLE 45 l-amino-3- (3- (3-aminopropyl) phenyl) -3,4-dihydroisoquinoline hydrochloride a) l-amino-3- (3- (3-aminopropyl) phenyl) -3,4-dihydroisoquinoline hydrochloride Prepared by the method of example 1 using 2-methylbenzonitrile and the intermediate of example I (f); colorless viscous oil, (M + H) + 306. b) l-amino-3- (3- (3-aminopropyl) phenyl) -3,4-dihydroisoquinoline hydrochloride, colorless solid. (M + H) + 280; 360 MHz XH nmr (de-DMSO) 10.38 (1H, br.s), 9.64 (1H, br.s), 9.08 (1H, br.s), 8.14 (1H, d, J 7.9), 8.02 (2H, br .s), 7.70 (1H, t, J 7.5 Hz), 7.53 (1H, t, J 7.7 Hz), 7.46 (1H, d, J 7.5 Hz), 7.33 (1H, t, J 7.6 Hz), 7.31 ( 1H, s), 7.21 (1H, t, J 7.8 Hz), 4.99 (1H, t, J 5.7 Hz), 3.35- 3.28 (2H, m), 2.75 (2H, br.s), 2.65 (2H, t , J 7.6 Hz), 1.86 (2H, pentet, J 7 Hz).

EXAMPLE 46 l-amino-3- (2-thiazolyl) -3,4-dihydroisoquinoline hydrochloride a) amino-3- (2- (5-trimethylsilyl) thiazolyl) -3,4-dihydroisoquinoline hydrochloride Prepared by the method of Example 1 using 2-methylbenzonitrile and the intermediate of Example P; foam chestnut, M + 301. b) l-amino-3- (2-thiazolyl) -3,4-dihydroisoquinoline hydrochloride. Tetra-n-butylammonium fluoride (1. OM in THF, 1.78 ml) is added dropwise to a solution of the hydrochloride of l-amino-3- (2- (5-trimethylsilyl) thiazolyl) -3,4-dihydroisoquinoline [example 46 (a)] (430 mg, 1.27 mmol). The mixture is stirred at room temperature for 30 minutes, concentrated in vacuo and the resulting crude material is purified by flash chromatography on untreated neutral alumina, eluted with 10% ethanol in dichloromethane, increasing the gradient of 100% ethanol. , to give a yellow foam (237 mg). Trituration of dichloromethane and THF to give a white solid, m.p. 219-221C (dec.).

EXAMPLE 47 l-amino-3- (2-imidazolyl) -3,4-dihydroisoquinoline hydrochloride a) l-amino-3- (2- (N- (2-trimethylsilylethoxymethyl) imidazolyl) -3,4-dihydroisoquinoline hydrochloride Prepared using 2-methylbenzonitrile and carboxaldehyde 2- (N- (2-trimethylsilylethoxymethyl)) imidazole; mp 134-135C. b) l-amino-3- (2-imidazolyl) -3,4-dihydroisoquinoline hydrochloride. 3N aqueous hydrochloric acid (10 ml) is added to a solution of l-amino-3- (2- (N-) hydrochloride. (2-trimethylsilylethyloxymethyl) imidazolyl) -3,4-dihydroisoquinoline [(example 47 (a)] (650 mg, 1.7 mmol) in ethanol (50 ml) and the mixture is refluxed for 20 hours, allowed to cool and Concentrate in vacuo to give a yellow foam This is recrystallized from methanol / diethyl ether to give pale yellow crystals (350 mg), mp 181-182C.

EXAMPLE 48 l-amino-3- (4-piperidyl) -3,4-dihydroisoquinoline hydrochloride A slurry of platinum oxide (8 mg, 10 mol) in methanol (1 ml) is added to a solution of 1-amino-1-hydrochloride. 3- (4-? Iridyl) -3,4-dihydroisoquinoline (example 28) (150 mg, 0.578 mmol) in methanol and concentrate the hydrochloric acid (0.4 ml), and stir in 3 atmospheres of hydrogen for 16 hours. The mixture is filtered through celite and evaporated. The residue is purified by RP-HPLC to give a white hygroscopic solid (126 mg). (M + H) + 230; 360 MHz * H n.m. r (d6-DMSO) 10.30 (1H, s), 9.43 (1H, s), 9.03 (1H, s), 8.80 (1H, br.s), 8.56 (1H, br.s), 8.05 (1H, t , J 7.8 Hz), 7.71 (1H, t, J 7.5 Hz), 7.54-7.50 (2H, m), 3.72-3.68 (1H, m), 3.27 (2H, d, J 13.2 Hz), 3.15 (1H, dd, J 17.4 Hz), 2.99 (1H, dd, J 17.2, 6.9 Hz), 2.80-2.74 (2H, m), 1.95-1.63 (3H,), 1.48-1.38 (2H, m).

EXAMPLE 49 L-amino-3-methyl-3,4-dihydroisoquinoline hydrochloride A mixture of l-ethylthio-3,4-dihydro-3-methylisoquinoline (M. Gittos et al, J. Chem. Soc., Perkin I, 1976, 33) (0.68 g, 3.3 mmol), ammonium iodide (0.48 g, 3.3 mmol) and ammonium (2M in methanol, 4 mL) in ethanol. { 4 ml) is heated at reflux for 4 hours. The mixture is allowed to cool and diethyl ether (100 ml) is added. The same dark oil which is separated on a support, is decanted and the remaining clear solution is kept at -20C for 24 hours. The resulting crystals are collected, washed with diethyl ether and dried to give the product as a pale yellow prism (370 mg), m.p. 114-116C.

EXAMPLE 50 l-amino-3- (4-hydroxyphenyl) -3,4-dihydroisoquinoline hydrochloride a] l-amino-3- (4-tert-butyldimethylsilyloxy) phenyl) -3,4-dihydroisoquinoline hydrochloride This is prepared by the method of Example 1 using the intermediate of Example M to give a colorless foam, M + 476; 360 MHz 2H n.m. r (d6-DMS0) 8.12 (1H, d, J 7.9 Hz), 7.70-7.65 (5H,), 7.53-7.34 (8H, m), 7.19 (2H, d, J 8.6 Hz), 6.74 (2H, d , J 8.6 Hz), 4.86 (1H, dd, J 5.9, 8.6 Hz), 3.28-3.16 (2H, m), 1.03 (9H, s). b) l-amino-3- (4-hydroxyphenyl) -3,4-dihydroisoquinoline hydrochloride, Tetra-n-butylammonium fluoride (1. OM in THF) is added, 3.3 ml) was added to a solution of 1-amino-3- (tert-butyldimethylsilyloxyphenyl) -3,4-dihydroisoquinoline hydrochloride (638 mg, 1.11 mmol) in THF (10 ml). After 15 minutes, the mixture is evaporated and the residue is purified by flash chromatography on untreated neutral alumina, eluted with 5% methanol in dichloromethane, the gradient of 40% methanol in dichloromethane is increased to give a colorless solid. (172 mg). This is recrystallized from methanol / dichloromethane: 2) to give the product as a white powder. M + 239; 360 MHz XH n.m. r (d6-DMSO) 9.65 (1H, br.s), 8.15 (1H, d, J 7.8 Hz), 7.69 (1H, t, J 7.5 Hz), 7. 52 (1H, t, J 7.6 Hz), 7.45.1H, d, J 7.5 Hz), 7.19.2H, d, J 8.6 Hz), 6.77 (2H, d, J 8.6 Hz), 4.87 (1H, t, J 7.3 Hz), 3.25 (2H, d, J 7.3 Hz).

EXAMPLE 51 7-amino-5-phenyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5-phenyl-2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride. Lithium hexamethyldisilyl azide (1.0M in THF, 2.56 ml, 2.56 mmol) is added dropwise to a solution of benzaldehyde (0.26 ml, 2.6 mmol) in dry THF (5 ml), to OC, and the imine solution is allowed to warm to OC for a period of 2 hours. Meanwhile, n-butyllithium (1.45 M in hexanes, 2.56 mmol, 1.77 mL) is added dropwise to a stirred solution of amino diisopropyl (0.40 mL, 2.8 mmol) in dry THF (10 mL) between -5 and 0 C and The solution is stirred for 30 minutes. DMPU (0.55 ml, 4.6 mmol) is added, the mixture is warmed to -78 C and added dropwise to a solution of 2-cyano-3-methyl-5-trimethylsilylthiophene (2.56 mmol, 0.500 g) in THF (2 g). ml). The orange anion is stirred for 30 minutes, and the freshly prepared imine solution is added dropwise. After 30 minutes, the mixture is heated to 0 C for 30 minutes, cooled with 6N aqueous hydrochloric acid, extracted twice with dichloromethane, the combined extracts are dried over sodium sulfate and evaporated to give an yellow color. This is purified by flash chromatography on untreated neutral alumina, eluted with 5% methanol in dichloromethane, the gradient in 10% methanol in dichloromethane is increased to give the title compound as an oily white solid (243 mg ). M + 300; 360 MHz XH nmr (CDCl3) 7.40-7.32 (1H, m), 7.1K1H, s), 4.96 (1H, dd, J 5.7, 10.8 Hz), 3.28 (1H, dd, J 5.8, 16.7 Hz), 3.17- 3.1 (1H, m), 0.36 (9H, b) 7-amino-5-phenyl-4,5-dihydrothieno hydrochloride [2, 3-cjjpi_ri_dine Tetra-n-butylammonium fluoride (l.OM in THF, 1.12 ml) is added dropwise to a solution of the hydrochloride of 7-amino-5-phenyl-2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine (0.13 mg, 0.37 mmol) in THF (2.5 ml)., evaporated and the residue was purified by chromatography of flash in untreated neutral alumina, eluting with 4% methanol in dichloromethane, increasing the gradient by increments of 20% methanol in dichloromethane to give a colorless glass. Recrystallize from dichloromethane to give the title compound as white crystals (51 mg), m.p. 234-236C. The compounds of Examples 52-54 are prepared from 2-cyano-3-methyl-5-trimethylsilylthiophene and the appropriate aldehyde using the method of Example 51.

EXAMPLE 52 7-amino-5- (3-pyridyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (3-pyridyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using carboxaldehyde 3-? iridine, pale yellow foam. (M + H) + 302; 360 MHz XH nmr (CDCl3) 8.43-8.41 (1H, m), 7.72 (1H, d, J 7.9 Hz), 7.20 (1H, dd, J 4.8, 7.9 Hz), 6.96 (1H, s), 4.91 (1H , dd, J 5.8, 10.0 Hz), 3.20 (1H, dd, J 5.8, 16.7 Hz), 3.02 (1H, dd, J 10.1, 16.7 Hz), 0.20 (9H, s). b) 7-amino-5- (3-pyridyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride, m.p. 201-202C.

EXAMPLE 53 7-amino-5-cyclopropyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5-cyclopropyl-2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using carboxaldehyde 3-pyridine, pale yellow foam. (M + H) + 265; 360 MHz XH nmr (CDCl3) 7.12 (1H, s), 3.17-3.11 (1H,), 3.03-2.92 (2H, m), 1.16-1.12 (1H, m), 0.80-0.76 (1H, m), 0.68 -0.64 (1H, m), 0.58-0.54 (1H, m), 0.37 (9H, s), 0.36-0.29 (1H, m). b) 7-amino-5-cyclopropyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride, m.p. 268-270C.

EXAMPLE 54 7-amino-5- (3-furyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (3-furyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using 3-furaldehyde, pale yellow foam. (M + H) + 291; 360 MHz XH n.m.r (CDCl3) 7. 54 (1H, s), 7.40 (1H, s), 7.14 (2H, s), 6.46 (1H, s), 4. 93 (1H, dd, J 5.7, 10.0 Hz), 3.28.1H, dd, J 5.7, 16.6 Hz), 3.10 (1H, dd, J 10.0, 16.6 Hz), 0.36 (9H, s). b) 7-amino-5- (3-furyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride, m.p. 225C (dec).

EXAMPLE 55 7-amino-5- (2-furyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (2-furyl) -2-trimethylsilyl-4 hydrochloride -dihydrothieno [2, 3-c] pyridine Prepared using 2-furaldehyde, pale yellow foam. (M + H) + 290; 360 MHz XH n.m.r (CDCl3) 7.69 (1H, s), 7.45 (1H, s), 6.45 (1H, dd, J 1.8, 3.2 Hz), 6. 36 (1H, d, J 3.3 Hz), 5.18 (1H, t, J 6.7 Hz), 3.43- 3.29 (2H, m), 0.35 (9H, s). b) 7-amino-5- (2-furyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride, m.p. 252-254C.

EXAMPLE 56 7-amino-5- (2-thienyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (2-thienyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Using carboxaldehyde 2-thiophene. b) 7-amino-5- (2-thienyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride, m.p. 243-245C.

EXAMPLE 57 7-amino-5- (l-benzyl-2-pyrrolyl) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride a) 7-amino-5- (l-benzyl-2-pyrrolyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Using l-benzyl-2-arylcarboaldehyde. b) 7-amino-5- (1-benzyl-2-pyrrolyl) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride, m.p. 250-252C.

EXAMPLE 58 7-amino-5- (l-methyl-2-pyrrolyl) -4,5-dihydrothieno [2,3-cjpyridine hydrochloride] a) 7-amino-5- (l-methyl-2-pyrrolyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Using carboxaldehyde l-methyl-2-pyrrolyl. b) 7-amino-5- (1-methyl-2-pyrrolyl) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride, m.p. 224-225C.

EXAMPLE 59 7-amino-5-ethynyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5-ethynyl-2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using trimethylsilylacetylene carboxaldehyde, white solid, M + 320. b) 7-amino-5-ethynyl-4,5-dihydrothieno [2, 3 c]? iridine hydrochloride, m.p. 268-270C.

EXAMPLE 60 7-amino-5-propynyl-4,5-dihydrothieno [2, 3-c]? iridine hydrochloride a) 7-amino-5-propynyl-2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using 2-butyral, chestnut-colored gum, M + 262; 360 MHz XH nmr (CDCl3) 7.13 (1H, s), 4.64 (1H, m), 3.14 (2H, ddd, J 16.5, 7.9, 5.9 Hz), 1.78 (3H, d, J 2.2 Hz), 0.37 (9H , s). b) 7-amino-5-propynyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride, m.p. 226-227C.

EXAMPLE 61 7-amino-5- (2-thiazolyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (2- (5-trimethylsilyl) thiazolyl) -2-trimethylsilyl-4,5-dihydrothieno [2, 3-c]? iridine hydrochloride Prepared from the intermediate of Example P, glass of chestnut color, [M + H] + 380; 360 MHz XH n.m.r (CDCl 3) 7.50 (1H, s), 6.92 (1H, s), 5.17 (1H, dd, J 6.5, 5.1 Hz), 3.37 (2H, ddd, J 16.9, 6.7, 4.9 Hz), 0. 14 (9H, s), 0.09 (9H, s). b) 7-amino-5- (2-thiazoliI) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride, pale yellow foam. [M + H] + 336.

Calculated for C? OH? ON3S2Cl + hydrochloric acid 0.5 mol + H20 2 mol: C 33.1, H 4.3, N 11.6%. Found: C 33.0, H 4.55, N 11.5%.

EXAMPLE 62 7-amino-5- (3, 3-dimethylbutinyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (tert-butylethynyl) -2- trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using 4,4-dimethyl-ent-2-inal, glass of yellow color, [M + H] + 305; 360 MHz XH nmr (CDCl3) 7.12 (1H, s), 4.6K1H, dd, J 9.1, 5.7 Hz), 3.12 (2H, ddd, J 16.4, 9.1, 5.6 Hz), 1.16 (9H, s), 0.37 ( 9H, s). b) 7-amino-5- (tert-butylethynyl) -4,5-dihydrothieno [2,3-c3pyridine hydrochloride, yellow foam. [M + H] + 223.

Calculated for C? 3H? 7N2SCl: C 58.1, H 6.4, N 10.4, S 11.9, Cl 13.2%. Found: C 58.15, H 6.6, N 10.1, S 11.6, Cl 13.2%.

EXAMPLE 63 7-amino-5- (phenylethynyl) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride a) 7-amino-5- (phenylethynyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using propyl phenyl, brown foam, M + 324. b) 7-amino-5- (phenylethynyl) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride, yellow waxy solid. [M + H] + 253.

Calculated for C15H? 3N2SCl + 0.5 mol HCl + 0.5 mol H20: C 57.0, H 4.6, N 8.9, S 10.1%.

Found: C 56.8, H 4.5, N 8.5, S 9.9% EXAMPLE 64 7-amino-5- (cyclobutyl) -4,5-dihydrothieno [2,3-c] pyridine hydrochloride a) 7-amino-5- (cyclobutyl) -2-trimethylsilyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Prepared using cyclobutyl carboxaldehyde, orange gum, M + 278. 7-amino-5- (cyclobutyl) -4,5-dihydrothieno [2, 3-c] pyridine hydrochloride, yellow crystals, m.p. > 260C. [M + H] + 207; 360 MHz XH n.m. r (d6-DMSO) 8.89 (1H, br.s), 8.14 (1H, d, J 4.9 Hz), 7.22 (1H, d, J 4.9 Hz), 3.76 (1H, q, J 8.0 Hz), 3.07 ( 2H, dd, J 17, 5.8 Hz), 2.66 (2H, dd, J 17, 9.5 Hz), 2.45.1H, q, J 8.2 Hz), 1.99 (2H, m), 1.84 (4H, m).

EXAMPLE 65 7-amino-5-ethynyl-2-methyl-4,5-dihydrothieno [2, 3-cj pyridine hydrochloride a) 7-amino-5-trimethylsilylethynyl-2-methyl-4,5-dihydrothieno [2, 3-c] pyridine hydrochloride This is prepared from 2,5-dimethyl-3-cyanothiophene and trimethylsilylacetylene carboxaldehyde, according to to the procedure of Example 51 (a) to give a brown / yellow solid, M + 299. b) 7-amino-5-ethynyl-2-methyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride. This is prepared from 7-amino-5-trimethylsilylethynyl-2-methyl-4-hydrochloride. , 5-dihydrothieno [2, 3-c] pyridine [example 62 (a)] according to the procedure of example 51 (b) to give the crystals white, mp 227-230C (dec).

EXAMPLE 66 7-amino-5-ethyl-4,5-dihydrothieno [2,3-c] pyridine hydrochloride Palladium in carbon (57 mg) is added as a slurry in ethanol to 7-amino-5-ethynyl-4 hydrochloride, 5-dihydrothieno [2,3-c] pyridine (example 56) (113 mg, 0.531 mol) in ethanol (6 ml) and the mixture is stirred for 16 hours under 3 atmospheres of hydrogen. The mixture is then filtered through celite, evaporated and triturated with diclotesmethane to give a white powder (75 mg), m.p. 221-223C.

EXAMPLE 67 Following the method of example 66, the representative compound is prepared from the hydrochloride of 7-amino-5-propynyl-4,5-dihydrothieno [2,3-c] pyridine (example 60): -7-amino-5- propyl-4, 5-dihydrothieno [2, 3-c] pyridine, white solid, M + (+ EI) 194; 360 MHz XH nmr (d6-DMS0) 9.30 (1H, br.s), 8.61 (1H, br.s), 8.14.1H, d, J 4.9 Hz), 7.23.1H, d, J 4.9 Hz), 3.82 (1H, m), 2.96 (2H, ddd, J 17, 10, 6 Hz), 1.55 (2H, m), 1.40 (2H, m), 0.90 (3H, t, J 7.2 Hz).

EXAMPLE 68 4-AMIN0-6-PHENYL-6,7-DIHYDRAINE [3, 2-C] PYRIDINE CHLORHYDRATE This is prepared by the method of Example 51, 3-cyano-2-methyl-5-trimethylsilylthiophene substituted by 2 -cyano-3-methyl-5-trimethylsilylthiophene and using the appropriate aldehyde. a) 4-amino-6-phenyl-2-trimethylsilyl-6,7-dihydrothieno [3, 2-c]? iridine hydrochloride Prepared using benzaldehyde, pale yellow foam (0.44 g), (M + H) + 301; 360 MHz XH n.m.r (d6- DMSO) 7.98 (1H, s), 7.44-7.22 (5H, m), 5.10 (1H, dd, J 6.0, 9. 2 Hz), 3.55 (1H, dd, J 6.0, 17.1 Hz), 3.43-3.34 (1H, m), 0.32 (9H, s). b) 4-amino-6-phenyl-6,7-dihydrothieno [3, 2-cjpyridine hydrochloride, m.p. 213-215C.

The compounds of examples 69-70 are prepared from 3-cyano-2-methyl-5-trimethylsilylthiophene and the appropriate aldehyde using the method of example 68.

EXAMPLE 69 CHLORHYDRATE OF 4-AMINO-6-ETINYL-6,7-DIHYDROTANE [3, 2-C] PYRIDINE a) 4-amino-6-trimethylsilylethynyl-2-tritynetilsilyl-6,7-dihydrothieno [3,2-c] pyridine hydrochloride Prepared using trimethylsilylacetylene carboxaldehyde, yellow solid, (M + H) + 321; 360 MHz XH n.m. r (d6-DMSO) 7.87 (1H, s), 4.83.1H, t, J 6. 6 Hz), 3.37 (1H, dd, J 5.9, 17.0 Hz), 3.24-3.18 (1H, m), 0. 22 (9H, s), 0.00 (9H, s). b) 4-amino-6-ethynyl-6,7-dihydrothieno [3,2-c] pyridine hydrochloride, m.p. 196-197C.

EXAMPLE 70 CHLORHYDRATE OF 4-AMINO-6-CICLOPROPIL-6, 7- DIHYDROTEIN [3,2-c] PYRIDINE a) 4-amino-6-cyclopropyl-2-trimethylsilyl-6,7-dihydrothieno hydrochloride [3, 2-c] ] pyridine Prepare using cyclopropylcarboxaldehyde, white solid, (M + H) + 265; 360 MHz XH nmr (d6-DMSO) 9.76 (1H, br.s), 9.40 (1H, br.s), 8.83 (1H, br.s), 7.97 (1H, s), 3.39-3.35 (lH, m ), 3.18-3.12 (2H, m), 1.12-1.02 (1H, m), 0.55-0.53 (2H,), 0.39-0.33 (2H, m), 0.32 (9H, s). b) 4-amino-6-cyclopropyl-6,7-dihydrothieno [3,2-c] pyridine hydrochloride, m.p. 236-238C.

EXAMPLE 71 7-AMINO-4, 5-DIHIDROTIENO [2, 3-c] PYRIDINE a) 7-Methylthio-4,5-dihydro [2, 3-c] pyridine hydroiodide A solution of 4,5-dihydro [2,3-c] pyridin-7 (6H) -thione (RV Davies et al. ., J Chem. Soc, Perkin 1, 1976, 138) (11.3 g, 66.8 mmol) in acetone (80 ml) is added to iodomethane (7.6 ml, 120 mmol). The solution is stirred for 6 hours and the resulting solid is collected to give the title compound as a yellow solid (20.3 g), m.p. 212-5C (dec.). b) 7-amino-4,5-dihydrothieno [2,3-c] pyridine A solution of iodhydric acid 7-methylthio-4,5-dihydro [2,3-c] pyridine in 150 ml of isopropanol containing concentrated aqueous ammonium (15 ml) is heated to reflux for 4 hours. After cooling, the solvent is evaporated and the residue is partitioned with diethyl ether (100 ml) and diluted with hydrochloric acid. The aqueous phase is basified with aqueous sodium hydroxide and extracted 4 times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated to give 7.6 g of the crude product which partially solidifies in the support. This residue is taken up in isopropanol (150 ml) and 6.55 g of oxalic acid dihydrate in 50 ml of isopropanol are added. After stirring for several hours the solid is collected to give 9.71 g of the title compound as a white solid, m.p. 158-160C (dec.).

EXAMPLE 72 HYDROCHLORIC 4-AMINO-6,7-DIHYDROTIENO [2, 3-c] PYRIDINE a) 4-Methylthio-6,7-dihydrothieno [3,2-c] pyridine hydrochloride A solution of phosphoric acid (205 g) at 175 ° C, 2- (2-thienyl) ethylisothiocyanate (RV Davies et al., J Chem. Soc., Perkin 1, 1976, 138) is added dropwise. The solution is stirred for 6 hours, poured into cold water (3 L), the mixture is stirred for 3 hours to decompose the phosphoric acid, extracted with chloroform, dried over magnesium sulfate and evaporated to give a dark oil. which solidifies in the support. This solid is taken up in acetone (250 ml) and iodomethane (12 ml) is added. The reaction mixture is stirred for 4 hours and the solid is collected to give the title compound as a yellow solid (26 g), m.p. 184-187C. b) 4-amino-6,7-dihydrothieno [2, 3-c] pyridine hydroiodic acid The ammonia gas is bubbled through a solution of 4-methylthio-6,7-dihydrothieno [3,2-c]? Iridine (6.00 g, 19.3 mmol) in isopropanol (40 ml) for 4 hours and the resulting solution Leave for 24 hours. The precipitate is filtered and dissolved in methanol (25 ml), treated with charcoal (1.5 g), filtered and the filtrate is diluted with diethyl ether (75 ml). The resulting solid is collected and dried to give the title compound (1.8 g) as a white solid, m.p. 160-163C. According to the invention, these examples and their pharmaceutically acceptable salts, enantiomers and tautomers are useful as pharmaceuticals, and are useful in the manufacture of a medicament for the treatment or prophylaxis of the aforementioned diseases and conditions, eg inflammatory disease. Therefore, the invention provides a method of treating, or reducing the risk of, inflammatory disease in a patient suffering from, or at risk of, the disease, wherein the method comprises administering to the patient a compound exemplified above, or a pharmaceutically acceptable salt, enantiomer and tautomer thereof.

PROTECTION The activity of the compounds according to the invention are tested in the following protection. The activity of the compounds of formula I, or a pharmaceutically acceptable salt, enantiomers or tautomers thereof, can be protected by the synthetic activity of nitric oxide by a method based on Forstermann et al. (1992) Eur. J. Pharm. 225, 161-165. The synthesis of nitric oxide is converted to 3H-L-arginine to 3H-L-citrulline which can be separated by cation exchange chromatography and quantified by liquid distillation. The enzyme is prepared, after induction, from the murine culture macrophase cell line J774A-K obtained from the main cancer research foundation laboratories). J774A-1 cells are cultured in Dulbeccos Modified Eagles Medium (DMEM) supplemented with 10% fetal bovine serum, 4mM L-glutamine and antibiotics (penicillin G 100 units / ml, streptomycin 100 mg / ml & amp;; amphotericin B 0.25 mg / ml). The cells develop ritually in a 225 cm2 flask containing 35 ml of the medium is maintained at 37 ° C and in a humidified atmosphere containing 5% C02, the synthesis of nitric oxide is produced by cells in response to interferon-g (IFNg ) and li? opolisacaride (LPS). The medium of the confluent culture flask is removed and replaced. with 25 ml (per flask) of the fresh medium containing 1 mg / ml LPS and 10 units / ml of IFNg. After a period of 17-20 hours in culture, harvesting the cells is done by curettage of the cell layer on the surface of the flask in the culture medium. The cells are collected by centrifugation (1000 g for 10 minutes) and the lysate is prepared by adding the cell pellet to a solution containing 50 mM tris-HCl (pH 7.5 at 20C), glycerol 10% (v / v) , triton-X-100 0.1% (v / v), 0.1 mM dithiothreitol and a cocktail of protease inhibitors comprising leupeptin (2 mg / ml), soybean trypsin inhibitor (10 mg / ml), aprotinin (5 mg / ml), mg / ml) & phenylmethylsulfonyl fluoride (50 mg / ml). For the test, the 25 μl substrate cocktail (50 mM ris-HCl (pH 7.5 at 20 ° C), 400 μM NADPH, 20 μM dinucleotide flavin adenine, 20 μM mononucleotide flavin, 4 μM tetrahydrobiopterin, 12 μM L-arsinin and is added. L- [3H] arginine 0.025? RtCi) for deposits from a 96 filtered tank plate (0.45 μM pore size) containing 25 μM of a solution of the test compound in 50 mM tris-HCl. The reaction is initiated by the addition of 50 μl of lysate cell (prepared as above) and then the incubation for 1 hour at room temperature is terminated by the addition of 50 μl of an aqueous solution of 3 mM nitroarginine and 21 mM EDTA. Classified L-citrulline is separated from the L-arginine classified using Dowex AG-50W. 150 μl of an aqueous slurry of Dowex 50W 25% (Na + form) is added to the test, then the total is filtered in 96 tank plates. 75 μl of the filtrate is shown and added to deposit tank tanks 96 which contains the distilled solid. After the samples are left to dryness, the L-citrulline is quantified by continuous distillation. In a fundamental activity, the typical experiment is 300 dpm per 75 μl of sample, which increases to 1900 dpm in active controls. The activity of the compound is expressed as IC50 (the concentration of drug substance which gives the inhibition of the enzyme at 50% in the test) and aminoguanidine, which gives an ICso (50% inhibition concentration) of 10 μM, it is tested as a standard to verify the procedure. The compounds are tested in a range of concentrations and the inhibitions of the IC50 values obtained are calculated. Compounds that inhibit the enzyme from at least 25% to 100 μM are classified as active and subjected to at least one retest. The aforementioned protection, the compounds of examples 2, 14-17, 22-29, 36-38, 41-46, 49, 51-56, 58-61 and 64-72 are tested and give IC50 values of the least 25 μM indicating that it is necessary to assume to show the useful pharmaceutical activity.

Claims (30)

1. - A compound of formula I wherein: R represents (i) phenyl, benzothiazolyl or a 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen atoms, which phenyl, benzo ring of benzothiazolyl or a heterocyclic aromatic ring is optionally substituted by alkyl Cl to 6, C1 to 6 alkoxy, halogen, hydroxy, Cl to 6 thioalkyl, benzyloxy, or a group -Q (CH2) PNR4R5; or (ii) Cl to 8 alkyl, C3 to 8 cycloalkyl, C2 to 8 alkynyl, piperidyl, phenyl to C7 to C14 alkyl, which alkyl, cycloalkyl, alkynyl, or piperidyl is optionally substituted by a group - (CH2) PNR4R5, the phenylalkyl is optionally substituted by a group - (CH 2) PNR 4 R 5, alkyl Cl 6, alkoxy Cl 6, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms is selected from 0, N or S, optionally substituted by C1 to 6 alkyl, C7 to 14 phenylalkyl or halogen; or (iv) hydrogen or phenylalkynyl C7 to 14; Q represents 0, NR6 or a link; R1 represents a hydrogen, Cl to 6 alkyl, Cl-alkoxy to 6, trimethylsilyl or halogen; R 2 represents a hydrogen, Cl to 6 alkyl or phenyl optionally substituted by Cl to 6 alkyl, Cl to 6 alkoxy, halogen or hydroxy; R3 represents hydrogen or halogen; R4, R5 and R6 independently represents a hydrogen or C1 to 6 alkyl, or -NR4R5 together represent piperidyl, pyrrolidinyl or morpholinyl; p represents a number from 1 to 5; and A represents a thieno or benzo ring; provided that when A represents a benzo ring and Q represents 0, p does not represent 1; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof; provided that when A represents a benzo ring, the compounds of the formula I in which R represents a hydrogen, Cl to 6 alkyl or phenyl, R1 represents a hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy or halogen, R2 represents a hydrogen, Cl to 6 alkyl or an unsubstituted phenyl and R3 represents an excluded hydrogen.

2. - A compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, characterized in that the compound is a [2, 3-c] pyridine or a thieno [3,2-c] pyridine of the compound of formula I.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, characterized in that R represents ethynyl, cyclopropyl, fluorophenyl, benzyloxyphenyl, thiomethylphenyl, methylphenyl, rethoxyphenyl, chlorophenyl, furyl, thienyl, pyridyl , phenylethynyl, aminopropyloxyphenyl, an inoethylphenyl, aminopropylphenyl, thiazolyl, imidazolyl, methyl, ((di? t? etila? r? ino) insipid) phenyl, propynyl, butynyl, phenylethynyl, benzylpyrrolyl, methylpyrrolyl, ethyl, cyclobutyl, hydroxyphenyl or propyl.

4. - A compound, is: l-ap? ino-3- (2-fluorophenyl) -3,4-dihydroisoquinoline; or l-amin? -3-phenyl-3,4-dihydr? isoquinoline; or l-ap? ino-3- (4- (benzyloxy) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (methylthio) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (methyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (methyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (methoxy) phenyl) -3,4-dihydroisoquinoline; or l-amino-5-methoxy-3-phenyl-3,4-dihydroisoquinoline; or l-apino-3- (2- (chloro) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (chloro) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (chloro) phenyl) -3,4-dihydroisoquinoline; or l-ap? ir? o -5-chloro-3-phenyl-3,4-dihydroisoquinoline; or l-amino-8-chloro-3-phenyl-3,4-dihydroisoquinoline; or l-amino-3- (4- (fluoro) phenyl) -3,4-dihydroisoquinoline; or 1-a-pine-3- (3- (fluoro) phenyl) -3,4-dihydroisoquinoline; or l-amino-5-fluoro-3-phenyl-3,4-dihydroisoquinoline; or l-ap? ino-8-fluoro-3-phenyl-3,4-dihydroisoquinoline; or l-amino-6-bromo-3-phenyl) -3,4-dihydroisoquinoline; or I-amino-3- (2- (methyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-7-methyl-3-phenyl-3,4-dihydroisoquinoline; or l-amino-5-p-ethyl-3-phenyl-3,4-dihydroisoquinoline; or l-amino-3- (2-furyl) -3, -dihydroisoquinoline; or l-amino-3- (3-furyl) -3,4-dihydroisoquinoline; or l-amino-3- (2-thienyl) -3,4-dihydroisoquinoline; or l-a ino-3- (3-thienyl) -3,4-dihydroisoquinoline; or l-amino-8-chloro-3- (2-furyl) -3,4-dihydroisoquinoline; or l-amino-3- (3-pyridyl) -3,4-dihydroisoquinoline; or l-amino-3- (4-pyridyl) -3,4-dihydroisoquinoline; or l-amit? o-3-cyclopropyl-3,4-dihydroisoquinoline; or l-amino-3- (2- (dimethylamine) phenyl-3,4-dihydroisoquinoline; or the ino-3- (3- (di-erylamino) rneyl) phenyl-3,4-dihydroisoquinoline; 3- (2-benzthiazolyl) -3,4-dihydroisoquinoline or l-ainino-8-chloro-3- (4-fluorolenyl) -3,4-dihydroisoquinoline or l-amino-3- (phenylethynyl) - 3, 4-dihydroisoquinoline, or I-a ino-8-i [butyl-3-phenyl-dihydroisoquinoline; or l-di? Inu-5-flu? Ro-3- (4-fluorophenyl) -3, 4- dihydrizoisoquinoline; or 1-dimino-8-riuoro-3- (4-fluorophenyl) -3,4-dihydroisoquinoline; or 1-amino-5,8-difluoro-3- (4-fluorophenyl) -3,4-dihydroisoquinolyl; or l-an? ino-6-fluoro-3- (4-fluorophenyl) -3,4-dihydroisoquinoline; or l-amino-7-fluoro-3- (4-fluoro-nil) -3,4-dihydroisoquinoline; l-amino-3-ethynyl-3,4-dihydroisoquinoline; or l-amino-3- (4- (3-a? ainopro? yloxy) phenyl) -3,4-dihydroisoquinoline; or l-dir? ino -3- (3- (2-anolenyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (2-aminoleyl) phenyl) -3,4-dihydroisoquinoline; or the? Nino- 3- (3- (3-amino? Ropil) f enyl) -3,4-dihydr? is? quinoline; or l-amin? -3- (2-thiazolyl) -3,4-dihydroisoquinoline; or l-amino-3- (2-imidazolyl) -3,4-dihydroisoquinoline; or l-amino-3- (4-piperidii) -3,4-dihydroisoquinoline; or l-a ino-3-methyl-3, 4-dihydroisoquinoline; or I-amino-3- (4-hydroxyphenyl) -3,4-dihydroisoquinoline; or 7-a? t? ino-5-phenyl-4, 5-dihidr? tien? [2, 3-c] pyridine; or 7-amino-5- (3-pyridyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-cyclo? pr? pil-4, 5-dihydrothieno [2, 3-c] pyridine; or 7-amino-5- (3-furyl) -4,5-dihydrothieno [2, 3-c]; or 7-a? t? ino-5- (2-furyl) -4,5-dihydrothieno [2,3-c] pyridine; or 7-amin? -5- (2-thienyl) -4,5-dihydrothieno [2, 3-c]; or 7-a ino-5- (1-benzyl-2-pyrrOlyl) -4,5-dihydroLieno [2,3-c] pyridine; or 7-amino-5- (1-methyl-2-pi rolyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-ethynyl-4,5-dihydrothieno [2,3-c] pyridine; or 7-amino-5-propynyl-4,5-dihydrothieno [2, 3-c]; or 7-amino-5- (2-thiazoliI) -4,5-dihydrothieno [2,3-c] pyridine; or 7-amino-5- (3, 3-dimethylbutinyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5- (phenylenyl) -4,5-dihydroLieno [2, 3-c] pyridine; or 7-amino-5- (cyclobutyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-ethynyl-2-methyl-4,5-dihydrothieno [2,3-c] pyridine; or 7-amin? -5-ethyl-4,5-dihydrothieno [2, 3-c]; or 7-amino-5-propyl-4,5-dihydrothieno [2, 3-c]; or 7-amino-6-phenyl-6,7-dihydrothieno [2, 3-c] pyridine; or 7-amino-6-ethynyl-6,7-dihydrothieno [2, 3-c]; or 7-amino-6-cyclopr pil-6, 7-dihydrothieno [2, 3-c] pyridine; or 7-amino-4, 5-dihydrothieno [2, 3-c]; or 4-amino-6,7-dihydrothieno [2, 3-c] pyridine; or a pharmaceutically acceptable salt, enantio ero or LauLomero thereof.

5. - A compound of formula I wherein: R represents (i) phenyl, benzothiazolyl or a 6-membered helerocyclic aromatic ring containing from 1 to 3 nitrogen atoms, which phenyl, benzyl ring; of the benzothidzolyl or a heterocyclic aromatic ring is substituted? pci? ridlmenLe by the dlquil? Cl d 6, dlkoxy Cl d 6, halogen, hydroxy, Cl to 6 thioalkyl, benzyloxy, or a group -Q (CH 2) PNR 4 R 5; or (ii) dlquil? Cl d 8, cycloalkyl C3 to 8, dlquinil? C2 d 8, piperidyl ?, phenyldiyl? C7 14, the alkyl, cycloalkyl, d-lkynyl, or piperidyl is replaced by pcioiidlirie Le by a group - (CH2) PNR4R5, the fenildlquil? it is optionally substituted by a group - (CH2) PNR4R5, C1 to 6 alkyl, C1 to 6 alkoxy, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms is selected from 0, N or S, subsiluid? ? nally by the alkyl Cl d 6, phenyl C 7 d 14 alkyl or the hdl? geno; or (iv) hydrogen or C7 d 14 fepilaiquiniio; Q represents 0, NR6 or a link; R1 represents a hydrogen, C1 to 6 alkyl, C1 to 6 alkoxy, trimethylsilyl? halogen; R 2 represents a hydrogen, Cl to 6 alkyl or phenyl optionally substituted by Cl to 6 alkyl, Cl to 6 alkoxy, halogen or hydroxy; R3 represents hydrogen or halogen; R4, R5 and R6 independently represents a hydrogen or C1 to 6 alkyl, or -NR4R5 together represent piperidyl, pyrrolidinyl or morpholinyl; p represents a number from 1 to 5; and A represents a thieno or benzo ring; provided that when A represents a benzo ring and Q represents 0, p does not represent 1; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof; provided that when A represents a benzo ring, the compounds of the formula I in which R represents a hydrogen, Cl to 6 alkyl or phenyl, R1 represents a hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy or halogen, R2 represents a hydrogen, Cl to 6 alkyl or an unsubstituted phenyl and R3 represents an excluded hydrogen.

6. - A compound, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, for use as a pharmaceutical in accordance with claim 5, characterized in that the compound is a thieno [2,3-c] pyridine or a thieno [3, 2] c] pyridine of the compound of formula I.

7. The compound according to claim 5 or 6, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, for use as a pharmaceutical, characterized in that R represents ethynyl ?, cyclic pr? Pyl, flu? R? Phenyl ?, benzyloxyphenyl ?, thi? methylphenyl ?, methylphenyl ?, meth? xyphenyl ?, cl? r? phenyl ?, furyl ?, thienyl, pyridyl, phenylethynyl, aminopropyloxyphenyl, amin? ethylphenyl ?, amin? pr? pylphenyl ?, thiazyl? , imidaz? ll ?, methyl, ((dimethylamin?) methyl) phenyl ?, propynyl, butynylnyl, phenylethynyl ?, benzylpyrr? lyl ?, methylpyrrolyl ?, ethyl, cyclobutyl, hydroxyphenyl? or propyl.

8. The compound according to claim 4, or a pharmaceutically acceptable salt, titanium or tautomer thereof, as a pharmaceutical use.

9. - A pharmaceutical composition that includes a compound according to claim 4,5, 6 or 7 or a pharmaceutically acceptable salt, enantiomer or chloride thereof, in a mixture with a pharmaceutically acceptable auxiliary, diluent or carrier.

10. - Use of a compound of formula I wherein: R represents (i) phenyl, benzothiazolyl or a 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen atoms, which phenyl, benzothiazolyl benzo ring or a heterocyclic aromatic ring is optionally substituted by alkyl Cl a 6, Cl 6 alkoxy, halogen, hydroxy, Cl a 6 thioalkyl, benzyloxy, or a group -Q (CH 2) PNR 4 R 5; or (ii) Cl to 8 alkyl, C3 to 8 cycloalkyl, C2 to 8 alkynyl, piperidyl, phenyl to C7 to C14 alkyl, which alkyl, cycloalkyl, alkynyl, or piperidyl is optionally substituted by a group - (CH2) PNR4R5, the phenylalkyl is optionally substituted by a group - (CH 2) PNR 4 R 5, alkyl Cl 6, alkoxy Cl 6, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms is selected from 0, N or S, optionally substituted by C1 to 6 alkyl, C7 to 14 phenylalkyl or halogen; or (iv) hydrogen or phenylalkynyl C7 to 14; Q represents 0, NR6 or a link; R1 represents a hydrogen, Cl to 6 alkyl, Cl-alkoxy to 6, trimethylsilyl or halogen; R 2 represents a hydrogen, Cl to 6 alkyl or phenyl optionally substituted by Cl to 6 alkyl, Cl to 6 alkoxy, halogen or hydroxy; R3 represents hydrogen or halogen; R4, R5 and R6 independently represent a hydrogen or, Cl to 6 alkyl, or -NR4R5 together represent piperidyl, pyrrolidinyl or morpholinyl; p represents a number from 1 to 5; and A represents a thieno or benzo ring; provided that when A represents a benzo ring and Q represents 0, p does not represent 1; or a pharmaceutically acceptable salt, enanti? mer? or tautomer of it; in the manufacture of a drug, for the treatment or prophylaxis of inflammatory disease.

11. The use according to claim 10, characterized in that the compound is a thieno [2,3-c] pyridine or a thieno [3,2-c] iridine of the compound of formula I.

12. The compound according to claim 10 or 11, characterized in that R represents ethynyl, cyclopropyl, fluorophenyl, benzyloxyphenyl, thiomethylphenyl, methylphenyl, ethoxyphenyl, chlorophenyl, furyl, thienyl, pyridyl, phenylethynyl, in. Propyloxyphenyl, aminoethylphenyl, aminopropylphenyl, Liazyl, imidazolyl, methyl, ((dimethylamino) elyl) faithyl, propynyl, butynyl, phenylethynyl, benzylpyrrolyl, methylpyrrolyl, ethyl, cyclobutyl, hydroxyphenyl or propyl.

13. - Use of a compound or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of the inflammatory disease, characterized in that the compound is: l-amino-3-. { 2-fluorophenyl) -3,4-dihydroisoquinoline; or l-amino-3-phenyl-3,4-dihydr? isoquinoline; or l-amino-3- (4- (benzyloxy) phenyl) -3,4-dihydroisoqui-olin; or l-amino-3- (4- (methylthio) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (methyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (methyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (methoxy) phenyl) -3,4-dihydroisoquinoline; or l-amino-5-methoxy-3-phenyl-3,4-dihydroisoquinoline; or l-amino-3- (2- (chloro) phenyl) -3,4-dihydroisoquininoin; or l-amino-3- (3- (chloro) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (chloro) phenyl) -3,4-dihydroisoquinoline; or l-amin? -5-cl? r? -3-phenyl-3,4-dihydroisoquinoline; or l-amino-8-chloro-3-phenyl-3,4-dihydroisoquinyl? a; or l-amino-3- (4- (fluoro) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (fluoro) phenyl) -3,4-dihydroisoquinoline; or l-amino-5-fluoro-3-phenyl-3,4-dihydroisoquinoline; or l-amino-8-fluoro-3-phenyl-3,4-dihydroisoquinoline; or 1-amino-6-bromo-3-pheny1) -3,4-dihydroisoquinoline; or l-amino-3- (2- (methyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-7-methyl-3-phenyl-3,4-dihydroisoquinoline; or l-amino-5-methyl-3-phenyl-3,4-dihydroisoquinoline; or l-amino-3- (2-furyl) -3,4-dihydroisoquinoline; or l-amino-3- (3-furyl) -3,4-dihydroisoquinoline; or l-amino-3- (2-thienyl) -3,4-dihydrois? quinoline; or l-amin? -3- (3-thienyl) -3,4-dihydroisoquinoline; or l-amino-8-chloro-3- (2-furyl) -3,4-dihydroisoquinoline; or l-amino-3- (3-pyridyl) -3,4-dihydr? isoquinoline; or l-amino-3- (4-pyridyl) -3,4-dihydroisoquinoline; or l-amino-3-cyclopropyl-3,4-uihydroisoquinoline; or l-amino-3- (2- (dimethylamino) phenyl-3,4-dihydroisoquinoline; or l-amino-3- (3- (dimethylamino) me il) phenyl-3,4-dihydroisoquinoline; or l-amino -3- (2-benzothiazolyl) -3,4-dihydroisoquinoline; or l-amino-8-chloro-3- (4-fluorophenyl) -3,4-dihydroisoquinoline; or l-amino-3-. {Phenylethynyl) -3,4-dihydroisoquinoline; or l-amino-8-methyl-3-pheny1-dihydroisoquinoline; or l-amino-5-fluoro-3- (4-fluorophenyl) -3,4-dihydr? is? quinoline; or l-a ino-8-fluoro-3- (4-fluorophenyl) -3,4-dihydroisoquinoline; or l-dn? n? -5, 8-difluor? -3- (4-flu? r? phenyl) -3,4-dihydroisoquinolind; or l-amin? -6-flu? r? -3- (4-flu? r? phenyl) -3,4-dihydrois? quinolind; or i-diaia? -7-flu? r? -3- (4-flu? r? phenyl) -3,4-dihydroisoquinolind; or 1-dmino-3-etinii-3, 4-dihydr? isoquinolirid; or l-dinin? -3- (4- (3-d in? pr? pil? xi) phenyl) -3,4-dihydr? is? quin? lind; or l-dmin? -3- (3- (2-aminyl) phenyl) -3,4-dihydrois? quinoline; ? 1-amino-3- (4- (2-amin? Lil) phenyl) -3,4-dihydrois? Quinoline; or l-a in? -3- (3- (3-amin? pr? pyl) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (2-thiazolyl) -3,4-dihydroisoquinoline; or 1-diamino-3- (2-imidazolyl) -3,4-dihydroisoquinylind; or 1-di? ino-3- (4-piperidyl) -3,4-dihydroisoquinoline; or l-amino-3-methyl-3, 4-dihydrois? quinoline; or 1-amino-3- (4-hydroxyphenyl) -3,4-dihydroisoquinolirid; or 7-dino-5-phenyl-4,5-dihydrothieno [2, 3-c] pyridirid; or 7-amino-5- (3-pyridyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-cyclo? propyl-4,5-dih? drot? ene [2, 3-c] iridine; or 7-amino-5- (3-furyl) -4,5-dihydrothieno [2, 3-c]; or 7-amin? -5- (2-furii) -4,5-dihydrothieno [2, 3-c] iridine; or 7-amino-5- (2-thienyl) -4,5-dihydrothieno [2, 3-c]; or 7-amin? -5- (l-benzyl-2-pyrr? lyl) -4,5-dihydr? lien? [2, 3-c] pyridine; or 7-amin? -5- (1-methyl-2-pyrroyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-ethynyl-4,5-dihydrothieno [2, 3-c] pyridine; or 7-dino-5-propynyl-4,5-dihydrothieno [2, 3-c]; or 7-dith? ipo-5- (2-tidzolyl) -4,5-dihydrothien? [2, 3-c] pyridirid; or 7-dmino-5- (3, 3-dimethylbutinyl) -4,5-dihydrothieno [2, 3-c]; or 7-diuin? -5- (phenylenyl) -4,5-dihydr? i n? [2, 3-c] pyridiid; ? 7-dinino-5- (cyclobutyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-ethynyl-2-methyl-4,5-dihydrothieno [2,3-c] pyridine; or 7-dino-5-ethyl-4,5-dihydrothien? [2, 3-c]; or 7-dino-5-propyl-4,5-dihydrothien [2, 3-c]; or 7-dmin? -6-phenyl-6,7-dihydrothieno [2, 3-c] pir idirid; or 7-dipino-6-ethynyl-6,7-dihydrothieno [2, 3-c]; or 7-dmin? -6-cyclopr? pyl-6,7-dihydrothieno [2,3-c] pyridid; or 7-dino-4,5-dihydrothieno [2, 3-c]; or 4-amino-6,7-dihydrothieno [2, 3-c] pyridine; or

14. - The use according to any of claims 10 to 13, characterized in that the disease is asthma.

15. - A method of treatment, or reduction of the risk of, the inflammatory disease in a patient suffering from said disease, characterized in that the method comprises the administration to the patient of a compound of formula I wherein: R represents 0 (i) phenyl, benzothiazolyl or an aromatic ring heler? cylic? of 6 members that contains 1 to 3 nitrogen atoms, which phenyl, benzothiazolyl benzo ring? ? an aromatic heterocyclic ring? is optionally substiluted by C1 to 6 alkyl, Cl to 6 akoxy, halogen, hydroxy, C1 to 6 thioalkyl, benzyloxy, or a -Q (CH2) PNR4R5 group; or (ii) Cl to 8 alkyl, C3 to 8 cycloalkyl, C2 to 8 alkynyl, piperidyl, phenyl to C7 to C14 alkyl, which alkyl, cycloalkyl, alkynyl, or piperidyl is optionally substituted by a group - (CH2) PNRR5, the phenylalkyl is optionally substituted by a group - (CH2) PNR4R5, C1 to 6 alkyl, C1 to 6 alkoxy, halogen or nitro; or (iii) a heterocyclic aromatic ring? of 5 members containing 1 to 3 heteroatoms is selected from 0, N or S, optionally substituted by the alkyl Cl to 6, "Miyl-C7 to 14 or the halogen, or (iv) hydrogen or phenylalkyl-C7 to 14; Q represents 0, NR6 or a bond, R1 represents a hydrogen, C1 to 6 alkyl, C1 alkoxy to 6, trimethylsilyl or halogen; R 2 represents a hydrogen, Cl to 6 alkyl or phenyl optionally substituted by Cl to 6 alkyl, alkoxy Cl to 6, halogen or hydroxy; R3 represents hydrogen or halogen; R4, R5 and R6 independently represents a hydrogen or C1 to 6 alkyl, or -NR4RS together represent pipepdyl, pyrridiazyl? or m? rf? iinii ?; p represents a number? from 1 to 5; and A represents a thieno or benz ring; as long as you cudiid? A representd a dnill? benz? and Q represents 0, p does not represent 1; or an acceptable salt fdrmdcéuticdiuente, endnti? mer? or tdut? mer? of the same.

16. - The method? of conformiddd with claim id 15, CdidcLerizdd? because the compound is a L? in? [2,3-cipyridiiid or a thieno [3, 2-c] pyridi? id of the compound of formula I.

17. The method according to claim 15 or 16, characterized in that R represents the ethinyl ?, icl? Pr? Pil ?, flu? R? Phenyl ?, benzyl? Xiphenyl ?, Li? IueLilfeuil ?, ethylphenyl ?, ethoxyphenyl, cl ? r? phenyl ?, furyl ?, lienyl ?, pyridyl ?, phenylethynyl ?, d? ip? pr? pyl? xiphenyl ?, amin? ethylphenyl ?, amin? pr? pylphenyl ?,? liayl?, imiddz? lyl, methyl? , ((dimethyldmin?) methyl) phenyl ?, pr? pinyl ?, butynylnyl ?, phenylethynyl ?, benzylpyrr? ilyl ?, methylpyrr? ilyl ?, ethyl, cyclobutyl, hydroxyphenyl? or propii ?.

18. - A method of treatment, or reduction of the risk of, the disease of inflammation in a patient suffering from, or risk of of said enfermeddd, carácte izad? because the method comprises the administration to the patient of a compound, the compound is: l-diain -3- (2-fluoro-phenyl) -3,4-dihydroisoquinolirid; or 1-amino-3-phenyl-3,4-dihydroisoquinoline; ? l-dmin? -3- (4- (benzyloxy) phenyl) -3,4-dihydr? is? quin? ind; or l-diain? -3- (4- (methylthi?) phenyl) -3,4-dii? idr? is? quinolyrid; or l-diain? -3- (4- (methyl) phenyl) -3,4-dihydr? isoquinoli? id; or i-diuin? -3- (3- (methyl) phenyl) -3,4-dihydr? isoquinoline; or l-amin? -3- (4- (met? xi) phenyl) -3,4-dihydroisoquinoline; or l-amin? -5-? t? ethoxy-3-phenyl-3,4-dihydroisoquinoline; or I-amino-3- (2- (cl? r?) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (3- (chloro) phenyl) -3,4-dihydroisoquinoline; or l-amino-3- (4- (cl? r?) phenyl) -3,4-dihydr? isoquinoline; or l-amin? -5-cl? ro-3-phenyl-3,4-dihydroisoquinoline; or l-amin? -8-cl? ro-3-f nyl-3, 4-dihydroisoquinoline; or l-amin? -3- (4- (fluoro) phenyl) -3,4-dihydroquinoline; or l-amin? -3- (3- (fluoro) phenyl) -3,4-dihydrois? quinoline; or l-amino-5-fluoro? -3-phenyl-3,4-d? hydr? is? quinoline; or l-dipin? -8-flu? r? -3-phenyl-3,4-dihydroisoquinoli? id; or I-dmino-6-br? m? -3-phenyl) -3,4-dihydr? isoquinoli? id; or i-diuin? -3- (2- (methyl) phenyl) -3,4-dihydr? isoquinoli? id; or 1-dmin? -7-methyl-3-phenyl-3, 4-dihydr? is? quinolyrid; or 1-dmin? -5-methyl-3-phenyl-3,4-dihydroisoquinoline; or l-diuin? -3- (2-furyl) -3,4-dihydr? is? quinoli? id; or 1-dmin? -3- (3-furyl) -3,4-dihydroisoquinoline; or l-diuin? -3- (2-thienyl) -3,4-dihydr? is? quinoline; or 1-dmino-3- (3-thienyl) -3,4-dihydrois? quinoline; or l-amin? -8-cl? r? -3- (2-furyl) -3,4-dihydr? is? quinoline; or l-amin? -3- (3-pyridyl) -3,4-dihydroisoquinoline; or l-amin? -3- (4-pyridyl) -3,4-dihydr? is? quinoline; or I-amin? -3-cycl? pr? pil-3, 4-dihydr? is? quinoline; or l-diuin? -3- (2- (dimethyl?) fenll-3, 4-dihydr? is? quin? l? a; or l-dmin? -3- (3- (dim? ilmin?) methyl) pheny1- 3, 4-dihydroisoquinolind; or l-dmino-3- (2-benzothidzolyl) -3,4-dihydr? Is? Quinolirid; or l-dmin? -8-cl? R? -3- (4-flu? R phenyl) -3,4-dihydrois? quinolind; or? t? ino -3- { phenylethynyl) -3,4-dihydr? is? quinoline; or l-amino-8-m ti1-3-f ni1-dihydroisoquinoline; or l-amin? -5-flu? -3- (4-flu? r? fea l) -3,4-dihydr? isoquinoline; or 1-amino-8-lu? r? -3- (4-flu? r? feayl) -3,4-dihydr? is? quin? or l-amiu? -5, 8-diflu? r? -3- (4- lu? r? phenyl) -3,4-dihydrois? quinoline; or 1-ditu non-6-f lu? r? -3- (4-f lu? r? phenyl) -3,4-dihydrizoisoquinoline; or l-amia? -7-flu? r? -3- (4-flu? r? feayl) -3,4-dihydroisoquinoline; or 1-dmin? -3-ethynyl-3, 4-dihydr? isoquinoline; or l-amia? -3- (4- (3-amia? pr? pil? xi) f nyl) -3,4-dihydr? isoquinolide; or l-amin? -3- (3- (2-amia? il) phenyl) -3,4-dihydr? is? a? i? a; or 1-amino-3- (4- (2-amin? eyl) phenyl) -3,4-dihydr? isoquinolia; or l-dmia? -3- (3- (3-dmin? pr? p? l) pheayl) -3,4-dihydroisoquinolind; or l-amin? -3- (2-thiazyl) -3,4-dihydroisoquinoline; or l-amino-3- (2-imidazolii) -3,4-dihydr? is? quinoline; or l-amino-3- (4-piperidyl) -3,4-dihydr? is? quinoline; or l-amin? -3-methyl-3, 4-dihydr? is? quinoline; or l-amin? -3- (4-hydr? xifenii) -3,4-dihydrois? quinoline; or 7-amin? -5-phenyl-4, 5-dihydrothien? [2, 3-c] iridine; ? 7-amino-5- (3-pyridyl) -4,5-dihydrothien [2, 3-c]; or 7-amino-5-cyclo? pr? pii-4, 5-dihydrothien? [2, 3-c] pyridine; ? 7-amin? -5- (3-furyl) -4,5-dihydr? Thieno [2, 3-c]; or 7-amino-5- (2-furyl) -4,5-dihydrothien? [2, 3-c] pyridine; or 7-amin? -5- (2-thienyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5- (l-benzyl-2-pyrrolyl) -4,5-dihydrothieno [2, 3-c] pyridine; or 7-amino-5- (i-methyl-2-pyrrolii) -4,5-dihydrothien? [2, 3-c]; or 7-amin? -5-ethynyl-4, 5-dihydrothien? [2, 3-c] pyridine; or 7-dmin? -5-pr? pinyl-4, 5-dihydr? thien? [2, 3-c]; or 7-amino-5- (2-thiazyl) -4,5-dihydrothien? [2, 3-c] iridine; or 7-amino-5- (3, 3-dimethylbutinii) -4,5-dihydrothien? [2, 3-c]; or 7-amino-5- (phenylethynyl) -4,5-dihydrothieno [2,3-c] pyridine; or 7-amino-5- (cyclobutyl) -4,5-dihydrothieno [2, 3-c]; or 7-amino-5-ethynyl-2-methyl-4,5-dihydrothieno [2,3-c] pyridine; or 7-aminc-5-ethyl-4,5-dihydrothieno [2, 3-c]; or 7-dmino-5-pr? pil-4, 5-dihydrothieno [2, 3-c]; or 7-amino-6-phenyl-6,7-dihydrothien? [2, 3-c] pyridine; or 7-amino-6-etin? l-6,7-dihydrothien? [2, 3-c]; or 7-amin? -6-cycl? pr? pil-6, 7-dihydr? thieno [2, 3-c] pyridine; or 7-dipin? -4,5-dihydrothieno [2, 3-c]; or 4-dir? a? -6, 7-dihidr? tiea? [2, 3-c] pyridirid; or undd sdl pharmaceutically acceptable, enanti? mer? or Laut? mei? of the ism ?.

19. - The confrrrity method with any of the reliviadicaci? Aes 15 d 18, cdrdcte izdd? Because the disease is asthma.

20. - A chemical intermediate for use in production of c? Mpuest? of the liquidity of any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, characterized in that the intermediate is: 3-methoxy-2-methylbenzonitrile; or 3-fluoro-2-methylbepzonitrile; or 3-fluoro-6-methylbenzonitrile ?; or 3-d? fluoro-2-methylbenzonityl ilo; or 4-fluoro-2-methylbenz? nitrile ?; or 3-fiu? ro-6-methyl-2-trimethylsilylbenzonitrile; or 4- (3-dzidopr? pii? xi) enzididehid ?; or 3- (2-dzid? ethyl) benzdldehyde; or 3- (3-dzid? pr? pil) benzdldehid ?; or 4- (2-azidoetiI) benzaldehid ?; or 2- (N, N-dimethyl) aminometiibenzaldehid ?; or 3- (N, -dimethyl) aminomethylbenzaldehyde; or 4-tert-butyldiphenyl ilyl? xibenzaldehid ?; or 2-cyano-3-methy1-5-trimethylsilylthiophene; or 3-cyan? -2-methyl-5-trimethylsilylthi? phen ?; or 5- (trimethylsilyl) thiazyl-2-cdrb? xdldehyde; or l-diuia? -3-. { 4- (3-dzid? Pr? Il? Xi) phenyl) -3,4-dihydroisoquinolind; or l-dm? a? -3- (3- (2-dzid? eyl)) phenyl-3,4-dihydr? is? quin? li? id; or l-dinin? -3- (4- (2-dmin? ethyl) phenyl) -3,4-dihydr? is? quin? ind; or l-dmin? -3- (3- (2-dzid? pr? pyl) pheayl) -3,4-dihydr? isoquinolind; or 4-m ilLio-6, 7-dihydrothien? [3, 2-c] iridiaa.

21. - A chemical intermediate for use in the production of the compound according to any of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, characterized in that the intermediate is of formula I as in the claim, or a salt pharmaceutically acceptable, enantiomer? tautomer thereof, with the exception that R represents trimethylsilylethynyl.

22. - A process for the preparation of the compuest? according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer? or tautomero del miso, characterized p? rque pr? ces? comprises: (a) hydrolysis and / or deprotection of a compound of formula II or a protected derivative thereof, or the hydrolysis and / or deprotection of a pharmaceutically acceptable salt, enantiomer or tautomer of a compound of formula II or dich? derived pr? tegid ?, wherein formula II is A, R, R, R 'and R is as defined above, P represents a protecting group and M represents an alkali metal; or (b) the deprotection of a compound of formula Illa or Ill or a pharmaceutically acceptable salt, enamate, or tautomer thereof wherein R, R and R 'is as defined above and P represents a pr? tect? r group; or (c) treatment of a compound of formula IV or a pharmaceutically acceptable salt, enantiomer? or taut? mer? of it with ammonia, where formula IV is wherein A, R, R1, R2 and R3 e3 as defined above and L is an output group; or (d) preparation of a c? mpuest? of formula I wherein R represents ethinyl, or a pharmaceutically acceptable salt, enantiomer or tautomer of such compound, by hydrolysis of a corresponding compound, which R represents trimethylsilylethynyl; or (e) reaction of a compound of formula V or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formula V is wherein A, R, R1, R2 and R3 is as defined above and M represents an alkali metal, with a compound of formula VI or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formula VI is wherein R is as defined in claim 1; or (f) preparation of a compound or pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the compound is of formula I in which R represents an alkyl Cl to 8 substituted by a group - (CH2) PNR4R5 and one or both of R4 and R5 represent an alkyl Cl to 6, by alkylation of a cpimp? corresponding in which one or more of R4 and. R5 represent a hydrogen; or (g) preparation of a c? mpuest? or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the compound is of formula I in which R represents a phenyl or a ring aromatizes heterocyclic? of 6 members, the phenyl or the heterocyclic aromatice ring is substituted by a -Q (CH2) PNR4R5 group and one or both of R4 and R5 represent a C1 to 6 alkyl,, by alkylation of a cpimp? corresponding in which one or more of R4 and R5 represent a hydrogene; or (h) preservation of a c? mpuest? of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer? thereof, in which one or both nitrogen atoms and / or other protected atoms; or (i) preparation of a compound or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the cimp? is of formula I in which R represents a phenyl or a 6-membered heterocyclic aromatic ring substituted by a -Q (CH2) PNH2 group, by the reduction of the corresponding azido; or preparation of a pharmacist, enantiomer, or tautomer? of the same, where the compound is of formula I in which R represents a piperidii ?, for the reduction of a cp? corresponding to which R represents the pyridyl ?.

23. - Use of a compound of formula (I) where; R represents (i) phenyl, benzothiazyl, or a ring? aromatic heterocyclic? of 6 members containing 1 to 3 nitrogen atoms, the cudl phenyl, ring benz? of benz? tiaz? lil? or a ring? The heterocyclic aromatic is substituted, optionally, with the alkyl Cl a 6, alkoxy Cl a 6, halogen, hydroxy, thioalkyl? Ci to 6, benzyloxy, or a group -Q (CH2) PNR4R5; or (ii) Cl to 8 alkyl, cycloalkyl? C3 to 8, alkylayl? C2 to 8, piperidyl ?, phealkylalkyl? C7 14, the cudl the dlquil ?, cycl? Dlquii ?, dlquinilo, or piperidilo is replaced? Pci? Adlmeate p? Rua grup? - (CH2) PNRR5, the feaildlquil? is it substituted? Would you like to ask for a group? - (CH 2) PNR 4 R 5, alkyl Cl 6, alkoxy Cl 6, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 3 heteroatoms is selected from 0, N or S, substituted? pci? aalmeate for the alkyl? Cl to 6, phenylalkyl? C7 to 14 or the halogen; or (iv) hydrogen? or C7 to phenylalkyl 14; Q represents 0, NR6 or a link; R1 represents a hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy, trimethylsilyl or hal? R2 represents a hydrogen, Cl to 6 alkyl or femlo optionally substituted by Cl to 6 alkyl, alkoxy Cl to 6, hal? Gen? or hydroxy; R3 represents hydrogen or halogen; R4, R5 and R6 independently represents a hydrogen or C1 to 6 alkyl, or -NRR5 together represent piperidyl, pyrididinii? or m? rf? linil ?; p represents a number from 1 to 5; and A represents a ring? Thieno or benz ?; coa Lal that when qua re A is a beazo ring and Q represents O, p does not represent 1; or a pharmaceutically acceptable sai, enantiomer? or taut? mer? of the same, in the manufacture of a medically, for the treatment or prophylaxis of the diseases or conditions in which the synthesis or on synthesis of the synthetic forms of nitric oxide of a part contributory.

24. The use according to claim 23, characterized in that it is predominantly the induced isoform of the nitric oxide synthesis that is involved.

25. - The use according to claim 23 or 24, characterized in that the disease is rheumatoid arthritis.

26. - The use according to claim 23 or 24, characterized in that the condition is pain.

27. - A method of treatment, or reduction of the risk of, a disease or condition in which the synthesis or over synthesis of the synthetic forms of nitric oxide of a coapribulent part which comprises the administration of a sick person from. or susceptible to such a disease or condition, a therapeutically effective amount of a compound of formula (I) wherein: R represents (i) phenyl, benzothiazolyl or a 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen atoms, which phenyl, benzothiazolyl benzo ring or a ring; aromatize heterocyclic? is optionally substituted by C1 to 6 alkyl, C1 to 6 alkoxy, halogen, hydroxy, C1 to 6 alkyl, benzyloxy, or a group -Q (CH2) pNRR5; or (ii) Cl to 8 alkyl, C3 to 8 cycloalkyl, C2 to 8 alkynyl, piperidyl, C7 to phenylalkyl, which alkyl, cycloalkyl, alkynyl, or piperidyl is optionally substituted by a group - (CH2) PNR4R5, the phenylalkyl is optionally optionally bridged by a group - (CH 2) PNR 4 R 5, alkyl Cl 6, alkoxy Cl 6, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms is selected from 0, N or S, optionally substituted by C1 to 6 alkyl, C7 to 14 phenylalkyl or hal?; or (iv) hydrogen or phenylalkynyl C7 to 14; Q represents 0, NR6 or a link; R1 represents a hydrogen, Cl to 6 alkyl, Cl-alkoxy to 6, trimethylsilyl? or halogen; R 2 represents a hydrogen, Cl to 6 alkyl or phenyl optionally substituted by Cl to 6 alkyl, alkoxy Cl to 6, hal? Gen? ? hydroxy; R3 represents hydrogen or halogen; R4, R5 and R6 independently represents a hydrogen or C1 to 6 alkyl, or -NR4R5 together represent piperidyl, pyrrolidinyl or morpholinyl; p represents a number from 1 to 5; and A represents a ring? Thieno or benzo; coa Ldl that cuaado A represaLa ua aaillo beazo and Q represents 0, p does not represent 1; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.

28. - A method of treatment according to claim 27, characterized in that it is predominantly the induced isoform of the synthesis of the nitric oxide that is involved.

29. - A method of treatment according to claim 27 or 28, characterized in that the disease is rheumatoid arthritis.

30. - A method of treatment according to claim 27 or 28, characterized in that the condition is pain. SUMMARY OF THE INVENTION The compounds of formula (I) wherein R represents (i) phenyl, benzothiazolyl or a ring? 6-membered heterocyclic aromatic containing 1 to 3 hydrogen atoms, which phenyl, benzyl ring of the benzothiazolyl or the heterocyclic aromatic ring are optionally substituted by the alkyl Cl a 6, alkoxy Cl a 6, halogen, hydroxy, thioalkyl Cl a 6, benzyloxy, or a group -Q (CH 2) PNR 4 R 5; or (ii) Cl to 8 alkyl, C3 to 8 cycloalkyl, C2 to 8 alkynyl, piperidyl, C7 to 14 phenylalkyl, which alkyl, cycloalkyl, alkynyl, or piperidyl are optionally substituted by a group - (CH2) PNR4RS ' phenylalkyl is optionally substituted by a group - (CH 2) PNR 4 R 5, alkyl Cl 6, alkoxy Cl 6, halogen or nitro; or (iii) a 5-membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from 0, N or S, optionally substituted by C1 to 6 alkyl, C7 to 14 phenylalkyl or halogen; or (iv) hydrogen or phenylalkynyl C7 to 14; Q represents 0, NR6 or a link; R1 represents hydrogen, C1 to 6 alkyl, Cl to 6 alkoxy, trimethylsilyl or halogen; R2 represents hydrogen, alkyl Cl to 6? phenyl optionally substituted by C1 to 6 alkyl, C1 to 6 alkoxy, halogen or hydroxy; R3 represents a hydrogen, or halogen; R4, R5 and R6 independently represent a hydrogen or C1 to 6 alkyl, or -NR4R5 together represent piperidyl, pyrrolidinyl or morpholinyl; p represents a number 1 to 5; and A represents a ring? have? or benz ?; c such that A represents a beazo ring and Q represents O, p does not represent 1; ? pharmaceutically acceptable salts, enantiomers? tautomeros of the same; It has been found to be useful as pharmaceuticals, especially for the treatment of inflammatory disease.