The Study of the Structure — Diuretic Activity Relationship in a Series of New N-( Arylalkyl )-6-hydroxy-2-methyl-4-oxo-2 , 4-dihydro-1 H-pyrrolo-[ 3 , 2 , 1-ij ] quinoline-5-carboxamides

Igor V. Ukrainets 1,* ID , Mykola Y. Golik 2, Lyudmila V. Sidorenko 1 ID , Valentina I. Korniyenko 3, Lina A. Grinevich 4, Galina Sim 5 and Olga V. Kryvanych 1 1 Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, Ukraine; slv.ludmila@i.ua (L.V.S.); olgabevz87@gmail.com (O.V.K.) 2 Department of Analytical Chemistry, National University of Pharmacy, 4 Valentynivska St., 61168 Kharkiv, Ukraine; aptekar4009@gmail.com 3 Department of Pharmacology and Toxicology, Kharkiv State Zooveterinary Academy, 1 Academicheskaya St., Malaya Danilovka, Dergachevsky District, 62341 Kharkiv, Ukraine; kornienko-valentina@ukr.net 4 Department of Medical Chemistry, National University of Pharmacy, 4 Valentynivska St., 61168 Kharkiv, Ukraine; grinevich.lina@gmail.com 5 Department of Pharmaceutical Chemistry, Far Eastern State Medical University, 35 Murav’eva-Amurskogo St., 680000 Khabarovsk, Russia; sim.hab@mail.ru * Correspondence: igor.v.ukrainets@gmail.com; Tel.: +38-0572-679-185


Introduction
Copying of existing and, first of all, commercially successful drugs with simultaneous introduction of minor chemical changes in their structure is well known in medical chemistry as the "me-too" technique [1].By definition, the drugs created in this way have the structure close to the prototype.At the same time, their molecule must be original; it allows the developer to protect it with a patent as an intellectual property.Often, "me-too "drugs have significant therapeutic benefits, become the "first "or even the "best in class" and completely replace their prototype.A striking example of such a successful "career" is "me-too" diuretic Hydrochlorothiazide, which permanently took the place of its predecessor Chlorothiazide [2].Ranitidine has become more popular than Cimetidine [3], Enalapril is gradually replacing Captopril [4], and Eplerenone is much more efficient and safer than Spironolactone [5], etc. (Figure 1).

Introduction
Copying of existing and, first of all, commercially successful drugs with simultaneous introduction of minor chemical changes in their structure is well known in medical chemistry as the "me-too" technique [1].By definition, the drugs created in this way have the structure close to the prototype.At the same time, their molecule must be original; it allows the developer to protect it with a patent as an intellectual property.Often, "me-too "drugs have significant therapeutic benefits, become the "first "or even the "best in class" and completely replace their prototype.A striking example of such a successful "career" is "me-too" diuretic Hydrochlorothiazide, which permanently took the place of its predecessor Chlorothiazide [2].Ranitidine has become more popular than Cimetidine [3], Enalapril is gradually replacing Captopril [4], and Eplerenone is much more efficient and safer than Spironolactone [5], etc. (Figure 1).Improved "copies" of the known drugs created by the "me-too" technique [1][2][3][4][5].
It should not be forgotten, however, that sometimes differences between actively implemented and advertised novelties are very conditional; they are mainly marketing rather than pharmacological ones.Hence, there are numerous disputes and discussions concerning the benefits of "me-too" drugs (medical or economic), and the feasibility of their development and implementation in medical practice in general Figure 1.Improved "copies" of the known drugs created by the "me-too" technique [1][2][3][4][5].
It should not be forgotten, however, that sometimes differences between actively implemented and advertised novelties are very conditional; they are mainly marketing rather than pharmacological ones.Hence, there are numerous disputes and discussions concerning the benefits of "me-too" drugs Sci.Pharm.2018, 86, 31 3 of 21 (medical or economic), and the feasibility of their development and implementation in medical practice in general [6][7][8][9][10].Nevertheless, the "me-too" technique has been and remains a powerful tool for reducing the cost of new drugs, their development time, clinical trials and launch to the pharmaceutical market.
Pharmacological tests have revealed the structural and biological regularities that are interesting and important for further studies.In particular, the presence of the aromatic nucleus in the terminal amide fragment was repeatedly noted as a mandatory factor for manifestation of diuretic properties by the substances under study.However, the distance of this aromatic nucleus from the 3-carbamide nitrogen atom on the diuresis is no longer uniquely affected.For example, in the case of 4-hydroxy-2-oxo-1,2-dihydroquinoline derivatives I, the diuretic activity decreases in the following sequence: 1-phenylethylamides > 2-phenylethylamides > benzylamides > anilides > 3-phenylpropylamides.
In general, highly active compounds were found in all groups I-VII without exception regardless of the structure of the underlying bicyclic heterocyclic system.However, much better results were achieved after transition to the tricyclic "me-too" clones of 4-hydroxyquinoline-2-one diuretics (Figure 3).The first group of derivatives of this type considered-6-hydroxy-4-oxo-2,4dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides VIII [22,23]-raised the studies to a new level and gave a promising lead structure (R = 4-methoxyphenyl) characterized by a high diuretic activity, low toxicity, and, which is particularly interesting, the ability to inhibit the production of aldosterone.It is interesting that, in the whole group of pyrroloquinolines VIII, the need for the presence of the aromatic nucleus in the amide fragment is retained, but the diuretic effect is modified in a different order: anilides > benzylamides > 3-phenylpropylamides > 2-phenylethylamides > 1-phenylethylamides > cycloalkyl-amides >> alkylamides.achieved after transition to the tricyclic "me-too" clones of 4-hydroxyquinoline-2-one diuretics (Figure 3).The first group of derivatives of this type considered-6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides VIII [22,23]-raised the studies to a new level and gave a promising lead structure (R = 4-methoxyphenyl) characterized by a high diuretic activity, low toxicity, and, which is particularly interesting, the ability to inhibit the production of aldosterone.It is interesting that, in the whole group of pyrroloquinolines VIII, the need for the presence of the aromatic nucleus in the amide fragment is retained, but the diuretic effect is modified in a different order: anilides > benzylamides > 3-phenylpropylamides > 2-phenylethylamides > 1-phenylethylamides > cycloalkyl-amides >> alkylamides.Annelation of the five-membered oxazole cycle along the quinoline edge а as a variant of the chemical modification of pyrroloquinolines VIII appeared to be extremely unsuccessful since, unfortunately, 2-bromomethyl-(IX) and 2-methylene-(X) 5-oxo-1,2-dihydro-5H-oxazolo[3,2-a] quinoline-4-carboxamides easily obtained did not have any significant diuretic properties [14].

XII
The transition to pyridoquinolines XI did not meet the expectations.Based on the tests conducted, it can be argued that, as a rule, the diuretic activity is somewhat reduced as a result of such a transformation, and the structure of the amide fragments affects the biological properties in the same way as in the pyroloquinolines VIII group [24,25].At the same time, it has been found that bromination of the pyridoquinoline nucleus in position 9 (amides XII) leads to a significant increase in diuresis and, in principle, opens a new direction of "me-too" optimization of tricyclic 4-hydroxyquinoline-2-one diuretics [26].
Finally, there are 2-methylsubstituted pyrroloquinolines XIII.The experimental study (white rats, per os) of a large series of various anilides conducted by us to date has clearly demonstrated a generally positive impact on the diuretic effect of the 2-methyl group, while the nature of the effect of substituents in arylamide residues compared with non-methylated analogs VIII significantly changes [27,28].Based on these facts, N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1Hpyrrolo[3,2,1-ij] quinoline-5-carboxamides are of great interest as objects for our research, and this work is devoted to them.Annelation of the five-membered oxazole cycle along the quinoline edge a as a variant of the chemical modification of pyrroloquinolines VIII appeared to be extremely unsuccessful since, unfortunately, 2-bromomethyl-(IX) and 2-methylene-(X) 5-oxo-1,2-dihydro-5H-oxazolo[3,2-a] quinoline-4-carboxamides easily obtained did not have any significant diuretic properties [14].
The transition to pyridoquinolines XI did not meet the expectations.Based on the tests conducted, it can be argued that, as a rule, the diuretic activity is somewhat reduced as a result of such a transformation, and the structure of the amide fragments affects the biological properties in the same way as in the pyroloquinolines VIII group [24,25].At the same time, it has been found that bromination of the pyridoquinoline nucleus in position 9 (amides XII) leads to a significant increase in diuresis and, in principle, opens a new direction of "me-too" optimization of tricyclic 4-hydroxyquinoline-2-one diuretics [26].
Finally, there are 2-methylsubstituted pyrroloquinolines XIII.The experimental study (white rats, per os) of a large series of various anilides conducted by us to date has clearly demonstrated a generally positive impact on the diuretic effect of the 2-methyl group, while the nature of the effect of substituents in arylamide residues compared with non-methylated analogs VIII significantly Sci.Pharm.2018, 86, 31 5 of 21 changes [27,28].Based on these facts, N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1Hpyrrolo[3,2,1-ij] quinoline-5-carboxamides are of great interest as objects for our research, and this work is devoted to them.

Chemistry
In principle, all target N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij] quinoline-5-carboxamides 2-7 can be obtained by the method proven effective in the synthesis of anilides, i.e., thermolysis of a mixture of equimolar quantities of tricyclic ester 1 and the the corresponding primary arylalkylamine at a temperature of 130-140 • C [27,28].However, it must be understood that, unlike anilines, which have much higher reactivity for the interaction, such strict conditions are not obligatory for arylalkylamines with ester 1.Another moment requiring attention is that many of arylalkylamines (this is especially true of benzyl amines) tend to form inert carbonates with carbon dioxide of the air extremely easily and quickly.Therefore, it is much more expedient to perform amidation of ester 1 with arylalkylamines in the medium of any solvent, such as boiling ethanol (Scheme 1).
It can also be noted that a significant decrease in temperature allows for carrying out the synthesis of arylalkylamides 2-7 without fear of partial decomposition of ester 1, which is typical of the abovementioned thermolysis [27,28].Under mild conditions, hydrolysis of this compound does not compete its amidation; therefore, the preliminary dehydration of the solvent and amines is not required.As a result, arylalkylamides 2-7 are formed in high yields and purity (see Section 2.2).
understood that, unlike anilines, which have much higher reactivity for the interaction, such strict conditions are not obligatory for arylalkylamines with ester 1.Another moment requiring attention is that many of arylalkylamines (this is especially true of benzyl amines) tend to form inert carbonates with carbon dioxide of the air extremely easily and quickly.Therefore, it is much more expedient to perform amidation of ester 1 with arylalkylamines in the medium of any solvent, such as boiling ethanol (Scheme 1).The chemical structure of all N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo [3,2,1-ij]quinoline-5-carboxamides 2-7 synthesized was confirmed by the data of elemental analysis, NMR spectroscopy ( 1 H and 13 C), mass spectrometry, and polarimetry.
When interpreting 1 H NMR spectra of arylalkylamides 2-7, the attention is drawn to the tricyclic nucleus, which is common for all samples and, first of all, its 2-methylpyrroline fragment.Protons and the methyl group of this "hard" heterocycle have a fixed orientation, which is a source of problems in detailed structural analysis.For example, in the 1 H NMR spectrum of benzylamide 2a a multiplet for a methine proton at 4.97 ppm, a doublet at 1.54 ppm for the 2-methyl group, and two double doublets for the methylene group protons with the centers at 3.66 and 2.99 ppm correspond to protons of this fragment.Everything is simple and clear with the first two signals, but the specific assignment of the methylene group proton signals requires additional effort.Such stereochemical tasks can be solved in different ways.One of the versions is to use Karplus formula or its graphical representation [32] correlating the value of the dihedral angle between the interacting protons with the vicinal ( 3 J) spin-spin coupling constant (SSCC).The simple calculations of the theoretical torsion angles and the vicinal SSCC described in detail earlier [27] and their subsequent comparison with the experimental values allow us to easily and unambiguously determine that, in a weaker field, there is the signal of a methylene proton, which by spin-spin coupling is a cis partner of a metine proton (Figure 4).
representation [32] correlating the value of the dihedral angle between the interacting protons with the vicinal ( 3 J) spin-spin coupling constant (SSCC).The simple calculations of the theoretical torsion angles and the vicinal SSCC described in detail earlier [27] and their subsequent comparison with the experimental values allow us to easily and unambiguously determine that, in a weaker field, there is the signal of a methylene proton, which by spin-spin coupling is a cis partner of a metine proton (Figure 4).Interpretation of the proton signals of the second component of the tricyclic nucleus of arylalkylamides 2-7-the quinolone fragment-is much easier.The protons of the 6-hydroxy groups appear as narrow singlets in the area that is typical for enols: 17.31-16.92ppm.Aromatic quinolone protons in all 1 H NMR spectra present a very stable picture, which consists of two doublets (H-7 and H-9) and one triplet (H-8) and does not experience any influence from the terminal amide fragments (Figure 5).Interpretation of the proton signals of the second component of the tricyclic nucleus of arylalkylamides 2-7-the quinolone fragment-is much easier.The protons of the 6-hydroxy groups appear as narrow singlets in the area that is typical for enols: 17.31-16.92ppm.Aromatic quinolone protons in all 1 H NMR spectra present a very stable picture, which consists of two doublets (H-7 and H-9) and one triplet (H-8) and does not experience any influence from the terminal amide fragments (Figure 5).The mass spectra registered under conditions of electron impact ionization confirm the structure of N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides 2-7 by determining their molecular weight, first of all.In addition, the analysis of the fragmentation ions that are formed during the primary fragmentation of molecular ions also provides the analytically important information about the components of the molecule under study (Scheme 2).It has been shown in the example of benzylamide 2a, which is typical for the whole group studied, that this process proceeds by the ketene type that is common for 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides and their tricyclic analogs [25,26], namely after breaking of the acyclic amide bond two characteristic fragments-the ion of tricyclic ketene 8 with m/z 227 and the ion of arylalkylamine 9, which is specific for each sample, are formed.provides the analytically important information about the components of the molecule under study (Scheme 2).It has been shown in the example of benzylamide 2a, which is typical for the whole group studied, that this process proceeds by the ketene type that is common for 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides and their tricyclic analogs [25,26], namely after breaking of the acyclic amide bond two characteristic fragments-the ion of tricyclic ketene 8 with m/z 227 and the ion of arylalkylamine 9, which is specific for each sample, are formed.According to the data of polarimetry, it has been found that chiral 1-phenylethylamides 3а-е rotates the polarization plane in the opposite direction compared to the original amines.We already observed a similar phenomenon in optically active N-(1-phenylethyl)-4-hydroxy-2-oxo-1,2dihydroquinoline-3-carboxamides [33].The detailed analytical study conducted at that time with the use of X-ray diffraction analysis convincingly proved that there was neither the configuration conversion, nor racemization in these reactions.In general, the substance configuration and the direction of the polarization plane rotation, as is known [34], are not related to each other's characteristics.In addition, unlike the true configuration (S or R), the specific rotation indicators and their signs (+ or −) are not constant values and depend on many external factors (concentration, solvent, temperature, etc.).Therefore, it can be stated with complete certainty that the chiral centers of 1-phenylethylamides 3а-е retain the configuration of the original amines.

Evaluation of the Diuretic Activity
The analysis of the results of the experimental study (Table 1), including the effect of
According to the data of polarimetry, it has been found that chiral 1-phenylethylamides 3a-e rotates the polarization plane in the opposite direction compared to the original amines.We already observed a similar phenomenon in optically active N-(1-phenylethyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides [33].The detailed analytical study conducted at that time with the use of X-ray diffraction analysis convincingly proved that there was neither the configuration conversion, nor racemization in these reactions.In general, the substance configuration and the direction of the polarization plane rotation, as is known [34], are not related to each other's characteristics.In addition, unlike the true configuration (S or R), the specific rotation indicators and their signs (+ or −) are not constant values and depend on many external factors (concentration, solvent, temperature, etc.).Therefore, it can be stated with complete certainty that the chiral centers of 1-phenylethylamides 3a-e retain the configuration of the original amines.

Evaluation of the Diuretic Activity
The analysis of the results of the experimental study (Table 1), including the effect of N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2a, 3a and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35].  2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35].  2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35]. 2-7 synthesized on the urinary function of the kidneys, revealed curious and rather unexpected structural and biological regularities.First of all, the fact that in all groups of compounds with the phenyl nuclei in the amide fragments the unsubstituted derivatives 2а, 3а and 4a appeared to be the most active should be noted.The negative impact on the diuretic properties of the test substances of all the substituents without exception and especially the methoxy groups was extremely surprising since, prior to this, the presence of the 4-methoxysubstituted aromatic ring in terminal amide fragments was considered as a desirable and even necessary factor [15,23,35].
14.03 ± 0.43 +174 14.03 ± 0.43 +174 14.03 ± 0.43 +174 14.03 ± 0.43 +174 Replacement of the phenyl nucleus in benzylamide 2а with the isosteric heterocycle (2-, 3-or 4-pyridine, furan, 5-methylfuran or thiophene) leads to a significant decrease in activity and even the total loss of the diuretic properties, and it deprives the entire group of hetarylmethylamides 6a-g of any prospects as diuretics.Hydrogenation of the aromatic nucleus (amides 6f and 7), as well as Replacement of the phenyl nucleus in benzylamide 2а with the isosteric heterocycle (2-, 3-or 4-pyridine, furan, 5-methylfuran or thiophene) leads to a significant decrease in activity and even the total loss of the diuretic properties, and it deprives the entire group of hetarylmethylamides 6a-g of any prospects as diuretics.Hydrogenation of the aromatic nucleus (amides 6f and 7), as well as Figure 1.Improved "copies" of the known drugs created by the "me-too" technique [1-5].

2 .
Scheme 2. The primary fragmentation of the molecular ion of benzylamide 2a.
C-NMR (100 MHz, DMSO-d 6 ): δ 172.4 (6-C-OH), 171.6 (5-C=O), 160.4 (4-C=O), 141.4,130.7, 126.5, were carried out in full accordance with the European Convention on the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes and the Ukrainian Law No. 3447-IV "On protection of animals from severe treatment" [29] (project ID 1674U13 approved 22 September 2012).The biological experiments were carried out with the permission and under the supervision of the Commission on Bioethics (Kharkiv State Zooveterinary Academy, Kharkiv region, Ukraine).