FR2791677A1 - New imino- or pyridyl-substituted lipoic acid derivatives, as nitrogen monoxide synthase inhibitors and antioxidant regenerating agents, useful e.g. for treating nervous system or cerebrovascular disorders or cancer - Google Patents

Abstract

Imino- or pyridyl-substituted lipoic acid derivatives (Ia) or (Ib) are new. Imino- or pyridyl-substituted lipoic acid derivatives of formulae (Ia) or (Ib) and their salts are new. R1, R2 = H or D'; or R1+ R2 = direct bond; D' = 1-6C alkyl; A = (CH2)mN(R3)CO(CH2)n, (CH2)mCON(R3)(CH2)n, (CH2)mN(R3)(CH2)n, (CH2)mCON(R3)(CH2)p-N(R4)(CH2)n, (CH2)mN(R3)CON(R4)(CH2)n or (CH2)m; m, n = 0-6; p = 2-6; R3, R4 = H or D'; X = phenylene or phenylene-alkylene group of formula -C6H3(R5)-T-; or (CH2)q; T = (CH2)i, T being attached to Y'; R5 = H, D', -(CH2)mQ or 5- or 6-membered heterocycle (containing O, N(R6) or S); i, q = 0-6; Q = halo, OH, CN, NH2, alkoxy, alkylthio, alkylamino or dialkylamino; R6 = H, D' or the bond to the phenyl ring; Y' = -N=C(B)-NH2 or R7-substituted 2-aminopyridinyl; B' = D', NR8R9, SR10 or 5- or 6-membered aryl or 5-or 6-membered heteroaryl (containing 1-4 O, S and N, especially thiophene, furan, pyrrole or thiazole), both optionally substituted by D', 2-6C alkenyl or OD'; R8R9 = H or D'; or NR8R9 = 5- or 6-membered non-aromatic heterocycle in which the ring members are CH2, NH, O or S; R7, R10 = H or D'. Independent claims are included for the preparation of (Ia) or (Ib).

Description

New derivatives of lipolic acid, their preparation, their application to

  The subject of the present invention is novel derivatives of lipoic acid, which have an inhibitory activity on the NO-synthase enzymes producing NO nitric oxide and / or are agents allowing regeneration. antioxidants or trapping entities of reactive oxygen forms (ROS for "reactive oxygen species") and intervening more generally in the redox status of thiol groups. These antioxidants or trapping entities of reactive forms of oxygen can be of natural origin, such as for example vitamin E or glutathione, or of synthetic origin such as certain ROS trapping products or products exhibiting both an inhibitory activity NO synthases and a ROS trapping activity. Examples of such products of synthetic origin can in particular be found in the

  PCT patent applications WO 96/09653, WO 98/42696 and WO 98/58934.

  The invention therefore relates in particular to the derivatives corresponding to the general formula (I) defined below, their methods of preparation, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as inhibitors of NO-synthases and / or agents allowing the regeneration of antioxidants or trapping entities of ROS and intervening more generally in the status

redox of thiol groups.

  Given the potential role of NO, ROS and the metabolism of glutathione in pathophysiology, the new derivatives described corresponding to general formula (I) can produce beneficial or favorable effects in the treatment of pathologies o nitric oxide and glutathione metabolism as well as the redox status of the thiol groups are involved, and in particular: * cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, high blood pressure, septic shock, infarctions

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  ischemic or hemorrhagic heart or cerebral origin, ischemia and thrombosis; disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases where one can in particular cite the cerebral infarctions, the sub arachnoid hemorrhage, aging, senile dementias, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob's disease and prion diseases, amyotrophic lateral sclerosis but also pain, trauma to the brain or spinal cord, addiction to opiates, alcohol and addictive substances , erectile and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia ...); * skeletal muscle and neuromuscular junction disorders (myopathy,

  myositis) as well as skin diseases.

  * proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis , inflammation of the gastrointestinal system (colitis, Crohn's disease) or the pulmonary and airways (asthma, sinusitis, rhinitis) as well as

  contact or delayed hypersensitivities.

* organ transplants.

  * autoimmune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies.

* the cancer.

  * autosomal genetic diseases such as UnverrichtLunborg disease * neurological diseases associated with poisoning (Cadmium poisoning, inhalation of n-hexane, pesticide, herbicide), treatments

  (radiation therapy) or genetic disorders (Wilson's disease).

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  all pathologies characterized by production or dysfunction of nitric oxide and / or glutathione metabolism and the redox status of

thiol group.

  In all of these pathologies, there is experimental evidence demonstrating the involvement of nitric oxide or a dysfunction of glutathione metabolism (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med Chem. 38, 4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology & Medicine 19, 227-250, 1995). This is particularly the case in Parkinson's disease which illustrates the invention (Beal MF, Excitotoxicity and nitric oxide in Parkison's disease pathogenesis, Ann. Neurol. 44 [Suppl 1], S 110-S 114, 1998; Donato A and al., Gluthathione in Parkinson's disease: a link between oxidative stress and mitochondrial damage, Ann. Neurol. 32, S111-S115, 1992). In this context, drugs that can inhibit the formation of nitric oxide or restore the biological functionality of thiol groups or glutathione can provide

benefits.

  Furthermore, the inventors have already described in prior patents inhibitors of NO Synthases and their use (US Patents 5,081,148; US 5,360,925), and more recently the association of these inhibitors with products having antioxidant or anti-free radical properties (application PCT Patent WO 98/09653). They also described amidine derivatives in PCT patent applications WO 98/42696 and

  WO 98/58934 and derivatives of aminopyridines in a not yet published application.

  These amidine or aminopyridine derivatives have the particularity of being both

  NO Synthases inhibitors and ROS inhibitors.

  The subject of the present invention is new derivatives of lipoic acid, their

  preparation and their application in therapy.

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  The invention therefore relates to a product of general formula (I), characterized in that it comprises the products of sub-formulas (I) a and (I) b

<A-X-Y A-X-Y

  s -s SH SH (I) a (I) b in which A represents one of the radicals - (CH2) m-CONRI- (CH2) n-, - (CH2) m- NRI- (CH2) n, - (CH2) m-CONRI- (CH2) p-NR2- (CH2) n- or - (CH2) m-, m and n being integers between O and 6, p being an integer between 2 and 6, and R1 and R2 independently representing a hydrogen atom or a linear or branched alkyl radical of 1 to 6 carbon atoms; X represents a phenylene radical or - (CH2) q- in which q represents an integer between 0 and 6 and finally Y represents one of the radicals R5 B -N e_ "NH2 N NH2 or in which B represents a linear alkyl radical or branched having from 1 to 6 carbon atoms, 5 or 6-membered carbocyclic or heterocyclic aryl containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or B represents NR3R4, in which R3 and R4 independently represent a hydrogen atom or an alkyl radical linear or branched having from 1 to 6 carbon atoms, or one of R3 and R4 represents a nitro radical while the other represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 atoms carbon, or R3 and R4 taken together form with the nitrogen atom a heterocycle not

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  aromatic of five to six members, the elements of the chain being chosen from a group composed of -CH2-, -NH-, -O- or -S-, or else B represents a radical SR6 in which R6 represents an atom of hydrogen or a linear or branched alkyl radical having 1 to 6 carbon atoms, and R5 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;

  or a salt of a product of general formula (I).

  In particular, the invention relates to the following products described in the examples:

  - N- (4 - [[(2-thienyl) (imino) methyl] amino] phenyl} hydrochloride] phenyl} -1,2dithiolane-

3-pentanamide;

  - N- {(2- {4 [[(2-thienyl) (imino) methyl] amino] phenyl ethyl} -1,2dithiolane-

3-pentanamide;

  - N- (2- 4 [[((2-thienyl) (imino) methyl] amino] phenyl} ethyl) hydrochloride) -

  1,2-dithiolane-3-acetamide; - N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] 1,2-dithiolane-3-pentanamide;

  - N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] fumarate - 1,2-dithiolane3-acetamide.

  The invention further provides a number of methods for accessing the products of general formula (I) described above, methods whose preferred conditions are

described later.

  The invention therefore relates in particular to a process for the preparation of an amidine of general formula (I) as defined above, characterized in that one reacts

  the intermediary of general formula (II).

A-X -NH2

  dS lal ') -s in which A and X are as defined above,

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  with the intermediary of general formula (I.i) B L "NH (I.i) in which B is as defined above and L represents a leaving group, for example

  an alkoxy, thioalkyl, sulfonic acid, halide, aryl alcohol or tosyl radical.

  The invention also relates to a process for the preparation of a product of general formula (I) in which B is an amine, characterized in that the intermediate is reacted with general formula (II)

OA-X-NH

  (II) in which A and X are as defined above, a) with the intermediary of general formula (I.ii)

H2N NH

  (I.ii) in which L represents a leaving group, for example an alkoxy, thioalkyl, sulfonic acid, halide, aryl or tosyl alcohol, b) or with the intermediary of general formula (I. iii) L GpNL'NGp (I.iii) in which L represents a leaving group, for example an alkoxy, thioalkyl, sulphonic acid, halide, aryl or tosyl alcohol radical, and Gp a protective group of carbamate type, for example the t-butoxycarbonyl group, this reaction being followed, in the case where one opts for the reaction with the compound of general formula (I.iii), by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid,

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  c) or with the derivative of formula (I.iv) (N-methyl-N'-nitro-Nnitrosoguanidine) H

I I

02N "'N" -N'O

  NH (I.iv) d) or finally with the derivative of formula (Iv) in which Gp represents a protective group S = C = N-NGp (Iv) In certain cases, the compounds according to the present invention may contain atoms of asymmetric carbon, and therefore have two possible enantiomeric forms, that is to say the "R" and "S" configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the "RS" racemic mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and

their mixtures are shown.

  A subject of the invention is also, as medicaments, the compounds described above or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or their pharmaceutically acceptable salts for manufacturing medicaments intended to inhibit neuronal NO synthase or inducible NO synthase, to regenerate anti oxidants, which can be natural or synthetic) or to ensure the double function of inhibition of NO synthase

  and regeneration of antioxidants.

  The term “pharmaceutically acceptable salt” is intended to mean in particular addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate, oxalate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutical salts

  acceptable, reference may be made to "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977).

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  A subject of the invention is also the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product for manufacturing a medicament intended for treating pathologies in which nitric oxide and / or redox status of thiol groups are involved, pathologies such as disorders of the central or peripheral nervous system particularly well represented by Parkinson's disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, septic shock, pathologies resulting from irradiation radioactive, solar radiation or organ transplants, autoimmune and autosomal diseases, cancer and all pathologies characterized by a production or a dysfunction involving nitric oxide and / or involving the redox status of

thiol groups.

  Another subject of the invention is the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended for treating cerebrovascular disorders such as migraine, cerebral infarctions

  of ischemic or hemorrhagic origin, ischemia and thrombosis.

  A subject of the invention is finally the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product for manufacturing a medicament intended for treating disorders of the central or peripheral nervous system such as neurodegenerative diseases , pain, trauma to the brain or spinal cord, addiction to opioid drugs, alcohol and addictive substances, erectile and reproductive disorders, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, disorders

  sleep and eating disorders.

  The pharmaceutical compositions can be in the form of a solid, for example

  powders, granules, tablets, capsules, liposomes or suppositories.

  Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, the

polyvinylpyrrolidine and wax.

  The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their

  mixtures, in varying proportions, in water.

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  The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc. The administration dose envisaged for the medicament according to the invention is between

  0.1 mg to 10 g depending on the type of active compound used.

  In accordance with the invention, the compounds of general formula (I) can be prepared by

the process below.

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  A) Preparation of the compounds of general formula (I) o Y represents B

-N NH2

  The compounds of general formula (I) can be prepared from the intermediates of general formula (II) and (III) according to the scheme 1 o A, B, X and Y, are as defined

  above and Gp is a carbamate-type protecting group.

A-X-NGp (III)

A-X-NH 2 L

  (A - N H2NI NH (I.ii) S-S (I. IU @ GpN "NGP (I.iii

L. NHL

\ PN NG

L NH 2) H +

H I

A-X-Y N NIO (j.iv

(1) \ NH

  SS S == N-NGp (Iv) Scheme 1 The aniline and amine derivatives of general formula (II), can be condensed on compounds of general formula (Ii), in which L represents a leaving group (in in particular an alkoxy, thioalkyl, sulfonic acid, halide, aryl or tosyl alcohol radical), to lead to the final compounds of general formula (I) of substituted amidine type (cf. diagram 1). For example, for B = thiophene, the derivatives of general formula (II) can be condensed on S-methylthiophene thiocarboxamide iodhydrate, prepared according to a method of the literature (Ann. Chim. (1962), 7, 303-337 ). The condensation

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  can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature preferably between 50 and 100 C for a period generally between a few hours

and one night.

  In cases where B = SR6, for example S-CH3, these can be prepared by the condensation of the amines or anilines of general formula (II) with the isothiocyanate (I.v)

  in which Gp represents a protective group such as for example the benzoyl group.

  It is then deprotected by cleavage of the protecting group under suitable conditions and the thiourea formed is finally treated with, for example, a halo-alkane to

  lead to the final compounds of general formula (I).

  In cases where B = NR3R4, the final compounds of general formula (I) are guanidines. These can be prepared, for example, by the condensation of the amines or anilines of general formula (II) with the derivatives of general formula (I.ii) or (I.iii). The reagents of general formula (I.ii) in which L represents, for example, a pyrazole ring are condensed on the amines of general formula (II) according to the conditions described in the literature (J. Org. Chem. (1992) 57 , 2497-2502) similarly for the reagents of general formula (I.iii) in which L represents, for example, a pyrazole ring and Gp the group tBuOCO (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the group -N-SO2-CF3 and Gp the group tBuOCO (J. Org. Chem. (1998) 63, 3804-3805). During the final stage of the synthesis, the deprotection of the guanidine function is carried out in the presence of an acid

  strong such as for example trifluoroacetic acid.

  In cases where B = -NHNO2 the final compounds of general formula (I) can be prepared, for example, by the condensation of amines or anilines of general formula (II) with the reagent of formula (I.iv) (N- methyl-N'-nitro-N-nitrosoguanidine) according to

  conditions described in the literature (J. Amer. Chem. Soc. (1947), 69, 3028-3030).

  Preparation of the compounds of general formula (II): The intermediates of general formula (II), are obtained from the cleavage of a protective group. The intermediates of general formula (I), in which A and X are as defined above, can be prepared from the intermediates of general formula (III), scheme 1, which are compounds comprising a protected amine or an aniline protected (NGp) in the form, for example, of a carbamate. In the particular case

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  BOC groups, these are conventionally unprotected using TFA or HCI, to

  finally lead to the primary amines and anilines of general formula (II).

  Preparation of the compounds of general formula (III: Synthesis of the carboxamides of general formula (III): The carboxamides of general formula (III), scheme 2, in which X and R1 are as defined above, are prepared by condensation of the acids of formula general (I. vi) with the mono-protected amines or anilines of general formula (I. vii). The carboxamide bonds are formed under conventional conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), l, l'-carbonyldiimidazole (CDI) (J. Med. Chem . (1992), 35 (23), 4464-4472) or 1 (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, The syntheses of carboxylic acids of general formula (I. vi) non-commercial are

described later.

  jCOH 2 C O2H / CH2) -CONRr-X-NHGp SH + NHR-X-NHGp HGp (I.vi) (I.vii) (III) Scheme 2 B) Preparation of the compounds of general formula () o Y represents: R5

N NH2

  The compounds of general formula (I) in which A, X, Y and R5 are as defined

  above, can be prepared from intermediates of general formula (II).

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A-X A-X-Y

  (II) (I) Scheme 3 The final molecules of general formula (I) are obtained after cutting off the 2,5-dimethylpyrrole protecting group of the compounds of general formula (II) by heating in the presence of hydroxylamine hydrochloride, at a temperature varying from 60 C to 100 C, in a solvent such as for example ethanol according to an experimental protocol described in J. Chem. Soc. Perkin Trans. (1984), 12, 2801-2807. Preparation of the compounds of general formula (II: The compounds of general formula (II) can be prepared according to the following synthetic schemes: 1) Methods of access to substituted 2- (2,5dimethylpyrrol-1-yl) pyridine of general formula i0 (II.x): 1.1) The synthetic precursors which lead to the intermediates of general formula (II) are prepared from the compounds of general formula (I.1), such as for example 2- (2,5-dimethylpyrrol- 1-yl) -4,6dimethylpyridine. This is obtained from commercial 6-amino-2,4lutidine according to an experimental protocol described in J. Chem. Soc. Perkin Trans., (1984), 12, 2801-2807. Treatment of the compounds of general formula (II.1) with a strong base such as, for example, nBuLi, at a temperature varying from -50 C to -30 C in an anhydrous solvent such as ethyl ether, under an inert atmosphere and optionally in the presence of N, N, N ', N'-tetramethylethylenediamine makes it possible to form the lithiated derivative (intermediate (H.2)) which, in the presence of an electrophile E +, leads to the adducts of general formula (II.x).

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R5 R5 R

  B-Li + E + Li (Ih) (II2) (ix) Scheme 4 1.2) Among the E + electrophiles which can react on the lithiated species of general formula (II.2), are for example protected haloamines. The amines of general formula (II.3) are prepared from the intermediate (II.2) which is condensed for example on protected halogeno-amines (for example in the form of silylated derivatives or phthalimides) under conditions previously described . The amines of general formula (II.4) are finally obtained after deprotection under conditions described in the literature (T.W. Greene and P.G.M. Wuts, Protective

  Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).

  Pg. 1%,? N-A-Hal Rg gos pgg 4Rs5 R5 Pg 1 "" -b.N "A H2N '-A Li"

(II) (I3) (II4)

  Diagram 5 2) Methods of access to the compounds of general formula (II): 2.1) The carboxamides of general formula (Im: 2.1.1) The carboxamides of general formula (IH), in which A, X, and R5 are such as defined above, can also be prepared by condensation of the carboxylic acids of general formula (I.vi) with the amines of general formula (11.4) under the conditions previously described. Acid synthesis

  non-commercial carboxylic acids of general formula (I.vi) is described below.

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R5 (CH2) m-CO2H H2N - (CH2) n

S +

  (I.vi) (II.4) f R5 (CH2) m -CONH- (CH2) n (II)

S \ N N \

  Diagram 6 Preparation of certain non-commercial synthesis intermediates The non-commercial acids of general formula (I.vi), in which m is as defined above are accessible from methods of the literature. For example, norlipoic acid is obtained in 5 steps according to an experimental protocol described in

  Tetrahedron Letters. (1997), 38 (33), 5785-5788.

  The following examples are presented to illustrate the above procedures and should not be

  in no case be considered as a limit to the scope of the invention.

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EXAMPLES

  Example 1: N- {4 - [[(2-thienyl) (imino) methyl] amino] phenyl)} hydrochloride} - 1,2-dithiolane-3-pentanamide: 1.1) N- {4 - [(1,1dimédthyléthoxy ) carbonylamino] phenylJ-1,2-dithiolane-3-pentanamide To a solution of 2 g (9.694 mmol) of (DL) -thioctic acid in 40 ml of dichloromethane, 1.84 g (8.81 mmol) are added successively ) N-BOC-1,4phenylene diamine, 1.6 ml of triethylamine, 1.7 g (12.6 mmol) of hydroxybenzotriazole, 4.82 g (25.2 mmol) of 1- (3dimethylaminopropyl) hydrochloride - 3-ethyl-carbodiimide and 1.6 ml of triethylamine. After having stirred the reaction mixture overnight at 25 ° C., the whole is diluted with 100 ml of water and the stirring is continued for a further 30 minutes. The product is extracted using 3 times 100 ml of dichloromethane. The

  organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo.

  The red powder obtained is suspended in ether (100 ml), filtered and rinsed with the same volume of ether to yield a salmon pink powder with a yield of 80.5%. Melting point: 190-195 C 1 H NMR (DMSO d6, 400 MHz, 5): 1.39 (m, 2H, CH2); 1.57 (s, 9H, BOC); 1.61 (m, 4H, CH2); 1.88 (m, 1H, CH2); 2.27 (m, 2H, CH2); 2.50 (m, 1H, CH2); 3.15 (m, 2H, CH2); 3.63 (m, 1H, -S-CH-); 7.34 (d, 2H, Arom, J = 8.70 Hz); 7.45 (d, 2H,

  Arom, J = 9.00 Hz); 9.24 (s, 1H, CONH); 9.77 (s, 1H, CONH-BOC).

  1.2) N- (4-aminophenyl) -1,2-dithiolane-3-pentanamide A solution of intermediate 1.1 (6.5 g; 16.4 mmol) in a mixture (200 ml) of ether / ethanol / acetone / dichloromethane (1/1/1/1), a stream of HCl gas bubble to bubble is passed at 0 C. It is allowed to rise to ambient temperature overnight. An Argon stream is passed through the reaction mass and the solvents are evaporated to dryness. The evaporation residue is then poured into 100 ml of a saturated solution of cold NaHCO3 and extracted with 3 x 100 ml of dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification is then carried out on a silica column (eluent = heptane at 50% ethyl acetate then dichloromethane at% ethanol) to yield a beige solid with a yield of 29%. Point of

fusion: 55-60 C.

  1 H NMR (DMSO d6, 400 MHz, 8): 1.38 (m, 2H, CH2); 1.57 (m, 4H, CH2) 1.87 (m, 1H, CH2); 2.22 (m, 2H, CH2); 2.40 (m, 1H, CH2); 3.18 (m, 2H, CH2) 3.62 (m, 1H, -S-CHI); 4.78 (s, 2H, NH2); 6.48 (d, 2H, Arom, J = 8.64 Hz) 7.20 (d, 2H, Arom J = 8.64 Hz); 9.39 (s, 1H, CONH).

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  1.3) N- {4 - [[(2-thienyl) (imino) methyl] amninolphenyl / -1,2dithiolane- hydrochloride

  3-pentanamide: Intermediate 1.2 (0.703 g; 2.37 mmol) is dissolved in 2-propanol (15 ml) and 1.014 g of Smethyl-2-thiophene thiocarboximide iodhydrate (3.56 mmol) is added ) (Ann. Chim., (1962), 7, 303-337). After heating at 60 ° C. for hours, the reaction mixture is concentrated to dryness under vacuum. The residue is taken up in dichloromethane and a saturated aqueous solution of NaHCO3. After decantation, the organic phase is washed successively with 50 ml of a saturated solution of NaHCO3, water and brine. The organic solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The free base is then dissolved in 30 ml of dichloromethane and the solution is cooled using an ice bath before the dropwise addition of 6.3 ml of an IN HCl solution in anhydrous ethyl ether . After hours of stirring at 25 ° C., the crystals obtained are filtered and rinsed with diethyl ether to obtain, after drying, 1.6 g of a light beige solid product with a yield of 77%. Melting point: 258.7-258.9 C 1 H NMR (DMSO d6, 400 MHz, 5): 1.43 (m, 2H, CH2); 1.62 (m, 4H, CH2) 1.88 (m, 1H, CH2); 2.38 (m, 3H, CH2); 3.18 (m, 2H, CH2); 3.63 (m, 1H, -S- H-) 7.20-8.20 (m, 7H, Arom); 8.79 (br s, 1H, NH +); 9.78 (broad s, 1H, NH +)

  , 36 (s, 1H, CONH); 11.49 (br s, 1H, NH +).

  IR: VC = N (amidine): 1580 cm-; Vc = o (amide): 1659 cm-l.

  Example 2: N- {2- {4 [[((2-thienyl) (imino) methyl] amino] phenyl} ethyl} -1,2-

  dithiolane-3-pentanamide: The experimental protocol used is the same as that described for compound 1. Solid

yellow. Melting point: 146-148 C.

  1H NMR (DMSO d6, 400 MHz, 8): 1.32 (m, 2H, CH2); 1.60 (m, 4H, CH2) 1.88 (m, 1H, CH2); 2.07 (t, 2H, CH2, J = 7.36 Hz); 2.41 (m, 1H, CH2); 2.65 (m, 2H, CH2); 3.10-3.30 (m, 4H, CH2); 3.60 (m, 1H, -S-CH-); 6.33 (br s, 2H, NH2 amidine); 6.78 (d, 2H, Arom J = 8.04 Hz); 7.08 (m, 1H, thiophene); 7.12 (d, 2H,

  Arom, J = 8.16 Hz); 7.60 - 7.80 (m, 2H, thiophene); 7.81 (t, 1H, CONH J = 5.56 Hz).

  IR: VC = N (amidine): 1590 cm-1; VC = O (amide): 1629 cm-1.

  Example 3: N- {2- {4 [[(2-thienyl) (imino) methyl] amino] phenyliethyl} -1,2-dithiolane-3-acetamide hydrochloride: The experimental protocol used is the same as that described for compound 1, norlipoic acid {2- (1,2-dithiolan-3-yl) acetic acid} (prepared according to Tetrahedron Letters,

  (1997), 38, 33, 5785) replacing lipoic acid. Solid yellow.

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  1 H NMR (DMSO d6, 400 MHz, 8): 1.91 (m, 1H, CH2); 2.30-2.60 (m, 3H, CH2); 2.70-2.90 (m, 2H, CH2); 3.17 (m, 2H, CH2); 3.40 (m, 2H, CH2); 3.93 (m, 1H, -S-CH-); 7.30-7.50 (m, 5H, Arom); 8.10-8.30 (m, 3H, Arom + CONH)

  8.86 (br s, 1H, NH +); 9.80 (br s, 1H, NH +); 11.50 (broad s, 1H, NH +).

MS: MH + = 392.1.

  Example 4: N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] -1,2-dithiolane-

  3-pentanamide: 4.1) 6- (2,5-dimethyl-IH-pyrrol-l -yl) -4-methyl-2pyridinebutanamine

  Under an argon atmosphere, 1 g (5 mmol) of 2- (2,5-dimethyl-1Hpyrrol-) is dissolved

  1-yl) -4,6-dimethylpyridine (prepared from 6-amino-2,4-lutidine according to J. Chem. Soc. Perkin Trans., 1984, 12, 2801) in 10 ml of anhydrous ethyl ether and 1.132 ml (7.5 mmol) of N, N, N, Ntetramethylethylenediamine (TMEDA). The reaction mixture is cooled to -20 ° C. and 2.4 ml (6 mmol) of a 2.5 M solution of BuLi in hexane are added dropwise. After 5 hours at -20 ° C., the reaction mixture

  is cooled to -45 ° C. and 1.68 g (6 mmol) of 1- (3bromopropyl) are added -

  2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane and allowed to rise to room temperature overnight. 50 ml of a saturated ammonium chloride solution are added and the whole is stirred for 2 hours at 25 C. The organic phase is decanted and washed successively with 40 ml of water and 40 ml of brine, dried over sulphate. magnesium, filtered and concentrated in vacuo. The residue obtained is purified on a silica column (eluent = dichloromethane at 5% ethanol) to yield a yellow oil with a

62% yield.

  1 H NMR (CDCI3, 400 MHz, 8): 1.52 (m, 2H, CH2); 1.78 (m, 2H, CH2); 2.11 (s, 6H, 2 x CH3 pyrrole); 2.39 (s, 3H, CH3 pyridine); 2.72 (t, 2H, CH2 J = 7.02 Hz) 2.79 (t, 2H, CH2 J = 7.62 Hz); 5.87 (s, 2H, pyrrole); 6.85 (s, 1H, pyridine)

6.98 (s, 1H, pyridine).

  4.2) N- {4- [6- (2,5-dimethyl-JH-pyrrol-1-yl) -4-methyl-2-pyridinyllbutyl] -1, 2-dithiolane-

  3-pentanamide The experimental protocol used is the same as that described for intermediate 1.1, intermediate 4.1 replacing NBOC-1,4-phenylenediamine. A yellow oil is obtained.

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  1H NMR (CDCl3, 400 MHz, 5): 1.30-2.00 (m, 11H, CH2); 2.07 (m, 2H, CH2) 2.11 (s, 6H, 2 x CH3 pyrrole); 2.40 (s, 3H, CH3 pyridine); 2.45 (m, 1H, CH2) 2.82 (m, 2H, CH2); 3.10-3.30 (m, 4H, CH2); 3.57 (m, 1H, -S-CH-); 5.87 (s, 2H,

  pyrrole); 5.94 (br s, 1H, CONH); 6.87 (s, 1H, pyridine); 6.99 (s, 1H, pyridine).

MS: MH + = 446.2

  4.3) N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] -1,2-dithiolane-3pentanamide Intermediate 4.2 (1.53 g; 3.43 mmol) is dissolved in 55 ml ethanol supplemented with 18 ml of water and 1.2 g (17.2 mmol) of hydroxylamine hydrochloride are added. The reaction mixture is heated at reflux for 24 hours. After returning to 25 ° C., the whole is diluted with 20 ml of a saturated sodium bicarbonate solution and the product is extracted with 100 ml of dichloromethane. After decantation, the organic solution is washed successively with 40 ml of a saturated solution of sodium bicarbonate and 40 ml of brine, dried over magnesium sulphate, filtered and concentrated in vacuo. The evaporation residue is purified on a silica column (eluent = dichloromethane at

  2.5% ethanol) to yield a yellow oil with a yield of 76%.

  1H NMR (CDCI3, 400 MHz, 5): 1.30-1.80 (m, 10H, CH2); 1.89 (m, 1H, CH2) 2.16 (m, 2H, CH2); 2.19 (s, 3H, CH3 pyridine); 2.40 (m, 1H, CH2); 2.58 (m, 2H, CH2); 3.05-3.30 (m, 4H, CH2); 3.56 (m, 1H, -S-CH-); 4.35 (br s, 2H, NH2); , 80 (broad s, 1H, CONH); 6.17 (s, 1H, pyridine); 6.35 (s, 1H, pyridine).

IR: vc = o (amide): 1637 cm-1.

  Example 5: N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] fumarate -

  1,2-dithiolane-3-acetamide: The experimental protocol used is the same as that described for compound 4, norlipoic acid {2- (1,2dithiolan-3-yl) acetic acid} (prepared according to Tetrahedron Letters, 1997, 38, 33, 5785) replacing lipoic acid. The free base is then salified using fumaric acid in a mixture of acetone / methyl ethyl ketone solvent (50/50). We get the

  fumarate in the form of a cream powder with a yield of 14.8%.

  1 H NMR (DMSO d6, 400 MHz, 8): 1.40 (m, 2H, CH2); 1.57 (m, 2H, CH2) 1.92 (m, 1H, CH2); 2.15 (s, 3H, CH3 pyridine); 2.30-2.70 (m, 5H, CH2) 3.033.18 (m, 4H, CH2); 3.94 (m, 1H, -S-CH-); 6.17 (s, 1H, pyridine) 6.26 (s, 1H, pyridine); 6.00-6.60 (broad s, 2H, -CO2H fumaric acid)

  6.60 (s, 2H, H = CH, fumaric acid); 7.90 (broad s, 1H, CONH).

IR: Vc = o (amide): 1649 cm-1.

MS: MH + = 326.2

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  Pharmacological study of the products of the invention Study of the effects on the neuronal constitutive NO synthase of rat cerebellum The inhibitory activity of the products of the invention is determined by measuring their effects on the NO synthase transformation of [3H ] L-arginine in [3H] L-citrulline in accordance with the modified method of Bredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: 682-685). Cerebellum of Sprague-Dawley rats (300g - Charles River) are quickly removed, dissected at 4 C and homogenized in a volume of extraction buffer (H-IEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg / ml, leupeptin

  mg / ml). The homogenates are then centrifuged at 21,000 g for 15 min at 4 C.

  The assay is carried out in glass test tubes in which 100 1 l of incubation buffer containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5 mM of CaCl 2, 2 mM are distributed. dithiotreitol, 2 mM reduced NADPH and 10 gg / ml calmodulin. 25 g of a solution containing 100 nM of [3 H] L-arginine (specific activity: 56.4 Ci / mmol, Amersham) and 40 gM of non-radioactive L-arginine are added. The reaction is initiated by adding 50 g of homogenate, the final volume being 200 g (the 25 g missing are either water or the product tested. After 15 min, the reaction is stopped with 2 ml of buffer d stop (20 mM HEPES, pH 5.5, 2 mM EDTA) After passing the samples through a column of 1 ml of DOWEX resin, the radioactivity is quantified

  by a liquid scintillation spectrometer.

  The compounds of Examples 1, 2, 3, 4, 5 described above have a lower IC50

at 4.5 gM.

  Study of the effects on oxidative stress induced by glutamate on cultured cells

(HT-22).

  The inhibitory activity of the products of the invention is determined by measuring their capacity to protect the cells of a hippocampal mouse line (HT-22) from oxidative stress caused by glutamate. Glutative biosynthesis, an essential element in the cellular detoxification of free radicals, requires the active transport of cystine inside the cell. Glutamate by opposing the penetration of cystine causes a reduction in the gluthation rate which leads to cell death by oxidative stress (Davis, JB and Maher, P., Brain Res., (1994) 652: 169 -173; Murphy, TH et al., Neuron, (1989) 2: 1547-1558). The cells are cultured at 37 ° C. in a DMEM medium supplemented with 10% of fetal calf serum. The tests are carried out in 96-well plates containing 5000 cells per well. Glutamate (5 mM) is added to the medium containing or not containing the products to be tested. Cell viability is tested after 24 h

  by the MTT method (Hansen, M.B. et al., J Immunol.Methods (1989) 119: 203-

- 21 - 2791677

  210). The capacity of the compounds to protect cells from the toxic action of glutamate is estimated in EC50, calculated relative to the viability of cells not subjected to the action of

  glutamate considered as 100% viability.

  The compounds of Examples 1, 2, 3, 5 described above have an EC50 of less than 30 pM.

- 22 - 2791677

Claims (12)

Claims   1. Product of general formula (I), characterized in that it comprises the products of sub-formulas (I) a and (I) b AX-Y A-X - Y S - S SH SH   (I) a (I) b in which A represents one of the radicals - (CH2) m-CONRI- (CH2) n-, - (CH2) m-NRI- (CH2) n-, - (CH2) m -CONRI (CH2) p-NR2- (CH2) n- or - (CH2) m-, m and n being integers between O and 6, p being an integer between 2 and 6, and R1 and R2 representing independently a hydrogen atom or a linear or branched alkyl radical of 1 to 6 carbon atoms; X represents a phenylene radical or - (CH2) q- in which q represents an integer between 0 and 6 and finally Y represents one of the radicals R5 B - -N; 1N NH2NH2   or in which B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan radicals, pyrrole or thiazole, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or B represents NR3R4, in which R3 and R4 represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, or -23- 2791677   one of R3 and R4 represents a nitro radical while the other represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, or alternatively R3 and R4 taken together form with the atom of nitrogen a non-aromatic heterocycle of five to six members, the elements of the chain being chosen from a group composed of -CH2-, -NH-, -O- or -S-, or else B represents a radical SR6 in which R6 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, and R5 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;   or a salt of a product of general formula (I).   2. Product according to claim 1, characterized in that it is one of the following compounds:   - N- {4 - [[(2-thienyl) (imino) methyl] amino] phenyl} hydrochloride phenyl} -1,2dithiolane- 3-pentanamide;   - N- {2- {4 [[(2-thienyl) (imino) methyl] amino] phenyl} ethyl} - 1,2dithiolane- 3-pentanamide;   - N- {2- {4 [[(2-thienyl) (imino) methyl] amino] phenyl) ethyl hydrochloride} -   1,2-dithiolane-3-acetamide; - N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] 1,2-dithiolane-3-pentanamide;   - N- [4- (6-amino-4-methyl-2-pyridinyl) butyl] fumarate - 1,2-dithiolane3-acetamide.   3. Process for the preparation of an amidine of general formula (I) according to claim   1, characterized in that the intermediate of general formula (II) is reacted. A-X -NH2   (II) in which: A represents one of the radicals - (CH2) m-CONH- (CH2) n-, - (CH2) m-NRI- (CH2) n, - (CH2) mi-CONH- (CH2 ) p-NR I- (CH2) n- or- (CH2) m-, m and n being integers between 0 and 6, p being an integer between 2 and 6, -24- 2791677   and R1 representing a hydrogen atom or a linear or branched alkyl radical of 1 to 6 carbon atoms; and X represents a phenylene radical or - (CH2) q- in which q represents an integer between 0 and 6, with the intermediary of general formula (Ii) B (Ii) in which: B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 links containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, and L represents a leaving group, for example an alkoxy, thioalkyl, acid radical   sulfonic, halide, aryl alcohol or tosyle.   4. Method for preparing a product of general formula (I) according to claim 1 wherein B is an amine, characterized in that the intermediate of general formula (II) is reacted A-X-NH2   (II) in which: A represents one of the radicals - (CH2) m-CONH- (CH2) n-, - (CH2) m-NRI- (CH2) n, - (CH2) m-CONH- (CH2 ) p-NRI - (CH2) n- or - (CH2) m-, m and n being integers between 0 and 6, p being an integer between 2 and 6, and R1 representing a hydrogen atom or a linear or branched alkyl radical of 1 to 6 carbon atoms; and X represents a phenylene radical or - (CH2) q- in which q represents an integer between 0 and 6, a) with the intermediary of general formula (I.ii) -25- 2791677   H 2H (I.ii) in which L represents a leaving group, for example an alkoxy, thioalkyl, sulphonic acid, halide, aryl or tosyl alcohol radical, b) or with the intermediary of general formula (I. iii) L GpN N Gp (I.iii) in which L represents a leaving group, for example an alkoxy, thioalkyl, sulfonic acid, halide, aryl or tosyl alcohol radical, and Gp a protective group of carbamate type, for example the t-butoxycarbonyl group, this reaction being followed, in the case where one opts for the reaction with the compound of general formula (I.iii), by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid, c) or with the derivative of formula (I.iv) (N-methyl-N'-nitro-N-nitrosoguanidine) H i I 02N 'TyN NH (I.iv) d) or finally with the derivative of formula (Iv) in which Gp represents a protecting group S = C = N-NGp (Iv) 5. As a medicament, a product of general formula (I) according to one of   claims 1 to 2, or a pharmaceutically acceptable salt thereof.   6. Pharmaceutical composition containing as active principle at least one product   according to one of claims 1 to 2, or a pharmaceutically acceptable salt of said product. -26- 2791677   7. Use of a product of general formula (I) according to one of claims 1 to 2,   or a pharmaceutically acceptable salt of this product, to make a medicine intended to inhibit NO synthase.   8. Use of a product of general formula (I) according to one of claims 1 to 2,   or a pharmaceutically acceptable salt of this product, to make a medicine   intended to regenerate antioxidants.   9. Use of a product of general formula (I) according to one of claims 1 to 2,   or a pharmaceutically acceptable salt of this product, to make a medicine   having both NO synthase inhibition and anti-regeneration activity oxidants.   10. Use of a product of general formula (I) according to one of claims 1 to   2, or a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended to treat pathologies in which nitric oxide and / or the redox status of thiol groups are involved, pathologies such as disorders of the central nervous system or peripheral particularly well represented by Parkinson's disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, septic shock, pathologies resulting from radioactive irradiation, solar radiation or organ transplants, autoimmune and autosomal diseases , cancer and all pathologies characterized by production or dysfunction involving nitric oxide and / or   involving the redox status of thiol groups.   11. Use of a product of general formula (I) according to one of claims 1 to   2, or a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended to treat cerebrovascular disorders such as migraine, cerebral infarctions of ischemic or hemorrhagic origin, ischemias and thromboses.   12. Use of a product of general formula (I) according to one of claims 1 to   2, or a pharmaceutically acceptable salt of this product, for the manufacture of a medicament intended to treat disorders of the central or peripheral nervous system such as neurodegenerative diseases, pain, brain or spinal cord injuries, addiction to opioid drugs, alcohol and addictive substances, erectile and reproductive disorders, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy,   sleep disorders and eating disorders.