Search

6-Hydroxy-N-(4-methoxyphenyl)-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, C 19 H 16 N 2 O 4 , possesses strong diuretic properties and can be used as a new hypertension remedy. Two polymorphic modifications of this compound have been found, namely the triclinic polymorph (space group P-1), with one molecule in the asymmetric unit, and the monoclinic polymorph (space group P2 1 /n), with two molecules in asymmetric unit. An analysis of the pairwise interaction energies between the molecules in the crystal phase revealed differences in the crystal packing. The triclinic form has only one level of organization, namely a chain/column, while the monoclinic form has two levels of organization, with a chain/column as the primary basic structural motif and a layer as the secondary basic structural motif.

In accordance with the principles of "me-too" technique, the preparative method for obtaining has been proposed, and the synthesis of a large series of new N -(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1 H -pyrrolo[3,2,1- ij ]quinoline-5-carboxamides as structurally close analogs of tricyclic pyrrolo- and pyridoquinoline diuretics has been carried out. All target compounds were obtained with high yields and purity by amidation of ethyl ester of the corresponding 2-methyl-pyrroloquinoline-5-carboxylic acid with arylalkylamines in boiling ethanol. Their structure was confirmed by the data of elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and polarimetry. Moreover, interpretations of their ¹H and 13 C-NMR spectra, their mass spectrometric behavior, as well as peculiarities of the polarimetric studies were discussed. The effect of N -(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1 H -pyrrolo[3,2,1- ij ]quinoline-5-carboxamides on the urinary function of the kidneys was studied in white rats by the standard method of oral administration in the dose of 10 mg/kg compared to hydrochlorothiazide. According to the results of the primary pharmacological screening, the structural and biological regularities that were unexpected, but interesting for further studies were revealed. Among the substances studied, the samples, which by their diuretic effect are not inferior and even superior to both the known hydrochlorothiazide and the lead structure of the pyrroloquinoline group, have been found. On this basis, it can be argued that the introduction of the methyl group made by us in position 2 of pyrrolo[3,2,1- ij ]quinoline nucleus can be considered as a successful and promising implementation of the "me-too" cloning of tricyclic 4-hydroxyquinoline-2-one diuretics.

Continuing a targeted search for new leading structures with diuretic action among tricyclic derivatives of hydroxyquinolines, which are of interest as potential inhibitors of aldosterone synthase, the synthesis of a series of the corresponding pyrido[3,2,1- ij ]quinoline-6-carboxanilides was carried out by amidation of ethyl-7-hydroxy-5-oxo-2,3-dihydro-1 H ,5 H -pyrido[3,2,1- ij ]quinoline-6-carboxylate with aniline, aminophenols and O -alkylsubstituted analogs with high yields and purity. The optimal conditions of this reaction are proposed; they make it possible to prevent partial destruction of the original heterocyclic ester and thereby avoid formation of specific impurities of 7-hydroxy-2,3-dihydro-1 H ,5 H -pyrido[3,2,1- ij ]quinolin-5-one. To confirm the structure of all substances obtained, elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry were used. Moreover, the peculiarities of their ¹H and 13 C-NMR spectra, as well as their mass spectrometric behavior under conditions of electron impact ionization, were discussed. The effect of pyrido[3,2,1- ij ]quinoline-6-carboxanilides on the urinary function of the kidneys was studied in white rats of both genders by the standard method of oral administration at a dose of 10 mg/kg. Testing was conducted in comparison with hydrochlorothiazide, as well as with structurally close pyrrolo[3,2,1- ij ] quinoline-5-carboxanilides studied earlier with the same substituents in the anilide fragments. It was found that addition of one methylene unit to the heterocycle partially hydrogenated and annelated with the quinolone core has a positive impact on biological properties-most of the substances studied exhibit a statistically significant diuretic effect exceeding the activity of not only hydrochlorothiazide, in some cases, but also the action of the structural analogs. The important structural and biological regularities, which are common with pyrroloquinolines and introduced by a chemical modification, were revealed. The importance of the presence in the structure of terminal amide fragments of tricyclic quinoline-3-carboxamides of a 4-methoxy-substituted aromatic ring was particularly marked. The expediency of further study of pyridoquinolines as promising diuretic agents has been shown.

In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N- benzyl-4-hydroxy-1-methyl-2,2-dioxo-1 H -2λ⁶,1-benzothiazine-3-carboxamide, its 4- O -sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N- benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N- benzyl-4-hydroxy-1-methyl-2,2-dioxo-1 H -2λ⁶,1-benzothiazine-3-carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam., Competing Interests: The authors declare no conflict of interest.

A new, effective preparative method has been proposed and the synthesis of a series of N-(arylalkyl)-1-R-4-hydroxy-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-car-boxamides has been carried out. It has been shown that amidation of alkyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-carboxylates with arylalkyl-amines in boiling xylene proceeds with good yield and purity to the corresponding N-(arylalkyl)-amides. However, the presence of water in the reaction mixture has been shown to cause the formation of specific impurities: N-(arylalkyl)-1-R-2,2-dioxo-1H-2λ(6),1-benzothiazin-4-amines. According to the results of the pharmacological studies, powerful analgesics have been found among the substances synthesized.

The asymmetric unit of the title compound, 4C(20)H(22)N(4)O(5)·2C(2)H(6)O·CH(4)O, contains two pyridine-3-carboxyl-ate mol-ecules, one ethanol mol-ecule and one methanol mol-ecule disordered about in a centre of symmetry. The pyridinone ring, the carbamide group and the bicyclic fragment in both independent mol-ecules are planar within 0.03 Å due to the formation of intra-molecular O-H⋯O and N-H⋯O hydrogen bonds. The formation of these latter inter-actions also causes the redistribution of the electron density within the hydroxy-pyridone fragment, with the result that some bonds are elongated compared with values in the literature and some others are shorter. In the crystal phase, the pyridine-3-carboxyl-ate mol-ecules form layers parallel to (010), which are inter-linked through hydrogen bonds mediated by the bridging solvate mol-ecules. A terminal ethyl group in one of the mol-ecules is disordered over two sites of equally occupancy.