Derivatives of pyridazinoquinoline

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinoquinoline of the formula (II): or their tautomers, or their pharmaceutically acceptable salts wherein ring A represents ortho-condensed phenyl and monosubstituted with R4 wherein R4 means halogen atom; R1 represents -(CH2)nL wherein n means a whole number from 1 to 6; L is chosen from unsubstituted phenyl or its benzo-derivative, or L is chosen from phenyl or its benzo-derivative and substituted with one or two groups chosen from -CN, -CF3, (C1-C4)-alkyl, or L is chosen from -OH, -OCOR', -SOmR' wherein m means 0, 1 or 2, -NR'R'' under condition that -NR'R'' differs from -NH2, -NR'COR'', or L is chosen from heterocycle or heteroaryl wherein in each abovementioned case any group from R' or R'' is chosen from hydrogen atom, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl, phenyl-(C1-C4)-alkyl and wherein any group from R' or R'' is unsubstituted or substituted 1, 2 or 3 times with phenyl, -OH, O-(C1-C4)-alkyl at carbon atoms wherein in any abovementioned case heterocycle is chosen from five- or six-membered heterocyclic ring comprising 1, 2 or 3 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) atoms or its condensed benzo-derivative, indicated heterocycle wherein carbon atom is disubstituted to form (C5-C7)-spiro-group and indicated heterocycle wherein carbon atom © is substituted for oxygen atom (O) to form carbonyl group and wherein in any case heteroaryl is chosen from unsubstituted thiophene, furan, imidazole, triazole, tetrazole. Compounds of the formula (II) are antagonists of glycine-receptors and can be used in preparing pharmaceutical agents designated for treatment or prophylaxis of ischemic disease.

EFFECT: valuable medicinal properties of compounds.

5 cl, 8 tbl, 148 ex

 

This invention relates to a derivative of pyridazinedione used in the treatment of neurological diseases, mainly in mammals such as man. More specifically, the compounds used in the treatment of seizures and/or other neurodegenerative disorders, such as hypoglycemia, cortical paralysis, transient ischemic cortical cerebral blood flow, perinatal asphyxia, epilepsy, psychosis, Huntington's chorea (Huntington), amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, olivopontocerebellar atrophy caused by virus neurodegeneration, such as acquired immune deficiency syndrome and related dementia, hypoxia, caused by drowning, spinal cord injury or brain, and chronic disease prevention drug alcohol withdrawal symptoms, and suppression of tolerance and drug dependence analgesics. In particular, the invention relates to new derivatives of pyridazinedione used when restoring neurological degeneration, which can be caused by a blow, and the resulting associative functional failure. Treatment using the compounds according to the invention can be curative or therapeutic with the introduction of the connection after manifestations of ischemia is La mitigate the effects of this disease. The treatment may be prophylactic or promising with the introduction of connections in anticipation of the possibility of ischemia, for example, the patient who is prone to ischemia.

It is known that ischemia may be a triggering mechanism is very strong increase extracellular concentrations of excitatory amino acids glutamate and aspartate, which can, in turn, can cause long-term neural excitation, leading to a massive influx of calcium from extracellular to intracellular sites sites in the neural cells of the brain. Thereby can be created calcium overload, which leads to a cascade of events leading to catabolism of cells and ultimately expressed in cell death. It is assumed that N-methyl-D-aspartate (NMDA) receptor complex plays a significant role in the flow of events leading to cell necrosis that follows the manifestation of ischemia.

In the present invention compounds may be useful in a number of neurodegenerative disorders, because they act as antagonists of excitatory amino acids. They can do it indirectly, by allosteric modulation of binding sites of glutamate, in particular, by acting as antagonists at the strychnine-insensitive glycine receptor on the NMDA receptor complex. They can also make etoposide, by binding to the glutamate site of the NMDA receptor complex.

In EPO room 0516297 A1 describes some of pyridazinedione. In addition, compound (I) thieno[2',3':5,6]pyrido[2,3-d]pyridazin-5,8,9(4H,6N,7N)-Trion and (2) thieno[3',2':5,6]-pyrido[2,3-d]pyridazin-4,5,8(6N,7N,N)-Trion known, for example from J. Heterocyclic Chem., 28, 205, (1991).

Other derivatives of pyridazinedione known, for example, from Beilstein''s Handbuch der Organischen Chemic; Goodard et al., Bull. Soc. Chim. Fr., 1588, (1972); and Reid et al., Chem. Bet., 85, 204, (1952).

Compounds of the present invention relate to novel 2-or 3-substituted pyridazinones or their tautomers represented by the compounds having General formula II:

where

ring a is ortho-condensed phenyl or pyridium or formed by phenyl or pyridium, mono - or disubstituted R4where R4in each case, independently selected from the group comprising halogen, (C1-C4)alkyl, NO2CN, (C1-C3)perfluoroalkyl, HE OCF3, (C2-C4)alkenyl, (C2-C4)quinil, O-(C1-C4)alkyl, NR'r R", SO2NR'r R", SOmR', heterocycle, NR'r COR", COR", NR'r CO2R"CO2R' and CONR'R";

R1represents (CH2)nL, where n is an integer taking values from 1 to 6, where:

L is selected from unsubstituted phenyl or lansoprozole,

or L is selected from the dryer is La or lansoprozole, substituted 1, 2, 3, or 4 groups selected from HE, halogen, NO2CN, CF3, (C1-C4)alkyl,-(C1-C4)alkyl, (C1-C6alkyl)NR'r R"O-(C1-C6alkyl)NR'r R", O-phenyl, NH(C=O)R', R NR'r", NR'(C1-C6alkyl)R NR'r", NR'(C1-C6)alkyloxy, NR'(C1-C6alkylperoxy), C(=O)OR', C(=O)NR'r R", SOmR' (where m takes on the values 0, 1 or 2), SO2NR'r R", (C1-C6)alkyloxy (C1-C6)alkyloxy, hydroxy(C1-C6)alkyloxy, aryloxy(C1-C4)alkyloxy (C1-C4)alkyl, (C1-C6)alkyloxy(C1-C6)alkoxy(C1-C6)alkyloxy or hydroxy (C1-C6)alkyloxy(C1-C6)alkyloxy, O-(C2-C4)alkenyl, O-(C2-C4)quinil, O-(C1-C6alkyl)phenyl, (C1-C4)CF3, hydroxy(C1-C6)alkyloxy, which forms a cyclic ring attached to the phenyl ring in ortho-position, (C1-C4)perfluoroalkyl,-(C1-C4)perfluoroalkyl, (C1-C4alkyl)hydroxy(C1-C4alkyl), O-(C1-C4alkyl)COOR', (C1-C4alkyl)OR', NR'(CH2)qCOOR' (where q takes on the values 1, 2, 3 or 4), SOm(C1-C4alkyl)hydroxy(C1-C4alkyl), SOm(C1-C4alkyl)hydroxy(C1-the 4alkyl)hydroxy(C1-C4alkyl), NR'(C1-C4alkyl)hydroxy(C1-C4alkyl), NR'(C1-C4alkyl)hydroxy(C1-C4alkyl)hydroxy(C1-C4alkyl) or tetrazole,

or L is selected from HE, OR', OCOR', SOmR', SOmNR'r R", halogen, CF3, R NR'r", provided that NR'r R" is different from the NH2; COR', NR'r COR", NR'r CO2R", (C3-C6)cycloalkyl, NRCONR'R"CO2R', or CONRR',

or L is selected from heterocycle or heteroaryl;

where in each above case, R' and R" are independently selected from H, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)quinil, (C3-C6)cycloalkyl, phenyl, phenyl(C1-C4)alkyl, heterocycle, heterocycle(C1-C4)alkyl, heteroaryl or heteroaryl(C1-C4)alkyl, or where any of the groups R' or R" is either unsubstituted or substituted in position 1, 2 or 3 carbon atoms by halogen, H, (C1-C4)alkyl, (C3-C6) cycloalkyl, phenyl, NO2CN, CF3HE,-(C1-C4)alkyl, or where any of the groups R NR'r" forms a ring N-alkyl(C1-C3)oxyalkyl(C2-C3);

where in any of the above cases, heterocycle selected from five-, six - or semichasnoho heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, N or S, or aryl and the and heteroaryl lansoprozole, any heterocycle, where the carbon atom is disubstituted with education5-C7Spiro group, and any heterocycle, where the atom or S substituted On education respectively carbonyl or sulfonyloxy group; and

where in any of the above cases, heteroaryl selected from pyridyl, teinila, furanyl, pyrazole, imidazole, isoxazol, oxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, triazole, oxadiazole, triazine, tetrazole, which is unsubstituted, or any of the above may be mono - or disubstituted by oxo, hydroxy, alkoxy, halogen or cyano

and their pharmaceutically acceptable salts.

Preferred are the compounds of formula II, where R4is halogen.

Even among the preferred compounds are the compounds of formula II where a is a 7-chlorophenyl or 7.9-dichlorophenyl.

More particularly preferred are the following compounds:

7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione or N-methylglucamine salt;

7-chloro-2-(4-chloro-2-were)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3,4-dihydroxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-d is he;

7-chloro-2-(3,4-acid)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2-methylthioethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2-methyl-2-hydroxypropylamino)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(furan-2-ylmethyl)-1,2,5,10-tetrahydropyridine [4,5-b]quinoline-1,10-dione; and

7,9-dichloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

In addition, the preferred compounds are the following:

7-chloro-4-hydroxy-2-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

4-hydroxy-8-nitro-2-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-chlorophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-isopropylphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7,9-dichloro-4-hydroxy-2-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(1-naphthyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(4-forfinal)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]is inolin-1,10-dione;

2-(4-bromophenyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(3-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(3-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-trifloromethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione; and

7-chloro-4-hydroxy-2-(2-methoxyphenyl-5-yl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

Preferred are also compounds:

2-(4-benzyloxyphenyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,4-dichlorophenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3-chloro-4-hydroxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-hydroxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(4-chloro-2-were)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7,9-dichloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2-methyl is enyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,4-acid)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,5-acid)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,5-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3-chlorophenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(3-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-methylthiophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3-chloro-4-were)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,3-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(4-ethylphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(4-fluoro-2-were)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3,5-acid)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-itfeel)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(4-bromo-2-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3-forfinal)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2-forfinal)-4-guide the hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(3,5-deformational)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,4-differenl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-2-(2,5-differenl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-nitrophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-triptoreline)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(3-nitrophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-methylsulfinylphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2,5-dihydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-carboxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-carbamoylphenoxy)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(4-tetrazol-5-ylphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione; and

7-chloro-4-hydroxy-2-(4-N,N-diethylcarbamoyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

Especially preferred are the following compounds:

7-chloro-2-(4-ethoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2(2-isopropylphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione; and

7-chloro-4-hydroxy-2-(4-ethoxycarbonylphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The present invention relates also to pharmaceutical compositions containing the preferred compound of formula II, above, and a pharmaceutically acceptable carrier.

Further, the invention relates to a method of treatment or prophylaxis of coronary disease involving the introduction of a mammal in need of such treatment, an effective amount of the compounds according to the invention, as defined above, or its pharmaceutically acceptable salt, or a composition as defined above.

Pharmaceutically effective amount of a compound, as claimed in the claims and disclosed in the present invention, may be injected immediately after ischaemic attack to prevent the destruction and/or programmed cell death. The present invention relates also to a method of prevention and/or treatment of disorders caused by exciting amino acids such as L-glutamate. The invention also relates to a method for preventing excessive influx of calcium ions in the Central neurons. The invention relates to a method for prevention of ischemic neuronal damage after transient global ischemia and to a method of reducing infarct size after local ischemic stroke.

iridociliary formula II can be obtained by means including methods known in the chemical technique for obtaining structurally similar compounds.

For example, the method of obtaining the compounds of formula II include:

FORMULA

FORMULAS (CONTINUED)

SCHEMES 1 and 2

SCHEME 1

SCHEME 2

SCHEMES 3 and 4

SCHEME 3

SCHEME 4

SCHEME 5

SCHEME 6

SCHEME 7

(a) treatment of compounds of formula V or XIV acid selected from lower alkyl(C1-C4)sulfonic acid, in a suitable organic solvent, or

(b) treatment of compounds of formula IV' alkylaryl or alterglobalization in the environment of the polar solvent and weak acids; or

(c) treatment of compounds of formula IV', where y is selected from-OH, -SH or other, where R is a (C1-C4)alkyl, with a reagent selected from (i) R2NC(O)Cl; or (ii) RC(O)X, or (iii) ROC(O)Cl; or (IV) HBr/NaCN/H2O or ROH; or (v) RNCO, or R R NC(O)Cl, or other electrophilic groups listed here, with education, in particular, the compounds of formula XXI; or

(d) treatment of compounds of formula XV, where X about the mean halogen, the nucleophilic reagent selected from a heterocycle or benzo-or heteroarylboronic; or

(e) treatment of compounds of formula XXII substituted hydrazine to form compounds of formula XVII in an organic solvent in appropriate conditions; or

(f) processing the compounds of formula XVIII binding reagent selected from diimide, and disubstituted hydrazine of the formula R'-NHNHC(O)O-tert-butyl in an organic solvent in the presence of an appropriate acid, or

(g) further processing of the compounds of formula II, as defined in claim 2, where the compound contains a phenyl ring, substituted by a methoxy group or groups, acid obtaining phenyl substituent or substituents, or further processing of the compounds of formula II, where the connection is not in the form of salts, pharmaceutically acceptable base with obtaining pharmaceutically acceptable salt, or further processing of the compounds of formula II, where the compound contains a phenyl ring, substituted by cyano or groups, (i) a base with a receiving carboxilate Deputy or deputies, or (ii) acid to obtain an amide substituent, or (iii) azide with getting tetrazole Deputy, where carboxylates Deputy can then be processed halogenation agent and substituted amine of the formula HNR'R, obtaining samisen the th amide substituent, or carboxylates radical may be further processed by the alcohol (C1-C6in the presence of acid to obtain the ester substituent (C1-C6), or

(h) further processing of the compounds of formula II, where the compound contains oxazolidinedione, base in aqueous solution with obtaining aminopyrrolo Deputy as W, end (CH2)ncarbon chain with n equal to 1 to 4; or

(i) further processing of the compounds of formula II, where the compound contains a sulfide group, an oxidizing agent in suitable conditions for the formation of S(O)1or S(O)2group.

If they are not commercially available, the necessary starting materials for the above transformations can be obtained by methods which are selected from standard organic chemical techniques, methods, similar to the synthesis of known, structurally similar compounds, or techniques, similar to those described above, or methods described in the examples.

Some complex diesters of the formula IV for use in the reactions with substituted hydrazine order to obtain the compounds of formula I, can be obtained by treating compounds of formula VII with a suitable base, such as an alcoholate of an alkali metal (for example, tert-piperonyl potassium) in a suitable solvent, such as tert-butanol, for the implementation for the acania cycle and, thus, the desired complex diapir. In the specified compound of the formula VII, the value corresponds to the next, to obtain the corresponding values for Z, as indicated:

A. SNO, if the desired value of Z is hydrogen;

b. COOR15where R15means (C1-C3)alkyl if the desired value of the Z - hydroxy (tautomeric equivalent oxo). States that can be used alkylsilane esters, but they do not give any synthetic advantages.

C. CSOR15or CSSR15if Z preferably is digitoxin (SH); and

d. CN, if the desired value of Z - amino.

Does not require the allocation of compounds of formula VII to obtain the corresponding compound of formula IV'. It is better to get complex fluids of formula IV' in the same reactor, without isolating the compounds of formula VII from the reaction mixture.

Complex diethyl ether of the formula IV', where Z represents hydroxy (or oxo), can also be obtained by treating the anhydride of N-carboxyanhydrides acid of the formula X directly sodium or potassium salt (C1-C3)Olkiluoto (for example, diethyl) ether 2-oxenfree acid in a suitable solvent, such as dimethylformamide.

Complex fluids of formula IV', where Z denotes digitoxin, can be obtained by treatment of the corresponding complex diapir formula IV, where R3 denotes hydroxy, reagent Lawesson (Lawesson's), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide in a suitable solvent, such as toluene or dimethoxyethane, at a temperature of 50-110°C.

Substituted imide of formula V', where In-ring N loses N, and Z denotes, for example, NH2can be obtained by processing complex diapir formula IV', where the value of Z corresponds to a halogen group such as chlorine or bromine, ammonia with the formation of phthalimide, which then interacts with arylhydrazines, forming V', which then reacts in the usual way (Scheme 1), forming the final pyridazinedione.

Compound of formula VII where y represents CN, Cho, COOR15, CSOR15or CSSR15where R15stands With1-C10alkyl, alkenyl or quinil group, can be obtained by treating the corresponding eighth dialkyldithiocarbamato, such as diethylazodicarboxylate, in a suitable solvent, such as (C1-C4)alcohol. As the preferred solvent of tert-butanol.

Ortho-amine of formula VIII' can be obtained by esterification of the corresponding acid of formula VIII' in the usual ways. In turn, the acid of formula VIII' can be obtained by removing the protection of the corresponding derivative of formula VIII, where the amino group was protected by a conventional protecting group Pr (such as the pet-butoxycarbonyl, t-BOC). The compound of formula VIII, in turn, can be obtained by the sequential interaction of the amine of formula IX first with two equivalents of organolithium compounds (for example, tert-utility) with the formation of delicioso derived, which can be carboxylative by reacting with carbon dioxide. Amine of the formula IX can be obtained by appropriate protection (unprotected) amine in the usual way.

Ortho-amine of formula VIII, where y denotes COOR15can also be obtained in a way that differs from that just described above, the fact that the stage of esterification is carried out, using a base (e.g. sodium hydride) and then alkylating agent R15X with protected acid of formula VIII, not acid of formula VIII'.

Ortho-amine of formula VIII', where y denotes COOR15can also be obtained by treating the corresponding anhydride N-carboxyanhydrides acid of formula X with base (such as hydrooxide alkali metal in an alcohol solvent of the formula R15OH.

The anhydride of N-carboxyanhydrides acid of formula X can be obtained by treatment of isatin of formula XI with chromium trioxide in the presence of acetic anhydride, or gadoksetovoy acid, such as a magnesium salt monoatomically acid, in a suitable solvent, such as acetic acid is the same.

Isatin of formula XI can be obtained by cyclization of hydroxybenzamide formula XII in concentrated sulfuric acid at a temperature of 60-80°C.

Hydroxyindolacetic formula XII can be obtained by treating an amine of formula XIII with chloralhydrate in the presence of sodium sulfate and hydroxylamine hydrochloride in a suitable solvent such as water. N-tert-butoxycarbonylmethyl used in the present invention can be obtained according to the method set forth in example S. For example, N-tert-butoxycarbonyl-N'-pendaftar-benzylpiperazine; N-tert-butoxycarbonyl-N'-2-cyanobenzylidene; N-tert-butoxycarbonyl-N'-3-chlorobenzylidene; N-tert-butoxycarbonyl-N' - for 3,5-dateformatlength; N-tert-butoxycarbonyl-N'-3-phenylpropylamine; N-tert-butoxycarbonyl-N'-4-methylbenzylidene; N-tert-butoxycarbonyl-N'-4-triftormetilfullerenov; N-tert-butoxycarbonyl-N'-4-cyanobenzylidene and N-tert-butoxycarbonyl-N'-2,4-dimethylphenylacetate. In addition, the present invention relates also to these new hydrazinophenyl and method of their production and use as intermediate products for the connection with the key intermediate 2-pyrrolidinecarboxylic-3-carboxylic acid to form the compounds of formula II with a new and original way as described is here as a result of which selectively formed N-2-substituted PQD. Intermediate hydrazines used to obtain N-2-aryl or N-2-substituted aryl PQD, can also be obtained according to non-limiting example 42A. N'-tert-butoxycarbonyl-N'-aryl or substituted arylphosphonate get with this new method, enabling selective receiving N-2-substituted PQD. This method may be preferable for aryl-substituted derivatives, listed here and in the claims.

It should be noted that many of the starting compounds for the above-described methods of synthesis are commercially available and/or widely known in the scientific literature.

Examples of suitable pharmaceutically acceptable salts are salts formed with bases, which give physiologically acceptable cation, such as alkali metal (especially lithium, sodium and potassium), alkaline earth metal (especially calcium and magnesium), aluminum salts, or ammonium, and salts obtained with suitable organic bases, such as kolingerova, triethylamine, morpholine, piperidine, Ethylenediamine, lysine, ethanolamine, diethanolamine, triethanolamine, N-methyl-D-glucamine (meglumine), arginine and Tris(hydroxymethyl)aminomethan. The preferred sodium and potassium salts of choline and meglumine. The sodium and potassium salts of choline CCA the military preferred.

When intravenous therapeutic use, after the attack, pyridazinedione formula II, is usually administered as an appropriate pharmaceutical composition which contains a compound according to the invention specified above, together with a pharmaceutically acceptable diluent or carrier, the composition is selected taking into account the specific route of administration. Such compositions comprise the following object of the invention. They can be obtained by conventional means using conventional additives or binders, and can be in the form of various dosage forms. For example, they may be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of suppositories for rectal administration; in the form of sterile solutions or suspensions for administration by intravenous or intramuscular injection or infusion; and in powder form together with a pharmaceutically acceptable inert solid diluents such as lactose, for administration by insufflation.

The dose of injected compounds according to the invention must necessarily vary in accordance with the rules, well known in this field, taking into account the route of administration, the degree of postischemic damage, weight and age of the patient. Usually, the connection according to the invention is introduced warm-blooded animal (such as man) in to the number, required to achieve an effective dose, usually a dose in the range from about 0.01 to 100 mg/kg body weight. For example, if the compound is administered intravenously, its quantity is approximately in the range of from 0.5 to 100 mg/kg body weight.

Specialist in the art will understand that the connection according to the invention can be administered in conjunction with other therapeutic or preventive agents and/or medicaments that are not with them medical incompatible.

The action of the compounds according to the invention as antagonists for the glycine receptor of the NMDA receptor complex can be demonstrated by one or more standard research such as the study on the binding of [3H]-glycine (test A) and in vivo studies, such as ischemia induced carotid occlusion, on the model of gerbils (test In). In addition to these tests, the compounds of this invention are checking test red cell nuclei (test) and test on the middle cerebral artery in rats (test D). These tests confirm that the compounds according to the invention are NMDA receptor antagonists in vitro and in vivo. Some compounds according to the invention are highly active NMDA receptor antagonists. Some of these compounds (i.e., 3-(2-Aceto Sitel), 3-(p-methoxyphenyl or 3-(p-hydroxyphenyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione) have the value of the IC50[3H]Gly test above 100 micromoles and, thus, less active than their more active counterparts. In particular, the compounds of the present invention with R1denoting alkyl, aryl or a heterocycle, as defined here, and R2equal to N, are strongly active receptor (glycine antagonists.

Test And

In the study on the binding of [3H]-glycine neuronal synaptic membranes obtained from adults (about 250 g) of male rats Sprague Dawley. Svejeispechennyi samples of the cerebral cortex and hippocampus homogenizers of 0.32 M sucrose (110 mg/ml). Synaptosome allocate by centrifugation (1000 rpm, 10 min), the supernatant precipitated (20,000 rpm, 20 min) and re-suspended in double-distilled water. The suspension is centrifuged for 20 min at 8000 rpm Obtained supernatant and leucocytes film washed twice (48000 rpm, 10 min again suspended in double-deionized water). The precipitate is quickly frozen (bath of dry ice/ethanol) under a layer of double-deionized water and stored at -70°C.

On the day of the experiment otchajannye synaptic membrane homogenizers in tissue homogenizer (Brinkmann transmitter station (tm. Brinkmann Instruments, Westbury, N.Y.) is 50 mm Tris(hydroxymethyl)aminonicotinate, pH of 7.1. Membranes incubated with 0.04% of Surfact-AMPS X100 (tm. Pierce, Rockford, IL) in buffer for 20 minutes at 37°and washed six times by centrifugation (48000 rpm, 10 min) and re-suspended in the buffer. The final precipitate homogenized at 200 mg wet weight/ml buffer for studies on the binding.

For [3H]-glycine binding N-methyl-D-aspartate receptor, 20 nanomoles of [3H]-glycine (40-60 Ci/mmol, New England Nuclear, Boston, MA) and incubated with membranes, suspender-EN in 50 mm Tris(hydroxymethyl)aminonicotinate, pH 7,1, for 30 minutes at 4°C. Glycine, 1 mm, are used to determine nonspecific binding. Associated [3H]-glycine is separated from the free by using the harvester cells Brandel (Biomedical Research and Development Laboratories, Gaithersburg, MD) for vacuum filtration through filters of glass fiber (Whatman GF/B from Brandel, Gaithersburg, MD), pre-impregnated 0,025% polyethylenimine. Samples remaining on the glass fiber filter, washed 3 times in total 2.5 ml of cold buffer. Radioactivity is measured liquid scintillation counter. The value of the IC50obtained from the regression based on the least squares logit-log (long logarithms) data. Typical IC50values for the compounds according to the invention are typically less than 50 microns (micromol) and are illustrated by the compound of example 1 (IC50=0 μm), example 2 (IC50=0,50 ám), example 10 (IC50=0,12 µm). Other the examples given here describe the glycine antagonists.

Test

When tested in vivo, using an ischemic model of gerbils, adult Mongolian gerbils (50-70 g) anaesthetize 2-3% halothane gas (halothane). Bilateral common carotid artery of the neck open and put microaneurysm clamps. After 10 min (unless otherwise stated) the clamps are removed, restore the blood flow through the carotid artery and the skin sewn together. The compounds administered intraperitoneally, both before and after occlusion, for example, 45 minutes before and 5 minutes after occlusion of the carotid arteries. Animals, which simulated the operation is treated in a similar way, except that artery are clamped. Observe the General behavior associated with motor activity, carried out within 2 hours of the first (24 hours) days after occlusion. After 4 days of animals slaughtered (decapitation), remove the brain, fix, cut, and stained with hematoxylin/eosin and crazyville.

Section of the brain to assess neuronal lesions hippocampus using the following evaluation scale:

0 = unaffected, normal

1 = weak defeat (25%) - limited CAI/subject fabric outside

2 = moderate lesions (50%) - obvious is oragene, limited to less than half of the CAI region

3 = visible lesions (75%) - including more than half of the CAI region

4 = lesions beyond CAI region

Sections (7 μm) of each brain evaluated. Can be marked random, asymmetric lesions, and the rating value is the average value of the two sides. Record the average rating value of brain damage, and the indicators of impairment for the processed drug groups compared with the group treated with solvent, using test Wilcoxon-Rank Sum.

Normal values obtained in these tests for the compounds according to the invention, are illustrated by the following results: 35% neuroprotection (relative to control with a simulated operation) for compounds of example 4, and over 80% of neuroprotection for compounds of example 10, when each connection is injected intraperitoneally (ip) at 10 mg/kg body weight according to the above mode.

Test

Test red nuclei of cells

The purpose of this test is to determine the impact of introduced intravenous glycine antagonists on the induced stimulating reaction cells containing the red nucleus. ON-966 (racemic) and CGP 37849 are standard agents active in this test (ID50 of 7.9 and 1.7 mg/kg, intraperitoneally, who respectively).

Test method red nuclei of cells below. Rats anaesthetize chloralhydrate (400 mg/kg, intraperitoneally), and introduce the catheter into the femoral vein for intraperitoneal administration of the drug. Five-cylinder micropipette placed stereotaxically red nuclei of cells. Usually, three to four of the five cylinders are filled as follows: the cylinder for registration-2M potassium citrate, cylinder common mapping 4M NaCl, cylinder for medicines - 25 mm NMDA, and the other cylinder for drug - 2.5 mm Kiseleva (quisqualic) acid (QA use only in research selectivity). NMDA apply ionophoretically at a constant current, which is adjusted depending on the sensitivity of each individual cell has a red core. NMDA moves in a circle forward and backward (usually 30-60 seconds forward and 60-120 seconds ago) and the degree of excitation of the cell during each period is recorded. As soon as the zero degree of excitation is installed, start intravenous enter the test connection. The impact of drugs on NMDA-induced stimulating reaction cells containing red nucleus, can be evaluated both qualitatively and quantitatively from registered and accumulated raw data. Compounds according to the invention exhibit a mn is significant antagonistic reaction.

Test D

Test the middle cerebral artery in rats

In this test, the use of male SHR rats weighing 280-320 g Method used for continuous occlusion of middle cerebral artery (MCA), described Brint and others (1988). In short: local ischemia cause by the first occlusion of the left common carotid artery and then the left middle cerebral artery, which is located just above the nasal orifice. After occlusion, drugs injected through the neck catheter. Twenty-four hours after MCA/common carotid artery occlusion slaughtered and quickly remove the brain. Coronary tissue slices 1 mm thick make using vibrator, and paint 2,3,5-triphenyl-2H-tetrachloride dye (IDT). After staining necrotic tissue is easily separated from the intact brain and the site of infarction of the cerebral cortex research on image analyzer. The size of infarction for each plot to determine quantitatively the image analyzer and the total infarction volume calculated using the program, summarizing the volume of the entire interval. Cm. S. Brint et al., J. Cerebral Blood Flow 8: 474-485 (1988). Statistical analysis differences between the volume of the ischemic lesion in control with the solvent and processed drugs in animals is based on T-test Stud the NTA. All data are presented as mean ±S.E value for n animals. Compounds according to the invention to reduce ischemic damage.

Further, the invention is illustrated by the following non-limiting examples. In the examples, unless otherwise indicated:

(i) temperatures are given in degrees Celsius (°); this operation is carried out at room temperature or at ambient temperature, i.e. at temperatures in the range of 18-25°C;

(ii) evaporation of solvent is performed using a rotary evaporator under reduced pressure (600-4000 Pascals: 4.5 to 30 mm Hg) with a bath temperature of up to 60°C;

(iii) flash chromatography carried out on Merck Kieselgel (Art 9385) and column chromatography on Merck Kieselgel 60 (Art 7734); [these materials receive from the company Emags Darmstadt, W.Germany]; thin-layer chromatography (TLC-TLC) carried out on Analtech 0.25 mm silikagelevye HPLC plates (Art 21521), received from the company Analtech Newark, DE, USA;

(iv) generally, the reaction course is monitored with TLC and HPLC and reaction times are given for illustration only;

(v) melting point represented as the melting point, and (decomp.) indicates decomposition; the melting point is the temperature obtained for the products obtained as described; polymorphism may result in the selection of substances with different melting temperatures in the same way to obtain;

(vi) all finished the diversified products mostly cleared TLC and HPLC and give satisfactory nuclear magnetic resonance spectrum (NMR) (300 MHz PMR in D-DMSO, unless otherwise indicated) and microanalytical data;

(vii) the outputs are given for illustration only;

(viii) low pressure expressed as absolute pressures in Pascals (PA); other pressure expressed as manometrically pressures in bars;

(ix) chemical symbols have their usual meanings; used also the following notations: vol. (volume), weight (weight), TPL (melting point), l [liter(s)], ml (milliliters), mm (mmol), g [gram(s)], mg [milligram(s) ], min (minute), h (hours); and

(x) the ratio of the solvents are given in volume:volume (v/v) terms.

As for N-2 aryl compounds within the present invention, ortho-substituents on the phenyl ring have a significant impact on the solubility (water) glycine receptor antagonists. In particular, ortho-metaltometal increase the solubility and activity in vivo. In addition, the path presented in figure 7 (see below), refers to efficient method of obtaining N-2 heteroaryl in the framework of the present invention. In addition, the claimed invention relates to a method for removal of N-benzyl groups using methansulfonate.

The following NMR spectra, the following notation:

s - singlet,

m - multiplet

p> d - doublet,

br - broadened signal,

t - triplet,

dd = double doublet.

vbr is a very broad

Example 1

7-chloro-1-hydroxy-3-(2-hydroxyethyl)-3,4,5,10-Tetra-hydro-pyridazino[4,5-b]quinoline-4,10-dione;

To a stirred mixture of dimethyl 7-chloro-1-hydroxy-quinoline-2,3-in primary forms (50.0 g, 0,169 M)in ethanol (750 ml) is added 2-hydroxyethylhydrazine (286 g, 3,38 M 90% purity of the substance). The obtained dark brown mixture is heated at the boiling point under reflux for 18 hours and then allowed to cool to room temperature without stirring. The mixture is filtered and the collected solid product was washed once with ethanol and then heated at boiling temperature under reflux for 3 hours in glacial acetic acid (1.0 l). The mixture is allowed to cool to room temperature and then filtered, separating the yellow solid product. This product is dried overnight in a vacuum, receiving (41,83 g) a mixture of isomeric 2 - and 3-(2-hydroxyethyl) compounds in the form of a yellow solid product. This mixture is separated into two fractions on 20, 23 and 21.6 g, a Smaller fraction (on 20, 23 g) was dissolved under vigorous stirring in water (2700 ml)containing N-methylglucamine (54,0 g). This solution is carefully acidified with glacial acetic acid to achieve a pH of exactly 7.0 and formed during acidification the precipitate was separated by filtration. SOBR is by solids, washed once with water, dried and stored. The filtrate and wash water also combine and save. Larger of the two original fractions similarly dissolved in water (2880 ml)containing N-methylglucamine (57.6 g), and similarly acidified with glacial acetic acid to pH 7.0, receiving the second portion of the solid products. The filtrate and the appropriate wash water obtained in this acidification will also be combined and stored. The two portions of the collected solid products unite and get named in the title of 3-(2-hydroxyethyl) compound as a light yellow solid product (19,27 g, 37,0%). Recrystallization of this product from acetic acid gives the analytical sample, named the title compound as light yellow crystals, TPL 377-378°C; MS (CI): 308 (M+H).

Analysis for C13H10ClN304:

Calculated: C, 50,75; N, Or 3.28; N, 13,66

Found: C, 50,65; N, 3,39; N, 13,78.

NMR: 13,19 (s, 1H, capable of currency), 12,32 (s, 1H, capable of currency), by 8.22 (d, J=9.0 Hz, 1H), 8,15 (d, J=1.8 Hz, 1H), 7,56 (dd, J=9,0, 1.8 Hz, 1H), a 4.83 (br s, 1H, capable of currency), 4,10 (t, J=5.7 Hz, 2H), 3,75 (t, J=5.7 Hz, 2H).

Source dimethyl 7-chloro-4-hydroxyquinoline-2,3, in primary forms obtained as follows:

A. dimethyl 7-chloro-4-hydroxyquinoline-2,3, in primary forms.

Stir a mixture of methyl 2-amino-4-chlorobenzoate (2.50 g, 13.5 mm) and dimethyl of acetylenedicarboxylate (2,05 g, 14.4 mm) in tert-butanol (22 is l) heated at boiling temperature under reflux, within 7 hours in a nitrogen atmosphere. After adding additional quantities of dimethyl acetylenedicarboxylate (1,16 g, 8,13 mm) and additional heating at the boiling point under reflux, for 2.5 hours, the reaction mixture is allowed to cool to room temperature and add one portion of potassium tert-butylate (1.56 g, 13.9 mm). The precipitate and the resulting mixture is heated at boiling temperature under reflux for 1.5 hours. The reaction mixture is cooled to room temperature and filtered to separate the solid product, which was washed with tert-butanol and diethyl ether. Solid products are dissolved in water and acidified with 1 N. sulfuric acid to the sludge. The resulting mixture was extracted with methylene chloride and the combined extracts washed with salt solution and water, dried (MgSO4), filtered and concentrated, obtaining a green solid product. Recrystallization of this solid from methanol gives dimethyl 7-chloro-4-hydroxyquinoline-2,3, in primary forms (1,15 g, 28,94) not quite white solid product. TPL 232-233°C; MS (CI): 296 (M+H).

Analysis for C13H10ClNO5:

Calculated: C, 52,81; N, To 3.41; N, 4,74

Found: C, 52,75; N, 3,47; N, 4,69.

Example 2

7-chloro-4-hydroxy-2-(2-hydroxyethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

All the filtrates and Romania water remaining from Example 1 are combined and then acidified with glacial acetic acid to pH 5.0. The precipitate is collected, washed with water and dried, obtainingnamed the title compound as a pale yellow solid product (12,27 g, 23.5 per cent). Recrystallization of this substance from acetic acid gives an analytical sample of the above compound in the form of not-quite-white crystalline substance. TPL 335-336°C; MS (CI): 308 (M+H).

Analysis for C13H10ClN3O4:

Calculated: C, 50,75; N, Or 3.28; N, 13,66

Found: C, 50,54; N, 3,39; N, 13,65.

NMR: of 12.53 (br s, 1H, capable of being. for exchange), 11.87 per (br s, 1H, capable of being. for exchange), 8,17 (d, J=8.7 Hz, 1H), 8,04 (s, 1H), 7,45 (d, J=8,7 Hz, 1H), 4,82 (br s, 1H, capable of being. to the exchange)to 3.99 (t, J=6,1 Hz, 2H), 3,70 (t, J=6,1 Hz, 2H).

Example 3

2-(2-Acetoxyethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The orange suspension of 7-chloro-4-hydroxy-2-(2-hydroxyethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0,250 g, 0.81 mm) in 30%solution of Hydrobromic acid in glacial acetic acid (5 ml) was gently heated at boiling temperature under reflux for 16 hours under nitrogen atmosphere. The mixture is cooled to room temperature and diluted with water (20 ml) before the formation of sludge. The collected solids washed with water and methanol and then dried, obtaining mentioned in the title compound (0,242 g, 86%) as a reddish brown solid.

TPL 307-309°C; MS (CI): 350 (M+H)./p>

Analysis for C15H12ClN3O5·0,2CH3CO2H:

Calculated: C, 51,10; N, Of 3.57; N, 11,60

Found: C, 50,81; N, Of 3.45; N, Up 11,86.

NMR: 12,64 (br s, 1H, capable of being. for exchange), 11,91 (br s, 1H, capable of being. to the exchange)to 8.14 (d, J=8,64 Hz, 1H), 8,02 (d, J=1,74 Hz, 1H), 7,43 (dd, J=1,74, 8,64 Hz), 4,32 (t, J=5,54 Hz, 2H), 4,13 (t, J=5,54 Hz)to 1.98 (s, 3H).

Example 4

7-chloro-4-hydroxy-2-(2-phthalimidomethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

2-(2-Bromacil)-7-chloro-4-hydroxy-1,2,5,10-tetrahydro-pyridazino[4,5-b]quinoline-1,10-dione (5,00 g, 13,50 mm) and phthalimide potassium (10,50 g, 56,70 mm) is stirred and refluxed in DMF (100 ml) for 22 hours. Chilled yellow suspension was poured into diluted hydrochloric acid (1 n, 1.0 l) with good stirring. A white precipitate is formed, which is collected. This solid product resuspended in aqueous methanol (50%, 1.0 l) and stirred/effect ultrasound, getting a good suspension. Filtering and re-suspension in methanol (0.25 l) give freely the current white suspension after treatment with ultrasound and short heating at the boiling point under reflux. Solid products are finally collected and washed with methanol, getting named the title compound (4,65 g, 79%) as a white powder. TPL 349-352°C; MS (CI): 437 (M+H).

Analysis for C21H13ClN4O5·0,35H2O·0,SN 3HE:

Calculated: C, 56.78 Has; N, 3,18; N, 12,55

Found: C, 56,40; H, Was 2.76; N, 12,59.

NMR: 12,54 (br s, 1H, capable of being. for exchange), 11,88 (br s, 1H, capable of being. for exchange), 8,11 (d, J=8,67 Hz, 1H), 8,00 (br s, 1H), 7,83 (s, 4H), 7,42 (d, J=8,67 Hz, 1H), 4,13 (br m, 2H), 3,93 (br m, 2H).

The original 2-(2-bromacil)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione prepared as described below:

A. 2-(2-Bromacil)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione

7-Chloro-4-hydroxy-2-(2-hydroxyethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (8.00 g, 26,00 mm) is stirred in a mixture: aqueous Hydrobromic acid (50%, 80 ml), 30% Hydrobromic acid in glacial acetic acid (160 ml) and methanesulfonate (8 ml)to give a red solution. This solution is heated at the boiling point under reflux for 20 hours, during which time a precipitate. The yellow suspension is cooled to room temperature and stirred for 2 hours. The solid product is collected and washed with a mixture of acetonitrile/diethyl ether and diethyl ether and dried powder in the air. MS (CI): 370 (M+H).

NMR: 13,00 (br s, 1H, capable of being. for exchange), 8,23-8,18 (m, 2H), 7,60 (dd, J=2,04, 5,73 Hz), 5,20 (t, J=9, 37 Hz, 2H), 4,56 (t, J=9,37 Hz, 2H).

Example 5

Kalinova salt of 7-Chloro-1-hydroxy-3-phenyl-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

6-Chloro-2-aniline-2,3,4,9-tetrahydro-1H-pyrrolo-[3,4-b]quinoline-1,3,9-Trion (1.70 g, 5.0 mm) is stirred in methanol (,85 l) and add methansulfonate (85 ml). The yellow suspension is heated three boiling point under reflux for 16 hours and cooled to room temperature. The resulting mixture was filtered (the filtrate saved for use in Example 6) and the collected solids washed with methanol and dried, obtaining 7-chloro-4-hydroxy-3-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione (0,48 g, 28%) as a yellow powder. This powder is stirred in methanol and add choline hydroxide (45 wt.% in methanol, 0.5 ml)to give solution amber color. This solution is concentrated and the residue diluted with toluene and concentrated. The residue is dissolved in toluene and concentrated two additional times, and the obtained solid residue triturated with a mixture of ethanol/toluene (20%, 25 ml)to give a crystalline solid product. The solid product is collected, getting named the title compound (0,49 g, 78%) as a yellow powder. TPL 253-257°C; MS (CI): 340 (M+H).

Analysis for C17H10ClN3About3·C5H14NO·0,3H2About:

Calculated: C, 58,90; N, 5,31; N, 12,50

Found: C, 58,88; N, 5,18; N, 12,41.

NMR: 15,00 (s, 1H, capable of being. to the exchange), by 8.22 (d, J=8,79 Hz, 1H), a 7.85 (d, J=a 2.01 Hz, 1H), to 7.61 (d, J=7,53 Hz, 2H), 7,45 (t, J=7,53 Hz, 2H), 7,38-7,28 (m, 2H), 5,31 (s, 1H, capable of being. for exchange), 3,83 (br m, 2H), 3,39 (br m, 2H), 3,10 (s, 9H).

The original 6-chloro-2-aniline-2,3,4,9-tetrahydro-1H-pyrrolo-[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 6-the ENT-2-aniline-2,3,4,9-tetrahydro-1H-pyrrolo-[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl 7-chloro-4-hydroxy-quinoline-2,3-in primary forms (2.50 g, 8,45 mm) in ethanol (35 ml) was added phenylhydrazine (of 5.82 ml, 59,20 mm)to give a brown solution. This solution is heated at the boiling point under reflux for 16 hours, during which time a precipitate. The suspension is filtered hot and the collected solids washed with ethanol, getting phenyl-hydrazine powered salt mentioned in the title compound as a white powder (2.10). This product is stirred and heated at boiling temperature under reflux in glacial acetic acid (50 ml) for 2 hours. The obtained yellow suspension is cooled to room temperature and filtered, getting named the title compound (1.70 g, 59%) as a yellow solid product. TPL 397°C; MS (CI): 340 (M+H).

Analysis for C17H10ClN3About3:

Calculated: C, 60,10; N, Of 2.97; N, 12,40

Found: C, 59,96; N, And 2.79; N, 12,45.

NMR: 13,80 (br s, 1H, capable of being. for exchange), 8, (s, 1H, capable of being. for exchange), 8,23 (d, J=to 8.70 Hz, 1H), 7,89 (d, J=1.89 Hz, 1H), 7,58 (dd, J=1,89, to 8.70 Hz, 1H), 7,18 (t, J=8,01 Hz, 2H), PC 6.82 (m, 3H).

Example 6

7-Chloro-4-hydroxy-2-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 5 was diluted with water (0,80 l) and the resulting reddish-brown suspension is stirred for 1 hour. Solids collected and washed with water meters is canola (50%), getting named the title compound (1.20 g, 71%) as not quite white powder. TPL 347-349°C; MS (CI): 340 (M+H).

Analysis for C17H10ClN3About3·0,10H2About:

Calculated: C, 59,80; N, A 3.01; N, 12,30

Found: C, 59,64; H, Was 2.76; N, 12,27.

NMR: 12,8 (br s, 1H, capable of being. to share), compared to 12.1 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8,67 Hz, 1H), of 8.06 (d, J=1.80 Hz, 1H), 7,56-7,33 (m, 6H).

Example 7

7-Chloro-1-hydroxy-3-(4-methoxyphenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

6-Chloro-2-(4-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion (2,72 g, 7,40 mm) is stirred in methanol (200 ml) and add methansulfonate (50 ml). Reddish-brown suspension is heated at the boiling point under reflux for 16 hours, during which it becomes yellow. This yellow suspension is cooled to room temperature and filtered (the filtrate saved for use in Example 8). The collected solids washed with methanol, getting named the title compound as a yellow powder (1.19 g, 44%). TPL 371-373°C; MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4:

Calculated: C, 58,50; N, Of 3.27; N, 11,36

Found: C, 58,30; N, To 3.41; N, 10,92.

NMR: 13,33 (br s, 1H, capable of being. for exchange), 12,47 (s, 1H, capable of being. for exchange), 8,30 (d, J=8,73 Hz, 1H), 8,23 (br s, 1H), to 7.61 (m, 3H), was 7.08 (d, J=8,90 Hz, 2H), 3,83(s, 3H).

The original 6-Chloro-2-(4-methoxyaniline)-2,3,4,9-tetrahydro-lH-pyrrole,4-b]quinoline-1,3,9-Trion receive the following way:

A. 6-Chloro-2-(4-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl 7-chloro-4-hydroxy-quinoline-2,3-in primary forms (0,500 g, 1,69 mm) in ethanol (17 ml) is added 4-methoxyphenyl hydrazine hydrochloride (2,07 g, 11,83 mm). Add triethylamine (of 1.88 ml, 13,52 mm) and the mixture is heated at boiling temperature under reflux for 40 hours. The resulting suspension was filtered hot, and the collected solids washed with ethanol, getting salt 4-methoxyphenyl hydrazine named in the title compound (0,700 g) as a light tan solid product. This product is heated at boiling temperature under reflux in glacial acetic acid (20 ml) for 2 hours, obtaining a brown suspension. The suspension is cooled to room temperature, the solids collected and washed with glacial acetic acid, methanol and diethyl ether, getting named the title compound (0,331 g, 53%) as a reddish brown powder. TPL 365°C (decomp.); MS (CI): 370 (M+H).

Analysis for C18H12ClN3C4:

Calculated: C, 58,50; N, Of 3.27; N, 11,36

Found: C, 58,29; N, To 3.41; N, 11,14.

NMR: 13,79 (br s, 1H, capable of being. to the exchange), by 8.22 (br d, J=to 8.70 Hz, 2H, 1H capable of being. for exchange), 7,88 (d, J=1,79 Hz, 1H), EUR 7.57 (dd, J=1,79, to 8.70 Hz, 1H), 6,78 (s, 4H), to 3.67 (s, 3H).

Example 8

7-Chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-Tetra is dropyridine[4,5-b]quinoline-l,10-dione.

Saved the filtrate from Example 7 was diluted with water (250 ml)to give a yellow suspension. Collect solids and washed with aqueous methanol (50%), getting named the title compound (1.22 g, 45%) as a yellowish powder. TPL 351-353°C; MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4:

Calculated: C, 58,50; N, Of 3.27; N, 11,36

Found: C, 58,51; N, 3,44; N, 11,03.

NMR: 12,74 (s, 1H, capable of being. for exchange), 12,01 (s, 1H, capable of being. for exchange), of 8.15 (d, J=to 8.70 Hz, 1H), with 8.05 (br s, 1H), 7,44 (multiplet, 3H), 7,02 (br d, J=of 6.96 Hz, 2H), 3,80 (s, 3H).

Example 9

7-Chloro-1-hydroxy-3-(4-hydroxyphenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

7-Chloro-1-hydroxy-3-(4-methoxyphenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione (0.800 to g, 2,16 mm) is stirred in methansulfonate (16 ml)to give an amber-yellow solution. This solution is heated at 160°With 6 hours and cooled to room temperature. Add diethyl ether (250 ml) gives a reddish-brown precipitate, which is stirred for 1 hour. The solid product is collected and washed with a mixture of methanol/diethyl ether, getting named the title compound (0,661 g, 77%) as a reddish brown powder. TPL 393-395°C; MS (CI): 356 (M+H).

Analysis for C17H10ClN3O4·0,2CH3SO3N·1,3H2O:

Calculated: C, 51,86; N, 3,39; N, 10,55;

Found: C, 51,76; N, To 3.02; N, 10,37.

NMR: 13,30 (s, 1H, capable of being. of the exchange), 12,5 (v br s, 1H, capable of being. for exchange), and 10.8 (br s, 1H, capable of being. for exchange), 8,29 (d, J=8,76 Hz, 1H), 8,23 (br s, 1H), to 7.61 (br d, J=8,76 Hz, 1H), 7,45 (d, J=8,81 Hz, 2H), to 6.88 (d, J=8,81 Hz, 2H), 2,32 (3, 0,5H).

Example 10

7-Chloro-4-hydroxy-2-(4-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0.800 to g, 2,16 mm) is stirred in methansulfonate (16 ml)to give solution amber color. This solution is heated at 150°With 6 hours and cooled to room temperature. Adding diethyl solution (250 ml) and methanol (50 ml) gives a reddish-brown precipitate. The solid product is collected and washed, getting named the title compound (0,530 g, 51%) as a reddish brown powder. TPL 316-318°C; MS (CI): 356 (M+H).

Analysis for C17H101N3O4·CH3SO3N·1,3H2O:

Calculated: C, 45,49; N, To 3.52; N, 8,84;

Found: C, 45,45; N, 3,24; N, 8,64.

NMR: 12,80 (v br s, 1H, capable of being. for exchange), of 8.15 (d, J=8,68 Hz, 1H), 8,04 (s, J=1,84 Hz, 1H), 7,44 (dd, J=1,84, 8,68 Hz, 1H), 7,28 (d, J=a total of 8.74 Hz, 2H), for 6.81 (d, J=a total of 8.74 Hz, 2H), 2.35MM(3, 3H).

Example 11

4-Hydroxy-8-nitro-2-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

2-Aniline-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion (0,830 g, 2,37 mm) is dissolved with stirring in methansulfonate (42 ml)to give a dark orange solution. Add methanol (420 ml) and the resulting yellow is th solution is heated at the boiling point under reflux for 2 hours, getting a yellow suspension. Heat is removed and the suspension is stirred at room temperature for 3 hours. Solid products are separated by filtration and the filtrate is left to stand for 20 hours. During this time, the filtrate is the formation of additional quantities of solid products and the suspension is again filtered. This filtrate is then concentrate to approximately 250 ml and diluted with water (400 ml)to give a yellow precipitate. These solids are collected and washed with aqueous methanol (50%) and then diethyl ether, getting named the title compound (0,590 g, 71%) as a yellow powder. TPL 382-385°C; MS (CI): 351 (M+H).

Analysis for C17H10N4O5·0,14H10About·1,1H2O:

Calculated: C, 55,40; N, To 3.52; N, 14,80;

Found: C, To 55.42; H, Of 3.46; N, 14,60.

NMR: 12,91 (br s, 1H, capable of being. for exchange), to 12.44 (br s, 1H, capable of being. for exchange), 8,86 (s, 1H), 8,53 (d, J=9,18 Hz, 1H), 8,15 (d, J=9,18 Hz, 1H), EUR 7.57-to 7.35 (m, 5H).

The original 2-aniline-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 2-Aniline-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of diethyl-6-nitro-4-hydroxy-quinoline-2,3-in primary forms (1,670 g, 5.00 mm) in ethanol (30 ml) was added phenylhydrazine (3,44 ml, 35,00 mm)to give a dark red solution. The solution is heated at the boiling point under reflux for 1 hour and concentrated AP is sustained fashion to 15 ml. Further heating gives a thick suspension which was diluted with ethanol (5 ml) and heated at boiling temperature under reflux an additional 16 hours. The mixture is cooled to room temperature and filtered, obtaining phenyl hydrazine powered salt mentioned in the title compound as a tan solid. This product is heated at boiling temperature under reflux in glacial acetic acid (25 ml) for 2 hours and cooled to room temperature. Filtering network named the title compound (1.01 g, 58%) as a reddish brown powder. TPL 368°C (decomp.); MS (CI): 351 (M+H).

Analysis for C17H10N4O5:

Calculated: C, 58,30; N, Is 2.88; N, 16,00;

Found: C, 58,21; N, Of 3.07; N, 16,15.

NMR: 8,91 (d, J=2.76 Hz, 1H), at 8.60 (dd, J=was 2.76, 9,18 Hz, 1H), of 8.06 (d, J=9,18 Hz, 1H), 7,18 (t, J=7.23 percent Hz, 2H), PC 6.82 (m, 3H).

Example 12

2-Benzyl-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-in primary forms (5,00 g, 16,90 mm) and benzylpiperazine dihydrochloride (46,15 g, 236,50 mm) in ethanol (100 ml), add triethylamine (75,8 ml, 541,0 mm). The mixture is heated, getting a brown solution, which is heated at boiling temperature under reflux for 40 hours, during which time a precipitate. The suspension is cooled to room temperature and the filter is t, getting benzoylhydrazone salt mentioned in the title compounds as containing an admixture of yellow solid. Repeated crystallisation from ethanolic hydrogen chloride and methanol gives named the title compound (0,370 g, 6%) as a white powder. TPL 347-350°C; MS (CI): 354 (M+H).

Analysis for C18H12ClN3O3:

Calculated: C, 61,10; N, Of 3.42; N, 11,90;

Found: C, 60,68; N, 3,61; N, 11,80.

NMR: 12,65 (br s, 1H, capable of being. for exchange), 11,93 (br s, 1H, capable of being. for exchange), of 8.15 (d, J=8,67 Hz, 1H), 8,02 (d, J=1,83, 1H), 7,43 (d, J=8,55 Hz, 1H), was 7.36-7.23 percent (m, 5H), 5,11 (s, 2H).

Example 13

7-Chloro-4-hydroxy-2-[2-(4-phenylpiperazine)-ethyl]-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

2(2-Bromacil)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0,500 g, 1.35mm) is stirred in dimethylformamide (10 ml) and add N-phenylpiperazin (10 ml, 10.6 g, 65,5 mm). The obtained yellow suspension is heated to 110°receiving a transparent yellow solution. The solution is heated for 6 hours, during which time a precipitate. The suspension is cooled to room temperature and stirred for five days. The obtained yellow suspension was dissolved in aqueous methanol (500 ml, 50%). the pH of this solution is carefully brought to pH 6 with 1 N. hydrochloric acid (˜20 ml), giving a yellow precipitate. This suspension is stirred for 1 hour and filtered, obtaining mentioned in the title compound, for razdelnoe N-phenylpiperazine (0,753 g). This product is recrystallized from ethanol (200 ml), getting named the title compound (0,428 g, 70%) as a yellow powder. TPL 361-364°C ; MS (CI): 452 (M+H).

Analysis for C23H22ClN5O3:

Calculated: C, 61,10; N, 4,91; N, 15,50;

Found: C, RUR 60,72; N, Of 5.06; N, 15,30.

NMR: of 7.95 (d, J=8,67 Hz, 1H), to 7.64 (br s, 1H), 7,26-to 7.18 (m, 3H), 6,95 (d, J=8,07 Hz, 2H), 6,78 (t, J=7,32 Hz, 1H), 4,15 (br s, 2H), 3,55-to 2.85 (br m, 10 H).

Example 14

Kalinova salt of 7-Chloro-1-hydroxy-3-(2-phenethyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

To a stirred solution of sodium hydroxide (9,46 g, 236,6 mm) in ethanol (100 ml) at 45°With add-sulfate salt of 2-penitenciaria (27,6 g, 118,3 mm) along with an additional quantity of ethanol (50 ml). Received a thick white suspension is stirred for 2 hours. The solid product is removed by filtration and washed with ethanol (50 ml). Transparent combined filtrate concentrated to ˜70 ml and add dimethyl 7-chloro-4-hydroxyquinoline-2,3, in primary forms (2.50 g, 8,45 mm), giving a brown solution. The solution is heated at the boiling point under reflux for 16 hours, during this time a yellow precipitate is formed. The suspension is filtered hot and washed with ethanol (50 ml)to give 2-phenerganbuy salt of 7-chloro-1-hydroxy-3-(2-phenethyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione as a yellow powder (2,90 g). This product is heated at a temperature of Kipen what I under reflux in glacial acetic acid (50 ml) for 2 hours and after cooling to room temperature, the resulting suspension is filtered, obtaining a mixture of 7-chloro-1-hydroxy-3-(2-phenethyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione and the corresponding 2-substituted phenethyl isomer as a yellow solid (2.20 g, 68%). The mixture is stirred in methanol (250 ml) and a solution of methyl-D-glucamine (15.0 g of methyl-D-glucamine in 250 ml of water). Then add a solution of choline hydroxide (9.0 ml, 50 wt.% in water), getting solution of saturated amber color. This solution is carefully acidified to pH 9 glacial acetic acid, after which the formed yellow precipitate. After stirring this yellow suspension for 1 hour, the solids collected and washed successively aqueous methanol (50%), a mixture of methanol/ether and diethyl ether, getting named the title compound (free acid, 1.13 g, 54%) as a yellow powder. The filtrate and the washing water is collected and saved for use in Example 15.

Previously allocated 7-chloro-1-hydroxy-3-(2-phenethyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione (1,00 g of 2.72 mm)that was previously allocated, stirred in methanol (50 ml) and add a solution of choline hydroxide (1.0 ml, 45 wt.% in methanol). The resulting suspension is stirred and treated with ultrasound for 1 hour, giving a solution of an amber color. This solution three times subjected to azeotropic distillation of MESI methanol/toluene (10%, 50 ml)to give an orange solid product. Rubbing with toluene (50 ml)containing ethanol (3 ml), gives freely the current suspension, which is stirred for 16 hours. The solid product is collected and washed with toluene and diethyl ether, obtaining reddish-brown powder (1.19 g). This powder is dried under high vacuum (50 MT) at 100°C for 72 hours, which gives you named the title compound (1,00 g, 78%) as a powder Golden brown. TPL 227-229°C; MS (CI): 368 (M+H).

Analysis for C19H13ClN3O3·C5H14NO·0,2N2About:

Calculated: C, 60,70; N, Of 5.82; N, 11,81;

Found: C, 60,41; N, 5,74; N, 11,68.

NMR: 14,86 (s, 1H, capable of being. for exchange), 8,17 (d, J=8,82 Hz, 1H), 7,80 (s, 1H), 7,33-7,19 (m, 6N), lower than the 5.37(br s, 1H, capable of being. for exchange), of 4.13 (t, J=7.29 trend Hz, 2H), 3,84 (br s, 2H), 3,37 (m, 2H), 3,10 (s, 9H), of 3.00 (t, J=7.29 trend Hz, 2H).

Example 15

7-Chloro-4-hydroxy-2-(2-phenethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate and the washing water stored from Example 14, acidified with glacial acetic acid, which gives a precipitate. Solids collected and washed sequentially with methanol, water, methanol and diethyl ether, getting named the title compound (0,81 g, 39%) as a pale yellow powder. TPL 327-330°C; MS (CI): 368 (M+H).

Analysis for C19H14ClN3About3·0,1 h2O:

Calculated: C, 61,70; N, A 3.87 N, 11,36;

Found: C, 61,60; N, 3,99; N, 10,98.

<> NMR: 12,60 (v s, 1H, capable of being. to Razlog.), 11,95 (vbrs, 1H, capable of being. to Razlog.), of 8.15 (d, J=8,63 Hz, 1H), 8,01 (d, J=1.35 Hz, 1H), 7,43 (d, J=8,63 Hz, 1H), 7,33-7,22 (m, 5H), 4,11 (t, J=7,46 Hz, 2H), 2,99 (t, J=7,46 Hz, 2H).

Example 16

7-Chloro-1-hydroxy-3-(4-chlorophenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Stir a suspension of 6-chloro-2-(4-Chloroaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0,670 g, 1,79 mm) in methanol (60 ml) and methanesulfonate (15 ml) is heated at the boiling point under reflux for 3 hours and cooled to room temperature. The mixture is filtered (the filtrate saved for use in Example 17), and the collected yellow solid foods, washed with methanol and diethyl ether, giving named the title compound (0.156 g, 23%) as a yellow powder. TPL >400°C; MS (CI): 374 (M+H).

Analysis for C17H9Cl2N3About3:

Calculated: C, 54,60; N, 2,42 N, 11,23;

Found: C, 54,29; N, 2,19; N, 11,20

NMR: 13,40 (s, 1H, capable of being. for exchange), 12,54 (s, 1H, capable of being. for exchange), 8,30 (d, J=8,79 Hz, 1H), 8,23 (d, J=1.89 Hz, 1H), of 7.75 (d, J=6,90 Hz, 2H), 7,63 (m, 3H).

The original 6-chloro-2-(4-Chloroaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive as described below:

A. 6-chloro-2-(4-Chloroaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,8-Trion

To a stirred suspension of dimethyl 7-chloro-4-hydroxy-quinoline-2,3-in primary forms (2.50 g, 8,45 mm) and 4-chlorophenyl-hydrazine (or 10.60 g, 59,20 mm) in ethanol (50 ml add triethylamine (9,43 ml), getting a brown solution. This solution is heated at the boiling point under reflux for 24 hours and then cooled to room temperature. Dilution with water (25 ml) gives a brown precipitate. This suspension is stirred for 16 hours and filtered to separate the solid products which are discarded. After storage of the filtrate within seven days formed another residue. This solid product is collected and washed with methanol (50%) and diethyl ether, obtaining salt of 4-chlorophenylhydrazone named in the title compound, as a brown powder (1.20 g). This product is heated at boiling temperature under reflux in glacial acetic acid (25 ml) for 3 hours and cooled to room temperature. The obtained orange suspension is filtered and the solids washed with glacial acetic acid and diethyl ether, getting named the title compound (0.810 g, 25%) as a pale orange powder. TPL 399-401°C; MS (CI): 374 (M+H).

Analysis for C17H9Cl2N3O3:

Calculated: C, 54,60; N, 2,42; N, 11,23;

Found: C, 54,29; N, 2,61; N, 11,12.

NMR: 13,80 (v br s, 1H, capable of being. for exchange), 8,67 (s, 1H, capable of being. to the exchange), by 8.22 (d, J=8,67 Hz, 1H), 7,88 (d, J=1.73 Hz, 1H), EUR 7.57 (dd, J=1,73, 8,67 Hz, 1H), 7,21 (d, J=8,79 Hz, 2H), 6.87 in (d, J=8,79 Hz, 2H).

Example 17

7-Chloro-4-hydroxy-2-(4-chlorophenyl)-1,2,5,10-tetrahydro-pyridazino[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 16 was diluted with water (75 ml)to give a white slurry, which is stirred for 16 hours. This suspension is filtered and the collected solids washed successively with water, aqueous methanol, Metha-Nol/diethyl ether and diethyl ether, getting named the title compound (0,420 g, 63%) as white solid powder. TPL 359-360°C; MS (CI): 374 (M+H).

Analysis for C17H9Cl2N3About3·0,5H2O·0,2CH3SO3H:

Calculated: C, 51,30; N, A 2.71; N, the 10.40;

Found: C, 51,44; N, 2,64; N, 0,60.

NMR: 12,91 (br s, 1H, capable of being. for exchange), 12,07 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8,64 Hz, 1H), of 8.06 (d, J=1,62 Hz, 1H), 7,63-7,46 (m, 5H).

Example 18

7-Chloro-1-hydroxy-3-(4-were)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Stir a suspension of 6-chloro-2-(4-methylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.60 g, 4,53 mm) in a solution of methanol (128 ml) and methanesulfonate (32 ml) is heated at the boiling point under reflux for 4 hours and cooled to room temperature. The obtained yellow suspension was stirred at room temperature for five days and then filtered (the filtrate saved for use in Example 19). The collected solids washed with methanol and then diethyl ether, getting named the title compound (0,594 g, 37%) as a yellow powder. PL >400°C; MS (CI): 354 (M+H).

Analysis for C18H12ClN3O3·0,4H2O:

Calculated: C, 59,89; N, Of 3.57; N, 11,64;

Found: C, 59,47; N, 3,14; N, 11,57.

NMR: 13,34 (s, 1H, capable of being. for exchange), 12,48 (s, 1H, capable of being. for exchange), 8,30 (d, J=8,75 Hz, 1H), they were 8.22 (br s, 1H), 7.62mm (d, J=8,75 Hz, 1H), 7,55 (d, J=8,01 Hz, 2H), 7,33 (d, J=8,01 Hz, 2H), of 2.38 (S, 3H).

The original 6-chloro-2-(4-methylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 6-Chloro-2-(4-methylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl 7-chloro-4-hydrochinon-2,3-in primary forms (3,90 g, 13,3 mm) and 4-were-hydrazine hydrochloride (14.8 g, 93,2 mm) in ethanol (140 ml), add triethylamine (14,8 ml of 106.4 mm). The obtained brown solution is heated at the boiling point under reflux for 16 hours, during which time precipitation. The resulting suspension is cooled to room temperature and filtered, obtaining salt of 4-methylphenylhydrazine named the title compound as a gray powder (2.30 g). This product is heated at boiling temperature under reflux in glacial acetic acid (45 ml) for 2 hours and cooled to room temperature. The obtained brown suspension is filtered, getting named the title compound (1.60 g, 34%) as a reddish brown powder. TPL 380-382°C; MS (CI): 354 (M+H).

Analysis for C18/sub> H12ClN3About3·0,2N2O:

Calculated: C, 60,49; N, 3,50; N, 11,76;

Found: C, 60,66; N, 3,26; N, 11,76.

NMR: 13,81 (v br s, 1H, capable of being. for exchange), 8,39 (s, 1H, capable of being. to the exchange), by 8.22 (d, J=8,58 Hz, 1H), 7,89 (d, J=1.97 Hz, 1H), 7,58 (dd, J=1,97, 8,58 Hz, 1H), 6,98 (d, J=of 8.28 Hz, 2H), 6.73 x (d, J=of 8.28 Hz, 2H), 2,19 (s, 3H).

Example 19

7-Chloro-4-hydroxy˜2-(4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate stored in the Example 18 was diluted with water (160 ml)to give a reddish-brown suspension, which is stirred for 3 hours. The suspension was filtered and the collected solids washed successively with water, methanol/ether and diethyl ether, getting named the title compound (0,855 g, 53%) as a reddish brown powder. TPL 368-370°C; MS (CI): 354 (M+H).

Analysis for C18H12ClN3About3·0,2N2O:

Calculated: C, Of 60.50; H, 3,50; N, 11,76;

Found: C, 60,52; N, 3,23; N, To 11.79.

NMR: was 12.75 (br s, 1H, capable of being. for exchange), 12,00 (br s, 1H, capable of being. for exchange), of 8.15 (d, J=8,61 Hz, 1H), 8,04 (d, J=1.50 Hz, 1H), 7,43 (t, 3H), 7,26 (d, J=of 8.25 Hz, 2H), a 2.36 (s, 3H).

Example 20

7-Chloro-1-hydroxy-3-(4-isopropylphenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Stir a suspension of 6-chloro-2-(4-isopropylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.13 g, 2,98 mm) in a solution of methanol (90 ml) and methanesulfonate (23 ml) is heated at boiling point with a reflux is m 7 hours and cooled to room temperature. The mixture is filtered (the filtrate saved for use in Example 21), the collected yellow solid foods, washed with methanol and diethyl ether, getting named the title compound (0,401 g, 35%) as a yellow powder. TPL 393-394°C; MS (CI): 382 (M+H).

Analysis for C20H16ClN3About3·0,2N2About:

Calculated: C, 62,33; N, The 4.29; N, 10,90;

Found: C, 62,16; N, 3,98; N, 10,82.

NMR: 13,33 (s, 1H, capable of being. for exchange), 12,48 (s, 1H, capable of being. for exchange), of 8.28 (d, J=8,76 Hz, 1H), they were 8.22 (d, J=1.77 Hz, 1H), 7,63-7,58 (m, 3H), 7,40 (d, J=8,49 Hz, 2H), 2,98 (septet, J=of 6.96 Hz, 1H), 1,25 (d, J=of 6.96 Hz, 6H).

The original 6-chloro-2-(4-isopropylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 6-Chloro-2-(4-isopropylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl 7-chloro-4-hydrochinon-2,3-in primary forms (2,01 g, 6.80 mm) and 4-isopropylpiperazine hydrochloride (8.90 g, 47,6 mm) in ethanol (72 ml), add triethylamine (7,6 ml, 54,5 mm)to give a brown solution. This solution is heated at the boiling point under reflux for 16 hours, cooled to room temperature and then added slowly to a mixture of hydrochloric acid (12 N., 100 ml) with vigorous stirring, resulting in a pink suspension. The suspension is filtered and the collected solids washed with chilled solution, th is prepared by mixing methanol (100 ml), hydrochloric acid (100 ml, 12 N.) and ice, getting salt of 4-isopropylpiperazine named in the title compound in the form of a powder purple (1.80 g). This product is heated at boiling temperature under reflux in glacial acetic acid (15 ml) for 3 hours, getting a tan suspension. The suspension is cooled to room temperature and filtered. The collected solids washed with glacial acetic acid (10 ml) and diethyl ether, getting named the title compound (1,125 g, 43%) as a reddish brown powder. TPL 367-369°; MC (CI): 382 (M+H).

Analysis for C20H16ClN3About3·0.1 n2O:

Calculated: C, 62,60; H, 4.26 Deaths; N, 10,95;

Found: C, 62,60; H, 4.35; N, of 10.73.

NMR: 13,82 (v br s, 1H, capable of being. for exchange), to 8.41 (s, 1H, capable of being. for exchange), 8,23 (d, J=8,64 Hz, 1H), 7,89 (d, J=1,98 Hz, 1H), to 7.61 (dd, J=1,98, 8,64 Hz, 1H),? 7.04 baby mortality (d, J=8,42 Hz, 2H), 6,74 (d, J=8,42 Hz, 2H), 2,78 (septet, J=6.87 in Hz, 1H)and 1.15 (d, J=6.87 in Hz, 6N).

Example 21

7-Chloro-4-hydroxy-2-(4-isopropylphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate is saved in Example 20 was diluted with water (115 ml)to give a light yellow suspension, which is stirred for 5 hours at room temperature. The suspension is filtered and the collected solids washed successively with water, aqueous methanol (50%), methanol/diethyl ether and diethyl ether, giving named in the title with the unity (0,418 g, 37%) as a reddish brown powder. TPL 323-326°C; MS (CI): 382 (M+H).

Analysis for C20H16ClN3About3·0,5H2O·0,1 CH3SO3H:

Calculated: C, 60,29; N, To 4.38; N, 10,49;

Found: C, 60,13; N, 4,10; N, The 10.40.

NMR: of 12.73 (br s, 1H, capable of being. for exchange), 12.00 (br s, 1H, capable of being. for exchange), of 8.15 (d, J=to 8.70 Hz, 1H), with 8.05 (d, J=1,74 Hz, 1H), 7,45 (m, 3H), 7,33(d, J=8,40 Hz, 2H), 2.95 and (septet, J=6,90 Hz, 1H), 1,24 (d, J=6,90 Hz, 6N).

Example 22

7,9-Dichloro-1-hydroxy-2-phenyl-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

6,8-Dichloro-2-aniline-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion (0,60 g, 1,60 mm) is stirred in methanol (200 ml) and methanesulfonate (20 ml) is added with cooling, keeping the temperature below 20°C. the Obtained orange solution is stirred over night at room temperature. Formed during the night the precipitate and the orange suspension is heated at boiling temperature under reflux for 1 hour. The suspension is cooled to room temperature and left to stand overnight without stirring. The suspension is filtered and the filtrate is slowly diluted with water (200 ml)to give a yellow suspension. This suspension is stirred for 2 hours and the solid product is collected and washed with water, aqueous methanol, 50% methanol/diethyl ether and diethyl ether, getting named the title compound (0,368 g, 61%) as a light reddish-brown, the second powder. TPL 361-363°C; MS (CI): 374 (M+H).

Analysis for C17H9Cl2H3About3·0,N2O:

Calculated: C, 53,80; N, 2,55 N 11,07;

Found: C, 53,71; N, 2,64; N, 10,97.

1H NMR: 12,84 (s, 1H, capable of being. for exchange), 11,96 (s, 1H, capable of being. for exchange), of 8.04 (d, J=2,02 Hz, 1H), 7,55 was 7.45 (m, 5H), was 7.36 (t, J=6,84 Hz, 1H).

Source 6,8-Dichloro-2-aniline-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 6,8-Dichloro-2-aniline-2,3,4,9-tetrahydro-1H-pyrrolo-[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl 5,7-dichloro-4-hydroxyquinoline-2,3-in primary forms (3.00 g, which is 9.09 mm) in ethanol (42 ml) was added phenylhydrazine (6,26 ml, 63,6 mm). Received green solution is heated at the boiling point under reflux for 16 hours, during this time formed a small amount of red precipitate. This suspension is cooled to room temperature with stirring, causing further precipitation of the product and the formation of a thick reddish-brown suspension. Solids collected and washed with ethanol (ethanol rinse water save). The collected solid product is recrystallized from ethanol (1.20 l), receiving phenyl hydrazine powered salt mentioned in the title compounds (1,17 g) as a reddish brown powder. This product is stirred and heated at boiling temperature under reflux in glacial acetic acid is the acid (15 ml) for 2.5 hours and then cooled to room temperature under stirring. The obtained orange suspension is filtered, getting named the title compound (0,629 g, 19%) as an orange powder, which is slightly dirty. An analytical sample named in the title compound is obtained from left earlier ethanol wash water by filtering the precipitate formed after these washing waters were standing within a few hours. Recrystallization of this collected reddish-brown powder (0.126 g) of glacial acetic acid (2 ml) gives the net named the title compound (0.083 g) as an orange powder. TPL 364-367°C; MS (CI): 374 (M+H).

Analysis for C17H9Cl2H3About3·0,N2About·0,SN3CO2H:

Calculated: C, 53,60; N, 2,61; N, 10,90;

Found: C, 53,49; N, 2,77; N, 10,82.

1H NMR: 8,53 (s, 1H, capable of being. for exchange), a 7.85 (d, J=1,94 Hz, 1H), 7,65 (d, J=1,94 Hz, 1H), 7,18 (t, J=7,84 Hz, 2H), PC 6.82 (d, J=7,84 Hz, 3H).

Example 23

7-Chloro-1-hydroxy-3-(1-naphthyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

6-Chloro-2-(1-naphthylamine)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion (1.30 grams, 3,34 mm) is stirred in methanol (0.65 l) and add methansulfonate (65 ml). The brown suspension is heated at the boiling point under reflux for 16 hours, during which time the solids dissolved, forming a brown solution. This solution is cooled to room temperature. To the providing of ice (10 ml) gives a reddish-brown suspension, which is stirred for 1.5 hours. The suspension was filtered (the filtrate saved for use in Example 24) and the collected solids washed with methanol and diethyl ether, getting named the title compound (0,560 g, 43%) as laboratore powder. TPL 374-376°C; MS (CI): 390 (M+H).

Analysis for C21H12ClN3O3·0,2N2About:

Calculated: C, 64,10; N, 3,18; N is 10.68;

Found: C, 63,91; N, Of 3.42; N, 10,61.

1H NMR: 13,40 (s, 1H, capable of being. for exchange), to 12.58 (s, 1H, capable of being. for exchange), 8,35 (d, J=to 8.70 Hz, 1H), 8,25 (d, J=1,76 Hz, 1H), 8,12-8,07 (m, 2H), 7,74-7,53 (m, 6H).

The original 6-chloro-2-(1-naphthylamine)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive as described below:

A. 6-Chloro-2-(1-naphthylamine)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl-7-chloro-4-hydroxy-quinoline-2,3-in primary forms (2.00 g, 6.80 mm) and 1-naphthyl hydrazine hydrochloride (9,26 g, 47,6 mm) in ethanol (72 ml), add triethylamine (7,60 ml)to give a brown solution. After heating at the boiling point under reflux for 4 days, the solution is cooled to room temperature and diluted with ethyl acetate (0.30 liter)to give a tan suspension. This suspension is filtered, removing solid products that can cast. Then the filtrate was poured into ethyl acetate (500 ml), washed with hydrochloric acid (3×500 ml, 1 n). P the washed solution was diluted with diethyl ether (250 ml), getting a tan suspension. The solid products collected, receiving 1-naphthyl hydrazine powered salt mentioned in the title compound as a tan powder (2,09 g). This product is heated at boiling temperature under reflux in glacial acetic acid (50 ml) for 2 hours, cooled to room temperature and filtered. The collected solids washed with glacial acetic acid and diethyl ether, getting named the title compound (1.44 g, 54%) as a reddish brown powder. TPL 368°C (decomposition); MS (CI): 390 (M+H).

Analysis for C21H12ClN3O3·0,SN3CO2H:

Calculated: C, 63,60; N, 3,26 N, 10,30;

Found: C, 63,90; N, 3,43; N, Becomes 9.97.

1H NMR: 9,06 (s, 1H, capable of being. for exchange), 8,27 is 8.22 (m, 2H), 7,92-7,88 (m, 2H), 7,63-7,52 (m, 3H), 7,41 (d, J=8,17 Hz, 1H), 7,27 (t, J=7,86 Hz, 1H), 6,80 (d, J=7,86 Hz, 1H).

Example 24

7-Chloro-4-hydroxy-2-(1-naphthyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 23, diluted with water (0.75 l) and then partially concentrated on a rotary evaporator, getting a brown suspension. Solids in the slurry is collected and washed with water, methanol/diethyl ether and diethyl ether, obtaining a brown powder (0,535 g). This product is heated at boiling temperature under reflux in methanol (23 ml) and filtered hot m to remove nerastvorim solid products, that drop. The filtrate is concentrated to dryness and diluted with ethyl acetate (20 ml). The resulting suspension is filtered and the collected solids washed with ethyl acetate and diethyl ether, getting named the title compound (0,240 g, 18%) as a gray powder. TPL 335-337°C; MS (CI): 390 (M+H).

Analysis for C21H12ClN3O3·0,N2About·0,SN3SO3N·0,-20 ° C4H10About·0,15C4H8O2:

Calculated: C, 58,60; N, 3,88 N 9,00;

Found: C, 58,37; N, Of 3.53; N, 9,14.

1H NMR: 12,80 (br s, 1H, capable of being. to share), compared to 12.1 (br s, 1H, capable of being. for exchange), 8,15-8,03 (br m, 4H), to 7.67-7,50 (br m, 6H).

Example 25

7-Chloro-3-(4-forfinal)-1-hydroxy-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Stir a suspension of 6-chloro-2-(4-ftoranila)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.40 g, 3,90 mm) in a solution of methanol (0,73 l) and methanesulfonate (73 ml) is heated at boiling temperature under reflux for 16 hours and cooled to room temperature. The obtained orange suspension was filtered (the filtrate saved for use in Example 26) and the collected solids washed with methanol and diethyl ether, getting named the title compound (0,374 g, 27%) as a pale orange powder. TPL >400°C; MS (CI): 358 (M+H).

Analysis for C17H9ClN3About3·N2 About:

Calculated: C, 54,30; N, 2,95; N, 11,20;

Found: C, 54,08; N, 2,62; N, 10,98.

1H NMR: 13,38 (s, 1H, capable of being. for exchange), 12,51 (s, 1H, capable of being. for exchange), 8,30 (d, J=8,75 Hz, 1H), they were 8.22 (d, J=1,78 Hz, 1H), 7,76-7,71 (m, 2H), 7,63 (dd, J=1,78, is 8.75 Hz, 1H), 7,40-7,35 (m, 2H).

The original 6-chloro-2-(4-ftoranila)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive as described below:

A. 6-Chloro-2-(4-ftoranila)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl-7-chloro-4-hydroxy-quinoline-2,3-in primary forms (2,59 g, 8,79 mm) and 4-forfinal hydrazine hydrochloride (10,00 g, 61,5 mm) in ethanol (48 ml), add triethylamine (9.8 ml, 70,3 mm). The obtained brown solution is heated at the boiling point under reflux for 48 hours, cooled to room temperature and diluted with ethyl acetate (150 ml)to give a white crystalline precipitate, which is removed by filtration and discarded. The filtrate is washed with hydrochloric acid (3×500 ml, 1 BC), which causes sedimentation in an ethyl acetate layer. The precipitate is collected and washed successively ethyl acetate/diethyl ether and diethyl ether, receiving 4-forfinal hydrazine powered salt named the title compound (2.14 g). This product is heated at boiling temperature under reflux in glacial acetic acid (20 ml) for 2 hours. After cooling, the acetic acid solution to room temperature, formed the I residue and the solid products collected, getting named the title compound (1.48 g, 47%) as a yellow powder. TPL 390-392°C; MS (CI): 358 (M+H).

Analysis for C17H9ClFN3O3·0,N2O:

Calculated: C, 55,95; N, 2,71 N, 11,51;

Found: C, 56,01; N, To 2.67; N, 11,54.

1H NMR: 13,78 (br s, 1H, capable of being. for exchange), charged 8.52 (s, 1H, capable of being. to the exchange), by 8.22 (d, J=8,71 Hz, 1H), 7,89 (d, J=a 2.01 Hz, 1H), 7,58(dd, J=2,01, 8,71 Hz, 1H), 7,05-6,98 (m, 2H), 6.89 in-6,85 (m, 2H).

Example 26

7-Chloro-2-(4-forfinal)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 25, diluted with water (0.800 to l), receiving light green suspension, which is stirred for 3 hours. The suspension is filtered and the collected solids washed with water, methanol/diethyl ether and diethyl ether, getting named the title compound (0.910 g, 65%) as a gray powder. TPL 353-356°C; MS (CI): 358 (M+H).

Analysis for C17H9ClFN3About3·2,00H2O·0,SN3SO3H:

Calculated: C, 51,30; N, To 3.34; N, 10,52;

Found: C, 51,58; N, 3,00; N, 10,47.

1H NMR: 11,95 (br s, 1H, capable of being. for exchange), 12,50 (br s, 1H, capable of being. for exchange), 8,15 (br d, J=compared to 8.26 Hz, 1H), 8,07 (br s, 1H), 7,58 (br s, 2H), 7,43 (br d, J=compared to 8.26 Hz, 1H), 7,29-7,24 (br m, 2H).

Example 27

3-(4-Bromophenyl)-7-chloro-1-hydroxy-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Stir a suspension of 2-(4-bromaniline)-6-chloro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1,00 g, 2.39 mm) vrestore methanol (500 ml) and methanesulfonate (50 ml) heated at boiling temperature under reflux for 16 hours and cooled to room temperature. The obtained yellow suspension was filtered (the filtrate saved for use in Example 28). The collected solids washed with methanol and then diethyl ether, getting named the title compound (0,222 g, 22%) as a yellow powder. TPL >400°C; MS (CI): 420 (M+H).

Analysis for C17H9BrClN3About3·0,N2O:

Calculated: C, 48,15; N, 2,28; N, to 9.91;

Found: C, 48,15; N, A 2.36; N, 9,88.

1H NMR: made 13.36 (s, 1H, capable of being. for exchange), 12,51 (s, 1H, capable of being. for exchange), to 8.25 (d, J=8,73 Hz, 1H), 8,19 (d, J=1,55 Hz, 1H), 7,75-to 7.67 (m, 4H), 7,60 (dd, J=1,55, 8,73 Hz, 1H).

The original 2-(4-bromaniline)-6-chloro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 2-(4-Bromaniline)-6-chloro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-in primary forms (1.90 g, 6,40 mm) and 4-bromophenyl hydrazine hydrochloride (10,00 g, 44.7 mm) in ethanol (35 ml), add triethylamine (7,1 ml, 51,1 mm). The obtained brown solution is heated at the boiling point under reflux for 22 hours, during this time formed a reddish-brown precipitate. This mixture is cooled to room temperature and filtered, obtaining 4-bromophenyl hydrazine powered salt mentioned in the title compound as a white powder (1,69 g). This product is heated at boiling temperature under reflux in glacial UKS the red acid (20 ml) for 3 hours and cooled to room temperature. The obtained reddish-brown suspension is filtered and the solids washed with glacial acetic acid and then dieti-ash ether, getting named the title compound (1,15 g, 43%) as a reddish brown powder. TPL 393-394°C; MS (CI): 420 (M+H).

Analysis for C17H9BrClN3About3·0,N2About:

Calculated: C, 48,77; N, 2,17; N, 10,04;

Found: C, 48,52; N, Of 2.26; N, 10,00.

1H NMR: at 13.84 (br s, 1H, capable of being. for exchange), 8,71 (s, 1H, capable of being. for exchange), 8,23 (d, J=8,63 Hz, 1H), 7,89 (d, J=1,98 Hz, 1H), 7,58 (dd, J=1,98, 8,63 Hz, 1H), 7,32 (d, J=to 8.70 Hz, 2H), at 6.84 (d, J=to 8.70 Hz, 2H).

Example 28

2-(4-Bromophenyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 27, diluted with water (550 ml)to give a reddish-brown suspension, which is stirred for 2 hours. The suspension is filtered and washed successively with water, methanol/diethyl ether and diethyl ether, getting named the title compound (0,716 g, 72%) as a reddish brown powder. TPL 359-361°C; MS (CI): 420 (M+H).

Analysis for C17H9BrClN3About3·1,N2About:

Calculated: C, 46,20; N, 2,64; N, 9,51;

Found: C, 46,26; N, To 2.66; N, 9,37.

1H NMR: 12,60 (br s, 1H, capable of being. for exchange), 11,95 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8,61 Hz, 1H), of 8.06 (d, J=1,67 Hz, 1H), to 7.64 (d, J=8,78 Hz, 2H), 7,55 (d, J=8,78 Hz, 2H), 7,43 (d, J=8,61 Hz, 1H).

Example 29

7-Chloro-1-hydroxy-3-(2-methoxyphenyl-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Stir a suspension of 6-chloro-2-(2-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.78 g, 4,81 mm) in a solution of methanol (285 ml) and methanesulfonate (89 ml) is heated at boiling temperature under reflux for 8 hours, during this time formed a reddish-brown precipitate. The resulting suspension is cooled to room temperature and stirred for 16 hours. The suspension was filtered (the filtrate saved for use in Example 30), the collected solids washed with methanol and diethyl ether, getting named the title compound (0.889 g, 50%) as a yellow powder. TPL 356-359°C; MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4·1,SN3HE:

Calculated: C, 56,50; N, 4,15; N, 10.30 a.m.;

Found: C, 56,50; N, 4,15; N, 10,55.

1H NMR: 13,34 (s, 1H, capable of being. for exchange), 12,45 (s, 1H, capable of being. for exchange), 8,30 (d, J=8,61 Hz, 1H), 8,21 (s, 1H), 7,63 (d, J=8,61 Hz, 1H), of 7.48 (t, J=8,10 Hz, 1H), 7,40 (d, J=7,46 Hz, 1H), 7.23 percent (d, J=8,10 Hz, 1H), 7,10 (t, J=7,46 Hz, 1H), of 3.77 (s, 3H).

The original 6-chloro-2-(2-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion prepared in the following way:

A. 6-Chloro-2-(2-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl-7-chloro-4-hydroxy-quinoline-2,3-in primary forms (0,218 g, 0,74 mm) and 2-methoxyphenyl hydrazine hydrochloride (to 0.900 g, 5,20 mm) in ethanol (4 ml), add triethylamine (0,83 ml, 51,9 mm). The floor is obtained brown solution is heated at the boiling point under reflux for 22 hours. The solution is cooled to room temperature and the deposition of the formed suspension reddish-brown color, which is stirred for 16 hours. The suspension is filtered and the collected solid product drop. The filtrate is diluted with ethyl acetate (50 ml) and washed with hydrochloric acid (3×50 ml, 1 BC) and salt solution (50 ml). The concentration of the washed solution in a current of nitrogen gas gives a reddish-brown powder (0,527 g). This product is heated at boiling temperature under reflux in glacial acetic acid (5 ml) for 2 hours, getting a thick reddish-brown suspension. This suspension is cooled to room temperature and stirred for 16 hours. The suspension is filtered and the collected solids washed with glacial acetic acid and then diethyl ether, obtaining reddish-brown powder (0,378 g). This product is stirred in a solution of water (5 ml) and methanol (1 ml)to give a reddish-brown suspension, which is stirred for 16 hours. The suspension is filtered and the collected solids washed successively with water, methanol and then diethyl ether, getting named the title compound (0.126 g, 46%) as a reddish brown powder. TPL 390°C (decomp.); MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4·0,20N2O:

Calculated: C, 57,90; N, At 3.35; N, 11,25;

Found Is:, 57,92; N, 3,48; N, OF 10.93.

1H NMR: 13,80 (br s, 1H, capable of being. for exchange), 8,23 (d, J=8,67 Hz, 1H), 7,89 (d, J=1,98 Hz, 1H), 7,79 (s, 1H, capable of being. for exchange), 7,58 (dd, J=1,98, 8,67 Hz, 1H), 6,97 (d, J=a 7.62 Hz, 1H), 6,80-of 6.73 (m, 3H), 3,86 (s, 3H).

Example 30

7-Chloro-4-hydroxy-2-(2-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 30, diluted with water (600 ml)to give a reddish-brown suspension, which was stirred at 0°C for 1 hour, filtered, removing solid products. The filtrate is partially concentrated in a stream of nitrogen gas, getting a white suspension. This suspension is filtered and the combined solids washed with water, getting named the title compound (0,347 g, 19%) as a white powder. TPL 347-349°C; MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4·1,N2O·0,SN3SO3H:

Calculated: C, 54,00; N, Of 3.75; N, 10,43;

Found: C, 54,07; N, To 3.33; N, 10,41.

1H NMR: 12,68 (br s, 1H, capable of being. for exchange), 12,00 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8,61 Hz, 1H), 8,07 (s, 1H), of 7.48-7,40 (m, 2H), 7,32 (d, J=to 7.59 Hz, 1H), 7,16 (d, J=8,31, Hz, 1H), 7,05 (t, J=to 7.59 Hz, 1H, in), 3.75 (s, 3H).

Example 31

7-Chloro-4-hydroxy-2-(2-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

A solution of 7-chloro-4-hydroxy-2-(2-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (in 0.288 g, 0,78 mm) in methansulfonate (5 ml) is heated at 140°With 7 hours and cooled to the room temperature. The brown solution was diluted with water (5 ml), causing an exothermic heating to 80°and precipitation with the formation of the brown suspension. This suspension is then diluted with water (10 ml) and filtered. The collected solids washed with water (25 ml) and diethyl ether, giving a brown solid product (0,23 g). This product is suspended in water (13 ml) and add a solution of choline hydroxide (45 wt.% in methanol, 0.5 ml)to give a brown solution. This solution is heated to 50°C for 2 hours and cooled to room temperature. Add hydrochloric acid (5 ml, 1 N.), receiving a gray suspension. This suspension is filtered and the collected solids washed with water and then diethyl ether, getting named the title compound (0,225 g, 81%) as a gray powder. TPL >400°C; MS (CI): 356 (M+H).

Analysis for C17H10ClN3O4·0,80H2O·0,10S4H10About:

Calculated: C, 55,35; N, 3,36 N, 11,13;

Found: C, 55,53; N, 3,00; N, 10,89.

1H NMR: 12,68 (s, 1H, capable of being. for exchange), 12,01 (s, 1H, capable of being. for exchange), at 9.53 (s, 1H, capable of being. for exchange), 8,16 (d, J=8,18 Hz, 1H), of 8.06 (s, 1H), 7,46 (d, J=8,18, Hz, 1H), 7.23 percent (m, 2H), 6,95 (d, J=7,80 Hz, 1H), 6.87 in (t, J=7,17 Hz, 1H).

Example 32

7-Chloro-4-hydroxy-3-(3-methoxyphenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione

Stir a suspension of 6-chloro-2-(3-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]hinali the -1,3,9-trione (1.85 g, 5.00 mm) in a solution of methanol (0,93 l) and methanesulfonate (93 ml) was heated at boiling temperature under reflux for 16 hours, getting a tan suspension. This suspension is cooled to room temperature and stirred for 24 hours. The suspension was filtered (the filtrate saved for use in Example 33), the collected solids washed with methanol and then diethyl ether, giving named the title compound (0,385 g, 21%) as a reddish brown powder. TPL 393-395°C; MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4·0,50N2O·0,SN3HE:

Calculated: C, 57,00; N, 3,50; N, 11,05;

Found: C, 56,73; N, 3,11; N, 10,98.

1H NMR: 13,35 (s, 1H, capable of being. for exchange), 12,47 (s, 1H, capable of being. for exchange), of 8.28 (d, J=8,75 Hz, 1H), to 8.20 (d, J=1,83 Hz, 1H), 7,60 (dd, J=1,83, is 8.75 Hz, 1H), 7,47-7,42 (t, J=of 8.06 Hz, 1H), 7,28-7,26 (m, 2H), 7,01 (dd, J=1,38, of 8.06 Hz, 1H), 3,81 (s, 3H).

The original 6-chloro-2-(3-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion receive the following way:

A. 6-Chloro-2-(3-methoxyaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-Trion.

To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-in primary forms (4.61 in g, 15,6 mm) and 3-methoxyphenyl hydrazine hydrochloride (19,10 g, 109 mm) in ethanol (84 ml) was added triethylamine (of 17.4 ml, 125 mm). The obtained brown solution is heated at the boiling point under reflux for 40 h, the owls and cooled to room temperature. Add ethyl acetate (430 ml) to obtain a reddish-brown suspension. This suspension was filtered to remove solids that drop. The filtrate is washed with hydrochloric acid (3×750 ml, 1N.), what causes the precipitation of an ethyl acetate layer. This an ethyl acetate solution is filtered, getting a tan solid product (0,940 g). The filtrate is stored. United chloride-hydrogen washing water re-extracted with ethyl acetate and the extracts combined with left earlier with an ethyl acetate filtrate. This solution concentrate, getting a solid product, which was triturated with diethyl ether/ethyl acetate, getting a tan suspension. This suspension is filtered, which gives the second portion is reddish-brown solid (1.60 g). The filtrate is concentrated until a solid product with diethyl ether/ethyl acetate, obtaining a suspension. This suspension is filtered, receiving the third collection of reddish-brown solid product (0,70 g). Solid products are stored after the above filtering unite (3,24 g) and heated at boiling temperature under reflux in glacial acetic acid (32 ml) for 3 hours. The resulting suspension is cooled to room temperature and stirred for 16 hours. This suspension is filtered and the collected solids washed with ice at ssnoi acid and then diethyl ether, getting named the title compound (1,93 g, 33%) as a reddish brown powder. TPL 369°C (decomp.); MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4·0,50H2O:

Calculated: C, 57,10; N, Of 3.46; N, 11,10;

Found: C, 57,21; N, Of 3.53; N, 10,86.

1H NMR: of 13.75 (br s, 1H, capable of being. for exchange), 8,51 (br s, 1H, capable of being. for exchange), 8,23 (d, J=8,69 Hz, 1H), 7,89 (d, J=1,87 Hz, 1H), 5,58 (dd, J=1,87, 8,69 Hz, 1H), was 7.08 (t, J=of 7.96 Hz, 1H), 6.42 per-6,39 (m, 3H), of 3.69 (s, 3H).

Example 33

7-Chloro-4-hydroxy-2-(3-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate, unused and stored from Example 32, diluted with water/ice (1.0 l)to give a brown suspension, which is stirred for 16 hours. The suspension is filtered and the collected solids washed with water and then diethyl ether, getting named the title compound (1.04 g, 56%) as a reddish brown powder. TPL 312-315°C; MS (CI): 370 (M+H).

Analysis for C18H12ClN3O4·0,20N2About·0,SN3SO3H:

Calculated: C, 56,80; N, 3,37; N, 10,97;

Found: C, 56,90; N, 3,55; N, Of 10.93.

1H NMR: 8,17 (d, J=8,64 Hz, 1H), of 8.06 (d, J=l,71 Hz, 1H), 7,43 (dd, J=1,71, 8,64 Hz, 1H), was 7.36 (t, J=8,49 Hz, 1H), 7,15 for 7.12 (m, 2H), 6,93 (d, J=8,49 Hz, 1H), 3,79 (s, 3H).

Example 34

7-Chloro-4-hydroxy-2-(3-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

A solution of 7-chloro-4-hydroxy-2-(3-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]x the nolin-1,10-dione (0,600 g, 1,62 mm) in methansulfonate (12 ml) is heated at 130-140°3.5 hours and cooled to room temperature. The brown solution was diluted with water (36 ml), causing an exothermic heat and sedimentation, forming a brown suspension. This suspension is filtered and the resulting solids washed with water (50 ml) and diethyl ether, obtaining a brown solid product (0,447 g). This product is suspended in water (26 ml) and add a solution of choline hydroxide (45 wt.% in methanol, 1.5 ml)to give a brown solution. This solution is heated to 50°With 3 hours and cooled to room temperature. Add hydrochloric acid (10 ml, 1N.) and get a brown suspension, which was filtered. The collected solids washed with water and then diethyl ether, obtaining a brown powder (0,302 g). This brown powder is suspended in methanol and the resulting suspension is concentrated to the remaining brown solid product. The solid product is suspended in methanol and concentrate two more times, getting named the title compound (0,260 g, 45%) as a brown powder. TPL 333°C (decomp.); MS (CI): 356 (M+H).

Analysis for C17H10ClN3O4·1,0H2O·1,40HCl:

Calculated: C, 48,1; N, 3,18; N, 9,89;

Found: C, 48,5; N, And 3.16; N, 9,45.

1H NMR: a 9.6 (br s, 1H, capable of being. for exchange) of 8.15 (br s, 1H), of 8.06 (br s, 1H), 7,46 (br s, 1H), 7.23 percent (br s, 1H), 6,95 (br s, 1H), 6.75 in (br s, 1H).

Example 35

7-Chloro-4-hydroxy-2-(4-trifloromethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid N-2-(4-trifloromethyl)hydrazide (600 mg, 1.3 mm) in methanol (85 ml) at ambient temperature add methansulfonate (3 ml). The reaction mixture is heated at the boiling point under reflux for 68 hours, during this time formed a small amount of sediment. The solid product removed by filtration. Add water (150 ml) to the filtrate, receiving light suspension, which is separated by vacuum filtration and dried over pjatiokisi phosphorus, getting named the title compound (467 mg, 84%) as a solid peach color. TPL 320-322°C; MS (CI): 424 (M+H).

Analysis for C18H9N3About4F3Cl·0,8H2O:

Calculated: C, 49,34; N, 2,44; N, 9,59;

Found: C, 49,01; N, 2,10; N, Of 9.55.

1H NMR: 12,07 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8,64 Hz, 1H), of 8.06 (s, 1H), 7,71 (d, 2H, J=8,82 Hz), 7,45 is 7.50 (m, 3H).

The original 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid N-2-(4-trifloromethyl)hydrazide receive the following way:

A. 3 Carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid

To a stirred suspension of dimethyl-7-chloro-4-hydroxyI the Olin-2,3-in primary forms (1.0 g, 3,38 mm) in water (20 ml) is added an aqueous solution of hydroarsenate (0,27 ml of 6.75 mm). In the process of adding the suspension dissolved. The reaction mixture is heated at 60°With 1 hour. At the end of this time the reaction mixture is cooled to room temperature, and acidified with concentrated hydrochloric acid. The product is then extracted with diethyl ether and diethylacetal. The organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo, getting named the title compound in the form of a crude solid product (900 mg). This product cleaned by recrystallization using a mixed solvent system ethyl acetate/hexane, giving named the title compound (571 mg, 60%) as a white solid. TPL 296°C (decomp.); MS (CI)=238 (M+H).

Analysis for C12H8NO5Cl·0,SN3CO2CH2CH3·0,10H2About:

Calculated: C, 51,30, N, 3,68; N, 4,34;

Found: C, 51,28; N, 3,62; N, 3,97.

1H NMR: by 8.22 (d, J=8.7 Hz, 1H), 7,92 (d, J=1.8 Hz, 1H), 7,28 (dd, J=8,7, and 1.8 Hz, 1H), 3,90 (s, 3H).

b. 3 Carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid N-2-(4-trifloromethyl)hydrazide.

The free base 4-(triptoreline)of phenylhydrazine is obtained from the hydrochloric salt by processing the suspended salt (400 mg, about 1.75 mm) in ethyl acetate (50 ml), 2n. sodium hydroxide (50 ml). Organic is Loy separated, dried over magnesium sulfate and concentrated in vacuo, obtaining the free base 4-(triptoreline)of phenylhydrazine (325 mg, 1,69 mm). This product is placed in anhydrous tetrahydrofuran (5 ml) and cooled to 0°C in nitrogen atmosphere. At the same time, 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carbonyl chloride derived from 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid (121 mg, 0,43 mm) by heating at 60°in thionyl chloride (4 ml). After 3 hours, the crude acid chloride allocate distillation of the excess thionyl chloride. Crude 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carbonyl chloride (130 mg, 0,43 mm) placed then in anhydrous tetrahydrofuran (3 ml) at ambient temperature and added dropwise through a glass tube to a solution of 4-(triptoreline)phenyl hydrazine. After 30 minutes the reaction mixture was poured 1.0 N. hydrochloric acid to cause precipitation. The solid product exhale, getting named the title compound (185 mg, 95%) as not quite white solid. TPL 346-350°C; MS 456 (M+H).

1H NMR 12,67 (s, 1H, capable of being. for exchange), 10,79 (s, 1H, capable of being. for exchange), of 8.37 (br s, 1H, capable of being. for exchange), 8,13 (d, J=8,61 Hz, 1H), 7,83 (d, J=1,76 Hz, 1H), of 7.48 (dd, J=8,61, to 1.76 Hz, 1H), 7,21 (d, J=8,50 Hz, 2H), 6,94 (d, J=8,50 Hz, 2H), 3,70 (s, 3H).

Example 36

7-Chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione;

Stir a solution of 3-carb is methoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid N-2-(3-chloro-4-methoxyphenyl) hydrazide (2.25 g, 5,16 mm) in methanol (1.13 l) and methanesulfonate (113 ml) is heated at the boiling point under reflux for 1 hour, during this time, the formed brown precipitate. This suspension is cooled to room temperature, stirred for 16 hours and filtered (the filtrate saved for use in Example 37). The collected solids washed with methanol and then diethyl ether, getting named the title compound (0,153 g, 7%) as a yellow powder. TPL 395-396°C; MS (CI): 404 (M+H).

Analysis for C18H11Cl2N3O4·1,20N2About:

Calculated: C, 50,70; N, 3,17; N, 9,87;

Found: C, 50,33; N, 2,87; N, Being 9.61.

1H NMR: made 13.36 (s, 1H, capable of being. for exchange), 12,50 (s, 1H, capable of being. for exchange), of 8.28 (d, J=8,78 Hz, 1H), they were 8.22 (d, J=1,74 Hz, 1H), to 7.77 (d, J=2,42, Hz, 1H), to 7.67 (dd, J=2,42, 8,91 Hz, 1H), 7.62mm (dd, J=1,74, 8,78 Hz, 1H), 7,30 (d, J=8,91 Hz, 1H), 3,94 (s, 3H).

The original 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid N-2-(3-chloro-4-methoxyphenyl) hydrazide receive the following way:

A. 3-Chloro-4-methoxyphenylhydrazine

A solution of 3-chloro-p-anisidine hydrochloride (10 g, 52 mm) in hydrochloric acid (48 ml, 12 N.) cooled to -10°C. To the reaction mixture slowly add a solution of sodium nitrite (of 3.56 g, 52 mm) in water (19,5 ml)so that the temperature did not exceed -5°C. Then the reaction mixture is stirred 1 hour at 0°C. the resulting solution of diazonium salts added for the eat to the cooled (0° C, ice bath) solution of chloride dihydrate tin (44 g, 193 mm) in hydrochloric acid (29 ml, 12 N.) at such a rate that the temperature did not exceed 5°C. Forms a purple foam suspension, and after adding water (20 ml), the mixture is stirred for 3 hours at 0°C. Purple solid product filtered off, washed with ethyl acetate and then added an aqueous solution of sodium bicarbonate. The resulting mixture is dissolved in ethyl acetate and the whole mixture was filtered to separate the insoluble salts of tin. The collected salt tin washed with water and ethyl acetate. An ethyl acetate layer from the initial filtration and the ethyl acetate from the wash water for salts of tin combine, dried over magnesium sulfate and concentrated to obtain named in the title compounds (4,49 g, 51%) as a brown solid MS (CI): 172 (M-I).1H NMR 6,94-of 6.90 (m, 2H), of 6.71 (dd, J=2,70, of 9.00 Hz, 1H,), of 3.73 (s, 3H).

b. 3 carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid N-2-(3-chloro-4-methoxyphenyl)hydrazide.

To a solution of 3-chloro-4-methoxyphenyl hydrazine (4.26 deaths / g, 24,7 mm) in tetrahydrofuran (200 ml) add a solution of 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carbonyl chloride (3,54 g, 11.8 mm, as obtained in example 35b) in tetrahydrofuran (100 ml) at 0°C. the yellow suspension was stirred at 0°With 30 minutes and diluted with water (200 ml)to give a yellow solution. This solution rasb the keys then hydrochloric acid (600 ml, 1H.), getting the suspension reddish-brown color, which is stirred for 1 hour. The suspension was filtered (the filtrate retain) and the collected solids washed with water and then diethyl ether, getting named the title compound (2.30 g, 45%) as a powder reddish-brown, MS (CI): 436 (M+H)used in the previously described synthesis of 7-chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

1H NMR: 12,69 (s, 1H, capable of being. for exchange), of 10.72 (s, 1H, capable of being. to the exchange)to 8.14 (d, J=8,50 Hz, 1H), 8,00 (br s, 1H, capable of being. for exchange), 7,76 (s, 1H), of 7.48 (d, J=8,50 Hz, 1H), 7,05 (d, J=8,80 Hz, 1H), 6,98 (d, J=2,28, Hz, 1H), 6,85 (dd, J=2,28, 8,80 Hz, 1H), of 3.78 (s, 3H), 3,70 (s, 3H).

After incubation for five days there is a further sediment stored in the above-mentioned acid filtrate. The solid products collected, receiving substance (1,80 g)containing a mixture named the title compound (60%). 7-chloro-2-(3-chloro-4-methoxyphenyl)-1-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (35%) and 7-chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione(5%).

Example 37

7-Chloro-2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine [4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 36, concentrated to approximately 500 ml and diluted with water/ice (1.1 l), receiving light green suspension, which odorou stirred for 3 hours. The suspension is filtered and the collected solid products resuspended in water (500 ml) and stirred for 16 hours. This suspension was filtered and the collected solids washed subsequently with water, acetonitrile/diethyl ether and then diethyl ether, getting named the title compound (1.42 g, 68%) as a green powder. TPL 348-351°C; MS (CI): 404 (M+H).

Analysis for C18H11Cl2N3O4·1,20N2About·0,SN3SO3H:

Calculated: C, 46,89; N, Of 3.27; N, 8,87;

Found: C, 46,54; N, 2,96; N, 8,91.

1H NMR: 12,82 (br s, 1H, capable of being. for exchange), a 12.05 (br s, 1H, capable of being. for exchange), 8,16 (d, J=9,01 Hz, 1H), of 8.06 (d, J=1,56 Hz, 1H), to 7.64 (dd, J=2.37 Hz, 1H), 7,52 (dd, J=2,37, 8,89 Hz, 1H), 7,45 (dd, J=1,56, 9,01 Hz, 1H), 7.23 percent (d, J=8,89 Hz, 1H), 3,91 (s, 3H).

Example 38

7-Chloro-2-(2-methoxyphenyl-5-yl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a chilled (ice bath) stirred solution of 5-hydrazino-2-methoxypyridine (0,839 g, 6,03 mm) in anhydrous THF (40 ml) is added dropwise a solution of 3-carbomethoxy-7-chloro-4-hydroxy. the quinoline-2-carbonylchloride (1,67 g, 5,59 mm) in THF (40 ml). After stirring at 0°C for 3 hours the reaction mixture is allowed to cool to room temperature and stirred for a further 17 hours. The reaction mixture was diluted with water/ethyl acetate (30 ml/40 ml) and the pH of the mixture was adjusted to 4 by adding 2n. the sodium hydroxide. Poluchenno the mixture is filtered and the collected organic products then grind in warm methanol (10 ml) and filtered, highlighting named the title compound (0.17 g, 5,7%) as a brown solid product. TPL 235-237°C (decomp.); MS (CI): 371 (M+H).

Analysis for C17H11ClN4O4·1,N2O:

Calculated: C, 51,45; N, Of 3.53; N, 14,12;

Found: C, 51,26; N, 2,95; N, 14,18.

1H NMR: 12,88 (br s, 1H, capable of being. for exchange), 12,09 (br s, 1H, capable of being. for exchange), to 8.34 (d, J=2,24 Hz, 1H), 8,16 (d, J=7,65 Hz, 1H), with 8.05 (s, 1H), a 7.85 (dd, J=8,7, 2,24 Hz, 1H), 7,46 (d, J=7,6 Hz, 1H), 6,93 (d, J=8.7 Hz, 1H), 3,88 (s, 3H).

The original 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carbonylchloride and 5-hydrazine-2-methoxypyridine receive the following way

A. 3 Carbomethoxy-7-chloro-4-hydroxyquinolin-2-carbonyl chloride.

After heating under reflux a mixture of 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid (1.56 g, 5.6 mm) and thionyl chloride (5 ml, 68,5 mm) in methylene chloride (12 ml) for 2 hours, the resulting turbid solution was concentrated, leaving solid products, which are again treated with THF and concentrated, after which the remains untreated named the title compound (1,67 g, 100%) as a cream solid color.

b. 5-Hydrazine-2-methoxypyridine

To a stirred cooled solution (-10° (C) 5-amino-2-methoxypyridine (5,01 g, 40,4 MM) in concentrated hydrochloric acid (50 ml) is added dropwise a solution of sodium nitrite (2.9 g, 42 mm) in water (10 ml). After stirring at -10°during the course the e 10 min the reaction mixture was added in portions to a cooled (-20° C) mixed solution of chloride dihydrate divalent tin (22.9 grams, 101 mm) in concentrated hydrochloric acid (15 ml). Received a thick mixture was diluted with water (10 ml) and concentrated hydrochloric acid (15 ml) and continue stirring at -10°With an additional 1 hour. The mixture is then filtered and the collected solids washed with diethyl ether (three portions 40 ml) and dried in vacuo to obtain the crude hydrochloride salt (7,03 g, 125%) named in the title compound in a solid pink color. Part (of 3.97 g, 22 mm) this substance is suspended in ethyl acetate/diethyl ether (75 ml/25 ml) and add 2n. the sodium hydroxide to the resulting stirred suspension until reaching a pH of 6.5. After stirring for 15 min the organic phase is separated and the aqueous phase is extracted twice with 50 ml portions of ethyl acetate/diethyl ether (1:1). The combined organic phases, dried (MgSO4), filtered and concentrated to obtain named in the title compounds (0,839 g, 27%) as a crude solid product, which is used without further purification.

Example 39

7-Chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-methoxy-2-were)hydrazide (3.0 mg, 7.2 mm) and t is erdich product (0.6 g, 1.6 mm of a mixture of 7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione and 6-chloro-2-(4-methoxy-2-methylaniline)-2,3,4,9-tetrahydro-1H-pyrrole[3,4-b]quinoline-1,3,9-trione collected from the concentrated filtrate described in Example 1A)below, in methanol (500 ml) add methansulfonate acid (50 ml) and the resulting stir the suspension is heated at boiling temperature under reflux for 7 hours. The resulting solution was stirred at room temperature overnight and then diluted with 600 ml of ice/water, getting a tan suspension. After stirring for 2 hours, the suspension is filtered, obtaining solid product (2.8 g, 100%). Recrystallization of this substance from boiling methanol (500 ml) gives named the title compound as a white powder (1.7 g, 61%). TPL 354-356°C.

Analysis for C19H14ClN3O4·1,5H2O·0,2CH3HE·0,2(C2H5)2O:

Calculated: C, 55,60; N, To 4.62; N, 9,73;

Found: C, 55,25; N, Of 4.35; N, 9,60.

1H NMR (DMSO-d6): 12,74 (br s, 1H, capable of being. for exchange), 12,00 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8,8 Hz, 1H), of 8.06 (s, 1H), 7,46 (d, J=8,8 Hz, 1H), 7,21 (d, J=8.6 Hz, 1H), 6,91 (s, 1H), 6,85 (d, J=8.6 Hz, 1H), 3,79 (s, 3H), of 2.08 (s, 3H).

The original 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid N-2-(4-methoxy-2-were)-hydrazide get after the existing method:

A. 7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-methoxy-2-were)hydrazide.

4-Methoxy-2-methylphenylhydrazine hydrochloride (4.7 g, 25 mm) partitioned between diethyl ether (300 ml) and 2n sodium hydroxide (50 ml). The ether layer is separated and the aqueous layer was extracted with additional diethyl ether (300 ml). The combined ethereal extract is dried (MgSO4), filtered and concentrated to a residual free hydrazine in the form of a yellow powder. This hydrazine dissolved in anhydrous tetrahydrofuran (180 ml). After cooling, the obtained transparent solution to 0°With a solution of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonylchloride (3.0 g, 10.0 mm) in THF (90 ml) is added dropwise over 15 minutes. Upon completion of the addition, the obtained yellow suspension was stirred at 0°C for 30 minutes and then 2 hours at room temperature. The reaction is interrupted, adding ˜200 g of water/ice and then 500 ml of chilled hydrochloric acid. The obtained yellow suspension is stirred for 1 hour and the yellow solids are collected by filtration, washed with water, then diethyl ether and dried in air to obtain named the title compound as a white solid powder (3.3 g, 79%). The filtrate is partially concentrated to remove the main part of THF, and the resulting suspension is filtered, which shows the additional ˜ 0.6 g solids containing (VGH analysis) 35% 7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione and 65% 6-chloro-2-(4-methoxy-2-methylaniline)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonylchloride used in Example 39A receive the following way:

b. 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride.

To a stirred suspension of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (obtained from complex ether) (35,0 g, 0,124 M) free from alcohol chloroform (850 ml) under nitrogen atmosphere add one portion of thionyl chloride (60,3 g, 37 ml, 0,507 M). The resulting mixture is heated at boiling temperature under reflux until conversion in solution (1,5 hours). After cooling to room temperature the solution is concentrated using a rotary evaporator (bath temperature = 25° (C)to obtain a reddish brown solid. This product is dried in vacuum at room temperature for two days, which gives named in the title acid chloride (34,7 g, 93,2%) as a reddish brown solid.

2-Methyl-4-methoxyphenylhydrazine hydrochloride used in Example 39A receive the following way:

C. 2-Methyl-4-methoxyphenylhydrazine hydrochloride.

The solution n is a waste of the sodium (the ceiling of 5.60 g, 81,2 mm) in water (56 ml) is added during 20 minutes to a mechanically stirred suspension of 2-methyl-4-methoxyaniline (10,42 ml, 81.0 mm) in a mixture of 12 N. HCl (60 ml) and water (64 ml), maintained at -5°C. the Dark solution is cooled to -15°With 15 minutes and added dropwise within 30 minutes a solution of SnCl2·2H2O (53,3 g, 236,2 mm) 12 N. HCl (36 ml), keeping the temperature between -15 and -10°C. Rose the suspension is stirred for 30 minutes at -15°and added dropwise ethanol (25 ml). The suspension is stirred at -15°With 3 hours and filtered in N2(gas). Filtering is performed at -10° (funnel with double walls) and takes 2 hours. The Packed sediment being sucked to dryness and washed with 50% ethanol/diethyl ether (200 ml) and diethyl ether (500 ml). The solid product is dried in a current of N2(gas) 20 hours, getting hydrochloric salt mentioned in the title compounds (at 8.60 g, 56%) as a gray powder. TPL=107°C (decomp.); MS (CI): 152 (M+H).

Analysis for C8H12N2O·HCl·H2O:

Calculated: C, 46,49; N, To 7.32; N, 13,55;

Found: C, 46,46; N, 6,92; N, 13,00.

300 MHz1H NMR (DMSO-d6): of 10.01 (s, 3H, capable of being. for exchange), of 7.48 (br s, 1H, capable of being. to exchange)6,94 (d, J=8,8 Hz, 1H), 6,77-6,74 (m, 2H), 3,70 (s, 3H), 2,19 (s, 3H).

Example 39(2)

Alternative synthesis of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-methoxy-2-were)hydrazide below.

4-Methoxy-2-methylphenylhydrazine hydrochloride (11,38 g, 60,32 mm) are suspended in dry tetrahydrofuran (264 ml) in an argon atmosphere and treated with 2,6-lutidine (14,06 ml 120,6 mm). This reaction mixture is cooled in an ice bath and add a solution of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride (18,14 g, 60,32 mm) in THF (328 ml) at a rate that permits to maintain the temperature of the reaction mixture at 2-5°C. After complete addition, the reaction mixture is stirred for 25 minutes at 0-2°and then added under stirring to a cooled ice 1,0N. HCl (1300 ml). Stirring is continued for several hours until the mixture will turn freely in the current suspension. Solid products are separated by filtration, washed with water and dried in the air, getting named the title compound (17,57 g, 70%) as a tan solid product, which cyclist to the named in the title compound (39), using standard conditions.

Note: 2,6-di-tert-butylpyridinium can be used instead of 2,6-lutidine(2,6-dimethylpyridine) in the above method.

Example 40

N-Methyl-glucagonoma salt of 7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0.45 g, 1,17 mm) is stirred in methanol (2 ml) and add N-methyl-D-glucamine (0,23 g, 1,17 mm) to obtain a clear yellow solution. This solution is concentrated and the residue is dissolved in water (20 ml)to give a yellow solution. This solution is filtered through Gelman 0,45 um Acrodisc and concentrate, receiving a yellow residue. The residue is dissolved with 2-propanol (20 ml)to give a yellow suspension. Solids collected and washed with 2-propanol, getting named the title compound (0.20 g, 29%) as a yellow powder. TPL 177°C (decomp.).

Analysis for C19H14ClN3O4·C7H18NO5·1,5H2O:

Calculated: C, 51,53; N, The 5.65; N, 9,24;

Found: C, 51,17; N, 5,28; N, 8,88.

300 MHz1H NMR (DMSO-d6): to 8.14 (s, 1H), 8,10 (d, J=8.6 Hz, 1H), 7,33 (d, J=8.6 Hz, 1H), 7,06 (d, J=8.0 Hz, 1H), 6,76 (br, m, 2H), 3,84 (m, 1H), 3,76 (s, 3H), 3,65 of 3.56 (m, 2H), 3,48-to 3.38 (m, 3H), 2.95 and-2,87 (m, 2H), of 2.51 is 2.46 (m, 3H), 2,02 (3, 3H).

Example 41

7-Chloro-3-(4-chloro-2-were)-4-hydroxy-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-chloro-2-were)hydrazide (2.00 g, 4.76 mm) suspended in methanol (1.0 l) and add quick drops with good stirring methansulfonate (100 ml). The obtained yellow suspension is heated under reflux for four days, getting an orange solution. Methanol (500 ml) is distilled off and the concentrated solution is cooled to room temperature, receiving a yellow suspension. This WM is enzio filtered (the filtrate saved for use in Example 42). The collected solids washed with methanol and diethyl ether, getting named the title compound (0,72 g, 39%) as a yellow powder. TPL 336-339°C; MS (CI): 388 (M+H).

Analysis for C18H11Cl2N3About3·1,15H2O:

Calculated: C, 52,87; N, Of 3.27; N, 10,28;

Found: C, 52,51; N, 2,87; N, 10,12.

300 MHz1H NMR (DMSO-d6): 13,40 (s, 1H, capable of being. for exchange), 12,55 (s, 1H, capable of being. for exchange), 8,30 (d, J=8,8 Hz, 1H), to 8.20 (s, 1H), 7.62mm (d, J=8,8 Hz, 1H), 7,53 (s, 1H), 7,43 (s, 2H), 2,16 (s, 3H).

Example 42

7-Chloro-2-(4-chloro-2-were)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

The filtrate saved from Example 41, diluted with water (1.0 l) and the resulting suspension is stirred for 2 hours. Solids are collected, washed with water and then diethyl ether, getting named the title compound (0.54 g, 29%) as not quite white powder. TPL 355-357°C; MS (CI): 388 (M+H).

Analysis for C18H11Cl2N3About3·1,20N2About:

Calculated: C, 55,18; N, At 2.93; N, of 10.72;

Found: C, 55,00; N, 2,62; N, 10,66.

300 MHz1H NMR (DMSO-d6): 12,84 (br s, 1H, capable of being. for exchange), 12,07 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8.6 Hz, 1H), 8,07 (s, 1H), 7,47-7,33 (m, 4H), 2,12 (s, 3H).

Example 42A

Alternative named in the title compound was prepared as described in General form in figure 6, and in conditions similar to those described in Example 82, where PE is elsepayday suspension 2-pyrrolidinecarbonyl-7-chloro-4-hydroxy chinoline 3-carboxylic acid in THF added DCC. Immediately the above-described suspension added THF solution of N-tert-butoxy carbonyl-N'-4-chloro-2-were of hydrazine. The reaction mixture was stirred at room temperature for 4 hours. Upon completion of the combination (after checking the appropriate chromatographic method, for example, TLC or VGH) urea, which is a by-product, is removed by vacuum filtration. Partial purification using flash chromatography and using 5% methanol/CH2Cl2gives the specified hydrazide. The hydrazide suspended in THF add methansulfonate. The reaction mixture was stirred at room temperature for 24 hours and then poured into ice water. The precipitate is separated, dried and grind/handle ultrasound with methanol and exhale, getting named the title compound.

The original 2-pyrrolidinecarbonyl-7-chloro-4-hydroxyquinolin-3-carboxylic acid and related source products are obtained according to the methods described in Example a and b (below).

The source of N-tert-butoxycarbonyl-N'-4-chloro-2-hydrazine were getting the following way:

To a suspension of 4-chloro-2-methylphenylhydrazine (992 mg, 6,33 MM) and potassium carbonate (1.44 g, 10...4 MM) in a saturated aqueous solution add a solution of di-tert-butyl bicarbonate (1.52 g, of 6.96 MM) in THF (24 ml). After 2.5 hours the mixture was partitioned between diethyl ether and water layer. Organic the ski extracts are combined and washed with water and salt solution, dried (MgSO4), filtered and concentrated in vacuo. The crude product clean flash column chromatography with 25% diethyl ether-hexane as eluent, getting named the title compound (1.56 g, 96%) as a reddish brown solid, MS (CI): 256 (M).

300 MHz1H NMR (DMSO-d6): 8,81 (br s, 1H), 7,17 (br s, 1H), 7,00-was 7.08 (m, 2H), 6,55-6,62 (m, 1H), 2,09(s, 1H), of 1.41 (s, 9H).

Example 43

7-Chloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dimetilfenil)hydrazide (3.80 g, 9,50 mm) suspended in methanol (330 ml) and add quick drops with good stirring methansulfonate (83 ml). Received the orange suspension is heated at boiling temperature under reflux for 20 hours, getting the amber-colored solution. This solution is cooled to room temperature and added dropwise water (75 ml)to give a yellow suspension, which is stirred for 2 hours. Solids filtered off and the filtrate is diluted with water (300 ml)to give a yellow suspension, which is stirred for 20 hours. Solids collected and washed with water, methanol/diethyl ether, then diethyl ether, receiving untreated named the title compound (1.80 g). Recrystallization from methanol gives a named connection (0,58 g, 17%) in VI is e reddish-brown powder. TPL=349-351°C; MS (CI): 368 (M+H).

Analysis for C19H14Cl2N3O3·N2O·0,SN3HE:

Calculated: C, 56,25; N, 4,34; N, 10,06;

Found: C, 56,01; N, 4,36; N, 9,90.

300 MHz1H NMR (DMSO-d6): 12,72 (br s, 1H, capable of being. for exchange), 12,02 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8.7 Hz, 1H), of 8.06 (s, 1H), 7,46 (d, J=8, 7 Hz, 1H), 7,18 (m, 3H), of 2.33 (s, 3H), 2,07 (s, 3H).

Source hydrazide is obtained from the corresponding acid chloride, which is obtained from the corresponding complex di-ether.

Example 43A

Alternatively, the original connection get the General procedure described in 42, except that the corresponding N-tert-butoxy carbonyl-N'-2,4-methylphenylhydrazine, which is obtained as described in 42A, except 2,4-dimethylphenylimino, interaction with di-tert-BUTYLCARBAMATE.

Example 44

7-Chloro-2-(3,4-dihydroxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-4-hydroxy-2-(3,4-dihydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (1,00 g, 2.50 mm) heated at boiling temperature under reflux in 48% HBr (40 ml) for 6 hours, getting a orange suspension. Heat is removed and the suspension is filtered while it is still warm. The collected solids washed with water and then diethyl ether, obtaining the crude product (0,94 g) as a yellow powder. This product is recrystallized from copaseltel (600 ml), getting named the title compound (0,63 g, 68%) as a yellow powder. TPL=269-272°C; MS (CI): 372 (M+H).

Analysis for C17H10ClN3O5·0,5H2About·0,SN3HE:

Calculated: C, 52,67; N, To 3.49; N, 10,38;

Found: C, 52,66; N, To 3.64; N, 10,14.

300 MHz1H NMR (DMSO-d6): 12,67 (br s, 1H, capable of being. for exchange), of $ 11.97 (br s, 1H, capable of being. for exchange), 9,19 (br s, 1H, capable of being. for exchange), 9,10 (br s, 1H, capable of being. for exchange), of 8.15 (d, J=8,3 Hz, 1H), 8,04 (s, 1H), 7,44 (d, J=8,3 Hz, 1H), 6.89 in-of 6.73 (m, 3H).

The original 7-Chloro-4-hydroxy-2-(3,4-acid)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione receive as described in Example 45.

Example 45

7-Chloro-4-hydroxy-2-(3,4-acid)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride (7,00 g, 23,3 mm) dissolved in tetrahydrofuran (210 ml) and added dropwise over 20 min to a cooled (0° (C) to a solution of 3,4-dimethoxyphenylacetone (9.80 g, 58,3 mm) in tetrahydrofuran (420 ml) under stirring. The obtained brown suspension was stirred at 0°With 30 minutes and 2 hours at room temperature. Slurry ice/water (450 ml) is added to the reaction mixture and subsequently 1H. HCl (1.2 l) and the brown suspension is stirred for 1 hour. Solid products are separated by filtration and washed with water and then di-ethyl ether to obtain 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroxyindole the-2-carboxylic acid N-2-(2,4-acid)hydrazide (15 g, humid.). The combined filtrate and wash water is partially concentrated by removing THF, resulting in a precipitate. This precipitate is collected and washed with water, then diethyl ether to give crude product named in the title compound (2.00 g). Recrystallization of this crude product from boiling methanol (500 ml) gives named the title compound (0,98 g, 10%) as a reddish brown powder. TPL=334-336°C; MS (CI): 400 (M+H).

Analysis for C19H14ClN3O5·CH3HE:

Calculated: C, 55,63; N, 4,20; N, 9,73;

Found: C, 55,27; N, Or 4.31; N, 9,56.

300 MHz1H NMR (DMSO-d6): was 12.75 (s, 1H, capable of being. for exchange), 12,01 (s, 1H, capable of being. for exchange), 8,16 (d, J=8.6 Hz, 1H), with 8.05 (s, 1H), 7,45 (d, J=8.6 Hz, 1H), 7,13 (s, 1H), 7,03 (s, 2H), 3,80 (s, 3H), 3,76 (s, 3H).

Example 46

7-Chloro-4-hydroxy-2-(2-methylthioethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a suspension of timelocked sodium (230 mg, 3.2 mm) in dimethylformamide (20 ml), add one 2-(2-bromacil)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0.4 g, 1,08 mm obtained in Example 4 and proposal No. 37811) in the form of a dry powder. The mixture is heated to a gentle boil for about three hours. At this time, heat is removed and the reaction mixture is poured into ice 1,2n. HCl (100 ml) and stirred for about one hour. The obtained precipitate was separated by vacuum filtration and washed with water, dieti the new ether, then dried in vacuum at 50°receiving 330 mg (91%) named in the title compound in the form of not-quite-white powder. TPL=275-277°C; MS (CI): 338 (M+H).

Analysis for C14H12ClN3About3S:

Calculated: C, 49,78; N, To 3.58 N, to 12.44;

Found: C, 49,73; N, To 3.73; N, 12,30.

1H NMR: 2,11 (s, 3H), and 2.79 (t, 2H, J=7,13 Hz), 4.09 to(t, 2H, J=7,08 Hz), 7,42 (dd, 1H, J=8,59, and 1.6 Hz), to 8.57 (d, 1H, J=1.77 Hz), 8,13 (d, 1H J=8,64 Hz), and 11.8 (br s, 1H), 12,64 (br s, 1H).

Example 47

7,9-Dichloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of 5,7-dichloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dimetilfenil)hydrazide (of 3.60 g, 8,31 mm) in methanol (151 ml) slowly add methansulfonate (7.2 ml) and the resulting mixture is heated to boiling point. After 2 hours of heating at the boiling point under reflux the reaction mixture is allowed to cool to room temperature and then filtered to separate the precipitated solid products. The filtrate is diluted with water (150 ml), resulting in a white precipitate falls. This mixture is stirred over night at room temperature and the solids collected by filtration, then washed with water and di-ethyl ether, and dried in the air, getting named the title compound as a white powder (2,78 g, 84%). TPL 335-336°C; MS (CI): 402 (M+H).

Analysis for C19 H13Cl2N3O3·0,2N2About:

Calculated: C, 56,25; N, 3,37; N, of 10.09;

Found: C, 56,23; N, To 3.33; N, 10,35.

NMR: of 12.73 (br s, 1H, capable of being. for exchange), 11,92 (br s, 1H, capable of being. for exchange), 8,03 (s, 1H), 7,51 (s, 1H), 7,17-was 7.08 (m, 3H), 2,32 (s, 1H), 2.06 to (s, 1H).

Source 5,7-dichloro-3-methoxycarbonyl-4-oxo-1,4-di-hydroxyquinolin-2-carboxylic acid N-2-(2,4-dimetilfenil)hydrazide receive the following way:

A. 3 Carbomethoxy-5,7-dichloro-4-hydroxyquinolin-2-carboxylic acid.

To a stirred suspension of dimethyl 5,7-dichloro-4-hydroxyquinoline-2,3-in primary forms (4.0 g, 12.2 mm) in water (72 ml) is added an aqueous solution of sodium hydroxide (0.97 g, 24,2 mm in 22 ml of water). Solid foods immediately dissolved and the resulting solution was heated at 55°30 minutes the Reaction mixture was then slowly cooled to 20°and acidified by adding 6N. hydrochloric acid (4 ml), while maintaining the temperature below 20°C. a precipitate, and after stirring the suspension for 2 hours, the mixture was filtered and the collected solids washed successively with water, ethanol/methanol and diethyl ether. Air drying gives a named connection (2,82 g, 74%). An analytical sample named in the title compound is obtained by recrystallization of a small portion of selected solids from ethyl acetate to obtain a reddish brown solid product. TPL 339-340&#HWS;

Analysis for C12H7Cl2N3O5N:

Calculated: C, To 45.6; H, 2,23; N, 4,43;

Found: C, 45,78; N, 2,43; N, To 4.52.

1H NMR (MeOD): of 7.82 (d, J=2.0 Hz, 1H), 7,44 (d, J=2.0 Hz, 1H), 3,86 (s, 3H).

b. 3 Carbomethoxy-5,7-dichloro-4-hydroxyquinolin-2-carbonyl chloride.

Thionyl chloride (1.50 g, 12.6 mm) is added to a stirred suspension of 3-carboethoxy-5,7-dichloro-4-hydroxyquinolin-2-carboxylic acid (1.0 g, 3.17 mm) free from ethanol-chloroform (25 ml). The resulting suspension is heated at boiling temperature under reflux for 5 hours, resulting in a solution. The reaction mixture is allowed to cool to room temperature and then concentrated, getting the balance mentioned in the title acid chloride (0.88 g, 83%) as a reddish brown solid product. This product is used as is, to obtain the hydrazide acid.

C. 5,7-Dichloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dimetilfenil)hydrazide.

3 Carbomethoxy-5,7-dichloro-4-hydroxyquinolin-2-carbonyl chloride (3,65 g, 11,0 mm) dissolved in tetrahydrofuran (274 ml) and added dropwise to a cooled (0° (C) to a solution of 2,4-dimethylphenylimino (3.13 g, 23.0 mm) in tetrahydrofuran (172 ml) under stirring. Slowly forms a brown-red suspension and the resulting mixture was stirred at 0°30 minutes the Reaction is interrupted by adding klaeden the th water (223 ml) and followed by the addition of 1N. HCl (669 ml). The resulting mixture was stirred for 1 hour, then filtered to separate osadivshih solids. The collected solids washed with water and then diethyl ether, obtaining, after air drying, named the title compound (3,60 g, 76%) as a white powder, MS (CI): 434 (M+H).

1H NMR (DMSO-d6): 12,55 (br s, 1H, capable of being. for exchange), 10,67 (br s, 1H, capable of being. for exchange), 7,76 (d, J=1.6 Hz, 1H), 7,54 (d, J=1.6 Hz, 1H), 7,19 (br s, 1H, capable of being. for exchange), 6,91-6,76 (m, 3H), of 3.69 (s, 2H), 2,19 (s, 6H).

Example 48

7-Chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione sodium salt.

To a stirred suspension of 7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (2.00 g, 5,22 mm) in 0,1N. the sodium hydroxide (52,2 ml, 5,22 mm) add water (100 ml) and methanol (3 ml). After a short ultrasonic treatment solids are dissolved and the resulting solution was filtered through a Gelman Glass Acrodisc filter (0,45 to ultra) and concentrate to dryness. The residue is triturated with isopropanol (100 ml) and filtered, separating the solid products. The solids washed several times with isopropanol and then dried in vacuum at 100°during the night, getting named the title compound (1.64 g, 78%) as a yellow powder. TPL 356 (decomp.).

Analysis for C19H13ClN3O4·1,0Na·0,02(CH3)22O:

Calculated: C, 52,10; N, Of 3.84; N, 9,56;

Found: C, 52,10; N, 3,71; N, 9,40.

1H NMR (DMSO-d6): 8,15-8,17 (m, 2H), 7,31 (dd, J=8,7, 2.0 Hz, 1H), 7,11 (d, J=8,4 Hz, 1H), 6,83-6,76 (m, 2H), 3,76 (s, 3H), 2,07 (s, 3H).

Example 49

Kalinova salt of 7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of 7-chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (400 mg, of 1.03 mm) in methanol (4 ml) is added choline hydrochloride (45% by weight in methanol, 295,6 ultra-l, of 1.03 mm). After a short ultrasonic treatment, all solids dissolved and the resulting solution was passed through a Gelman Glass Acrodisc filter (0,45 ultra-m) along with an additional quantity of methanol (8 ml). The filtrate is concentrated to dryness and the remaining oil is stirred with isopropanol (15 ml) and ethanol (8 ml), causing crystallization. Solids collected and dried in vacuum at 100°during the night, getting named the title compound (411 g, 81%) as a yellow solid product. TPL 229-230°C.

Analysis for C19H13ClN3O4·C5H14NO·1,1H2O:

Calculated: C, A 56.88; H, Of 5.81; N, 11,06;

Found: C, 56,91; N, 5,47, N, 10,98.

1H NMR (DMSO-d6): 8,09-to 8.12 (m, 2H), 7,31 (dd, J=8,6, and 2.1 Hz, 1H), 7,07 (d, J=8.5 Hz, 1H), 6.75 in-PC 6.82 (m, 2H), 3,80-of 3.85 (m, 2H), of 3.77 (s, 3H), 3,37 is 3.40 (m, 2H), 3,09 (s, 9H), 2,04 (s, 3H).

<> Example 50

Kalinova salt of 2-(4-benzyloxyphenyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione

To a stirred suspension of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-benzyloxyphenyl) hydrazide (1.19 g, 2.50 mm) in methanol (50 ml) add methansulfonate (2.4 ml) and the resulting mixture is heated at boiling temperature under reflux for 1 hour. After cooling to room temperature, the reaction mixture was filtered and the collected solids washed with diethyl ether and dried in the air, receiving 900 mg of product, which is retained for further purification. The filtrate is diluted with an equal volume of water and, after stirring for 30 min, the resulting suspension was filtered and the collected solids washed with water and diethyl ether and dried in the air, getting named the title compound (to 151.8 mg) in the form of free acid. Solid products (900 mg), which were originally collected and stored will recrystallized by rastvoreniya in a hot mixture of methanol (3.8 l) and methanesulfonate (63 ml) and then allowed to cool to room temperature. The resulting suspension was filtered to remove the precipitate and the filtrate is diluted with an equal volume of water and stirred over night. The resulting precipitate is collected, washed with water, diethyl shall FYROM and then dried in air, getting named the title compound (422,2 mg) in the form of the free acid (total combined output named in the title compound in the form of the free acid (574 mg, 52%)); MC (CI): 446 (M+H).

300 MHz1H NMR (DMSO-d6): 12,71 (br s, 1H, capable of being. for exchange), 11,98 (br s, 1H, capable of being. to the exchange)to 8.14 (d, J=8.6 Hz, 1H), 8,03 (s, 1H), 7,47-to 7.32 (m, 9H), 7,07(d, J=8,9 Hz, 1H), 5,14 (s, 2H).

To a stirred suspension of 2-(4-benzyloxyphenyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (515 mg, 1,16 mm) in methanol (77 ml) is added choline hydroxide (45% by weight in methanol, of 0.36 ml, 1,28 mm). The resulting mixture was filtered to separate a small amount of small solid particles and the filtrate is concentrated, resulting in residual oil. The residue is diluted with a mixture of toluene/ethanol (70 ml/20 ml) and concentrated. The residue is diluted final portion of toluene (70 ml) and concentrate getting Kalinovo salt named the title compound (640 mg, 99%) as a yellow-green solid product. TPL 304-306°C; MS (FAB); 446 (M+I). 444 (M-I).

Analysis for C24H16ClN3O4·0,5H2O·1,0 ° C5H14NO:

Calculated: C, Of 61.95; H, 5,43 N 9,89;

Found: C, 62,31; N, 5,59, N, 10,02.

300 MHz1H NMR (DMSO-d6): 8,11-of 8.09 (m, 2H), of 7.48-7,28 (m, 8H), 7,00 (d, J=8,88 Hz, 2H), 5,13 (s, 2H), 3,83 (br s, 2H), 3,39 (br s, 2H), 3,09 (br s, 9H).

A. 7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-Benzino Setenil)hydrazide.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(4-benzyloxyphenyl)hydrazide used in Example 50, receive according to the method used in Example 41 except for using 4-benzyloxyaniline instead of 4-chloro-2-methylphenylhydrazine.

Example 51

7-Chloro-2-(2,4-dichlorophenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dichlorophenyl)hydrazide (3.00 g, for 6.81 mm) in methanol (1500 ml) add methanesulfonate (150 ml). The resulting suspension is heated at boiling temperature under reflux for 9 days and the resulting solution is then cooled to ambient temperature and concentrated to half the original volume using a rotary evaporator. The resulting suspension is stirred at room temperature for 30 min and filtered to separate the solid product. The filtrate is diluted with an equal volume of water, whereupon a precipitate. This mixture stirred at ambient temperature overnight and then filtered. The collected solids washed with diethyl ether and then suspended in methanol (500 ml) and treated with ultrasound for 5 minutes the mixture is filtered to separate the solids and the filtrate will contentresult. The residue is suspended in diethyl ether and filtered. The collected solids washed with water and diethyl ether and then dried in the air, getting named the title compound (198,5 g, 7%) as a yellow solid product. TPL 360-361°C; MS (CI); 408 (M+I).

Analysis for C17H8ClN3About3·0,2N2O·0,SN3SO3H:

Calculated: C, 49,02; N, 2,35; N, 9,75;

Found: C, 48,69; N, 2,10, N, 9,96.

300 MHz1H NMR (DMSO-d6): 12,99 (br s, 1H, capable of being. for exchange), 12,12 (br s, 1H, capable of being. for exchange), of 8.15 (d, J=8,67 Hz, 1H), 8,07 (d, J=1.23 Hz, 1H), a 7.85 (d, J=1,02 Hz, 1H), 7,60 (s, 2H), 7,47 (dd, J=1,61, 8,63 Hz, 1H).

A. 7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dichlorophenyl)hydrazide

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dichlorophenyl) hydrazide used in Example 51, receive according to the method used in Example 41A, except that 2,4-dichloropyridazin used instead of 4-chloro-2-methylphenylhydrazine.

Example 52

7-Chloro-2-(2,4-dichlorophenyl)-1-hydroxy-3,4,5,10-Tetra-hydropyridine[4,5-b]quinoline-4,10-dione

To a stirred suspension of 7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dichlorophenyl)hydrazide (1.28 g, 2,92 mm) in methanol (645 ml) add methansulfonate (65 ml). The resulting suspension is heated at the boiling point with britishtelecom 10 days and the resulting solution is cooled to ambient temperature, resulting in precipitation. The mixture is filtered, separating the solids, and the filtrate is diluted with water (300 ml) to education other sediment. This precipitate is collected and dried, obtaining mentioned in the title compound (266.5 Azerbaijani mg, 22%) as a yellow solid. TPL 342-343°C; MS (CI); 408 (M+I).

Analysis for C17H8Cl3N3About3·0,SN3SO3N·0,2N2About:

Calculated: C, 48,73; N, 2,16; N, 9,95;

Found: C, 48,69; N, 2,10, N, 9,96.

300 MHz1H NMR (DMSO-d6): 13,50 (br s, 1H, capable of being. for exchange), 8.29 (d, J=8,76 Hz, 1H), 8,19 (d, J=1,26 Hz, 1H), 7,92 (d, J=1,71 Hz, 1H), 7,70-to 7.61 (m, 3H).

A. 7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dichlorophenyl)hydrazide.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dichlorophenyl)hydrazide used in Example 52, receive according to the method used in Example 51.

Example 53

7-Chloro-4-hydroxy-2-[2-(4-methoxyaniline)ethyl]-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

2-(2-Bromacil)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (1,00 g, 2.7 mm)obtained in Example 4A and p-anisidine (1,33 g, 10.8 mm) is stirred and heated at boiling temperature under reflux in DMF (20 ml) for 1.5 hours, getting a brown solution. The solution is cooled to room temperature and add diethyl ether (80 ml), is learn the dark suspension. The suspension is stirred for two hours and filtered. The collected solids washed with diethyl ether (150 ml), getting named the title compound as a tan powder (1,17 g, 60%). TPL 239-241°C; MS (CI): 413.

Analysis for C20H17ClN4O4·HBr·3,0 C3H7NO·0,5H2About:

Calculated: C, 48,24; N, To 5.58; N, of 13.58;

Found: C, 47,80; N, 5,20; N, 13,93.

300 MHz1H NMR (DMSO-d6): to 8.14 (d, J=8.7 Hz, 1H), of 8.09 (d, J=1.9 Hz, 1H), 7,35 (d, J=8.7 Hz, 1H), 6.75 in (d, J=8,9, Hz, 2H), return of 6.58 (d, J=8,9 Hz, 2H), 3.96 points (t, J=6,8 Hz, 2H), 3,62 (s, 3H), of 3.27 (t, J=6,8 Hz, 2H).

Example 54

7-Chloro-2-(3-chloro-4-hydroxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (obtained in Example 37, and 1.00 g, 2,47 mm) is stirred in methansulfonate (20 ml)to give a black solution. This solution is heated at 145°With 6 hours and cooled to room temperature. Add water (60 ml) to obtain a reddish-brown suspension, which is stirred for 3 hours and filtered. The collected solids washed with water and diethyl ether, obtaining mentioned in the title compound in the form of a powder Golden brown (0,98 g, 76%). TPL 350-353°C; MS (CI): 390.

Analysis for C17H9Cl2N3O4·H2O·1,2CH3SO3H:

Calculated: C, 41,76; N,3.04 From; N, 8,02;

Found: C, 41,74; H, Was 2.76; N, 7.68 Per.

300 MHz1H NMR (DMSO-d6): 8,15 (d, J=8.5 Hz, 1H), with 8.05 (d, J=1.9 Hz, 1H), 7,53 (d, J=2.2 Hz, 1H), 7,45 (d, J=8.5 Hz, 1H), 7,33 (dd, J=2,2, 8.7 Hz, 1H), 7,03 (d, J=8.7 Hz, 2H).

Example 55

7-Chloro-4-hydroxy-2-(4-hydroxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

7-Chloro-4-hydroxy-2-(4-methoxy-2-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (1,00 g, 2,61 mm) is stirred in methansulfonate (10 ml)to give a brown solution. This solution is heated at 150°With 3 hours and cooled to room temperature. The cooled solution is added dropwise to water (50 ml) under stirring, obtaining a gray suspension, which is stirred for 20 hours and filtered. The collected solids washed with water and then suspended in water (50 ml). To this suspension is added a solution of choline hydroxide (2 ml, 45 wt.% in methanol), dissolving solids, gives a brown solution. This solution is heated at the boiling point under reflux for 1 hour, bring an additional quantity of a solution of choline hydroxide (2 ml) and the solution heated at boiling temperature under reflux for 3 hours. The solution is cooled to room temperature and acidified to pH 1 1H. HCl, getting a brown suspension. The suspension is filtered and the collected solids washed with water, getting a brown solid. NESCO who are recrystallization from hot methanol to give named in the title compound in the form of not quite white powder (0.35 g, 36%). TPL 287°C (decomp.); MS (CI): 370.

Analysis for C18H12ClN3O4·N2About·0,SN3HE:

Calculated: C, 54,75; N, 4,13; N, 10,24;

Found: C, 54,75; N, A 3.87; N, 10,18.

300 MHz1H NMR (DMSO-d6): 12,60 (br s, 1H, capable of being. for exchange), 12,00 (br s, 1H, capable of being. for exchange), of 9.55 (br s, 1H, capable of being. for exchange), 8,16 (d, J=8.6 Hz, 1H), of 8.06 (s, 1H), 7,45 (d, J=8.6 Hz, 1H), 7,07 (d, J=8,4 Hz, 1H), 6,70 (s, 1H), 6,66 (d, J=8,4 Hz, 1H), from 2.00 (s, 3H).

Example 56

7-Chloro-2-(4-chloro-2-were)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione. Presents an alternative synthesis of this compound, previously described in Example 42.

3-Benzyl-7-chloro-2-(4-chloro-2-were)-1,2,3,4,5,10-hexahydropyrazino[4,5-b]quinoline-1,4,10-Trion, (0,61 g, 1,28 mm) is stirred in methansulfonate (12 ml)to give a viscous amber solution. This solution is heated at 45°6.5 hours, obtaining a suspension of green peas, which is cooled to room temperature. Add ice (50 ml) under stirring, obtaining a light green suspension, which is filtered. The collected solids washed with water and diethyl ether, getting a grey powder (0,49 g). Part of this powder (0.36 g) was stirred in methanol and add a solution of choline hydroxide (2 ml, 1M). Most of the solids dissolved and the mixture is filtered, removing insoluble substances. The filtered solution is acidified to pH 1 with the aid of the d 1H. HCl, getting a tan suspension. Methanol (2 ml) is removed in a stream of gaseous N2and the suspension filtered. The collected solids washed with water and diethyl ether, obtaining mentioned in the title compound in the form of not quite white powder (0,30 g, 82%)identified as substance obtained earlier in Example 42.

The original 3-benzyl-7-chloro-2-(4-chloro-2-were)-1,2,3,4,5,10-hexahydropyrazino[4,5-b]quinoline-1,4,10-Trion receive the following way:

A. 2 Benzylidene-1-(4-chloro-2-were)hydrazine.

To a stirred suspension of 4-chloro-2-methylphenylhydrazine hydrochloride (1,00 g, 5,18 mm) in ethanol (15 ml) was added benzaldehyde (0.66 g, 6,22 mm) and sodium acetate (0.51 g, 6.2 mm). After stirring the mixture for 3 hours at room temperature, add the additional amount of benzaldehyde (0.11 g, 1.3 mm) and stirring is continued for 30 minutes, the Reaction mixture was poured into water and the resulting mixture extracted with diethyl ether. The combined ether extracts are dried (MgSO4), filtered and concentrated to a residual yellow oil (1,71 g)containing named in the title compound, mixed with diethylacetal benzaldehyde. Acetal is distilled off by heating (70° (C) mixture in high vacuum. The rest is pure named the title compound (1.23 g, 97%) as an orange solid substance, is which is used as it is in the next stage.

300 MHz1H NMR (CDCl3): 7,79 (s, 1H), 7,68 (s, 1H), 7,65 (s, 1H), 7,49 (d, J=6.3 Hz, 1H), 7,42-7,26 (m, 4H), 7,16 (dd, J=2.5 and 6.0 Hz, 1H), 7,06 (d, J=2.5 Hz, 1H), of 2.21 (s, 3H).

b. 1-Benzyl-2-(4-chloro-2-were)hydrazine.

To a stirred solution of 2-benzylidene-1-(4-chloro-2-were)hydrazine (2,40 g, 9,81 mm) in anhydrous tetrahydrofuran (43 ml) is added dropwise a solution of borane in tetrahydrofuran (4.6 ml, 1M solution, 4.6 mm). Gas evolution is observed during the addition and thereafter. Upon completion of addition the reaction mixture was stirred 20 min at room temperature and then thoroughly saturated with gaseous hydrogen chloride at room temperature. Gradually adding gaseous HCl to the reaction mixture, a white precipitate is formed. After addition of HCl, the reaction mixture is stirred for 20 minutes and then the reaction is interrupted careful adding dropwise successively water (150 ml) and 10% hydrochloric acid (5 ml). The resulting solution was concentrated to remove the majority of tetrahydrofuran. Wednesday in the remaining compounds make alkaline by adding solid potassium carbonate and then extracted with diethyl ether. The combined extracts dried (MgSO4), filtered and concentrated to a residual pale yellow oil (2.38 g). This product is subjected to flash chromatography on silica gel, using as eluent hexane/diethyl EPE is (3:1). The fractions that contain the product are combined and concentrated to a residual named the title compound as a yellow oil (1.30 grams, 53,7%); MS (CI): 247(M+H).

300 MHz1H NMR (CDCl3): 7,22-7,41 (m, 6H), 7,14 (d, J=2.4 Hz, 1H), 7,01 (d, J=2.4 Hz), the 4.90 (br s, 1H, capable of being. for exchange), of 3.95 (s, 2H), of 3.77 (br s, 1H, capable of being. for exchange), to 1.98 (s, 3H).

C. 7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-1-benzyl-N-2-(4-chloro-2-were)-hydrazide

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride (0,58 g, 1,93 mm) dissolved in tetrahydrofuran (50 ml) and added dropwise over 15 minutes to a solution of 1-benzyl-2-(4-chloro-2-were)hydrazine (1,00 g, 4.05 mm) in tetrahydrofuran (100 ml) at 0°C. the resulting amber solution is stirred for 45 minutes at 0°and diluted with water (75 ml)maintaining at 0°With cooling. The resulting solution was then diluted with 0°1H. HCl (180 ml) before the formation of a white suspension. The suspension is stirred at 0°With 1 hour and filtered. The collected solids washed with 1N. HCl, water and diethyl ether, obtaining after air drying, named the title compound as a white powder (0,83 g, 84%). TPL 172-175°C.

Analysis for C26H21Cl2O4·0,6N2O·0,4C4H10About:

Calculated: C, 60,18; N, 4,79; N, 7,63;

Found: C, 60,21; N, Of 4.44; N, 7,70.

300 MHz1H NMR (DMSO-d6): 2,44 (s, 1H, capable of being. for exchange), of 8.04 (d, J=8.6 Hz, 1H), 7,52 (d, J=1.4 Hz, 1H), 7,43-7,31 (m, 6H), 7,11-6,85 (m, 3H), around 4.85 (br s, 2H), 3,69 (s, 3H), of 1.76 (s, 3H).

d. 3-Benzyl-7-chloro-2-(4-chloro-2-were)-1,2,3,4,5,10-hexahydropyrazino[4,5-b]quinoline-1,4,10-Trion.

7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-1-benzyl-N-2-(4-chloro-2-were)hydrazide (0,92 g, 1,80 mm) is stirred in methanol (37 ml) and add a solution hydrooxide choline (of 1.03 ml, 45% by weight in methanol)to give a pale brown solution. This solution is heated at the boiling point under reflux for 12 hours to room temperature. The methanol is removed in a stream of nitrogen gas, getting the rest of the amber color. Add a solution of choline hydroxide (1 ml, 45 wt.% in methanol) and the resulting thick solution was stirred for 1 hour. Add methanol (40 ml) and the solution is cooled to -15°C. is Added dropwise 1N. HCl (10 ml) at -15°and With stirring, obtaining a white suspension. Methanol (15 ml) is removed in a stream of gaseous N2and the suspension filtered. The collected solids washed with water and diethyl ether, obtaining mentioned in the title compound in the form of not quite white powder (0,76 g, 89%). TPL 279-281°C; MS (CI): 478.

Analysis for C25H17Cl2N3O3·H2O·0,SN3HE:

Calculated: C, 60,06; H, Was 4.02; N, 8,31;

Found: C, 60,14; N, Are 3.90; N, 8.34 Per.

300 MHz1H NMR (DM what About the-d 6): 12,68 (s, 1H, capable of being. for exchange), 8,19 (d, J=1.97 Hz, 1H), 8,16 (d, J=8.6 Hz, 1H), 7,50 (dd, J=1,9, 8.6 Hz, 1H), 7,35-7,24 (m, 6H), 6,94-6,91 (m, 2H), 5,28 (d, J=16,3 Hz, 1H), 4,60 (d, J=16,3 Hz, 1H), 1.69 in (s, 3H).

Example 57

Sodium salt of 7,9-dichloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione. The sodium salt of the compound obtained in Example 47.

7,9-Dichloro-2-(2,4-dimetilfenil)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (obtained as described in Example 47, 375 mg, 0,925 mm) dissolved in water (20 ml)containing 0.1 N. sodium hydroxide (a 9.25 ml, 0,925 mm) and methanol (4 ml) at rotation and sonication. The resulting solution was filtered through a Gelman Glass Acrodisc filter (0.45 μm) and the filtrate concentrated to dryness. The residue is triturated with isopropanol (10 ml) and the resulting mixture filtered. The collected solids washed with isopropanol (5 ml) and then dried in high vacuum at 100°during the night, getting named the title compound as a yellow solid product (310,4 mg, 79%). TPL 369-370°C.

Analysis for C19H12Cl2N3O3·1,0Na·1,N2About·0,02(CH3)2SNON:

Calculated: C, 50,32; N, 3,12; N, the remaining 9.08;

Found: C, 50, 20mm; N, 3,44; N, Of 9.21.

1H NMR (DMSO-d6): 8,01 (d, J=2.2 Hz, 1H), 7,28 (d, J=2.0 Hz, 1H), 7,01-was 7.08 (m, 3H), of 2.30 (s, 3H), 2,04 (s, 3H).

Examples 58-81 presented in Table 1 on pages adjacent pages containing f is raly and schemes before the claims.

Example 82

7-Chloro-4-hydroxy-2-(2-terbisil)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a stirred suspension of 2-pyrrolidinecarbonyl-7-chloro-4-hydroxyquinolin-3-carboxylic acid (1,068 g, 3 mm) in tetrahydrofuran (60 ml) at ambient temperature add dicyclohexylcarbodiimide (0,795 g of 3.85 mm). Tertrahydrofuran ring solution (20 ml) of N-tert-butoxycarbonyl-N'-2-forbindelserna (1.10 g, 4,59 mm, obtained as described in s) are added directly to the above suspension. The reaction mixture was stirred at room temperature for four hours. Upon completion of the combination, urea as a by-product is removed by vacuum filtration. Partial purification flash column chromatography using 5% methanol in methylene chloride gives the specified hydrazide (1,67 g, 3.0 mm, 92%). To hydrazide, suspended in tetrahydrofuran (80 ml) add methansulfonate (9.0 ml, 139 mm). The reaction mixture was stirred at room temperature for 24 hours and then poured into ice water (600 ml). The precipitate produce, dry and grind/handle ultrasound with methanol (20 ml) and exhale, getting after drying in vacuum at 50°0,733 g (65,9%) named in the title compound in the form of not quite white solid product. TPL >300°C; MS (CI): 372 (M+H).

Analysis for C18H11 3About3FCl:

Calculated: C, 58,16; N, 2,98 N; 11,30;

Found: C, 57,81; N, 3,20; N, 11,08

300 MHz1H NMR (DMSO-d6): 12,68 (s, 1H, capable of being. for exchange), 11,96 (s, 1H, capable of being. for exchange), of 8.15 (d, J=8.7 Hz, 1H), 8,03 (s, 1H), 7,43 (d, 1H, J=8,6 Hz), 7,15-to 7.32 (m, 4H), to 5.17 (s, 2H).

A. The original 2-pyrrolidinecarbonyl-7-chloro-4-hydroxyquinolin-3-carboxylic acid is obtained in the following way:

To a suspension of 3-carbomethoxy-2-pyrrolidinecarbonyl-7-chloro-4-hydroxyquinoline solution (2,52 g, 7.5 mm) in deionized water (40 ml) is added dropwise a solution (20 ml), aqueous potassium hydroxide (882 mg, of 15.75 mm). Upon completion of addition, the reaction mixture is heated to 60°C. After 3 hours the reaction mixture is filtered to remove small amounts of insoluble substances. The filtrate is then acidified to pH 1, which gives a white precipitate. The solid product emit vacuum filtration, washed with water and dried at 30°C in vacuum for 16 hours. This gives the set named in the title compound (1.5 g, 64%) as a white solid. TPL= 225-8°C; MS (CI): 321 (M+H).

300 MHz1H NMR (DMSO-d6): of 8.28 (d, J=8,8 Hz, 1H), to 7.77 (s, 1H), to 7.64 (d, 1H, J=8.7 Hz), 3,52 is 3.57 (m, 2H), 3,17-3,19 (m, 2H), 1,83-to 1.98 (m, 4H).

b. The original 3-carbomethoxy-2-pyrrolidinecarbonyl-7-chloro-4-hydroxyquinolin receive the following way:

To a suspension of 3-carbomethoxy-7-chloro-4-hydroxyquinolin-2-carboxylic acid (2.25 g, 8.0 mm) in tetrahydrofuran (20 ml) in temp is the temperature of the environment in an atmosphere of N 2add dicyclohexylcarbodiimide (1.65 g, 8.0 mm) and pyrrolidine (0,596 g, 8.4 mm). The reaction mixture was stirred at room temperature for 15 hours, after this time, the urea as a by-product, is removed by vacuum filtration. The specified product clean flash chromatography on a column using 5% methanol in chloroform to obtain named in the title compounds (2,52 g, 94,3%) as a reddish brown solid. TPL 215°C; MS (CI): 335 (M+H).

300 MHz1H NMR (DMSO-d6): to 8.12 (d, J=8.7 Hz, 1H), 7,60 (d, 1H, J=1.8 Hz), 7,47 (dd, 1H, J=8,8, 2.0 Hz), of 3.69 (s, 3H), 3,40-to 3.49 (m, 2H), 3.27 to to 3.33 (m, 2H), 1,80 is 1.96 (m, 4H).

The source of N-tert-butoxycarbonyl-N'-2-ftorangidridy receive the following way:

C. To a mixture of tert-BUTYLCARBAMATE (17,84 g, 135 mm) and 2-ftorangidridy (3.2 ml, 26.5 mm) in dimethylformamide (30 ml) heated to 50°With add triethylamine (7.4 ml, 53,1 mm). After stirring at 50°C for 30 min, the reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts washed with water, salt solution, dried over MgSO4and concentrated in vacuo. The crude product clean flash column chromatography using 1:1 diethyl ether:hexane as eluent. This gives you named the title compound (5,13 g, 80%) as a white solid, MS (CI): 241 (M+H).

300 MHz1H NMR (DMSO-d6): of 8.27 (br s, 1H), 7,0-to 7.50 (m, 1H), 7,25 was 7.36 (m, 1H), 7,09-7,20 (m, 2H), 4,48 (br s, 1H), a 3.87-of 3.94 (m, 2H), of 1.37 (s, 9H).

Example 83

7-Chloro-1-hydroxy-3-(3-nitrophenyl)-3,4,5,10-tetrahydropyridine[4,5-b]quinoline-4,10-dione.

Named in the title compound are extracted as previously described in Example 14, using the corresponding suitable starting compound to obtain named in the title compound and butanol instead of ethanol. In addition, the product emit before processing in methanol by methansulfonate.

Analysis for C17H9N4O5Cl:

Calculated: C, 53,07; N, A 2.36; N, 11,02;

Found: C, 53,55; N, 2,54; N, 10,94.

1H NMR (DMSO-d6): 7,63 (d, J=8,9 Hz, 1H), 7,80-to $ 7.91 (m, 1H), 8,18-at 8.36 (m, 4H), 8,64 (s, 1H), 12,71 (br s, 1H), made 13.36 (br s, 1H).

MC (CI): 385(M+H).

TPL (°C): >250

Example 84

7-Chloro-2-(3-forfinal)-4-hydroxy-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

Named in the title compound are extracted as previously described in Example 15, using the corresponding suitable starting compound to obtain the listed compounds.

Analysis for C17H9N3About3ClF:

Calculated: C, 53,57; N, Of 3.07; N, 14,56;

Found: C, 53,55; N, To 2.94; N, 14,44.

1H NMR (DMSO-d6): 7,18-7,32 (m, 1H), 7,46-of 7.60 (m, 4H), of 8.06 (s, 1H), 8,17 (d, J=8.7 Hz, 1H), 12,09 (br s, 1H), 12,92 (br s, 1H).

MC (CI): 358(M+H).

TPL (°C): >250

Examples 85-94 get, basically as described previously in Example 35, use the I appropriate corresponding starting compound. The physical characteristics and the outputs from the previous acylhydrazides presented in Table 2, pages preceding the claims.

Examples 95-103 obtained mainly as previously described and Example 80, using the corresponding suitable starting compounds of the 2-pyrrolidino the quinoline precursors, physical characteristics and outputs are presented in Table 3 before the claims.

Example 104

7-Chloro-4-hydroxy-2-(2,5-dihydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

A suspension of 7-chloro-4-hydroxy-2-(2,5-acid)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0,5618 g, 1.4 mm) left to simmer in 50 ml of 48% Hydrobromic acid. After approximately 45 minutes, the suspension turns into an orange solution. After 2 hours of heating at the boiling point under reflux, VGH analysis shows that the reaction was completed. After cooling, the solution gives a precipitate which is removed by filtration and washed with water until the absence of an acid reaction of wash water. Then the solids are dissolved in 4 ml of 45% choline hydroxide in methanol and filtered through a Buechner funnel with a fine glass filter to separate the solid particles. Acidification with conc. HCl gives a reddish-brown precipitate, which is removed by filtration. The wet solid product is dissolved is in methanol and the solvent evaporated, receiving the specified product (0,230 g, 44,3%) as a reddish brown solid.

Analysis for C17H11N3About3Cl·0,7HBr:

Calculated: C, Of 47.55; H, 2,75; N, 9,78;

Found: C, 47,85; N, Of 3.85; N, 9,70.

Chemical ionisation: m+I: 372

300 MHz proton NMR (DMSO-d6/TN-d): 12,65 (5 br, 1H, capable of being. for exchange), and 8.2 (d, 1H, J=9.0 Hz), to 8.12 (s, 1H), 7,47 (d, J=9.0 Hz), to 6.80 (d, 1H, J=6.0 Hz), 6,74 (d, 1H), 6,70 (s, 1H).

Example 105

7-Chloro-4-hydroxy-2-(4-carboxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

A suspension of 7-chloro-4-hydroxy-2-(4-cyanophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0.400 g, 1.04mm) in 50 ml of 1 n KOH heated at boiling temperature under reflux for 5 hours, the duration of the reaction is controlled VGH. The original suspension slowly turns into a yellow solution. As shown VGH full transformation into a new substance is completed within 5 hours. The solution is cooled to 0°and acidified with conc. HCl. Upon acidification immediately a precipitate, which is removed by filtration with sedimentation. Yellow caked residue washed with water and then suspended in 1:1 solution of ethanol:methanol and the solvent is removed in vacuum at 50°C. the Procedure is repeated up until a yellow powder will not turn freely in presuposes solid product (0.400 g, 100%)corresponding to the specified connection.

Analysis for C18H10N3O 5Cl·2,7HCl:

Calculated: C, 44,38; N, 2,87 N, 9,15;

Found: C, 44,83; N, 2,65, N, 8,71;

Chemical ionisation: m+I: 384.

300 MHz proton NMR (DMSO-d6/TN-d): 13,04 (br s, 1H, capable of being. for exchange), 12,20 (br s, 1H, capable of being. for exchange)and 8.1 (d, 1H, J=9.0 Hz), 8,08 (s, 1H), 8,03 (d, 2H, J=9.0 Hz), of 7.70 (d, 2H, J=9.0 Hz), 7,465 (d, 1H).

Example 106

7-Chloro-4-hydroxy-2-(4-hydroxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To a 50 ml solution of 5:1 48% HBr:methansulfonate add 7-chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (1,0328 g of 27.9 mm). The resulting suspension is heated at 110°3.5 hours. VGH shows the complete transformation into a new connection. The suspension is cooled to room temperature and filtered through a Buechner funnel. The yellow solid product is washed with 2×100 ml portions of distilled water and then 200 ml of 1:1 solution of THF:diethyl ether. The product is then washed with hexane to until the solid becomes freely presuposes. Prior to analysis the substance dried for 72 hours in air. For this reaction the percentage output is not registered.

Analysis for C17H9N3O4Cl2·2,3HBr:

Calculated: C, 35,43; N, 1,97; N, 7,29;

Found: C, 35,40; N, 1,95; N, 6,85;

Chemical ionisation: m+I: 390.

300 MHz proton NMR (DMSO-d6/TN-d): 8,08 (s, 1H), 7,49 (s, 1H), 7,30 (d, 2H, J=8,73 Hz), 6,8 (d, 2H, J=8,73 Hz).

Example 107

7-the ENT-4-hydroxy-2-(4-carboxamidine)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

In a 50 ml round bottom flask was placed 7-chloro-4-hydroxy-2-(4-cyanophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0,2040 g, 0,558 mm). This substance is dissolved in 6 ml of H2S04and heated to 50°C. the Warm solution is poured out then 10.0 g of ice chips, resulting in a yellow solid product. The solid product is removed from the aqueous solution by filtration with suction and washed with 60 ml of distilled water and then 30 ml of 1N. NaHCO3. The yellow paste is suspended in 1:1 ethanol:methanol and the solvent is removed in vacuum until a solid product will not be free to precipates. Additional washing with 60 ml of methanol and then 200 ml of THF gives a yellow solid product, which is freely interspersed. After air drying receive the specified product (0.187 g, 87.7 per cent) in the form of a yellow solid substance.

Analysis for C18H11N4O4Cl·1,3H2SO2:

Calculated: C, 42,37; N, 2,68; N, 10,98;

Found: C, 42,75; N, 3,10; N, 10,61;

FAB: m+1 277,2, 257,1, 299,1, 383,1.

300 MHz proton NMR (DMSO-d6/TN-d): 8,23 (s, 1H), 8,10 (s, 1H), with 8.05 (d, 2H, J=8,49 Hz), of 7.70 (d, 2H, J=8,49 Hz), 7,465 (d, J=8,49 Hz).

Example 108

7-Chloro-4-hydroxy-2-(4-tetrazolyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

To 10 ml of NMP added 7-chloro-4-hydroxy-2-(4-cyanophenyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0.5 g, of 1.37 mm) and subsequently three is Tramin (0,206 g, 1,57 mm) and sodium azide (0.534 g, by 8.22 mm). This suspension is vigorously stirred and heated at 170°6 hours. By this time VGH analysis shows that the reaction was completed. The solution is allowed to cool, when it begins to form a precipitate. To a chilled suspension add diethyl ether to prevent further sedimentation. The solid product is removed by filtration with suction and washed with diethyl ether, to becoming a solid substance in a freely presuposes reddish-brown powder. The powder is then suspended in 100 ml of 1N. HCl to remove the excess of sodium azide and triethylamine hydrochloride. The solid product is removed by filtration and washed with 1:1 methanol:diethyl ether solution to becoming reddish-brown solid product in a freely presuposes powder. After air drying registered the specified product (0,552 g of 99.1%).

Analysis for C18H11N4O4Cl·2,4H2O:

Calculated: C, 47,93; N, 3,30; N, 21,73;

Found: C, 47,36; N, Of 3.32; N, 10,57;

FAB: m+1 277.2 M., 257,1.

300 MHz proton NMR (DMSO-d6/TN-d): 12,10 (br s, 1H, capable of being. for exchange), 8,19-to 8.12 (m, 4H), 8,065 (s, 1H), a 7.85(d, 3H, J=9,00 Hz).

Example 109

7-Chloro-4-hydroxy-2-(4-N,N-dimethylcarbamoyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

In 20 ml of anhydrous THF suspended 7-chloro-4-hydroxy-2-(4-carboxyphenyl)-1,2,5,10-tet is hydropyridine[4,5-b]quinoline-1,10-dione (0,3436 g, 0,897 mm) under nitrogen atmosphere. To this suspension is added SOCl2(0,13 ml, 1,79 mm). The mixture is then heated at the boiling point under reflux for about 60 minutes and add 1 ml of DMF. After addition of DMF suspension immediately turns into a light yellow solution, which after five minutes again becomes, ultimately, a yellow suspension. THF is removed under reduced pressure and add 10 ml of DMF at room temperature. The obtained dark-orange solution is cooled to -10°C. To this solution add diethylamine (0,27 ml, 2,69 mm). Immediately after adding diethylamine formed a dark red precipitate. This suspension is cooled support during slow addition of 50 ml of 1N. HCl along with 50 ml saturated NaCl, resulting in a yellow precipitate. The precipitate was separated by filtration and washed with 200 ml of water and subsequently 100 ml of diethyl ether. Additional flushing 4:1 diethyl ether:methanol leads to freely pereymayemosya solid substance. After air drying receive the specified product (0,1485 g, 38,1%) as a yellow solid.

Analysis for C22H19N4O4Cl·1,7HCl:

Calculated: C, 52,75; N, 4,16; N, 11,18;

Found: C, 52,63; N, Of 4.45; N, 10,85;

Chemical ionisation: m+I: 439.

300 MHz proton NMR (DMSO-d6/TN-d): 12,90 (br s, 1H, capable of being. for exchange), 12,08 (br s, 1H, is poson. for exchange), 8,21 (s, 1H, J=9,00 Hz), 8,11 (s, 1H), 87,67 (d, 2H, J=9,00 Hz), of 7.48-7,46 (m, 3H, J=6, 15 Hz), 3,47 is 3.25 (br m, 4H)and 1.15 (br s, 6H).

Example 110

7-Chloro-4-hydroxy-2-(4-carboxymethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-l,10-dione.

To 50 ml of absolute methanol is added 7-chloro-4-hydroxy-2-(4-carboxyphenyl)-1,2,5,10-tetrahydropyridine-[4,5-b]quinoline-1,10-dione (0,30 g, 0,785 mm). To this white suspension add two drops of concentrated H2SO4and the slurry is heated at the boiling point under reflux, controlling the reaction HPLC for 26 hours. The suspension is allowed to cool to room temperature, after which the suspension was diluted with diethyl ether (100 ml), causing an additional deposition. The precipitate is removed by filtration with suction and washed with 50 ml of 7:1 diethyl ether:methanol. After air drying receive the specified product (0,327 g, 100%)as a white solid.

Analysis for C19H12N3O5Cl·1,5HCl:

Calculated: C, 50,43; N, A 3.01; N, of 9.21;

Found: C, 50,91; N, Of 3.60; N, 9,36;

Chemical ionisation: m+I: 398.

300 MHz proton NMR (DMSO-d6/TN-d): 8,15(d, 1H, J=9,00 Hz), with 8.05 (d, 3H), of 7.75 (d, 2H, J=9,00 Hz), 7,47 (d, 1H, J=9,00 Hz), a 3.87 (s, 3H).

Example 111

7-Chloro-4-hydroxy-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-retil)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione.

Sodium hydride, 60% in mineral oil (150 mg, 3.75 mm) washed with shemekia and suspended in dimethylformamide (20 ml). 4,4-Dimethyl-oxazoline-2,5-dione (580 mg, 4.5 mm) is added portion 15 minutes at room temperature. The resulting mixture is stirred for 15-20 minutes at room temperature. At the end of this time the original 7-chloro-4-hydroxy-2-(2-bromacil)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione are added and the reaction mixture is quickly heated to 150°C. After about three hours at this temperature, the heat is removed and the reaction mixture was poured into ice 1H. HCl (100 ml). This mixture is stirred for about 5-10 minutes and filtered with suction. Obtained on the filter cake washed with water and diethyl ether, then dried in vacuum, obtaining the specified product as a white solid (280 mg, 67%).

Example 112

7-Chloro-4-hydroxy-2-(2-methyl-2-hydroxypropylamino)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (9740-178-1).

The original 7-chloro-4-hydroxy-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-retil)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (400 mg, of 0.95 mm) suspended in water (30 ml) at room temperature. To a suspension type 1H. NaOH (2.0 ml). Formed a clear solution, which is heated at 50°2 hours. After this time add 1,2n. HCl (5 ml). The mixture is stirred for further 30 minutes at 50°, then cooled to room temperature. A white precipitate are filtered and dried, obtaining specified in sahlawi the connection in the form of a white solid (330 mg, 89%).

Example 113

7-Chloro-4-hydroxy-2-(2-methylthioethyl)-1,2,5,10-tetrahydropyridine [4,5-b]quinoline-1,10-dione.

To a suspension of Na3SCH3(230 mg, 3.2 mm) in dimethylformamide (20 ml) is added in one portion of 7-chloro-4-hydroxy-2-(2-bromacil)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione in the form of a dry powder. This mixture is heated to a gentle boil under reflux for approximately three hours. Then the heat is removed and the reaction mixture is poured into ice HCl (100 ml) and stirred for about one hour. The obtained precipitate was separated by vacuum filtration and washed with water and diethyl ether, then dried in vacuum at 50°receiving 330 mg (91%) not quite white powder. TPL=275-277°C; MS: 338(M+I).

NMR: 2,11 (s, 3H), and 2.79 (t, 2H, J=7,13 Hz), 4.09 to (t, 2H, J=7,08 Hz), 7,42 (dd, 1H, J1=8,59 Hz, J2=1.6 Hz), to 8.57 (d, 1H, J=1.77 Hz), 8,13 (d, 1H, J=8,64 Hz), and 11.8 (br s, 1H), 12,64 (br s, 1H).

Example 114

7-Chloro-4-hydroxy-2-(2-methylsulfonylamino)-1,2,5,10-tetrahydropyridine [4,5-b]quinoline-1,10-dione.

To a solution of 7-chloro-4-hydroxy-2-(2-methylthioethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione (0.11 g, 0.33 mm) in methanol (5 ml) and stir at room temperature add Oxon, monopersulfate compound (250 mg, 1.0 mm)dissolved in water (1 ml). The resulting mixture was stirred at room temperature for 17 hours. Add water (10 ml) and the reaction mixture is filtered. The crude product SNO is and mix with water to remove the developer. Filtration and vacuum dried to give analytically pure product as a white solid. Allocated 95 mg, 75%.

Example 115

7-Chloro-4-hydroxy-2-(thiophene-2-ylmethyl)-1,2,5,10-Tetra-hydropyridine[4,5-b]quinoline-1,10-dione.

To a solution of 2-(thiophene-2-ylmethyl)-tert-BUTYLCARBAMATE (1.0 g, 4.4 mm) and 2-pyrrolidide-3-carboxy-7-chlorhydrin-4-it (1.2 g, 3.6 mm) in tetrahydrofuran (75 ml), stir at room temperature add aminobutiramida-carbodiimide (from 0.84 ml, 5.4 mm). This mixture is stirred at room temperature for 2.5 hours, then filtered with suction in the second reaction vessel. To the filtrate (stir at room temperature) add methansulfonate (12 ml, 185 mm). The resulting solution was stirred at room temperature for 17 hours. TLC analysis to this time shows completion of the reaction. The reaction mixture was poured into ice water (200 ml). This suspension is stirred for about 15 minutes and filtered. Vitrified residue after filtration was washed with water and diethyl ether, then dried in vacuum, obtaining analytically pure a specified compound (1.1 g, 84%).

Physical characteristics for sample 111-144 presented in tables 4-8 before the claims.

Alkyl(C1-C6)amino compounds readily react with benzoylchloride, forming alkylbenzene PQDs. For example, the received R12-ethylbenzamide p is vizvolnogo, active as a glycine receptor antagonist.

Example 145

The following illustrated pharmaceutical dosage forms containing the compounds of formula I or its pharmaceutically acceptable salt, given for example the use in therapeutic and prophylactic purposes of any of the preceding examples, the compounds (hereinafter called here "compound X"):

(a) Tabletm/g
Compound X50,0
Mannitol, USP223,75
Sodium crosscarmellose6,0
Maize starch15,0
The hypromellose (receiver array)
USP2,25
Magnesium stearate3,0
(b) Capsule
Compound X10,0
Mannitol, USP488,5
Sodium crosscarmellose15,0
Magnesium stearate1,5

The above formulations may be obtained by conventional means, well known in pharmaceutical technology. Tablets can be coated intersolubility sheath obseravation, for example, the shell of cellulose azettftalat.

Example 146

The composition suitable for parenteral use, obtained by using the compound of example 2:

Parenteral composition:mg/ml
Connection10,0
Meglumin19,5
Destrose, anhydrous39,5
Sterile water for injection, up to1 ml

The solution was prepared using conventional techniques well known in the pharmaceutical field. Typically, the compositions for this class of compounds and their salts, non-acylated compounds can be obtained by dissolving the active compound in an aqueous solution of meglumine (N-methylglucamine), containing equimolar amount or, if dissolution is difficult, a molar excess of meglumine to the connection. In the manufacture of the compositions of the preferred salts of choline. Additives such as dextrose may be added to maintain the osmolality of the composition. Water for injection is added to bring the solution to final volume. Or else, amino acids & bases, such as tromethamine, or L-arginine, can be used for dissolving the active connection.

Example 147

Getting the number is ichno Example 146, but Kalinova salt of compound X is used instead of the compound in Example 2.

Example 148

The receipt includes the use of a 5%aqueous solution of dextrose at a concentration of 10 mg/ml in Kalinovo salt of Compound X.

The previous examples show that there are no restrictions on the use of compounds of formula I or I' (or II or III) and pharmaceutical compositions containing these compounds, for the treatment and/or prevention of paralysis and other diseases associated with it. The following presents the diagrams and formulas clarify how to obtain the compounds of the invention. The compounds described in examples 5, 7, 16 and 20, were inactive in in vitro glycine receptor in the sample and specifically excluded from the compounds of formula I or III.

1. Derivatives pyridazinedione formula II, or tautomers, or pharmaceutically acceptable salt:

where

ring a is ortonormirovannymi by phenyl, monosubstituted R4where R4is halogen;

R1represents (CH2)nL, where n is an integer taking values from 1 to 6, and where L is selected from unsubstituted phenyl or lansoprozole,

or L is selected from phenyl or be zaposlednie, substituted 1 or 2 groups selected from halogen, CN, CF3, (C1-C4)alkyl,

or L is selected from HE, OCOR', SOmR' where m takes on the values 0, 1 or 2, R NR'r", provided that NR'r R" is different from the NH2, NR'r COR",

or L is selected from heterocycle or heteroaryl;

where in each above case, any of the groups R' or R" is independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, phenyl(C1-C4)alkyl, and where any of the groups R' or R" is either unsubstituted or have 1, 2 or 3 substituted at the carbon atoms of the phenyl, HE, O-(C1-C4)alkyl

where in any of the above cases, the heterocycle selected from a five-or six-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, N or S, or its condensed lansoprozole specified heterocycle, where the carbon atom is disubstituted with education5-C7spirography, and the specified heterocycle, where the atom is substituted With About with the formation of carbonyl groups, and where in any of the above cases, heteroaryl selected from thiophene, furan, imidazole, triazole, tetrazole, which is unsubstituted.

2. The compound according to claim 1, where R4is chlorine.

3. The compound according to claim 1 in which the ring a is a 7-chlorophenyl.

4. The compound according to claim 1, selected from the gr is PPI, including

7-chloro-4-hydroxy-2-(2-methylthioethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(2-methyl-2-hydroxypropylamino-ethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

7-chloro-4-hydroxy-2-(furan-2-ylmethyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione;

or pharmaceutically acceptable salt of any of the above compounds.

5. The compound according to claim 4, representing 7-chloro-4-hydroxy-2-(2-furan-2-yl-methyl)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione and has the following structural formula



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

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

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

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, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

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