Heterocyclic compounds comprising 2-aminopyridine-3-sulfomic fragment, methods for their preparing (variants), focused library and pharmaceutical composition

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

 

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, compounds leaders and drug candidates that can be derived from the combinatorial or screening of focused libraries of compounds, and to pharmaceutical compositions.

More specifically, the present invention relates to new heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment of interest as a potential physiologically active substances (agonists, antagonists and modulators of receptors, enzyme inhibitors, oncolytic, antibacterial and antiparasitic agents, etc), to the focused library and pharmaceutical compositions containing as active substance new new heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment.

There are a large number of physiologically active heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment, including 2-aminopyridine-3-sulphonamide [Kotovsky S. Kaliev and other Chem. Pharm. J., 1979, 13(4), 54-57], 2-aminopyridine-3,4-disulfonic [Grapoe E.J. et al. J. Med, Pharm. Chem. 1961, 4, 369-383] phenyl ester 2-amino-5-bromopyridin-3-sulfonic [Fischer, M.; Troschuetz, R. Synthesis, 2003, 10, 1603-1609]below

The cyclization of 2-aminopurin the n-3-sulfonamides and aldehydes and acids obtained the corresponding 2(4)H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxides D and E, presented below in Table 1.

Table 1

Known 2(4)H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxides D and E.

Connection.RaRbRcRdLiterature
DHNnNand
DNNSO2NH2CH3b
DHNSO2NH2NH2b
DNHSO2NH2HEb
DNHSO2NH2Clb
ENHNH
ECH3HNHa, C
ENH2HNHand
E3-pyridylHH Hd
ENC2H5SO2NH2He
ECH2SCH2PhNSO2NH2Hb
ENHSO2NH2CH3b
ENHSO2NH2NH2b
ENHSO2NH2HEb
ENHSO2NH2Clb
ECH2SCH2PhHSO2NH2CH3b
and Kotovsky S. Kaliev and other Chem. Forms. J., 1979, 13(4), 54-57.

b Grapoe E.J. et al. J. Med, Pharm. Chem., 1961, 4, 369-383.

with P. de Tullio; et al. Tetrahedron, 1995, 51(11), 3221-3234.

d Osselaere J.P. Eur. J. Med. Chem. 1974, 9, 310-312.

e Yale H.L., Sheehan, T. J. J. Org. Chem., 1961, 26, 4315-4325.

It should be noted that among the known 2(4)H-pyrido[2,3-e][1,2,4]thiadiazine 1,1-dioxides E includes cardio antigipertenzivnye drugs that act as angiotensinii AT1 recipe is R antagonists F [Squibb & Sons, 1995, Pat. US 5378704] and activators of K (ATP) channels G [University of Liege, Drug Data Rep. 2000, 22(7), 600], and heterocycles, including 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-4-one-1,1-dioxideis fragment, are, for example, inhibitors of signal transduction pathways [Bristol-Meers Squibb, 1998, Pat. US 6156746].

New heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment and 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-4-one-1,1-dioxideis fragment of interest as neuroprotectors. Glutamatergic system is the main excitatory neurotransmitter system in the brain and is involved in the implementation of a series of physiological and pathological processes. It is known that a wide range of neurological diseases (such as BA, Huntington's chorea, amyotrophic lateral sclerosis, and ischemia of the brain) is associated with excitotoxicity the action of the excitatory neurotransmitter amino acids (HAC) - glutamate and aspartate (Excitatory Ammo Acids and Drug Research, Ed. by M.R.Szewczak & N.J.Hrib, Alan R. Liss, Inc., New York, 1989, p.380; The NMDA Receptor, Eds. Watkins & Collngridge G., 1989, IRL Press). In accordance with this mechanism, the membrane depolarization of neurons during prolonged activation of glutamate receptors of the CNS, namely receptors N-methyl-D-aspartate (NMDA), and the so-called "non-NMDA"receptors, including receptors amino-3-hydroxy-5-methylisoxazole-4-propionic key is lots / kainic acid (AMPA/KA), leads to disruption of calcium homeostasis in nerve cells and initiates a number of pathological metabolic processes (including the formation of free radical metabolites), which ultimately loss of nerve cells (D.W.Choi, Neuron, 1988, v.1, p.623-634).

The possibility of regulating the pool of intracellular calcium defines great pharmacological importance of specific blockers of the transport of calcium associated with glutamate receptors in the Central nervous system. Currently, a number of antagonists of NMDA and AMPA/KA receptors has been proposed as an antidepressant [J.Maj, V.Klimek, Z.Rogoz, G.Skuza - Pol. J. Pharmacol., 1993, v.45, pp.549-553; R.Trullas, P.Skolnick - Eur. J. Pharmacol., 1990, v.185, No 1, pp.1-10], anxiolytic [R.W.Dunn, R.Corbet, L.L.Martin, J.F.Payack, L.Laws-Ricker, C.A.Wilmot, D.K.Rush, J.F.Cornfeldt, S.Fielding - Prog. Clin. Biol. Res., 1990, v.361, (Curr. Future Trends Anticonvulsant Anxiety, Stroke Ther.), pp.495-512], anticonvulsants [J.M.Ferkany, W.J.Krezotarski - Prog. Clin. Biol. Res., 1990, v.361 (Curr. Future Trends Anticonvulsant Anxiety, Stroke Ther.), pp.525-541; W.J.Schmidt, B.Zadow, B.D.Kretschmer. - Aminoacids, 1991, v.1, No 2, pp.225-237) and neuroprotection (S.Fielding, J.Wilker, J.C.Chernack, V.Ramizer, C.A.Wilmot, M.L.Cornfeldt, K.A.Rudolphi, L.L.Martin, J F.Payck, D.K.Rush - Prog. Clin. Biol. Res., 1990, v.361, pp.495-512 (Curr. Future Trends Anticolvunsant Anxiety, Stroke Ther.); T.Nakao, A.Nishiyama, H.Tanaka, Y.Morimot, S.Takehara - Pat. Jap. 04,257,589 [92,257,589] (C 07 D 495/14) from 12.02.1991).

In the case of BA, in particular, it is assumed that one of the basic mechanisms of neuronal cell death is associated with a significant increase in the susceptibility of neurons to x ototoksicescoe action HAC as a result of exposure to nerve cells of pathological forms β -amyloid peptide, which plays a key role in the pathogenesis of BA. As a result of this non-toxic under normal conditions the concentration of the neurotransmitter glutamate are in developing β-amyloidosis toxic to neurons and cause their death (Koh et al., Brain Res., 1990, v.533, p.315; Mattson et al., J. Neuroschi., 1992, v.12, p.376).

In this regard, the search for effective blockers of glutamate-induced transport of calcium ions, in particular in the range of antagonists of NMDA receptors in the brain that can protect nerve cells from the neurotoxic effects of excessive concentrations of calcium ions is a novel and promising approach to the development of new neuroprotective agents for the treatment and protection against a wide range of neurodegenerative diseases (Danysz et al., Drug News &Perspectives, 1995, v.8, No. 5, p.261).

Given the high potential physiological activity of heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment and 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-4-one-1,1-dioxideis fragment, it is important to develop new compounds of this type, focused libraries and pharmaceutical compositions comprising these compounds.

As a result of research aimed at finding new physiologically active substances, compounds leaders, inventors received not previously known new heterocyclic is soedineniya, includes 2-aminopyridine-3-sulfonovy fragment, which possess physiological activity, focused library and pharmaceutical composition comprising these compounds.

It should be noted that despite the considerable number of heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment, published in the patent and scientific literature, some of them hitherto known were not.

Below are definitions of terms used in the description of this invention:

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search Lida or optimize the biological activity of lead compounds, with each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Focused library" means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, and so what.) certain biological targets (enzymes, receptors, ion channels, and so on).

"Lead compound" means a compound with outstanding activity related to a particular disease.

"Scaffold" means the General structural formula, or molecular skeleton, or invariant connections area common to all compounds included in the combinatorial library.

"Gametip" means a series of compounds having a common structural formula and with a certain common property, such as some form fiziologicheskii activity. We can say, for example, "new gametip activators of potassium channels", or "known gametip kinase inhibitors", etc. As a rule, the presence of common structural fragment of compounds within one chemotype is a necessary and sufficient condition for the existence of common properties.

"Deputy" means a chemical moiety or group that is attached to another moiety or group to scaffold, including, but not limited to the halogen atom, the "inert Deputy", a nitro group, sulfo group, a sulfa group, hydroxyl group, amino group, carboxialkilnuyu group, alkoxycarbonyl group, carnemolla group and others

"Inert Deputy" ("Non-interfering substituent"means low or directionspanel radical inert to further transformations and the environment, including but not limiting To 1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl, where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

"Substituted group, substituted radical or scaffold" means, respectively, group, radical or scaffold, which has the Xia Deputy, including, but not limited to inert Deputy, halogen atom, nitro group, cyano group, sulfo group, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, carnemolla group. For example, substituted alkyl means alkyl which has one or more substituents, such as hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-methyl, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonyl-ethyl and others; substituted amino group means an amino group which has one or two substituent, for example, acylamino group, N,N-dialkylamino group, N-acyl-N-aryl-amino group, acetyl-methoxycarbonylmethyl-amino group and others; substituted phenyl means phenyl, which has one or more substituents, for example 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

"Optionally substituted group optionally substituted radical or scaffold" means, respectively, group, radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group include an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including, but not limited to acylamino group, N,N-dialkylamino groups, N-acyl-N-aryl-amino gr is PPI, acyl-methoxycarbonylmethyl-amino group and others

"Aryl" means one or more aromatic cycles, each of which contains 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene or unfused, such as biphenyl. "Substituted aryl" has one or more "not interfering" deputies.

"Halogen" means fluorine atom, chlorine, bromine or iodine.

"Heterocycle" means one or more saturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. "Heterocycle" may be condensed political, such as benzimidazole, benzoxazole. benzthiazole, quinoline, or unfused, for example, as bipyridyl.

"Azaheterocycle" means a heterocycle comprising at least one nitrogen atom, such as benzimidazole, benzoxazole, benzthiazole, quinoline.

"Substituted heterocycle" means a heterocycle having one or more "not interfering" deputies.

"Parallel synthesis" means a method for chemical synthesis of combinatorial libraries of individual connections.

The aim of the present invention are new heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment.

The village is Alanna goal is achieved heterocyclic compounds, includes 2-aminopyridine-3-sulfonovy fragment of General formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

R1represents a hydrogen atom;

R2represents a chlorine atom, optionally substituted hydroxyl group, optionally substituted amino group, optionally substituted azaheterocycle;

or R1and R2together with nitrogen atoms and sulfur, to which they are attached, form an optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazin or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-he, excluding phenyl ester 2-amino-5-bromopyridin-3-sulfonic acids.

According to the invention preferred heterocyclic compounds comprising 2-aminopyridine-3-sulfonovy fragment, are 2-aminopyridine-3-sulfonic acids and their derivatives of General formula 1.1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

R2has the above value.

According to the invention preferred heterocyclic compounds comprising 2-aminopyridine-3-sulfonovy fragment, the two who are 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine with optionally substituted annulated by carbocycles or heterocycles of General formula 1.2

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

R3and R4independently from each other represent a hydrogen atom, a halogen atom, an inert Deputy, optionally substituted hydroxyl group, optionally substituted by an amino group, optionally substituted C1-C3allyloxycarbonyl1-C3alkyl, optionally substituted aminocarbonyl, optionally substituted aminocarbonyl1-C3alkyl or optionally substituted aminocarbonyl1-C3alkyl,

or R3and R4together with the carbon atoms to which they are attached, form an optionally substituted and optionally condensed cycloalkyl or cycloalkenyl, optionally substituted aryl or heterocyclyl.

According to the invention preferred heterocyclic compounds comprising 2-aminopyridine-3-sulfonovy fragment are 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-ones of General formula 1.3

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

R5and R6independently from each other represent a hydrogen atom or an inert Deputy, and R7and R8independently from each other represents the t of a hydrogen atom, inert Deputy, the remaining amino acids or optionally substituted ethylene group.

According to the invention preferred heterocyclic compounds comprising 2-aminopyridine-3-sulfonovy fragment, are amides of 3-(1,1-dioxo-1,4-dihydropyrido[2,3-e][1,2,4]thiadiazin-3-yl)-propionic acid of General formula 1.4

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

R3, R4and R5have the above significance, and R9is optionally substituted by an amino group or optionally substituted azaheterocycle.

New 2-amino-5-bromopyridin-3-sulfonamides 1.1 is obtained using well-known methods of synthesis, in particular, sulphochlorination 2-amino-5-bromopyridine 2 and formed by the interaction of sulfochloride 3 with amines or Azeglio cycles and the General formula 4 according to the following scheme 1:

Scheme 1

in which R2have the above value.

This invention relates to a process for the preparation of 7-bromo-1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine with optionally substituted annulated by carbocycle General formula 1.2, which is in the interaction of 2-amino-5-bromopyridin-3-sulphonamide 1.1(1) with cyclic anhydrides of dicarboxylic acids of the General the formula 5 scheme 2:

Scheme 2

This invention relates to a method for the preparation of 3-bromo-5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-ones of General formula 13, which lies in the interaction of 2-amino-5-bromopyridin-3-sulfochloride 3 α-amino acids or their esters 6 and subsequent cyclization of the resulting compounds 1.1(a) according to scheme 3

Amides of 3-(1,1-dioxo-1,4-dihydropyrido[2,3-e][1,2,4]thiadiazin-3-yl)-propionic acid of General formula 1.4 receive from 5,5-dioxo-3,5-dihydro-2H-5-thia-4,9,9b-triaza-cyclopent[a]naphthalene-1-ones of General formula 1.2 on the following scheme 4:

Scheme 4

in which R3and R4have the above meaning; R9represents optionally substituted amino group, optionally substituted azaheterocycle.

The aim of the present invention are focused library to search for biologically active compounds leaders.

This goal is achieved by the focused library comprising at least one heterocyclic compound with 2-aminopyridine-3-sulfonovy fragment of General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

The aim of the present invention are a new pharmaceutical composition of formatblock, capsules, or injections, placed in pharmaceutically acceptable packing.

This goal is achieved by a pharmaceutical composition comprising at least one heterocyclic compound with 2-aminopyridine-3-sulfonovy fragment of General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

Pharmaceutically acceptable salts of the compounds can be obtained in a traditional way, for example by the action of the compounds corresponding acid or base. N-oxides can be obtained by oxidation of the corresponding nitrogen-containing compounds. Hydrates of compounds can be obtained, for example, by recrystallization from aqueous solutions, or are formed spontaneously in the synthesis process.

Below the invention is described using the examples of the preparation of specific compounds and focused libraries. The structure of the obtained compounds was confirmed by chromatographic and spectral data analysis.

The following examples illustrate but do not limit the invention.

Example 1. 2-Amino-5-bromopyridin-3-sulphonamide 1.1(1). Was added in small portions to 2-amino-5-bromopyridin 2 [54 g (0.31 mol)] cooled in an ice bath chlorosulfonic acid [200 ml (3 mol)]. The mixture was boiled in a flask with reflux condenser for 3 hours After cooling, the mixture was poured into 500 g IU is to crushed ice with vigorous stirring. The resulting yellow precipitate of 2-amino-5-bromopyridin-3-sulfochloride 3 was filtered, washed with cold water, then with petroleum ether and dried. Got to 72.4 g (86%), 2-amino-5-bromopyridin-3-sulfochloride 3 TPL 151-153°C. the resulting product 3 [72.4 g (0.27 mol)] suspended with stirring in 1000 ml of 10% aqueous ammonia solution. After 0.5 hours, the suspension was concentrated under vacuum to a volume of 300 ml. of the Resulting precipitate of 2-amino-5-bromopyridin-3-sulphonamide 1.1(1) was filtered, washed with water and petroleum ether. Received 41.5 g (61%) of 2-amino-5-bromopyridin-3-sulphonamide 1.1(1) (table 2).

Example 2. General synthesis technique replaced 2-amino-5-bromopyridin-3-sulfonamides 1.1(2-169). A method of obtaining a focused library of 2-amino-5-bromopyridin-3-sulfonamides 1.1(2-169). A solution of 0.27 g (of 0.003 mol) 2-amino-5-bromopyridin-3-sulfochloride 3 in 3 ml of dioxane was cooled in an ice bath to a temperature of 5°and under vigorous stirring was added a solution of 0.003 mol of amine 4 and 0.28 g (0,0035 mol) of pyridine in 2 ml of dioxane. The reaction mixture was stirred at room temperature for 2 h, and then at a temperature of 50°C for 1 hour. The mixture was left overnight at room temperature. The mixture is then poured into water. The precipitate was purified by recrystallization from propanol-2, was filtered, washed with cold water and drying the Lee. Received focused library consisting of replaced 2-amino-5-bromopyridin-3-sulfonamides 1.1(2-169), are presented in table 2.

/tr> td align="center"> 98
Table 2
No. p.p. Conn. 1.1FormulaMol. Weight.Analytical data
1252,09An NMR spectrum1N: 6,4 (s, 2H, NH2), and 7.3 (s, 2H, SO2NH2), and 7.9 (d, 1H, J=2,3 Hz4CH)and 8.1 (d, 1H, J=2,3 Hz6CH). LC / MS m/z 253 (M+1).
2364,17LC / MS m/z 365 (M+1)
3370,23LC / MS m/z 371 (M+1)
4388,24LC / MS m/z 389 (M+1)
5421,11LC / MS m/z 422 (M+1)
6360,28LC / MS m/z 361 (M+1)
7446,37LC / MS m/z 447 (M+1)
8368,25LC / MS m/z 369 (M+1)
9396,19LC / MS m/z 397 (M+1)
10430,63LC / MS m/z 432 (M+1)
11343,20LC / MS m/z 344 (M+1)
12329,18LC / MS m/z 330 (M+1)
13358,22LC / MS m/z 359 (M+1)
14358,22LC / MS m/z 359 (M+1)
15356,24LC / MS m/z 357 (M+1)
16308,20LC / MS m/z 309 (M+1)
17308,20LC / MS m/z 309 (M+1)
18362,63TPL 196-198°C. an NMR Spectrum1N: 2,90 (s, 3H, CH3),6,62(s, 2H, NH2), to 7.09 (d, 2H, J=9,3 Hz, 2ArH), 7,18(d, 2H, J=9,3 Hz, AGN), 7,87 (d, 1H, J4-6=2,3 Hz4CH), 8,10 (d, 1H, J6-4=2,3 Hz6CH), 10,38 (c, lH, NH). LC / MS m/z 364 (M+1)
19 376,66LC / MS m/z 378 (M+1)
20422,69LC / MS m/z 424 (M+1)
21376,66LC / MS m/z 378 (M+1)
22390,69LC / MS m/z 392 (M+1)
23348,26LC / MS m/z 349 (M+1)
24334,24LC / MS m/z 335 (M+1)
25362,29LC / MS m/z 363 (M+1)
26320,21LC / MS m/z 321 (M+1)
27364,17LC / MS m/z 365 (M+1)
28388,24LC / MS m/z 389 (M+1)
29388,24LC / MS m/z 389 (M+1)
30416,30LC / MS m/z 417 (M+1)
31 356,24LC / MS m/z 357 (M+1)
32356,24LC / MS m/z 357 (M+1)
33336,25TPL 137-139°C. an NMR Spectrum1: 0,89 (t, 6N, 2CH3), 1.55V (Sextus, 4H, SN2C)3,14 (t, 4H, CH2NCH2), of 6.49 (s, 2H, NH2), 7,86 (d, 1H, J4-6=2,3 Hz4CH), 8,17 (d, lH, J6-4=2,3 Hz6CH). LC MS, m/z 337 (M+1)
34400,25LC / MS m/z 401 (M+1)
35356,24LC / MS m/z 357 (M+1)
36356,24LC / MS m/z 357 (M+1)
37356,24LC / MS m/z 357 (M+1)
38392,27LC / MS m/z 393 (M+1)
39393,26LC / MS m/z 394 (M+1)
40348,26LC / MS m/z 349 (M+1)
41346,18LC / MS m/z 347 (M+1)
42346,18LC / MS m/z 347 (M+1)
43334,24LC / MS m/z 335 (M+1)
44354,23LC / MS m/z 355 (M+1)
45363,24LC / MS m/z 364 (M+1)
46372,24LC / MS m/z 373 (M+1)
47427,32LC / MS m/z 428 (M+1)
48427,32LC / MS m/z 428 (M+1)
49356,24LC / MS m/z 357 (M+1)
50334,24LC / MS m/z 335 (M+1)
51334,24LC / MS m/z 335 (M+1)
52334,24LC / MS m/z 335 (M+1)
53372,24LC / MS m/z 373 (M+1)
54397,30LC / MS m/z 398 (M+1)
55386,23LC / MS m/z 387 (M+1)
56306,18TPL 166-168°C. an NMR Spectrum1N: of 1.88 (m, 4H, SN), 3,29 (t, 4H, CH2NCH2), is 6.61 (s, 2H, NH2), 7,86 (d, 1H,J4.6=2,3 Hz4CH), 8,19 (d, 1H, J6-4=2,3 Hz6CH). LC / MS m/z 307 (M+1)
57407,27LC / MS m/z 408 (M+1)
58384,30LC / MS m/z 385 (M+1)
59431,74LC / MS m/z 433 (M+1)
60403,34LC / MS m/z 404 (M+1)
61425,35TPL 171-173°C. an NMR Spectrum1N: and 2.14 (s, 3H, CH3), 2,24 (s, 3H, CH3), 2,89 (m, 4H, CH2NCH2), 3,29 (m, 4H, CH2NCH2), of 6.65 (s, 2H, NH2), at 6.84 (m, 2H,4',6'CH), 6,98 (t, 1H,5'CH), 7,86 (d, 1H, J4-6=2,3 Hz4CH), 8,24 (d, 1H, J6-4=2,3 Hz
6CH). LC / MS m/z 426 (M+1)
62425,35LC / MS m/z 426 (M+1)
63368,25LC / MS m/z 369 (M+1)
64342,22LC / MS m/z 343 (M+1)
65418,27LC / MS m/z 419 (M+1)
66376,66LC / MS m/z 378 (M+1)
67370,27LC / MS m/z 371 (M+1)
68348,26LC / MS m/z 349 (M+1)
69294,17LC / MS m/z 295 (M+1)
70351,27LC / MS m/z 352 (M+1)
71400,25LC / MS m/z 401 (M+1)
72388,24LC / MS m/z 389 (M+1)
73421,11LC MS, m/z 422 (M+1)
74376,66LC / MS m/z 378 (M+1)
75356,24LC / MS m/z 357 (M+1)
76322,23LC / MS m/z 323 (M+1)
77356,24LC / MS m/z 357 (M+1)
78335,22LC / MS m/z 336 (M+1)
79336,21LC MS, m/z 337 (M+1)
80370,27LC / MS m/z 371 (M+1)
81394,29LC / MS m/z 395 (M+1)
82439,33LC / MS m/z 440 (M+1)
83411,32LC / MS m/z 412 (M+1)
84356,24LC / MS m/z 357 (M+1)
85370,23LC / MS m/z 371 (M+1
86374,28LC / MS m/z 375 (M+1)
87384,30LC / MS m/z 385 (M+1)
88465,29LC / MS m/z 466 (M+1)
89403,34LC / MS m/z 404 (M+1)
90398,28LC / MS m/z 399 (M+1)
91370,27LC / MS m/z 371 (M+1)
92372,24LC / MS m/z 373 (M+1)
93372,24LC / MS m/z 373 (M+1)
94322,23LC / MS m/z 323 (M+1)
95360,21LC / MS m/z 361 (M+1)
96370,27LC / MS m/z 371 (M+1)
97356,24LC / MS m/z 357 (M+1)
322,23LC / MS m/z 323 (M+1)
99382,28LC / MS m/z 383 (M+1)
100348,26LC / MS m/z 349 (M+1)
101348,26LC / MS m/z 349 (M+1)
102464,19LC / MS m/z 465 (M+1)
103348,26LC / MS m/z 349 (M+1)
104392,27LC / MS m/z 393 (M+1)
105425,35LC / MS m/z 426 (M+1)
106362,29LC / MS m/z 363 (M+1)
107407,29LC / MS m/z 408 (M+1)
108348,24LC / MS m/z 349 (M+1)
109360,21LC / MS m/z 361 (M+1)
11 396,19LC / MS m/z 397 (M+1)
111392,66LC / MS m/z 394 (M+1)
112392,66LC / MS m/z 394 (M+1)
113372,24LC / MS m/z 373 (M+1)
114446,37LC / MS m/z 447 (M+1)
115384,30LC / MS m/z 385 (M+1)
116349,25LC / MS m/z 350 (M+1)
117380,62LC / MS m/z 382 (M+1)
118400,27LC / MS m/z 401 (M+1)
119427,32LC / MS m/z 428 (M+1)
120384,30LC / MS m/z 385 (M+1)
121324,20LC / MS m/z 325 (M+1)
122 352,25LC / MS m/z 353 (M+1)
123415,29LC / MS m/z 416 (M+1)
124435,32LC / MS m/z 436 (M+1)
125368,25LC / MS m/z 369 (M+1)
126360,21LC / MS m/z 361 (M+1)
127412,19LC / MS m/z 413 (M+1)
128372,24LC / MS m/z 373 (M+1)
129416,30LC / MS m/z 417 (M+1)
130370,27LC / MS m/z 371 (M+1)
131425,35LC / MS m/z 426 (M+1)
132413,34LC / MS m/z 414 (M+1)
133356,24LC / MS m/z 357 (M+1)
134img src="https://img.russianpatents.com/821/8215848-s." height="31" width="39" > 356,24LC / MS m/z 357 (M+1)
135342,22LC / MS m/z 343 (M+1)
136346,18LC / MS m/z 347 (M+1)
137362,63LC / MS m/z 364 (M+1)
138376,66LC / MS m/z 378 (M+1)
139332,18LC / MS m/z 333 (M+1)
140425,31LC / MS m/z 426 (M+1)
141342,22LC / MS m/z 343 (M+1)
142308,20LC / MS m/z 309 (M+1)
143320,21LC / MS m/z 321 (M+1)
144322,18LC / MS m/z 323 (M+1)
145386,27LC / MS m/z 387 (M+1)
146/img> 308,20LC / MS m/z 309 (M+1)
147386,23LC / MS m/z 387 (M+1)
148342,22LC / MS m/z 343 (M+1)
149358,22LC / MS m/z 359 (M+1)
150444,35LC MS, m/z 445 (M+1)
151370,27LC / MS m/z 371 (M+1)
152376,30LC / MS m/z 377 (M+1)
153379,32LC / MS m/z 380 (M+1)
154376,66LC / MS m/z 378 (M+1)
155386,27LC / MS m/z 387 (M+1)
156391,33LC / MS m/z 392 (M+1)
157402,27LC / MS m/z 403 (M+1)
158 412,35LC / MS m/z 413 (M+1)
159400,30LC / MS m/z 401 (M+1)
160438,27LC / MS m/z 439 (M+1)
161398,32LC / MS m/z 399 (M+1)
162414,32LC / MS m/z 415 (M+1)
163386,27LC / MS m/z 387 (M+1)
164376,32LC / MS m/z 377 (M+1)
165458,36LC / MS m/z 459 (M+1)
166385,29LC / MS m/z 386 (M+1)
167372,24LC / MS m/z 373 (M+1)
168402,27LC / MS m/z 403 (M+1)
169376,30LC / MS m/z 377 (M+1)

Example 3. General methods of synthesis of 2-amino-5-bromopyridin--sulfamethoxazole acids 1.1(170, 171). To a solution of 0.15 mol of amino acids and 12 g (0.3 mol) of NaOH in 300 ml of water with vigorous stirring was added 27,15 g (0.1 mol) 2-amino-5-bromopyridin-3-sulfochloride 3. The mixture was stirred at room temperature for 1.5-2 hours until a clear solution is formed. Then to the resulting solution were added acetic acid to pH = 6. The resulting white precipitate was filtered and recrystallized from dioxane. Received 2-amino-5-bromopyridin-3-sulfamethoxazole acid 1.1(170, 171) (table 3).

Example 4. General method for the synthesis of amides of 2-amino-5-bromopyridin-3-sulfamethoxazole acids 1.1(172-241). A method of obtaining a focused library of amides of 2-amino-5-bromopyridin-3-sulfamethoxazole acids 1.1(172-241). A mixture of 2-amino-5-bromopyridin-3-sulfamethoxazole acid 1.1(170, 171) [0.3 g (0.001 mol)] and carbodiimide [0.15 g (0,0009 mol)] was dissolved in 3 ml of dioxane. The solution was stirred at a temperature of 40°C for 1.5 hours. The mixture was cooled, then added 0.001 mole amine 4 and stirred the resulting mixture at a temperature of 50°C for 1 hour and then at a temperature of 80°C for 2 hours. The reaction mixture was left overnight at room temperature. The mixture is then poured into water. The precipitate was filtered and recrystallized from propanol-2. Received focused library of amides of 2-amino-5-bromo is iridin-3-sulfamethoxazole acids 1.1(172-241), presented in table 3.

Table 3
No. p.p. Conn. 1.1FormulaMol. Weight.Analytical data
170324,15The output of 25.3 g (78%), TPL 225-227°C. an NMR Spectrum1N: 2,89 (s, 3H, NCH3), of 4.00 (s, 2H, NCH2), only 6.64 (s, 2H, NH2), of 7.90 (d, 1H, J4-6=2,3 Hz4CH), 8,17 (d, 1H, J6-4=2,3 Hz6CH), 12,12 (s, 1H, COOH). IR, cm-1: 3463 (NH2), 1717 (C=O), 1633 (NH2), 1322 (SO2), 1240(C-O-), 1139 (SO2). LC / MS m/z 325 (M+1)
171324,15The output of 27.2 g (84%), TPL 201-203°C. an NMR Spectrum1H: 2,39 (t, 2H, J=6,4 Hz, COCH2), to 3.02 (K, 2H, J=6,4 Hz, J=5,8 Hz, NCH2), 6,55 (s, 2H, NH2), a 7.85 (t, 1H, J=5,8 Hz, SO2NH), to $ 7.91 (d, 1H, J4-6=2,3 Hz4CH), 8,15 (d, 1H, J6-4=2,3 Hz6CH), 12,16 (s, 1H, COOH). LC / MS m/z 325 (M+1)
172459,32LC / MS m/z 460 (M+1)
173414,28Yield 77%, TPL 125-127°C. an NMR Spectrum1N: 2,87 (s, 3H, sit3), 3,93 (s, 2H, NCH2CO), of 4.44 (d, 2H, J=5,7 Hz, NCH2), 6,76 (s, 2H, NH2), 7,18 (t, 1H,4′CH), 7,30 (d, 1h,3′ ch), 7,68 (i.e 1h,5′ch), 7,95 (d, 1H, J4-6=2,3 Hz4CH), 8,18 (d, 1H, J6-4=2,3 Hz6CH), of 8.47 (t, 1H, J=5,7 Hz, NH). LC / MS m/z 415 (M+1)
174414,28LC / MS m/z 415(M+1)
175429,30LC / MS m/z 430(M+1)
176429,30LC / MS m/z 430(M+1)
177427,32LC / MS m/z 428(M+1)
178447,74LC / MS m/z 449(M+1)
179419,34LC / MS m/z 420(M+1)
180433,37LC / MS m/z 434(M+1)
181391,29LC / MS m/z 392 (M+1)
182459,32Yield 83%, TPL 143-145°C. an NMR Spectrum1N: only 2.91 (s, 3H, NCH3), of 3.78 (s, 3H, och3), the 3.89 (s, 3H, och3), 4,07 (s, 2H, NCH2), 6,41 (DD, 1H, J5'-6'=8,8 Hz, J5'-3'=1,9 Hz5'CH), of 6.49 (d, 1H, J3'-5'=1,9 Hz3'CH), 6.75 in (s, 2H, NH2),7,88 (d, 1H, J6'-5'=8,8 Hz,6'CH), of 7.97 (d, 1H, J4-6=2,3 Hz4CH), to 8.20 (d, 1H, J6-4=2,3 Hz6CH), 8,88 (s, 1H, NH). LC / MS m/z 460 (M+1)
183459,32LC / MS m/z 460 (M+1)
184427,32LC / MS m/z 428 (M+1)
185427,32LC / MS m/z 428 (M+1)
186443,32LC / MS m/z 444 (M+1)
187427,32Yield 87%, TPL 180-182°C. an NMR Spectrum1N: of 2.33 (s, 3H, CLO3), 2,84 (s, 3H, NCH3), 3,86 (s, 2H, NCH2CO), 4,27 (d, 2H, J=5,4 Hz, NCH2Ar), for 6.81 (s, 2H, NH2), to 7.09 (d, 2H, J=7,2 Hz, 2ArH), to 7.15 (d, 2H, J=7,2 Hz, 2ArH), to 7.95 (d, 1H, J4-6=2,3 Hz4CH), 8,19 (d, 1H, J6-4=2,3 Hz6CH), a 8.34 (t, 1H, J=5,4 Hz, NH). LC / MS m/z 428 (M+1)
188468,38LC / MS m/z 469 (M+1)
189441,35LC / MS m/z 442 (M+1)
190427,32LC / MS m/z 428 (M+1)
191 469,36LC / MS m/z 470 (M+1)
192441,35Yield 86%, TPL 161-163°C. an NMR Spectrum1N: 1,24 (d, 6N, J=7,7 Hz, 2CH3), of 2.86 (Sept, 1H, J=7,7 Hz, CH), 2.91 in (s, 3H, NCH3), of 4.05 (s, 1H, NCH2), 6,72 (s, 2H, NH2), to 7.09 (d, 2H, J=7,9 Hz, 2ArH), 7,46 (d, 2H, J=7,9 Hz, 2ArH), of 7.97 (d, 1H, J4-6=2,3 Hz4CH), 8,19 (d, 1H, J6-4=2,3 Hz6CH), 9,73 (s, 1H, NH). LC / MS m/z 442 (M+1)
193427,32LC / MS m/z 428 (M+1)
194419,34LC / MS m/z 420 (M+1)
195433,37LC / MS m/z 434 (M+1)
196431,29LC / MS m/z 432 (M+1)
197451,70LC / MS m/z 453 (M+1)
198463,74LC / MS m/z 465 (M+1)
199443,32LC / MS m/z 444 (M+1)
200420,33The yield was 73%, TPL 120-122°C. Range sup> 1N with 1.07 (t, 3H, J=7,0 Hz, CH3), 2,39 (K, 2H, J=7,0 Hz, NCH2C)2,82 (s, 3H, NCH3), 2,89 (m, 4H, CH2NCH2), of 3.48 (m, 4H, CH2NCH2), 4,13 (s, 1H, NCH2CO), 6,72(c, 2H, NH2), to 7.93 (d, 1H, J4-6=2,3 Hz4CH), 8,17 (d, 1H, J6-4=2,3 Hz6CH). LC / MS m/z 421 (M+1)
201443,32LC / MS m/z 444 (M+1)
202417,26LC / MS m/z 418 (M+1)
203447,74LC / MS m/z 449 (M+1)
204391,29LC / MS m/z 392 (M+1)
205413,30LC / MS m/z 414 (M+1)
206447,38LC / MS m/z 448(M+1)
207447,74LC / MS m/z 449(M+1)
208465,33LC / MS m/z 466(M+1)
209368,38Yield 87%, TPL 180-182°C. an NMR Spectrum1N: of 2.53 (t, 2H, J=6,4 Hz, COCH2), 3,12 (K, 2H, J=6,4 Hz, J=5,8 Hz, NCH2 ), of 3.60 (m, 4H, CH2NCH2), of 3.69 (m, 4H, CH2NCH2), 6,46 (s, 2H, NH2), to 6.80 (t, 1H,4'CH), 6.89 in (d, 2H,2′,6′CH), 7,20 (m, 2H,3′,5′CH), 7,73 (t, 1H, J=5,8 Hz, SO2NH), 7,95 (d, 1H, J4-6=2,3 Hz4CH), 8,14 (d, 1H, J6-4=2,3 Hz6CH). LC / MS m/z 369 (M+1)
210406,28Yield 74%, TPL 232-234°C. an NMR Spectrum1N: to 2.65 (t, 2H, J=6,4 Hz, COCH2), 3,15 (K, 2H, J=6,4 Hz, J=5,8 Hz, NCH2), 6,51 (s, 2H, NH2), 6,92 (d, 1H, J=3,4 Hz5′CH), 7,35 (d, 1H, J and 3.4 Hz,4'CH), a 7.85 (t, 1H, J=5,8 Hz, SO2NH), to 7.93 (d, 1H, J4-6=2,3 Hz4CH), 8,14 (d, 1H, J6-4=2,3 Hz6CH), a 12.05 (s, 1H, NH). LC / MS m/z 407 (M+1).
211441,31LC / MS m/z 442 (M+1)
212459,32LC / MS m/z 460 (M+1)
213420,31LC / MS m/z 421 (M+1)
214431,35LC / MS m/z 432 (M+1)
215467,27LC / MS m/z 468 (M+1)
216434,70LC / MS m/z 436 (M+1)
217414,28Yield 82%, TPL 153 to 155°C. an NMR Spectrum1N: is 2.40 (t, 2H, J=6,4 Hz, COCH2), is 3.08 (K, 2H, J=6,4 Hz, J=5,8 Hz, NCH2), 4,39 (D., 2H, J and 5.4 Hz, CONCH2), 6,51 (s, 2H, NH2), 7,17 (t, 1H,4'CH), 7,31 (d, 1H3'SN), to 7.68 (t, 1H,5'CH), 7,87 (t, 1H, J=5,8 Hz, SO2NH), 7,98 (d, 1H, J4-6=2,3Hz,4CH), 8,15 (d, lH, J6-4=2,3 Hz6CH), 8,30 (t, 1H, J=5,4 Hz, NH), of 8.47 (d, 1H,6'CH). LC / MS m/z 415 (M+1)
218414,28LC / MS m/z 415 (M+1)
219414,28Yield 80%, TPL 214-216°C. an NMR Spectrum1H: of 2.21 (s, 3H, CH3), 2,61 (t, 2H, J=6,4 Hz, COCH2), 3,12 (K, 2H, J=6,4 Hz, J=5,8 Hz, NCH2), to 6.57 (s, 2H, NH2), 7,10 (m, 1H, ArH), at 7.55 (d, 1H, ArH), 7,89 (t, 1H, J=5,8 Hz, SO2NH), 7,95 (d, 1H, J4-6=2,3 Hz4CH), 8,15 (d, 1H, J6-4=2,3 Hz6CH), to 8.20 (d, 1H, ArH). LC / MS m/z 415 (M+1)
220414,28LC / MS m/z 415 (M+1)
221400,26LC / MS m/z 401 (M+1)
222429,30LC / MS m/z 430 (M+1)
223427,32 Yield 87%, TPL 158-160°C. an NMR Spectrum1N: of 2.56 (t, 2H, J=6,4 Hz, SON), 2,89 (s, 3H, NCH3), 3,10 (K, 2H, J=6,4 Hz, J=5,8 Hz, NCH2), to 4.52 (s, 2H, NCH2), to 6.57 (s, 2H, NH2), 7,27 (m, 5H, ArH), of 7.82 (t, 1H, J=5,8 Hz, SO2NH), 7,94 (d, 1H, J4-6=2,3 Hz4CH), 8,16 (d, 1H, J6-4=2,3 Hz6CH). LC / MS m/z 428 (M+1)
224379,28LC / MS m/z 380 (M+1)
225433,71LC / MS m/z 435 (M+1)
226447,74LC / MS m/z 449 (M+1)
227461,77LC / MS m/z 463 (M+1)
228419,34LC / MS m/z 420 (M+1)
229405,32LC / MS m/z 406 (M+1)
230433,37LC / MS m/z 434 (M+1)
231391,29LC / MS m/z 392 (M+1)
232435,25LC / MS m/z 436 (M+1)
233 459,32LC / MS m/z 460 (M+1)
234459,32LC / MS m/z 460 (M+1)
235427,32LC / MS m/z 428 (M+1)
236407,33LC / MS m/z 408 (M+1)
237471,33LC / MS m/z 472 (M+1)
238427,32LC / MS m/z 428 (M+1)
239433,71LC / MS m/z 434 (M+1)
240435,25LC / MS m/z 436 (M+1)
241429,30LC / MS m/z 430 (M+1)

Example 4. General methods of synthesis of pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides 1.2. A mixture of 25.2 g (0.1 mol) 2-amino-5-bromopyridin-3-sulphonamide 1.1(1) and (0.2 mol) of anhydride 6 boiled in 200 ml of ortho-xylene for 4 hours. The reaction mixture was cooled and was extracted with a solution of 8 g (0.2 mol) of NaOH in 200 ml of water. The layers were separated, the aqueous layer was added acetic acid to achieve a pH = 6. Formed white is Sadok, which was filtered and recrystallized from dioxane. Received pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides, are presented in Table 4.

Example 5. General methods of synthesis of 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-ones 1.34. To a mixture of 0.01 mol of acid 1.1 and 1.6 g (0.01 mol) CBI was added 10 ml of dioxane and stirred at a temperature of 40°C for 1 hour and then at a temperature of 100°C for 3 hours. The reaction mixture was left overnight at room temperature. Then the mixture was poured into 10 ml of water. The resulting white precipitate was filtered and recrystallized from dioxane. Received 5.5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-ons 1.3 with the release of 70-95% (table 4).

Example 6. General methods of synthesis of pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides 1.4. To a mixture of 0.001 mol pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides 1.2 and 0.15 g (0,0009 mol) of carbodiimide was added 3 ml of dioxane and stirred at a temperature of 70°C for 1.5 hours. Then to the mixture was added 0.001 mole amine 4 and stirred at a temperature of 100°C for 3 hours. The mixture was left overnight at room temperature. The mixture is then poured into water. The precipitate was filtered and recrystallized from propanol-2. Received pyrido[2,3-e][1,2,4]thiadiazine-1,1-dioxides 1.4 are presented in Table 4.

Table 4
No. Conn.FormulaMol. Weight.Analytical data
1.2(1)316,13Yield 59%, TPL 229-231°C. an NMR Spectrum1N: 2,69 (t, 2H, J=7,2 Hz, CH2), 2,89 (t, 2H, 3=1,2 Hz, COCH2), with 8.33 (d, 1H, J=2,3 Hz6CH), 8,67 (d, 1H, J=2,3 Hz8CH). IR, cm-1: 1604 (-C(O)-Nt), 1291 (SO2), 1154 (SO2). An NMR spectrum15N δ, ppm/Int: -83,88/0,92 (1N), -152,72/12,66 (4N), -232,45/4,36 (2N), LCMS, m/z 317 (M+1)
1.2(2)364,18LC / MS m/z 365 (M+1)
1.3(1)305,14Yield 92%, TPL 205-208°C. an NMR Spectrum1N: or 2.9 (s, 3H, NCH3), 4,35(s, 2H, HCH2),and 8.2(d, 1H, J4-2=2,3 Hz4CH), and 8.6 (s, 1H, J2-4=2,3 Hz2CH), and 10.8 (s, 1H, NH). IR, cm-1: 3192 (NH), 1673 (C=O), 1568 (δNH), 1356 (SO2), 1170 (SO2). LC / MS m/z 306 (M+1)
1.4(1)424,28Yield 51%, TPL 216...219°C. an NMR Spectrum1N: of 2.72 (t, 2H, J=7,2 Hz, CH2), 2,98 (t, 2H, J=7,2 Hz, COCH2), to 4.41 (d, 2H, J=5,7 Hz, NCH2), 7,13 (m, 1H, HetH), 7,32 (d, 1H, HetH), to 7.64 (t, 1H, HetH), 8,40 (t, 1H, 8,43 (m,1H, HetH), 8,31 (d, 1H, J=2,3 Hz8CH), 8,40 (t, 1H, J=5,7 Hz, CONH), 8,67 (d, 1H,J=2,3 Hz 6CH), 12,84 (c, 1H, NH). LC / MS m/z 425 (M+1)
1.4(2)435,30LC / MS m/z 436 (M+1)
1.4(3)417,28LC / MS m/z 418 (M+1)
1.4(4)429,34LC / MS m/z 430 (M+1)
1.4(5)423,29Yield 54%, TPL 245-248°C. an NMR Spectrum1N: to 2.29 (s, 3H, CH3), of 2.81 (t, 2H, J=7,2 Hz, CH2), to 2.99 (t, 2H, J=7,2 Hz, PINES2), 7,01 (d, 2H, J=7,9 Hz, 2ArH), 7,44 (d, 2H, J=7,9 Hz, 2ArH), with 8.33 (d, 1H, J=2,3 Hz8CH), 8,68 (d, 1H, J=2,3 Hz6CH), 9,78 (s, 1H, CONH), 12,87 (s, 1H, NH). IR, cm-1: 3354 (NH), 1665 (OS), 1530 (δNH), 1304 (SO2), 1150 (SO2). LC / MS m/z 424 (M+1)
1.4(6)423,29Yield 61%, TPL 293...6°C. an NMR Spectrum1N: to 2.67 (t, 2H, J=7,2 Hz, CH2), is 2.74 (t, 2H, J=7,2 Hz, COCH2), of 3.32 (s, 3H, CH2), 6,83 (d, 1H,4'SN), to 7.15 (t, 1H,5'CH), 7,41 (d, 1H,6′SN), to 7.50 (s, 1H,2'CH), 8,02 (d, 1H, J=2,3 Hz8CH), 8,53 (d, 1H, J=2,3 Hz6CH), and 8.50 (s, 1H, CONH), of 10.25 (s, 1H, NH). LC / MS m/z 424 (M+1)
1.4(7)403,26LC / MS m/z 404 (M+1)

Example 7. A method of obtaining a pharmaceutical composition in the form of a table is current. Mix 800 mg of starch, 800 mg of powdered lactose, 200 mg of talc and 500 mg of 3-(7-bromo-1,1-dioxo-1,4-dihydropyrido[2,3-e][1,2,4]thiadiazin-3-yl)-1-morpholine-4-yl-propane-1-it 1.4(7) and spracovavat in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 280 mg each. Similarly receive pharmaceutical composition in the form of tablets containing as active ingredient other 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1.

Example 8. A method of obtaining a pharmaceutical composition in capsule form. Thoroughly mix 3-bromo-6-methyl-5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-it 1.3(1) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 9. A method of obtaining a pharmaceutical composition in the form of injection for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg 2-amino-5-bromopyridin-3-sulfonic acids (4-chloro-3-triptoreline)-amide 1.1(10) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed and sterilized in an autoclave.

Example 10. Evaluation of the calcium-blokatory properties connect the deposits of the General formula 1. Was focused library, including the famous antiprotease ligands and 253 heterocyclic compounds of General formula 1, are presented in tables 2, 3 and 4. The interaction of compounds with the glutamate-dependent CA2+capture was investigated on P2-fraction synaptosomes structures isolated from the brain of the newborn (8-11 days) rats according to the method described previously [Solyakov L.S. and others, neurochemistry, 1989, Vol.8, No. 3, s]. Synaptosome were placed in incubation buffer (132 mm NaCl, 51 mm KCl, 5 mm HEPES) and was maintained at a temperature of 0°during the whole experiment. The aliquots synaptosomes structures (50 μl) were placed in a medium containing the analyte and drug45CA2+. The capture of CA2+stimulated by the introduction of a mixture of 10 ml of a solution of 20 μl of glutamate. After 5-minute incubation at 30°the process was stopped by filtration through GF/B filters, and the product washed three times with cold acetic acid, after which the scintillation counter "SL-4000" was carried out for detection of radioactive labels. Specific capture of CA2+was measured by the following formulas:

K(42/21)=[(CA4-CA2)/(CA2-Ca1)]100%,

where C2- capture of CA2+- in the presence of glutamate (glutamate-induced seizure CA2+);

CA3- capture of CA2+- in the presence of a test substance (without the GLA is Amata);

CA4- capture of CA2+in the presence of glutamate and the test substance.

In some cases, the specific capture of calcium were also assessed by the formulas:

To(43/21)=[(CA4-CA3)/(CA2-Ca1)]100%

or(3/1)=(CA3)/(CA1)]100%.

Found that many of the compounds of formula I are able to effectively inhibit glutamate-dependent calcium intake (IC50≈ 10-50 μM) and, hence, show a marked neuroprotective effect.

1. Heterocyclic compounds, including 2-aminopyridine-3-sulfonovy fragment of General formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which R1represents a hydrogen atom;

R2represents a chlorine atom, optionally substituted hydroxyl group, optionally substituted by an amino group, optionally substituted azaheterocyclic;

or R1and R2together with nitrogen atoms and sulfur, to which they are attached, form an optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazin or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazapentadiene-8-he, excluding phenyl is new ester 2-amino-5-bromopyridin-3-acid.

2. Heterocyclic compounds according to claim 1, represents 2-aminopyridine-3-sulfonic acids and their derivatives of General formula

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which R2has the above value.

3. Heterocyclic compounds according to claim 1, represents 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine with optionally substituted annulated by carbocycle General formula 1.2

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which R3and R4independently from each otherrepresent a hydrogen atom, a halogen atom, an inert Deputy, optionally substituted hydroxyl group, optionally substituted by an amino group, optionally substituted C1-C3allyloxycarbonyl1-C3alkyl, optionally substituted aminocarbonyl, optionally substituted aminocarbonyl1-C3alkyl, or optionally substituted aminocarbonyl1-C3alkyl or

R3andR4together with the carbon atoms to which they are attached form an optionally substituted and optionally condensed cycloalkyl or cycloalkenyl, optionally substituted aryl or het is recycler.

4. Heterocyclic compounds according to claim 1, representing a 5.5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triaza-benzocycloheptene-8-ones of General formula 1.3

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which R5andR6independently from each otherrepresent a hydrogen atom or an inert Deputy,

R7and R8independently from each otherrepresent a hydrogen atom, an inert Deputy, the remaining amino acids or optionally substituted ethylene group.

5. Heterocyclic compounds according to claim 1, represents amides of 3-(1,1-dioxo-1,4-dihydropyrido[2,3-e][1,2,4]thiadiazin-3-yl)-propionic acid of General formula 1.4

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which R3,R4andR5have the above meaning,

R9is optionally substituted by an amino group or optionally substituted azaheterocycle.

6. The way to obtain 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine General formula 1.2 in section 3 of the interaction of 2-amino-5-bromopyridin-3-sulphonamide of the formula with cyclic anhydrides of dicarboxylic acids of General formula 5

where R3 and R4have the values listed in item 3.

7. Method for the preparation of 3-bromo-5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazapentadiene-8-ones of General formula 1.3 according to claim 4, the interaction of 2-amino-5-bromopyridin-3-sulfochloridewith the appropriate α-amino acid or its ester of the General formula 6

and subsequent cyclization of the resulting (2-amino-5-bromopyridin-3-sulfonylamino)-acetic acidthe General formula1.1(a)

where R6,R7and R8have the above value.

8. The method of obtaining the amides of 3-(1,1-dioxo-1,4-dihydropyrido[2,3-e][1,2,4]thiadiazin-3-yl)-propionic acid 1.4according to claim 5 consecutive action 5.5-dioxo-3,5-dihydro-2H-5-thia-4,9,9b-triazacyclohexane[a]naphthalene-1-ones of General formula 1.2 according to claim 3carbodiimides, and then the amine or optionally substituted azaheterocycle.

9. Focused library to search for biologically active compounds leaders, including at least one heterocyclic compound of General formula 1 according to claim 1.

10. Pharmaceutical composition having the properties of blockers of glutamate-induced transport of calcium ions, in particular neuroprotective action in the form of tablets, capsules, or injections, placed in pharmaceutically who ramlau packaging containing as active substance pharmaceutically effective amount of the compounds of General formula 1 according to claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to an improved process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f] xanthine of the formula I, causing the induction of microsomal liver enzymes

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

The invention relates to new derivatives of 2-aminopyridine of General formula (I)

where And denotes the radical

in which R1, R2and R3mean hydrogen, halogen, HE, alkyl or alkoxy and the other,

or radical

in which R8means hydrogen, x is the radical -(CH2)m-Q, m is an integer from 0 to 6, Y represents alkyl, alkenylphenol or alkenylphenol chain or other, R10is hydrogen or alkyl, or their salts

The invention relates to a method of producing alkanesulfonyl General formula 1: where R1is (C1-C6) alkyl, the interaction of the compounds of formula 2 with a Grignard reagent, processing of the received product (C1-C6) alkylsulfonamides reagent and, if necessary, the resulting product of formula 1, where R1represents methyl, are hydrazines in the presence of an amine in a suitable solvent to obtain compounds of formula 3

The invention relates to an improved process for the preparation of compounds of formula (I), where R4represents N or CH3that includes the interaction of the compounds of formula 2 in which R1represents a group of NO2with thiosemicarbazide with getting thiosemicarbazone formula ТS1, and subsequent reduction of the obtained compound

The invention relates to a method for producing 2-phenyl-3-aminopyridine or substituted phenyl derivatives, which is that the connection f-crystals (VIII) is subjected to interaction with connection f-crystals (IV) in which the substituents have the following meanings: X is Cl, Br or J; Z is H, (C1-C4)alkyl, methoxy, triptoreline, F or CL; Ar is (C6-C10)aryl; R3and R4selected from H4(C1-C6)alkyl

The invention relates to a new derived pyridonecarboxylic acid of the formula I or salts thereof, which possess high antibacterial activity and can find application in medicine
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