SK281442B6 - Bicyclic amidine derivatives, method of preparing thereof, pharmaceutical compositions containing theses derivatives and their use - Google Patents

Abstract

Disclosed are bicyclic amidine derivatives of formula (I) wherein D is a five membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from O, N or S, optionally substituted on a carbon atom by halogen, trifluoromethyl, C1-6 alkyl, nitro or cyano and which is attached to the remainder of the compound of formula (I) via 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, b, m, X and Y are defined in the specification, together with methods for their preparation and compositions containing them. The compounds of formula (I) are NO-synthase inhibitors and are useful in therapy

Description

Technical field

The present invention relates to bicyclic amidine derivatives, processes for their preparation, compositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

Some amidine derivatives have been reported to be useful in therapy. According to U.S. Pat. 3669974 (USV Pharmaceutical Corp.) and UK Patent Application 2226562 (Boots) disclose the use of N-phenylamidine derivatives for the treatment of diabetes. Intemational Patent Application WO 92/04054 (University of Oregon) describes the use of N ', N-disubstituted admidines in the treatment of hypertension, depression and hallucinogenic conditions. The use of certain amidines and symmetrical bisamidines as analgesics in the treatment of inflammation and in the treatment of hypertension is described in Belgian patent no. No. 717740 and in UK patent no. 1180629 (both patents to Delaland). German Patent Application DE-OS-2321330 (Bayer) discloses the use of amidine derivatives as herbicides.

Also described is the use of nitric oxide synthetase (NO) synthase inhibitors in the treatment of diseases, e.g. in International Patent Applications WO 94/12163 (Abbott), WO 93/13066 and WO 94/12165 (both Wellcome) and European Patent Application 446699 (Merrell Dow), 547558 and 558468 (both Washington University). The use of nitric oxide synthease inhibitors in therapy is also described in WO 95/00505, WO 95/09619, WO 95/09621 (all Wellcome), WO 95/10266 (Otsuka), WO 95/11231 and WO 95 / 11014 (both Searle), six of which were published after the earliest priority date you give to this application.

The Applicant has previously described the use of guanidine derivatives and amidine derivatives which are inhibitors of NO synthase in the treatment of, inter alia, neurodegenerative diseases (WO 94/21621, WO 95/05363). The second of these patents was published after the earliest possible priority date of this application.

SUMMARY OF THE INVENTION

We have now found a new class of bicyclic amidine derivatives having useful pharmaceutical activity.

According to a first aspect of the present invention we have prepared a bicyclic amidine derivative of the general formula (1) 1 Ί1-NK

D (I), where

D represents a five membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from O, N or S, optionally substituted on a carbon atom with halogen, trifluoromethyl, C1-6 alkyl, nitro or cyano, and which is attached to the remainder of the compound of formula ( 1) through a carbon atom;

A is N (X) or CH (-CH ₂ ) _m -NXY);

U represents NH, O or _CH2;

W represents (CH _{2) a;} W represents (CH ₂ ) _b ;

a and b independently represent integers from 0 to 3, provided that a and b are in the range of 1 to 3;

X and Y independently represent hydrogen, alkyl Cl to 6, or - (CH _{2) n} Q, or NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl;

Q is biphenyl or phenyl, optionally substituted with one or more groups selected from alkyl groups C1-6, alkoxy C1-6, perfluoroalkyl C1-6, halogen, nitro- or cyano-;

m is an integer from 0 to 5; n is an integer from 0 to 6;

or the chain U-V-A-W is already defined but may be unsaturated;

UVAW chain or the chain can be _{-NH-CH2 -CH2} -O- substituted at a carbon atom with - (CH) _m NXY, wherein m, X and Y are defined as above, and the corresponding pharmaceutically acceptable salts.

A preferred group of compounds of formula (I) is defined by formula (IA)

D (IA), where

T represents C ₃ . _A saturated or unsaturated alkylene chain, substituted with - (CH ₂ ) _m -NXY; -O (CH ₂ ) ₂ -NHsubstituted - (CH ₂ ) _m -NXY; or -U- (CH ₂ ) _and -N (X) - (CH ₂ ) b -;

X and Y independently represent hydrogen, alkyl Cl to 6, or - (CH _{2) n} Q, or NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl; Q is phenyl optionally substituted with C1-6 alkyl, C1-6 alkoxy, trifluoromethyl, halogen, nitro or cyano; and

U, m, n, a, b and D are as defined above, but provided that when T is -U- (CH ₂ ) _and -N (X) - (CH ₂ ) _b - and X is - (CH _{2) n} is an integer between 0 and 5, and the corresponding pharmaceutically acceptable salts.

Preferably, D represents a five membered heterocyclic aromatic ring containing one heteroatom selected from O, N or S, optionally substituted on a carbon atom by halogen. It is particularly preferred that D represents thienyl, furyl or pyrrolyl, especially thienyl or furyl, especially thienyl and 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 by - (CH _{2) m} NXY, in particular C ₃ _ ₄ saturated alkylene chain substituted by - (CH _{2) m} NXY.

If T represents C ₃ . _A saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m -NXY; or O- (CH ₂ ) ₂ -NH- substituted - (CH ₂ ) _m -NXY, we prefer that X and Y independently represent hydrogen, C 1-6 alkyl or - (CH ₂ ) _n Q. We particularly prefer that X and Y independently represents hydrogen, methyl, ethyl or - (CH ₂ ) n Q, and in particular that either X or Y represents hydrogen and the other symbol represents hydrogen or - (CH ₂ ) n Q.

We prefer m to be 0 or 1, especially 0.

If T represents -U- (CH ₂ ) _and -N (X) - (CH ₂ ) _b -, we prefer U to represent CH ₂ .

If T is -U- (CH ₂ ) _and -N (X) - (CH ₂ ) _b -, we prefer that a + b be 1 or 2.

SK 281442-6

When T is -U- (CH ₂ ) _and -N (X) - (CH ₂ ) _b -, it is preferred that X is hydrogen, C 1-6 alkyl or - (CH ₂ ) n Q.

If X and / or Y is - (CH ₂ ) _n Q, we prefer that n be 0, 1 or 2, especially 1.

We prefer Q to represent phenyl optionally substituted with C1-6 alkyl or halogen, although it is particularly preferred that Q is unsubstituted phenyl.

According to the present invention, there is further provided a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof, comprising:

a) preparing a compound of formula (I) by reacting a corresponding compound of formula (II)

(II), wherein U, V, A and W are as defined by the symbols, with a compound of formula (III)

(III), wherein D is as defined above and L is a leaving group;

b) preparing a compound of formula (I) by reacting a corresponding compound of formula (IV)

(IV) wherein U, V, A and W are as defined above and HA is an acid, with a compound of formula (V) wherein U, V, W, X, Y and D are as defined above;

f) preparing a compound of formula (1) wherein A is CH (- (CH ₂ ) _m -NXY) and both X and Y are hydrogen by reduction of the corresponding compound of formula (VIII)

(VIII), wherein U, V, W, m and D are as previously defined;

g) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY), X is hydrogen and _m is an integer from 1 to 5, by reducing the corresponding compound of formula (IX)

(K), wherein U, V, W, D and Y are as previously defined;

h) preparing a compound of formula (1) wherein A is CH (- (CH ₂ ) _m -NXY), X or Y is hydrogen and the other is - (CH ₂ ) n Q, in which n is an integer a number from 1 to 6, by reducing the corresponding compound of formula (X)

wherein Q, m, U, V, W and D are as defined above;

i) preparing a compound of formula (I) wherein: A is CH (- (CH ₂ ) _m -NXY), X or Y is hydrogen and the other is - (CH ₂ ) n Q, wherein n is an integer from 1 to 6, by reducing the corresponding compound of formula (XI)

D --- = N (V), where D is already defined;

c) a compound of formula (I) in which A represents N (X) and X represents alkyl Cl to 6 or - _(CH2) "Q by reacting a corresponding compound of formula (I) wherein X represents hydrogen with a compound of formula ( VI)

R ⁹ L (VI) wherein R ⁹ represents C 1-6 alkyl or - (CH ₂ ) n Q and L is a leaving group;

d) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY) and at least one X or Y is C 1-6 alkyl or - (CH ₂ ) n Q, by reacting the corresponding compound of the general formula of formula (1) wherein one or both of X and Y represent hydrogen with a compound of formula (VI);

e) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY) and _m is an integer from 1 to 5, by reducing the corresponding compound of formula (VII)

XYNCCKCHAn-l - »

(VII),

(XI), wherein Q, m, U, V, W, and D are as previously defined; or

j) preparing a compound of formula (I) wherein A is CH (-NXY) and X is hydrogen by reducing the corresponding compound of formula (XII)

(XII), wherein U, V, W, D and Y are as previously defined;

and if desired or necessary converting the resulting compound of formula (I) or another salt thereof into a pharmaceutically acceptable salt, or vice versa.

In process a), the reaction is carried out while stirring the mixture of reactants in a suitable solvent, e.g. in a lower alkanol such as ethanol, isopropanol or tertiary butanol at a temperature between room temperature and the reflux temperature of the solvent used. The reaction time depends, inter alia, on the solvent and the nature of the leaving group, and can be up to 48 hours, but typically is from 1 to 5 hours. The corresponding leaving group L may be thioalkyl, sulfonyl, trifluoromethylsulfonyl (trifluorocarbon sulphonyl), halide, alkyl and aryl alcohols and a tosyl group; other groups are listed in "Advanced Organic Chemistry", J.March (1985), third edition, McGraw-Hill on p. 315; these groups are well known in the art.

In process b), the reaction is preferably carried out by refluxing a mixture of the two compounds for several hours in the presence of a suitable solvent, the reaction temperature being high enough to condense the solvent in the reflux condenser but not so high as to cause decomposition. of the amidine formed. The reaction temperature can range from room temperature to about 250 ° C, but is preferably carried out at temperatures between about 100 ° C and 200 ° C. It has been found that a particularly good solvent is dichlorobenzene and that it is preferable to add 4-dimethylaminopyridine as a catalyst. Upon cooling, two layers are formed, the solvent can be decanted and the reaction mixture treated after addition of aqueous base.

In those cases where the reactants are soluble in the solvent, the solvent can be evaporated under reduced pressure and the reaction mixture treated with water. HA 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 process c), the reaction is carried out under conventional conditions, for example by reacting the two compounds in an inert solvent under basic conditions at room temperature for up to 12 hours. It has often been found that it was convenient to treat the amine with NaH prior to reaction with the compound of formula (VI). Preferably, L is a halide, especially bromide.

Process d) can be carried out under the conditions described in process c).

In process e) the reduction can be carried out by treatment with diborane in an inert solvent such as THF. Alternatively, although less overcoated, the agents may include lithium aluminum hydride and catalytic hydrogenation agents, for example II ₂ to Pd / C. Further details of the reaction conditions that can be used in these reactions can be found in J. March: "Advanced Organic Chemistry", p. 1099 including references cited herein.

In process f), the reduction can be carried out under various reaction conditions, for example those described in J. March: "Advanced Organic Chemistry" on p. 1103-1104. These conditions include catalytic hydrogenation, use of metallic Zn, Sn or Fe, AlH ₃ -AlCl, sulfides and others. We prefer to carry out this reaction by hydrogenation at atmospheric pressure for 3 to 6 hours in the presence of a palladium-carbon catalyst.

In processes g), i) and j), the reduction can be carried out by treatment with sodium borohydride or sodium cyanoborohydride under standard conditions.

In process h), the reaction may be carried out under conditions analogous to those described in process (e).

Salts of the compounds of formula (I) may be prepared by reacting the free base or a salt, enantiomer, tautomer or protected derivative of the compound in question with one or more equivalents of the corresponding acid. This reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, such as e.g. water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or in a mixture of solvents that can be removed in vacuo or lyophilized. This reaction may be performed as a metathetical exchange reaction or may be performed on an ion exchange resin.

The compound of formula (II) may be prepared by reducing the corresponding compound of formula (XIII) ¢O (XIII), where U, V, A and W are as defined above.

The reduction can be carried out under conditions analogous to those described for process f).

Some of the compounds of formula (II) are either known or can be prepared by conventional methods known per se. Other compounds of formula II can be prepared from known compounds with simpler substituents according to analogous procedures described for processes c) to j). For example, analogous to process j), it has been found advantageous to prepare some compounds of formula (XIII) wherein A is CH (-NXY) and X is hydrogen by reduction of the corresponding imine formed by reaction of a compound of formula NH ₂ Y with a nitrated bicyclic ketone .

Compounds of formula (IV) may be prepared by analogous procedures to those described for the preparation of compounds of formula (II). Compounds of formula (IV) may be converted to the corresponding compounds of formula (II) by treatment with a base. Compounds of formula (II) may be converted to the corresponding compounds of formula (IV) by treatment with protic acid HA, e.g. one of said acids.

Compounds of formula (III) are either known or can be prepared by known methods. So eg. compounds of formula (III) in which L represents thioalkyl may be prepared by treatment with the corresponding thiamide of formula (XIV)

With D 4 -NHa (xiv), where D is as defined above, with an alkyl iodide.

Compounds of formula (VII), (VIII), (IX), (X), (XI), and (XII) may be prepared by analogous procedures to those described for the preparation of compounds of formula (I). These compounds can be readily prepared from simpler substituent compounds using conventional methods, e.g. amide formation (VII, X) by reaction of an amine with a carboxylic acid or an activated derivative thereof, or imine formation (IX, XI, XII) by reaction of an amine with an aldehyde.

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

The skilled artisan would appreciate that it may be desirable to protect an amine or other reactive group with the protecting group described in "Protecting Groups in Organic Synthesis" 2nd Edition (1991) by Greene and Wuts. The amino protecting groups which may be mentioned include C 2 to C 7 alkoxycarbonyl, e.g. t-butyloxycarbonyl, C 8-13 phenylalkoxycarbonyl, e.g. benzyloxycarbonyl or especially trifluoroacetate. The deprotection is generally carried out by treatment with aqueous base, acid or hydrogen.

The compounds of this invention and intermediates can be isolated from the respective reaction mixtures by conventional procedures.

The term "C1-C6 alkyl" refers to straight, branched, saturated, unsaturated, aliphatic or cyclic alkyl groups having 1 to 6 carbon atoms.

The compounds of formula (I) may exist as tautomers, enantiomers or diastereomers, all of which forms are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of these compounds using conventional procedures, e.g. by traction crystallization or by HPLC. Alternatively, the individual enantiomers may be prepared by reacting an appropriate optically active starting material with conditions such that racemization is avoided.

Intermediates may also exist as enantiomers and may be used as purified enantiomers, diastereoisomers, racemates or mixtures.

The compounds of formula (I) exhibit useful pharmacological action on animals. In particular, these compounds have a beneficial NO-synthase inhibitory action and are believed to be useful in the treatment or prophylaxis of human diseases under conditions in which the synthesis or over-synthesis of nitric oxide is essential; such as e.g. hypoxia, e.g. in cardiac arrest or stroke, neurovegetative disorders including nerve degeneration and / or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy and external injuries (such as spinal cord and head injuries), hyperbaric oxygen attacks and toxicity, dementia, e.g. . presenile dementia, Alzheimer's and AIDS-related dementia, Sydenham's disease (S.chorea), Parkinson's disease, Tourette's syndrome, Huntington's disease, amyotropic lateral sclerosis, Korsakoff's disease, cerebral vascular disorders, sleep disorders, depression, schizophrenia , seasonal disorders, time zone change disorders, depression or other symptoms associated with premenstrual syndrome (PMS), anxiety states and septic shock. It is expected that the compounds of formula (I) will also exhibit activity in preventing and altering opioid and diazepine tolerance, in treating drug addictions, relieving pain, and can be used in the treatment of migraine and other vascular headaches. The compounds of the present invention may also exhibit advantageous immunosuppressive activity, may be used in the treatment or prophylaxis of inflammation, neurogenic inflammation, transient aircraft disorders including asthma and adult respiratory distress syndrome (ARDS), treatment of gastrointestinal motility disorders, cancer, induction of labor, to reduce gastric acid secretion and to increase the contractile strength of skeletal muscles.

The compounds of formula (I) appear to be most interesting in the treatment of neurodegenerative diseases, migraine or in the prevention and alteration of opiate and diazepine tolerance or in the treatment of drug addictions and in particular in the treatment of neurodegenerative diseases.

According to another aspect of the invention, we propose a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical preparation.

According to a further feature of the present invention, we propose the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of said diseases and conditions.

Also contemplated is a method of treating or prophylaxis of one of said diseases or conditions, which comprises administering therapeutically effective doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a person suffering from or susceptible to such diseases or conditions.

Of course, in the indicated therapeutic indications, the dosage of the compositions to be administered will vary with the compound employed, the route of administration and the treatment desired. In general, however, satisfactory results are obtained when administered in human medicine at a daily dose of between 1 mg and 2000 mg (based on solid substance).

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as such or in the form of the corresponding medicinal preparations for oral or parenteral administration.

According to the present invention, there is provided a pharmaceutical formulation 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 suitable diluents and carriers are well known to those skilled in the art.

The nitric oxide synthetase enzyme has a number of isomeric forms and the effect of the compounds of formula (I) or pharmaceutically acceptable salts thereof on NO synthase activity can be evaluated (screen) according to the procedure suggested by Bredt and Snyder in Proc. Nat. Acad. Sci (1990) 87, 682-685 and Forstermann et al., Eur. J. Pharm. (1992) 225,161-165. NO-synthase converts HL-arginine to ³ HL-citrulline, which can be separated by cation exchange chromatography and quantified by scintillation counting. .

Screen A,

A. Screening for neuronal NO-synthase activity

The enzyme was isolated from the rat brain hippocampus or small brain. The small brain or hippocampus of male Sprague-Dawley rats (250-275 g) is removed after CO ₂ anesthesia and head removal. A small brain or hippocampus supernatant was prepared by homogenization in 50 mM Tris-HCl buffer with 1 mM EDTA (pH 7.2 at 25 ° C) and centrifugation for 15 minutes at 20000 g. Residual L-arginine was removed from the supernatant by chromatography on a Dowex AG-50W-X8 ion exchange column on a sodium cycle and on a hydrogen cycle column and then centrifugation at 1000 g for 30 seconds.

In this evaluation, 25 μΐ of the final supernatant was added to 12 tubes containing 25 μΐ of L-arginine solution (18 μΐ 'HL-arginine, 96 nM ³ HL-arginine) and either 25 μΐ of assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl ₂ , pH 7.4) or 25 μΐ of test compound in this buffer at 22 ° C. To each tube was added 75 μΐ of complete assay buffer (assay b.) (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl ₂ , 1 mM DTT, 100 µΜ NADPH, 10 µg / ml calmodulin, pH 7.4) to initiate the reaction and this reaction was stopped after 10 minutes by the addition of 2 ml of stop buffer (20 mM HEPES, 2 mM EDTA, pH 5.5).

Labeled L-citrulline was separated from labeled L-arginine by chromatography on a Dowex AG-50W-X8 ion exchange column with a particle size of 200-400 mesh. 1 ml of each completed reaction was added to a separate 1 ml column and the eluate was combined with the eluate from two washes of 1 ml distilled water and 16 ml of scintillation "cocktail". L-citrulline was then quantified by scintillation counting.

In a typical experiment using a small brain supernatant, basal activity increased by 20000 dpm / ml of sample

2816 above the reagent blank, which was 7000 dpm / ml. N-nitro-L-arginine, which showed 60% inhibition of NO-synthase at a concentration of 1 μΜ, was used to verify the procedure.

Screen B

B. Screening for macrophage NO synthase activity

The enzyme is prepared from cultured murine macrophage murine J774A-1 cells (obtained from the Imperial Cancer Research Fund). J774A-1 cells were cultured in Dulbecco Modified Eagles Medium (DNEM) broth enriched with 10% fetal bovine serum, 4 mM L-glutamine and antibiotics (100 U / ml penicillin G, 100µg / ml steptomycin and 0.25µg / ml). amphotericin B). Cells were routinely cultured in 225 cm ³ flasks containing 35 ml nutrient medium at 37 ° C and in a humidified atmosphere containing 5% CO ₂ .

NO-synthase is produced by cells in response to interferon (INF) and lipopolysaccharide (LPS). Nutrient medium from the culture flasks was removed and replaced with 25 ml (into each flask) of fresh medium containing 1 µg / ml LPS and 10 units / ml INF. After 17-20 hours of culture, the cells were harvested by scraping their layer off the surface of the flask into the culture medium. Cells were harvested after centrifugation (1000 g for 10 minutes) and the lysate was prepared by adding the centrifuged cells to a solution containing 50 mM Tris-HCl buffer (pH 7.5 at 20 ° C), 10% (v / v) glycerol, 0.1 % (v / v) Triton-X-100, 0,1 μΜ ditiotreitol and a 'cocktail' of protease inhibitors containing leupeptin (2 pg / ml), soya trypsin inhibitor (10 pg / ml), aprotinin (5 pg / ml) and phenylmethylsulfonylfluoride (50 µg / ml).

In this assay, 25 µl of substrate "cocktail" (50 mM Tris-HCl (pH 7.5 at 20 ° C), 400 µM NADPH, 20 µM flavinadenine dinucleotide, 20 µM flavin mononucleotide, 4 µM tetrahydrobiopterin, 12 µM L-arginine and 0.025 pCi of L- [ ³ H] arginine) was added to wells on a well filter plate (pore size 0.45 µM) containing 25 µl of a test compound solution in 50 mM Tris-HCl. The reaction was initiated by the addition of 50 µl of cell lysate (prepared as described) and after incubation for 1 hour at room temperature, the reaction was terminated by the addition of 50 µl of an aqueous solution of 3 mM nitroarginine and 21 mM EDTA.

Labeled L-citrulline was separated from labeled L-arginine using a Dowex AG-50W ion exchanger. 150 µl of a 25% aqueous Dowex 50W (Na ⁺ form) ion suspension is added to the assay and then all of the material is filtered onto 96-well plates. 70 µL of the filtrate is collected and added to the wells of the 96 well plates containing the solid scintillant. After drying the samples, the L-citrulline content is determined by quantitative scintillation counting.

In a typical experiment, a basal activity of 300 dpm per 70 µl sample was found, and this value increased to 1900 dpm in reagent controls. Aminoguanidine, whose IC ₅₀ (50% inhibitory concentration) was 10 pM, was used as a standard to verify the procedure.

Screen C

C. Screening for endothelial NO-synthase activity

This enzyme can be isolated from human umbilical vein endothelial cells (HUVEC) by the procedure of Pollock et al. (1991) Proc. Natl. Acad. Sci., 88, 10480-10484. These HUVEC cells were obtained from Clonetics Corp (San Diego, CA, USA) and cultured until confluency. These cells were maintained through 3540 passages without significantly reducing the yield of NO synthase. When the cells formed, they were resuspended in Dulbecco's salt-containing phosphate buffer, centrifuged at 800 rpm. for 10 minutes, and the cell pellet (pellet) was homogenized in ice-cold pH 4.2 buffer containing 50 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM phenylmethylsulfonyl fluoride, 2 µM leupeptin. Then centrifugation was performed at 34000 rpm. For 60 minutes, the obtained pellet was solubilized in homogenization buffer, which also contained 20 mM CHAPS. After a 30 minute incubation on ice, the suspension was centrifuged at 34000 rpm for 30 minutes. The supernatant obtained was stored at -80 ° C until use.

In this evaluation, 25 µl of the final supernatant was added to 12 tubes containing 25 µl L-arginine solution (12 µM HL-arginine, 64 nM ³ HL-arginine) and either 25 µl assay buffer (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl _{2 (} pH 7.4) or 25 µl of test compound in this buffer at 22 ° C. 25 µl complete assay buffer (assay b.) (50 mM HEPES, 1 mM EDTA, 1.5 mM CaCl ₂ , 1 mM DTT, 100 µM NADPH, 10 µg / ml calmodulin, 12 µM tetrahydrobiopterin, pH was added to each tube. 7.4) to initiate the reaction and this reaction was stopped after 10 minutes by the addition of 2 ml of stop buffer (20 mM HEPES, 2 mM EDTA, pH 5.5).

Labeled L-citrulline was separated from labeled L-arginine by chromatography on a Dowex AG-50W-X8 ion exchange column with a particle size of 200-400mesh. Then, 1 ml of each completed reaction was added to a separate 1 ml column and the eluate was combined with the eluate from two washes of 1 ml of distilled water and 16 ml of scintillation cocktail. L-citrulline was then quantified by scintillation counting.

In a typical experiment, basal activity was increased by 5,000 dpm / ml of the sample above the reagent blank that showed an activity of 1500 dpm / ml. N-nitro-L-arginine, which showed 70-90% inhibition of NO-synthase 'at a concentration of 1 μΜ, was used to verify the procedure.

These compounds can also be tested in ex-vivo experiments to assess the rate of their penetration into the brain.

Screen D

Ex-vivo experiments to determine neuronal NO-synthase activity

Male Sprague-Dawley rats (250-275 g) were treated intravenously with 10 mg / kg of the test compound dissolved in 0.9% saline or in saline control alone. After a designated time (typically 2 to 24 hours) after administration, the animals were sacrificed, the cerebellum was removed and the supernatant was prepared and evaluated for nitrate synthetase activity according to the procedure described in Screen A.

In a further validation experiment, a proportion of small brain supernatant was loaded onto a column packed with 2'-5'-ADP Sepharose (which binds NO-synthase) and then eluted with NADPH. The eluate obtained was tested for NO synthase activity according to the procedure described in Screen A.

Compounds that penetrate the rat brain and inhibit neuronal NO-synthase exhibit a decrease in NO-synthase activity both in the prepared supernatant and in the eluate from the column packed with 2'-5'-ADP Sepharose.

When screening for NO-synthase activity, the activity of the individual compounds was expressed as IC ₅₀ o (concentration of the substance that caused a 50% decrease in activity when evaluated).

SK 281442-6

IC ₅₀ values of test substances were initially determined by the inhibitory activity of 1, 10 and 100 μΜ solutions of these compounds. Compounds that inhibited this enzyme by at least 50% at a concentration of 10 μΜ were tested again at the corresponding concentrations that allowed a more accurate determination of the IC 50 value.

In the above-mentioned screening A (evaluation of activity against the neuronal isoform of NO-synthase), the compound of Example 1 below gave an IC ₅₀ value of less than 10 μΜ, indicating possible therapeutic utility. In screening B and C (evaluation of activity against the macrophage and endothelial isoform of NO-synthase), the compound of Example 1 below gave an IC ₅₀ value greater than ten times that of screening A above, indicating advantageous selectivity.

The compounds of Examples 2-9, 10 a) f), 11-13 and 19-24 were also tested in screening A and also gave an IC ₅ value of less than 10 µΜ. Thus, useful therapeutic activity is also expected with these agents.

The compounds of formula (I) and their pharmaceutically acceptable salts have the advantage of being less toxic, more potent, more selective, having a longer duration of action, having a broader spectrum of activity, more potent, causing fewer side effects, easier to absorb or other suitable pharmaceutical properties as compared to substances previously known and used in the above mentioned therapeutic fields.

The compounds of formula (I) and their pharmaceutically acceptable salts may also have the advantage of having a more selective effect on the neuronal isoform of NO-synthase, and therefore can be expected to have advantageous therapeutic utility with reduced side effects for inhibiting other isoforms.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples:

Example 1 N - ((2- (Phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate

(a) 5-Nitro-2-indanone

The compound was prepared according to the procedure of Heusler and Schieffer Ber., (1899) 32.33.

b) 5-Nitro-2- (phenylmethyl) aminoindane

The flask was charged with: 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 sieve (20 mL), THF (15 mL) and MeOH (15 mL), and this mixture was cooled to 0 ° C. Sodium cyanoborohydride (1.05 g, 16.7 mmol) was then added portionwise over 5 minutes. The mixture was stirred for 14 hours, filtered through celite and concentrated to a syrup. The mixture was basified 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). Yield of 5-nitro-2- (phenylmethyl) -aminoindan: (1.18 g, 53%); weight. spectra:

(M + H) < ^{+ &gt}; = 269.

c) 2- (5-Nitroindanyl) -N- (phenylmethyl) trifluoroacetamide

To a stirred solution of 5-nitro-2- (phenylmethyl) aminoindan (1.18 g, 4.40 mmol) and triethylamine (0.61 mL, 4.40 mmol) in methylene chloride (50 mL) was added dropwise trifluoroacetic anhydride (0). , 63 ml, 4.40 mmol). After stirring for 1 minute, the reaction mixture 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 pad of silica gel (20% ethyl acetate / hexane) to give 2- (5-nitroindanyl) -N- (phenylmethyl) trifluoroacetamide: (1.17 g, 73%); Mass Spec (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. hydrogenated at 50 psi (1 psi = 0.689.10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to give 2- (5-aminoindanyl) -N- (phenylmethyl) trifluoroacetamide which was homogeneous by TLC and used immediately in reaction step (f).

e) S-methyl-2-thiophenethio carboximide hydroiodide

To a solution of 2-thiophenecarboxthioamide (Maybridge Chemical) (11.1 g) in acetone (60 mL) was added iodomethane (13.4 g). After 6 hours at 22 ° C, a yellow solid formed by filtration, washed with acetone (2 x 25 mL) and dried to give 18.45 g of S-methyl-2-thiophenothiocarboximide hydroiodide, b. 1.195 ° C.

f) N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide 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 S-methyl-2-thiophenethiocarboximide - hydroiodide (0.85 g, 3.0 mmol). The mixture was stirred for 14 h, diluted with methanol (6 mL) and 2N NaOH (6 mL) and heated to 50 ° C for 0.5 h. This mixture was poured into water and extracted with ethyl acetate (3.times.30 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered and chromatographed on silica gel (20% methanol / methylene chloride) to afford the title compound as the free base. Treatment with IPA / oxalic acid gave N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate as a white solid: (0.47 g, 30%); b. Mp 1.130-135 ° 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 was prepared according to the method described in J. Med. Chem. (1989), 32.2128.

b) 7-Nitro-2 - ((phenylmethyl) amino) -1,2,3,4-tetrahydronaphthalene

Charge the flask with 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 A molecular sieve (20 mL), THF (15 mL) and MeOH (15 mL) and the mixture was cooled to 0 ° C. Sodium cyanoborohydride (0.99 g, 15.7 mmol) was then added portionwise over 5 minutes. The mixture was stirred for 14 hours, filtered through celite and concentrated to a syrup. It was then basified with 2N NaOH and extracted with ether (3 x 50 mL). The combined extracts were washed with water, dried over magnesium sulfate, filtered 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 spec. (M + H) < ^{+ &gt}; = 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 methylene chloride (50 mL) was added dropwise trifluoroacetic anhydride (1.05 mL, 7.45 mmol). After stirring for 1 minute, the mixture was poured into water and extracted with methylene chloride (3 x 20 mL). The combined extracts were then washed with water, dried over magnesium sulfate and filtered through a short pad of silica gel (20% ethyl acetate / hexane) to give 2- (7-nitro- (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) ) trifluoroacetamide: (2.55 g,

%); weight. Spectra. (M + H) < ^{+ &gt}; = 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) a catalytic amount of 10% PD / C was added. This mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to give 2- (7-amino- (1,2,3,4-tetrahydronaphthyl)). -N- (phenylmethyl) trifluoroacetamide, which was homogeneous by TLC and used immediately in the next reaction 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 isopropanol (10 mL) was added S-methyl -2-thiophenethiocarboximide hydroiodide (1.72 g, 6.07 mmol). The mixture was stirred for 14 h, diluted with methanol (6 mL) and 2N NaOH (6 mL) and heated at 50 ° C for 0.5 h. The 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 give a solid which, after recrystallization (methylene chloride / hexane), gave N - ((2-phenylmethyl) amino) -1,2,3,4-tetrahydronaphtha. -7-yl) -2-thiophenecarboximidamide as a white solid: (0.66 g, 30%); b. t. Mp 119-120 ° C.

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

Charge the flask with 7-nitro-1-tetralone (1.50 g, 7.85 mmol), ammonium acetate (6.05 mL, 78.5 mmol), acetic acid (8.0 mL), 4 A molecular sieve (20 mL), THF (15 mL) and MeOH (15 mL), and this mixture was cooled to 0 ° C.

Sodium cyanoborohydride (0.99 g, 15.7 mmol) was added portionwise over 5 minutes. The resulting mixture was stirred for 1 hour, filtered through celite and concentrated to a syrup. The mixture was basified 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 oily product. The compound was isolated as the hydrochloride: 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride: (1.00 g, 56%), b. mp> 300 ° 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 methylene chloride (50 mL) Trifluoroacetate hydride (0.62 mL, 4.39 mmol) was added dropwise. After stirring for 1 minute, the mixture was poured into water and extracted with methylene chloride (3 x 20 mL). The combined extracts were then washed with water, dried over magnesium sulfate and filtered through a short pad of silica gel (20% ethyl acetate / hexane) to give 2- (7-nitro- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide: (0.78 g, 62%); weight. Spectra. (M + H) < ^{+ &gt}; = 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. added a catalytic amount of 10% Pd / C. This mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to give 2- (7-amino- (1,2,3,4-tetrahydronaphthyl)) - N-Trifluoroacetamide, homogeneous by TLC and used immediately in the next step.

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 isopropanol (10 mL) was added S-methyl-2- thiophenothiocarboximide hydroiodide (0.77 g, 2.71 mmol). The mixture was stirred for 14 h, diluted with methanol (6 mL) and 2N NaOH (6 mL) and heated at 50 ° C for 0.5 h. The 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, concentrated and chromatographed on silica gel (20% methanol / methylene chloride) to give an oily product which was converted to the dihydrobromide: N - ((2-amino) -1,2) 3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dihydrobromide: (0.37 g, 32%); decomposition > 210 ° C.

Example 4 N - ((1-Amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dioxalate

a) 7-Nitro-1-amino-1,2,3,4-tetrahydronaphthalene

7-Nitro-1-amino-1,2,3,4-tetrahydronaphthalene was also prepared as 7-Nitro-2-amino-1,2,3,4-tetrahydronaphthalene. This compound was isolated as the hydrochloride: (0.30 g, 12%); b. mp> 300 ° C.

b) 1- (7-Nitro- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide 1- (7-Nitro- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide was prepared as well as 2- (7-Nitro- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide: (0.35 g, 95%); weight. Spectra. (M + H) < ^{+ &gt}; = 289.

c) 1- (7-Amino- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide 1- (7-Amino- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide was prepared as well as 2- (7-amino- (1,2,3,4-tetrahydronaphthyl)) - N-trifluoroacetamide and was 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-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dioxalate was also prepared as N - ((2-amino) 8).

SK 281442-6

-1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dihydrobromide except that it was isolated as the oxalic acid salt: (0.18 g, 33%); decomposition > 155 ° C.

Example 5 N - ((2-Amino) -mdan-5-yl) -2-thiophenecarboximidamide dioxalate

(a) 5-Nitro-2-aminomannan hydrochloride

To 2-aminoindan hydrochloride (19.11 g, 0.112 mol) at 0 ° C was added sulfuric acid (60 mL) followed by potassium nitrate (11.84 g, 0.117 mol). This mixture was allowed to warm to room temperature, stirred for an additional 2 hours and then poured onto ice / 50% NaOH (total 500 mL). The mixture was extracted with ether (3 x 200 mL), the combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oily product which was converted to the hydrochloride. Recrystallization from isopropanol / methanol gave 5-nitro-2-aminoindan hydrochloride: (14.58 g, 60%); b. t.> 300 ° C.

b) 2- (5-Nitroindanyl) -N-trifluoroacetamide

To a stirred solution of 5-nitro-2-aminoindan hydrochloride (1.00 g, 5.89 mmol) and triethylamine (0.82 mL, 5.89 mmol) in methylene chloride (50 mL) was added dropwise trifluoroacetic anhydride (0.83 mL). , 5.89 mmol). After stirring for 1 minute, the mixture was poured into water and extracted with methylene chloride (3 x 20 mL). The combined extracts were then washed with water, dried over magnesium sulfate and filtered through a short pad of silica gel (20% ethyl acetate / hexane) to give 2- (5-nitroindanyl) -N-trifluoroacetamide: (1.51 g, 93%); b. t. 153-154 [deg.] 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. This mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to give 2- (5-Aminoindanyl) -N-trifluoroacetamide homogeneous by TLC and used immediately in the next reaction step.

d) N - ((2-Amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate

To a solution of 2- (5-ammoindanyl) -N-trifluoroacetamide (0.52 g, 2.25 mmol) in isopropanol (6 mL) and DMF (0.5 mL) was added S-methyl-2-thiophenothiocarboxymide hydroiodide ( 0.64 g, 2.25 mmol). The mixture was stirred for 14 h, diluted with methanol (6 mL) and 2N NaOH (6 mL) and heated at 50 ° C for 0.5 h. The 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 / melylene chloride) to give the title compound as the free base. Treatment with IPA / oxalic acid gave N - ((2-amino) indan-5-yl) -2-thiophenecarboximidamide dioxalate as a white solid: (0.60 g, 50%); b. t. decomposition 70 ° C.

Example 6 N - ((2-) Methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dihydrobromide

a) 5-Nitro-2- (phenylmethyl) aminoindan hydrochloride

To 5-nitro-2-aminoindan hydrochloride (3.00 g, 14.00 mmol) in DMF (60 mL) was added triethylamine (4.07 mL, 29.40 mmol) followed by benzyl bromide (1.74 mL, 14 mL). , 68 mmol). The mixture was stirred at room temperature for 1 hour, poured into water (200 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a short pad of silica gel, and concentrated to a syrup. The subtitle compound was obtained as the hydrochloride: (2.29 g, 54%); b. t. decomposition 266 ° C.

b) 5-Nitro-2- (methyl) (phenylmethyl) aminoindan hydrochloride

To 5-nitro-2- (phenylmethyl) aminoindan hydrochloride (2.29 g, 7.52 mmol) in DMF was added potassium carbonate (2.60 g, 18.80 mmol) followed by methyl iodide (0.47 mL, 7 mL). 52 mmol). This mixture was warmed to room temperature, stirred for 16 hours, poured into water (400 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a short pad of silica gel, and concentrated to a syrup. The title compound was obtained as the hydrochloride: (1.08 g, 45%); b. t. decomposition 280 ° C.

c) 5-Amino-2- (methyl) (phenylmethyl) aminoindanediol hydrochloride

To 5-nitro-2- (phenylmethyl) aminoindan hydrochloride (1.08 g, 3.39 mmol) in 85% acetic acid in water was added zinc powder (3.0 g). The mixture was stirred for 1 minute, filtered through celite and concentrated. The resulting concentrate was 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 a syrup. IPA / HCl was added to the obtained oily product, the reaction mixture was concentrated and used in the next reaction 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 S-methyl-2-thiophenethiocarboximide hydroiodide (0.98 g, 3.45 mmol) and pyridine (0, 2-thiophenothiocarboximide hydroiodide). 27 ml, 3.29 mmol). The mixture was stirred for 14 h, poured into water 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 chromatographed on silica gel (10% methanol / methylene chloride) to give the title compound as the free base. Treatment with IPA / oxalic acid gave N - ((2-) methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide dihydrobromide as a white solid: (0.43 g, 25%); b. Mp 1.196-200 ° C.

Example 7

N - ((1-amino) indan-6-yl) -2-thiophenecarboximidamide dihydrochloride

a) 6-Nitro-1-aminoindan hydrochloride

1-Aminoindane (10.0 g, 75.08 mmol) was added to concentrated sulfuric acid (40 mL) at 0 ° C. This mixture was allowed to warm to room temperature to aid dissolution and then cooled to 0 ° C. Potassium nitrate (7.60 g, 75.08 mmol) was added portionwise and the mixture was stirred at room temperature for 1 hour, then poured onto ice with 50% NaOH. The resulting aqueous solution was extracted with chloroform (3 x 100 mL). The combined extracts were washed with water, decolourised with charcoal, dried with magnesium sulfate, filtered and concentrated to an oily product. Treatment with IPA / HCl gave the title compound: (6.90 g, 43%); b. mp: decomposition 280 ° C.

SK 281442-6

b) 6-Amino-1-aminoindan hydrochloride

To a solution of 6-nitro-1-aminoindan hydrochloride (1.00 g, 4.66 mmol) in MeOH (100 mL) was added a catalytic amount of 10% Pd / C. This mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite, and concentrated. 6-Amino-1-aminoindan hydrochloride was obtained which was homogeneous by TLC and used immediately in the next reaction step.

c) N - ((1-amino) indan-6-yl) -2-thiophenecarboximidamide dihydrochloride

To 6-amino-1-aminoindan hydrochloride (0.74 g, 4.01 mmol) in DMFA / IPA (4 mL, 1: 1) was added S-methyl-2-thiophenethio carboximide hydroiodide (1.26 g, 4, 41 mmol). This mixture was heated to 50 ° C, stirred for 16 hours, poured into water 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 oily product. Treatment with IPA / oxalic acid gave N - ((1-amino) indan-6-yl) -2-thiophenecarboximidamide dihydrochloride as a white solid: (0.79 g, 60%) b. decomposition> 200 ° C.

Example 8 N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide dioxalate

a) 6-Nitro-1- (phenylmethyl) aminoindan hydrochloride

To 6-nitro-1-aminoindan hydrochloride (1.90 g, 8.85 mmol) in DMF (30 mL) was added triethylamine (2.50 mL, 18.06 mmol) followed by benzyl bromide (1.07 mL, 9, 03 mmol). This mixture was warmed to room temperature, stirred for 3 hours, poured into water (100 mL) and extracted with ethyl acetate (3 x 70 mL). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a short pad of silica gel, and concentrated to an oil. The title compound was isolated as the hydrochloride: (1.34 g, 50%); b. t. Mp 234-235 ° C.

b) 6-Amino-1- (phenylmethyl) aminoindan hydrochloride

To 6-nitro-1- (phenylmethyl) aminoindan hydrochloride (1.34 g, 4.40 mmol) in MeOH (100 mL) was added a catalytic amount of 10% Pd / C. This mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite, and concentrated. 6-Amino-1- (phenylmethyl) aminoindan hydrochloride was obtained which was homogeneous by TLC and used immediately in the next reaction step.

c) N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide dioxalate

To 6-amino-1- (phenylmethyl) aminoindan hydrochloride (1.21 g, 4.40 mmol) in DMF (20 mL) was added S-methyl-2-thiophenethiocarboximide hydroiodide (1.38 g, 4.84 mmol). This mixture was heated at 50 ° C for 16 h, poured into water 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 oily product. Treatment with IPA / oxalic acid gave N - ((1- (phenylmethyl) amino) indan-6-yl) -2-thiophenecarboximidamide dioxalate as a white solid: (1.06 g, 46%); b. decomposition> 120 ° C.

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-nitroindan hydrochloride (1.5 g, 7.0 mmol) in methylene chloride (50 mL) at 0 ° C was added triethylamine (2.1 mL, 15.0 mmol) followed by 3-chlorobenzoyl chloride ( 1.0 ml, 7.5 mmol). This 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 oily product, which was homogeneous by TLC and used immediately in the next step: Mass. (M + H) < ^{+ &gt}; = 317.

b) 2 - ((3-Chlorophenyl) methyl) amino-6-nitroindane

To 2 - ((3-chlorophenyl) carbonyl) amino-6-nitromdan (2.2 g, 7.0 mmol) in THF (75 mL) was added dropwise BH ₃ .THF (1.0 M, 35 mL, 35 mmol). The mixture was heated to reflux for 12 hours, cooled to 0 ° C, 4N HCl (60 mL) was added and the mixture was refluxed for 1 hour. The resulting solution was evaporated to an oily product, basified with 50% NaOH and extracted with methylene chloride (3 x 20 mL). The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to an oil. Treatment with IPA / HCl gave 2 - ((3-chlorophenyl) methyl) amino-6-nitroindane: (2.1 g, 88% over two steps); mp 234-237 ° C.

c) 2 - ((3-Chlorophenyl) methyl) amino-6-aminoindan

To 2 - ((3-chlorophenyl) methyl) amino-6-nitroindan hydrochloride (2.1 g, 6.13 mmol) in 85% AcOH / H ₂ O (40 mL) was added zinc metal (1.6 g, 24 mL). , 5 mmol). The mixture was stirred for 5 minutes, filtered through celite and concentrated to 0. The 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. Treatment with IPA / HCl gave 2 - ((3-chlorophenyl) methyl) amino-6-aminoindan: (1.5 g, 70%); mp > 270 ° C.

d) N - ((2 - ((3-Chlorophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine

A mixture of 2 - ((3-chlorophenyl) methyl) amino-6-aminoindanedihydrochloride (1.5 g, 4.2 mmol), S-methyl-2-thiophenethiocarboximide hydroiodide (1.3 g, 4.6 mmol) and pyridine (0). (34 mL, 4.2 mmol) in DMF (10 mL) was stirred for 24 hours. The mixture was then poured into water, basified 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 chromatographed on silica gel (12% methanol / methylene chloride) to give a colorless oil. Treatment with IPA / HCl gave N - ((2 - ((3-chlorophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxymidine: (0.75 g, 40%); b. t. 297-299 ° C.

Example 10

Following the procedure of Example 9, the following compounds were prepared:

a) N - ((2 - ((2-Methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine: b. t.l83 C

b. N - ((2 - ((3-Methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine: b. mp 195 ° C

c) N - ((2 - ((4-Methylphenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine: b. 1.182 ° C

d) N - ((2 - ((Ethyl) amino) indan-5-yl) -2-thiophenecarboxamidine: mp 236-238 ° C)

e) N - ((2 - (((4-Phenyl) phenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine: b. 1.182 ° C

f) N - ((2 - (((4-Hexyl) phenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine: b. mp 125 ° C

g) N - ((2 - ((3-Bromophenyl) methyl) amino) indan-5-yl) -2-thiophenecarboxamidine: b. 1.182 ° C

Príkladll

N - ((2 - ((3-Chlorophenyl) methyl) amino) -1,2,3,4-tetrahydro-7-yl-2-thiophenecarboximidamide

a) 7-Nitro-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene

A mixture of 7-methyl-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 A molecular sieve (20 mL), THF (15 mL) and MeOH (15 mL) were charged to a flask and cooled to 0 ° C. To this mixture, sodium cyanoborohydride (0.99 g, 15.7 mmol) was added portionwise over 5 minutes. The mixture was stirred for 14 hours, filtered through celite and concentrated to a syrup. It was then basified 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 a colorless oil. Treatment of the oil with IPA / HCl gave 7-nitro-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene hydrochloride: (1.34 g, 50%); weight. Spectra. (M + H) < ^{+ &gt}; = 317.

b) 7-Amino-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene

To 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) was added. The 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 oily product. Treatment with IPA / HCl gave 7-amino-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene (1.4 g, 99%); weight. Spectra. (M + H) < ^{+ &gt}; = 288.

c) N - ((2 - ((3-Chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl-2-thiophenecarboximidamide

A mixture of 7-amino-2 - (((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphthalenedihydrochloride (1.32 g, 3.70 mmol), S-methyl-2-thiophenethiocarboximide hydroiodide (1.3 g) , 4.6 mmol) and pyridine (0.30 mL, 3.7 mmol) in DMF (15 mL) were stirred for 24 hours. This mixture was then poured into water, basified 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 oily product. Treatment with IPA / oxalic acid gave N - ((2 - ((3-chlorophenyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl-2-thiophenecarboximidamide dioxalate: (0.71 g, 33%), decomposition above 100 ° C.

Example 12 N - ((2- (Phenylmethyl) methyl) amino) -1,2,3,4-tetrahydronaphth-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 DMF (30 mL) was added potassium carbonate (1.5 mL). g, 10.8 mmol) and methyl iodide (0.36 mL, 5.8 mmol). The 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 oily product. Treatment with IPA / HCl gave 7-nitro-2 - ((phenylmethyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene hydrochloride: (0.89 g, 50%); Mass spec. (M + H) < ^{+ &gt}; = 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 metal zinc (3.5 g, 54.0 mmol). The mixture was stirred for 5 minutes, filtered through celite and evaporated to an oily product. This oily product 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 oily product. Treatment with IPA / HCl gave 7-amino-2 - ((phenylmethyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene: (0.81 g, 88%); weight. Spectra. (M + H) < ^{+ &gt}; = 267.

c) N - ((2- (Phenylmethyl) methyl) amino) -1,2,3,4-tretrahydronaphth-7-yl-2-thiophenecarboxymidamide

A mixture of 7-amino-2 - ((phenylmethyl) methyl) amino) -1,2,3,4-tetrahydronaphthalene dihydrochloride (0.81 g, 2.4 mmol), S-methyl-2-thiophenethiocarboximide hydroiodide (0.74 g, 2.6 mmol) and pyridine (0.19 mL, 2.4 mmol) in DMF (15 mL) were stirred for 24 hours. Then the mixture was poured into water, basified with 2N NaOH and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed on silica gel (15% MeOH / methylene chloride). Concentration of the fraction gave a solid which, after recrystallization from ethyl acetate / hexane, gave N - ((2-phenylmethyl) methyl) amino) -1,2,3,4-tetrahydronaphth-7-yl-2-thiophenecarboximidamide dihydrochloride: (0, 14 g, 16%); b. t. M.p. 176-178 ° C.

Example 13

N - ((1- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-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) were mixed and stirred for 1 day. hours. This mixture was then diluted with absolute ethanol (12 mL), sodium cyanoborohydride (0.44 g, 7.0 mmol) was added and stirred for 20 hours. The solid (soilds) was filtered off and washed with ethanol. The ethanol portion was concentrated and the remaining oily product was used immediately in the next reaction: wt. (M + H) < ^{+ &gt}; = 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, 10.50 mmol) and diethylamine (1.46 mL, 10.50 mmol) in methylene chloride (50 ml) was added dropwise trifluoroacetic anhydride (1.46 ml,

10.50 mmol). After stirring for 1 minute, the mixture was poured

The reaction mixture was extracted with methylene chloride (3 x 20 ml). The combined extracts were washed with water, dried over magnesium sulfate and filtered through a short pad of silica gel (20% ethyl acetate / hexane) to give 1- (7-nitro (1,2,3,4-tetrahydronaphthyl)) - N- (phenylmethyl) trifluoroacetamide (1.90 g, 48%, two steps); weight. Spectra. (M + H) < ^{+ &gt}; = 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) a catalytic amount of 10% Pd / C was added. This mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to give 1- (7-amino (1,2,3,4-tetrahydronaphthyl)) - N - (phenylmethyl) trifluoroacetamide, which was homogeneous by TLC and used immediately in the next reaction step.

d) N - ((1-Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-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 isopropanol (10 mL) was added S-methyl -2-thiophenethiocarboximide hydroiodide (1.44 g, 5.05 mmol). The resulting mixture was stirred for 14 h then diluted with methanol (6 mL) and 2N NaOH (6 mL) and heated to 50 ° C for 0.5 h. Then the 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 oily product. Treatment with IPA / HBr gave N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide dihydrobromide as a white solid: (0.53 g, 20% ); b. mp 260-262 ° C.

Example 14

N - ((1- (Phenylmethyl) amino) indan-5-yl) -2-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) were mixed and stirred for 1 day. hours. The resulting mixture was diluted with absolute ethanol (30 mL), treated with sodium cyanoborohydride (1.2 g, 19.3 mmol) and stirred for 20 hours. The solid was filtered and washed with ethanol. The ethanol was concentrated and the remaining oil was dissolved in ethyl acetate and extracted with 1N HCl (3 x 50 mL). The aqueous layer was 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 evaporated to give an oily product 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 was refluxed with 4N HCl (50 mL) for 20 minutes, then cooled and extracted with ethyl acetate (3 x 50 mL). The aqueous layer was 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 oily product. This oil was dissolved in IPA and treated with IPA / HCl to afford the dihydrochloride: (2.0 g, 24% over two steps); b. decomposition above 250 ° C.

c) N - ((1- (Phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide

To 6-amino- (1 - ((phenyl) methyl) amino) indane dihydrochloride (2.0 g, 6.4 mmol) in DMF (20 mL) was added S-methyl-2-thiophenethiocarboximide 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, then poured into alkaline 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 were concentrated to an oily product, which was then dissolved in methanol, IPA / HCl and ether were added. The solids were collected by filtration and washed with ether: (1.1 g, 40%); b. decomposition above 180 ° C.

Example 15

The following compound was prepared according to the method of Example 14;

N - ((1- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-6-yl) -2-thiophenecarboximidamide: b. decomposition above 200 ° C.

Example 16

N - ((2- (phenylmethyl) amino) -1,2,3,4-tetrahydronaphthalen-7-yl) -2-furancarboximidamide

a) 2 - ((Phenyl) carbonyl) amino-7-nitrotetralin

To 2-amino-7-nitrotetralin (2.8 g, 14.5 mmol) in THF (50 mL) and 10% potassium carbonate solution (100 mL) was added benzoyl chloride (1.7 mL, 15.3 mmol). After the addition was complete, the reaction mixture was diluted with water to a volume of 250 mL. The precipitated solids were collected by filtration, washed with water and dried in vacuo: (4.2 g, 98%), b. t. Mp 194-198 ° C.

b) 2 - ((Phenyl) methyl) amino-7-metrotetraldehyde hydrochloride

To 2 - ((phenyl) carbonyl) amino-7-nitrotetralin (4.2 g, 14.1 mmol) in anhydrous THF (100 mL) was added borane-THF (49.3 mL, 1M THF, 49.3 mmol). ). The mixture was heated to reflux for 5 hours, cooled to 0 ° C and quenched by the dropwise addition of 4N HCl. The mixture was then refluxed for 1 hour, concentrated in vacuo and the solid was filtered (washed with water) and dried in vacuo: (3.5 g, 78%), b. t. above 300 ° C.

c) 2 - ((Phenyl) methyl) amino-7-aminotetraline 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. This reaction mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to an oily product which was homogeneous by TLC and used immediately in the next reaction step.

d) N - ((2- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-furancarboximidamide

To 2 - ((phenyl) methyl) amino-7-aminotetraline hydrochloride (1.8 g, 6.3 mmol) in DMF (20 mL) was added S-methyl-2-furanthiocarboximide hydroiodide (2.0 g, 7.5 mmol). The mixture was stirred for 2 hours at 45 ° C, then poured into alkaline 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 oily product. The oil obtained was dissolved in methanol, IPA / HCl and ether were added. The solids were collected by filtration and washed with ether: (2.2 g, 84%), b. mp: decomposition above 195 ° C.

Preparation of Chiral Intermediates for Examples 17 and 18

Cleavage of 2-amino-7-nitrotetralin

2-Amino-7-nitrotetraline (30 g, 156 mmol) dissolved in 200 ml acetone was added to dibenzoyl-D-tartaric acid (58.7 g 164 mmol) also dissolved in 200 ml acetone. The thick paste obtained was filtered and washed with acetone. This paste was refluxed with 3 L water / ethanol / acetonitrile (1: 1: 1) and then filtered hot. The solid obtained by filtration was recrystallized from the above solvent mixture (3x): (5.25 g, 6%) of one isomer was obtained as shown by chiral capillary zone electrophoresis, b. t. Mp 240-242 ° C.

Similarly, dibenzoyl-L-tartaric acid could be used to obtain the opposite enantiomer using the same solvent system described above: (5.3 g, 6%) of one isomer was obtained as shown by chiral capillary zone electrophoresis, b. mp 240-242 ° C.

Example 17 (+) - N - ((2- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide

a) (+) - 2 - ((Phenyl) carbonyl) amino-7-nitrotetralin

To 2-amino-7-nitrotetraline (1.8 g, 9.39 mmol, obtained via dibezoyl-D-tartaric acid) in THF (50 mL) and 10% potassium carbonate solution (100 mL) was added benzoyl chloride (1, 2 ml, 10.1 mmol). After the addition was complete, the reaction mixture was diluted with water to a volume of 250 mL. The precipitated solids were collected by filtration, washed with water and dried in vacuo: (2.8 g, 100%), mp 208-209 ° C, [α] _D + 21.9 (c 0.33 DMSO).

b) (+) - 2 - ((Phenyl) methyl) amino-7-nitrotetraline hydrochloride

To (+) - 2 - ((phenyl) carbonyl) amino-7-nitrotetralin (2.8 g, 9.4 mmol) in anhydrous THF (100 mL) was added borane-THF (32.8 mL, 1M THF, 32.8 mmol). The mixture was heated to reflux for 5 hours, cooled to 0 ° C and quenched by dropwise addition of 4N HCl. The mixture was then refluxed for 1 hour, evaporated in vacuo and the solid filtered off (washed with water) and dried in vacuo: (2.8 g, 94%), mp above 300 ° C, [a] _D +51.0 (c 0.33 DMSO).

c) (+) - 2 - ((Phenyl) methyl) amino-7-aminotetraline 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 reaction mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to a solid glassy product which was homogeneous by TLC; [α] _D +73.3 (c 0.87 DMSO).

d) (+) - N - ((2- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide

To (+) - 2 - ((phenyl) methyl) amino-7-aminotetraline hydrochloride (2.5 g, 8.7 mmol) in DMF (20 mL) was added S-methyl-2-thiophenethiocarboximide hydroiodide (3.0 g, 10.4 mmol). The mixture was stirred for 4 hours at 45 ° C, then poured into alkaline 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 oily product. The oil obtained was dissolved in methanol, IPA / HCl and ether were added. The solids were collected by filtration and washed with ether. Recrystallization from IPA / MeOH / Et ₂ O gave a white solid:

(2.5 g, 66%), bt: decomposition above 260 ° C, [α] _D +44.5 (c 0.62 DMSO).

Example 18 (-) - N - ((2- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide

a) (-) - 2 - ((Phenyl) carbonyl) amino-7-nitrotetralin

To 2-amino-7-nitrotetralin (1.8 g, 9.39 mmol, obtained via dibenzoyl-L-tartaric acid) in THF (50 mL) and 10% potassium carbonate solution (100 mL) was added benzoyl chloride (1, 2 ml, 10.1 mmol). After the addition was complete, the reaction mixture was diluted with water to a volume of 250 mL. The precipitated solids were collected by filtration, washed with water and dried in vacuo: (2.8 g, 100%), mp 208-209 ° C, [α] _D -24.0 (e 0.87 DMSO).

b) (-) - 2 - ((Phenyl) methyl) amino-7-nitrotetraline hydrochloride

To (-) - 2 - ((phenyl) carbonyl) amino-7-nitrotetralin (2.8 g, 9.4 mmol) in anhydrous THF (100 mL) was added borane-THF (32.8 mL, 1M THF, 32.8 mmol). The mixture was heated to reflux for 5 hours, cooled to 0 ° C and quenched by dropwise addition of 4N HCl. The mixture was then refluxed for 1 hour, evaporated in vacuo and the solid filtered off (washed with water) and dried in vacuo: (2.8 g, 94%), mp above 300 ° C, [a] _D -50.4 (c 0.39 DMSO):

c) (-) - 2 - ((Phenyl) methyl) amino-7-aminotetralin 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 reaction mixture was hydrogenated at 50 psi (1 psi = 0.689 x 10 ⁴ Pa) for 1 hour, filtered through celite and concentrated to a solid glassy product which was homogeneous by TLC; [α] _D +74.6 (c 0.80 DMSO).

d) (-) - N - ((2- (Phenylmethyl) amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide

To (-) - 2 - ((phenyl) methyl) amino-7-aminotetraline hydrochloride (2.5 g, 8.7 mmol) in DMF (20 mL) was added S-methyl-2-thiophenethiocarboximide hydroiodide (3.0 g, 10.4 mmol). The mixture was stirred for 4 hours at 45 ° C, then poured into alkaline 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 oily product. The obtained oil was dissolved in methanol, IPA / HCl ether was added. The solids were collected by filtration and washed with ether. After recrystallization from a solvent mixture of IPA / MeOH / Et ₂ O a solid was obtained: (2.7 g, 71%), mp: decomposition above 260 ° C, [α] _D -44.5 (c 0.57 DMSO) ).

Example 19 N- (2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl) thiophene-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 ethanol (100 mL) was added 5% palladium on carbon (0.2 g). ), the solution was placed in a Paar hydrogenation apparatus and 45 psi hydrogen (1 psi = 0.689.10 ⁴ Pa) was admitted. After reaching the theoretical consumption of hydrogen (2 h), the catalyst was filtered off and washed with water (25 ml). The filtrate was evaporated. Then absolute ethanol was added and the reaction mixture was evaporated to evaporate

SK 281442-6

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 carbon (3.0 g) in decalin (75 mL) was heated at reflux for 3 hours. After cooling, the solution was filtered and the catalyst was washed with chloroform (200 mL). After distilling off the solvent in vacuo, 7-nitroisoquinoline was obtained as a tan solid. MS: 175 ([M + H]).

b) Isoquinolin-7-amine

7-Nitroisoquinoline (1.62 g, 9.25 mmol) in ethanol (150 mL) was hydrogenated in a Paar hydrogenation apparatus with a 5% palladium on carbon catalyst (0.2 g) for 3 hours at 50 psi ( 1 psi = 0.689.10 ^{I * * 4} Pa). The reaction mixture was then filtered and the solvent was evaporated under reduced pressure. Recrystallization of the solid in ethanol (3 mL) gave isoquinolin-7-amine (0.98 g) as a tan solid. MS 145 (M + H), NMR (CDCl 3) 9.02 (s, 1H), 8.29 (d, 1H), 7.63 (d, 1H), 7.47 (d, 1H), 13 (dd, H), 7.03 (d, 1H), 4.00 (broad, 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-thiophenethiocarboximide (2.42 g, 8.36 mmol) in isopropanol (4 mL) and DMF (4 mL) was stirred for 18 hours. This solution was then poured into dilute sodium hydroxide and extracted with methylene chloride. The extract obtained was dried over magnesium sulfate and the solvent was evaporated to give an oily product which solidified on standing. The material was purified by silica gel column chromatography (5% methanol in chloroform saturated with ammonia gas) to give 1.31 g of a solid. This material was recrystallized from ethyl acetate (25 mL) to give 1.05 g of the title compound as an off-white product. B. t. 177.5-178.5 ° C.

Claims (18)

PATENT CLAIMS 1. A bicyclic amidine derivative of the general formula (I) I Ti — NIí D (I), where D represents a five membered heterocyclic aromatic ring containing from 1 to 4 heteroatoms selected from O, N or S, optionally substituted on a carbon atom by halogen, trifluoromethyl, C1-6 alkyl, nitro or cyano, and which is attached to the remainder of the compound of formula ( I) through a carbon atom; A is N (X) or CH (-CH ₂ ) _m -NXY); U represents NH, O or _CH2; W represents (CH _{2) a;} W is (CH ₂ ) b; a and b independently represent integers from 0 to 3, provided that a + b is in the range of 1 to 3; X and Y independently represent hydrogen, alkyl Cl to 6, or - _(CH2) "Q, or NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl; Q represents biphenyl or phenyl optionally substituted with one or more groups selected from alkyl groups C1-6, alkoxy C1-6, perfluoroalkyl C1-6, halogen, nitro- or cyano-; m is an integer from 0 to 5; n is an integer from 0 to 6; or the chain U-V-A-W is already defined, but may be unsaturated; UVAW or chain-chain can be represented by _{-NH-CH2 -CH2} -O- substituted at a carbon atom with - (CH _{2) m} NXY, wherein m, X and Y are defined as above, and the corresponding pharmaceutically acceptable salts and enantiomers of said of these compounds. A compound of formula (I), according to claim 1, having the structure defined by formula (IA): D (IA), where T represents C ₃ . _A saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m -NXY; -O (CH ₂ ) ₂ -NHsubstituted - (CH ₂ ) _m -NXY; or -U- (CH ₂ ) _and -N (X) - (CH ₂ ) b -; X and Y independently represent hydrogen, alkyl Cl to 6, or - _(CH2) "Q, or NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl; Q is phenyl, optionally substituted with C1-6 alkyl, C1-6 alkoxy, trifluoromethyl, halogen, nitro or cyano; and U, m, n, a, b and D are as defined above, but provided that when T is -U- (CH ₂ ) _and -N (X) - (CH ₂ ) _b and X is - (CH ₂ ) "Q, n represents an integer between 0 and 5, ₄ . and the pharmaceutically acceptable salts and enantiomers thereof. A compound of formula (I) according to claim 2, wherein T is C ₃ . _A saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m -NXY; or -O _{(CH2) 2} -NH- substituted by - (CH _{2) m} NXY; and X and Y independently represent hydrogen, alkyl Cl to 6 or - _(CH2) "Q. A compound of formula (I), according to claim 2 or claim 3, wherein T is C ₃ . ₅ saturated or unsaturated alkylene chain substituted with - (CH ₂ ) _m -NXY. A compound of formula (I) according to any one of claims 1 to 4, wherein m is 0 or 1. A compound of formula (I), according to claim 2, wherein T represents -U-CH _{2 N 1} X 1 -CH 3, and X represents hydrogen, C 1-6 alkyl, or - (CH ₂ ) _n Q. A compound according to claim 2 or claim 6 wherein T represents -U- (CH ₂ ) _and -N (X) - (CH ₂ ) b - and U represents CH ₂ . A compound according to claim 2, 6 or 7, wherein T represents -U- (CH ₂ ) _and -N (X) - (CH ₂ ) _b - and a + b are 1 or 2. A compound according to any one of the preceding claims wherein n is 0, 1 or 2 and X and / or Y is - (CH ₂ ) n Q. A compound according to any one of the preceding claims, wherein X and / or Y is - (CH ₂ ) n Q and Q is phenyl, optionally substituted with C1-6 alkyl or halogen. A compound of formula (I) according to any one of the preceding claims, wherein D represents a five membered heterocyclic ring containing one heteroatom selected from O, N or S, optionally substituted on a carbon atom by halogen. A compound of formula (I) according to claim 11, wherein D is thienyl, pyrrolyl or furyl. A compound of formula (I) according to claim 12, wherein D is 2-thienyl. A compound of formula (I) which is: N - ((2- (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide N - ((2- (phenylmethyl) amino) -1,2,3) , 4-tetrahydro-7-yl) -2-thiophenecarboximidamide; N - ((2-amino) -l, 2,3,4-tetrahydro-7-yl) -2-thiophenecarboximidamide; N - ((1-amino) -1,2,3,4-tetrahydronaphth-7-yl) -2-thiophenecarboximidamide; N - ((2-amino) indan-5-yl) -2-thiophenecarboximidamide; N - ((2- (methyl) (phenylmethyl) amino) indan-5-yl) -2-thiophenecarboximidamide; N - ((1-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-thiophenecarboximidamide; N - ((2- (Ethyl) amino) indan-5-yl) -2-thiophenecarboxamidine; N - ((2 - (((4-phenyl) 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) -l, 2,3,4-tetrahydro-7-yl) -2-thiophenecarboximidamide; N - ((2- (phenylmethyl) (methyl) amino) -1,2,3,4-tetrahydro-7-yl) -2-thiophenecarboximidamide; N - ((l- (phenylmethyl) amino) -l, 2,3,4-tetrahydronaphthalen-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) -l, 2,3,4-tetrahydro-7-yl) -2-íuránkarboximidamid; N- (2,3,4,5-tetrahydro-3-benzazepin-7-yl) thiophene-2-carboximidamide; N- (l, 2,3,4-tetrahydroisoquinolin-7-yl) thiophene-2-carboximidamide; N- (2-benzyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) thiophene-2-carboximidamide; N- (1,2,3,4-tetrahydroisoquinolin-5-yl) -thiophene-2-carboximidamide; N- (1,2,3,4-tetrahydroisoquinolin-6-yl) -thiophene-2-carboximidamide; N- (isoquinolin-7-yl) thiophene-2-carboximidamide; or a pharmaceutically acceptable salt or enantiomer thereof. A compound according to any preceding claim for use as a pharmaceutical preparation. 16. A process for the preparation of a compound of formula (I), comprising: a) preparing a compound of formula (I) by reacting a corresponding compound of formula (II) wherein U, V, A and W are as defined in claim 1, with a compound of formula (III) r z (III), wherein D is as defined in claim 1 and L is a leaving group; b) preparing a compound of formula (I) by reacting a corresponding compound of formula (IV) (IV), wherein U, V, A and W are as defined in claim 1 and HA is acid, with a compound of formula (V) D- (V) wherein D is as defined in claim 1; c) a compound of formula (I) in which A represents N (X) and X represents alkyl C1 to 6 or - (CH _{2) n} Q by reacting a corresponding compound of formula (1) wherein X is hydrogen with a compound of formula (VI) R ⁹ L (VI), wherein R 1 is C 1-6 alkyl or - (CH ₂ ) _n Q and L is a leaving group; d) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY) and at least one X or Y is C 1-6 alkyl or - (CH ₂ ) _n Q, by reacting the corresponding compound of formula (I) wherein one or both of X and Y is hydrogen with a compound of formula VI; e) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY) and _m is an integer from 1 to 5, by reducing the corresponding compound of formula (VII) I XYNCOíCHj) ^! - HC .. (VII), wherein U, V, W, X, Y and D are as defined in claim 1; f) a compound of formula (I) in which A represents CH (- (CH _{2) m} NXY) and both X and Y represent hydrogen, by reduction of a corresponding compound of formula (VIII) OjN-CHAN- ^H (VIII), Wherein U, V, W, m and D are as defined in claim 1; g) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY), X is hydrogen and _m is an integer from 1 to 5, by reducing the corresponding compound of formula (IX) Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prophylaxis of neurodegenerative diseases, migraine or the prevention and alteration of tolerance to opiates and diazepines or for the treatment of drug addictions. Y-N'CHCCHJm.r ^- NH 2 = NH D End of document (IX), wherein U, V, W, D and Y are as defined in claim 1; h) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _{r and} -NXY), X or Y is hydrogen and the second is - (CH ₂ ) n - wherein n is an integer from 1 to 6, reducing the corresponding compound of formula (X) ^H (X), wherein Q, m, U, V, W and D are as defined in claim 1; (i) preparing a compound of formula (I) wherein A is CH (- (CH ₂ ) _m -NXY), X or Y is hydrogen and the other is - (CH ₂ ) n - wherein n is an integer from 1 to 6, by reducing the corresponding compound of formula (XI) (XI) wherein Q, m, U, V, W and D are as defined in claim 1; or j) preparing a compound of formula (I) wherein A is CH (-NXY) and X is hydrogen by reduction of the corresponding compound of formula (XII) (ΧΠ), where U, V, W, D and Y are as defined in Claim 1; and if desired or necessary converting the resulting compound of formula (I) or another salt thereof into a pharmaceutically acceptable salt thereof, or vice versa. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 14 together with a pharmaceutically acceptable diluent or carrier. Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions to which the synthesis or over-synthesis of NO-synthase contributes.