New derivatives of lipoic acid, the retrieval method (variants), pharmaceutical composition

 

(57) Abstract:

The present invention relates to new derivatives of lipoic acid formula Ia

where And denotes the radical -(CH2)m-CO-NR3-(CH2)n- or -(CH2)m-, R3is hydrogen or an alkyl radical C1-C6X denotes the radical

T together with Y represents the radical -(CH2)i-, R5is an alkyl radical, alkoxy, dialkylamino, 5-membered heterocycle. The compounds possess inhibitory activity against the enzyme NO-synthase, producing nitric monoxide NO and/or are agents that allows you to regenerate antioxidants. The subject invention are methods of obtaining these compounds, containing pharmaceutical preparations and their use for therapeutic purposes. 5 N. C. and 3 C.p. f-crystals.

The present invention relates to new derivatives of lipoic acid, which has inhibitory activity against the enzyme NO-synthase, producing nitric monoxide NO and/or an agent that allows you to regenerate antioxidants or traps for reactive oxygen species (ROS=reactive oxygen species) and, more generally, bleuse the main forms of oxygen may be of natural origin, for example vitamin E or glutathione, or synthetic origin, for example, some compounds, which are traps for ROS or compounds simultaneously possessing inhibitory activity against the enzyme NO-synthase and the ability to capture ROS. Examples of such compounds having synthetic origin, can be, in particular, found in patent applications PCT WO 96/09653, WO 98/42696 and WO 98/58934.

The invention thus relates, in particular, to derive corresponding to the particular below of General formula I, methods for their preparation, containing pharmaceuticals and, in particular, to their use as inhibitors of NO-synthase and/or agents, allowing to regenerate antioxidants or traps for ROS and, more generally, affect the redox characteristics of thiol groups.

Given the potential role in the pathophysiology of NO, ROS and metabolism of glutathione describes the new derivatives corresponding to General formula I, can have a positive or beneficial effect in the treatment of pathologies involving monoxide and nitrogen metabolism of glutathione and redox characteristics of thiol groups. In cha is with, for example, atherosclerosis, migraine, hypertension, septic shock, cardio - and cerebral infarction ischemic or hemorrhagic origin, ischemia and thrombosis;

disorders of the Central or peripheral nervous system, such as neurodegenerative disease, which can, in particular, called cerebral infarcts, hemorrhage under the arachnoid membrane of the brain, aging, symptoms of dementia, including Alzheimer's disease, horey Huntington's, Parkinson's disease Creutzfeldt-Jakob disease and prion disease, amyotrophic lateral sclerosis, pain, brain or spinal cord, addiction to drugs, alcohol and substances that contribute to addiction, erectile dysfunction, and reproductive function, mental disorders, encephalopathy viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleep disorders, nutritional disorders (anorexia, bulimia...);

diseases of skeletal muscle and neuromuscular ligaments (myopathy, myositis), and skin diseases;

proliferative and inflammatory diseases, such as atherosclerosis, pulmonary hypertension, respiratory nedostatochnaia, inflammation of the gastro-intestinal tract (colitis, Crohn's disease) or pulmonary system and Airways (asthma, sinusitis, rhinitis), as well as contact hypersensitivity or inhibited reaction; organ transplantation;

autoimmune and viral diseases, such as lupus, AIDS, parasitic and viral infections, diabetes and its complications, including retinopathy, nephropathy, polyneuropathy, multiple sclerosis, myopathy;

cancer;

autosomal genetic disease, such as disease Unverricht-Lonborg;

neurological disease caused by intoxication (poisoning by cadmium inhalation of n-hexane, pesticide, herbicide), treatments (radiotherapy) or genetic disorders (Wilson's disease);

impotence caused by diabetes;

all pathology characterized by the production or dysfunction of nitrogen monoxide and/or metabolism of glutathione and redox properties of thiol groups.

In relation to the totality of these pathologies, there are experimental evidences proving the participation of nitrogen monoxide or dysfunction of the metabolism of glutathione (Kerwin et al., Nitric oxide: a new regalsysteme, in particular, the example associated with Parkinson's disease (Beal MF, Excitotoxicity and nitric oxide in PA's disease pathogenesis, Ann. Neurol. 44 [Supplemented by I], S110-S114, 1998; Donato A et al., Gluthathion in PA's disease: a link between oxidative stress and mitochondrial damage, Ann. Neurol. 32, S111-S115, 1992). In this context, the drugs able to inhibit the formation of nitrogen monoxide or restore biological function of thiol groups and glutathione, can have a beneficial effect.

Along with this, the authors of this invention have been described in earlier patents inhibitors of NO synthases and their application (patents US 5081148, US 5360925), and the Association of these inhibitors products with antioxidant and antiradical properties (patent application PCT WO 98/09653). They also described derivatives amidino in the patent applications PCT WO 98/42696 and WO 98/58934 and derivatives aminopyridine in the patent application PCT WO 00/02860. These derivatives amidino and aminopyridines are characterized by the fact that they are both inhibitors MO-synthase inhibitors and ROS.

The object of the present invention is new derivatives of lipoic acid, method for their production and their use as therapeutic agents.

The invention applies in particular to the connection is a normal or branched alkyl radical with 1-6 carbon atoms or may form a simple link;

And refers to the radical - (CH2)m-NR3- (CH2)n-, -(CH2)m-CO-NR3-(CH2)n-, -(CH2)m-NR3-(CH2)n-, - (CH2)m-CO-HR3-(CH2)p-NR4-(CH2)n-, -(CH2)m-NR3-CO-NR4-(CH2)n- or -(CH2)m-,

where m and n denote integers from 0 to 6 and

p denotes an integer from 2 to 6;

R3and R4independently represent a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms;

X denotes the radical

in which T, coupled with the group Y represents the radical -(CH2)i- where i denotes an integer from 0 to 6, a R5 denotes a hydrogen atom, normal or branched alkyl radical with 1-6 carbon atoms or the radical -(CH2)m-Q, in which Q denotes a halogen atom, a hydroxy radical, cyano, amino, alkoxy, alkylthio, alkylamino or dialkylamino, or R5can also denote a 5 - or 6-membered heterocycle, in which the heterocyclic units selected from the radicals-O-, -N(R6)- and-S-, where R6denotes a hydrogen atom, norms who="ptx2">

or X represents the radical -(CH2)q-in which q denotes an integer from 0 to 6;

and, finally, Y denotes one of the radicals

which indicates a normal or branched alkyl radical with 1-6 carbon atoms, 5 - or 6-membered carbocyclic or heterocyclic aryl containing 1 to 4 heteroatoms selected from O, S, N and, in particular, radicals, thiophene, furan, pyrrole or thiazole, and the aryl radical may be substituted by one or more groups selected from normal or branched alkyl radicals, alkenyl or alkoxy having from 1 to 6 carbon atoms, or denotes NR8R9in which R8and R9independently represent a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms or one of R8and R9denotes a nitro radical, and the other a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms, or R8and R9together with the nitrogen atom form a five - or six-membered nonaromatic a heterocycle, the elements of the link which is selected from the group comprising-CH2-, -NH-, -O - or-S-;

or can also denote a radical SR10in which R

and R7denotes a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms;

or salt compounds of General formula I.

Preferably, when R5denotes a 5 - or 6-membered heterocycle, R5mainly denotes one of the following heterocyclic compounds: pyrrole, imidazole, pyrazole, triazole, thiazolidin, pyrrolidine, piperidine, piperazine, N-alkylpiperazine, thiomorpholine, morpholine, azetidine.

The invention concerns, in particular, compounds defined above General formula I, in which independently of one another have the following features:

And denotes one of the radicals - (CH2)m-NR3-CO-(CH2)n-,

-(CH2)m-CO-NR3-(CH2)n- or - (CH2)m-NR3-CO-NR4- (CH2)n,

m denotes an integer from 0 to 4, a n an integer from 0 to 6,

and R3and R4independently represent a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms;

X denotes the radical

in which T, coupled with the group Y represents the radical -(CH2)i- in which i is 0 or 1. and R2)m-Q, in which Q denotes a halogen atom, a hydroxy radical, cyano, amino, alkoxy, alkylamino or dialkylamino, or R5 denotes a 5 - or 6-membered heterocycle, in which the heterocyclic units selected from the radicals-O-, -N(R6)- and-S-, where R6denotes a hydrogen atom, normal or branched alkyl radical with 1-6 carbon atoms or a bond with the phenyl cycle of the radical X; or

Y denotes a radical

which indicates a normal or branched alkyl radical with 1-6 carbon atoms, 5 - or 6-membered carbocyclic or heterocyclic aryl containing 1 to 4 heteroatoms selected from O, S, N and, in particular, radicals, thiophene, furan, pyrrole or thiazole, and the aryl radical may be substituted by one or more groups selected from normal or branched alkyl radicals, alkenyl or alkoxy having from 1 to 6 carbon atoms.

The compounds of formula (I) in which R1and R2form a simple link represented by formula (Iand)

where A, X and Y have the above values.

The compounds of formula (I) in which R1and R2have the meanings specified above, except the value is to be placed.

More specifically, the invention relates to the following described in the examples of the compounds (sometimes in the form of salts):

- N-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}-1,2-ditiolan-3-pentanone;

- N-{2-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}ethyl}-1,2-ditiolan-3-pentanone;

- N-{2-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}ethyl}-1,2-ditiolan-3-ndimethylacetamide;

- N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-ditiolan-C-pentanone;

- N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-ditiolan-C-ndimethylacetamide;

- N-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-2-(1,2-ditiolan-3-yl)ndimethylacetamide;

- N-(4-{[amino(2-thienyl)methylidene]amino}benzyl)-5-(1,2-ditiolan-3-yl)pentanone;

- N-(5-{[amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-5-(1,2-ditiolan-Z-yl)pentanone;

- N-[5-{[amino(2-thienyl)methylidene]amino}-2-(dimethylene)benzyl]-5-(1,2-ditiolan-3-yl)pentanone;

- N-[5-{[amino(2-thienyl)methylidene]amino}-2-(1H-pyrrol-1-yl)benzyl]-5-(1,2-ditiolan-3-yl)pentanone;

and salts of these compounds.

The invention also provides several ways to obtain the above products of General formula I, the preferred conditions are described below.

The invention concerns, in particular, the act is of General formula II

in which a and X have the meanings indicated above,

enter into interaction with the intermediate connection total

formula (i)

which has the above specified values, a, L denotes the deleted group, such as alkoxy radical, alkylthio, the remainder of the sulfonic acid, halogen, balance kilowog alcohol or tonilou group.

The invention concerns also a method of obtaining compounds of General formula I, in which And indicates the above-defined radical - (CH2)m-CO-NR3-(CH2)n- consists in the fact that an intermediate compound of General formula (VII)a

where R3X and Y are defined above value, and represents the radical -(CH2)n-, in which n is defined above, enter into interaction with the compound of General formula (I. vi)

where m is defined above.

The invention concerns also a method of obtaining compounds of General formula I, in which And indicates the above-defined radical - (CH2)m-NR3-CO-NR4- (CH2)n- consists in the fact that an intermediate compound of General formula (VII)b

HN(R4)-A-X-Y

(VII)b

where R4 is a journey with a compound of General formula (I. vi)

where m is defined above, and diphenylphosphorylacetate in the presence of a base such as triethylamine.

The invention relates also to method of obtaining compounds of General formula I, which denotes Amin, namely, that the intermediate compound of General formula II

in which a and X are defined above,

enter into interaction

a) with an intermediate compound of General formula (ii)

in which L represents a group to delete, for example, an alkoxy radical, alkylthio, the remainder of the sulfonic acid, halogen, balance kilowog alcohol or tosyl,

b) or with an intermediate compound of General formula (I)

in which L represents a group to delete, for example, an alkoxy radical, alkylthio, the remainder of the sulfonic acid, halogen, balance kilowog alcohol or tosyl, a Gp represents a protective group of the urethane type, for example tert-butoxycarbonyl group

moreover, in the case when interact with the compound of General formula (I), for this reaction is followed by hydrolysis in the presence of a strong acid, for example, trifter-acetic acid;

c) or derived forms of oznachaet protective group

In some cases, the compounds according to the invention may contain asymmetric carbon atoms and therefore have two possible enantiomeric forms, i.e., configurations of R and S. the Present invention includes two enantiomeric forms and all combinations of these forms, including racemic mixtures RS. The purpose of simplicity, if the structural formulas do not indicate any specific configuration, it should be assumed that presents two enantiomeric forms and mixtures thereof.

On the other hand, if it is not given to other refiners, under the alkyl refers to a normal or branched alkyl radical with 1-6 carbon atoms. Under alkenyl, if it is not given to other refiners, assumes a normal or branched alkyl radical with 1-6 carbon atoms, having at least one unsaturation (double bond).

Under radicals, alkylthio, alkoxy, alkylamino, dialkylamino and alkenyl means, respectively, radicals, alkylthio, alkoxy, alkylamino, dialkylamino and alkenyl, where the alkyl moiety has the above values.

Under normal or branched alkyl radical with 1-6 carbon atoms implies, in particular, radicals of Texel. Under the halogen are fluorine atoms, chlorine, bromine or iodine.

The object of the invention is also the above compounds or their pharmaceutically acceptable salts as a drug. The invention also concerns pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or their pharmaceutically acceptable salts for the preparation of pharmaceuticals for inhibition of neuronal NO-synthase or inducible NO-synthase, for regenerating antioxidants (which may be natural or synthetic) or to provide a double function: inhibition of NO-synthase and regenerating antioxidants.

Under the pharmaceutically acceptable salts refers, in particular, additive salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate, oxalate and stearate. In the scope of the present invention also includes when they are usable, salt, formed the basis of what we can refer to "Pharmaceutical salts", J. Pharm. Sci. 66:1 (1977).

The object of the invention is also the use of products of General formula I or pharmaceutically acceptable salts of these products for the preparation of drugs intended for the treatment of pathologies involving the nitric monoxide and/or redox characteristics of thiol groups; such pathologies as disorders of the Central or peripheral nervous system, which is primarily Parkinson's disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, septic shock, diseases caused by the radiation, solar radiation or transplants of organs, autoimmune and autosomally disease, cancer and all pathology characterized produced or dysfunction, in which play the role of nitrogen monoxide and/or redox characteristics of thiol groups.

The object of the invention is also the use of products of General formula I or pharmaceutically acceptable salts of these products for the preparation of drugs intended for the treatment of cerebrovascular disorders such as migraine, cerebral ischemic infarcts are also the products of General formula I or pharmaceutically acceptable salts of these products for the preparation of drugs, intended for the treatment of disorders of the Central or peripheral nervous system, such as neurodegenerative disease, pain, injury, brain or spinal cord, addiction to drugs, alcohol and substances that contribute to addiction, erectile dysfunction, and reproductive function, mental disorders, encephalopathy, depression, anxiety, schizophrenia, epilepsy, sleep disorders, and nutritional disorders.

The pharmaceutical compositions can be in solid form, for example in the form of powders, granules, tablets, gelatin capsules, liposomes or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl-pyrrolidine and wax.

Pharmaceutical compositions containing the compounds of the invention may also be in liquid form, for example in the form of solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, and mixtures thereof in water in different ratios.

Introduction of medicines according to the invention m is olaguera injected dose of medicines according to the invention is from 0.1 mg to 10 g, depending on the type of active compounds.

According to the invention, compounds of General formula I can be obtained using the following methods.

Obtaining compounds of General formula I

A) Obtaining compounds of General formula I, in which Y denotes

The first variant

Compounds of General formula I can be obtained from intermediate products of General formulas II, III and IV according to scheme 1, where a, b, X and Y have the meanings indicated above, a Gp is a protective group of the urethane type.

SCHEME 1

Derivatives of aniline and amines of General formula (II) is subjected to the condensation reaction with compounds of General formula (i) in which L is removed by the group (in particular, an alkoxy group, alkylthio, sulfonic acid, allowin alcohol or tosilos) to obtain the target of the substituted compounds of General formula I amidnogo type (see diagram 1). In particular, if = thiophene derivatives of the General formula II can be condensing with hydroiodide 3-methylthiosemicarbazone, obtained as described in the literature method (Ann. Chim. (1962), 7, 303-337). The condensation can be carried out by heating in alcohol (for example methanol or from whom kih hours or during the night.

In the case when B=SR10for example S-CH3these compounds can be obtained by condensation of amines or anilines of General formula II with isothiocyanates (I. v), where Gp is a protective group, such as benzoline group. Subsequent removal of the protection is realized by the removal of protective groups in suitable conditions, and the resulting thiourea process, for example, halogenoalkanes to obtain the final compounds of General formula I.

In the case when B=NR8R9, the final compounds of General formula I are guanidine. The latter can be obtained, for example, by condensation of the amines or anilines of General formula II with a derivative of General formula (ii) or (I. iii). Compounds of General formula (ii) in which L represents, for example, pyrazol cycle, condense with amines of General formula II are described in the literature conditions (J. Org. Chem. (1992), 2497-2502). The same applies to compounds of General formula (I) in which L represents, for example, pyrazol cycle, and Gp group tBuOCO {Tetrahedron Lett. (1993) 34 (21), 3389-3392), or L is a group-N-SO2-CF3and Gp group tBuOCO (J. Org. Chem. (1998) 63, 3804-3805). At the last stage of the synthesis, release guanidino functions carried out in presets is inane General formula I can be obtained, for example, the condensation of amines or anilines of General formula II with a reagent of formula (I. iv) (N-methyl-N’-nitro-N-nitrosoguanidine) under the conditions described in the literature (J. Amer. Chem. Soc. (1947), 69, 3028-3030).

Compounds of General formula (I)b is obtained from compounds of General formula (I), where A, X and Y are defined above. The transformation of lipovich compounds of General formula (I)and dihydrolipoamide derivatives of General formula (I)b, in which R1=R2=H, is carried out in an alcohol solvent, such as methanol, in the presence of a reducing agent such as NaBH4The N3JV or LiAlH4. Compounds of General formula (I)b, in which R1and R2are not hydrogen, is produced by interaction of the compounds of General formula (I)b, in which R1= R2=H, with a compound of formula R1-Hal and/or R2-Hal (H1=halogen), where R1and R2are as defined above, and the halogen atom is removed by the group. The reaction is carried out, for example, in a suitable solvent such as THF, acetone, or ethyl acetate in the presence of a base, such as Cssos or triethylamine, receiving the intermediate products of General formula (1) (b).

Obtaining compounds of General formula II

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The intermediate products of General formula II in which a and X are such as defined above, can be obtained from the intermediates of General formula III or IV, scheme 1, which are compounds containing, respectively, a protected amine or aniline (NHGp) in the form of, for example, carbamate or nitro. In the particular case of the SIDE-bands of the last removed classic by using triperoxonane acid or model HC1, receiving at the end of primary amines and anilines of General formula II. Restoration of microfunction intermediate products of General formula IV, scheme 1, in which a and X are such as defined above, is carried out, for example, by heating the product in an appropriate solvent, such as ethyl acetate with a small amount of ethanol, in the presence of SnCl2(J. Heterocyclic Chem. (1987), 24, 927-930;

Tetrahedron betters(1984), 25 (8), 839-842), in the presence of SnCl2/Zn (Synthesis (1996), 9, 1076-1078), or by using NaBH4-BiCl3(Synth. Corn. (1995) 25 (23), 3799-3803) in a solvent such as ethanol or using Raney Ni with the addition of hydrazine hydrate is added (Monatshefte fur Chemie, (1995), 126, 725-732), or with the help of India in boiling ethanol-ammonium chloride (Synlett (1998), 9, 1028). Next, the product of the double recovery re-oxidize in the presence of chloride in Zilina again containing ditiolan General formula II.

Obtaining the compounds of General formulas III and IV

Synthesis of carboxamides General formulas III and IV

Carboxamide General formulas III and IV, scheme 2, in which A, X, R3and m such as defined above, is obtained by condensation of the acids of General formula (1.vi) metasystem amines or aniline General formula V or with nitro-derivatives of General formula VI in which a is the radical -(CH2)n-. The radical Rxin the schemes of synthesis of the present application refers to R3or R4. Carboxamide bonds are formed in the classical 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 combining reagent, such as dicyclohexylcarbodiimide (DCC), 1,G-carbonyldiimidazole (CBI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (HDAC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) or in the presence of isobutylacetate and M-methylmorpholine (Org. Prep. Proced. Int. (1975), 35, 215). Synthesis of carboxylic acids of General formula (I. vi) and amines/anilines of General formulas V and VI (not sales) is described below.

SCHEME 2

The second variant

Soy And, In, X and Y are as defined above, a is a radical -(CH2)n-, Rxdenotes the R3or R4and Gp is a protective group, for example a protective group of the urethane type.

SCHEME 3

Synthesis of carboxamides General formula I

Carboxamide General formula I, scheme 4, in which A , X, K3, Y and m are as defined above, is obtained by condensation of the acids of General formula (I. vi) with amines/aniline General formula VII. Carboxamide bonds are formed in the classical 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 combining reagent, such as dicyclohexylcarbodiimide (DCC), 1,1-carbonyldiimidazole (CBI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (HDAC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) or in the presence of isobutylacetate and N-methylmorpholine (Org. Prep. Proced. Int., (1975), 35, 215). Syntheses neprodazhnyh carboxylic acids of General formula (1.vi) described below.

Synthesis of ureas of General formula I

Urea of General formula I, scheme 5, in which A , R4X and Y are such as defined above is to toluene in the presence of diphenylphosphinite (DFA) and the base, such as triethylamine, mostly in 2-3 hours and when heated mainly to a temperature of from 40 to 110 C, for example at a temperature of 80 C.

SCHEME 5

Obtaining the compounds of General formulas VII, VIII, IX and X

Compounds of General formula VII are obtained by removal of protective groups. Compounds of General formula VII, in which RxAnd , X and Y are as defined above, can be obtained from compounds of General formula VIII, scheme 3, which are compounds containing a protected amine (NGp) in the form of, for example, the carbamate. In the specific case of the SIDE-bands of the last removed in the usual way using triperoxonane acid (TFA) or Hcl, getting eventually amines of General formula VII.

Compounds of General formula VIII can be obtained from intermediate products of General formulas IX and X in figure 3, where a, A', X, Y, and Rxsuch as defined above, a Gp is a protective group, for example the carbonate type.

Derivatives of aniline/amines of General formula IX can be condensed with compounds of the General formulas (1.i), (1.ii) and (I. iii) in which L is removed by the group, or with compounds of the General formulas (1.iv) and (1.v), as previously described for soedineniya R3denotes the radical of 2-hydroxy-4,6-dimethoxybenzyl, a Gp denotes tert-butoxy-carbonyl (SIDE), reaction conditions lead to N-dibenzylamino in situ with direct formation of compounds of General formula VIII, 6.

SCHEME 6

Compounds of General formula IX is obtained by restoring the nitro group of compounds of General formula X. Restoration of microfunction compounds of General formula X, scheme 3, in whichxA and X are as defined above, is carried out, for example, by heating the product in a suitable solvent, such as ethyl acetate with a small amount of ethanol, in the presence of SnCl2(J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters(1984), 25 (8), 839-842), in the presence of SnCl2/Zn (Synthesis (1996), 9, 1076-1078), or by using NaBH4-BiCl3(Synth. Corn. (1995) 25 (23), 3799-3803) in a solvent such as ethanol or using Raney Ni with the addition of hydrazine hydrate is added {Monatshefte fur Chemie (1995), 126, 725-732), or with the help of India in boiling ethanol-ammonium chloride (Synlett (1998), 9, 1028), receiving at the end of primary amines and anilines of General formula IX.

Getting neprodazhnyh compounds of General formula X are described below.

C) Obtaining compounds of General formula I, in which Y oboznachit be obtained from intermediates of General formula II according to reaction illustrated in figure 7.

SCHEME 7

The ultimate molecules of General formula I are obtained after removal of 2,5-dimethylpyrrole protective group from compounds of General formula II by heating in the presence of hydroxylaminopurine at a temperature of from 60 to 100 in a solvent, such as ethanol, according to the experimental Protocol described in J. Chem. Perkin Trans. (1984), 12, 2801-2807.

Obtaining compounds of General formula II

Compounds of General formula II can be obtained in accordance with the following synthesis schemes:

1) how to obtain the substituted 2-(2,5-dimethylpyrrole-1-yl)pyridines of General formula (II).x)

1.1) Synthetic precursors, leading to the intermediate products of General formula II, get, scheme 8, compounds of General formula (II).1), such as 2-(2,5-dimethylpyrrole-1-yl)-4,6-dimethylpyridin. The latter is obtained from the sales of 6-amino-2,4-lutidine experimental recipe given in J. Chem. Soc. Perkin Trans. (1984), 12, 2801-2807. Treatment of compounds of General formula (II).1) a strong base, such as n-BuLi, at a temperature of from -50 to -30 C in anhydrous solvent such as diethyl ether in an inert atmosphere, and, possibly, prestore in the presence of the electrophile E+gives adducts of General formula (II).x).

SCHEME 8

1.2) Among electrophiles E+that can react with litrownik compound of General formula (II).2), there are, for example, protected halogenide. Amines of General formula (II).3) is obtained from the intermediate product (II.2), which is condensed, for example, protected halogenating (for example in the form of similarbank derivatives or phthalimido) in the above-described conditions. Amines of General formula (II).4) get in the end after removing the protection in conditions that are described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).

SCHEME 9

2) the Means of obtaining compounds of General formula II

Getting carboxamido General formula II

Carboxamide General formula II in which m, R3And R7such as defined above, can be obtained, diagram 10, the condensation of carboxylic acids of General formula (I. vi) with amines of General formula (II).4) in the above-described conditions. Synthesis neprodazhnyh carboxylic acids of General formula (I. vi) described below.

SCHEME 10

3) Getting some neprodazhnyh intermediate blow synthesis

Narodnye acid Odow. For example, Tris-nurliboev acid is obtained in 5 stages in accordance with the experimental letters (Tetrahedron letters(1997), 38 (33), 5785-5788).

When X represents the radical -(CH2)q-, selectively monoamine primary amines of General formula V and IX in which R3denotes H, can be obtained as described in the literature methods (for example: Synthesis (1984), 12, 1032-1033; Synth. Commit.(1990), 20 (16), 2559-2564; J. Amer. Chem. Soc. (1993), 115 (9), 3548-3557; J. Med. Chem. (1989), 32 (2), 391-396; J. Amer. Chem. Soc. (1995), 117 (11), 3308-3309). Primary nitroamine General formula VI, in which R3denotes H, can be obtained as described in the literature methods (for example: J. Chem. Soc. (1947), (1487).

When X represents a phenylene radical, and n and R5such as described above, amines/anilines of General formula V, in which R3denotes H, can be obtained by the methods illustrated in the diagram below 2.1.

SCHEME 2.1

Compounds of General formula V, scheme 2.1, derived from nitroamines or nitroanilines General formula (VI.1). Protection of the amine or aniline functions by, for example, in a suitable solvent such as dioxane, dichloromethane or acetonitrile in the presence of Fmoc-Cl (Tetrahedron Letters(1989), 30 (11), 1401-1404) or (SIDE)2or PressTV (V. 2) (or compounds of General formula X). Restoration of microfunction in the intermediate products of General formula (V. 2) is usually carried out by catalytic hydrogenation in ethanol in the presence of 10% Pd/C, or using other previously described methods, getting anilines (V. 3) (or compounds of General formula (IX). Protection of the aniline function General formula (V. 3) is carried out, for example, in the presence of Fmoc-Cl or (SIDE)2or predecessors of other well-known specialists of the protective groups (Gp), provided that Cf1Cf2scheme 2.1. The last stage of the synthesis consists in regenerierung primary amine by montelaterone. When, for example, Gp1=Fmoc, the release may be, for example, carried out in any suitable solvent, such as DMF or dioxane in the presence of a base such as piperidine, morpholine, 4-dimethylaminopyridine or diisopropylethylamine (Tetrahedron Letters(1989), 30 (11), 1401-1404). When Gp2=SIDE, releasing carried out in the traditional way using triperoxonane acid or model HC1, getting eventually montedison anilines of General formula V. the compounds of General formulae IX and X, in which R3is a radical 2-hydroxy-4,6-dimethoxyphenyl, Gp is a group SIDE, and n and R5such as you described is inane General formulas IX and X get scheme 6.1, the condensation of 2-hydroxy-4,6-dimethoxybenzaldehyde with amine/aniline of General formula (VI.1) in a reducing environment. The reaction proceeds in an alcohol solvent such as methanol, in the presence of a reducing agent such as NaBH4or N3The JV. Protection of the resulting secondary amine is carried out after this the standard way using the (SIDE)2in dichloromethane, obtaining the compounds of General formula X. Restoration of microfunction compounds of General formula X is carried out by catalytic hydrogenation in ethanol in the presence of 10% Pd/C, receiving anilines IX.

When X represents a phenylene radical, a Rs denotes a 5 - or 6-membered heterocycle containing one nitrogen heteroatom, or a group containing a heteroatom W (group, denoted by W , where W=0, N or S, denotes alkyl and absent when W=0 or S, or denotes H or alkyl when W=N), scheme 3.1 and 3.2, narodnye amines/anilines of General formula X, in which R3is hydrogen, is obtained using the methods described in the literature (for example J. Med. Chem. (1980), 23, 973-975; J. Med. Chem. (1990), 33, 633-641; Chem. Heterocycl. Compd. (EN), (1969), 5, 683-687; J. Org. Chem. USSR (EN) (1989), 3, 599-600; J. Med. Chem. (1994), 37, 467-475; J. Med. Chem. (1999), 42, 4362-4379). Compounds of General formula the SCHEME 3.1

Compounds of General formula X, scheme 3.1, in which n, Het and Wo are as defined above, is obtained from halogennitroethylenes General formula (H. 2). The restoration of the nitrile function of the intermediate products of General formula (Z 2), scheme 3.1, implement, for example, in a suitable solvent such as ether or THF, in the presence of DIBORANE or LAH. After that, the formed halogennitroalkane/amines (H. C) protect in the form of a SIDE (X. 4), or using other well-known specialists of the protective groups (Gp), after which the compounds of General formula (X. 4) is subjected to nucleophilic substitution of the heterocyclic group (het) in a solvent such as DMSO or DMF in the presence of a base, such as2CO3, KOH or NaOH to obtain intermediate products of General formula X.

Compounds of General formula X are such as defined above, can also be obtained using a method similar to the method presented in the diagram below 3.2:

SCHEME 3.2

Compounds of General formula X, scheme 3.2, in which R5denotes a 5 - or 6-membered heterocycle containing a heteroatom nitrogen or a group containing a heteroatom W (defined above W ), derived from halogen-natstown reagent in any solvent, such as DMSO or DMF, in the presence of a base, such as2CO3, KOH or NaOH to obtain intermediate products of General formula (H. 5).

The restoration of the nitrile function of the intermediate products of General formula (H. 5), scheme 3.2, implement, for example, in a suitable solvent such as ether or THF, in the presence of DIBORANE or LAH. After that, the formed halogennitroalkane/amines (H. 6) protect in the form of a SIDE, or using other well-known specialists of the protective groups (Gp) in order to ultimately obtain a intermediate products of General formula X, scheme 3.2.

The following examples are presented to illustrate the procedures below and in no way should be construed as limiting the scope of the invention.

EXAMPLES

Example 1

The hydrochloride of N-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}-1,2-ditiolan-3-pentanone

1.1) N-{4-[{1,1-Dimethylmethoxy)carbylamine]phenyl}-1,2-ditiolan-3-pentanone

To a solution of 2 g (9,694 mmol) of DL-lipoic acid in 40 ml of dichloromethane successively added 1.84 g (8,81 mmol) N-BOC-1,4-phenylenediamine, 1.6 ml of triethylamine, 1.7 g (12.6 mmol) of hydroxybenzotriazole, 4,82 g of 25.2 mmol) hydrochloridee night at 25 mixture is diluted with 100 ml of water and continue stirring for another 30 minutes The product is extracted three times with 100 ml dichloromethane. The organic solution is dried on magnesium sulfate, filtered and evaporated in vacuum. The obtained reddish residue is suspended in ether (100 ml), filtered and washed in the same volume of ether, receiving pale pink with orange shimmer powder with a yield of 80.5 per cent, so pl. 190-195 C.

NMR1H (DMSO-d6, 400 MHz ): 1.39 in (m, 2H, CH2); of 1.57 (s, N, SIDE); to 1.61 (m, 4H, CH2); of 1.88 (m, 1H, CH2); and 2.27 (m, 2H, CH2); of 2.50 (m, 1H, CH2); 3.15 in (m, 2H, CH3); 3,63 (m, 1H, -S--); 7,34 (d, 2H, arene., J=8,70 Hz); was 7.45 (d, 2H, arene., J=9,00 Hz); 9,24 (s, 1H, CONH), made up 9.77 (s, 1H, CONH-SIDE).

1.2) N-(4-AMINOPHENYL)-1,2-ditiolan-3-pentanone

Through a solution of intermediate 1.1 (6.5 g; 16.4 mmol) in a mixture (200 ml), the ether/ethanol/acetone/dichloromethane (1/1/1/1) is passed through the gaseous ozonation model HC1 at 0 C. the Temperature was raised to room temperature during the night, passed through the reaction stream of argon and evaporated to dryness solvents. After that, the evaporation residue poured into 100 ml of cold saturated solution Panso3and thrice extracted with 100 ml dichloromethane. The organic phase is dried on magnesium sulfate, filtered and evaporated in vacuum. After that make cleanup on to the beige color with 29%, so pl. 55-60 C.

NMR 1H (DMSO-d6, 400 MHz ): to 1.38 (m, 2H, CH2); of 1.57 (m, 4H, CH2); to 1.87 (m, 1H, CH2); 2,22 (m, 2H, CH2); 2.40 a (m, 1H, CH2); 3,18 (m, 2H, CH2); 3,62 (m, 1H, -S--); 4,78 (s, 2H, NH2); 6.48 in (d, 2H, arene., J=8,64 Hz); then 7.20 (d, 2H, arene., J=8,64 Hz); 9,39 (s, 1 H ).

1.3) of the Hydrochloride of N-14-[[(2-thienyl) (imino)methyl]amino]phenyl} -1,2-ditiolan-C-pentanolide

Intermediate 1.2 (0,703 g; is 2.37 mmol) dissolved in 2-propanol (15 ml) and add 1,014 registered g hydroiodide S-methyl-2-titaniumoxide (of 3.56 mmol) (Ann. Chim. (1962), 7, 303-353). After heating for 15 hours at 60 the reaction mixture is evaporated to dryness in vacuum. The remainder absorb dichloromethane and a saturated aqueous solution of N. After separating layers, the organic phase is successively washed with 50 ml saturated aqueous solution Panso3, water and brine. The organic solution is dried on magnesium sulfate, filtered and evaporated under reduced pressure. After this free base is dissolved in 30 ml of dichloromethane, cooled the solution in an ice bath and added dropwise to 6.3 ml of a 1N solution of Hcl in anhydrous diethyl ether. After stirring for 15 hours at 25 With the resulting crystals are filtered and washed with diethyl ether, UP>H (DMSO-d6, 400 MHz ): USD 1.43 (m, 2H, CH2); of 1.62 (m, 4H, CH2); a 1.88 (m, 1H, CH2); of 2.38 (m, 3H, CH2); 3,18 (m, 2H, CH2); 3,63 (m, 1H, -S--); 7,20-to 8.20 (m, 7H, arene.); 8,79 (user., 1H, NH+); 9,78 (user., 1H, NH+); 10,36 (s, 1H ); 11,49 (user., 1H, NH+).

IR: vc=N(amidon): 1580 cm-1; Vc=o(amide): 1659 cm-1.

Example 2

N-{2-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}ethyl}-1,2-ditiolan-3-pentanone

2.A. The first variant of the method

Used the same sequence of operations described for compound 1. The yellow solid product with so pl. 146-148 C.

NMR1H (DMSO-d6, 400 MHz ): 1,32 (m, 2H, CH2) and 1.60 (m, 4H, CH2); a 1.88 (m, 1H, CH2); 2/07 (t, 2H, CH2, J=of 7.36 Hz); 2,41 (m, 1H, CH2); to 2.65 (m, 2H, CH2); 3,10-3,30 (m, 4H, CH2); of 3.60 (m, 1 H, -S--); 6,33 (user., 2H, NH, amidon); is 6.78 (d, 2H, arene., J=8,04 Hz); was 7.08 (m, 1H, thiophene); for 7.12 (d, 2H arene., J=8,16 Hz); 7,60-7,80 (m, 2H, thiophene); 7,81 (t, 1H , J=5,56 Hz).

IR: vC=N(amidon): 1590 cm-1; V=o (amide): 1629 cm-1.

2.In. The second variant of the method

The synthesis of compounds of example 2 can also be carried out by the method illustrated in schemes 3 (Gp=SIDE and R3=2-hydroxy-4,6-dimethoxybenzyl) and 6.

2.B.1) 3,5-Dimethoxy-2-({sledovatelno added 9.0 g (49.4 mmol) of 4,6-dimethoxybenzaldehyde, 11.6 g (to 54.3 mmol) of the hydrochloride of 4-nitrophenylamino and 7.5 ml of triethylamine. The reaction mixture was intensively stirred for 15 min, after which portions add 2.1 g (of 55.5 mmol) NaBH4. Stirring is continued for another 10 hours and add 10 ml of water. A quarter of an hour, the reaction mixture was twice extracted with 100 ml of CH2CL2. The organic phase is successively washed with 50 ml water and 50 ml of brine, dried on sodium sulfate, filtered and evaporated in vacuum. The residue is then purified on a column of silica gel (eluent: CH2Cl2/EtOH, 20/1) to give an orange oil with a yield of 58%.

2.In.2) Tert-butyl ester 2-hydroxy-4, 6-dimethoxy-benzyl{2-(4-nitrophenyl)ethyl]carbamino acid

Used the same sequence of operations described for intermediate 7.B.1, with the replacement of nitrobenzylamine on the intermediate product 2.In.1. Get a white solid with a yield of 60%, so pl. 133,5-134,4 C.

2.In.3) Tert-butyl ether 2-(4-AMINOPHENYL)ethyl(2-hydroxy-4, 6-dimethoxybenzyl)carbamino acid

Used the same sequence of operations described for intermediate 7.In.2, with the replacement of the intermediate product 7.1 on the intermediate product 2.In.2-den]amino}phenyl)ethylcarbamate acid

Used the same sequence of operations described for intermediate product 1.3, replacing intermediate 1.2 intermediate product 2.In.3. In these conditions is N-dibenzylamine with the formation of a primary amine, monoamino group SIDE. Receives a yellow solid with a yield of 79%, so pl. 144 C.

2.In.5) N -[4-(2-amino-ethyl)phenyl]-2-thiophenecarboxylate

Used the same sequence of operations described for intermediate product 1.2, with the replacement of intermediate 1.1 to the intermediate product 2.In.4.

Get a white solid with a yield of 79%, so pl. 169,2-170,5 C.

2.In.6) N-{2-{4-[[2-Thienyl) (imino)methyl]amino]phenyl}ethyl}-1,2-ditiolan-3-pentanone

Used the same sequence of operations described for intermediate product 1.1, with replacement M-BOC-1,4-phenylenediamine for the intermediate product 2.In.5. Receives a yellow solid with a yield of 79%, so pl. 146-148 C.

NMR1H (DMSO-d6, 400 MHz ): 1,32 (m, 2H, CH2) and 1.60 (m, 4H, CH2); a 1.88 (m, 1H, CH2); 2,07 (t, 2H, CH2, J=of 7.36 Hz); 2,41 (m, 1H, CH2); to 2.65 (m, 2H, CH2); 3,10-3,30 (m, 4H, CH2); of 3.60 (m, 1H, -S--); 6,33 (user., 2H, NH2amidin); is 6.78 (d, 2H, arene., J=8,INF): 1590 cm-1; vC=O(amide): 1629 cm-1.

2.With. Another method according to the second variant

Can also be used another synthesis is illustrated in scheme 3, where Gp=SIDE. The sequence of operations in this case are similar to those described below for method 7.

In replacing p-nitrobenzylamine 4-nitrophenylamino.

Example 3

Hydrochloride N-{2-{4-[[(2-thienyl)(imino)methyl]amino]

phenyl}ethyl}-1,2-ditiolan-3-ndimethylacetamide 3.A. The first variant of the method

Used the same sequence of operations described for compound 1, with the replacement of lipoic acid on Tris-nurliboev acid [2-(1,2-ditiolan-3-yl)acetic acid] (obtained by the method of Tetrahedron Letters, (1997), 38, 33, 5785). Yellow solid.

NMR1H (DMSO-d6, 400 MHz ): 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--); 7,30-to 7.50 (m, 5H, arene.); 8,10-8,30 (m, 3H), arene. + ; 8,86 (user., 1H,NH+); 9,80(user., 1H, NH+); 11,50 (user., 1H, NH+). MS:MH+=392,1.

3.In. The second variant of the method

The synthesis of compounds of example 3 can also be carried out by the method illustrated in schemes 3 (Gp=SIDE and R3=2-hydroxy-4,6-dimeth the traveler to method 2.In, with the replacement of lipoic acid on Tris-nurliboev acid [2-(1,2-ditiolan-3-yl)acetic acid] (obtained by the method of Tetrahedron Letters(1997), 38, 33, 5785). Yellow solid.

3.With. Another method according to the second variant

Can also be used another synthesis is illustrated in scheme 3, where PD=the SIDE. The sequence of operations in this case are similar to those described below for method 7. In replacing p-nitrobenzylamine on nitrophenylamino and lipoic acid on Tris-nurliboev acid [2-(1,2-ditiolan-3-yl)acetic acid] (obtained by the method of Tetrahedron Letters(1997), 38, 33, 5785)).

Example 4

N-[4-(6-Amino-4-methyl-2-pyridinyl)butyl]-1,2-ditiolan-3-pentanone

4.1) 6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methyl-2-pyridinylamino

Dissolved in an argon atmosphere, 1 g (5 mmol) of 2-(2, 5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyridine (derived from 6-amino-2,4-lutidine method J. Chem. Soc., Perkin Trans., 1984, 12, 2801) in 10 ml of anhydrous diethyl ether with 1,132 ml (7.5 mmol) of N,N,N,N-tetramethylethylenediamine (TMEDA). Reaction mixture cooled down to -20 ° C and added dropwise 2.4 ml (6 mmol) of a 2.5 M solution of BuLi in hexane. The reaction mixture is kept for 5 hours at -20 ° C, cooled to -45 With add 1.68 g (6 mmol) of 1-(3-bromopropyl)-of 2.2.5.5-tetramethyl room. Add 50 ml of saturated solution of ammonium chloride and stirred the mixture for 2 hours at 25 C. the Organic phase is separated and washed successively with 40 ml water and 40 ml of brine, dried on magnesium sulfate, filtered and evaporated in vacuum. The obtained residue is purified on a column of silica gel (eluent: dichloromethane with 5% ethanol) to give a yellow oil with a yield of 62%.

NMR1H (Dl3, 400 MHZ ): of 1.52 (m, 2H, CH2); of 1.78 (m, 2H, CH2); 2,11 (s, 6N, 2 CH3pyrrole); 2,39 (s, 3H, CH3, pyridine); a rating of 2.72 (t, 2H, CH2, J=7,02 Hz); and 2.79 (t, 2H, CH2, J=a 7.62 Hz); by 5.87 (s, 2H, pyrrole); 6,85 (s, 1H, pyridine); 6,98 (s, 1H, pyridine).

4.2) N-{4-[6- (2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-2-pyridinyl]butyl}-1, 2-ditiolan-3-pentanone

Used the sequence of operations is the same as described for intermediate product 1.1, replacing N-BOC-1,4-phenylenediamine intermediate product 4.1. Receives a yellow oil.

NMR1H (CDCl3, 400 MHz ): 1,30-2,00 (m, 11N, CH2); 2,07 (m, 2H, CH2); 2,11 (s, 6N, 2 CH3pyrrole); 2.40 a (s, 3H, CH3 the pyridine); of 2.45 (m, 1H, CH2); 2,82 (m, 2H, CH2); 3,10-3,30 (m, 4H, CH2); 3,57 (m, 1H, -S--); by 5.87 (s, 2H, pyrrole); 5,94 (s OSiR., 1H ); 6.87 in (s, 1H, pyridine); 6,99 (s, 1 H, pyridine). MS:MH+ = 446,2

4.3) N- [4-[6-amino-4-methyl-2-feast of the Nola with the addition of 18 ml of water and add 1.2 g (17,2 mmol) of hydroxylamine hydrochloride. The reaction mixture is boiled for 24 hours. After the fall of temperature to 25 mixture is diluted with 20 ml of saturated solution of sodium bicarbonate and extracted the product with 100 ml of dichloromethane. After separation of the phases the organic solution is washed sequentially with 40 ml saturated sodium bicarbonate solution and 40 ml of brine, dried on magnesium sulfate, filtered and evaporated in vacuum. The evaporation residue purified on a column of silica gel (eluent: dichloromethane with 2.5% ethanol) to give a yellow oil with a yield of 76%.

NMR1H (CDCl3, 400 MHz ): of 1.30 and 1.80 (m, 10H, CH2); 1,89 (m, 1H, CH2); of 2.16 (m, 2H, CH2); 2,19 (s, 3H, CH3the pyridine); 2.40 a (m, 1H, CH2); of 2.58 (m, 2H, CH2); 3,05-3,30 (m, 4H, CH2); to 3.56 (m, 1H, -S--); 4,35 (user., 2H, NH2); 5,80 (user., 1H ); of 6.17 (s, 1H, pyridine); 6,35 (s, 1H, pyridine). IR: Vc=0(amide): 1637 cm-1.

Example 5

Fumarate of N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-ditiolan-3-ndimethylacetamide

Used the sequence of operations is the same as the sequence of operations described for compound 4, with the replacement of lipoic acid on Tris-nurliboev acid [2-(1,2-ditiolan-3-yl)acetic acid] (obtained by the method of Tetrahedron Letters(1997), 38, 33, 5785). Free base after this is Marat in the form of a cream-coloured powder with a yield of 14.8%.

NMR1H (DMSO-d6, 400 MHz ): 1,40 (m, 2H, CH2); of 1.57 (m, 2H, CH2); of 1.92 (m, 1H, CH2); to 2.15 (s, 3H, CH3the pyridine); 2,30-2,70 (m, 5H, CH2); 3,03-3,18 (m, 4H, CH2); of 3.94 (m, 1H, -S--); of 6.17 (s, 1H, pyridine); of 6.26 (s, 1H, pyridine); 6,00-6,60 (user., 2H, -CO2H fumaric acid); 6,60 (s, 2H, =, fumaric acid); of 7.90 (user., 1H ). IR: Vc=0(amide): 1649 cm-1. MS: ME+ = 326,2.

Example 6

N-[4-{[Amino(2-thienyl)methylidene]amino}phenyl]-2-(1,2-ditiolan-3-yl)ndimethylacetamide

Used the sequence of operations is the same as the sequence of operations described for compound 1, with the replacement of lipoic acid on Tris-nurliboev acid [2-(1,2-ditiolan-3-yl)acetic acid] (obtained by the method of Tetrahedron Letters, (1997), 38, 33, 5785). Yellow foam.

NMR 1H (DMSO-d6, 400 MHz ): 2,00 (m, 1H, CH2); 2,40 is 2.80 (m, 3H, CH2); 3,00-3,30 (m, 2H, CH2); 4,10(m, 1H, -S--); 6,50-6,80 (user., 2H, NH+); 6,80-7,10 (m, 3H), arene.); 7,50-7,80 (m, 4H, arene.); to 9.93 (s, 1H ). NH+ = 364,1.

Example 7

N-[4-{[Amino(2-thienyl)methylidene]amino}benzyl)-5-(1,2-ditiolan-3-yl)pentanone

7.A. The first variant of the method

Used the sequence of operations is the same as the sequence of operations described for compound 1, with the substitution of N-BOC-1,4-what.

7.In. The second variant of the method

7.In.1) Tert-butyl-4-nitrobenzylamine

Dissolve to 5.66 g (30.0 mmol) of the hydrochloride of p-nitrobenzylamine in a mixture of 100 ml of dichloromethane with 9.2 ml of triethylamine. The reaction mixture was cooled in an ice bath and add a few servings of 7.2 g (33.0 mmol) (SIDE)20, stirred for 12 h at 23 C and poured into a mixture of ice water. The organic phase is separated, washed successively with 20 ml water and 20 ml brine. After drying on magnesium sulfate, filtration, evaporation in vacuo and trituration in diisopropyl ether get a white solid with a yield of 67.4%, so pl. 107,8 C.

7.In.2) Tert-butyl-4-aminobenzylidene

In a stainless steel autoclave with a magnetic bar download solution of intermediate 7.B.I (5,1 g; a 20.2 mmol) in 66 ml of a mixture of dichloromethane, ethyl acetate and THF (1 ml/60 ml/5 ml), and 1.0 g of 10% Pd/C. the Reaction mixture is stirred under hydrogen pressure (1.5 bar) for 12 hours at a temperature of 20 C. then Pd/C was removed by filtration, and the filtrate evaporated in vacuum. The evaporation residue is cleaned by rubbing with Diisopropylamine ether, receiving a grayish-white powder with a yield of 42%, so pl. 74,4 C.

7.In.3) Tert-butyl ether 4-{[amino(2-thienyl)were labeled d is egovernance operations, described for intermediate product 1.3, replacing intermediate 1.2 intermediate product 7.In.2. Get orange oil with a yield of 99%.

NMR1H (AMCO-d6, 400 MHz ): 1,40 (s, N, HSN3); 4,19 (d, 2H, CH2, J=6,00 Hz); 7,30-7,40 (m, 5H, arene.); 7,46 (t, 1H, CONH, J=6,00 Hz); 8,10-to 8.20 (m, 2H, thiophene); 9,00-10,00 (user., 2H, NH, amidon); 11, 10-11,40 (user., 1H, HI). MN+ = 332,2.

7.8.4) N -[4-(aminomethyl)phenyl]-2-thiophenecarboxylate

Used the sequence of operations is the same as the sequence of operations described for intermediate product 1.2, with the replacement of the intermediate product 1.1 the intermediate product 7.In.3. Get a white solid with a yield of 92%, so pl. 241,1-241,6 C.

7.8.5) N-(4-{[Amino(2-thienyl)methylidene]amino}benzyl)-5-(1,2-ditiolan-3-yl)pentanone

Used the sequence of operations is the same as the sequence of operations described for intermediate product 1.1, with the substitution of N-BOC-1,4-phenylenediamine intermediate product 7.In.4. Get a white solid with a yield of 40%, so pl. 151,9-152,1 C.

Example 8

N-(5-{[Amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-5-(1,2 ditiolan-3-yl)pentanone

(obtained according to the second variant of the method)

8.1. 50 ml of DMF added sequentially to 3.36 g (21,0 mmol) 2-methoxy-5-nitroaniline, the triethylamine (6.0 ml), 3.0 g (22,0 mmol) of hydroxybenzotriazole and 4,21 (22,0 mmol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring for 18 hours at 80 reaction mixture is diluted with 400 ml of water and continue stirring for an additional 30 minutes the Product is extracted three times with 200 ml dichloromethane. The organic solution is dried on magnesium sulfate, filtered and evaporated in vacuum. The obtained solid is filtered off and washed with diethyl ether, obtaining after drying, 2.6 g of a yellow solid product (yield 37%), so the square of 116.7-117,1 C.

8.2. N-(5-Amino-2-methoxyphenyl)-5-(1,2-ditiolan-3-yl)pentanone

To a solution of 2.6 g (13,20 mmol) of the intermediate product 8.1 in 40 ml of ethanol are added sequentially with 10 ml of a saturated aqueous solution of ammonium chloride and 12.0 g (0,183 mol) powder India. After that the reaction mixture boiled for 4.5 hours (Synlett (1998), 9, 1028), cooled to room temperature and filtered on celite. The filtrate is alkalinized 50% sodium hydroxide solution to pH 10. The recovered product 4 times with 150 ml dichloromethane. The organic solution is dried on magnesium sulfate, filtered and evaporated in vacuum, obtaining oil chestnut color. The oil is dissolved is carbonate potassium in water, stir the mixture for about 10 min at 0 C and added dropwise a solution of iodine (0.8 g in 10 ml ethyl acetate) to stable iodine staining. The product is extracted with 4 times 100 ml of ethyl acetate, then the organic solution is dried on magnesium sulfate, filtered and evaporated in vacuum. Next, perform a purification on a column of silica gel (eluent: 5% ethanol in dichloromethane) to give the chestnut colored oil (1.0 g, yield 63%). MH+= 327,20.

8.3. N-(5-{[Amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-5-(1, 2-ditiolan-Z-yl)pentanone MN+=436,10.

Example 9

N-[5-{[Amino(2-thienyl)methylidene]amino}-2-(dimethylamino)benzyl]-5-(1,2 ditiolan-3-yl)pentanone

(obtained according to the second variant of the method)

9.1. 2-(Dimethylamino)-5-nitrobenzonitrile

Dissolved in argon atmosphere 1.66 g (10.0 mmol) 2-fluoro-5-nitrobenzonitrile, 1.22 g (15.1 mmol) of dimethylamine hydrochloride and 3.46 g (a 25.1 mmol) of potassium bicarbonate in DMF (30 ml), after which the reaction medium was heated for 18 h at 80 C, cooled to 0 C, add ice water and extracted with ethyl acetate. The organic phase is washed successively with 50 ml water and 50 ml of brine, dried on magnesium sulfate, filtered and evaporated in vacuum. The remainder UPrev what isopentane, getting after drying, 2.0 g of a yellow solid product (yield 100%), so pl. 109-110,5 C.

9.2. 2-(Aminomethyl)-N,N-dimethyl-4-nitroaniline

The intermediate product 9.1 (1.5 g, 7.85 mmol) is dissolved in an atmosphere of argon in THF (40 ml) and add a solution of DIBORANE (16 ml, 1 M in THF). After that, the reaction mixture is boiled for 6 hours, add methanol (30 ml) and then for 15 min bubbled through a mixture of gaseous Hcl. Reaction medium was evaporated to dryness, absorb with sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed successively with 50 ml water and 50 ml of brine, dried on magnesium sulfate, filtered and evaporated in vacuum. The evaporation residue purified by crystallization from a mixture of diisopropyl ether-dichloromethane, receiving a yellow solid product with a yield of 82%, so pl. 196-200 C.

9.3. Tert-butyl ester 2-(dimethylamino)-5-nitrobenzyl-carbamino acid

Used the sequence of operations is the same as the sequence of operations described for stage 7. B. 1 of example 7, with the replacement of the hydrochloride of p-nitrobenzylamine intermediate product 9.2. Receives a yellow solid with a yield of 100%, so pl. 101-102 C.

9.4. Tert-butyl ester 5-amino-2-(dimethylamino)benzo is th operations described for stage 7. Century 2 of example 1, with the replacement of the intermediate product 7.In.1 at an intermediate product 9.3. Get the chestnut colored oil with a yield of 15%. MH+= 266,20.

9.5. Tert-butyl ester 5-{[amino(2-thienyl)methylidene]amino}-2-(dimethylamino)benzylcarbamoyl acid

Used the sequence of operations is the same as the sequence of operations described for stage 1.3 of example 1, by replacing intermediate 1.2 intermediate product 9.4. Receives a yellow solid with a yield of 64%, so pl. 175,8-177,0 C.

9.6. N -[3-(aminomethyl)-4-(dimethylamino)phenyl]-2-thiophenecarboxylate

Used the sequence of operations is the same as the sequence of operations described for stage 1.2 of example 1, with the replacement of intermediate 1.1 to intermediate product 9.5. Receives a yellow solid with a yield of 66%, so pl. 169,0-170,0 C.

9.7. N-[5-{[Amino(2-thienyl)methylidene]amino}-2-(dimethylamino)benzyl]-5-(1, 2-ditiolan-Z-yl)pentanone

Used the sequence of operations is the same as the sequence of operations described for stage 1.1 of example 1, by replacing N-BOC-1,4-phenylenediamine intermediate product 9.6. Get white solid with yield the 1,2 ditiolan-3-yl)pentanone

Used the sequence of operations is the same as the sequence of operations described for the compound of example 9, with replacement at the first stage of dimethylamine hydrochloride in pyrrole. Get a white solid with a yield of 72%, so pl. 156,1-157, 6 S.

Pharmacological study of the compounds according to the invention

Study of the effect on the constitutional neuronal NO synthase of rat cerebellum

The inhibitory activity of the products of the invention is determined by measuring their impact on the transformation using MO-synthase [3N]L-arginine [3H-citrulline using a modified method of Bredt and Snyder (Proc. Nat. Acad. Sci. USA (1990) 87: 682-685). The cerebellum of rats breed Sprague-Dawley (300 g Charles River) just select, prepare at 4 C and homogenized in a volume of extraction buffer (HEPES 50 mm, EDTA 1 mm, pH 7.4, pepstatin A, 10 mg/ml leupeptine 1 mg/ml). The homogenates are then centrifuged at 21000 g for 15 min at 4 C. the Measurement is made in glass tubes, which are distributed 100 μl of incubation buffer containing 100 mm HEPES (pH 7.4), 2 mm 3DTA, 2.5 mm CaCl2, 2 mm dithiothreitol, 2 mm restored NADP and 10 μg/ml of calmoduline. Add 25 ál of a solution containing 100 nm of [3N]L-Arsenium 50 μl of homogenate, resulting in a final volume of 200 μl (missing 25 ál are either water or test the product). After 15 min the reaction is stopped with 2 ml of stop buffer (20 mm HEPES, pH 5.5, 2 mm DTA). After passing the samples through a column of 1 ml resin DOWEX quantitatively measure the radioactivity in a liquid acquired scintillation spectrometer.

The above compounds of examples 1, 2, 3, 4, 5 show the values CI50below 4.5 microns.

Study of the effect on oxidative stress induced by glutamate in culture cells (HT-22)

Inhibitory activity of the compounds according to the invention is determined by measuring their ability to protect hippocampal cells in mice (HT-22) from oxidative stress induced by glutamate. The biosynthesis of glutathione, an essential element for detoxification of the cells against free radicals requires the active intracellular transport of cystine. Glutamate, preventing the penetration of cystine causes a decrease in the level of glutathione, which leads to cell death from oxidative stress (Davis, J. B. and Maher, P., Brain Res. (1994), 652: 169-173; Murphy, T. N. et al.. Neuron (1989) 2: 1547-1558). Cells were cultured at 37 C in DMEM to which was added 10% p cells. Glutamate (5 mm) is added to a medium containing or not containing the tested products. Cell survival test after 24 hours by MTT method (Hansen, M. B. et al., J. Immunol. Methods (1989), 119, 203-210). The ability of compounds to protect cells from the toxic effects of glutamate appreciate in value CE50calculated in relation to the survival of cells exposed to glutamate, the survival of which is taken for 100%.

The above compounds of examples 1, 2, 3, 5 show the values of CE50below 30 μm.

1. Derivatives of lipoic acid of General formula (Ia)

where And denotes the radical -(CH2)m-CO-NR3-(CH2)nor

-(CH2)m-, where m and n denote integers 0-6,

R3denotes a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms;

X denotes the radical

in which T, coupled with the group Y represents the radical -(CH2)i- where i denotes an integer of 0-6, a R5denotes a hydrogen atom, normal or branched alkyl radical with 1-6 carbon atoms or alkoxy radical or dialkylamino containing 1-6 nya selected from the radicals-O-,-NH - and-S-; or X represents the radical -(CH2)q-, in which q denotes an integer of 0-6;

Y denotes one of the radicals:

which indicates a normal or branched alkyl radical with 1-6 carbon atoms, 5 - or 6-membered carbocyclic or heterocyclic aryl containing 1-4 heteroatoms selected from O, S, N, in particular, radicals, thiophene, furan, pyrrole or thiazole, and the aryl radical may be substituted by one or more groups selected from normal or branched alkyl radicals or alkoxy;

R7 denotes a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms.

2. Derivatives of lipoic acid on p. 1, characterized in that X denotes the radical

in which T, coupled with the group Y represents the radical -(CH2)i- where i denotes an integer of 0-6,

R5denotes the radical pyrrole, imidazole, pyrazole, triazole, thiazolidin, pyrrolidine, piperidine, piperazine, N-alkylpiperazine, thiomorpholine, morpholine or azetidin.

3. Derivatives of lipoic acid on p. 1, characterized in that they represent one of the following compounds is about)methyl]amino]phenyl}ethyl}-1,2-ditiolan-3-pentanone;

-N-{2-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}ethyl}-1,2-ditiolan-3-ndimethylacetamide;

-N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-ditiolan-3-pentanone;

-N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-ditiolan-3-ndimethylacetamide;

-N-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-2-(1,2-ditiolan-3-yl)ndimethylacetamide;

-N-(4-{[amino(2-thienyl)methylidene]amino}benzyl)-5-(1,2-ditiolan-3-yl)pentanone;

-N-(5-{[amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-5-(1,2-ditiolan-3-yl)pentanone;

-N-[5-{[amino(2-thienyl)methylidene]amino}-2-(dimethylamino)benzyl]-5-(1,2-ditiolan-3-yl)pentanone;

-N-[5-{[amino(2-thienyl)methylidene]amino}-2-(1H-pyrrol-1-yl)benzyl]-5-(1,2-ditiolan-3-yl)pentanone;

4. The method of obtaining derivatives of lipoic acid of General formula Ia under item 1, characterized in that an intermediate compound of General formula (II)

where And denotes the radical -(CH2)m-CONH-(CH2)n- or -(CH2)m-, where m and n denote integers 0-6,

X denotes a phenylene radical or -(CH2)q- where q denotes an integer of 0-6,

enter into reaction with an intermediate compound of General formula (i):

which means normal or once the sludge, containing 1-4 heteroatoms selected from O, S, N, in particular, radicals, thiophene, furan, pyrrole or thiazole, and the aryl radical may be substituted by one or more groups selected from normal or branched alkyl radicals or alkoxy having 1-6 carbon atoms,

L denotes the deleted group, such as alkoxy radical, alkylthio, the remainder of the sulfonic acid, halogen, balance kilowog alcohol or tosyl.

5. The method of obtaining derivatives of lipoic acid of General formula Ia under item 1, where And denotes the radical -(CH2)m-ONR3-(CH2)n-, where R3denotes a hydrogen atom or normal or branched alkyl radical with 1-6 carbon atoms, characterized in that the intermediate product of General formula (VII)a:

HN(R3)-A’-X-Y

(VII) a

where R3the same as defined above;

X and Y are such as defined in paragraph 1;

A’ represents the radical -(CH2)n-, in which n is an integer 0-6,

enter into interaction with the compound of General formula (I. vi):

where m is an integer of 0-6.

6. Derived lipoic acid of General formula Ia, as described in one of paragraphs.1-NGO inhibitory activity against NO-synthase and the ability to regenerate antioxidants.

7. Derived lipoic acid on p. 6 for the preparation of medicines intended for the treatment of pathologies involving the nitric monoxide and/or redox characteristics of thiol groups.

8. Pharmaceutical composition having inhibitory activity against NO-synthase and the ability to regenerate antioxidants, containing as active principle at least one compound according to one of paragraphs.1-3, or a pharmaceutically acceptable salt of this compound.

Priority items:

24.02.2000 on PP.1, 2, 4, and 5;

31.03.2000 on PP.3, 6-8.

 

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