ES2331282A1 - Hydrazides of heterocyclic systems and use thereof in the treatment of neurodegenerative diseases - Google Patents

Abstract

The present invention relates to a family of compounds with the structural characteristic of a hydrazide group linked to a heterocyclic system, to pharmaceutical compositions containing same, and to the use thereof as agents for the treatment of diseases of the central nervous system, caused by a series of processes included in what is generically referred to as neurodegeneration.

Description

Hydrazides of heterocyclic systems and their use in the treatment of neurodegenerative diseases.

The present invention is included in the field of Research and pharmaceutical industry. In particular, it focuses in chemical compounds derived from hydrazides and their use as agents for the treatment of diseases of the nervous system central, caused by a series of processes included in what It is generically called neurodegeneration.

State of the art

The progressive aging of the world population brings with it the unwanted consequence of an increase in neurodegenerative diseases and senile dementias. Among these, Alzheimer's disease, EA hereafter, is the most common neurodegenerative disease, responsible for approximately two thirds of the total dementia cases (varying between 42 and 81% according to different studies), with a prevalence closely related to age, which approaches 50% in the population over 85 years of age, and which affects women more than men ( N. Engl. J. Med . 2003 , 348 , 1356-1364).

There are several biochemical processes affected in the brains of AD patients: abnormal metabolism and aggregation of the amyloid protein, hyperphosphorylation of the tau protein, neuronal loss, problems in cholinergic neurotransmission, etc. Undoubtedly, an improvement of any of these pathologies separately would be a correct, if incomplete, approach to the treatment of the disease. Currently, the drugs used for the treatment of AD are agents that improve cholinergic neurotransmission, capable of relieving cognitive and memory deficits associated with AD, although only temporarily ( Arch. Gerontol. Geriatr. Suppl . 2004 , 9 , 297-307).

Given this situation, it is obvious the convenience of having drugs capable of acting in the early stages of the disease or, better yet, producing a presymptomatic protective activity, in the ideal case of having an adequate early diagnosis system ( Ann. Neurol . 2007 , 61 , 120-129), and that are capable of restoring or, at least, maintaining the physiological processes affected in neurodegenerative diseases at the levels closest to functional normality.

Studies carried out in both animal and human models show that the loss of balance between the oxidizing species generated by brain metabolism and antioxidant protective mechanisms produces so-called oxidative stress, when these defensive systems decrease their effectiveness and are overwhelmed. This oxidative stress increases with age and is among the first causes of the pathogenesis of AD ( Prog. Neurobiol . 1999 , 57 , 301-323) possibly associated with dysfunctions of neuronal mitochondria ( Antioxid. Redox Signal . 2007 , 9 , 1647-1658).

Description of the invention brief description

The invention is precisely related to the discovery of antioxidant properties and, in general, preventive of certain pathological processes of a family of compounds described in the present invention, whose possible biological activities were, until now, unknown for not having been studied from a pharmacological point of view.

More specifically, the present invention is refers to a family of compounds with the characteristic structural of a hydrazide group attached to a heterocyclic system that present potentially useful pharmacological properties for the treatment of neurodegenerative diseases such as example, Alzheimer's disease.

Detailed description

The present invention is based on the fact that inventors have observed in compounds of general formula I interesting pharmacological properties that make them useful as therapeutic agents with application in possible treatments of neurodegenerative diseases such as, for example, Alzheimer's

In the pharmacological studies that have been submitted, the compounds of the invention have shown a series of potentially very useful activities in treatments neurodegenerative diseases, notwithstanding that, in studies deeper, new biological properties of possible interest The activities studied, and that have shown Positive results have been:

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\ vtcortauna Antioxidant activity by free radical uptake.

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\ vtcortauna Modulation of calcium channels decreasing the entry of these ions.

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\ vtcortauna Butyrylcholinesterase inhibitors.

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\ vtcortauna Ability to cross the blood brain barrier and penetrate the central nervous system.

As described above, and there is a growing number of experimental evidence, the presence of oxidizing species above physiologically acceptable levels, the so-called oxidative stress, is very much at the origin of Alzheimer's disease ( Neurobiol. Aging 2007 , 28 , 1009-1014), and in turn is strongly related to uncontrolled entries of Ca 2+ ions ( Life Sci . 2000 , 66 , 1879-1892). Likewise, the inhibition of the enzymes acetyl and butyrylcholinesterase favors cholinergic neurotransmission ( Proc. Natl. Acad. Sci. USA . 2005 , 102 , 17213-17218) being able to stop, at least temporarily, the deterioration of cognitive processes characteristic of the first symptomatic phases of this disease. Finally, a drug whose therapeutic target is inside the brain or, in general, the central nervous system, must have the property of penetrating into said system crossing the blood brain barrier.

Therefore, a first aspect of the present invention refers to a compound of general formula I, or a isomer, pharmaceutically acceptable salt and / or solvate thereof:

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one

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where:

Het

It represents a heterocyclic, preferably tricyclic system derived from the azaanthracene system, for example, 10 H -9-thia-10-azaanthracene

R_ {1}

represents an alkyl group, straight chain or branched which may include double or triple bonds, haloalkyl, aryl, alkylaryl, aminoalkyl, ammoniumalkyl or, in general, any alkyl group with or without substituents, including both enantiomers or mixtures thereof in any proportion in the case of that there are chiral carbons or, in general, any type of isomerism

R2, R3 are the same or different and each one is selected independently of the group comprising (C 1 -C 6) alkyl, alkoxy, halogen, haloalkyl, nitro, amino, aminoalkyl or, in In general, any substituent group of aromatic rings, located in any position.

A second aspect of the present invention is refers to the use of the compounds represented by the formula general (I) in the preparation of a medicine or composition pharmaceutical, and preferably that medication or composition Pharmaceutical is used for the treatment of pathologies or diseases caused by oxidative processes, dysfunctions of the Homeostasis of Ca2 + ions or in neurotransmission cholinergic or, in general, of diseases susceptible to benefit from the biological activities shown by products described in the present invention, or of a salt, pharmaceutically acceptable derivative, prodrugs or solvate of same.

The compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple links (for example, Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers. Isomers, enantiomers or individual diastereoisomers and mixtures thereof fall within the scope of the present invention. The enantiomers or individual diastereoisomers, as well as mixtures thereof, can separated by conventional techniques.

The term "alkyl" refers to the present invention to aliphatic, linear or branched chains, having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, etc. Preferably the alkyl group has between 1 and 6 atoms of carbon. The alkyl radicals may optionally be substituted by one or more substituents such as a cycloalkyl, aryl, heteroaryl, alkoxy, halogen, haloalkyl, nitro, amino, aminoalkyl, aminocycloalkyl, ammoniumalkyl, ammoniumcycloalkyl or, in general, any substituent located in any position.

In the present invention, the term "heterocycle" refers to a ring that contains at least one N, O or S atom in the cycle, preferably an N atom, such as for example, but not limited to, piperidine, piperazine, pyrrolidine or pyrazolidine. The heterocycle can be attached to the rest of the molecule of formula (I) through any atom and can be optionally substituted by one or more selected groups regardless of halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, haloalkyl, nitro, amino, aminoalkyl, aminocycloalkyl, ammoniumalkyl, ammoniumcycloalkyl or, in general, Any substituent The substituent (s), when there is more than one, can be found in any available position of the heterocycle.

As used herein, the term "derivative" includes both pharmaceutical compounds acceptable, that is, derivatives of the compound of formula (I) that they can be used in the preparation of a medicine, such as pharmaceutically acceptable derivatives since these may be useful in the preparation of pharmaceutically acceptable derivatives. The nature of the pharmaceutically acceptable derivative is not Critical, as long as it is pharmaceutically acceptable.

Also, within the scope of this invention the prodrugs of the compounds of formula (I) are found. He term "prodrug" as used herein includes a any compound derived from a compound of formula (I), by example, esters, including esters of carboxylic acids, esters of amino acids, phosphate esters, sulphonate esters of salts metallic, etc., carbamates, amides, etc., which, when manages an individual is able to provide, directly or indirectly, said compound of formula (I) in said individual. Advantageously, said derivative is a compound that increases the bioavailability of the compound of formula (I) when administered to an individual or that enhances the release of the compound of formula (I) in a biological compartment. The nature of said derivative it is not critical as long as it can be administered to a individual and provide the compound of formula (I) in a biological compartment of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.

The compounds of the invention may be in crystalline form as free compounds or as solvates and it It is intended that both forms are within the scope of this invention. In this sense, the term "solvate", such as Here it is used, includes both pharmaceutically solvates acceptable, that is, solvates of the compound of formula (I) which they can be used in the preparation of a medicine, such as pharmaceutically acceptable solvates, which may be useful in the preparation of solvates or pharmaceutically salts acceptable. The nature of the pharmaceutically acceptable solvate It is not critical as long as it is pharmaceutically acceptable. In A particular embodiment, the solvate is a hydrate. The solvates they can be obtained by conventional methods of solvation well known to those skilled in the art.

For its application in therapy, the compounds of formula (I), its isomers, salts, prodrugs or solvates, are will find, preferably, in a pharmaceutically acceptable or substantially pure, that is, it has a level of pharmaceutically acceptable purity excluding additives normal pharmacists such as diluents and carriers, and not including material considered toxic at dosage levels normal. The purity levels for the active substance are preferably higher than 50%, more preferably higher 70%, more preferably greater than 90%. In one embodiment preferred, are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.

Unless otherwise indicated, the Compounds of the invention also include compounds that differ only in the presence of one or more atoms isotopically enriched For example, compounds having said structure, except for the replacement of a hydrogen by a deuterium or by tritium, or the substitution of a carbon for a carbon enriched in 13C or 14C or a nitrogen enriched in 15N, are within the scope of this invention.

The compounds described herein invention, its pharmaceutically acceptable salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other additional drugs to Provide a combination therapy. Such drugs additional may be part of the same composition pharmaceutical or, alternatively, can be provided in of a separate composition for simultaneous administration or not to that of the pharmaceutical composition comprising a compound of formula (I), or a prodrug, solvate, derivative or salt pharmaceutically acceptable thereof.

The compounds of the present invention of formula (I) can be obtained or produced by a route synthetic chemistry or obtained from a natural matter of different origin. In another aspect of the present invention, describes a method of obtaining the compounds of the invention of formula (I) or an isomer, pharmaceutically salt acceptable and / or solvate thereof characterized by the following stages:

to)

reaction of a diaryl product of formula (II)

2

quad

in which R 2 and R 3 represent the aromatic substituents indicated above, when describing the general formula (I), and X represents a methylene group (CH2) or a thioether group (S), under nitrosation conditions, for example with an alkaline nitrite in acid medium. This reaction would lead to an N-nitrosoamine, which in general does not need to be isolated and purified for the next reaction, being reduced to the corresponding hydrazine (III) by some general procedure, well known in organic synthesis such as treatment with tin dichloride or lithium aluminum hydride.

3

b)

acylation of hydrazine (III) by some acylating agent under the usual conditions, for example a acid chloride or anhydride in the presence of a base such as triethylamine or pyridine, in an aprotic solvent such as methylene, the same pyridine, etc., to obtain the hydrazide (IV).

4

quad

where R_ {1} has the meaning indicated in the description of the general formula (I).

C)

finally, this hydrazide (IV) is cycled by a classic reaction in organic synthesis in that by treatment with a strong base in an aprotic polar solvent, the hydrazides derived from the azaanthracene system of general formula (I).

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The following compounds are examples according to present invention:

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\ vtcortauna Compound 1: N- (4-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide.

?

\ vtcortauna Compound 2: N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) acetamide

?

\ vtcortauna Compound 3: N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide.

?

\ vtcortauna Compound 4: N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide.

?

\ vtcortauna Compound 5: N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide.

?

\ vtcortauna Compound 6: N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (4-methylpiperazin-1-yl) acetamide.

?

\ vtcortauna Compound 7: N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide.

?

\ vtcortauna Compound 8: N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide.

?

\ vtcortauna Compound 9: N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide.

?

\ vtcortauna Compound 10: 10-Amino-10 H -9-thia-10-azaantracene.

?

\ vtcortauna Compound 11: N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide.

?

\ vtcortauna Compound 12: N- (10 H -9-Tia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide.

?

\ vtcortauna Compound 13: N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide.

?

\ vtcortauna Compound 14: N- (10 H -9-Tia-10-azaantracen-10-yl) acetamide.

?

\ vtcortauna Compound 15: N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide.

?

\ vtcortauna Compound 16: N- (10 H -9-Tia-10-azaantracen-10-yl) -3-dimethylaminopropionamide.

?

\ vtcortauna Compound 17: N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide.

?

\ vtcortauna Compound 18: N- (2-Nitro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide.

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\ vtcortauna Compound 19: N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide.

?

\ vtcortauna Compound 20: N- (10 H -9-Tia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide.

?

\ vtcortauna Compound 21: N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide.

?

\ vtcortauna Compound 22: N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide.

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Another preferred embodiment of the present invention relates to a pharmaceutical composition useful for the treatment of pathologies or diseases of the nervous system that may be caused by oxidative processes, or that at least these processes play a pathologically significant role or, in In general, of diseases that can benefit from biological activities shown by the products described in the present invention, hereinafter pharmaceutical composition of the invention, which comprises a compound, in therapeutically quantity effective, of formula (I), or mixtures thereof, a salt, pharmaceutically acceptable prodrug, solvate or stereoisomer thereof together with a carrier, adjuvant or vehicle pharmaceutically acceptable, for administration to a patient.

Another preferred embodiment of the present invention refers to the pharmaceutical composition of the invention in the group of diseases of the nervous system of character neurodegenerative to which they belong, for illustrative purposes and without limit the scope of the invention: Alzheimer's diseases, Creutzfeldt-Jakob, Parkinson or Huntington, the dementia with Lewy bodies or, in general, diseases result of a deterioration of neurons caused by processes of oxidation or other such as imbalances in the calcium ion concentration, neurotransmission systems, etc, that the nervous system of the affected patient is not able to control.

The scope of a neurodegenerative process in the present invention is that such as neuronal loss, failures in neurotransmission processes or processes derived from failures in the control of the oxidizing species created in the brain that give place to pathological oxidative stress.

Another preferred embodiment of the invention comprises the pharmaceutical composition of the invention in which the compound of formula (I) is a compound, or mixture of compounds, belonging, by way of illustration and without limiting the scope of the invention, to the following group:

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\ vtcortauna N- (4-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

?

\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) acetamide,

?

\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide,

?

\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide,

?

\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (4-methylpiperazin-1-yl) acetamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide,

?

\ vtcortauna 10-Amino-10 H -9-thia-10-azaanthracene,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) acetamide,

?

\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (2-Nitro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

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?

\ vtcortauna N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide or

?

\ vtcortauna N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide,

or any of its enantiomeric forms R1 S and / or racemic mixtures.

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Pharmaceutical adjuvants and vehicles acceptable that can be used in said compositions are adjuvants and vehicles known to those skilled in the art and commonly used in the preparation of compositions therapeutic

In the sense used in this description, the expression "therapeutically effective amount" refers to the amount of agent or compound capable of carrying out the action therapeutic determined by its pharmacological properties, calculated to produce the desired effect and, in general, will come determined, among other causes, by the characteristics of the compounds, including the age, condition of the patient, the severity of the disorder or disorder, and of the route and frequency of administration.

In another particular embodiment, said therapeutic composition is prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided by this invention may be administered by any appropriate route of administration, for which said composition will be formulated in the pharmaceutical form appropriate to the route of administration chosen. In one embodiment in particular, the administration of the therapeutic composition provided by this invention is performed orally, topically, rectal or parenteral (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.). A review of the different pharmaceutical forms of administration of medications and of the excipients necessary to obtain they can be found, for example, in the "Treaty of Farmacia Galenica ", C. Faulí i Trillo, 1993, Luzán 5, S.A. Ediciones, Madrid, or other usual or similar of the Spanish and United States Pharmacopoeias.

The use of the compounds of the invention is compatible with its use in protocols in which the compounds of the formula (I), or mixtures thereof are used by themselves or in combinations with other treatments or any medical procedure.

In another aspect, this patent presents a method for the treatment of patients affected by diseases of the central nervous system in which processes take place uncontrolled oxidants or other processes in which products of the present invention produce a beneficial effect. This treatment consists of administration to affected individuals for these diseases of therapeutically effective amounts of a compound of formula (I), or a pharmaceutical composition that include By way of example, diseases contemplated in this invention are Alzheimer's diseases, Creutzfeldt-Jakob, Parkinson or Huntington, the dementia with Lewy bodies or, in general, diseases result of a deterioration of neurons caused by processes of type oxidative stress, ionic imbalances or failures in some neurotransmission system that the patient's nervous system Affected is not able to control.

Throughout the description and the claims the word "comprises" and its variants not they intend to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be partly detached of the description and in part of the practice of the invention. The The following examples are provided by way of illustration, and are not It is intended to be limiting of the present invention.

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Examples

The invention will be illustrated below through tests carried out by the inventors, which develop the process of selecting the compounds of the invention.

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1. Obtaining the compounds of the invention

Compounds whose biological activity is object of the present invention were synthesized following a General procedure in organic synthesis. Said procedure It is represented in the following scheme 1:

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Scheme one

Chemical synthesis of compounds of formula (I)

5

This synthesis in several steps starts from diaryl compound (II), obtained by usual procedures in organic synthesis, easily executed by any Expert in this field. This compound (II) was subjected to conditions nitrosation, which can be done by the general procedure of react the amine with sodium nitrite in an acidic medium. The resulting nitrosamine was obtained with sufficient purity as so that isolation and purification are not generally necessary, being reduced to the corresponding hydrazine (III) by some general procedure, well known in organic synthesis such as treatment with tin dichloride or lithium hydride and aluminum. This hydrazine (III) was acylated by means of some agent acylating agent under the usual conditions, for example a chloride of acid or anhydride in the presence of a base such as triethylamine or pyridine, in an aprotic solvent such as methylene chloride, the same pyridine, etc., to obtain the hydrazide (IV) that, finally, it was cyclized by a classic reaction in synthesis organic by treatment with a strong base in a polar solvent aprotic, obtaining hydrazides derived from the system azaantracene of general formula (I).

In particular, and following the protocol of synthesis represented in scheme 1, were obtained and characterized the following compounds:

Compound 1: Synthesis of N- (4-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide . Description of said compound: White solid. Melting point = 173-175 ° C. MS (ES): m / z = 374 [M] +, 376 [M + 2H] +, 396 [M + Na] +, 769 [2M + Na] + . 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.23 (s, 1H); 7.12 (m, 2H); 6.97 (m, 2 H); 6.92 (td, 1H, J = 7.6 Hz, J = 1.2 Hz); 6.67 (td, 1H, J = 8.3 Hz, J = 1.5 Hz); 6.59 (dd, 1H, J = 7.6 Hz, J = 2.7 Hz); 3.28 (s, 2 H); 2.65 (m, 4 H); 1.67 (m, 4 H); 1.51 (m, 2H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 16.4 (C); 143.9 (C); 142.2 (C); 131.2 (C); 127.6 (C); 127.3 (C); 127.2 (C); 123.9 (C); 123.8 (C); 120.5 (C); 119.3 (C); 112.9 (C); 111.2 (C); 61.8 (C); 55.7 (2C); 26.2 (2C); 23.5 (C). HPLC: Purity (99%).

Compound 2: Synthesis of N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) acetamide. Solid white. Melting point =
213-215 ° C. MS (ES): m / z = 313 [M + Na] +, 603 [2M + Na] +. 1 H-NMR (400 MHz, DMSO-d 6), δ (ppm): 10.49 (s, 1H, NH, amide); 7.12 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 7.09 (d, 1H, J = 8.2 Hz); 7.08 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.97 (dd, 1H, J = 8.2 Hz, J = 2.3 Hz); 6.93 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.82 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.79 (d, 1H, J = 2.3 Hz); 2.13 (s, 3H). 13 C-NMR (100 MHz, DMSO-d 6), δ (ppm): 168.4 (C); 144.3 (C); 142.1 (C); 132.2 (C); 127.8 (2C); 126.6 (C) 123.8 (C); 122.9 (C); 117.7 (C); 117.2 (C); 113.7 (C); 113.1 (C); 20.6 (C). HPLC: Purity (99%).

Compound 3: Synthesis of N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide . Solid white. Melting point = 219-221 ° C. MS (ES): m / z = 360 [M + H] +, 362 [M + 2H] +, 382 [M + Na] +, 741 [2M + Na] ^ { +}. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.29 (s, 1H); 7.02 (td, 1H, J = 7.6 Hz, J = 1.5 Hz); 6.97 (dd, 1H, J = 7.6, J = 1.5 Hz); 6.87 (d, 1H, J = 8.2 Hz); 6.86 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.81 (dd, 1H, J = 8.2 Hz, J = 2.1 Hz); 6.70 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.67 (d, 1H, J = 2.1 Hz); 3.52 (s, 2H); 2.77-2.82 (m, 4H); 1.86-1.89 (m, 4H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.1 (C); 144.3 (C); 142.1 (C); 132.2 (C); 127.8 (2C); 126.6 (C); 123.8 (C); 122.9 (C); 117.7 (C); 117.2 (C); 113.7 (C); 113.1 (C); 57.84 (C); 54.5 (C); 23.4 (C). HPLC: Purity (99%).

Compound 4: Synthesis of N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide. Solid white. Melting point = 216-218 ° C. MS (ES): m / z = 334 [M + H] +, 336 [M + 2H] +, 358 [M + Na] +, 689 [2M + Na] +}. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.23 (s, 1H); 7.05 (td, 1H, J = 7.6 Hz, J = 1.5 Hz); 6.97 (dd, 1H, J = 7.6 Hz, J = 1.5 Hz); 6.87 (d, 1H, J = 8.2 Hz Hz); 6.86 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.81 (dd, 1H, J = 8.2 Hz, J = 2.1 Hz); 6.70 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.67 (d, 1H, J = 2.1 Hz); 3.25 (s, 2H); 2.44 (s, 6H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 168.3 (C); 143.3 (C); 141.4 (C); 132.2 (C); 126.7 (C); 126.5 (C); 126.1 (C); 123.1 (C); 122.4 (C); 119.0 (C); 117.9 (C); 112.53 (C); 112.2 (C); 61.5 (C); 45.6 (2C). HPLC: Purity (100%).

Compound 5: Synthesis of N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide. Solid white. Melting point = 197-199 ° C. MS (ES): m / z = 374 [M + H] +, 376 [M + 2H] +, 396 [M + Na] +, 768 [2M + Na] ^ { +}. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.22 (s, 1H); 7.09 (td, 1H, J = 7.6 Hz, J = 1.5 Hz); 7.06 (dd, 1H, J = 7.5 Hz, J = 1.5); 6.98 (d, 1H, J = 8.2 Hz); 6.95 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.90 (dd, 1H, J = 8.2 Hz, J = 2.1 Hz); 6.73 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.71 (d, 1H, J = 2.1 Hz); 3.31 (s, 2 H); 2.68 (m, 4 H); 1.65 (m, 4 H); 1.50 (m, 2H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.5 (C); 144.5 (C); 142.7 (C); 133.5 (C); 127.9 (2C); 127.4 (C); 124.7 (C); 123.7 (C); 120.2 (C); 119.2 (C); 113.6 (C); 113.3 (C); 62.2 (C); 55.9 (2C); 26.4 (2C), 23.8 (2C). HPLC: Purity (99.5%).

Compound 6: Synthesis of N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (4-methylpiperazin-1-yl) acetamide. Solid yellow. Melting point = 207-209 ° C. MS (ES): m / z = 389 [M + H] +, 391 [M + 2H] +, 799 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 10.80 (s, 1H); 7.05 (td, 1H, J = 7.6 Hz, J = 1.3 Hz); 7.03 (dd, 1H, J = 7.6 Hz, J = 1.3 Hz); 7.00 (dd, 1H, J = 8.7 Hz, J = 2.3 Hz); 6.97 (d, 1H, J = 2.3 Hz); 6.90 (td, 1H, J = 7.6 Hz, J = 1.3 Hz); 6.66 (dd, 1H,
J = 7.6 Hz, J = 1.3 Hz); 6.57 (d, 1H, J = 8.7 Hz); 3.32 (s, 2H); 2.55-2.73 (m, 8H); 2.31 (s, 3 H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.0 (C); 142.5 (C); 141.6 (C); 128.6 (C); 127.5 (C); 127.1 (C); 126.9 (C); 126.5 (C); 123.9 (C); 122.3 (C); 119.6 (C); 113.7 (C); 112.9 (C); 60.9 (C); 54.7 (2C); 54.5 (2C); 45.6 (C). HPLC: Purity (99%).

Compound 7: Synthesis of N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide. Solid white. Melting point = 197-199 ° C. MS (ES): m / z = 374 [M] +, 376 [M + 2H] +, 396 [M + Na] +, 769 [2M + Na] + . 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.15 (s, 1H); 6.85 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.81 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.78 (dd, 1H, J = 7.6 Hz, J = 2.3 Hz); 6.74 (d, 1H, J = 2.3 Hz); 6.68 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.46 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.36 (d, 1H, J = 7.6 Hz); 3.05 (s, 2H); 2.41 (m, 4 H); 1.43 (m, 4 H); 1.30 (m, 2H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.7 (C); 143.1 (C); 142.4 (C); 1289.1 (C); 128.0 (C); 127.6 (2C); 126.9 (C); 124.9 (C); 122.7 (C); 120.1 (C); 114.3 (C); 113.4 (C); 62.2 (C); 56.1 (2C); 26.5 (2C); 23.8 (C). HPLC: Purity (100%).

Compound 8: Synthesis of N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide. Solid white. Melting point = 189-191 ° C. MS (ES): m / z = 334 [M] +, 336 [M + 2H] +, 689 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.17 (s, 1H); 7.09 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 7.07 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 7.03 (dd, 1H, J = 7.6 Hz, J = 2.3 Hz); 7.01 (d, 1H, J = 2.3 Hz); 6.93 (td, 1H, J7.8 = 7.7 Hz, J = 1.2 Hz); 6.73 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.63 (d, 1H, J = 7.6 Hz); 3.29 (s, 2 H); 2.49 (s, 6H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.2 (C); 142.6 (C); 141.8 (C); 128.6 (C); 127.6 (C); 127.2 (C); 126.9 (C); 126.5 (C); 123.9 (C); 122.4 (C); 119.7 (C); 113.9 (C); 113.1 (C); 62.5 (C); 46.7 (2C). HPLC: Purity (99%).

Compound 9: Synthesis of N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide. Solid white. Melting point = 184-186 ° C. MS (ES): m / z = 360 [M] +, 362 [M + 2H] +, 382 [M + Na] +, 741 [2M + Na] + . 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.23 (s, 1H); 7.09 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 7.05 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 7.03 (dd, 1H, J = 7.6 Hz, J = 2.3 Hz); 7.00 (d, 1H, J = 2.3 Hz); 6.93 (td, 1H, J = J = 7.7 Hz, J = 1.2 Hz); 6.72 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.62 (d, 1H, J = 7.6 Hz); 3.51 (s, 2H); 2.80 (m, 4 H); 1.88 (m, 4H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.7 (C); 142.5 (C); 141.6 (C); 128.5 (C); 127.6 (C); 127.1 (C); 127.0 (C); 126.4 (C); 123.9 (C); 122.2 (C); 119.5 (C); 114.0 (C); 113.2 (C); 58.5 (C); 55.2 (2C); 24.1 (2C). HPLC: Purity (100%).

Compound 10: Synthesis of 10-Amino-10 H -9-thia-10-azaantracene. Solid white. Melting point = 123-125 ° C. MS (ES): m / z = 214 [M] +. 1 H-NMR (300 MHz, CDCl 3), δ (ppm): 6.7-7.3 (m, 8H); 3.8 (s, 2H). HPLC: Purity (100%).

Compound 11: Synthesis of N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide. Solid white. Melting point = 201-203 ° C. MS (ES): m / z = 340 [M + H] +, 362 [M + Na] +. 701 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.25 (s, 1H); 6.7-7.3 (m, 8H); 3.28 (s, 2 H); 2.65 (m, 4 H); 1.67 (m, 4 H); 1.56 (m, 2 H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.2 (COCH 3); 143.0 (2C); 127.27 (2C); 127.12 (2C); 123.71 (2C); 119.6 (2C); 112.94 (2C); 61.8 (C); 55.7 (2C); 26.2 (2C); 23.5 (C). HPLC: Purity (96.7%).

Compound 12: Synthesis of N- (10 H -9-Tia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide. Solid white. Melting point = 195-197 ° C. MS (ES): m / z = 300 [M + H] +, 301 [M + 2H] +, 322 [M + Na] +, 621 [2M + Na] ^ { +}. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.17 (s, 1H); 6.7-7.3 (m, 8H); 3.29 (s, 2 H); 2.52 (s, 6H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.2 (C); 143.0 (2C); 127.27 (2C); 127.12 (2C); 123.71 (2C); 119.6 (2C); 112.94 (2C); 62.58 (C); 46.66 (2C). HPLC: Purity (100%).

Compound 13: Synthesis of N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide. Solid white. Melting point = 182-184 ° C. MS (ES): m / z = 326 [M + H] +, 348 [M + Na] +, 673 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.17 (s, 1H); 6.7-7.3 (m, 8H); 3.29 (s, 2 H); 2.82 (m, 4 H); 1.88 (m, 4H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.7 (C); 142.9 (2C); 127.3 (2C); 127.1 (2C); 123.7 (C); 120.4 (C); 119.5 (2C); 113.1 (2C); 58.6 (C); 55.2 (2C); 24.2 (2C). HPLC: Purity (99%).

Compound 14: Synthesis of N- (10 H -9-Tia-10-azaantracen-10-yl) acetamide. Solid white. Melting point = 230-232 ° C. MS (ES): m / z = 257 [M + H] +. 1 H-NMR (400 MHz, DMSO-d 6), δ (ppm): 10.5 (s, 1H); 6.7-7.3 (m, 8H); 2.11 (s, 3H). 13 C-NMR (100 MHz, DMSO-d 6), δ (ppm): 168.3 (C); 142.3 (C); 141.8 (C); 127.8 (C); 127.1 (C); 126.8 (C); 126.6 (C); 125.6 (C); 123.5 (C); 120.3 (C); 117.2 (C); 114.7 (C); 113.5 (C); 20.5 (C). HPLC: Purity (100%).

Compound 15: Synthesis of N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide. Solid
White. Melting point = 179-181 ° C MS (ES): m / z = 348 [M + H] +, 350 [M + 2H] +, 717 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 10.85 (s, 1H); 7.07 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 7.03 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 7.00 (dd, 1H, J = 7.6 Hz, J = 2.3 Hz); 6.98 (d, 1H, J = 2.3 Hz); 6.91 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.72 (dd, 1H, J = 7.7 Hz, J = 1.2 Hz); 6.63 (d, 1H, J = 7.6 Hz); 2.82 (t, 2H, J = 5.7 Hz); 2.71 (t, 2H, J = 5.7 Hz); 2.43 (s, 6H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 171.4 (C); 142.9 (C); 142.0 (C); 128.5 (C); 127.8 (C); 127.2 (2C); 126.5 (C); 123.9 (C); 121.9 (C); 119.2 (C); 114.0 (C); 113.2 (C); 54.8 (C); 44.7 (2C); 32.2 (C). HPLC: Purity (99%)

Compound 16: Synthesis of N- (10 H -9-Tia-10-azaantracen-10-yl) -3-dimethylaminopropionamide . Solid white. Melting point = 176-178 ° C. MS (ES): m / z = 368 [M + H] +, 390 [M + Na] +, 757 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.17 (s, 1H); 6.7-7.3 (m, 8H); 2.89 (t, 2H, J = 5.7 Hz); 2.71 (t, 2H, J = 5.7 Hz); 2.55-2.73 (m, 8H); 2.31 (s, 3 H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.2 (C); 143.0 (2C); 127.27 (2C); 127.12 (2C); 123.71 (2C); 119.6 (2C); 112.94 (2C) 54.8 (C); 54.7 (2C); 54.5 (2C); 45.6 (C), 32.2 (C). HPLC: Purity (98%).

Compound 17: Synthesis of N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide. Solid
White. Melting point = 187-189 ° C. MS (ES): m / z = 403 [M + H] +, 405 [M + 2H] +, 428 [M + Na] +, 829 [2M + Na] ^ { +}. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.22 (s, 1H); 7.09 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 7.06 (d, 1H, J = 8.2 Hz); 6.98 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.95 (dd, 1H, J = 8.2 Hz, J = 2.3 Hz); 6.90 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.73 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.71 (d, 1H, J = 2.3 Hz); 3.65 (t, 2H, J = 5.7 Hz); 2.50 (t, 2H, J = 5.7 Hz); 2.55-2.73 (m, 8H); 2.31 (s, 3H, CH 3). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.5 (C); 144.5 (C); 142.7 (C); 133.5 (C); 127.9 (2C); 127.4 (C); 124.7 (C); 123.7 (C); 120.2 (C); 119.2 (C); 113.6 (C); 113.3 (C); 54.8 (C); 54.7 (2C); 54.5 (2C); 45.6 (C), 32.2 (C). HPLC: Purity (99%).

Compound 18: Synthesis of N- (2-Nitro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide. Solid white. Melting point = 191-193 ° C. MS (ES): m / z = 414 [M + H] +, 436 [M + Na] +, 849 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 10.49 (s, 1H); 7.68 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 7.61 (d, 1H, J = 8.2 Hz); 7.42 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 7.21 (dd, 1H, J = 8.2 Hz, J = 2.3 Hz); 7.20 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 7.16 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.97 (d, 1H, J = 2.3 Hz); 3.65 (t, 2H, J = 5.7 Hz); 2.50 (t, 2H, J = 5.7 Hz); 2.55-2.73 (m, 8H); 2.31 (s, 3 H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 168.4 (C); 144.3 (C); 142.1 (C); 140.5 (C); 127.8 (2C); 126.6 (C); 123.8 (C); 122.9 (C); 117.7 (C); 117.2 (C); 113.7 (C); 113.1 (C); 54.8 (C); 54.7 (2C); 54.5 (2C); 45.6 (C), 32.2 (C). HPLC: Purity (100%).

Compound 19: Synthesis of N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide. Solid white. Melting point = 201-203 ° C. MS (ES): m / z = 399 [M + H] +, 421 [M + Na] +, 817 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.53 (s, 1H); 7.01 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.87 (d, 1H, J = 8.2 Hz); 6.86 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.83 (dd, 1H, J = 8.2 Hz, J = 2.3 Hz); 6.71 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.62 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.60 (d, 1H, J = 2.3 Hz); 3.83 (s, 3 H); 3.65 (t, 2H, J = 5.7 Hz); 2.50 (t, 2H, J = 5.7 Hz); 2.55-2.73 (m, 8H); 2.31 (s, 3 H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.9 (C); 153.1 (C); 145.4 (C); 143.2 (C); 128.9 (2C); 127.8 (C); 125.5 (C); 124.3 (C); 120.9 (C); 120.2 (C); 114.6 (C); 114.3 (C); 55.8 (C); 54.8 (C); 54.7 (2C); 54.5 (2C); 45.6 (C), 32.2 (C). HPLC: Purity (99%).

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Compound 20: Synthesis of N- (10 H -9-Tia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide. Solid white. Melting point = 194-196 ° C. MS (ES): m / z = 340 [M + H] +, 362 [M + Na] +, 701 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.17 (s, 1H); 6.7-7.3 (m, 8H); 2.89 (t, 2H, J = 5.7 Hz); 2.71 (t, 2H, J = 5.7 Hz); 2.80 (m, 4 H); 1.88 (m, 4H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 168.4 (C); 144.3 (C); 142.1 (C); 132.2 (C); 127.8 (2C); 126.6 (C); 123.8 (C); 122.9 (C); 117.7 (C); 117.2 (C); 113.7 (C); 113.1 (C); 55.2 (2C); 54.8 (C); 45.6 (C); 24.1 (2C). HPLC: Purity (97%).

Compound 21: Synthesis of N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide. Solid white. Melting point = 185-187 ° C. MS (ES): m / z = 375 [M + H] +, 397 [M + Na] +, 771 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.22 (s, 1H); 7.09 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 7.06 (d, 1H, J = 8.2 Hz); 6.98 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.95 (dd, 1H, J = 8.2 Hz, J = 2.3 Hz); 6.90 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.73 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.71 (d, 1H, J = 2.3 Hz); 3.65 (t, 2H, J = 5.7 Hz); 2.50 (t, 2H, J = 5.7 Hz); 2.80 (m, 4 H); 1.88 (m, 4H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.5 (C); 144.5 (C); 142.7 (C); 133.5 (C); 127.9 (2C); 127.4 (C); 124.7 (C); 123.7 (C); 120.2 (C); 119.2 (C); 113.6 (C); 113.3 (C); 54.8 (C); 55.2 (2C); 32.2 (C); 24.1 (2C). HPLC: Purity (99%).

Compound 22: Synthesis of N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide. Solid white. Melting point = 179-181 ° C. MS (ES): m / z = 370 [M + H] +, 392 [M + Na] +, 761 [2M + Na] +. 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 9.53 (s, 1H); 7.01 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.87 (d, 1H, J = 8.2 Hz); 6.86 (dd, 1H,
J = 7.6 Hz, J = 1.1 Hz); 6.83 (dd, 1H, J = 8.2 Hz, J = 2.3 Hz); 6.71 (td, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.62 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz); 6.60 (d, 1H, J = 2.3 Hz); 3.83 (s, 3 H); 3.65 (t, 2H, J = 5.7 Hz); 2.50 (t, 2H, J = 5.7 Hz); 2.80 (m, 4 H); 1.88 (m, 4H). 13 C-NMR (100 MHz, CDCl 3), δ (ppm): 169.9 (C); 153.1 (C); 145.4 (C); 143.2 (C); 128.9 (2C); 127.8 (C); 125.5 (C); 124.3 (C); 120.9 (C); 120.2 (C); 114.6 (C); 114.3 (C); 55.8 (C); 54.8 (C); 55.2 (2C); 32.2 (C) 24.1 (2C). HPLC: Purity (99%).

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2. Biological activities studied in the compounds of the invention 2.1 Neuroprotective properties of the compounds object of the invention

The cytoprotective effect of the compounds in human neuroblastoma cells was evaluated, specifically the neuroprotective potential of these compounds against oxidative stress produced in two different study models, on the one hand with hydrogen peroxide as an exogenous free radical generator, and on the other with rotenone and oligomycin A, mitochondrial respiratory chain blockers as described in J. Neurochem . 1992 , 59 , 1609-1623 and in Toxicological Sciences 2004 , 79 , 137-146, respectively. The viability parameter that was measured in both models was the activity of the enzyme lactate dehydrogenase (LDH hereinafter), an enzyme that is released to the extracellular medium when the cell dies ( J. Pharmacol. Exp. Ther . 2005 , 315 , 1346 -1353).

The experimental method used, following a previously described procedure ( Neuropharmacology 2004 , 46 , 103-114) is as follows: SH-SY5Y human neuroblastoma cells were seeded and cultured in a DMEM (Dulbecco's modified Eagle's medium) medium containing 15 non-essential amino acids and supplemented with 10% fetal calf serum, 1 millimolar glutamine, 50 units per milliliter of penicillin and 50 micrograms per milliliter of streptomycin, keeping them at 37 ° C in humidified air containing 5% carbon dioxide. In the assays, SH-SY5Y cells were subcultured in 48-well plates with a seeding density of 1x105 cells per well, or in 96-well plates with a seeding density of 2x105 cells per well. In the cytotoxicity experiments, the cells thus prepared were treated with the compounds to be measured, in serum-free DMEM.

To study the cytoprotective action of different compounds against cell death induced by 60 micromolar hydrogen peroxide, or a combination of rotenone with oligomycin A 30 micromolar and 10 micromolar respectively, the compounds were added to the medium and maintained for 24 hours. Afterwards, the media were replaced by fresh media which still contained the compound plus the cytotoxic agent, and were thus maintained for an additional period of 24 hours. Viability cell was checked by measuring the activity of the LDH enzyme, as explained above, using the kit "Cytotoxicity Cell Death "(Roche-Boehringer Mannheim) following the manufacturer's instructions for said kit. Total LDH activity was defined as the sum of intra and intra LDH activities extracellular LDH activity released by cells upon death was defined as the percentage of extracellular LDH activity versus total LDH activity. The samples were analyzed spectrophotometrically in a plate reader (Labsystems iEMS Reader MF), using the appropriate filter (490 nm), obtaining the absorbance values using the DeltaSOFTII Version program 3.71 EMS.

In all pharmacological trials, a positive control was used as a comparison and to assess the goodness of the method used. In this case, he used trolox, a well-known free radical scavenger, the active core of the natural antioxidant vitamin E ( New. Eng1. J. Med . 2005 , 352 , 2379-2388); The results obtained for the compounds described as compounds 1.1 to 1.22, which are shown below, are expressed as a percentage of the neuroprotective activity.

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2.1.1 Neuroprotection against a toxic stimulus of 60 micromolar hydrogen peroxide , referring to the percentage of cell survival induced by each compound, to the concentration that is expressed, and which gave rise to maximum protection in each case:

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\ vtcortauna Compound 1: 39.70% at 30 micromolar.

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\ vtcortauna Compound 2: 37.90% at 10 micromolar.

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\ vtcortauna Compound 3: 56.51% at 10 micromolar.

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\ vtcortauna Compound 4: 40.76% at 10 micromolar.

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\ vtcortauna Compound 5: 76.37% at 3 micromolar.

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\ vtcortauna Compound 6: 6.30% at 3 micromolar.

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\ vtcortauna Compound 7: 51.96% at 3 micromolar.

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\ vtcortauna Compound 8: 62.69% at 3 micromolar.

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\ vtcortauna Compound 9: 79.91% at 10 micromolar.

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\ vtcortauna Compound 10: 6.70% at 3 micromolar.

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\ vtcortauna Compound 11: 28.81% at 1 micromolar.

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\ vtcortauna Compound 12: 39.81% at 10 micromolar.

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\ vtcortauna Compound 13: 37.00% at 3 micromolar.

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\ vtcortauna Compound 14: 52.17% at 3 micromolar.

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\ vtcortauna Compound 15: 44.4% at 30 micromolar.

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\ vtcortauna Compound 16: 87.69% at 1 micromolar.

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\ vtcortauna Compound 17: 68.60% at 30 micromolar.

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\ vtcortauna Compound 18: 46.50% at 3 micromolar.

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\ vtcortauna Compound 19: 65.81% at 10 micromolar.

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\ vtcortauna Compound 20: 90.07% at 1 micromolar.

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\ vtcortauna Compound 21: 57.24% at 3 micromolar.

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\ vtcortauna Compound 22: 17.80% at 1 micromolar.

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\ vtcortauna Trolox: 57.7% at 30 micromolar.

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2.1.2 Neuroprotection against a toxic stimulus of a combination of 30 micromolar rotenone and 10 micromolar oligomycin A , based on the percentage of cell survival induced by each of the compounds selected for this test, at the concentration expressed, and which was the one that gave rise to maximum protection in each case:

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\ vtcortauna Compound 9: 58.95% at 3 micromolar.

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\ vtcortauna Compound 15: 52.3% at 30 micromolar.

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\ vtcortauna Compound 18: 42.02% at 0.3 micromolar.

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\ vtcortauna Compound 19: 50.80% at 1 micromolar.

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\ vtcortauna Compound 20: 58.83% at 0.1 micromolar.

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\ vtcortauna Trolox: 52.9% at 3 micromolar.

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These results indicate that the compounds object of the present invention are able to reduce the presence of radicálicas species, so much exogenous as endogenous, with the consequent neuroprotective effect, which makes them potential drugs for the treatment of pathologies generated or favored by oxidative stress or presence of radicálicas species in general.

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2.2 Properties of the compounds object of the invention as inhibitors of the enzyme butyrylcholiesterase

AD, like all neurodegenerative diseases, is a very slow process, with an average time of at least 8 years between the onset of the first symptoms and death. The first symptoms appear as short-term memory loss, which leads to the non-recognition of family members or the forgetting of normal abilities for the individual, language problems, cognitive disorders, loss of learning capacity and orientation difficulties, which they increase to total loss of cognitive abilities as the disease progresses ( Ann. Intern. Med . 2004 , 140 , 501-509).

The immediate cause of these cognitive failures, at least in the early stages, is the decrease in the levels of cholinergic neurotransmission that constitute synaptic communication. Therefore, in the early stages of the disease it is advisable to use acetylcholinesterase inhibitors to reduce the acetylcholine deficit. But in more advanced stages of the disease, acetylcholinesterase begins to perform another function (favoring the aggregation of amyloid peptide), with which another enzyme, butyrylcholinesterase, performs the degradation function of the neurotransmitter acetylcholine ( Nat. Rev. Neurosci . 2003 , 4 , 131-138). It follows from this the importance that, for the long-term treatment of the disease, butyrylcholinesterase inhibitors have, as are the compounds object of the present invention. This evaluation was carried out using the so-called Ellman method ( Biochem. Pharmacol . 1961 , 7 , 88-90). The test solution was formed by 0.1 M phosphate buffer at pH 8, 200 µM 5,5'-dithiobisnitrobenzoic acid (DTNB, Ellman reagent), butyrylcholinesterase (BuChE) 0.02 pc / mL (from the company Sigma, obtained from horse serum) and 400 µM butyrylthiocholine iodide as a substrate for the enzymatic reaction. The tested compounds were added to the test solution and pre-incubated with the enzyme for 10 minutes at 30 ° C. After this time, the substrate was added and the absorbance changes at 412 nm were measured every 5 minutes by a Perkin Elmer 550 SE UVNIS spectrometer. The reaction rates were compared and the percentages of inhibition due to the presence of the compounds being analyzed were calculated. IC 50 values were defined as the concentrations of each compound that reduced enzymatic activity by 50% with respect to the absence of inhibitor.

The results of inhibition of BuChE, expressed as the concentration that inhibits 50% of the activity (IC 50) for the compounds of the invention, are the following:

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\ vtcortauna Compound 1: 2.2 micromolar.

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\ vtcortauna Compound 2:> 100 micromolar.

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\ vtcortauna Compound 3: 4.3 micromolar.

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\ vtcortauna Compound 4: 7.0 micromolar.

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\ vtcortauna Compound 5:> 100 micromolar.

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\ vtcortauna Compound 6: 0.5 micromolar.

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\ vtcortauna Compound 7: 0.7 micromolar.

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\ vtcortauna Compound 8: 5.0 micromolar.

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\ vtcortauna Compound 9: 1.0 micromolar.

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\ vtcortauna Compound 10:> 100 micromolar.

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\ vtcortauna Compound 11: 0.4 micromolar.

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\ vtcortauna Compound 12: 1.7 micromolar.

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\ vtcortauna Compound 13: 0.8 micromolar.

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\ vtcortauna Compound 14:> 100 micromolar.

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\ vtcortauna Compound 15: 0.7 micromolar.

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\ vtcortauna Compound 16: 1.3 micromolar.

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\ vtcortauna Compound 17: 0.9 micromolar.

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\ vtcortauna Compound 18: 1.5 micromolar.

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\ vtcortauna Compound 19: 2 micromolar.

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\ vtcortauna Compound 20: 1.4 micromolar.

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\ vtcortauna Compound 21: 3 micromolar.

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\ vtcortauna Compound 22: 0.8 micromolar.

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These results show that the family of compounds object of this patent can also be drugs useful for the long-term symptomatic treatment of AD.

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2.3 Measurement of the antioxidant capacity of Compounds: Hydrogen peroxide uptake by compounds object of the invention

In order to determine if the compounds object of the invention had antioxidant capacity, the three compounds that best resulted as neuroprotectors were selected from among the 22 compounds shown in this patent, compounds 9, 15 and 20. The evaluation was It was carried out using a probe, DCFH-DA (2,7-dichlorofluorescein diacetate), which crosses the cell membrane and is hydrolyzed by cell esterases into its non-fluorescent form DCFH2, which undergoes an oxidation reaction with the radicals of oxygen passing into its fluorescent form DCF ( Brain. Research . 2004 , 1009 , 9-16). The decrease in fluorescence in the presence of the compounds under evaluation, added at the same time as the toxic, would indicate a free radical sequestering effect.

The protocol followed consisted of sowing the cells at a density of 2x105 cells per well in plates 96-well blacks, and keep them for 24 hours in the incubator Next, the cells were loaded with 10 µM of DCFH-DA, were incubated for about 45 minutes and, next, the toxic rotenone plus oligomycin A (30:10 µM), a mixture that induces the formation of radicals, plus compound at the most neuroprotective concentrations for 2 hours. After this time, the cells were lifted and measured the fluorescence in a flow cytometer (Cytomics FC 500 MPL from Beckman Coulter, 2 lasers: blue (488 nm) and red (633 nm), 5 PMT for fluorescence with a range of 185 to 900 nm).

The results of antioxidant capacity, expressed as% fluorescence of the combination rotenone 30 micromolar / oligomycin 10 micromolar, ROS generator, for Compounds of the invention are the following:

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\ vtcortauna Compound 9: 71.5%

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\ vtcortauna Compound 15: 79.3%

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\ vtcortauna Compound 20: 72.8%

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\ vtcortauna Trolox: 70.4%

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As in section 2.1, these results they are a new test of the antioxidant and capture capacity of free radicals of the compounds object of the invention, reinforcing its attractiveness as potential drugs useful for treatment of pathologies in which at least one of the causes is oxidative stress

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2.4 Activity of the compounds object of the invention as modulators of cytosolic calcium concentration

Finally, it was studied whether the neuroprotective mechanism of the compounds object of the invention could also have some relationship with a decrease in cytosolic calcium overload. Indeed, it is known that the alteration of calcium homeostasis may be involved in the development of different neurodegenerative diseases ( J. Neurochem. 1992 , 12 , 376-389; Brain Res. 1993 , 16 , 409-415; Exp. Neurol 1994 , 128 , 1-12; J. Neurochem . 1997 , 68 , 265-271). A neuronal calcium overload can activate different pathological processes such as the alteration of the mitochondrial membrane potential or the production of free radicals that will eventually lead to cell death ( Acta Clin. Belg . 1999 , 54 , 302-305). Therefore, a blockage of excessive calcium entry into the cells could be related to the observed neuroprotective effect. For this purpose, based on their interesting neuroprotective profile, 4 were selected from the 22 compounds shown in this patent, compounds 9, 17, 19 and 20. SH-SY5Y cells were seeded in opaque 96-well plates, and they were kept for 24 hours in the incubator; They were then incubated in the dark for 40 min at 37 ° C in a Krebs-HEPES solution (consisting of: NaCl (144 mM), KCl (5.9 mM), MgCl 2 (1.2 mM), CaCl 2 ( 2 mM), HEPES (10 mM), glucose (11 mM)) containing the fluorescent fluo-4 / AM probe (10 µM), pluronic acid F-127 (0.02%) and probenecid (1 mM). Pluronic acid is a low toxicity detergent that is used to prevent the formation of micelles and thus facilitate the loading of cells with the fluo-4 / AM, a calcium ion chelator, which emits fluorescence when bound to it. Probenecid is an inhibitor of the anionic plasma membrane transporter and its use reduces the loss of the fluorescent probe.

Once the incubation with the solution is finished loading, the cells were washed with Krebs-HEPES and, subsequently, they were kept 30 min in dark at temperature ambient, to allow hydrolysis of the ester linkage of the probe by intracellular esterases. The following were injected compounds at the desired concentrations, in the different wells of the plate, after introducing it into a fluorescence reader in Fluostar Optima model plates (BMG Labtechnologies) where quantified the fluorescence emitted by the Fluo-4 / AM measuring at wavelengths of 485 nm (excitation) and 520 nm (emission).

In all experiments with the different treatments the state of the cell culture was verified, applying a depolarizing pulse (70 mM KCl) to a control well and as positive control was used nifedipine, a nonspecific blocker of voltage-dependent calcium channels.

The results of the concentration blockade of calcium, expressed as% fluorescence for compounds of the invention, are the following:

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\ vtcortauna Compound 9: 24.3% at 10 micromolar.

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\ vtcortauna Compound 17: 5t5% at 10 micromolar.

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\ vtcortauna Compound 19: 16.6% at 10 micromolar.

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\ vtcortauna Compound 20: 23.9% at 10 micromolar.

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\ vtcortauna Nifedipine: 35.8% at 10 micromolar.

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The results described indicate as very likely a double mechanism for neuroprotective action that show the compounds object of this invention:

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\ vtcortauna As an antioxidant by free radical uptake

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\ vtcortauna Promoting the decrease of calcium ions in the cytosol by modulation of the voltage-dependent calcium channels.

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The neuroprotective activity through this double mechanism makes these compounds very attractive for their potential utility for the treatment of diseases neurodegenerative

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2.5 Penetration capacity in the nervous system central

Taking into account the central role that the brain plays in the organism, it can be expected that evolution itself has protected it in a special way. Indeed, the entire central nervous system, but in particular the brain, appears as an armored organ, a separate system within the body as a whole, separated by a membrane of special characteristics called the blood brain barrier (hereafter BHE) that selects the passage of certain molecules in both directions. That is, it is useless to obtain a product that shows high activity in vitro , with great potential for the treatment of, for example, neurodegenerative diseases if in vivo it is not able to reach its therapeutic target. It is therefore of great importance to know if the molecule or family of molecules object of an investigation of the type presented in this patent are capable of crossing the BHE before reaching later phases of the development of the potential drug, in order to introduce new modifications in the molecule or even stop the line of investigation if the inability of the products to penetrate the central nervous system through the BHE is confirmed, with the consequent saving of increasingly high investments.

There are some in vitro methods to evaluate such penetration capacity, the so-called PAMPA methodology ( Parallel Artificial Membrane Permeation Assay, described in Eur. J. Med. Chem . 2003 , 38 , 223-232) the most used due to the maximum precision and likelihood that their results offer. In the case of the products object of this invention, their ability to cross the BHE was studied using said PAMPA methodology in the manner described below. The experiments were performed using two 96-well microplates in a sandwich assembly. The upper microplate (Millipore Ref. MAIPS4510) is provided with 96 hydrophobic PVDF filters, where a solution of pig brain lipid extract (Avanti Polar Lipids) is deposited in dodecane. The lower microplate has 96 tear-shaped wells (Millipore Ref. MAMCS9610).

The receiving microplate was filled with 180 µL per well of a mixture composed of phosphate buffer pH 7.4 saline (PBS) and EtOH in proportion 70:30. The filter of the donor plate was covered with 4 µL of a solution of the lipid extract of pig brain in dodecane (20 mg mL -1). Next, 180 µL of a PBS: EtOH solution was added (70:30) of the compounds to be evaluated on the donor microplate, which was carefully placed on the receiving plate. After 280 minutes of incubation at 25 ° C the donor plate was separated carefully and the concentration of the compounds in the receiving plate by UV spectroscopy. The method measures the permeability, expressing as such the speed of passage of a barrier of a given thickness in millionths of a centimeter (cm x 10-6) per second. The results are expressed as the value mean plus / minus the standard deviation of three trials independent containing each of them four repetitions of Each compound to analyze. Previously, the method was validated with the evaluation of 15 commercial drugs: testosterone, verapamil, imipramine, desipramine, astemizole, progesterone, promazine, chlorpromazine, clonidine, corticosterone, piroxicam, hydrocortisone, caffeine, aldosterone, lomefloxazine, enoxazine and ofloxazine, which offered values between 22.9 ± 0.1 (testosterone) and 0.6 ± 0.01 (ofloxazine), consistent with the permeability values described for said compounds.

The results obtained were:

6

The conclusion drawn from these results is that the products object of the present invention, being capable of crossing the blood brain barrier, they are also able to reach their therapeutic targets in the brain, a almost essential condition to be part of useful drugs for the treatment of diseases of the nervous system in general and neurodegeneratives in particular, such as the disease of Alzheimer's

Claims (18)

1. A compound of general formula (I): 8 where:

Het

It represents a tricyclic system derived from azaantracene system.

R_ {1}

represents a group selected from the list that comprises (C 1 -C 6) alkyl, haloalkyl, aryl, alkylaryl, aminoalkyl or ammoniumalkyl.

R2, R3 are the same or different and each one is selected independently of the group comprising (C 1 -C 6) alkyl, alkoxy, halogen, haloalkyl, nitro, amino or aminoalkyl or a atom of hydrogen. or an isomer, pharmaceutically acceptable salt and / or solvate thereof.

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2. A compound according to claim 1 wherein Het represents the 10 H -9-thia-10-azaanthracene system. 3. Compound according to any of the claims 1-2 wherein R1 is a group linear or branched C 1 -C 6 alkyl. 4. Compound according to claim 3 in the that the alkyl is substituted by at least one functional group. 5. Compound according to claim 4 in the that the functional group is an aryl group or a heterocycle. 6. Compound according to claim 4 in the that the functional group is selected from the list comprising halogen, ester, ether, substituted or unsubstituted amino or ammonium including three alkyl groups. 7. Compound according to claim 1 wherein R1 is a derivative of the 2-aminoethyl radical. 8. Compound according to claim 7 wherein the amino group is substituted by alkyl radicals (C_ {1} -C_ {6}) open or cyclic chain. 9. Compound according to claim 1 wherein R 2 and R 3 are the same or different and represent a group (C 1 -C 6) alkyl substituted or not replaced. 10. Compound according to claim 9 wherein R 2 or R 3 or both, are an alkyl group (C 1 -C 6) substituted by at least one group which is selected from the list comprising trifluoromethyl, ether, ester, amide, nitro, amine or nitrile. 11. Compound according to claim 1 selected from the list comprising:

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\ vtcortauna N- (4-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

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\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) acetamide,

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\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide,

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\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide,

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\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

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\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (4-methylpiperazin-1-yl) acetamide,

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\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

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\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide,

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\ vtcortauna 10-Amino-10 H -9-thia-10-azaanthracene,

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\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (piperidin-1-yl) acetamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -2-dimethylaminoaacetamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -2- (pyrrolidin-1-yl) acetamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) acetamide.

?

\ vtcortauna N- (3-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (2-Nitro-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

?

\ vtcortauna N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3-dimethylaminopropionamide,

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\ vtcortauna N- (10 H -9-Tia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide,

?

\ vtcortauna N- (2-Chloro-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide, or

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\ vtcortauna N- (2-Methoxy-10 H -9-thia-10-azaantracen-10-yl) -3- (pyrrolidin-1-yl) propionamide.

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12. Pharmaceutical composition characterized in that it comprises a compound of formula I according to any one of claims 1 to 11, together with one or more pharmaceutically acceptable excipients. 13. Composition according to claim 12 characterized in that it further comprises one or more active therapeutic agents. 14. Use of a compound of general formula (I) for the preparation of a medicine. 15. Use of the compound according to claim 14 for the preparation of a medicine for prevention and / or treatment of disorders or diseases in which they are oxidative processes involved as etiology of these disorders or diseases 16. Use according to claim 15 characterized in that the disorders or diseases are those in which a deficit or dysfunction of cholinergic neurotransmission is involved. 17. Use according to any of claims 15 and 16 characterized in that the disorder or disease belongs to the group of neurodegenerative diseases. 18. Use according to claim 17 characterized in that said neurodegenerative disease is Alzheimer's disease, Parkinson's disease or Huntington's disease.