6-sulfamoylbenzoic-4-carboxylic acid, their derivatives and combinatorial library

 

(57) Abstract:

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims. Also described a combinatorial library based on these compounds. The technical result obtained new compounds possess valuable biological properties. 2 C. and 13 C.p. f-crystals, 1 PL.

The scope of the invention

This invention relates to new chemical substances and new physiologically active substances, compounds leaders and drug candidates (drug-candidates) that can be derived from the screening of combinatorial libraries, as well as to methods for novel compounds and combinatorial libraries.

More specifically the present invention relates to new 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives, physiologically active substances in this series, a combinatorial library of compounds in this series, physiologically active substances (potentially antibacterial, anti-inflammatory, antiviral, immunomodulatory, and so on), as well as to methods of production and use of substances.

are antagonists tachykinins (Tachykinin NK2 and/or NK3) receptors and possess a wide spectrum of physiological activity, which allows to consider them as potential analgesic, anti-inflammatory, anti-arthritis, immunomodulatory drugs (GlaxoSmithKline SpA; Laboratoire GlaxoSmithKline SAS. WO 0238547, 2002).

On the other hand, 6-sulfhemoglobinemia derivatives of the following structure:

are inhibitors of NAD+ ADP-Ribosyltransferase, very promising agents for the treatment of a wide spectrum of neurodegenerative diseases and cancer (Guilford Pharmaceuticals Inc. WO 0190077, 2001).

In this regard, the design of the new 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives, synthesis of new physiologically active substances in this series, the development of methods of their production and the creation of combinatorial libraries of these compounds is a promising approach to the discovery of new compounds leaders with high affinity to tachykinin receptors and devoid of side properties.

As a result of studies on the STN earlier 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives, which possess physiological activity, have developed methods for their production and combinatorial library of compounds.

First 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives, namely 2-phenyl-6-sulfamoylbenzoic-4-carboxylic acid and 2-phenyl-6-(2-pyridinemethanol)quinoline-4-carboxylic acid were described in 1942 [R. Ciusa. Gazzeta Chemica Italiana, 1942, 72, 567 To 570]. Recently it was found that amides of the quinoline-4-carboxylic acids and their derivatives are NK3antagonists [SmithKline Beecham Farmaceutici S. P. A. Pat. PCT WO 9602509 A1, 1996; WO 97/19927, 1997; WO 97/19928, 1997].

in which among the various values of X, Rl, R2, R3, R4and R5the values presented for X=O, R3=SO2NH2(sulfonamide).

In addition, it is known that compounds of a number of 4-carboxyaniline or 6-sulfamoylbenzoyl can have a wide range of physiological activities such as antibacterial [X. Y. Yu, et al. Structure-activity relationship of biphenylquinoline analogs as inhibitors of S. aureus methionyl-TRNA synthetase. 218th ACS Nati Meet (Aug 22-26, New Orleans) 1999, Abst MEDI 296], anti-inflammatory [GlaxoSmithKline SpA; Laboratoire GlaxoSmithKline SAS. WO 0238547 May 16, 2002], antihypertensive [Bristol-Myers Squibb Co. US 6117885 September 12, 2000], immunomodulatory [Kyowa Hakko Kogyo Co., Ltd. E is bretania.

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

“Lead compound” is a compound with outstanding activity related to a particular disease.

“Parallel synthesis” method of conducting combinatorial chemical synthesis library.

“Scaffold” is a General structural formula, or molecular korkas, or invariant connections area common to all compounds included in the combinatorial library.

“Deputy” is a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis.

“Nucleophilic” - electron-excess reagent.

“Electrophilic” - electron-deficient reagent.

“Inert Deputy” ("Non-interfering substituent") - low or directionspanel radical including, but not limited to C1-C7alkyl, C2-C7alkenyl, C1-C7quinil, C2-C7alkoxy, C7L, C7-C12alkaryl, C3-C10cycloalkyl, C3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl, C2-C10alkylsulfonyl, C2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, C7-C12alkaryl, C3-C10cycloalkyl, C3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

“NH-Protective Deputy” is a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds including, but not limited to: amide Deputy, such as the sory substituted benzoyl and others; urethane Deputy, such as optionally substituted C1-C7allyloxycarbonyl, such as methyloxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and others; optionally substituted C1-C7alkyl substituent, such as tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorene and others; sulfanilic the Deputy, for example benzazolyl, p-toluensulfonyl and other More “NH-Protective substituents” described in the book: Protective groups in organic synthesis. Third Edition, Greene, T. W. and Wuts, P. G. M. 1999, p. 494-653. Publisher John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

“Nucleophilic Deputy” is a chemical moiety that is attached to scaffold in the reaction with the nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

“Electrophilic Deputy” is a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example selected from the group of organic halides (optionally substituted C1-C7alkyl halides, optionally substituted aryls1-C7alkyl halides, long is optionally substituted heterocyclyl halides), organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothiocyanatobenzene.

“Aryl” is one or more aromatic cycles, each of which contains 5 or 6 carbon atoms. “Aryl” may be condensed political, such as naphthalene or unfused, such as biphenyl. “Substituted aryl” has one or more “namekawa” deputies.

“Halogen” is fluorine atom, chlorine, bromine or iodine.

“Heterocycle” is one or more saturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. “Heterocycle” may be condensed or frame political, such as benzimidazole, benzoxazole, benzthiazole, quinoline, 1,5,6,8-tetrahydro-2H,4H-1,5-methane-pyrido-[1,2-a][1,5]diasorin, 8-Aza-bicyclo-[3,2,1]octane, octahydro-1,5-methane-pyrido[1,2-a][1,5]diasorin or unfused, for example, as bipyridyl, 3,4,5,6-tetrahydro-2H-[2,3’]bipyridyl.

“Azaheterocycle” - is a quinoline.

“Substituted heterocycle” is a heterocycle having one or more “namekawa” deputies.

The aim of the present invention are new 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives of the General formula (1):

in which R1represents a hydrogen atom, methyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl;

R2represents a hydrogen atom, -C(O)HE;

R1and R2together represent polymethene fragment -(CH2)m;

m has a value from 3 to 7;

R3represents-OH, -O-N+HR5R6R7, -NH2or nucleophilic Deputy selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols;

R2and R3together represent the group-C(O)O - or-C(O)N(R8)-;

R4represents a nucleophilic Deputy selected from the group of primary amines, secondary amines, optionally substituted, the optional frame and optionally condensed heterocyclic compounds containing in the cycle at least one secondary amino group, for example neobyazatelno substituted 1-azepane; optionally substituted 1-piperazinil, optionally substituted 8-azabicyclo[3,2,1]Oct-8-yl, optionally substituted 3,7-diazabicyclo[3.3.1]nonanal, optionally substituted 1,2,3,4,5,6-hexahydro-1,5-methane-pyrido[1,2-a][1,5]diazoline, optionally substituted, decahydro-1,5-methane-pyrido[1,2-a] [1,5]diazoline;

R5, R6and R7independently of one another represent optionally substituted C1-C7-alkyl;

R8is inert Deputy selected from the group comprising optionally substituted C1-C7alkyl, optionally substituted C2-C7alkenyl, optionally substituted C2-C7quinil, optionally substituted C1-C7alkoxy, optionally substituted in the alkyl or aryl fragment C7-C12aralkyl, optionally substituted in the alkyl or heterocyclic fragment C7-C12geterotsiklicheskikh, optionally substituted in the alkyl or aryl fragment C7-C12alkaryl, C3-C10optionally substituted cycloalkyl, optionally substituted C3-C10cycloalkenyl, optionally substituted phenyl, optionally substituted aryl, neobyazatelnoe as the heteroatoms nitrogen, oxygen, sulfur, which may be optional kondensirovannoi with benzene or heterocyclic ring or may enter the frame politics, for example 8-azabicyclo[3,2,1]Oct-3-yl, and azaheterocyclic means a nitrogen-containing 5 to 7-membered heterocycle, which may have an additional heteroatom selected from nitrogen, oxygen or sulfur, and may be condensed with a benzene or heterocyclic ring, excluding the compound (1) in which both R1= phenyl, R2= N, R3= HE, R4= NH(2-pyridyl).

The aim of the present invention is also a new combinatorial library 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives of the General formula (1).

The preferred option of the invention are new 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives of the General formula (1) and a combinatorial library of new 6-sulfamoylbenzoic-4-carboxylic acid and its derivatives of the General formula (1).

Particularly preferred new compounds are:

6-Sulfamoylbenzoic-4-carboxylic acids and their derivatives of the General formula (1):

in which R1represents a hydrogen atom, methyl, optionally substituted FeNi who is hydrogen, -C(O)HE;

R1and R2together are: polymethene fragment -(CH2)m;

m has a value from 3 to 7;

R3represents-OH, -O-N+HR5R6R7, -NH2or nucleophilic Deputy selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols;

R2and R3together represent the group-C(O)O - or-C(O)N(R8)-;

R4represents a nucleophilic Deputy selected from the group of primary amines, secondary amines, optionally substituted, the optional frame and optionally condensed heterocyclic compounds containing in the cycle at least one secondary amino group, such as optionally substituted 1-pyrrolidinyl, optionally substituted morpholine, optionally substituted 1-piperidinyl, optionally substituted 1-azepane; optionally substituted 1-piperazinil, optionally substituted 8-azabicyclo[3,2,1]Oct-8-yl, optionally substituted 3,7-diazabicyclo[3.3.1]nonanal, optionally substituted 1,2,3,4,5,6-hexahydro-1,5-methane-pyrido[1,2-a][1,5]diazoline, optionally substituted, decahydro-1,5-methane-pyrido[1,2-a] [1,5]diazoline;

R5

R8is inert Deputy selected from the group comprising optionally substituted C1-C7alkyl, optionally substituted C2-C7alkenyl, optionally substituted C2-C7quinil, optionally substituted C1-C7alkoxy, optionally substituted in the alkyl or aryl fragment C7-C12aralkyl, optionally substituted in the alkyl or heterocyclic fragment C7-C12geterotsiklicheskikh, optionally substituted in the alkyl or aryl fragment C7-C12alkaryl, C3-C10optionally substituted cycloalkyl, optionally substituted C3-C10cycloalkenyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl, and all values radicals heterocyclyl means a 5-7 membered ring, containing as heteroatoms nitrogen, oxygen, sulfur, which may be optionally condensed with a benzene or heterocyclic ring or may enter the frame politics, for example 8-azabicyclo[3,2,1]Oct-3-yl, and azaheterocyclic means a nitrogen-containing 5 to 7-membered heterocycle, which may have additional gets the m ring, excluding the compound (1) in which both R1= phenyl, R2= N, R3= HE, R4= NN(2-pyridyl).

Even more preferred compounds according to the present invention from 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives of the General formula (1) are:

6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1):

in which R1, R2and R4have the above value excluding connection (1.1), in which both R1= phenyl, R2= N, R3= HE, R4= -NH2and the connection (1.1), in which both R1= phenyl, R2= N, R3= HE, R4= -NH(2-pyridyl).

6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1.1):

in which R4have the above meaning.

6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1.2):

in which R1and R4have the above meaning.

6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1.3):

in which R4have the above significance; p = 1-3.

6-sulfamoylbenzoic-3,4-dicarboxylic acid of General formula (1.1.4):

in which R1, R2and R4have the above meaning;

R3represents-NH2or nucleophilic Deputy selected from the group of primary or secondary amines.

6-sulfamoylbenzoic-4-carboxamide General formula (1.2.1):

in which R3and R4have the above meaning.

6-sulfamoylbenzoic-4-carboxamide General formula (1.2.2):

in which R1, R3and R4have the above meaning.

6-sulfamoylbenzoic-4-carboxamide General formula (1.2.3):

in which R3, R4and R have the above significance.

esters or thioesters 6-sulfamoylbenzoic-4-carboxylic acids of General formula (1.3):

in which R1, R2and R4have the above meaning, R9represents a nucleophilic Deputy selected from the group of alcohols, phenols, mercaptans and thiophenols;

ammonium salt of 6-sulfamoylbenzoic-4-carboxylic acids of General formula (1.4):

in which R1, R2, R4, R5, R6and R7have the above meaning.

8-sulfamoyl the above value.

8-sulfamoyl-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-diones of General formula (1.6):

in which R4and R8have the above meaning.

Preferred are also a combinatorial library of compounds in which each of the constituent compound is 6-sulfamoylbenzoic-4-carboxylic acid or its derivative of the General formula (1).

Used as initial reagents in most cases, are commercially available or easily obtained well-known literature methods. For example, used as starting compounds 6-sulfamerazine (2) are obtained according to the method described in [A. V. Ivachtchenko, A. P. Il yin, V. V. Kobak, D. A. Zolotarev, L. V. Guro, A. S. Trifilenkov, D. M. Ugoleva, J. Combinat. Chem. 2002, 4, 419-428. D. Lee, S. A. Long, J. H. Murray, J. L. Adams, M. E. Nuttall, D. P. Nadeau, K. Kikly, J. D. Winkler, C. M. Sung, M. D. Ryan, M. A. Levy, P. M. Keller, W. E. DeWolf. J. Med. Chem. 2001, 44, 2015-2026].

Below the invention is described using specific examples of the preparation of specific compounds and combinatorial libraries. The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis. Liquid-phase parallel synthesis of new compounds and combinatorial libraries was carried out with ispolzovaniya [Technology Platform, In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p. 5].

The following examples illustrate but do not limit the invention.

General information. All solvents and reagents were obtained from commercial sources, such as ACROS (Belgium), Sigma-Aldrich (USA), Lancaster (England) and Chemdiv (USA). The melting point (so square) were obtained on the instrument company Buchi (Switzerland) model-520.13The NMR spectra were obtained on a spectrometer of the company Bruker model AM-300 and model DRX-500 in dimethyl sulfoxide-d6. Chemical shifts are given in a scale of 5 (ppm). The internal standard tetramethylsilane was. Mass spectra were measured on a device Kratos Model MS-890.

Analytical TLC was performed on silica gel on aluminum plates Silufol UV254(515 cm) (Kavalier, Czech Republic) or on glass plates with 0.25 mm layer of silica gel 60 F254(Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40 μm (Chemapol, Czech Republic). In accordance with these LC/MS all the synthesized compounds had a basic substance content above 95%.

Combinatorial library 6-sulfamoylbenzoic-4-carboxylic General formula (1.1).

Parallelua at 0.97 g (of 10.21 mmol) of KOH in a mixture of 15 ml of water and 10 ml of ethanol, successively added under stirring at room temperature for 5,11 mmol of the corresponding 6-sulfamerazine General formula (2) and 6,13 mol methylene-active carbonyl compounds of General formula (3), pre-dissolved in 5 ml of ethanol. The reaction mixture is boiled for 5-18 hours until the disappearance of the original isatin (2). Control is carried out using thin-layer chromatography (TLC) on silica gel, as eluent a mixture of chloroform with ethanol in a volume ratio of 19:1. For TLC control 0.1 ml of the reaction mixture is dissolved in 1 ml of water. Obtained in each reactor, the solutions are neutralized with 5% hydrochloric acid to pH 3 and extracted with 0.25 ml of ethyl acetate. The organic layers separated and chromatographic on the plates “Silufol UV254” firm Kavalier (Czech Republic).

After the process of the reaction mixtures is distilled off in vacuum, the alcohol, the remains of filtered and evaporated to dryness. The resulting residual was dissolved in minimum amount of water and add 10% hydrochloric acid to pH 2-3. The amount of precipitation is filtered off and dried in vacuum over claritim calcium. The resulting crystalline products extracted with ethyl acetate, chloroform or methylene chloride, the extracts dried bezvadnym sulfate is tx2">

Get a combinatorial library, including 11 6-sulfamoylbenzoic-4-carboxylic acid (1.1), which is a crystalline substance, soluble in ethyl acetate, chloroform, methylene chloride, sparingly soluble in ethanol and acetone, slightly soluble in ether and insoluble in hexane.

Listed below are the names of the acids (1.1) included in the combinatorial library used for the synthesis of methylene-active carbonyl compounds (3), the outputs, the melting point and spectral data.

Example 1.

6-(4-Diethylaminophenyl)-4-quinoline-carboxylic acid, (1.1.1) {1}: methylene-active carbonyl compounds (3) - malonic acid, or diethylmalonate, or 3-morpholino-3-oxopropionate; yield 47%; so pl. C (decomp.); IR: 1707 cm-1; N1TMR 1.068 (t, 6N), 3.246 (q, 4H), 8.1 (d, J=4.4 Hz, 1H), 8.1 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 8.3 (d, J=8.8 Hz, 1H), 9.2 (d, J=4.4 Hz, 1H), 9.3 (d, J=2.1 Hz, 1H), 14.17 (bs, 1H); MS m/z 309 (M+).

Example 2.

6-(4-Metilprednisolone)-4-quinoline-carboxylic acid, (1.1.1){2}: methylene-active carbonyl compounds (3) - malonic acid, or diethylmalonate, or 3-morpholino-3-oxopropionate; yield 41%; so pl. C (with decomp.); IR: 1705 cm-1; H1TMR 0.93 (d, 3H), 1.30 (m, 3H), 1.70 (d, 2H), 2.33 (m, 2H), 3.76 (d, 2H), 4.70 (bs, 1H) 8.00 (d, 1H), pyridyl)-4-quinoline-carboxylic acid, (1.1.2){1}: methylene-active carbonyl compound (3) - 2-acetylpyridine; yield 59%; so pl. >300C; 0.91 (d, J= 4.80 Hz, 3H), 1.20-1.38 (m, 3H), 1.71 (d, J=9.90 Hz, 2H), 2.27-2.38 (m, 2H), 3.77 (d, J=11.60 Hz, 2H), 7.46-7.52 (m, 1H), 7.93-7.99 (m, 1H), 8.01 (dd, J=1.40 Hz, J=8.25 Hz, 1H), 8.30 (d, J=8.90 Hz, 1H), 8.69 (d, J=8.25 Hz, 1H), 8.76 (d, J=4.40 Hz, 1H), 9.24 (s, 1H), 9.33 (br s, 1H);13C NMR 21.24, 29.17, 32.88, 46.01, 121.03, 121.41, 123.91, 125.54, 126.41, 127.07, 131.26, 135.10, 137.48, 137.65, 149.22, 149.55, 153.64, 157.66, 166.67; MS w/z 410 (M+).

Example 4.

6-(4-Metilprednisolone)-2-(3-pyridyl)-4-quinoline-carboxylic acid, (1.1.2){2}: methylene-active carbonyl compound (3) - 3-acetylpyridine; yield 80%; mp >300C;1N TMR , 0.90 (d, J=5.30 Hz, 3H), 1.17-1.38 (m, 3H), 1.71 (d, J=12.50 Hz, 2H), 2.29-2.40 (m, 2H), 3.75 (d, J=11.20 Hz, 2H), 7.55-7.61 (m, 1H), 8.05 (dd, J=1.00 Hz, J=8.70 Hz, 1H), 8.34 (d, J= 8.70 Hz, 1H), 8.60-8.74 (m, 2H), 8.68 (s, 1H), 9.25 (s, 1H), 9.46 (br s, J=1.00 Hz, 1H);13With NMR, 21.22, 29.18, 32.90, 45.99, 121.01, 123.02, 123.97, 126.29, 127.22, 131.22, 132.89, 135.04, 138.50, 148.54, 149.36, 151.08, 156.60, 166.65; MS m/z 410 (M+).

Example 5.

6-(4-Metilprednisolone)-2-(4-pyridyl)-4-quinoline-carboxylic acid, (1.1.2){1}: methylene-active carbonyl compound (3) - 4-acetylpyridine; yield 68%; so pl. >300C;1N TMR 0.92 (d, J=4.80 Hz, 3H), 1.22-1.35 (m, 3H), 1.71 (d, J=9.90 Hz, 2H), 2.28-2.38 (m, 2H), 3.78 (d, J=11.80 Hz, 2H), 8.04(dd, J=1.75 Hz, J=8.85 Hz, 1H), 8.22 (dd, J=1 Hz, J=4.75 Hz, 2H), 8.32 (d, J=8.85 Hz, 1H), 8.69 (s, 1H), 8.76 (dd, J=1 Hz,7=4.75 Hz, 2H), 9.31 (d, J=1.75 Hz, 1H);13C NMR 21.22, 29.14, 32.84, 45.88 Metilprednisolone)-2-(3-thienyl)-4-quinoline-carboxylic acid, (1.1.2){4}: methylene-active carbonyl compound (3) - 3-acetylthiophene; yield 27%; so pl. >S;1N TMR 0.91 (d, J=5.00 Hz, 3H), 1.21-1.34 (m, 3H), 1.70 (d, J=10.70 Hz, 2H), 2.26-2.36 (m, 2H), 3.75 (d, J=10.20 Hz, 2H), 7.21 (m, J=3.85 Hz, J=3.10 Hz, 1H), 7.65 (d, J=3.85 Hz, 1H), 7.95 (dd, J=1.00 Hz, J=8.90 Hz, 1H), 8.02 (d, J=3.10 Hz, 1H), 8.18 (d, J=8.90 Hz, 1H), 8.52 (s, 1H), 9.20 (br s, 1H);13C NMR 21.19, 29.12, 32.80, 45.95, 191.79, 122.71, 126.35, 127.22, 128.90, 129.04, 130.23, 131.43, 133.91, 138.55, 143.21, 149.25, 154.10, 166.67; MS m/z 410 (M+).

Example 7.

2-(5-Methyl-2-furyl)-6-(4-metilprednisolone)-4-quinoline-carboxylic acid, (1.1.2){5}: methylene-active carbonyl compound (3) - 2-acetyl-5-methylfuran; output 1.5%; so pl. >S;1N TMR 0.88 (d, J=5.00 Hz, 3H), 1.30 (m, 3H), 1.70 (d, J=10.65 Hz, 2H), 2.32 (m, 2H), 2.50 (s, 3H), 3.75 (d, J=10.15 Hz, 2H), 6.26 (d, J=3.45 Hz), 7.28 (d, J=3.45 Hz, 1H), 7.94 (dd, J=1.00 Hz, J=8.90 Hz, 1H), 8.12 (d, J=8.90 Hz, 1H), 8.41 (s, 1H), 9.23 (br s, 1H); MS m/z 414 (M+).

Example 8.

6-(4-Morpholinomethyl)-2-(2-pyridyl)-4-quinoline-carboxylic acid, (1.1.2){6}: methylene-active carbonyl compound (3) 2-acetylpyridine; yield 77%; so pl. >300C;1N TMR 2.96-3.12 (m, 4H), 3.61-3.76 (m, 4H), 7.44-7.52 (m, 1H), 7.91-8.00 (m, 1H), 8.02 (dd, J=1.80 Hz, J=9.10 Hz, 1H), 8.32 (d, J=9.10 Hz, 1H), 8.70 (d, J=7.90 Hz, 1H), 8.76 (d, J=4.70 Hz, 1H), 9.27 (s., 1H), 9.38 (br s, 1H).

Example 9.

6-(1-Azepane)-2-(3-pyridyl)-4-quinoline-carboxylic acid, (1.1.2){7}: methylene-active carbonyl compound (3) 3-acetylpyridine 1H), 8.63-8.76 (m, 2H), 8.66 (s, 1H), 9.26 (br s, 1H), 9.46 (s, 1H).

Example 10.

7-(4-Metilprednisolone)-1,2,3;4-tetrahydro-9-greencarbon acid, (1.1.3){7}: methylene-active carbonyl compounds (3) cyclohexanone; output 56.8%; so pl. >300C;1N TMR 0.91 (d, J=4.70 Hz, 3H), 1.17-1.34 (m, 3H), 1.69 (d, J=9.50 Hz, 2H), 1.88-2.05 (m, 4H), 2.18-2.32 (m, 2H), 2.98-3.17 (m, 4H), 3.71 (d, J=11.30 Hz, 2H), 7.84 (dd, J=1.00 Hz, J=8.70 Hz, 1H), 8.04 (d, J=8.70 Hz, 1H), 8.14 (br s, 1H);13C NMR 21.20, 21.70, 21.88, 26.41, 29.18, 32.82, 33.59, 45.95, 121.26, 124.78, 125.98, 128.04, 129.27, 133.67, 139.70, 146.51, 162.66, 167.74; MS m/z 388 (M+).

Example 11. 2-Methyl-6-(4-metilprednisolone)-3,4-hinolincarbonova acid, (1.1.4){1}: methylene-active carbonyl compounds (3) - ethyl of acetoacetate; yield 39%; so pl. 212-S;1H TMR 0.90 (d, J=5.90 Hz, 3H), 1.16-1.36 (m, 3H), 1.69 (d, J=12.30 Hz, 2H), 2.24-2.33 (m, 2H), 2.83 (s, 3H), 3.71 (d, J=11.90 Hz, 2H), 7.99 (dd, J=1.75 Hz, J=9.00 Hz, 1H), 8.15 (d, J=9.00 Hz, 1H), 8.46 (d, J=1.75 Hz, 1H);13C NMR 21.24, 24.25, 29.14, 32.83, 45.96, 120.68, 125.99, 126.64, 127.92, 130.31, 134.63, 139.50, 148.11, 158.59, 166.67. 167.70; MS m/z 392 (M+).

Example 12.

N-4-Benzyl-6-(4-metilprednisolone)-4-quinoline-carboxamide, (1.2.1) {7}:

Method A. To a suspension of 1.00 mmol of 6-(4-metilprednisolone)-4-quinoline-carboxylic acid (1.1.1) {2}, 10 ml of methanol was added 1.10 mmol of benzylamine and boil the reaction mass 5 minutes. From the resulting reaction mass platy and boil with azeotropic distillation of the water of 60 hours, then the reaction mass is then cooled and completely distilled off toluene under vacuum. The remainder chromatographic on silica gel with a mixture of methylene chloride : methanol (19:1 by volume). Get amide (1.2.1){1}, which is recrystallized from a mixture of methylene chloride-hexane. Yield 41%; so square 138-140 P;1H TMR of 0.94 (d, 3H), of 1.29 (m, 3H), 1.70 to (d, 2H), and 2.27 (m, 2H), 3,70 (d, 2H), 2,71 (d, 2H), 7,25-the 7.43 (m, 5H), 7,74 (d, 1H), 7,98 (d, 1H), 8,23 (d, 1H), total of 8.74 (s, 1H), 9,11 (d, 1H), to 9.32 (t, 1H).

Method B. To a suspension of 0.66 mmol acid (1.1.1){2} in 5 ml of dry dioxane are added to 1.32 mmol of benzylamine and stirred at 75S 12 hours. Dioxane is completely distilled off in vacuo and to the residue was added 15 ml of water, the precipitate is filtered off, washed with water, extracted with methylene chloride (310 ml), the extract is dried over anhydrous sodium sulfate, filtered and evaporated to dryness in a vacuum. Get amide (1.2.1){1} output is 63% identical to the obtained by the method of A.

Examples 12-25.

N-4-(3-triptoreline)-6-(4-metilprednisolone)-2-(4-pyridyl)-4-chinainternational, (1.2.2) {7}: To a suspension of 1 equivalent of acid (1.1.1) {2} in dry methylene chloride with vigorous stirring and at room temperature was added 1.2 equivalent of chloride tonila, stirred at room temperature until the formation of homogeneous solution. the complete disappearance of the original acid (1.1.1) {2} in the reaction mass (control by TLC, silica gel, chloroform: methanol = 19:1 by volume). To the resulting solution chlorhydric acid (1.1.7){2} add 1.05 equivalent of 3-triptorelin and 0.9 equivalent of triethylamine. The reaction mixture is stirred until completion of the reaction (TLC control). After the reaction to the reaction mass with stirring, add water, the organic layer is separated and washed with water and a 1% solution of hydrochloric acid and again with water, dried with anhydrous sodium sulfate, filtered and evaporated in vacuum to dryness. Get amide (1.2.2){7} exit 56%, so pl. 235-S;1H TMR of 0.93 (d, J=5,30 Hz, 3H), 1,22-to 1.38 (m, 3H), 1,73 (d, J=11,10 Hz, 2H), 2,30-to 2.42 (m, 2H), 3,79 (d, J=11,40 Hz, 2H), 7,43 (dd, J=1,00 Hz, J=7,60 Hz, 1H), to 7.59 (m, 1H,), 8,07 (dd, J=1,70 Hz, J=8,95 Hz, 1H), 8,15 (dd, J=1,00 Hz, J=to 8.20 Hz, 1H), they were 8.22 (br s, 1H), 8,31 (d, J=5,70 Hz, 2H), 8,35 (d, J=8,95 Hz, 1H), 8,59 (s, 1H), 8,75-8,82 (m, 3H), 11,08 (s, 1H);13C NMR 21,16, 29,14, 32,80, 45,93, 116,27, 119,10, 120,71, 121,45, 123,03, 123,64, 125,64, 127,51, 129,32, 129,74, 130,18, 131,41, 135,27, 139,25, 143,08, 144,23, 148,88, 150,57, 156,21, 164,51; MS m/z 554 (M+).

A combinatorial library of 6-(4-metilprednisolone)-quinoline-4-carboxamido General formula (1.2). Parallel synthesis of combinatorial libraries spend synthesizer "CombiSyn-012-3000". In each of the 7 reactors synthesizer download, 1.00 mmol acid (1.1.1) {2} in 10 ml of methanol was added 1.10 mmol of the corresponding amine (4) and who headed the remainder of the add 5 ml of phosphorus oxychloride or chloride tiomila and stirred for 3 hours at a low boil. Then the reaction mass is cooled and evaporated in vacuum to dryness. To the residues was added 25 ml of water and finely ground soda to a pH of 8-9.

The precipitation is filtered off, washed on the filter with water, dried and extracted with methylene chloride. The extracts are dried over anhydrous sodium sulfate, filtered and evaporated in vacuum to dryness. The products obtained is recrystallized from a suitable solvent and obtain a combinatorial library, including 7 6-(4-metilprednisolone)quinoline-4-carboxamide (1.2). Their names, outputs, melting point and spectral data are given below.

Example 12-1.

N-4-Benzyl-6-(4-metilprednisolone)-4-chinainternational, (1.2.1) {1}: yield 37%; the product is identical to that obtained in example 12.

Example 13.

6-(4-Metilprednisolone)-N-4-(2-thienylmethyl)-4-quinoline-carboxamide, (1.2.1){2}: yield 88%; so pl. 139-C (methylene chloride-hexane); 1H TMR of 0.90 (d, 3H), 1,25 (m, 3H), 1,68 (d, 2H), and 2.27 (m, 2H), 3,68 (d, 2H), 4,73 (d, 2H), 6,97 (t, 1H), 7,07 (d, 1H), 7,35 (d, 1H), 7,72 (d, 1H), to 7.99 (d, 1H), 8,24 (d, 1H), 8,71 (s, 1H), 9,12 (d, 1H), 9,48 (t, 1H).

Example 14.

Methyl-6-(4-metilprednisolone)-4-chinainternational-acetate, (1.2.1) {3}: yield 56%; so pl. 89-91P (methylene chloride-hexane); 1H TMR of 0.91 (d, 3H), of 1.29 (m, 3H), 1.70 to (d), 2,31 (m, 2H), 3 is C-carbonylation-3-yl)-6-(4-metilprednisolone)-4-chinainternational, (1.2.1) {4}: yield 76%; so pl. 207-C (with decomp.) (methylene chloride-hexane); 1H TMR to 0.92 (d, 3H), of 1.30 (m, 3H), 1,71 (d, 2H), 2,32 (m, 2H), of 3.77 (d, 2H), with 3.89 (s, 3H), 7,81 (d, 1H), 7,94 (d, 1H), 8,03 (d, 1H), 8,27 (d, 1H), 8,29 (d, 1H), 8,86 (s, 1H) which 9.22 (d, 1H), 11,04 (s, 1H).

Example 16.

N-4-(4-Ethoxycarbonylphenyl)-6-(4-metilprednisolone)-4-quinoline-carboxamide, (1.2.1) {5}: yield 92%; so pl. 237-S (methylene chloride-hexane); 1H TMR of 0.95 (d, 3H), 1,32 (m, 3H), of 1.42 (t, 3H), 1,73 (d, 2H), 2,34 (m, 2H), 3,74 (d, 2H), 4,33 (q, 2H), 7,89 (d, 1H), 7,97 (m, 5H), of 8.27 (d, 1H), to 8.70 (s, 1H) 9,18 (d, 1H), 10,98 (s, 1H).

Example 17.

N-4-(Diethyl)-6-(4-metilprednisolone)-4-chinainternational, (1.2.1) {6}: yield 52%; yield 31%; so pl. 127-C (cyclohexane); 1H TMR to 0.88 (d, 3H), of 1.01 (t, 3H), 1,22 (m, 3H), of 1.31 (t, 3H), 1.69 in (d, 2H), 2,28 (m, 2H), 3,10 m. 2H), 3,66 (m. 2H), 3,70 (d, 2H), 7,56 (d, 1H), 7,98 (d, 1H), 8,04 (s, 1H), 8,24 (d, 1H), 9,07 (d, 1H).

Example 18.

N-4-(2-Chloro-ethyl)-6-(4-metilprednisolone)-4-chinainternational, (1.2.1) {7}: yield 18%; so pl. 159-160S (methylene chloride-hexane); 1H TMR of 0.94 (d, 3H), 1,32 (m, 3H), 1,72 (d, 2H), 2,31 (m, 2H, in), 3.75 (m, 6H), of 7.69 (d, 1H) 8,54 (d, 1H), 8,18 (d, 1H), 8,72 (s, 1H), 9,01 (t, 1H), 9,06 (d, 1H).

Combinatorial library 6-sulfamoylbenzoic-4-carboxamido General formula (1.2). Parallel synthesis of combinatorial libraries is carried out in two synthesizers "CombiSyn-012-3000". In each of the 18 reactors used both synths segregates temperature, was added 1.1 equivalent of 1,1’-carbonyldiimidazole and continue to stir until complete dissolution of the acid. On 1 g of the acid (1.1) using 40 ml of methylene chloride. Depending on the acid while stirring until complete dissolution ranges from 30 minutes to several hours. Education imidazolidin acids (1.1.8) monitored by TLC (silica gel, chloroform : methanol = 19:1 by volume). After the formation of imidazolines to the reaction mixture under stirring and at room temperature was added 1.1 equivalent of the appropriate amine (4), after which the reaction mixture is boiled for 5 hours. The end of the reaction is controlled by TLC. After completion of the reaction to the reaction mass with stirring, add 2% soda solution, the organic layer was separated and sequentially washed with a 1% solution of soda, water and a 1% solution of hydrochloric acid and again with water, dried with anhydrous sodium sulfate, filtered and evaporated in vacuum to dryness. Get amides of (1.2), which is recrystallized from suitable solvents. Get a combinatorial library, including 18 6-sulfamoylbenzoic-4-carboxamide (1.2). Their names, outputs, melting point and spectral data are given below.

1H TMR to 0.92 (d, J=5,30 Hz, 3H), 1,19-to 1.37 (m, 3H), 1,46 and 1.80 (m, 8H), 1,87-to 1.98 (m, 2H), 2,28-of 2.36 (m, 2H), 3,23-to 3.34 (m, 2H), 3,74 (d, J=11,50 Hz, 2H), and 2.83 (s, 3H), 3.71 (d, J=11,90 Hz, 2H), 3,62-3,98 (m, 1H), 7,47-EUR 7.57 (m, 3H), 7,98 (dd, J=1,60 Hz, J=8,75 Hz, 1H), 8,08 (d, J=1,60 Hz, 1H), 8,12 (s, 1H), compared to 8.26 (d, J=8,75 Hz, 1H), 8,29-to 8.34 (m, 2H);13C NMR 21,19, 25,83, 27,10, 28,43, 29,13, 32,83, 44,68, 45,88, 48,81, 116,22, 121,83, 124,75, 126,92, 127,21, 128,51, 130,12, 130,79, 133,72, 137,02, 144,70, 148,35, 157,97, 165,63; MS m/z 394 (M+-C6H12N), 365 (M+-C6H12NCO), 330 (M+-C6H12NSO2).

Example 20.

N-4-(4-Methyl-phenethyl)-6-(1-asianlolitas)-2-(3-pyridyl)-4-chinainternational, 1.2.2) {2}: yield 80%; so pl. 246-S;1H TMR to 1.60 (br s, 4H), 1,72 (br s, 4H), 2,32 (s, 3H), 2,99 (m, 2H), 3,32 (br s, 4H), 3,57-and 3.72 (m, 2H), 7,07 (d, J=0,80 Hz, 2H), 7,19 (d, J=0,80 Hz, 2H), 7,52-7,58 (m, 1H), 8,04 (dd, J=1,00 Hz, J=8,90 Hz, 1H), to 8.20 (s, 1H), 8,25 (d, J=8,90 Hz, 1H), 8,60-to 8.70 (m, 2H), 8,80 (br s, 2H), to 9.45 (s, 1H).

Example 21.

N-4-(2-Furylmethyl)-6-morpholinomethyl-2-(2-pyridyl)-4-chinainternational (1.2.2){3}: yield 53%; so pl. 255-S;1H TMR 2,90-3,10 (m, 4H), 3,60-of 3.80 (m, 4H), 4,60 (d, J=5.10 Hz, 2H) 6,33 (d, J=1.00 Hz, 1H), 6.42 per (d, J=1.00 Hz, 1H), 7,55-to 7.61 (m, 2H), 8,03-8,10 (m, 2H), 8,35 (d, J= to 8.20 Hz, 1H), 8,65 is 8.75 (m, 1H), at 8.60 (br s, J=1,00 Hz, 1H), 8,75-8,83 (m, 1H), 8,78 (s, 1H), 9,58 (t, J=5,10 Hz, 1H).

Example 22.

N-4-(3-Methoxypropyl)-6-(4-methylpiperidino-sulfonyl)-2-(2-thienyl)-4-chinainternational (1.2.2){4}: yield 14%; mp 241-S;1H TMR of 0.91 (d, J=5,00 Hz, 3H), 1,20-1,40 (m), 1.70 to z, J=9,20 Hz, 1H), 8,01 (d, J=3,10 Hz, 1H), 8,14 (d, J=9,20 Hz, 1H), 8,17 (s, 1H), 8,67 (d, J=1,10 Hz, 1H), 8,80 (t, J=4,50 Hz, 1H).

Example 23.

N-4-(3-Ethyl-3-methylaminopropyl)-6-morpholinomethyl-2-(2-pyridyl)-4-chinainternational (1.2.2) {5}: yield 50%; so pl. 206-S;1N TMR of 1.02 (t, J=3,20 Hz, 3H), 1,90 (t, J=3,10 Hz, 3H), of 2.20 (s, 3H), 2,90 was 3.05 (m, 4H), 3,35 is-3.45 (m, 4H), 3,49 (q, J=3,20 Hz, 3H), 3,60-3,70 (m, 4H), 6.35mm (d, J=7,30 Hz, 1H), 6.48 in (s, 1H), of 6.49 (d, J=7,30 Hz, 1H), 6,99 (t, J=7,30 Hz, 1H), 7,54-to 7.61 (m, 1H), 8,00-8,10 (m, 2H), 8,35 (d, J=9,45 Hz), 8,63-8,73 (m, 1H), total of 8.74 (br s, 1H), 8,75-8,80 (m, 1H), 8,82 (s, 1H), 9,07 (t, J=6,30 Hz, 1H).

Example 24.

Ethyl 1-[6-morpholino-sulfonyl-2-(2-pyridyl)-4-finalisations]-4-piperidinecarboxylate (1.2.2){6}: yield 54%; so pl. 112-115S;1H TMR 1,17-4,80 (br m, 9H), to 1.22 (t, J=6,40 Hz, 3H), of 3.00 (m, 4H), to 3.67 (m, 4H), 4,10 (q, J=6,40 Hz, 3H), 4,40-5,80 (m, 1H), 7,46-rate of 7.54 (m, 1H), 7,94-with 8.05 (m, 1H), 8,04 (dd, J=1,00 Hz, J=9,90 Hz, 1H), 8,09-to 8.20 (m, 1H), a 8.34 (d, J=9,90 Hz, 1H), to 8.62 (br s, 1H), 8,66-8,80 (m, 2H).

Example 25 was 12-25.

Example 26.

N-4-Benzyl-6-morpholino-sulfonyl-2-(2-pyridyl)-4-chinainternational, (1.2.2) {8}: yield 40%; so pl. 268-270P (ethanol);1H TMR 2,80 was 3.05 (m, 4H), 3,50-3,75 (m, 4H), 4,60 (d, 2H, J=6,60 Hz), 7,20-of 7.70 (m, 6H), 7,95-8,10 (m, 4H), to 8.34 (d, J=of 7.90 Hz), 8,60 cent to 8.85 (m, 5H), of 9.56 (m, 1H, J=6,60 Hz).

Example 27.

N-4-ISO-Propyl-6-morpholinomethyl-2(2-pyridyl)-4-chinoline-carboxamid, (1.2.2){9}: yield 44%; so pl. 242-C (from ethanol);1H TMR of 1.30 (d, 6H, J=6,40 Hz), 2,92-3,10 (m, 4H), 3,60 of 3.75 (m, 4H), 3.20-4.32 2">

N-4-Benzyl-6-(4-metilprednisolone)-4-chinainternational (1.2.2) {10}: yield 24%; so pl. 266-C (from ethanol);1N TMR to 0.88 (d, J=5.00 Hz, 3H), 1,12-of 1.35 (m, 3H), 1,68 (d, J=10,80 Hz, 2H), 2,22 to 2.35 (m, 2H), 3,65 (d, J=10,20 Hz, 2H), br4.61 (d, J=6,20 Hz, 2H), 7,25 (m, J=3,90 Hz, J=3,10 Hz, 1H), 7,30 (t, J=6,30 Hz, 1H), 7,37 (t, J=6,30 Hz, J=7,50 Hz, 2H), 7,44 (d, J=7,50 Hz, 1H), of 7.75 (d, J=3,90 Hz, 1H), 7,95 (dd, J=1,15 Hz, J=9,20 Hz, 1H), 8,10 (d, J=3,10 Hz, 1H), 8,16 (d, J=9,20 Hz, 1H), 8.30 to (s, 1H), 8,68 (d, J=1,15 Hz, 1H), 9,45 (t, J=6,20 Hz, 1H).

Example 29.

N-4-(4-Were)-6-(1-asianlolitas)-2-(3-pyridyl)-4-chinainternational, (1.2.2) [11}: yield 80%; so pl. 246-C (from ethanol);1H TMR to 1.60 (br s, 4H), 1,72 (brs, 4H), 2,32 (s, 3H), 2,99 (m, 2H), 3,32 (br.s, 4H), 3,57-and 3.72 (m, 2H), 7,07 (d, J 0.80 Hz, 2H), 7,19 (d, J=0.80 Hz, 2H), 7,52-7,58 (m, 1H), 8,04 (dd, J=1.00 Hz, J=8,90 Hz, 1H), to 8.20 (s, 1H), 8,25 (d, J=8,90 Hz, 1H), 8,60-to 8.70 (m, 2H), 8,80 (br s, 2H), to 9.45 (s, 1H).

Example 30.

N-4-(3-ISO-Propoxyphenyl)-6-(metilprednisolone)-2-(3-pyridyl)-4-chinainternational, (1.2.2) {12}: method G - yield 73%; so pl. 222-C (from ethanol); 1H TMR of 0.91 (d, J=5,00 Hz, 3H), of 1.30 (d, J=7,40 Hz, 6H), 1,22-of 1.32 (m, 3H), 1,71 (d, J=the 10.40 Hz, 2H), 1,89 (t, J=7,45 Hz, 2H), 2,25-to 2.40 (m, 2H), 3,40-of 3.60 (m, 5H), 3,80 (d, J=the 10.40 Hz, 2H), of 7.48-7,53 (m, 1H), 7,98 (dd,7=1.00 Hz, J=to 8.70 Hz, 1H), 8,25 (d, J=to 8.70 Hz, 1H), with 8.33 (s, 1H), 8,64-8,72 (m, 2H), 8,77 (t, J=5,10 Hz, 1H), cent to 8.85 (br s, J=1.00 Hz, 1H), 9,48 (s, 1H).

Example 31.

N-4-(4-Methylbenzyl)-6-(metilprednisolone)-2-(3-pyridyl)-4-chinainternational, (1.2.2){13}: method G - yield 49%; so pl. 251-C (from alcohol is 2H), to 7.35 (d, J=to 8.45 Hz, 2H), 7,53-7,58 (m, 1H), 8,00 (dd, J=1,00 Hz, J=8,10 Hz, 1H), compared to 8.26 (d, J=to 8.70 Hz, 1H), scored 8.38 (s, 1H), 8,63-8,77 (m, 2H), 8,83 (br s, J=1,00 Hz, 1H), 9,37 (t, J=ceiling of 5.60 Hz, 1H), 9,50 (s, 1H).

Example 32.

N-4-(Methyl)-6-(metilprednisolone)-2-(2-pyridyl)-4-chinainternational, (1.2.2) {14}: method G - yield 52%; so pl. 275-C (from ethanol); 1H TMR to 0.92 (d, J=5,00 Hz, 3H), 1,21-of 1.40 (m, 3H), of 1.75 (d, J=10,00 Hz, 2H), 2,28 at 2.45 (m, 2H), to 3.02 (d, J=7,20 Hz, 3H), of 3.73 (d, J=10,00 Hz, 2H), 7,42-of 7.55 (m, 1H,), of 7.90-8.05 (m, 2H), of 8.25 (d, J=9,10 Hz, 1H), 8,68-8,88 (m, 5H).

Example 33.7.

N-4-(4-Methylbenzyl)-6-(metilprednisolone)-2-(2-pyridyl)-4-chinainternational, (1.2.2){75}: method G - output 80%; so pl. 267 -269 ° (from ethanol); 1H TMR of 0.91 (d, J=4.50 Hz, 3H), 1,22-to 1.38 (m, 3H), 1,70 (d, J=11,50 Hz, 2H), 2,25-to 2.40 (m, 2H), 2,35 (s, 3H), 3,74 (d, J=11,50 Hz, 2H), 4,69 (d, J=7.20 Hz, 2H), 7,15 (d, J=6,70 Hz, 2H), 7,38 (d, J=6.70 Hz, 2H), 7,38-of 7.48 (m, 1H), 7,80-with 8.05 (m, 2H), 8,24 (d, J=9,10 Hz, 1H), 8,68-8,73 (m, 2H), up 8.75 (d, J=4,20 Hz, 1H), 8,78 (s, 1H), of 9.30 (br s, 1H).

Example 34.

N-4-(2-furylmethyl)-6-morpholinomethyl-2-(2-pyridyl)-4-chinainternational, (1.2.2) {16}: method G - yield 53%; So pl. 255-C (from ethanol); 1H TMR 2,90-3,10 (m, 4H), 3,60-of 3.80 (m, 4H), 4,60 (d, 2H, J=5,10 Hz) 6,33 (d, J=1.00 Hz, 1H), 6.42 per (d, J=1,00 Hz, 1H), 7,55-to 7.61 (m, 2H), 8,03-8,10 (m. 2H), 8,35 (d, J=to 8.20 Hz, 1H), 8,65 is 8.75 (m, 1H), at 8.60 (br s, J=1,00 Hz, 1H), 8,75-8,83 (m, 1H), 8,78 (s, 1H), 9,58 (t, 1H, J= 5,10 Hz).

Example 35.

Ethyl [6-morpholinomethyl-2-(2-pyridyl)-4-finalisations]-4-piperidinecarboxylate, (1.2.2){17}: IU the, H), 7,46-rate of 7.54 (m, 1H), 7,94-with 8.05 (m, 1 H), of 8.04 (dd, J=1,00 Hz, J=9,90 Hz, 1H), 8,09-to 8.20 (m, 1H), 8.34 per (d, J=9,90 Hz, 1H), to 8.62 (br s, 1H), 8,66-8,80 (m, 2H).

Example 36.

N-4-(3-Methoxypropyl)-6-(metilprednisolone)-2-(2-thienyl)-4-chinainternational, (1.2.2){18}: method G out 14%; so pl. 241-C (from ethanol); 1H TMR of 0.91 (d, J=5.00 Hz, 3H), 1,20-1,40 (m, 3H), 1,70 (d, J=10,80 Hz, 2H), of 1.88 (t, J=7,00 Hz, 2H), 2,22-of 2.38 (m, 2H), 3,32 (s, 3H), 3,40-of 3.54 (m, 4H), of 3.75 (d, J= 10,80 Hz, 2H), 7,22 (m, J=3,90 Hz, J=3,10 Hz, 1H), 7,63 (d, J=3,90 Hz, 1H), to 7.93 (dd, J=1,10 Hz, J=9.20 Hz, 1H), 8,01 (d, J=3,10 Hz, 1H), 8,14 (d, J=9,20 Hz, 1H), 8,17 (s, 1H), 8,67 (d, J=1,10 Hz, 1H), 8,80 (t, J=4,50 Hz, 1H).

Example 37.

N-4-(3-Ethyl-3-methylaminopropyl)-6-morpholinomethyl-2-(2-pyridyl)-4-chinainternational, (1.2.2){19}: method G - output 50%; so pl. 206-C (from ether); 1H TMR of 1.02 (t, J=3,20 Hz, 3H), 1,90 (t, J=3,10 Hz, 3H), of 2.20 (s, 3H), 2,90 was 3.05 (m, 4H), 3,35 is-3.45 (m, 4H), 3,49 (q, J=3,20 Hz, 3H), 3,60-3,70 (m, 4H), 6.35mm (d, J=7,30 Hz, 1H), 6.48 in (s, 1H), of 6.49 (d, J=7,30 Hz, 1H), 6,99 (t, J=7,30 Hz, 1H), 7,54-to 7.61 (m, 1H), 8,00-8,10 (m, 2H), 8,35 (d, J=9,45 Hz, 1H), 8,63-8,73 (m, 1H), total of 8.74 (br s, J=1,00 Hz, 1H), 8,75-8,80 (m, 1H), 8,82 (s, 1H), 9,07 (t, J=6,30 Hz, 1H).

Example 38.

2-Methyl-6-(metilprednisolone)-4-chinainternational, (1.2.2){20}. Stirred at room temperature to 2.29 g (7.43 mmol) of 6-(metilprednisolone)isatin (2) {1}, 17 ml of acetone (229.20 mmol) in 85 ml (1200 mmol) of 25% aqueous ammonia for 2 hours, after which withstand the reaction mass for 15 hours PR is Tlisova of methylene chloride. Get 0,89 g (34%) of the product (1.2.2){20} with the so-sq >S.1H TMR of 0.91 (d, J=5,30 Hz, 3H), of 1.20 to 1.34 (m, 3H), 1,70 (d, J=the 10.40 Hz, 2H), 2,24 is 2.33 (m, 2H), 2,77 (s, 3H), of 3.73 (d, J=11,30 Hz, 2H), 7,63 (s, 1H), 7,72 (br s, 1H), 7,89 (dd, J=1,70 Hz, J=8,75 Hz, 1H), 8,07 (d, J=is 8.75 Hz, 1H), 8,14 (br s, 1H), up 8.75 (dd, J=1,75 Hz, 1H);13C NMR 21,20, 24,99, 29,15. 37,78, 45,94, 121,26, 121,75, 126,09, 126,60, 129,98, 133,27, 142,51, 148,68, 161,89, 167,72; MS m/z 347 (M+).

Example 39.

2-Terbisil 6-(metilprednisolone)-4-hyalinobatrachium, (1.3){1}: To a suspension of 0.39 g (1,27 mmol) of the acid (1.1.1){20} in 2 ml of dimethylsulfoxide was added under stirring at 20 ° C a solution of 0.07 g (1,27 mmol) of KOH in 4 ml of a mixture of ethanol-dimethyl sulfoxide (1:1). To the resulting solution was added a solution of 0.29 g (1.53 mmol) of 2-ftorangidridy (5) in 1 ml of dimethyl sulfoxide. The reaction mass is stirred for 3 hours at 20 ° C, add 50 ml of water, the precipitate is filtered off, washed with water (45 ml), dried and washed with 20 ml of boiling methanol. The crystals are filtered and obtain 0.39 g (1.3) {1}. Yield 74%; so pl. 122-C (methanol); IR: 1725 cm-1;1H TMR to 0.92 (d, 3H), 1.28 (in m, 3H), of 1.66 (d, 2H, in), 2.25 (m,), 3,70 (d, 2H), of 5.55 (s, 2H), 7,15 (m, 1H), 7,22 (m, 1H), 7,40 (m, 1H), 7,63 (m, 1H), 7,98 (d, 1H), 8,11 (d, 1H), 8,24 (d, 1H), 9,14 (d, 1H), 9,18 (s, 1H).

Example 40.

Ethyl [6-(4-metilprednisolone)-4-finalisations]thioglycolate, (1.3){2}: To a solution of 0.04 g (0.33 mmol) ethylglycine (5) in 5 ml shouhou mass dry. To the dry residue was added 25 ml of dioxane, 0.1 g (0.31 mmol) of acid chloride of acid (1.1.7){1}, the synthesis of which is described below. The reaction mass was stirred for 12 hours at 20 ° C, then evaporated in vacuum to dryness. The residue is stirred in 25 ml of water and neutralized with soda ash to a pH of 8-9, product extratour methylene chloride (315 ml), the extract is dried with anhydrous sodium sulfate, filtered and evaporated in vacuum to dryness. The residue is recrystallized from cyclohexane, to obtain 0.05 g of ester (1.3){2}. Yield 39%; so pl. 80-81s with**(cyclohexane);1H TMR of 0.96 (d, 3H), of 1.12 (m, 3H), of 1.13 (t, 3H), 1.70 to (d, 2H), 2,31 (m, 2H), of 3.77 (d, 2H), a 4.03 (s, 2H), 4,23 (q, 2H), 8,02 (m, 2H), compared to 8.26 (d, 1H), 8,68(s, 1H), 9,18(d, 1H).

Example 41.

6-(4-Metilprednisolone)-4-finalisations chloride, (1.1.7){1}: Mix 0.20 g (0.66 mmol) of the acid (1.1.1){2} in 5 ml of phosphorus oxychloride at 70 C until complete dissolution of the acid (15-20 minutes). The resulting solution was incubated for 12 hours at 20 ° C, then evaporated in vacuum to dryness. The residue was washed with 10 ml of dry ether, the precipitate is filtered and washed on the filter with hexane. Obtain 0.14 g of chloride (1.1.7){7}. Yield 74%; so pl. 286-S. The product should not be stored and used immediately in further syntheses.

Examples 42, 43. A common way to obtain the ammonium salt of 6-sulfamoylbenzoic-4-the With until complete dissolution of the acid (1 hour). The resulting solution was evaporated to dryness in a vacuum. Get salt as a white crystalline substance.

Example 42.

N,N-dimethylamino 6-(4-metilprednisolone)-4-hyalinobatrachium, (1.4){1}: yield 94%; so pl. C (decomp.); IR 2620 cm-1;1H TMR to 0.80 (d, 3H) and 1.15 (m, 3H), of 1.20 (t, 6H), and 1.63 (d, 2H), 2,24 (m, 2H), 2,92 (q, 4H), 3,63 (d, 2H), 7,69 (d, 1H), 7.88 (d, 1H), 8,14 (d, 1H), 8,97 (d, 1H), 8,50-9,50 (b s, 2H), 9,31 (s, 1H).

Example 43.

N,N,N-triethylamine 6-(4-methylpiperidino-sulfonyl)-4-hyalinobatrachium, (1.3){1}: yield 91%; oil;1H TMR of 0.91 (d, 3H), 1.18 to of 1.29 (m, N), 1.69 in (d, 2H), and 2.26 (m, 2H), 3.04 from (q, 6H), 3,70 (d, 2H), 7,87 (m, 2H), 8.14 (d, 1H), 9,01 (d, 1H) 9,42 (s, 1H).

Example 44.

4-Methyl-8-(4-metilprednisolone)-1,3-dihydrofuro[3,4-C]quinoline-1,3-dione, (1.5){1}. Stirred until complete dissolution at 100C 1.35 g (3,43 mmol) acid 2-methyl-6-(4-metilprednisolone)quinoline-3,4-dicarboxylic acid (1.1.4)){1} in 15 ml of acetic anhydride. The resulting solution was cooled to 0 C and kept at this temperature for 3-4 hours. The precipitation is filtered off, washed on the filter with ether and hexane and dried in vacuum at 50-60C. Get 0,69 g (54%) of product (1.5){1} with so pl. 141-S, MS m/z 373 (M+-1).

A combinatorial library of 4-methyl-8-(4-methylpiperidino-sulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-C]Hina the six reactors synthesizer download one of the 8-sulfamoyl-1,3-dihydrofuro[3,4-C]quinoline-1,3-d ions of General formula (1.5), one of the amines (7) and triethylamine in a molar ratio of 1:1:0.1 to 1 g of the anhydride used 20 ml of toluene. The reaction mass is stirred at boiling reaction mass for 20-48 hours before the end of the reaction. A control reaction carried out using TLC (silica gel, chloroform: methanol = 19:1). After completion of the reaction, the toluene is distilled off in vacuum to dryness, the residues in each reactor synthesizer add methylene chloride, stirred and filtered precipitation. The three filtrates are washed with 3% aqueous sodium hydroxide solution, water, 10% hydrochloric acid and again with water. Dried with anhydrous sodium sulfate, filtered, the solvent is distilled off in vacuum and the remaining chromatographic on silica gel with methylene chloride and then with a mixture of methylene chloride : methanol = 99:1. Get a combinatorial library consisting of six 4-methyl-8-(4-metilprednisolone)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline 1,3-diones (1.6), whose names, their output, so square and spectral data are given below.

Example 45.

2-Cyclohexyl-4-methyl-8-(4-metilprednisolone)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione, (1.6) {1}: yield 19%; so pl. 223-S;1H TMR of 0.91 (d, J=5,70 Hz, 3H), 1.17-1,50 (m, 6H), 1,64 of-1.83 (m, 5H), at 1.91 (d, J=11,60 Hz, 2H), 2,10-of 2.24 (m, 2H), 2,29-to 2.40 (m, 2H), 3,01 (s, 3H), of 3.78 (d, J=11,60 Hz122,93, 124,21, 128,69, 130,09, 136,23, 136,37, 150,79, 157,02, 167,07, 167,19; MS m/z 456 (M+H).

Example 46.

2-Cycloheptyl-4-methyl-8-(4-methylpiperidino-sulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione, (1.6) {2}: exit 42,0%, so pl. 221-S;1H TMR to 0.89 (d, J=6,40 Hz, 3H), 1,14-of 1.40 (m, 3H), 1,45 is 2.00 (m, 12H), 2,13-of 2.26 (m, 2H), 2,29-of 1.40 (m, 2H), 2,98 (s, 3H), of 1.95 (m, 2H), 2,31 (m, 2H), 3,74 (d, J=11,30 Hz, 2H), 4,16-4,27 (m, 1H), 8,13 (dd, J=1,45 Hz, J=9,05 Hz, 1H), compared to 8.26 (d, J=9,05 Hz, 1H), 9,02 (br s, 1H); 13C NMR 21,11, 21,81, 24,94, 27,34, 29,16, 32,05, 32,88, 45,93, 52,29, 119,21, 123,28, 124,52, 128,99, 130,36, 136,18, 136,74, 151,01, 157,30, 167,17, 167,31; MS m/z 470 (M+H).

Example 47. Methyl 2-[4-methyl-8-(4-metilprednisolone)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]acetate (1.6){3}: yield 23%; so pl. 128-130C;1H TMR of 0.93 (d, J=5,40 Hz, 3H), of 1.21 to 1.37 (m, 3H), 1,72 (d, J=10,90 Hz, 2H), 2,30-to 2.41 (m, 2H), 3,05 (s, 3H), 3,74-3,82 (m, 2H), 3,79 (s, 3H), 4,48 (s, 2H), 8,13 (dd, J=1,73 Hz, J=9,05 Hz, 1H), 8,24 (d, J=9,05 Hz, 1H), 9,02 (d, J=1,73 Hz, 1H);13C NMR 21,21, 22,01, 29,11, 32,81, 45,89, 118,74, 122,81, 124,05, 129,08, 130,12, 135,75, 136,26, 150,74, 156,99, 166,07, 166,15, 167,11; MS m/z 446 (M+H).

Example 48.

2-(2-Hydroxyethyl)-4-methyl-8-(4-metilprednisolone)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione, (1.6){4}: yield 25%; so pl. 134-S;1H TMR to 0.92 (d, J=5,10 Hz), 1,21-of 1.36 (m, 3H), 1,71 (d, J=11,50 Hz, 2H), 2,30-to 2.40 (m, 2H), 3,03 (s, 3H), to 3.67 (t, J=5,50 Hz, 2H), 3,74-3,82 (m, 4H), 8,10 (dd, J=1,63 Hz, J=9,00 Hz, 1H), they were 8.22 (d, J=9,00 Hz, 1H), 9,05 (d, J=1,63 Hz, 1H);13C NMR 21,21, 21,91, 29,14, 32,81, 40,52, 45,91, 57,69, 118,75, 123,05, 124,08, 128,75, 130,04, 135,55, 136,51�oxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]-2-thiophenecarboxylate, (1.6){5}: exit 17%; so pl. 234-S;1H TMR of 0.93 (d, J=5,70 Hz, 3H), 1,22-of 1.36 (m, 3H), 1,71 (d, J=11,60 Hz, 2H), 2,33-to 2.42 (m, 2H), is 3.08 (s, 3H), 3.75 to 3,82 (m, 2H), 3,79 (s, 3H), 7,26 (d, J=a 5.25 Hz, 1H), 7,95 (d, J=a 5.25 Hz, 1H), 8,16 (dd, J=1,67 Hz, J=9,00 Hz, 1H), 8,29 (d, J=9,00 Hz, 1H), 9,07 (d, J=1,67 Hz, 1H);13C NMR 21,21, 22,11, 29,12, 32,82, 45,89, 52,25, 118,82, 122,91, 124,08, 126,36, 128,18, 129,25, 130,24, 131,80, 132,52, 135,99, 136,36, 150,18, 157,22, 159,68, 164,96, 165,06; MS m/z 514 (M+H).

Example 50.

Ethyl 2-[4-methyl-8-(4-methylpiperidino-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]-1,3-thiazole-4-ylacetic, (1.6) {6}: yield of 11%; so PL 175-S;1H TMR of 0.93 (d, J=5,30 Hz, 3H), of 1.23 and 1.35 (m, 3H), of 1.31 (t, J=7,00 Hz, 3H), 1,72 (d, J=11,70 Hz, 2H), 2,31-to 2.40 (m, 2H), is 3.08 (s, 3H), 3,80 (d, J=11,10 Hz, 2H), 3,84 (s, 2H) to 4.17 (q, J=7,00 Hz, 2H), 7,49 (s, 1H), is 8.16 (dd, J=1,00 Hz, J=9.15, with Hz, 1H), 8,28 (d, J=9.15, with Hz, 1H), which is 9.09 (br s, 1H);13C NMR 14,12, 21,22, 22,15, 29,14, 32,80, 36,46, 45,93, 60,30, 116,79, 118,78, 122,75, 124,13, 129,24, 130,19, 135,88, 136,24, 145,49, 149,98, 150,66, 157,29, 163,85, 163,99, 169,10; MS m/z 543 (M+H).

A similar technique receive connections 1.6 {7-13}, is presented below.

1-[2-(2-Methoxycarbonyl-ethyl)-4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-sulfonyl]-piperidine-4-carboxylic acid 1.6 {7}: MS m/z 490 (M+H).

(S)-(+)-3-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-benzoic acid 1.6 {8}: MS m/z 510 (M+H).

(S)-(+)-4-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-diox the-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-1,3-Dion-2-yl]-3-methyl-butane acid 1.6 {10}: MS m/z 490 (M+H).

(S)-(+)-3-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-4-methyl-pentane acid 1.6 {11}: MS m/z 504 (M+H).

(S)-(+)-1-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-cyclohexyl-acetic acid 1.6 {12}: MS m/z 530 (M+H).

(S)-(+)-3-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-5-methyl-hexanoic acid 1.6 {13}: MS m/z 51S (M+H).

Examples 51. A combinatorial library of amides of 4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-sulfonic acid(1.6 {1-6, 14-}). In the reactor synthesizer load 0.2 mmol dicarboxylic acid 1.1.4 and 0.4 ml of freshly 1.1 M solution of carbonyldiimidazole in N-organic, the reaction mixture is stirred until the complete termination of allocation of CO2. Then add 0.2 ml of 1 M solution of the appropriate amine, the mixture is stirred at room temperature for 1 h, then 2 h at 80 ° C, cooled, with stirring, bring the volume of the reaction mixture with water to 3 ml, add 1 ml of saturated sodium bicarbonate solution, the mixture is stirred for 30 minutes, Dropped the precipitate centrifuged, washed with saturated sodium bicarbonate solution, three times with water, isop is every time separating the precipitate by centrifugation. The resulting material is dried in vacuum for 1 h, and analyzed by LC-MS. In cases where the product is contaminated with the starting amine, it is additionally washed with 1N Hcl solution, twice with water and twice with isopropanol. The outputs are 15-65%. Get a combinatorial library, including six amides of 4-methyl-1,3-dioxo-2,3-digitron-pyrrolo[3,4-C]quinoline-8-sulfonic acid, whose names and spectral data are given below:

2-Cyclohexyl-4-methyl-8-(4-metilprednisolone)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{1}: yield 64%; so pl. 223-S; MS m/z 456 (M+H).

2-Cycloheptyl-4-methyl-8-(4-metilprednisolone)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {2}: yield 60%, so pl. 221-S; MS m/z 470 (M+H).

Methyl 2-[4-methyl-8-(4-metilprednisolone)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]acetate 1.6{3}: yield 34%; so pl. 128-130C; MS m/z 446 (M+H).

2-(2-Hydroxyethyl)-4-methyl-8-(4-metilprednisolone)-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{4}: yield 35%; so pl. 134-S; MS m/z 418 (M+H).

Methyl 3-[4-methyl-8-(4-metilprednisolone)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]-2-thiophenecarboxylate 1.6{5}: yield 30%; so pl. 234-236C; MS m/z 514 (M+H).

Ethyl 2-[4-methyl-8-(4-metilprednisolone)-1,3-dioxo-2,3-dihydro-1H-pyrroloquinoline-4-sulfonyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{14}; MS m/z 420 (M+H).

3-(1H-Imidazol-4-yl)-2-[2-(2-methoxycarbonylethyl)-4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-sulfonylamino]-propionic acid methyl ester 1.6{15}; MS m/z 530 (M+H).

3-[4-Methyl-8-(1-octahydrophenanthrene)-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{16}; MS m/z 494 (M+H).

3-[8-(3-Hydroxymethyl-piperidine-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydropyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{17}; MS m/z 476 (M+H).

3-[4-Methyl-8-(4-methyl-[1,4]diazepan-1-sulfonyl)-1,3-Dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{18}; MS m/z 475 (M+H).

3-{4-Methyl-8-[(1-methyl-piperazine-4-yl)-sulfamoyl]-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{19}; MS m/z 461 (M+H).

1-[2-(2-Methoxycarbonyl-ethyl)-4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-sulfonyl]pyrrolidin-2-carboxylic acid methyl ester 1.6{20}; MS m/z 490 (M+H).

3-(8-Diisopropylphenol-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl)-propionic acid methyl ester 1.6{21}; MS m/z 462 (M+H).

3-(8-Dimethylsulphamoyl-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo [3,4-C]quinoline-2-yl)-propionic acid IU irolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{23}; MS m/z 505 (M+H).

3-[8-(Ethoxycarbonylmethyl-methyl-sulfamoyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{24}; MS m/z 478 (M+H).

3-{8-[Bis-(2-hydroxyethyl)-sulfamoyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{25}; MS m/z 466 (M+H).

3-[8-(2-Ethylpiperidine-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{26}; MS m/z 474 (M+H).

3-{8-[4-(2-Hydroxyethyl)-piperazine-1-sulfonyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{27}; MS m/z 491 (M+H).

3-[4-Methyl-8-(methyl-phenyl-sulfamoyl)-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6 {28}; MS m/z 468 (M+H).

3-[4-Methyl-8-(2-methyl-piperidine-1-sulfonyl)-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{29}; MS m/z 460 (M+H).

3-[4-Methyl-1,3-dioxo-8-(pyrrolidin-1-sulfonyl)-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{30}; MS m/z 432 (M+H).

3-[8-(Cyclohexyl-methyl-sulfamoyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{31}; MS w/z 474 (M+H).

3-{8-[2-(2-Hydroxyethyl)-piperidine-1-sulfonyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{33}; MS m/z 476 (M+H).

3-{8-[(2-Hydroxyethyl)-methyl-sulfamoyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{34}; MS m/z 436 (M+H).

3-[4-Methyl-8-(morpholine-4-sulfonyl)-1,3-dioxo-1,3-dihydro-pyrrolo [3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{35}; MS m/z 448 (M+H).

3-{4-Methyl-8-[methyl-(2-pyridin-2-yl-ethyl)-sulfamoyl]-1,3-dioxo-1,3-dihydropyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{36}; MS m/z 497 (M+H).

3-{8-[Ethyl-(2-hydroxyethyl)-sulfamoyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{37}; MS m/z 450 (M+H).

1-[2-(2-Methoxycarbonyl-ethyl)-4-methyl-1,3-dioxo-1,3-dihydro-1H-pyrrolo[3,4-C]quinoline-8-sulfonyl]-piperidine-3-carboxylic acid ethyl ester 1.6{38}; MS m/z 518 (M+H).

3-{8-[Bis-(2-hydroxypropyl)-sulfamoyl]-4-methyl-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{39}; MS m/z 494 (M+H).

3-[8-(Indol-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{40}; MS m is about acid methyl ester 1.6{41}; MS m/z 460 (M+H).

3-[4-Methyl-1,3-dioxo-8-(4-oxo-piperidine-1-sulfonyl)-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{42}; MS m/z 460 (M+H).

1-[2-(2-Methoxycarbonylethyl)-4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]-piperidine-4-carboxylic acid ethyl ester 1.6{43}; MS m/z 518 (M+H).

3-{8-[Benzyl-(2-hydroxyethyl)-sulfamoyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{44}; MS m/z 512 (M+H).

3-{4-Methyl-8-[4-(2-methylallyl)-piperazine derivatives-1-sulfonyl]-1,3-dioxo-1,3-dihydropyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{45}; MS m/z 501 (M+H).

3-[8-(4-Cyclopentyl-piperazine derivatives-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydropyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{46}; MS m/z 515 (M+H).

3-{8-[4-(1-Ethylpropyl)-piperazine derivatives-1-sulfonyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{47}; MS m/z 517 (M+H).

3-[8-(4-sec-Butyl-piperazine derivatives-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydropyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{48}; MS m/z 503 (M+H).

3-{4-Methyl-8-[4-(1-methylbutyl)-piperazine derivatives-1-sulfonyl]-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic cislerova[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{50}; MS m/z 508 (M+H).

3-{8-[(4-Forfinal)-methyl-sulfamoyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{51}; MS m/z 486 (M+H).

3-{8-[(2-Forfinal)-methyl-sulfamoyl]-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl}-propionic acid methyl ester 1.6{52}; MS m/z 486 (M+H).

3-[8-(2-Hydroxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{53}; MS m/z 462 (M+H).

3-[4-Methyl-1,3-dioxo-8-(3-oxo-3,4-dihydro-2H-cinoxacin-1-sulfonyl)-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{54}; MS m/z 509 (M+H).

(S)-(+)-2-(2-Azepin-1-yl-ethyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methylpyrazolo[3,4-C]quinoline-1,3-dione 1.6{55}; MS m/z 515 (M+H).

3-[8-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{56}; MS m/z 494 (M+H).

(S)-(+)-[4-Methyl-1,3-dioxo-8-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-acetic acid ethyl ester 1.6{57}; MS m/z 538 (M+H).

(S)-(+)-3-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-propionic acid methyl ester 1.6{55}; MS m/z 476-dio 1.6{59}; MS m/z 486 (M+H).

(S)-(+)-4-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3 dihydro-pyrrolo[3,4-C]quinoline-2-yl]-benzoic acid methyl ester 1.6{60}; MS m/z 524 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(3-methyl-isooxazolyl-5-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{61}; MS m/z 471 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-phenyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{62}; MS m/z 466 (M+H).

(S)-(+)-2-Isoquinoline-5-yl-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{63}; MS m/z 51.7 (M+H).

(S)-(+)-(4,5-Dihydro-thiazol-2-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]heylin-1,3-dione 1.6{64}; MS m/z 475 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(5-methyl-[1,3,4]thiadiazole-2-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{65}; MS m/z 488 (M+H).

(S)-(+)-2-(2-Hydroxy-1-methyl-ethyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dio 1.6{66}; MS m/z 448 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{67}; MS m/z 520 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(5-methyl-1H-pyrazole-3-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{68}; MS m/z 470 (M+H).

(M+N).

(S)-(+)-2-Isooctanol-3-yl-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{70}; MS m/z 457 (M+H).

(S)-(+)-3-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-benzoic acid methyl ester 1.6{77}; MS m/z 524 (M+H).

(S)-(+)-2-(1,3-Dioxo-2,3-dihydro-1H-isoindole-4-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{72}; MS m/z 535 (M+H).

(S)-(+)-2-(1H-Indol-6-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methylpyrazolo[3,4-C]quinoline-1,3-dione 1.6{73}; MS m/z 505 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(pyridine-4-ylmethyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{74}; MS m/z 481 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(2-pyrrolidin-1-yl-ethyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{75}; MS m/z 487 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(pyridine-2-ylmethyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{76}; MS m/z 481 (M+H).

(S)-(+)-2-(3-Hydroxypropyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methylpyrazolo[3,4-C]quinoline-1,3-dione 1.6{77}; MS m/z 448 (M+H).

(S)-(+)-2-(3-Dimethylamino-propyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{75}; MS m/z 475 (M+H).

(S)-(+)-2-(2-Dimethylamino-e is-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-quinoline-8-yl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{80}; MS m/z 517 (M+H).

(S)-(+)-2-Benzo[1,3]dioxol-5-ylmethyl-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]heylin-1,3-dione 1.6{57}; MS m/z 524 (M+H).

(S)-(+)-2-[2-(1H-Imidazol-4-yl)-ethyl]-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{52}; MS m/z 556 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-phenethyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{83}; MS m/z 466 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(tetrahydrofuran-2-ylmethyl)-pyrrolo[3,4-C|quinoline-1,3-dione 1.6{84}; MS m/z 474 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{85}; MS m/z 515 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(2-piperidine-1-yl-ethyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{86}; MS m/z 501 (M+H).

(S)-(+)-2-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{87}; MS m/z 390 (M+H).

(S)-(+)-2-(Benzo[1,3]dioxol-5-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{55}; MS m/z 510 (M+H).

(S)-(+)-2-(3-hydroxymethyl-phenyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {89}; MS m/z 496 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4--methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{91}; MS m/z 488 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(5-methyl-isooxazolyl-3-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{92}; MS m/z 471 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-quinoline-3-yl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6{93}; MS m/z 517 (M+H).

(S)-(+)-4-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-ylmethyl]-cyclohexanecarbonyl acid 1.6 {94}; MS m/z 530 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-2-(3-methoxypropyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {95}; MS m/z 462 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(1H-[1,2,4]triazole-3-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {96}; MS m/z 457 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(5-methyl-furan-2-ylmethyl)-pyrrolo[3,4-C]quinoline-1,3-dione 2 1.6 {97}; MS m/z 484 (M+H).

(S)-(+)-2-(1H-Indazol-5-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {98}; MS m/z 506 (M+H).

(S)-(+)-2-Indan-1-yl-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {99}; MS m/z 506 (M+H).

(S)-(+)-2-[4-(2-Hydroxyethyl)-phenyl]-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {100}; MS m/z 510 (M+H).

(S)-(+)-2-(1,3-Dioxo/z 535 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {102}; MS m/z 513 (M+H).

(S)-(+)-2-(1-Aza-bicyclo[2.2.2]OK-3-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {103}; MS m/z 499 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-[1,3,4]thiadiazole-2-almirola[3,4-C]quinoline-1,3-dione 2 1.6 {104}; MS m/z 474 (M+H).

(S)-(+)-2-[2-(1H-Indol-3-yl)-ethyl]-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {105}; MS m/z 533 (M+H).

(S)-(+)-2-Cyclopentyl-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {106}; MS m/z 458 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(2-trifluoromethyl-phenyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {707}; MS m/z 534 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(2-morpholine-4-yl-ethyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {108}; MS m/z 503 (M+H).

(S)-(+)-2-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-4-methyl-pentanol acid methyl ester 1.6 {109}; MS m/z 518 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(3-morpholine-4-yl-propyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {110}; MS m/z 517 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-naphthalene-1-yl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {112}; MS m/z 516 (M+H).

(S)-(+)-2-Benzyl-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {113}; MS m/z 480 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-pyridin-3-yl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {114}; MS m/z 467 (M+H).

(S)-(+)-2-(1-Ethyl-pyrrolidin-2-ylmethyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {115}; MS m/z 501 (M+H).

(S)-(+)-2-(2,5-Dimethyl-2H-pyrazole-3-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {116}; MS m/z 484 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(5-pyridin-3-yl-2H-[1,2,4]triazole-3-yl)-pyrrolo(3,4-C]quinoline-1,3-dione 1.6 {117}; MS m/z 534 (M+H).

(S)-(+)-2-(4,5-Dimethyl-thiazol-2-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {118}; MS m/z 501 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-[3-(4-methyl-piperazine-1-yl)-propyl]pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {779}; MS m/z 530 (M+H).

(S)-(+)-2-(3-Azepin-1-yl-propyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {120}; MS m/z 529 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-oxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-1,3-Dion-2-yl]-1H-pyrazole-4-carboxylic acid methyl ester 1.6 {122}; MS m/z 514 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-[2-(4-methyl-piperazine-1-yl)-ethyl]pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {123}; MS m/z 516 (M+H).

(S)-(+)-2-(3-Isopropyl-effect-free remedy propyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 2 1.6 {124}; MS m/z 506 (M+H).

(S)-(+)-2-(1-Hydroxymethyl-2-methyl-butyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {125}; MS m/z 490 (M+H).

(S)-(+)-2-(1-Hydroxymethyl-2-methyl-propyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {126}; MS m/z 476 (M+H).

(S)-(+)-2-(2-Hydroxy-1-phenyl-ethyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {127}; MS m/z 510 (M+H).

(S)-(+)-2-(1-Hydroxymethyl-3-methylsulphonyl-propyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C|quinoline-1,3-dione 1.6 {128}; MS m/z 508 (M+H).

(S)-(+)-2-(1-Hydroxymethyl-2-phenyl-ethyl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {129}; MS m/z 524 (M+H).

(S)-(+)-2-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-ethyl}-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {130}; MS m/z 518 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(1,3,5-treximet-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {132}; MS m/z 532 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-2-(5-methoxymethyl-[1,3,4]thiadiazole-2-yl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {133}; MS m/z 518(M+H).

(S)-(+)-2-(5-Dimethylaminomethyl-[1,3,4]thiadiazole-2-yl)-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {134}; MS m/z 531 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-(5-methylsulfonylmethyl-[1,3,4]thiadiazole-2-yl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {135}; MS m/z 534 (M+H).

(S)-(+)-8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-2-[2-(2-oxo-imidazolidin-1-yl)-ethyl]-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {136}; MS m/z 502 (M+H).

(S)-(+)-2[2-(4-Hydroxy-phenyl)-ethyl]-8-(2-methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {137}; MS m/z 510 (M+H).

(S)-(+)-[8-(2-Methoxymethyl-pyrrolidin-1-sulfonyl)-4-methyl-1,3-dioxo-1,3-dihydro-pyrrolo[3,4-C]quinoline-2-yl]-acetic acid ethyl ester 1.6 {138}; MS m/z 476 (M+H).

Methyl (R)-(-)-2-[4-methyl-8-(2-hydroxymethyl-pyrrolidine-1-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline-2-yl]acetate, 1.6 {139}; MS m/z 448 (M+H).

Methyl 2-[4-methyl-8-(morpholine-4-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo-[3,4-C]quinoline-2-yl]acetate, 1.6 {140}; MS m/z 434 (M+H).

Methyl 2-[4-methyl-8-([1,3]dioxolane-2-ylmethyl-methyl-sulfamoyl)-3]bipyridinyl-1-sulfonyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {142}; MS m/z 437 (M+H).

2-Methyl-8-(8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methane-pyrido-[1,2-a][1,5]diasorin-3-sulfonyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {143}; MS m/z 465 (M+H).

2-Ethyl-8-(3-hydroxy-8-Aza-bicyclo-[3,2,1]Octan-8-sulfonyl)-pyrrolo[3,4-C]Hanalei-1,3-dione 1.6 {144}; MS m/z 416 (M+H).

2-Methyl-8-(octahydro-1,5-methane-pyrido[1,2-a][1,5]diasorin-3-sulfonyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {145}; MS m/z 455 (M+H).

8-(8-Oxo-octahydro-1,5-methane-pyrido[1,2-a][1,5]diasorin-3-sulfonyl)-pyrrolo[3,4-C]quinoline-1,3-dione 1.6 {146}; MS m/z 455 (M+H).

Example 52. A combinatorial library of 4-methyl-8-sulfamoyl-1,3-dihydro-2H-pyrrolo[3,4-c]quinoline-1,3-diones (1.6). Parallel synthesis of combinatorial libraries spend synthesizer "CombiSyn-012-3000". In each of the six reactors synthesizer download one of the 8-sulfamoyl-1,3-dihydrofuro[3,4-C]quinoline-1,3-diones of General formula (1.5), one of the amines (7) and triethylamine in a molar ratio of 1:1:0.1 To 1 g of the anhydride used 20 ml of toluene. The reaction mass is stirred at boiling of the reaction mass 20-48 hours before the end of the reaction. A control reaction carried out using TLC (silica gel, chloroform : methanol =19:1). After completion of the reaction, the toluene is distilled off in vacuum to dryness, the residues in each reactor synthesizer add m the Yes sodium, water, 10% hydrochloric acid and again with water. Dried with anhydrous sodium sulfate, filtered, the solvent is distilled off in vacuum and the remaining chromatographic on silica gel with methylene chloride and then with a mixture of methylene chloride : methanol = 99:1. Get a combinatorial library of 4-methyl-8-sulfamoyl)-1,3-dihydro-2H-pyrrolo[3,4-C]quinoline-1,3-diones (1.6), are presented in the table.

1. 6-Sulfamoylbenzoic-4-carboxylic acids and their derivatives of the General formula (1)

in which R1represents a hydrogen atom, methyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl where heterocyclyl means an aromatic cycle with 5-7 atoms, one of which is a heteroatom selected from sulfur, oxygen and nitrogen, and heterocyclyl can be condensed politicla;

R2represents a hydrogen atom, -C(O)HE;

R1and R2together represent polymethene fragment -(CH2)m-;

m has a value from 3 to 7;

R3represents-OH, -O-N+HR5R6R7, -NH2or nucleophilic Deputy selected from the group of primary or secondary amines, alcohols, f)-;

R4represents a nucleophilic Deputy selected from the group of primary or secondary amines;

R5, R6and R7independently from each other represent1-C7-alkyl;

R8is inert Deputy selected from the group comprising optionally substituted C1-C7-alkyl, C2-C7alkenyl,2-C7-quinil, optionally substituted C1-C7-alkoxy, optionally substituted C3-C10-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl where heterocyclyl means saturated or aromatic cycle with 5-7 atoms, at least one of which is a heteroatom selected from oxygen, sulfur and nitrogen, and heterocyclyl can be condensed politicla;

excluding the compound (1) in which both R1=phenyl, R2=H, R3=HE, R4=-NH2and the connection (1), in which both R1=phenyl, R2=H, R3=HE, R4=-NH(2-pyridyl).

2. Connection on p. 1 representing the 6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1)

in co simultaneously R1=phenyl, R2=N, R3=HE, R4=-NH2and the connection (1.1), in which both R1=phenyl, R2=N, R3=HE, R4=-NH(2-pyridyl).

3. Connection PP.1 and 2, representing the 6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1.1)

in which R4have the above meaning.

4. Connection PP.1 and 2, representing the 6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1.2)

in which R1and R4have the above meaning.

5. Connection PP.1 and 2, representing the 6-sulfamoylbenzoic-4-carboxylic acid of General formula (1.1.3)

in which R4has the above meaning;

p=1-3.

6. Connection PP.1 and 2, representing the 6-sulfamoylbenzoic-3,4-dicarboxylic acid of General formula (1.1.4)

in which R1and R4have the above meaning.

7. Connection on p. 1, representing the 6-sulfamoylbenzoic-4-carboxamide General formula (1.2)

in which R1, R2and R4have the above meaning;

R3represents-NH2or nucleophilic Deputy selected and carboxamide General formula (1.2.1)

in which R3and R4have the above meaning.

9. Connection on p. 7, representing the 6-sulfamoylbenzoic-4-carboxamide General formula (1.2.2)

in which R1, R3and R4have the above meaning.

10. Connection on p. 7, representing the 6-sulfamoylbenzoic-4-carboxamide General formula (1.2.3)

in which R3, R4and p have the abovementioned meaning.

11. Connection on p. 1 representing esters or thioesters 6-sulfamoylbenzoic-4-carboxylic acids of General formula (1.3)

in which R1, R2and R4have the above meaning;

R3represents a nucleophilic Deputy selected from the group of alcohols, phenols, mercaptans and thiophenols.

12. Connection on p. 1, representing the ammonium salt of 6-sulfamoylbenzoic-4-carboxylic acids of General formula (1.4)

in which R1, R2, R4, R5, R6and R7have the above meaning.

13.Connection on p. 1, representing 8-sulfamoyl-1,3-dihydrofuro-[3,4-c]quinoline-1,3-diones of General formula (1.5)

in which R1and RRole[3,4-C]quinoline-1,3-diones of General formula (1.6)

in which R4and R8have the above meaning.

15. A combinatorial library of compounds, wherein each of the constituent compounds is 6-sulfamoylbenzoic-4-carboxylic acid or its derivative of the General formula (1).

 

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