RU2155761C2 - Bicyclic derivatives of amidine, method of their synthesis, pharmaceutical composition and method of inhibition of nitrogen oxide synthetase activity - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, pharmacy. SUBSTANCE: invention describes bicyclic derivatives of amidine of the formula (I)

where D means five-membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms taken among O, N or S and optionally substituted by carbon atom with halogen atom, trifluoromethyl, C_1-6-alkyl, nitro- or cyano-group and bound with other moiety of compound of the formula (I) through carbon atom; A means N(X) or CH (-(CH₂)_m-NXY); U means NH, O or CH₂; V means (CH₂)_a; W means (CH₂)_b; a, b, m, X and Y have values given in the invention claim. Invention describes also methods of synthesis of compounds and preparing the pharmaceutical composition containing thereof. Compounds of the formula (I) are inhibitors of nitrogen oxide synthetase activity and can be used in therapy. EFFECT: improved method of synthesis, valuable biochemical and therapeutic properties of compounds. 10 cl

Description

 The present invention relates to bicyclic derivatives of amidine, to methods for their preparation, to compositions containing them and to their use in therapy. The use of certain amidine derivatives for therapeutic purposes has been described. The use of N-phenylamidine derivatives for the treatment of diabetes has been described in US Pat. No. 3,669,974 (USV Pharmaceutical Corp.) and in British Patent Application 2226562 (Boots). The use of N'N '' - disubstituted amidines for the treatment of hypertension, depression and hallucinogenic conditions has been described in international patent application WO 92/04054 (University of Oregon). The use of certain amidines and symmetric bisamidines as analgesics in the treatment of inflammation and in the treatment of hypertension is disclosed in Belgian Patent No. 71740 and British Patent No. 1180629 (both Delalande). The use of amidine derivatives as herbicides has been disclosed in German Patent Application DE-OS-2321330 (Bayer).

 The use of nitric oxide synthetase inhibitors in the treatment of diseases has also been described, for example, in international patent applications WO 94/12163 (Abbott), WO 93/13066 and WO 94/12165 (both Wellcome) and in European patent applications 446699 (Merrell Dow), 547558 and 558468 (both from Washington University). The use of nitric oxide synthetase inhibitors is also disclosed in WO 95/00505, WO 95/09619, WO 95/09621 (all Wellcome), WO 95/10266 (Otsuka), WO 95/11231 and WO 95/12014 (both Searle).

 The applicant previously disclosed the use of guanidine derivatives and amidine derivatives, which are inhibitors of nitric oxide synthetase, in the treatment, among others, of a neurodegenerative disease (WO 094/21621, WO 95/05363).

 Currently, the authors have discovered a new group of bicyclic derivatives of amidine, which have useful pharmaceutical activity.

где D представляет пятичленное гетероциклическое ароматическое кольцо, содержащее от 1 до 4 гетероатомов, выбранных из O, N или S, необязательно замещенное по атому углерода галоидом, трифторметилом, алкилом C_1-6, нитро или циано, и которое соединено с остальной частью соединения формулы I через атом углерода;
А представляет N(X) или CH(-(CH₂)_m-NXY);
U представляет NH, O или CH₂;
V представляет (CH₂)_a;
W представляет (CH₂)_b;
a и b независимо представляют целое число от 0 до 3, при условии, что a+b находится в интервале от 1 до 3;
X и Y независимо представляют водород, алкил C_1-6, или группу -(CH₂)_nQ или -NXY представляет пиперидинил, пирролидинил, морфолинил или тетрагидроизохинолинил;
Q представляет бифенил или фенил, необязательно замещенный одной или более из групп, выбранных из алкил C_1-6, акокси C_1-6, перфторалкил C_1-6, галоида, нитро или циано,
m представляет целое число от 0 до 5;
n представляет целое число от 0 до 6;
или цепочка U-V-A-W имеет указанные ранее значения, за исключением возможности быть ненасыщенной, или цепочка U-V-A-W может представлять -NH-CH₂-CH₂-O-, замещенную по атому углерода группой -(CH₂)_m-NXY, где m, X и Y имеют указанные ранее значения, и его фармацевтически приемлемые соли.In accordance with a first aspect of the present invention, there is provided a compound of formula I:

where D represents a five-membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from O, N or S, optionally substituted at the carbon atom by halogen, trifluoromethyl, C _1-6 alkyl, nitro or cyano, and which is connected to the rest of the compounds of formula I through a carbon atom;
A represents N (X) or CH (- (CH ₂ ) _m —NXY);
U represents NH, O or CH ₂ ;
V represents (CH ₂ ) _a ;
W represents (CH ₂ ) _b ;
a and b independently represent an integer from 0 to 3, provided that a + b is in the range from 1 to 3;
X and Y independently represent hydrogen, C _1-6 alkyl, or the - (CH ₂ ) _n Q or —NXY group represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl;
Q represents biphenyl or phenyl optionally substituted with one or more groups selected from alkyl C _1-6, akoksi C _1-6, perfluoroalkyl, C _1-6, halogen, nitro or cyano,
m represents an integer from 0 to 5;
n represents an integer from 0 to 6;
either the UVAW chain is as previously defined except to be unsaturated, or the UVAW chain may be —NH — CH ₂ —CH ₂ —O— substituted at the carbon atom with the group - (CH ₂ ) _m —NXY, where m, X and Y are as previously defined, and pharmaceutically acceptable salts thereof.

где T представляет C_3-5 насыщенную или ненасыщенную алкиленовую цепочку, замещенную -(CH₂)_m-NXY; -O- (CH₂)₂-NH-замещенную -(CH₂)_m-NXY; или -U-(CH₂)_a-N(X)-(CH₂)_b-;
X и Y независимо представляют водород, алкил C_1-6, или группу - (CH₂)_nQ, или NXY представляет пиперидинил, пирролидинил, морфолинил или тетрагидроизохинолинил;
Q представляет фенил, необязательно замещенный алкил C_1-6, алкокси C_1-6, трифторметил, галоид, нитро или циано;
a U, m, n, b и D имеют указанные ранее значения, за исключением того, что если T представляет -U-(CH₂)_a-N(X)- (CH₂2)_b-, а X представляет -(CH₂)_nQ, n представляет целое число от 0 до 5, и его фармацевтически приемлемые соли.A preferred group of compounds of formula I is defined by formula IA:

where T is a C _3-5 saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m —NXY; -O- (CH ₂ ) ₂ -NH-substituted - (CH ₂ ) _m -NXY; or -U- (CH ₂ ) _a -N (X) - (CH ₂ ) _b -;
X and Y independently represent hydrogen, C _1-6 alkyl, or the - (CH ₂ ) _n Q group, or NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl;
Q represents phenyl optionally substituted by alkyl C _1-6, alkoxy C _1-6, trifluoromethyl, halogen, nitro or cyano;
a U, m, n, b and D have the meanings indicated above, except that if T represents -U- (CH ₂ ) _a -N (X) - (CH ₂ 2) _b - and X represents - ( CH ₂ ) _n Q, n is an integer from 0 to 5, and its pharmaceutically acceptable salts.

 Preferably, D is a five-membered heterocyclic aromatic ring containing one heteroatom selected from O, N or S, optionally substituted at the carbon atom by a halogen. It is particularly preferred that D is thienyl, furyl or pyrrolyl, especially thienyl or furyl, more preferably thienyl, most preferably 2-thienyl.

Preferably, T represents a C _3-5 saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m -NXY, especially C _3-5 a saturated alkylene chain substituted with - (CH ₂ ) _m -NXY, and especially C _{3 -5} saturated alkylene chain substituted with - (CH ₂ ) _m —NXY.

If T represents a C _3-5 saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m —NXY; or —O- (CH ₂ ) ₂ —NH substituted - (CH ₂ ) _m —NXY, preferably X and Y independently represent hydrogen, C _1-6 alkyl or a group - (CH ₂ ) _n Q. It is particularly preferred that X and Y independently represent hydrogen, methyl, ethyl or a group - (CH ₂ ) _n Q; it is most preferred that one of X or Y represents hydrogen and the other represents hydrogen or a group - (CH ₂ ) _n Q.

Preferably, m is 0 or 1, especially 0;
If T is —U— (CH ₂ ) _a —N (X) - (CH ₂ ) _b -, it is preferred that U is CH ₂ ,
If T is —U- (CH ₂ ) _a —N (X) - (CH ₂ ) _b -, it is preferred that a + b be 1 or 2;
If T is —U- (CH ₂ ) _a —N (X) - (CH ₂ ) _b -, it is preferred that X is hydrogen, C _1-6 alkyl or a group - (CH ₂ ) _n Q.

If X and / or Y represents - (CH ₂ ) _n Q, it is preferred that n represents 0, 1 or 2, especially 1.

Preferably, Q is phenyl, optionally substituted with C _1-6 alkyl or halogen, although Q is most preferably unsubstituted phenyl.

где U, V, A и W имеют указанные ранее значения, с соединением формулы III:

где D имеет указанные ранее значения, a L представляет отщепляемую группу;
(b) получение соединения формулы I путем взаимодействия соответствующего соединения формулы IV:

где U, V, A и W имеют указанные ранее значения, а HA представляет кислоту, с соединением формулы V:

где D имеет указанные ранее значения;
(c) получение соединения формулы I, в котором а представляет N(X), а X представляет алкил C_1-6 или группу -(CH₂)_nQ, путем взаимодействия соответствующего соединения формулы I, в котором X представляет водород, с соединением формулы VI:
R⁹-L
где R⁹ представляет C_1-6 или группу - (CH₂)_nQ и L представляет отщепляемую группу;
(d) получение соединения формулы I, где A представляет CH(-(CH₂)_m-NXY), и, по крайней мере, один из X и Y представляет алкил C_1-6 или группу - (CH₂)_nQ, путем взаимодействия соответствующего соединения формулы I, где один из X и Y (или оба) представляют водород, с соединением формулы VI;
(e) получение соединения формулы I, где A представляет CH(-(CH₂)_m-NXY), a m представляет целое число от 1 до 5, восстановлением соответствующего соединения формулы VII

где U, V, W, X, Y и D имеют указанные ранее значения;
(f) получение соединения формулы I, где A представляет CH(-(CH₂)_m-NXY), и оба X и Y представляют водород, восстановлением соответствующего соединения формулы VIII:

где U, V, W, n и D имеют указанные ранее значения
(g) получение соединения формулы I, где A представляет CH(-(CH₂)_m-NXY), X представляет водород, a m представляет целое число от 1 до 5, восстановлением соответствующего соединения формулы IX:

где U, V, W, D и Y имеют указанные ранее значения;
(h) получение соединения формулы I, где A представляет CH(-(CH₂)_m-NXY), один из X и Y представляет водород, а другой представляет -(CH₂)_nQ, где n представляет целое число от 1 до 6, за счет восстановления соответствующего соединения формулы X:

где Q, m, U, V, W и D имеют указанные ранее значения.The invention further provides a process for preparing compounds of formula I and their pharmaceutically acceptable salts, which comprises:
(a) obtaining a compound of formula I by reacting the corresponding compound of formula II:

where U, V, A and W have the meanings indicated above, with a compound of formula III:

where D has the meanings indicated above, a L represents a leaving group;
(b) obtaining a compound of formula I by reacting the corresponding compound of formula IV:

where U, V, A and W are as previously defined, and HA is an acid, with a compound of formula V:

where D has the previously indicated meanings;
(c) preparing a compound of formula I in which a represents N (X) and X represents alkyl C _1-6 or a group - (CH ₂ ) _n Q by reacting the corresponding compound of formula I in which X represents hydrogen with a compound formula VI:
R ⁹ -L
where R ⁹ represents C _1-6 or a group - (CH ₂ ) _n Q and L represents a leaving group;
(d) obtaining a compound of formula I, where A is CH (- (CH ₂ ) _m —NXY), and at least one of X and Y is C _1-6 alkyl or a group - (CH ₂ ) _n Q, by reacting the corresponding compound of formula I, wherein one of X and Y (or both) is hydrogen, with a compound of formula VI;
(e) obtaining a compound of formula I, where A is CH (- (CH ₂ ) _m —NXY), am is an integer from 1 to 5, by reduction of the corresponding compound of formula VII

where U, V, W, X, Y, and D are as previously defined;
(f) obtaining a compound of formula I, where A is CH (- (CH ₂ ) _m —NXY), and both X and Y are hydrogen, by reduction of the corresponding compound of formula VIII:

where U, V, W, n and D are as previously defined.
(g) obtaining a compound of formula I, where A is CH (- (CH ₂ ) _m —NXY), X is hydrogen, am is an integer from 1 to 5, by reduction of the corresponding compound of formula IX:

where U, V, W, D, and Y are as previously defined;
(h) obtaining a compound of formula I, where A is CH (- (CH ₂ ) _m —NXY), one of X and Y is hydrogen, and the other is - (CH ₂ ) _n Q, where n is an integer from 1 to 6, by reducing the corresponding compound of formula X:

where Q, m, U, V, W, and D are as previously defined.

где Q, m, U,V, W и D имеют указанные ранее значения или
(j) получение соединения формулы I, где A представляет CH(-NXY), а X представляет водород, восстановлением соответствующего соединения формулы XII

где U, V, W, D и Y имеют указанные ранее значения; и где, при желании или при необходимости, превращают полученное соединение формулы I или другую его соль, в фармацевтически приемлемую соль его или наоборот.(i) obtaining a compound of formula I, where A is CH (- (CH ₂ ) _m —NXY), one of X and Y is hydrogen, and the other is - (CH ₂ ) _n Q, where n is an integer from 1 to 6, reduction of the compounds of formula XI

where Q, m, U, V, W, and D are as previously defined, or
(j) obtaining a compound of formula I, where A is CH (-NXY) and X is hydrogen, by reduction of the corresponding compound of formula XII

where U, V, W, D, and Y are as previously defined; and where, if desired or necessary, the resulting compound of formula I or another salt thereof is converted into a pharmaceutically acceptable salt thereof or vice versa.

 In method (a), the reaction is carried out with stirring the mixture of reagents in a suitable solvent, for example, in a lower alkanol such as ethanol, isopropanol or tert. - butanol, at a temperature in the range from room temperature to the boiling point of the solvent under reflux. The reaction time (among others) depends on the solvent and the nature of the leaving group, and can be up to 48 hours, however, usually it is from 1 to 5 hours. A suitable leaving group L may be thioalkyl, sulfonyl, trifluorocarbonylsulfonyl, halogen, alkyl and aryl alcohols, and tosyl groups; others are indicated in Advanced Organic Chemistry, J. March (1985) 3 Ed., McGraw-Hill, pp 315, and are well known in the art.

In method (b), the reaction is preferably carried out at a boiling point under reflux for a mixture of the two compounds for several hours in the presence of a suitable solvent, whereby the reaction temperature is high enough to easily condense, but not high enough to decompose the resulting amidine. The reaction temperature may vary from room temperature to about 250 ^° C., although it is preferable to conduct the reaction at a temperature of from about 100 ^° C. to 200 ^° C. It has been found that o-dichlorobenzene is the most suitable solvent and that it is useful to add as a catalyst 4 dimethylaminopyridine. Upon cooling, two layers form, the solvent can be decanted, and the reaction mixture is treated by adding an aqueous base. In another embodiment, if the reactants are dissolved in a solvent, the solvent can be evaporated in vacuo and the reaction mixture is treated by adding water. The HA acid may be an organic or inorganic acid, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic or methanesulfonic acid.

 In method (c), the reaction occurs under standard conditions, for example, by reacting two compounds in an inert solvent under alkaline conditions at room temperature for up to 12 hours. It has been found that it is often desirable to treat the amine with NaOH before reacting with a compound of formula VI. Preferably, L is halogen, especially bromide.

 Method (d) can be carried out under conditions similar to those described previously for method (c).

In method (e), reduction can be carried out by treatment with diborane in an inert solvent, for example, in THF. Alternative, although less preferred, reagents that can be used include lithium aluminum hydride and reagents for catalytic hydrogenation, for example, H ₂ on Pd / C. Details of the reaction conditions when using these reactions are set forth in J. March "Advanced Organic Chemistry" on page 1099, including the references cited therein.

In method (f), the reduction reaction can be carried out under various conditions, for example, those described in J. March "Advanced Organic Chemistry" on pages 1103-1104. These include catalytic hydrogenation, the use of Zn, Sn or Fe metals, AlH ₃ -AlCl ₃ , sulfides, etc. It is preferable to carry out the hydrogenation reaction at atmospheric pressure for 3-6 hours in the presence of a palladium-carbon catalyst on carbon.

 In methods (g), (i) and (j), reduction can be carried out by treating the compound with sodium borohydride or sodium cyanoborohydride under standard conditions.

 In method (h), the reaction can be carried out under conditions similar to those described previously for method (e).

 Salts of the compounds of formula I can be obtained by reacting the free base or its salt, enantiomer, tautomer or protected derivative, with one or more equivalents of the corresponding acid. The reaction can be carried out in a solvent, or in an environment in which the salt is insoluble, or in a solvent in which this salt is soluble, for example, in water, dioxane, ethanol, tetrahydrofuran or in diethyl ether, or in a mixture of solvents that can be removed in vacuum or as a result of freeze-drying. Such a reaction may be an exchange process, or it may be conducted in an ion exchange resin.

где U, V, A и W имеют указанные ранее значения.Compounds of formula II can be prepared by reducing the corresponding compound of formula XIII:

where U, V, A and W are as previously defined.

 The reduction reaction can be carried out under conditions similar to those described for method (f).

Some compounds of formula II are either known or may be prepared by conventional methods known per se. Other compounds of formula II can be prepared from known compounds with simpler substituent groups in accordance with the methods previously described for methods (c) to (j). So, for example, by analogy with method (j) described previously, it was convenient to obtain some compounds of formula XIII, where A is CH (-NXY) and X is hydrogen, due to the reduction of the corresponding imine formed in the reaction of the compounds of formula NH ₂ Y with nitrated bicyclic ketone.

 Compounds of formula IV can be prepared by methods analogous to those described for the preparation of compounds of formula II. Compounds of formula IV can be converted to the corresponding compounds of formula II by treatment with a base. Compounds of formula II can be converted to the corresponding compounds of formula IV by treatment with protic acid HA, for example, one of those listed above.

где D имеет указанные ранее значения, алкилиодидом.Compounds of formula III are either known compounds or can be prepared by known methods. So, for example, compounds of formula II in which L is thioalkyl can be obtained by treating a thiamide of formula XIV

where D has the previously indicated meanings, an alkyl iodide.

 Compounds of formulas VII, VIII, IX, X, XI and XII can be prepared by methods analogous to the methods described for the preparation of compounds of formula I. Such compounds can be easily prepared from compounds with simpler substituent groups by conventional methods, for example, using the formation of amide (VII, X) by reaction of an amine with a carboxylic acid or an activated derivative thereof, or the formation of an imine (IX, XI, XII) due to the reaction of an amine with an aldehyde.

 Compounds of formulas V, VI, XIII and XIV are either known compounds or can be prepared by conventional methods per se.

Those skilled in the art will appreciate that it may be desirable to protect an amine or other reactive group using a protecting group as described in the standard text "Protecting groups in Organic Synthesis" and 2nd Ed. (1991) Greene and Wuts. Mention may be made of amine protecting groups such as C _2-7 alkoxycarbonyl, for example tert-butoxycarbonyl, C _8-13 phenylalkoxycarbonyl, for example benzyloxycarbonyl, or, preferably, trifluoroacetate. The protection is usually removed by treatment with an aqueous base, acid, or by treatment with hydrogen.

 The compounds of the present invention and intermediates can be isolated from the reaction mixtures by conventional methods.

The term “C _1-6 alkyl” includes branched and unbranched chains, saturated, unsaturated, aliphatic and cyclic alkyl groups containing from 1 to 6 carbon atoms.

 The compounds of formula I can exist in tautomeric, enantiomeric or diastereoisomeric forms, and all are included in the scope of the present invention. Various optical isomers can be isolated by separating the racemic mixture of compounds using conventional methods, for example, by fractional crystallization or by HPLC. In another embodiment, individual enantiomers can be obtained by reactions of the corresponding optically active starting materials under reaction conditions that do not cause racemization.

 Intermediates may exist in enantiomeric forms, and can be used in the form of purified enantiomers, diastereoisomers, racemates or mixtures.

 The compounds of formula I have useful pharmacological activity in animals. In particular, they have useful nitric oxide synthetase inhibiting activity and are expected to be useful in the treatment or prophylaxis of human diseases or conditions in which the synthesis or excessive synthesis of nitric oxide contributes; an example is hypoxia, for example, in cases of cardiac arrest or in strokes, neurodegenerative diseases, including nerve degeneration and / or necrosis of nerves in diseases such as hypoxia, hypoglycemia, epilepsy and external wounds (for example, lesions of the spine or head), hyperbaric oxygen convulsions and toxicity, dementia, such as senile dementia, Alzheimer's disease and AIDS-related dementia, Sydenham chorea, Parkinson's disease, Tourette’s syndrome, Huntington’s disease, amyotropic lateral sclera roses, Korsakov’s disease, cerebrovascular disturbance, sleep disturbance, schizophrenia, depression, autism, seasonal disturbances, circadian rhythm disorder, depression and other symptoms associated with premenstrual syndrome (PMS), anxiety and septic shock. The compounds of formula I are expected to show activity in the prevention and treatment of drug dependence, pain relief and in the treatment of migraines and other headaches of vascular origin. The compounds of the present invention can also demonstrate immunosuppressive activity, be useful in the treatment or prevention of inflammation, neurogenic inflammation, diseases leading to airway blockage, including asthma and adult respiratory distress syndrome (ARDS), in the treatment of gastrointestinal motility disorders, cancer, while stimulating labor, to reduce the secretion of stomach acid and to increase the strength of skeletal muscle contraction.

 The compounds of the present invention of formula I are of greatest interest in the treatment of neurodegenerative diseases, migraines, or for the prevention or treatment of tolerance to opiates and diazepines, or for the treatment of drug dependence, and especially for the treatment of neurodegenerative diseases.

 Thus, in accordance with a further aspect of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for use in pharmaceuticals.

 According to a further feature of the invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of medications for the treatment or prophylaxis of the above diseases or conditions.

 Also provided is a method of treating or preventing one of the above diseases or conditions, which comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient suffering from or susceptible to such a disease or condition.

 For the above therapeutic indications, the dose administered will naturally vary depending on the compounds used, the route of administration and the treatment required. However, usually satisfactory results can be achieved when these compounds are administered to people in a daily dose of 1 mg to 2000 mg (measurements for solid form).

 The compounds of formula I and their pharmaceutically acceptable salts can be used alone or in the form of appropriate medicaments for enteral or parenteral administration.

 The present invention provides a pharmaceutical composition comprising preferably less than 80%, and more preferably less than 50%, of a compound of formula I or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

 Examples of diluents and carriers that can be used are well known in the art.

The nitric oxide synthetase enzyme has a number of isoforms and the compounds of formula I or their pharmaceutically acceptable salts can be screened for nitric oxide synthetase activity by methods based on the methods of Bredt and Snyder "Proc. Natl. Acad. Sci. (1990) 87, 682 - 685, and Forstermann et.al., Eur. J. Pharm. (1992) 225, 161-165. Nitric oxide synthetase converts ³ HL-arginine to ³ HL-citrulline, which can be isolated by cation exchange chromatography and quantified using a scintillation counter.

Screening Example A
(A) Screening for nitric oxide synthetase activity
The enzyme is isolated from the hippocampus or cerebellum of rats. The hippocampus or cerebellum in rats of the Spraque-Dawley strain (250-275 g) is removed after animal anesthesia with CO ₂ and decapitation. The cerebellar or hippocampal supernatant was obtained by homogenization in 50 mM Tris-HCl with 1 mM EDTA buffer (pH 7.2 at 25 ^° C) and centrifugation for 15 minutes at 20,000 g. Residual L-arginine was removed from the supernatant by chromatography on a Dowex AG-50W-X8 (sodium form and hydrogen column form, sequentially), and then centrifuged at 1000 g for 30 seconds.

For analysis, 25 μl of the final supernatant are added to each of 12 test ampoules containing 25 μl of a solution of L-arginine (at a concentration of 18 μM ¹ HL-arginine, 96 nM ³ HL-arginine), and either 25 μl of analytical buffer ( 50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl ₂ , pH 7.4), or test compound in buffer at 22 ^° C. 75 μl of complete assay buffer (50 mM HEPES, 1 mM EDTA) is added to each test vial. , 1.5 mM CaCl ₂ , 1 mM DTT, 10 μM NADPH, 10 μg / ml calmodulin, pH 7.4) to initiate the reaction, and the reaction was stopped after 10 minutes by adding 2 ml of stopping buffer (20 mm HEPES, 2 mM EDTA, pH 5.5).

 Labeled L-citrulline is separated from labeled L-arginine by chromatography on a Dowex AG-50W-X8 200-400 mesh column. 1 ml of each of the stopped reaction mixtures is introduced into separate 1 ml columns, and the eluents are combined with two washes of 1 ml of distilled water and 16 ml of scintillation “cocktail”. Then the amount of L-citrulline is determined using a scintillation counter.

 In a typical experiment with cerebellar supernatant, the main activity is increased by 20,000 decays per minute / ml compared to the control, the activity for which is 7,000 decays per minute / ml. A comparative standard, N-nitro-L-arginine, which provides 60% inhibition of nitric oxide synthetase, at a concentration of 1 μM is also tested in the assay to control the procedure.

Screening Example B
(B) screening for macrophage nitric oxide synthetase activity
The enzyme is prepared, after induction, from cultured murine macrophage cells of the J774A-1 line (obtained from Imperial Cancer Research Fund laboratories). J774A-1 cells are cultured in Dulbeco-modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum, 4 mM L-glutamine and antibiotics (100 u / ml penicillin G, 100 μg / ml streptomycin and 0.25 μg / ml amphotericin IN). Cells are grown in the usual way in 225 cm ² bottles containing 35 ml of medium, maintained at 37 ^o C and in a humid atmosphere containing 5% CO ₂ .

Nitric oxide synthetase is produced by cells in response to interferon-γ (IFN γ) and lipopolysaccharide (LPS). The medium from the confluent culture bottles is removed and 25 ml (per bottle) of fresh medium containing 1 μg / ml LPS and 10 units / ml IFN γ is replaced. After 17-20 hours in culture, the collection of cells is carried out by removing the layer of cells from the surface of the flask into the culture medium. Cells are harvested by centrifugation (1000 g for 10 minutes) and a lysate is prepared by adding a cell pellet to a solution containing 50 mM Tris-HCl (pH 7.5 at 20 ^° C), 10% (v / v) glycerol, 0, 1% (v / v) Triton-X-100, 0.1 μM dithiothreitol and a protease inhibitor cocktail containing leupeptil (2 μg / ml), soybean trypsin inhibitor (10 μg / ml), aprotinin (5 μg / ml) and phenylmethylsulfonyl fluoride (50 μg / ml).

For analysis, 25 μg of the substrate cocktail (50 mM Tris-HCl (pH 7.5 at 20 ^° C), 400 μM NADPH, 20 μM flavin adenine dinucleotide, 20 μM flavin mononucleotide, 4 μ M tetrahydrobiopterin, 12 μ M L-arginine and 0.025 μ Ci L- [ ³ H] arginine) is added to the cells of the filter plate with 96 cells (0.45 μM mesh size) containing 25 μl of a solution of the test compound in 50 mm Tris-HCl. The reaction is initiated by adding 50 μl of the cell lysate (prepared as indicated above), and after incubation for 1 hour at room temperature, the reaction is completed by adding 50 μl of an aqueous solution of 3 mM nitroarginine and 21 mM EDTA.

Labeled L-citrulline is separated from labeled L-arginine using Dowex AG-50W. 150 μl of a 25% aqueous Dowex 50W suspension (Na ⁺ form) is added to the assay composition, which is completely filtered into 96-well plates. 70 μl filtrate samples were taken and added to 96-well plates containing a solid scintillating agent. After the samples are allowed to dry, the amount of L-citrulline is determined using a scintillation counter.

In a typical experiment, the main activity is 300 decays per minute for a sample of 70 μl, which rises to 1900 decays per minute for reagent controls. Aminoguanidine, which gives an IC ₅₀ (50% inhibitory concentration) in 10 μM, is tested as a standard to verify the procedure.

Screening Example C
(C) Screening for endothelial nitric oxide synthetase activity
An enzyme can be isolated from human umbilical vein endothelial cells (HUVECs) by a method based on the method of Pollock et.al (1991), Proc. Nat. Acad Sci. 88, 10480-10484. HUVECs purchased from Clonetics Corp. (San Diego, CA, USA) and cultivated before confluence. Cells can be maintained for up to 35–40 passages without noticeable loss of nitric oxide synthetase. When the cells merge, they are resuspended in Dulbecco phosphate-buffered saline, centrifuged at 8000 rpm for 10 minutes, the cell pellet is homogenized in ice-cold 50 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM phenylmethylsulfonyl fluoride, 2 μM leupeptin at a pH of 4.2. After centrifugation at 34,000 rpm for 60 minutes, the pellet was solubilized in a homogenizing buffer, which also contains 20 mM CHAPS. After 30 minutes of incubation on ice, the suspension is centrifuged at 34,000 rpm for 30 minutes. The resulting supernatant was stored at -80 ^° until use.

For analysis, 25 μl of the resulting supernatant is added to each of 12 test vials containing 25 μl of a solution of L-arginine (concentration of 12 μM ¹ HL-arginine, 64 nM ³ HL-arginine) and 25 μl of assay buffer (50 nM HEPES, 1 mM EDTA, 1.5 mM CaCl ₂ , pH 7.4), or 25 μl of test compound in buffer at 22 ^° C. A complete assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM) is added to each test ampoule. CaCl _2, 1 mM DTT, 100 .mu.M NADPH, 10 .mu.g / ml calmodulin, 12 .mu.M tetrahydrobiopterin, pH 7,4) to initiate the reaction, and the reaction was stopped after 10 minutes by adding 2 ml of stopping of buffer (20 mM HEPES, 2 mM EDTA, pH 5,5).

 Labeled L-citrulline is separated from labeled L-arginine by chromatography on a Dowex AG-50W-X8 200-400 mesh column. 1 ml of each of the stopped reaction solutions is introduced into a separate 1 ml column, and each eluent is combined with two washes of 1 ml of distilled water and 16 ml of scintillation cocktail. Then the amount of L-citrulline is determined using a scintillation counter.

 In a typical experiment, the main activity increases by 5000 decays per minute / ml for the sample compared to the reagent control, whose activity is 1500 decays per minute / ml. A comparative standard, N-nitro-L-arginine, which gives 70-90% inhibition of nitric oxide synthetase at a concentration of 1 μM, is tested in the assay to verify the procedure.

 Compounds can also be tested in an ex-vivo assay to determine the extent of penetration into the brain.

Screening Example D
(D) Ex-vivo assay for determining the activity of nitric oxide synthetase neurons
Male rats of the Spraque-Dawley strain (250-275 g) are injected intravenously with 10 mg / kg of the test compound dissolved in 0.9% saline or in saline alone as a control. At a predetermined time (usually 2-24 hours) after treatment, the animals are sacrificed, the cerebellum is removed, and the supernatant is prepared and analyzed for nitric oxide synthetase activity, as described in screening example A.

 As a further confirmatory test, the cerebellar supernatant fraction was introduced into a 2'-5'-ADP Sepharose column (which binds nitric oxide synthetase) and then eluted with NADPH. The eluent is tested for nitric oxide synthetase activity by the method of screening example A.

 Compounds that penetrate into the brain of rats and inhibit neuron nitric oxide synthetase lead to a decrease in nitric oxide synthetase activity both in the supernatant preparations and in the eluents from the 2'-5'-ADP column of Sepharose.

In examples of screening for nitric oxide synthetase inhibition activity, the activity of the compounds is expressed as IC ₅₀ (concentration of drug that provides 50% inhibition of the enzyme in the assay). The IC ₅₀ values for the test compounds are first evaluated from the inhibition activity of 1.10 and 100 μM solutions of the compounds. Compounds that inhibit the enzyme by at least 50% at a concentration of 10 μM are retested using appropriate concentrations to determine IC ₅₀ values.

In the screening example A (screening for activity against the neural isoform of nitric oxide synthetase), the compound of Example 1 below gives an IC _{50 of} less than 10 μM, which indicates that satisfactory therapeutic activity can be expected. In the screening examples B and C (screening for activity against macrophage and endothelial isoforms of nitric oxide synthetase), the compound of Example 1 shows IC ₅₀ values that are more than 10 times the values obtained in the screening example A, showing the desired activity.

The compounds of Examples 2-9, 10 (a) - (f), 11-13 and 19-24 are also tested in Screening Example A, and they also show IC ₅₀ values of less than 10 μM. Thus, it can also be expected that these compounds will have satisfactory therapeutic activity.

 The compounds of formula I and their pharmaceutically acceptable salts have the advantage that they are less toxic, more effective, more selective and have a longer effect, have a wider spectrum of activity and are more effective, cause fewer side effects, are more easily absorbed, or have other beneficial effects. pharmacological properties, compared with previously known compounds, and used in the previously indicated areas of therapy.

 The compounds of formula 1 and their pharmaceutically acceptable salts may also have the advantage that they are more selective for the neural isoforms of the nitric oxide synthase enzyme, and therefore satisfactory therapeutic activity can be expected while reducing side effects associated with the inhibition of other isoforms.

 The invention is further illustrated by the following examples.

Example 1
N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboxy-imidamide dioxalate
(a) 5-nitro-2-indanone
This compound is prepared according to the method of Heusler, Schief-fer Ber., (1899) 32, 33.

(b) 5-nitro-2- (phenylmethyl) aminoindane
5-nitro-2-indanone (1.48 g, 8.36 mmol), benzylamine (4.40 ml, 41.8 mmol), acetic acid (15.0 ml), 4 A molecular sieves (20 ml), THF (15 ml) and MeOH (15 ml) were charged into a flask and cooled to 0 ^° C. Sodium cyanoborohydride (1.05 g, 16.7 mmol) was then added in portions over 5 minutes. The resulting mixture was stirred for 14 hours, filtered through celite and concentrated to syrup. The resulting mixture was alkalinized with 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (3% methanol / methylene chloride) to give 5-nitro-2- (phenylmethyl) aminoindan: (1.18 g, 53%).

Mass spectrum: (M + H) ⁺ = 269.

(c) 2- (5-nitroindanyl) -N- (phenylmethyl) trifluoroacetamide
Trifluoroacetic anhydride (0.63 ml) was added to a stirred solution of 5-nitro-2- (phenylmethyl) aminoindane (1.18 g, 4.40 mmol) and triethylamine (0.61 ml, 4.40 mmol) in 50 ml of methylene chloride. 4.40 mmol) dropwise. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate / hexane) to give 2- (5-nitroindanyl) -N- (phenylmethyl) trifluoroacetamide: (1.17 g, 73%).

Mass spectrum (M + H) ⁺ = 365.

(d) 2- (5-aminoindanyl) -N- (phenylmethyl) trifluoroacetamide
To a stirred solution of 2- (5-nitroindanyl) -N- (phenylmethyl) trifluoroacetamide (1.17 g, 3.21 mmol) in THF / MeOH (100 ml, 1: 1) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to give 2- (5-aminoindanyl) -N- (phenylmethyl) trifluoroacetamide, which was homogeneous according to TLC and was used immediately in step (f).

(e) 3-methyl-2-thiopheniocarboximide hydroiodide
A solution of 2-thiophenecarbocstioamide (Maybridge Chemical) (11.1 g) in 60 ml of acetone was treated with iodomethane (13.4 g). After 6 hours at 22 ^° C., the resulting yellow solid was collected by filtration, washed with acetone (2 x 25 ml) and dried to obtain 18.45 g of S-methyl-2-thiopheniocarboxamide hydroiodide.

T. melting point 195 ^o C (decomposition).

(f) N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophene-carboximidamide dioxalate
To a solution of 2- (5-aminoindanyl) -N- (phenylmethyl) trifluoroacetamide (1.0 g, 3.0 mmol) in isopropanol (6 ml) / DMF (0.5 ml) was added 3-methyl-2-thiopheniocarboximide hydrochloride (0.85 g, 3.0 mmol). The resulting mixture was stirred for 14 hours, diluted with methanol (6 ml) and 2N. NaOH (6 ml) and heated to 50 ^o C for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered and chromatographed on silica gel (20% methanol / methylene chloride) to give the title compound
compounds in the form of a free base. After treatment with IPA / oxalic acid, N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate is obtained as a white solid (0.47 g, 30%).

T. melting point 130-135 ^o C.

Example 2
N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) - 2-thiophenecarboximidamide
(a) 7-nitro-3,4-dihydro-2 (1H) -naphthalenone
This compound is prepared according to method J. Med. Chem. (1989) 32, 2128.

молекулярные сита (20 мл), ТГФ (15 мл) и MeOH (15 мл) загружают в колбу и охлаждают до 0^oC. Затем порциями добавляют цианоборгидрид натрия (0,99 г, 15,7 ммоля) в течение 5 минут. Полученную смесь перемешивают в течение 14 часов, фильтруют через целит и концентрируют до сиропа. Полученную смесь подщелачивают 2н. NaOH и экстрагируют эфиром (3 х 50 мл). Объединенные экстракты промывают водой, сушат над сульфатом магния, фильтруют, концентрируют и хроматографируют на силикагеле (3% метанол/метиленхлорид) до получения 7-нитро-2- ((фенилметил)амино)-1,2,3,4-тетрагидронафталина: (2, 10 г, 95%).(b) 7-nitro-2 - ((phenylmethyl) amino) -1,2,3,4-tetrahydronaphthalene
7-nitro-3,4-dihydro-2 (1H) -naphthalenone (1.50 g, 7.85 mmol), benzylamine (4.30 ml, 39.3 mmol), acetic acid (8.0 ml), 4

molecular sieves (20 ml), THF (15 ml) and MeOH (15 ml) were charged into a flask and cooled to 0 ^° C. Sodium cyanoborohydride (0.99 g, 15.7 mmol) was then added in portions over 5 minutes. The resulting mixture was stirred for 14 hours, filtered through celite and concentrated to syrup. The resulting mixture was alkalinized with 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (3% methanol / methylene chloride) to give 7-nitro-2- ((phenylmethyl) amino) -1,2,3,4-tetrahydronaphthalene: ( 2, 10 g, 95%).

Mass spectrum (M + H) ⁺ 283.

(c) 2- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide
To a stirred solution of 7-nitro-2 - ((phenylmethyl) amino) -1, 2,3,4-tetrahydronaphthalene (2.10 g, 7.45 mmol) and triethylamine (1.07 ml, 7.45 mmol) in Trifluoroacetic anhydride (1.05 ml, 7.45 mmol) was added dropwise to 50 ml of methylene chloride. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate / hexane) to give 2- (7-nitro (1, 2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide : (2.55 g, 90%).

Mass spectrum (M + H) ⁺ = 379
(d) 2- (7-amino (1,2,3,4-tetrahydronaphthyl) -N- (phenylmethyl) trifluoroacetamide
To a stirred solution of 2- (7-nitro (1,2,3,4-tetrahydronaphthyl) -N- (phenylmethyl) trifluoroacetamide (2.55 g, 6.75 mmol) in THF / MeOH (100 ml, 1: 1 ) add a catalytic amount of 10% Pd / C. The resulting mixture is hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to obtain 2- (7-amino (1,2,3,4 -tetrahydronaphthyl)) - N- (phenylmethyl) - trifluoroacetamide, which according to TLC is homogeneous, and is immediately used in the next step.

(e) N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide
To a solution of 2- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide (2.11 g, 6.07 mmol) in 10 ml of isopropanol is added 3-methyl-2- thiopheniocarboximide hydrochloride (1.72 g, 6.07 mmol). The resulting mixture was stirred for 14 hours, diluted with methanol (6 ml) and 2 N. NaOH (6 ml), and heated to 50 ^o C for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered and concentrated to a solid, which is recrystallized (methylene chloride / hexane) to obtain N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaft-7- il) -2-thiophenecarboximidamide as a white solid (0.66 g, 30%).

T. melting point 119-120 ^o C.

молекулярные сита (20 мл), ТГФ (15 мл) и MeOH (15 мл) загружают в колбу и охлаждают до 0^oC. Затем добавляют цианоборгидрид натрия (0,99 г, 15,7 ммоля) порционно в течение 5 минут. Полученную смесь перемешивают в течение 1 часа, фильтруют через целит и концентрируют до сиропа. Полученную смесь подщелачивают 2н. NaOH и экстрагируют эфиром (3 х 50 мл). Объединенные экстракты промывают водой, сушат над сульфатом магния, фильтруют и концентрируют до получения масла. Это соединение выделяют в виде соли соляной кислоты: 7-нитро-2-амино- 1,2,3,4-тетрагидронафталингидрохлорида (1,00 г, 56%).Example 3
N - ((2-amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dioxalate
(a) 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride
7-nitro-1-tetralone (1.50 g, 7.85 mmol), ammonium acetate (6.05 ml, 78.5 mmol), acetic acid (8.0 ml), 4

molecular sieves (20 ml), THF (15 ml) and MeOH (15 ml) were charged into a flask and cooled to 0 ^° C. Sodium cyanoborohydride (0.99 g, 15.7 mmol) was then added portionwise over 5 minutes. The resulting mixture was stirred for 1 hour, filtered through celite and concentrated to syrup. The resulting mixture was alkalinized with 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. This compound is isolated in the form of a hydrochloric acid salt: 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (1.00 g, 56%).

Melting point more than 300 ^o C.

(b) 2- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide
To a stirred solution of 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (1.00 g, 4.39 mmol) and triethylamine (1.22 ml, 8.77 mmol) in 50 ml of methylene chloride is added trifluoroacetic anhydride (0.62 ml, 4.39 mmol) dropwise. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate / hexane) to give 2- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide (0 78 g, 62%).

Mass spectrum (M + H) ⁺ = 289.

(c) 2- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide
To a stirred solution of 2- (7-nitro (1,2,3,4-tetrahydronaphthyl)) -N-trifluoroacetamide (0.76 g, 2.21 mmol) in THF / MeOH (100 ml, 1: 1) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to give 2- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide, which TLC is homogeneous, and is used immediately in the next reaction.

(d) N - ((2-amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dihydrobromide
To a solution of 2- (7-amino (1,2,3,4-tetrahydronaphthyl) -N-trifluoroacetamide (0.70 g, 2.71 mmol) in 10 ml of isopropanol is added 3-methyl-2-thiopheniocarboximide hydroiodide (0, 77 g, 2.71 mmol.) The resulting mixture was stirred for 14 hours, diluted with methanol (6 ml) and 2N NaOH (6 ml) and heated to 50 ^° C. for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (20% methanol / methylene chloride) to give an oil a, which is converted into a dihydrobromide: N - ((2-amino) - 1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide dihydrobromide: (0.37 g, 32%).

T. melting point above 210 ^o C (decomposition).

Example 4
N - ((1-amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dioxal
(a) 7-nitro-1-amino-1,2,3,4-tetrahydronaphthalene
7-Nitro-1-amino-1,2,3,4-tetrahydronaphthalene is obtained in the same way as 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalene. The compound was isolated as the hydrochloride salt (0.30 g, 12%).

T. melting more than 300 ^o C.

(b) 1- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide
1- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide is obtained in the same way as 2- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N- trifluoroacetamide (0.35 g, 95%).

Mass spectrum (M + H) ⁺ = 289
(c) 1- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide
1- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide is obtained in the same way as 2- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N- trifluoroacetamide, and used immediately in the next reaction.

(d) N - ((1-amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dioxalate
N - ((1-amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide dioxalate is obtained in the same way as N - ((2-amino) -1,2,3,4-tetrahydronaft -7-yl) -2-thiophenecarboximidamide dihydrobromide except that it is isolated as dioxalate (0.18 g, 33%).

Melting point more than 155 ^o C with decomposition.

Example 5
N - ((2-amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate
(a) 5-nitro-2-aminoindanhydrochloride
Sulfuric acid (60 ml) was added at 2 ^° C to 2-aminoindane hydrochloride (19.11 g, 0.112 mol), followed by potassium nitrate (11.84 g, 0.117 mol). The resulting mixture was allowed to warm to room temperature, stirred for another 2 hours, then poured into a mixture of ice / 50% NaOH (total 500 ml). The resulting mixture was extracted with ether (3 x 200 ml) and the combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to an oil, which was converted into hydrochloride salt. Recrystallization from isopropanol / methanol gave 5-nitro-2-aminoindanohydrochloride (14.58 g, 60%).

Melting point more than 300 ^o C.

(b) 2- (5-nitroindanyl) -N-trifluoroacetamide
To a stirred solution of 5-nitro-2-aminoindanhydrochloride (1.00 g, 5.89 mmol) and triethylamine (0.82 ml, 5.89 mmol) in 50 ml of methylene chloride is added trifluoroacetic anhydride (0.83 ml, 5.89 mmol) dropwise. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate / hexane) to give 2- (5-nitroindanyl) -N-trifluoroacetamide (1.51 g, 93%).

T. melting point 153-154 ^o C.

(c) 2- (5-aminoindanyl) -N-trifluoroacetamide
To a stirred solution of 2- (5-nitroindanyl) -N-trifluoroacetamide (0.58 g, 2.25 mmol) in THF / MeOH (100 ml, 1: 1) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ), filtered through celite and concentrated to give 2- (5-aminoindanyl) -N-trifluoroacetamide, which was homogeneous according to TLC, and was used immediately in the next step.

(d) N - ((2-amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate
To a solution of 2- (5-aminoindanyl) -N-trifluoroacetamide (0.52 g, 2.25 mmol) in isopropanol (6 ml) DMF (0.5 ml) was added S-methyl-2-thiopheniocarboximide hydroiodide (0.64 g 2.23 mmol). The resulting mixture was stirred for 14 hours, diluted with methanol (6 ml) and 2N. NaOH (6 ml) and heated to 50 ^o C for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and chromatographed on silica gel (20% methanol / methylene chloride) to give the title compound as a free base. After treatment with IPA / oxalic acid, N - ((2-amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate is obtained as a white solid (0.60 g, 50%).

T. melting point 70 ^o C, with decomposition.

Example 6
N - ((2- (methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dihydrobromide
(a) 5-nitro-2- (phenylmethyl) aminoindanhydrochloride
To 5-nitro-2-aminoindanohydrochloride (3.00 g, 14.00 mmol) in 60 ml of DMF, triethylamine (4.07 ml, 29.40 mmol) is added, followed by benzyl bromide (1.74 ml, 14.68 mmol) ) The resulting mixture was warmed to room temperature, stirred for 1 hour, poured into water (200 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered through a small layer of silica gel and evaporated to syrup. The title compound was isolated as the hydrochloride salt (2.29 g, 54%).

T. melting decomposition 266 ^o C.

(b) 5-nitro-2- (methyl) (phenylmethyl) aminoindanhydrochloride
Potassium carbonate (2.60 g, 18.80 mmol) is added to 5-nitro-2- (phenylmethyl) aminoindanohydrochloride (2.29 g, 7.52 mmol) in 100 ml of DMF, followed by methyl iodide (0.47 ml, 7.52 mmol). The resulting mixture was warmed to room temperature, stirred for 16 hours, poured into 400 ml of water and extracted with ethyl acetate (3 x 100 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered through a small layer of silica gel and evaporated to syrup. The title compound was isolated as the hydrochloride salt (1.08 g, 45%).

T. melting point 280 ^o C (decomposition).

(c) 5-amino-2- (methyl) (phenylmethyl) aminoindanedihydrochloride
Zinc powder (3.0 g) was added to 5-nitro-2- (methyl) (phenylmethyl) aminoindanhydrochloride (1.08 g, 3.39 mmol) in 85% acetic acid / water. The resulting mixture was stirred for 1 minute, filtered through celite and concentrated. The resulting concentrate is neutralized with 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate and evaporated to syrup. The resulting oil was treated with IPA / HCl, concentrated and used immediately in the next step.

(d) N - ((2- (methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dihydrobromide
To 5-amino-2- (methyl) (phenylmethyl) aminoindanedihydrochloride in DMF (10 ml) was added 3-methyl-2-thiopheniocarboximide hydroiodide (0.98 g, 3.45 mmol) and pyridine (0.27 ml, 3.29 mmol). The resulting mixture was stirred for 14 hours, poured into a mixture of water / 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and chromatographed on silica gel (10% methanol / methylene chloride) to give the title compound as a free base. IPA / HBr treatment gave N - ((2- (methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dihydrobromide as a white solid (0.43 g, 25%).

T. melting point: 196-200 ^o C.

Example 7
N - ((1-amino) indan-6-yl) -2-thiophenecarboximidamide dihydrochloride
(a) 6-nitro-1-aminoindanhydrochloride
1-aminoindane (10.0 g, 75.08 mmol) was added to concentrated sulfuric acid (40 ml) at 0 ^° C. The resulting mixture was warmed to room temperature to aid dissolution, then cooled to 0 ^° C. Then nitrate was added portionwise. potassium (7.60 g, 75.08 mmol), and the resulting mixture was left under stirring at room temperature for 1 hour before pouring ice / 50% NaOH into the mixture. The aqueous solution was extracted with chloroform (3 x 100 ml). The combined extracts are washed with water, decolorized with charcoal, dried over magnesium sulfate, filtered and concentrated to an oil. The IPA / HCl treatment gave the subtitle compound (6.90 g, 43%).

T. melting point 280 ^o C (decomposition).

(b) 6-amino-1-aminoindanhydrochloride
To a solution of 6-nitro-1-aminoindanohydrochloride (1.00 g 4.66 mmol) in MeOH (100 ml) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to give 6-amino-1-aminoindanohydrochloride, which was homogeneous according to TLC, and was used immediately in the next step.

(c) N - ((1-amino) indan-6-yl) -2-thiophenecarboximidamide dihydrochloride
To 6-amino-1-aminoindanohydrochloride (0.74 g, 4.01 mmol) in DMF / IPA (4 ml, 1: 1) add 3-methyl-2-thiopheniocarboximide hydrochloride (1.26 g, 4.41 mmol) . The resulting mixture was heated to 50 ^o C, stirred for 16 hours, poured into a mixture of water / 2N. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. The IPA / HCl treatment gave N - ((1-amino) -indan-6-yl) -2-thiophenecarboximidamide dihydrochloride as a white solid (0.79 g, 60%).

T. melting 200 ^o C with decomposition.

Example 8
N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide dioxalate
(a) 6-nitro-1- (phenylmethyl) aminoindanhydrochloride
To 6-nitro-1-aminoindanohydrochloride (1.90 g, 8.85 mmol) in 30 ml of DMF, triethylamine (2.50 ml, 18.06 mmol) is added, followed by benzyl bromide (1.07 ml, 9.03 mmol) ) The resulting mixture was warmed to room temperature, stirred for 3 hours, poured into water (100 ml) and extracted with 70 ml portions of ethyl acetate three times. The combined extracts are washed with water, dried over magnesium sulfate, filtered through a small layer of silica gel and concentrated to syrup. The title compound was isolated as the hydrochloride salt (1.34 g, 50%).

T. melting point 234-235 ^o C.

(b) 6-amino-1- (phenylmethyl) aminoindanhydrochloride
A catalytic amount of 10% Pd / C is added to 6-nitro-1- (phenylmethyl) aminoindanhydrochloride (1.34 g, 4.40 mol) in 100 ml of MeOH. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm) for 1 hour, filtered through celite and concentrated to give 6-amino-1- (phenylmethyl) aminoindanohydrochloride, which was homogeneous according to TLC and was used immediately in the next step.

(c) N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide dioxalate
To 6-amino-1- (phenylmethyl) aminoindanohydrochloride (1.21 g, 4.40 mmol) in 20 ml of DMF was added 8-methyl-2-thiopheniocarboximide hydroiodide (1.38 g, 4.84 mmol). The resulting mixture was heated to 50 ^o C for 16 hours, then poured into a mixture of water and 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. Treatment with IPA / oxalic acid gives N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide dioxalate as a white solid (1.06 g, 46%).

T. melting point above 120 ^o C (with decomposition).

Example 9
N - ((2 - ((3-Chlorophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine
(a) 2 - ((3-Chlorophenyl) carbonyl) amino-6-nitroindane
To 2-amino-6-nitroindane hydrochloride (1.5 g, 7.0 mmol) in 50 ml of methylene chloride at 0 ^° C is added triethylamine (2.1 ml, 15.0 mmol), followed by 3-chlorobenzoyl chloride (1.0 ml, 7.5 mmol). The resulting mixture was immediately poured into water and the layers were separated. The aqueous layer was extracted with methylene chloride (2 x 20 ml), and the combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil which was homogeneous according to TLC, and it was used immediately in the next step.

Mass spectrum (M + H) ⁺ = 317.

(b) 2 - ((3-chlorophenyl) methyl) amino-6-nitroindane
To 2 - ((3-chlorophenyl) carbonyl) amino-6-nitroindane (2.2 g, 7.0 mmol) in 75 ml of THF add BH ₃ • THF (1.0 M, 35 ml, 35 mmol) dropwise . The resulting mixture was refluxed for 12 hours, cooled to 0 ^o C, quenched 4n. HCl (60 ml) and refluxed for 1 hour. The resulting solution was evaporated to an oil, made basic with 50% NaOH and extracted with methylene chloride three times in 20 ml portions. The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. Processing IPA / HCl gives 2 - ((3-chlorophenyl) methyl) amino-6-nitroindane: (2.1 g, 88% in two steps).

T. melting point 234-237 ^o C.

(c) 2 - ((3-chlorophenyl) methyl) amino-6-aminoindan
To 2 - ((3-chlorophenyl) methyl) amino-6-nitroindanhydrochloride (2.1 g, 6.13 mmol) in 40 ml of a 85% AcOH / H ₂ O mixture, metallic zinc (1.6 g, 24.5 mmol). The resulting mixture was stirred for 5 minutes, filtered through celite and evaporated to an oil. The resulting oil was poured into alkaline water and extracted with chloroform (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. The IPA / HCl treatment yields 2 - ((3-chlorophenyl) methyl) amino-6-aminoindan (1.5 g, 70%).

T. melting point over 270 ^o C
(d) N - ((2 - ((3-chlorophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine
2 - ((3-chlorophenyl) methyl) amino-6-aminoindanedihydrochloride (1.5 g, 4.2 mmol), 3-methyl-2-thiopheniocarboximide hydrochloride (1.3 g, 4.6 mmol) and pyridine (0, 34 ml, 4.2 mmol) in 10 ml of DMF is stirred for 24 hours. The resulting mixture was poured into water, alkalinized with 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts are washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (12% MeOH / methylene chloride) to give a colorless oil. IPA / HCl treatment affords N - ((2 - ((3-chlorophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine (0.75 g, 40%).

T. melting 297-299 ^o C.

Example 10
By the method of example 9 receive the following compounds:
(a) N - ((2 - ((2-methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
T. melting point 183 ^o C.

(b) N - ((2 - ((3-methylphenyl) methyl) amino) indan-5-yl) thiophenecarboxamidine;
T. melting point 195 ^o C.

(c) N - ((2 - ((4-methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
T. melting point 182 ^o C.

(d) N - ((2- (ethyl) amino) indan-5-yl) -2-thiophenecarboxamidine
T. melting point 236-238 ^o C.

(o) N - ((2 - (((4-phenyl) phenyl) methyl) amino) indan-5-yl) - 2-thiophenecarboxamidine;
T. melting point 182 ^o C.

(f) N - ((2 - (((4-hexyl) phenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
T. melting point 125 ^o C.

(g) N - ((2 - ((3-bromophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
T. melting point 182 ^o C.

молекулярные сита (20 мл), ТТФ (15 мл) и MeOH (15 мл) загружают в колбу и охлаждают до 0^oC. Порциями добавляют цианоборгидрид натрия (0,99 г, 15,7 ммоля) в течение 5 минут. Полученную смесь перемешивают в течение 14 часов, фильтруют через целит и концентрируют до сиропа. Полученную смесь подщелачивают 2н. NaOH и экстрагируют эфиром (3 х 50 мл). Объединенные экстракты промывают водой, сушат над сульфатом магния, фильтруют, концентрируют и хроматографируют на силикагеле (3% метанол/метиленхлорид). В результате обработки масла IPA/HCl получают 7-нитро-2- (((3-хлорфенил)метил)амино)-1,2,3,4-тетрагидронафталингидрохлорид (1,34 г, 50%).Example 11
N - ((2 - (((3-Chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) - 2-thiophenecarboximidamide
(a) 7-nitro-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene
7-Nitro-3,4-dihydro-2 (1H) -naphthalenone (1.50 g, 7.85 mmol), 3-chlorobenzylamine (4.70 ml, 39.3 mmol), acetic acid (6.0 ml ), 4

molecular sieves (20 ml), TTF (15 ml) and MeOH (15 ml) were charged into a flask and cooled to 0 ^° C. Sodium cyanoborohydride (0.99 g, 15.7 mmol) was added in portions over 5 minutes. The resulting mixture was stirred for 14 hours, filtered through celite and concentrated to syrup. The resulting mixture was alkalinized with 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (3% methanol / methylene chloride). Processing IPA / HCl oil gives 7-nitro-2- (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene hydrochloride (1.34 g, 50%).

Mass spectrum (M + H) ⁺ = 317.

(b) 7-amino-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene
K 7-nitro-2 - ((((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene hydrochloride (1.34 g, 3.80 mmol) in 85 AcOH / H ₂ O (75 ml) zinc metal (2.48 g, 38.0 mmol) is added. The resulting mixture was stirred for 5 minutes, filtered through celite and evaporated to an oil. The resulting oil was poured into alkaline water and extracted with chloroform (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. Processing IPA / HCl affords 7-amino-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene (1.4 g, 99%).

Mass spectrum (M + H) ⁺ = 288.

(c) N - ((2 - ((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide
7-amino-2 - ((((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene dihydrochloride (1.32 g, 3.70 mmol), 3-methyl-2-thiopheniocarboximide hydroiodide (1.3 g, 4.6 mmol) and pyridine (0.30 ml, 3.7 mmol) in 15 ml of DMF are stirred for 24 hours. The resulting mixture was poured into water, alkalinized with 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. Treatment with IPA / oxalic acid gives N - ((2 - ((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dioxalate (0.71 g, 33 %).

T. melting point above 100 ^o C with decomposition.

Example 12
N - ((2- (phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide
(a) 7-Nitro-2 ((phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphthalene
To a stirred solution of 7-nitro-2 - ((phenylmethyl) amino) -1, 2,3,4-tetrahydronaphthalene (1.5 g, 5.4 mmol) in 30 ml of DMF, potassium carbonate (1.5 g, 10 , 8 mmol) and methyl iodide (0.36 ml, 5.8 mmol). The resulting mixture was stirred for 24 hours, poured into water and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. Processing IPA / HCl gave 7-nitro-2 - ((phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphthalene hydrochloride (0.89 g, 50%).

Mass spectrum (M + H) ⁺ = 297.

b) 7-amino-2 - ((phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphthalene
To 7-nitro-2 - ((phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphthalene hydrochloride (0.89 g, 2.7 mmol) in 85% AcOH / H ₂ O (75 ml) was added zinc metal (3.5 g, 54.0 mmol). The resulting mixture was stirred for 5 minutes, filtered through celite and evaporated to an oil. The resulting oil was poured into alkaline water and extracted with chloroform (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. As a result of IPA / HCl treatment, 7-amino-2 - ((phenyl) methyl) (methyl) amino) -1,2,3,4-tetrahydronaphthalene (0.81 g, 88%) is obtained.

Mass spectrum (M + H) ⁺ = 267
(c) N - ((2- (phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide
7-amino-2 - ((phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphthalene dihydrochloride (0.81 g, 2.4 mmol), S-methyl-
2-thiopheniocarboximide hydrochloride (0.74 g, 2.6 mmol) and pyridine (0.19 ml, 2.4 mmol) in 15 ml of DMF are stirred for 24 hours. The resulting mixture was poured into water, alkalinized with 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water, dried over magnesium sulfate, concentrated and chromatographed on silica gel (% MeOH / methylene chloride). Concentration of the fraction gives a solid which, after recrystallization from ethyl acetate / hexane, gives N - ((2- (phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximamide dihydrochloride (0.14 g, 16%).

Melting point 176-178 ^o C.

Example 13
N - ((1-Phenylmethyl) amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide
(a) 7-Nitro-1 - ((phenylmethyl) amino) -1,2,3,4-tetrahydronaphthalene
7-Nitro-1-tetralone (2.0 g, 10.5 mmol), benzylamine (1.2 ml, 10.5 mmol) and titanium isopropoxide (3.9 ml, 13.1 mmol) are combined and stirred for 1 hour The resulting mixture was diluted with absolute ethanol (12 ml), treated with sodium cyanoborohydride (0.44 g, 7.0 mmol) and left under stirring for 20 hours. The solid is filtered off and washed with ethanol. Ethanol is concentrated, and the remaining oil is used immediately in the next reaction.

Mass spectrum (M + H) ⁺ = 283.

(b) 1- (7-Nitro (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide
To a stirred solution of 7-nitro-1 - ((phenylmethyl) amino) - 1,2,3,4-tetrahydronaphthalene (2.96 g, 10.5 mmol) and triethylamine (1.46 ml, 10.50 mmol) in Trifluoroacetic anhydride (1.46 ml, 10.50 mmol) was added dropwise to 50 ml of methylene chloride. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts are washed with water, dried over magnesium sulfate and filtered through a small layer of silica gel (20% ethyl acetate / hexane) to obtain 1- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide (1.90 g, 48%, two steps).

Mass spectrum (M + H) ⁺ = 379.

(c) 1- (7-amino- (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide
To a stirred solution of 1- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide (1.91 g, 5.05 mmol) in THF / MeOH (100 ml, 1: 1) add a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to give 1- (7-amino (1, 2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide, which according to TLC is homogeneous, and immediately used in the next stage.

(d) N - ((1- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaft-7-yl) - 2-thiophenecarboximidamide
To a solution of 1- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide (1.76 g, 5.05 mmol) in 10 ml of isopropanol is added S-methyl-2- thiopheniocarboximide hydrochloride (1.44 g, 5.05 mmol). The resulting mixture was stirred for 14 hours, diluted with methanol (6 ml) and 2N. NaOH (6 ml) and heated to 50 ^o C for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. As a result of IPA / HBr treatment, N - ((2-phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximamide dihydrobromide is obtained in the form of a white solid (0.53 g, 20% )

T. melting 260-262 ^o C.

Example 14
N - ((1- (Phenylmethyl) amino) indan-5-yl) -N-thiophenecarboximidamide
(a) 6-Acetamido- (1 - ((phenyl) methyl) amino) indane
6-Acetamido-1-indanone (5.0 g, 27.6 mmol), benzylamine (3.1 ml, 27.9 mmol) and titanium isopropoxide (10.2 ml, 34.5 mmol) are combined and stirred for 1 hour The resulting mixture was diluted with absolute ethanol (30 ml), treated with sodium cyanoborohydride (1.2 g, 19.3 mmol) and allowed to mix for 20 hours. The solid is filtered off and washed with ethanol. Ethanol was concentrated and the remaining oil was dissolved in ethyl acetate and extracted with 1N. HCl (3 x 50 ml). The aqueous layer is neutralized with 2n. NaOH and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil, which was used without further purification in the next step.

(b) 6-amino- (1 - ((phenyl) methyl) amino) indane
6-Acetamido- (1 - ((phenyl) methyl) amino) indane is refluxed in 4N. HCl (50 ml) for 20 minutes, cooled and extracted with ethyl acetate (3 x 50 ml). The aqueous layer is neutralized with 2n. NaOH and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. The resulting oil was dissolved in IPA and treated with IPA / HCl to give the dihydrochloride salt (2.0 g, 24%, two steps).

T. melting point above 250 ^o C (with decomposition).

(c) N - ((1- (Phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide
To 6-amino (1- (phenyl) methyl) amino) indandihydrochloride (2.0 g, 6.4 mmol) in DMF (20 ml) was added S-methyl-2-thiopheniocarboximide hydroiodide (2.2 g, 7.7 mmol) and pyridine (0.57 ml, 7.1 mmol). The resulting mixture was stirred at 50 ^° C. for 20 hours, poured into alkalized water and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (6% methanol / methylene chloride). The extracts obtained were concentrated to an oil, which was dissolved in methanol, treated with IPA / HCl and triturated with ether. The solid was filtered off and washed with ether (1.1 g, 40%).

The melting point is more than 180 ^o C (decomposition).

Example 15
The following compound was prepared according to the method of Example 14:
N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-6-yl) -2-thiophenecarboximidamide
T. melting more than 200 ^o C (with decomposition).

Example 16
N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) - 2-furancarboximidamide
(a) 2 - ((Phenyl) carbonyl) amino-7-nitrotetralin
Benzoyl chloride (1.7 ml, 15.3 mmol) is added to 2-amino-7-nitrotetralin (2.8 g, 14.5 mmol) in 50 ml THF and 10% K ₂ CO ₃ (100 ml). After complete addition, the resulting mixture was diluted with water to a volume of 250 ml. The precipitated solid was filtered off, washed with water and dried in vacuo (4.2 g, 98%).

T. melting point 194-198 ^o C.

(b) 2 - ((Phenyl) methyl) amino-7-nitrotetraline hydrochloride
To 2 - ((phenyl) carbonyl) amino-7-nitrotetraline (4.2 g, 14.1 mmol) in anhydrous THF (100 ml) was added borane-THF (49.3 ml, 1M THF, 49.3 mmol) . The resulting mixture was refluxed for 5 hours, cooled to 0 ^° C, and quenched by dropwise addition of 4N. HCl. The resulting mixture was again brought to a boil under reflux for 1 hour, concentrated in vacuo and the solid was filtered off (washed with water) and dried in vacuum (3.5 g, 78%).

T. melting more than 300 ^o C.

(c) 2 - ((Phenyl) methyl) amino-7-aminotetralining hydrochloride
To a stirred solution of 2 - ((phenyl) methyl) amino-7-nitrotetralin (2.0 g, 6.3 mmol) in MeOH (100 ml) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm2) for 1 hour, filtered through celite and concentrated to an oil that was homogeneous according to TLC, and was used immediately in the next step.

(d) N - ((2-Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-furancarboximidamide
To 2 - ((phenyl) methyl) amino-7-aminotetralining hydrochloride (1.8 g, 6.3 mmol) in 20 ml of DMF, S-methyl-2-furantiocarboximide hydroiodide (2.0 g, 7.5 mmol) is added. The resulting mixture was stirred for 2 hours at 45 ^o C, poured into alkalized water and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. This oil is dissolved in methanol, treated with IPA / HCl and triturated with ether. The solid is filtered off and washed with ether (2.2 g, 84%).

Melting point more than 195 ^o C (decomposition).

Obtaining chiral intermediates for examples 17 and 18
Separation of 2-amino-7-nitrotetralin
2-amino-7-nitrotetralin (30 g, 156 mmol) is dissolved in 200 ml of acetone, added to dibenzoyl-D-tartaric acid (58.7 g, 164 mmol), also dissolved in 200 ml of acetone. The thick paste is filtered and washed with acetone. This paste is refluxed in 3 L of a mixture of water / ethanol / acetonitrile (1: 1: 1), then filtered while hot. The solid is collected by filtration, recrystallized from this mixture (3x); receive (5.25 g, 6%) of one isomer (according to chiral capillary zonal electrophoresis).

T. melting point 240-242 ^o C.

 Similarly, dibenzoyl-L-tartaric acid can be used to separate opposite enantiomers using the same solvent system as previously described: (5.3 g, 6%) of one isomer is obtained (as determined by chiral capillary zonal electrophoresis) .

T. melting point 240-242 ^o C.

Example 17
(+) - N - ((2 - ((phenyl) methyl) amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide
(a) (+) - 2 - ((phenyl) carbonyl) amino-1-nitrotetralin
To 2-amino-7-nitrotetraline (1.8 g, 9.39 mmol obtained from dibenzoyl-D-tartaric acid) in THF (50 ml) and 10% K ₂ CO ₃ (100 ml) benzoyl chloride is added (1, 2 ml, 10.1 mmol). After complete addition, the resulting mixture was diluted with water to a volume of 250 ml. The precipitated solid was collected by filtration, washed with water and dried in vacuo (2.8 g, 100%).

T. melting point 208-209 ^o C,
[α] _D +21.9 ^° C (c 0.33, DMSO).

(b) (+) - 2 - ((phenyl) methyl) amino-2-nitrotetraline hydrochloride
To (+) - 2 - ((phenyl) carbonyl) amino-7-nitrotetraline (2.8 g, 9.4 mmol) in anhydrous THF (100 ml) was added borane-THF (32.8 ml, 1M THF, 32 , 8 mmol). The resulting mixture was refluxed for 5 hours, cooled to 0 ^° C, and quenched by dropwise addition of 4N. HCl. The resulting mixture was brought to a boil under reflux for 1 hour, concentrated in vacuo and the solid was filtered off (washed with water) and dried in vacuo (2.8 g, 94%).

T. melting more than 300 ^o C,
[α] _D +51.0 ^° C (c 0.33 DMSO).

(c) (+) - 2- (Phenyl) methyl) amino-7-aminotetraining hydrochloride
To a stirred solution of (+) - 2 - ((phenyl) methyl) amino-7-nitrotetralin (2.8 g, 8.7 mmol) in MeOH (100 ml) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to obtain a glassy solid, which was homogeneous according to TLC.

[α] _D +73.3 ^° C (c 0.87 DMSO).

(d) (+) - N - ((2-) Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) - 2-thiophenecarboximidamide
To (+) - 2 - ((phenyl) methyl) amino-7-aminotetralining hydrochloride (2.5 g, 8.7 mmol) in 20 ml of DMF, S-methyl-2-thiopheniocarboximide hydrochloride (3.0 g, 10.4 mmol). The resulting mixture was stirred for 4 hours at 45 ^o C, poured into alkalized water and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. This oil is dissolved in methanol, treated with IPA / HCl and triturated with ether. The solid is collected by filtration and washed with ether. After one recrystallization from IPA / MeOH / Et ₂ O, a white solid product is obtained (2.5 g, 66%), i.e., melting more than 260 ^° C. (with decomposition) [α] _D +44.5 ^° C. (s 0 , 62 DMSO).

Example 18
(-) - N - ((2 - ((Phenyl) methyl) amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide
(a) (-) - 2- (Phenyl) carbonyl) amino-7-nitrotetralin
To 2-amino-7-nitrotetraline (1.8 g, 9.39 mmol obtained from dibenzoyl-L-tartaric acid) in 50 ml of THF and 10% K ₂ CO ₃ (100 ml) benzoyl chloride (1.2 ml 10.1 mmol). After complete addition, the resulting mixture was diluted with water to a volume of 250 ml. The precipitate was collected by filtration, washed with water and dried in vacuo (2.8 g, 100%).

T. melting point 208-209 ^o C.

[α] _D -24.0 ^° C (c 0.87 DMSO).

(b) (-) - 2 - ((Phenyl) methyl) amino-7-nitrotetraline hydrochloride
To (-) - 2 - ((phenyl) carbonyl) amino-7-nitrotetraline (2.8 g, 9.4 mmol) in 100 ml of anhydrous THF, borane-THF (32.8 ml, 1M THF, 32.8 mmol). The resulting mixture was refluxed for 5 hours,
cooled to 0 ^o C and quenched by dripping 4n. HCl. The resulting mixture was again brought to a boil under reflux for 1 hour, concentrated in vacuo and the solid was filtered off (washed with water) and dried in vacuo (2.8 g, 94%).

T. melting more than 300 ^o C,
[α] _D -59.4 ^° C (with 0.39 DMSO).

(c) (-) - 2 - ((Phenyl) methyl) amino-7-aminotetraining hydrochloride
To a stirred solution of (-) - 2 - ((phenyl) methyl) amino-7-nitrotetralin (2.8 g, 8.7 mmol) in MeOH (100 ml) was added a catalytic amount of 10% Pd / C. The resulting mixture was hydrogenated at 50 psi (3.515 kg / cm ² ) for 1 hour, filtered through celite and concentrated to a glassy solid, which was homogeneous according to TLC; [α] _D -74.6 ^° C. (with 0.80 DMSO).

(d) (-) - N - ((2-Phenylmethyl) amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide
To (-) - 2 - ((phenyl) methyl) amino-7-aminotetralining hydrochloride (2.5 g, 8.7 mmol) in 20 ml of DMF add S-methyl-2-thiophenecarboximide hydroiodide (3.0 g, 10.4 mmol). The resulting mixture was stirred for 4 hours at 45 ^o C, poured into alkalized water and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. This oil is dissolved in methanol, treated with IPA / HCl and triturated with ether. The solid is filtered off and washed with ether. After one recrystallization from IPA / MeOH / Et ₂ O, a white solid is obtained (2.7 g, 71%).

T. melting point above 260 ^o C (with decomposition).

[α] _D -44.5 ^° C (with 0.57 DMSO).

Example 19
N- (2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl) thiophen-2-carboximidamide
(a) 2,3,4,5-Tetrahydro-1H-3-benzazepine-7-amine monohydrochloride
To a solution of 2,3,4,5-tetrahydro-7-nitro-1H-3-benzazepine hydrochloride (1.68 g, 7.35 mmol) in 100 ml of ethanol was added 5% palladium on carbon (0.2 g) and the resulting the solution is placed in a Paar apparatus for hydrogenation, the pressure is adjusted to 45 psi (3.164 kg / cm ² ) of hydrogen. After reaching the calculated hydrogen uptake (2 hours), the catalyst is filtered off and washed with water (25 ml). The resulting filtrate was concentrated. Absolute ethanol was added and evaporated until all the water had evaporated and a solid formed. The solid product was dissolved in hot ethanol (50 ml), and the resulting product was precipitated with ether (75 ml). The solid was collected and air dried to give the product as an off-white solid (2.43 g, 94%).

Melting point 288-91 ^o C.

(h) N- (2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl) thiophen-2-carboximidamide
Suspension of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine monohydrochloride (0.60 g, 3.0 mmol) and 5-methyl-2-thiophenecarboximide hydroiodide (1.1 g, 3.8 mmol) in 2.0 ml of dimethylformamide and 2.0 ml of isopropanol are stirred at room temperature for 20 hours. The solid of the reaction mixture was filtered and washed with isopropanol (5 ml) and ethyl acetate (15 ml). The air-dried solid weighs 1.18 g and is a mixed salt. It is dissolved in water, made basic and extracted with ethyl acetate. The solvent was dried over magnesium sulfate and concentrated to give the free base as a yellow solid. It is placed in 30 ml of isopropanol and acidified with hydrogen bromide in isopropanol until the solution becomes acidic. The product is precipitated with 35 ml of ethyl acetate. This product was collected and dried to give the product as the dihydrobromide salt (0.70 g, 54%).

T. melting point 281-3 ^o C.

Example 20
N- (1,2,3,4-Tetrahydroisoquinolin-7-yl) thiophen-2-carboximidamide
(a) 1,2,3,4-Tetrahydroisoquinoline-7-amine monohydrochloride
It is obtained by the method of example 19, stage (a). From 7-nitro-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride (3, 00 g, 14.0 mmol) and 5% palladium on carbon (0.3 g) in 150 ml of ethanol, the product is isolated as a pale pink solid substances (2.43 g, 94%).

Melting point 232-4 ^o C
(b) N - (- 1,2,3,4-Tetrahydroisoquinolin-7-yl-) thiophene-2-carboximidamide
It is obtained by the method of example 19, stage (b). After 1,2,3,4-tetrahydroisoquinoline-7-amine monohydrochloride (0.46 g) and 3-methyl-2-thiopheniocarboximide hydroiodide (0.95 g) in 2.0 ml of isopropanol and 2 ml of dimethylformamide, the above compound is isolated after treatment as free base (0.60 g, 94%). It is converted to the bisoxalate salt in a methanol / ethyl acetate solution to give the product as an off-white solid (0.59 g, 54%).

Melting point 199-200 ^o C (decomposition).

Example 21
N- (2-Benzyl-1,2,3,4-tetrahydroisoquinolin-7-yl-thiophen-2-carboximidamide
(a) 2-Benzyl-7-nitro-1,2,3,4-tetrahydroisoquinoline monohydrochloride
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline monohydrochloride (2.50 g, 11.6 mmol) and potassium carbonate (2.0 g) in 100 ml of acetonitrile, benzyl bromide (2.22 g, 13.0 mmol) in 10 ml of acetonitrile. This solution was stirred overnight, and then the solid was removed by filtration. The solvent was removed in vacuo to give a solid product, which was partitioned between methylene chloride and water. The dried (over magnesium sulfate) organic phase is concentrated, and the resulting oil is placed in ethanol (50 ml). This solution is acidified with hydrochloric acid in ethanol. The precipitate that forms is precipitated and 150 ml of ethanol and 50 ml of ether are added. The solid was collected and air dried to give 2-benzyl-7-nitro-1,2,3,4-tetrahydroisoquinolinhydrochloride as an off-white solid (2.78 g, 79%).

Melting point 256-8 ^o C (decomposition).

(b) 2-Benzyl-1,2,3,4-tetrahydroisoquinoline-7-amine hydrochloride
This compound is prepared according to the method of Example 19 (step a). From 2-benzyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.00 g, 6.56 mmol) and 5% Pd / C (0.2 g) in 100 ml of ethanol. The product was isolated as a yellow solid (1.05 g, 78%).

T. melting point 257-9 ^o C (decomposition).

(c) N- (2-Benzyl-1,2,3,4-tetrahydroisoquinolin-7-yl) thiophen-2-carboximidamide
It is obtained according to the method of example 19 (stage b). From 2-benzyl-1,2,3,4-tetrahydroisoquinoline-7-aminonohydrochloride (0.50 g, 1.8 mmol) and 5-methyl-2-thiopheniocarboximide hydroiodide (0.67 g, 2.3 mmol) in isopropanol (2.0 ml) and dimethylformamide (2.0 ml), the title compound was isolated as a yellow solid (0.53 g, 84%). It is converted to the oxalate salt in isopropanol. m / e = 348 (M + H).

Example 22
N- (1,2,3,4-tetrahydroisoquinolin-5-yl) thiophene-2-carboximidamide, dioxalate salt
This compound is prepared according to the method described in Example 20.

T. melting point 75 ^o C (decomposition).

Example 23
N- (1,2,3,4-Tetrahydroisoquinolin-6-yl) thiophene-2-carboxy-imidamide
(a) 1,2,3,4-Tetrahydroisoquinoline-6-amine monohydrochloride
Solution of isoquinolin-6-amine (Manske, RHF, et.al., J. Am. Chem. Soc., 72, 4997 (1950)) (4.40 g, 30.5 mmol) and platinum oxide (300 mg) in a solution of acetic acid (85 ml) and 2.5 M hydrochloric acid (30 ml) are placed in a Paar apparatus and a hydrogen pressure of 45 psi (3.164 kg / cm) is created for 16 hours. The solvent was removed in vacuo, and the resulting salt was partitioned between aqueous potassium carbonate and 20% isopropanol in methylene chloride. The dried (magnesium sulfate) organic phase was concentrated, and the resulting oil was chromatographed on silica gel using 2% methanol in chloroform as eluent to obtain 3.08 g (93%) of the product as a solid. This product (3.08 g, 20.8 mmol) was placed in 200 ml of ethanol and 1 equivalent of a 0.10 M hydrochloric acid solution was added. The solvent is removed to obtain monohydrochloride as a solid.
Mass spectrum 149 (M + H).

(b) N- (1,2,3,4-Tetrahydroisoquinolin-6-yl) thiophene-2-carboximidamide
It is obtained according to the method of example 19 (stage b). Of 1, 2, 3, 4-tetrahydroquinoline-6-aminonohydrochloride (0, 90 g, 4.9 mmol) and 8-methyl-2-thiopheniocarboximide hydroiodide (1.80 g, 6.2 mmol) in isopropanol (2.0 ml) and dimethylformamide (2.0 ml) were isolated after treatment and chromatography on silica gel, the compound as the free base (0.74 g, 57%).

T. melting point 170-5 ^o C.

Example 24
N- (Isoquinolin-7-yl) thiophene-2-carboximidamide
(a) 7-Nitroisoquinoline
A solution of 7-nitro-3,4-dihydroisoquinoline (3.00 g, 17.0 mmol) and 5% palladium on charcoal (3.0 g) in 75 ml of decalin is heated under reflux for 3 hours. After cooling, the solution is filtered and the catalyst washed with chloroform (200 ml). The solvent was removed in vacuo to give 7-nitroisoquinoline (1.63 g) as a tan solid.

 Mass spectrum 175 (M + H).

(b) Isoquinolin-7-amine
7-Nitroisoquinoline (1.62 g, 9.25 mmol) in 150 ml of ethanol is hydrogenated in a Paar apparatus over 5% Pd / C (0.2 g) as a catalyst for 3 hours at 50 psi (3.515 kg / cm ² ) The reaction mixture was filtered and the solvent was removed under reduced pressure. Recrystallization of the solid from ethanol (3 ml) gave isoquinolin-7-amine (0.98 g) as a tan solid.

Mass spectrum 145 (M + H),
NMR (CDCl ₃ ): δ 9.02 (s, 1H), 8.29 (d, 1H), 7.63 (d, 1H), 7.47 (d, 1H), 7.13 (dd, H ), 7.03 (d, 1H), 4.00 (br., 2H).

(c) N- (Isoquinolin-7-yl) thiophene-2-carboximidamide
A solution of isoquinolin-7-amine (0.96 g, 6.7 mmol) and S-methyl-2-thiopheniocarboxamide (2.42 g, 8.36 mmol) in 4 ml of isopropanol and 4 ml of DMF was stirred for 18 hours. The solution was poured into dilute sodium hydroxide and extracted with methylene chloride. The resulting extract was dried over magnesium sulfate, and the solvent was evaporated to an oil, which solidified upon standing. This sample was purified by silica gel column chromatography (5% methanol in chloroform saturated with gaseous ammonia) to obtain 1.31 g of a solid. This solid was recrystallized from ethyl acetate (25 ml) to obtain 1.05 g of the title compound as an off-white solid.

T. melting point 177.5-178.5 ^o C.

Claims (19)

1. Bicyclic derivatives of amidine of the formula I

where D represents a five-membered heterocyclic ring containing a heteroatom selected from O or S, and which is connected to the rest of the compound via a carbon atom;
A represents N (X) or CH (- (CH ₂ ) _m —NXY);
U represents NH or CH ₂ ;
V represents (CH ₂ ) _a ;
W represents (CH ₂ ) _b ;
a and b independently represent an integer from 0 to 3, provided that a + b represents an integer from 1 to 3;
X and Y independently represent hydrogen, C1-6 alkyl or a group - (CH ₂ ) _n Q;
Q represents biphenyl or phenyl optionally substituted with one or more of the groups selected from C1-6 alkyl, halogen, nitro;
m represents an integer from 0 to 5;
n represents an integer from 0 to 6;
or the UVAW chain has the previously indicated values, except that it cannot be saturated,
and its pharmaceutically acceptable salts and enantiomers. 2. The compound according to claim 1 of formula IA

where T represents a C3-5 saturated or unsaturated alkylene chain substituted with (CH _2a —NXV, or —U- (CH ₂ ) aN (X) - (CH ₂ ) b-;
X and Y independently represent hydrogen, C1-6 alkyl or a group - (CH ₂ ) _n Q;
Q represents phenyl, optionally substituted C1-6 alkyl, halogen, nitro;
U, m, n, a, b, and D are as previously defined, except that if T represents —U (—CH ₂ ) _a —N (X) - (CH ₂ ) _b and X represents - (CH ₂ ) _n Q;
n represents an integer from 0 to 5,
and its pharmaceutically acceptable salts and enantiomers. 3. The compound of formula I according to claim 2, where T represents a C _3-5 saturated or unsaturated alkylene chain substituted by (CH ₂ ) _m —NXY, and X and Y independently represent hydrogen, C1-6 alkyl or a group (CH ₂ ) _n Q. 4. The compound of formula I according to claim 2 or 3, where T is a C3-5 saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _n —NXY.  5. The compound of formula I according to any one of paragraphs 1 to 4, where m represents 0 or 1. 6. The compound of formula I according to claim 2, where T represents -U (-CH ₂ ) _a -N (X) - (CH ₂ ) _b and X represents hydrogen, C1-6 alkyl or a group - (CH ₂ ) _n Q -. 7. The compound according to claim 2 or 6, where T is —U (—CH ₂ ) _a —N (X) - (CH ₂ ) _b and U is CH ₂ . 8. The compound according to claim 2, 6 or 7, where T represents -U (-CH ₂ ) _a -N (X) - (CH ₂ ) _b , and a + b = 1 or 2. 9. The compound according to any one of the preceding paragraphs, where n represents 0, 1 or 2, and X and / or Y represents - (CH ₂ ) _n Q. 10. The compound according to any one of the preceding paragraphs, where X and / or Y represents - (CH ₂ ) _n Q, Q represents phenyl optionally substituted with C1-6 alkyl.  11. The compound of formula I according to any one of the preceding paragraphs, where D is a five-membered heterocyclic ring containing one heteroatom selected from O or S.  12. The compound of formula I according to claim 11, where D is thienyl or furyl.  13. The compound of formula I according to claim 12, wherein D is 2-thienyl. 14. The compound of formula I according to claim 1, which is:
N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide;
N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide;
N - ((2-amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide;
N - ((1-amino) -1,2,3,4-tetrahydronaft-7-yl) -2-thiophenecarboximidamide;
N - ((2-amino) -indan-5-yl) -2-thiophenecarboximidamide;
N - ((2-methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide;
N - ((2-amino) -indan-6-yl) -2-thiophenecarboximidamide;
N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide;
N - ((2 - ((3-chlorophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - ((2-methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - ((3-methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - ((4-methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2- (ethyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - (((4-phenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - (((4-hexyl) phenyl)) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - ((3-bromophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine;
N - ((2 - ((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide;
N - ((2- (phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide;
N - ((1- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide;
N - ((1- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide, N - ((1- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-6-yl) -2 -thiophenecarboximidamide;
N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-furancarboximidamide;
N- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) thiophene-2-carboximidamide;
N- (1,2,3,4-tetrahydroisoquinolin-7-yl) thiophen-2-carboximidamide;
N- (2-benzyl-1,2,3,4-tetrahydroisoquinolin-7-yl) thiophene-2-carboximidamide;
N- (1,2,3,4-tetrahydroisoquinolin-5-yl) thiophen-2-carboximidamide;
N- (1,2,3,4-tetrahydroisoquinolin-6-yl) thiophen-2-carboximidamide;
N- (isoquinolin-7-yl) thiophene-2-carboximidamide,
or their pharmaceutically acceptable salts or enantiomers.  15. The compound according to any one of the preceding paragraphs as a pharmaceutical agent.  16. A pharmaceutical composition having the property of a nitric oxide synthetase inhibitor comprising an amidine derivative in admixture with a pharmaceutically acceptable diluent or carrier, characterized in that it contains a compound according to any one of claims 1 to 14 in a therapeutically effective amount as an amidine derivative.  17. The bicyclic amidine derivative of the formula I according to claim 1, having the property of a nitric oxide synthetase inhibitor.  18. A method of inhibiting nitric oxide synthetase, comprising administering an amidine derivative, characterized in that a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 14 is used as an amidine derivative. 19. The method of obtaining bicyclic derivatives of amidine of the formula I according to claim 1, characterized in that the interaction of the compounds of formula II

with a compound of formula III

where D has the meanings indicated in claim 1;
L represents a leaving group
and, if necessary, the resulting compound I, in which X is hydrogen, is further reacted with a compound of formula VI
R ⁹ -L,
where R ⁹ represents alkyl Cl-6 or a group - (CH ₂ ) _n Q;
L represents a leaving group
to obtain a compound of formula I in which A represents a group —N (X), and X represents alkyl C1-6 or a group - (CH ₂ ) _n Q, or the obtained compound I, in which X and Y are hydrogen, is further reacted with a compound of formula VI
R ⁹ -L,
where R ⁹ represents C1-6 alkyl or a group - (CH ₂ ) _n Q;
L represents a leaving group
to obtain a compound of formula I in which A represents a group —CH - ((CH ₂ ) _m —NXY, and at least one of X and Y represents C1-6 alkyl or a group - (CH ₂ ) _n Q. 20 a method for producing bicyclic amidine derivatives of formula I according to claim 1, characterized in that the compounds of formula IV are reacted

where U, V, A and W have the meanings indicated in claim 1;
HA is an acid
with a compound of formula V

where D has the meanings indicated in claim 1,
and, if necessary, the resulting compound I, in which X is hydrogen, is further reacted with compound VI
R ⁹ -L,
where R ⁹ represents C1-6 alkyl or a group - (CH ₂ ) _n Q;
L represents a leaving group
to obtain a compound of formula I in which A represents a group —N (X), and X represents alkyl C1-6 or a group - (CH ₂ ) _n Q, or the obtained compound I, in which X and Y are hydrogen, is further reacted with a compound of formula VI
R ⁹ -L,
where R ⁹ represents C1-6 alkyl or a group - (CH ₂ ) _n Q;
L represents a leaving group
to obtain a compound of formula I in which A represents a group —CH - ((CH ₂ ) _m —NXY and at least one of X and Y represents C1-6 alkyl or a group - (CH ₂ ) _n Q.