Connection-modulators of steroid receptors and methods

 

(57) Abstract:

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors. Also described pharmaceutical composition comprising such compounds. Also disclosed are intermediate compounds suitable for the manufacture of these compounds, and methods of making compounds for modulators of steroid receptors. The invention can be used in medicine as a therapeutic agent modulator (i.e., agonist and antagonist) of steroid receptors (e.g., progesterone receptor, androgen, estrogen, and others). 8 C. and 41 C. p. F.-ly, 9 PL.

Text description of the invention in facsimile form (see graphic part). T T T T T T

1. Non-steroidal compounds of formulas I-XVIII (see graphic part).

where R1- 5 - or 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted C1-C4the alkyl, F, Cl, Br, NO2, CO2H, CO2R2CHO, CN, CF3CH2HE or PINES3where R2is hydrogen, C1-C4is alkyl or perfluoroalkyl, and where specified R1-heterocycle is attached to the soy is alkyl, hydroxymethyl;

R4-R6each independently is hydrogen, F, Cl, Br, I, NO2, CO2H, CO2R2, COR2CN, CF3CH2HE1-C4-alkyl, or perfluoroalkyl or phenyl;

R7, R9and R10each independently is hydrogen or C1-C6-alkyl;

R11-R15each independently is hydrogen, F, Cl, Br, I, NO2, COR2, CF3CH2OH, OR2, SR2, SO2R2WITH1-C4-alkyl, or perfluoroalkyl or phenyl, where R2is hydrogen, C1-C4-alkyl or CF3;

W IS O, NH, NR7CH2SNON, C=O or OS=O, where R7has the values specified above, except that when W is NH, CH2or in compounds of formula III, then R11-R14and R4can't all be hydrogen when R3, R9and R10all are CH3and they can't be one Deputy F, C1 or Br, and all other substituents are hydrogen, when R3, R9and R10all SN3and further except that when W is O or NH in the compounds of formula IV, then R5-R6and R11-R14can't all be hydrogen when R3, R9and R10all-CH3;

X - CH2OS1-C6-acyl; IT; OR17, SR17where R17- C1-C4is an alkyl group, phenylmethyl, phenyl, optionally substituted by 1 or 2 substituents which are the same or different and selected from halogen, CF3WITH1-C4-alkyl, C1-C4-alkoxyl or CH2HE; pyridyl, optionally substituted with halogen or C1-C10-alkyl; or thienyl, optionally substituted C1-C4-alkyl;

R18and R19each independently is hydrogen or C1-C6-alkyl;

R20- C1-C6-alkyl or phenyl, optionally substituted by 1 or 2 substituents which are the same or different and selected from halogen, C1-C4-alkyl or C1-C4-alkoxyl;

R21and R22each independently is hydrogen or C1-C4-alkyl;

R23is hydrogen, C1 or Br;

R24is hydrogen, C1-C4-alkyl, 3-furyl, CF3, with the exception that R24cannot be CH3when Z represents Oh, R22, R23, R26and R29everything is hydrogen and R3, R27and R28all - CH3;

R26is hydrogen;

R27-R29each independently - Wakil or were, optionally substituted with halogen;

R32and R33each is hydrogen;

n=0 or 1;

Y is O or S;

Z is O, S or NH;

the wavy line in the compounds of formulas VII, XII, XIII and XVI indicates olefinic bond or in CIS-or in transconfiguration;

the dashed lines in the structures represent an optional double bond, except that when there is a3-C4-double bond in the nitrogen-containing ring compounds of formula II, then R11-R15can't all be hydrogen and R3, R9and R10may not be all of the stands.

2. Connection on p. 1, where the compounds of formulas I-XVIII include connection-modulators of steroid receptors.

3. Connection on p. 2, where the compounds of formulas I-IV, X and XI include antagonists ETC.

4. Connection on p. 2, where the compounds of formulas V and VI include modulators, ETC.

5. Connection on p. 2, where the compounds of formulas VII, VIII, XII-XVI include agonists, ETC.

6. Connection on p. 2, where the compound of formula IX, XVII and XVIII include modulators of AR.

7. Connection on p. 6, where the compounds of formulas IX and XVII include antagonists of AR.

8. Connection-antagonist PR on p. 3, selected from the group yl)quinoline (compound 101); 1,2-dihydro-2,2,4-trimethyl-6-(1,3-oxazol-5-yl)quinoline (compound 102); 6-(4,5-dichloroimidazole-1-yl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 103): 6-(4-bromo-1-methylpyrazole-3-yl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 104); 1,2-dihydro-2,2,4-trimethyl-6-(3-pyridyl)quinoline (compound 105); 6-(4-forfinal)-1,2-dihydro-2,2,4-trimethylquinoline (compound 106); 1,2-dihydro-6-(3-triptoreline)-2,2,4-trimethylquinoline (compound 107); 1,2-dihydro-2,2,4-trimethyl-6-(4-nitrophenyl)quinoline (compound 108); 6-(2,3-dichlorophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 109); 1,2-dihydro-6-(2-hydroxycarbonyl-4-nitrophenyl)-2,2,4-trimethylquinoline (compound 110); 6-(3,4-dichlorophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 111); 4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylphenol (compound 112); 1,2-dihydro-2,2-dimethyl-6-phenyl-4-propilinian (compound 113); 6-(2-chlorophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 114); 1,2-dihydro-2,2,4-trimethylpentane[1,2-g]-quinoline (compound 115); 1,2-dihydro-2,2,4-trimethylpentane[2,1-f]quinoline (compound 116); 8-bromo-1,2-dihydro-2,2,4-trimethylpentane[1,2-g] quinoline (compound 117); 1,2-dihydro-2,2,4-trimethylpent[b] furano[3,2-g] quinoline (compound 118); 1,2-dihydro-2,2,4-trimethylpent[b] furano[2,3-f] the quinoline (compound 119); 6-fluoro-1,2-dihydro-2,2,4-trimethylpentane[2,1-f] quinoline (compound 120); 9-ft is inulin (compound 122); 8-chloro-1,2-dihydro-2,2,4-trimethylpentane[1,2-g] quinoline (compound 123); 8-fluoro-1,2-dihydro-2,2,4-trimethylpentane[1,2-g] quinoline (compound 124); 8-acetyl-1,2-dihydro-2,2,4-trimethylpentane[1,2-g]quinoline (compound 125); 6-fluoro-1,2-dihydro-2,2,4-trimethylpentane[1,2-g] quinoline (compound 126); 7-bromo-1,2-dihydro-2,2,4-trimethylpentane[2, l-f] quinoline (compound 127); 1,2-dihydro-2,2,4-trimethyl-7-nitroindole[2,1-f] quinoline (compound 128); 1,2-dihydro-2,2,4-trimethyl-8-nitrobenzene[1,2-g] quinoline (compound 129); 6,9-debtor-1,2-dihydro-2,2,4-trimethylpentane[1,2-g]quinoline (compound 130); 7-fluoro-1,2-dihydro-2,2,4-trimethyl-11-(thiomethyl)-indeno[2, l-f] quinoline (compound 131); 5,8-debtor-1,2-dihydro-10-hydroxy-2,2,4-trimethylpentane[1,2-g] quinoline (compound 132); 7,9-debtor-1,2-dihydro-10-hydroxy-2,2,4-trimethylpentane[1,2-g] quinoline (compound 133); 7,10-debtor-1,2-dihydro-2,2,4-trimethyl-5-oxoindole[3,2-f] quinoline (compound 134); 7,9-debtor-1,2-dihydro-2,2,4-trimethyl-10-oxoindole[1,2-g]quinoline (compound 135); 8-fluoro-1,2-dihydro-10-hydroxy-2,2,4-trimethylpentane[1,2-g] quinoline (compound 136); 8-fluoro-1,2-dihydro-2,2,4-trimethyl-10-oxoindole[1,2-g] the quinoline (compound 137); 7-fluoro-1,2-dihydro-2,2,4-trimethyl-8-nitrobenzene[1,2-g] quinoline (compound 138); 5-chloro-1,2-dihydro-10-hydroxy-2,2,4-trimethylpentane[1,2-g] quinoline (compound 139); 6-fluoro-1,2-dihydro-2,2,4-trimethyl-10-o); 5.8 debtor-1,2-dihydro-2,2,4-trimethyl-10-(triptoreline)indeno[1,2-g]quinoline (compound 142); 6-(3,5-differenl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (compound 143); 1,2-dihydro-2,2,4-trimethylpentane[3,2-g]quinoline (compound 144); 5-ethyl-1,2-dihydro-2,2,4-trimethylpentane[2,3-f] quinoline (compound 145); 6-(3-chlorophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 146); 6-(3,5-differenl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 147); 6-(3-forfinal)-1,2-dihydro-2,2,4-trimethylquinoline (compound 148); 1,2-dihydro-2,2,4-trimethyl-6-(4-pyridyl)quinoline (compound 149); 6-(3-cyanophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 150); 6-(3,5-dichlorophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 151); 6-(2,3-debtor-phenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 152); 1,2-dihydro-2,2,4-trimethyl-6-(pentafluorophenyl)quinoline (compound 153); 1,2-dihydro-2,2,4-trimethyl-6-[4-(TRIFLUOROACETYL)phenyl]quinoline (compound 154); 1,2-dihydro-2,2,4-trimethyl-6-(1,3-pyrimid-5-yl)quinoline (compound 155); 6-(3-cyanophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (compound 156); 5,8-debtor-1,2-dihydro-2,2,4-trimethylpentane[1,2-g]quinoline (compound 157); 7,10-debtor-1,2-dihydro-2,2,4-trimethylpentane[2,1-f]quinoline (compound 158); 8-cyano-1,2-dihydro-2,2,4-trimethylpentane[3,2-f] quinoline (compound 270); 6-(3-cyano-5-forfinal)-1,2-dihydro-2,2,4-trimethyl the 1,2-dihydro-2,2,4-trimethylquinoline (compound 273); 6-[5-fluoro-3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethylquinoline (compound 274); 6-(3-chloro-2-were)-1,2-dihydro-2,2,4-trimethylquinoline (compound 275); 1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (compound 276); 6-(3-acetylphenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 277); 6-(3-cyano-2-were)-1,2-dihydro-2,2,4-trimethylquinoline (compound 278); 1,2-dihydro-2,2,4-trimethyl-6-(3-were)quinoline (compound 279); 6-(5-(fluoro-3-nitrophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 280); 1,2-dihydro-6-(3-methoxyphenyl)-2,2,4-trimethylquinoline (compound 281); 6-(5-cyano-3-pyridyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 282); 1,2-dihydro-2,2,4-trimethyl-6-(2-methyl-3-nitrophenyl)quinoline (compound 283); 6-(2-amino-3,5-differenl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 284); 6-(3-bromo-2-chloro-5-forfinal)-1,2-dihydro-2,2,4-trimethylquinoline (compound 285); 6-(3-cyano-5-forfinal)-1,2-dihydro-2,2,4-trimethyl-3-chinoline (compound 286); 6-(3-fluoro-2-were)-1,2-dihydro-2,2,4-trimethylquinoline (compound 287); 1,2-dihydro-2,2,4-trimethyl-6-(3-methylthiophenyl)quinoline (compound 288); 6-(5-chloro-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 289); 1,2-dihydro-2,2,4-trimethyl-6-(3-methyl-2-thienyl)quinoline (compound 290); 8-fluoro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (compound 291); 1,2-dihydro-6-(s 293); 6-(3-bromo-2-pyridyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 294); 6-(3-bromo-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 295); 1,2-dihydro-6-(2,3,5,6-titrator-4-pyridyl)-2,2,4-trimethylquinoline (compound 296); 5,8-debtor-1,2-dihydro-6-(3-nitrophenyl)-2,2,4-trimethylquinoline (compound 297); 2,4-diethyl-8-fluoro-1,2-dihydro-2-methyl-6-(3-nitrophenyl)quinoline (compound 298); 6-(3-bromophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 299); 1,2-dihydro-2,2,4-trimethyl-6-(5-nitro-2-thienyl)quinoline (compound 300); 1,2-dihydro-6-(2,4,5-tryptophanyl)-2,2,4-trimethylquinoline (compound 301); 6-(3-bromo-5-forfinal)-1,2-dihydro-2,2,4-trimethylquinoline (compound 302); 6-(5-carboxaldehyde-3-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 303); 1,2-dihydro-2,2,4,7-tetramethyl-6-(3-nitrophenyl)quinoline (compound 304); 6-(5-fluoro-2-methoxy-3-nitrophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 305); 6-(3-chloro-2-methoxyphenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 306); 1,2-dihydro-2,2,4-trimethyl-6-(2,3,4-tryptophanyl)quinoline (compound 307); 6-(3-bromo-2-were)-1,2-dihydro-2,2,4-trimethylquinoline (compound 308); 7-chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl) quinoline (compound 309); 5-chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (compound 310); 8-chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (link,4-f] quinoline (compound 313); 1,2-dihydro-9-methoxy-2,2,4-trimethyl-5-cumarine[3,4-f] quinoline (compound 314); 9-fluoro-1,2-dihydro-2,2,4,11-tetramethyl-5-cumarine[3,4-f] quinoline (compound 315); 1,2-dihydro-2,2,4,9-tetramethyl-5-cumarine[3,4-f] quinoline (compound 316); 7-chloro-1,2-dihydro-2,2,4-trimethyl-5-cumarine[3,4-f]quinoline (compound 317); (R/S)-9-chloro-1,2-dihydro-5-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 319; (R/S)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 328); 6-(5-cyano-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 451); 6-(5-cyano-3-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 452); 6-(3-formylphenyl)-1,2-dihydro-2,2,4-trimethylquinoline (compound 453); 1,2-dihydro-2,2,4-trimethyl-6-[3-(methylsulphonyl)quinoline (compound 454); (R/S)-6-(3-cyano-5-forfinal)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (compound 455); and (R/S)-9-chloro-1,2-dihydro-2,2,4-trimethyl-5-phenyl-5H-chromeno[3,4-f]quinoline (compound 456).

9. Connection-modulator PR on p. 4, selected from the group comprising (R/S)-5-butyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 160); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-phenyl-5H-chromeno[3,4-f] quinoline (compound 161); (R/S)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5-phenyl-5H-chromeno[3,4-f] quinoline (compound 162); (R/S)-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compounds is phenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 165); (R/S)-5-(4-acetylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 166); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-(4-were)-5H-chromeno[3,4-f] quinoline (compound 167); (R/S)-1,2-dihydro-5-(4-methoxyphenyl)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 168); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-[4-(trifluoromethyl)phenyl] -5H-chromeno[3,4-f] quinoline (compound 169); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-(thiophene-3-yl)-5H-chromeno[3,4-f] quinoline (compound 170); (-)-1,2-dihydro-2,2,4-trimethyl-5-(4-were)-5H-chromeno[3,4-f] quinoline (compound 171); (-)-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 172); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-(3-were)-5H-chromeno[3,4-f] quinoline (compound 173); (+)-(41,51)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 174); (-)-(41,51)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 175); (R/S-41,5 u)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 176); (R/S)-5-(3-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 177); (R/S)-5-(3-chlorophenyl)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5H-chromeno[3,4-f] quinoline (compound 178); (R/S)-5-(4-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 179); (R/S)-5-(4-bromophenyl)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5H-Chr); (R/S)-5-(3-bromophenyl)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5H-chromeno[3,4-f] quinoline (compound 182); (R/S)-5-(3,4-dichlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline(compound 183); (R/S)-5-(3-bromo-2-pyridyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 184); (R/S)-1,2-dihydro-5-hydroxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 185); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-methoxy-5H-chromeno[3,4-f] quinoline (compound 186); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-propoxy-5H-chromeno[3,4-f] quinoline (compound 187); (R/S)-5-allyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 188); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-propyl-5H-chromeno[3,4-f] quinoline (compound 189); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-(2-pyridyl)-5H-chromeno[3,4-f] quinoline (compound 190); (R/S)-5-(3-forfinal)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 191); (R/S)-5-(3-forfinal)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5H-chromeno[3,4-f] quinoline (compound 192); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-propylthio-5H-chromeno[3,4-f] quinoline (compound 193); (R/S)-1,2-dihydro-5-(3-methoxyphenyl)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 194); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl]-5H-chromeno[3,4-f] quinoline (compound 195); (R/S)-5-(3-fluoro-4-were)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 196); (R/S)-5-(4-bro is N-chromeno[3,4-f] quinoline (compound 198); (R/S)-5-(4-chloro-3-forfinal)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 199); (R/S)-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f] quinoline (compound 200); (R/S)-1,2-dihydro-5-hexyl-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 201); 1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 202); (R/S)-1,2-dihydro-5-(3-methylbutyl)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 203); (R/S)-5-(4-chlorobutyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 204); (R/S)-5-benzyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 205); (R/S)-5-(4-bromobutyl)-1,2-dihydro-2,1,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 206); (R/S)-5-butyl-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 210); (R/S)-5-butyl-8-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 211); (R/S)-5-(3-chlorophenyl)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 212); (R/S)-5-(4-chloro-3-were)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-1]quinoline (compound 213); (R/S)-5-(4-chlorophenyl)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 214); (R/S)-9-fluoro-1,2-dihydro-5-(4-methoxyphenyl)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 215); (R/S)-8-fluoro-1,2-dihydro-5-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 216); (R/S)-5-(4-chlorophenyl)-8-fluoro-1,2-dihydro-2,2,4-Talin (compound 218); 9-chloro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 320); (R/S)-9-fluoro-1,2-dihydro-5-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 322); (R/S)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-dipropoxy-5H-chromeno[3,4-f] quinoline (compound 323); (R/S)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-propoxy-5H-chromeno[3,4-f] quinoline (compound 324); (R/S)-1,2-dihydro-9-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 329); (R/S)-1,2-dihydro-2,2,4,9-tetramethyl-5H-chromeno[3,4-f] quinoline (compound 330); (R/S)-7-chloro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 331); (R/S)-5-(4-bromo-3-pyridyl)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5H-chromeno[3,4-f] quinoline (compound 347); (R/S)-5-(3,5-differenl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 348); (R/S)-5-(3-bromo-5-forfinal)-1,2,3,4-tetrahydro-2,2-dimethyl-4-methylidene-5H-chromeno[3,4-f] quinoline (compound 352); (Z)-1,2-dihydro-5-(2,4,6-trimethylaniline)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 364); (Z)-5-benzylidene-9-fluoro-1,2-dihydro-2,2,4,11-tetramethyl-5H-chromeno[3,4-f] quinoline (compound 377); (R/S)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2-dimethyl-5H-chromeno[3,4-f] -4-quinoline (compound 378); (R/S)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,3,3-tetramethyl-5H-chromeno[3,4-f]-4-quinoline (compound 379); (R/S)-5-(4-chlorophenyl)-1,2-dihydro-2,2-dimethyl-5H-chromeno[3,4-f] -4-quinoline (Conn)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-chinoline (compound 382); (R/S)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2-dimethyl-5H-chromeno[3,4-f] -3-chinoline (compound 383); (R/S)-3-(3-terbisil)-5-(3-formanilide)-1,2,3,4-tetrahydro-3-hydroxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 384); (R/S)-3,5-dibutil-1,2,3,4-tetrahydro-3-hydroxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 385); (R/S)-5-butyl-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-chinoline (compound 386); (R/S-41,51)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5-phenyl-5H-chromeno[3,4-f] -3-chinoline (compound 387); (R/S-41,5 u)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5-phenyl-5H-chromeno[3,4-f] -3-chinoline (compound 388); (R/S-41,6 u)-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-phenyl-5H-isochroman[3,4-f] -3-chinoline (compound 390); (R/S-41,61)-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-phenyl-5H-isochroman[3,4-f] -3-chinoline (compound 391); (R/S-31,4 u,5u)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-3-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 397); (R/S-31,4 u, 51)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-3-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 398); (R/S-31,4 u,51)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-3-propyloxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 399); (R/S-31,4 u,5u)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-3-propyloxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 400) and (R/S-41,51)-3-benzylidene-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 401) the Il-5H-chromeno[3,4-f] quinoline (compound 219); (Z)-5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 220); (Z)-5-(4-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 221); (Z)-5-(4-bromobenzylamine)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 222); (Z)-5-(3-bromobenzylamine)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 223); (Z)-5-(3-chlorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 224); (Z)-5-(3-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] the quinoline (compound 225); (Z)-5-(2-chlorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 226); (Z)-5-(2-bromobenzylamine)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 227); (Z)-5-(2-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 228); (Z)-5-(2,3-differenziale)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 229); (Z)-5-(2,5-differenziale)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f] quinoline (compound 230); (Z)-9-fluoro-5-(3-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 231); (Z)-9-fluoro-5-(3-methoxybenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f] quinoline (compound 232); (Z)-8-fluoro-5-(3-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 233); (R/S-41,5 u)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-[3,4-f] -3-chinoline (compound 235); (R/S)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4,4-tetramethyl-5H-chromeno-[3,4-f] -3-chinoline (compound 236); 5-(3-terbisil)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 318); (R/S)-9-chloro-1,2-dihydro-2,2,4-trimethyl-5-propyloxy-5H-chromeno[3,4-f]the quinoline (compound 321); (R/S)-5-butyl-9-chloro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 325); (R/S)-5-butyl-1,2-dihydro-9-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-1] quinoline (compound 326); (R/S)-9-fluoro-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f] quinoline (compound 327); (R/S)-9-chloro-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f] quinoline (compound 332); (R/S)-5-(4-bromophenyl)-9-chloro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 333); (R/S)-9-chloro-5-(3-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 334); (R/S)-9-chloro-l,2-dihydro-2,2,4-trimethyl-5-(3-were)-5H-chromeno[3,4-f] quinoline (compound 335); (R/S)-9-chloro-5-(4-chloro-3-were)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 336); (R/S)-9-chloro-1,2-dihydro-5-[3-(trifluoromethyl)phenyl] -2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 337); (R/S)-9-chloro-5-(3,5-dichlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 338); (R/S)-9-chloro-1,2-dihydro-5-(4-methoxyphenyl)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 339); (R/S)-9-chloro-5-(3-fluoro-4-methoxyphenyl)-1,2-dihydro-2,2,4-three is h (compound 341); (R/S)-9-chloro-5-(3-chloro-4-methoxy-5-were)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 342); (R/S)-9-chloro-5-(4-fluoro-3-were)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 343); (R/S)-9-chloro-5-(3-forfinal)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 344); (R/S)-1,2-dihydro-2,2,4-trimethyl-5-[(3,4-methylenedioxy)phenyl] -5H-chromeno[3,4-f] quinoline (compound 345); (R/S)-5-(4-chloro-3-were)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 346); (R/S)-5-(3,5-dichlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 349); (R/S)-5-(3-bromo-5-were)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 350); (R/S)-5-(3-bromo-5-forfinal)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 351); (R/S)-5-[4-fluoro-3-(trifluoromethyl)phenyl] -1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 353); (R/S)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-(3-were)-5H-chromeno[3,4-f] quinoline (compound 354); (R/S)-1,2-dihydro-9-methoxy-2,2,4-trimethyl-5-(3-were)-5H-chromeno[3,4-f] quinoline (compound 355); (R/S)-9-fluoro-5-(3-fluoro-4-methoxyphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 356); (R/S)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl] -5H-chromeno[3,4-f] quinoline (compound 357); (R/S)-9-fluoro-5-(4-fluoro-3-were)-1,2-dihydro-2,2,4-trimet (compound 359); (Z)-5-(3,4-differenziale)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 360); (Z)-5-(3-formanilide)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 361); (Z)-5-(2,6-differenziale)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f] the quinoline (compound 362); (Z)-1,2-dihydro-5-(2-methylbenzylidene)-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 363); (Z)-9-chloro-5-(2,5-differenziale)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 365); (Z)-5-benzylidene-9-chloro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 366); (Z)-9-chloro-1,2-dihydro-2,2,4-trimethyl-5-(2-methylbenzylidene)-5H-chromeno-[3,4-f] quinoline (compound 367); (Z)-5-benzylidene-9-chloro-1,2-dihydro-2,2-dimethyl-5H-chromeno[3,4-f] the quinoline (compound 368); (Z)-9-chloro-5-(2-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 369); (Z)-9-chloro-5-(3-formanilide)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 370); (E/Z)-5-benzylidene-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f] quinoline (compound 371); (Z)-5-benzylidene-8-fluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 372); (Z)-5-benzylidene-1,2-dihydro-9-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 373); (Z)-9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-(2-methylbenzylidene)-5H-chromeno[3,4-f]quinoline (compound 374); (Z)-8-ft is rimatil-5-(2-methylbenzylidene)-5H-chromeno-[3,4-f] quinoline (compound 376); (Z)-(R/S)-5-(3-formanilide)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] quinoline (compound 389); (Z)-(R/S)-5-(benzylidene)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-chinoline (compound 392); (R/S-41,5 u)-5-(3-forfinal)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-quinoline (compound 393); (R/S-41,51)-5-(3-forfinal)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-quinoline (compound 394); (R/S-41,51)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl] -5H-chromeno[3,4-f] -3-chinoline (compound 395); (R/S-41,5 u)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl] -5H-chromeno[3,4-f] -3-chinoline (compound 396); (R/S-41,5 u)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-chinoline (compound 402); (R/S-41,51)-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-5H-chromeno[3,4-f] -3-chinoline (compound 403); and (R/S)-5-butyl-1,2-dihydro-2,2,4,9-tetramethyl-5H-chromeno[3,4-f]quinoline (compound 457).

11. Connection-modulator AR under item 6, selected from the group comprising 1,2-dihydro-2,2,4-trimethyl-6-methoxymethyl-8-pyranone[5,6-g]quinoline (compound 237); 1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 238); 1,2-dihydro-2,2,4-trimethyl-10-isocoumarin[4,3-g] quinoline (compound 239); 1,2-dihydro-2,2,4-trimethyl-10-isohedron[4,3-g] quinoline (compound 240); 1,2-dihydro-2,2,4,6-tetramethyl-8-peritonita-2,2,4,6-tetramethyl-8H-pyrano[3,2-g] quinoline (compound 243); (R/S)-1,2,3,4-tetrahydro-2,2,4-trimethyl-10-isohedron[4,3-g] quinoline (compound 244); 1,2-dihydro-2,2,4-trimethyl-10-thioethanolamine[4,3-g]quinoline (compound 245); (+)-1,2,3,4-tetrahydro-2,2,4-trimethyl-10-isohedron-[4,3-g] quinoline (compound 246); 1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g] the quinoline (compound 247); (R/S)-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 250); 1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-thiopyrano-[5,6-g]quinoline (compound 251); (R/S)-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-thiopyrano[5,6-g] quinoline (compound 252); 6-chloro(debtor)methyl-1,2-dihydro-2,2,4-trimethyl-8-pyranone[5,6-g] quinoline (compound 253); 9-acetyl-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 254); 1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 255); 1,2-dihydro-2,2,4-trimethyl-6-(1,1,2,2,2-pentafluoroethyl)-8-pyranone[5,6-g] quinoline (compound 256); (R/S)-6-chloro(debtor)methyl-1,2,3,4-tetrahydro-2,2,4-trimethyl-8-pyranone[5,6-g] quinoline (compound 257); 7-chloro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyranone[5,6-g]quinoline (compound 258); (R/S)-7-chloro-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 259); 1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 2 is tormentil-6-pyridone[5,6-g] quinoline (compound 262); 6-[dichloro(ethoxy)methyl]-1,2-dihydro-2,2,4-trimethyl-8-pyranone[5,6-g] quinoline (compound 263); 5-(3-furyl)-1,2-dihydro-2,2,4-trimethyl-8-pyranone[5,6-g] quinoline (compound 264); 1,2-dihydro-1,2,2,4-tetramethyl-6-trifluoromethyl-8-pyranone[5,6-g]quinoline (compound 265); 1,2-dihydro-6-trifluoromethyl-2,2,4-trimethyl-9-thiopyran-8-ono[5,6-g]quinoline (compound 266); 1,2-dihydro-1,2,2,4,9-pentamethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 267); 7-chloro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone-[5,6-g] quinoline (compound 268); and 6-chloro(debtor)methyl-1,2-dihydro-2,2,4-trimethyl-8-pyridone[5,6-g] quinoline (compound 269); (R/S)-1,2,3,4-tetrahydro-1,2,2,4-tetramethyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 404); (R/S)-5-(3-furyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl-8-pyranone[5,6-g] quinoline (compound 405); 5-(3-furyl)-1,2-dihydro-1,2,2,4-tetramethyl-8-pyranone[5,6-g] quinoline (compound 406); 5-(3-furyl)-1,2-dihydro-1,2,2,4-tetramethyl-8-thiopyrano[5,6-g]quinoline (compound 407); 6-chloro-5-(3-furyl)-1,2-dihydro-1,2,2,4-tetramethyl-8-piranha-[5,6-g] quinoline (compound 408); 1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridone[5,6-f] quinoline (compound 409); (R/S)-1,2,3,4-tetrahydro-4-methyl-6-trifluoromethyl-8-pyranone[5,6-g]quinoline (compound 410); 1,2-dihydro-2,2-dimethyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 411); 1,2,3,4-tetrahydro-2, the Olin (compound 413); (R/S)-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 414); (R/S)-1,2,3,4-tetrahydro-1,4-dimethyl-8-pyranone[5,6-g] quinoline (compound 415); (R/S)-4-ethyl-1,2,3,4-tetrahydro-1-methyl-8-pyranone[5,6-g]quinoline (compound 416); 2,2-dimethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridone-[5,6-f] quinoline (compound 417); (R/S)-1,2,3,4-tetrahydro-6-trifluoromethyl-2,2,4-trimethyl-8-pyridone[5,6-f] -3-chinoline (compound 418); 5-trifluoromethyl-7-pyridone[5,6-e] indoline (compound 419); 8-(4-chlorbenzoyl)-5-trifluoromethyl-7-pyridone[5,6-e] indoline (compound 420); 7-tert-butyloxycarbonyl-1,2-dihydro-2,2,8-trimethylquinoline (compound 421); 1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridone[5,6-f] quinoline (compound 422); 1,2-dihydro-6-trifluoromethyl-1,2,2,4-tetramethyl-8-pyridone[5,6-f] quinoline (compound 423); 3,3-dimethyl-5-trifluoromethyl-7-pyridone-[5,6-e] indoline (compound 424); (R/S)-1,2,3,4-tetrahydro-4-methyl-6-(trifluoromethyl)-8-pyridone[5,6-g] quinoline (compound 425); (R/S)-1,2,3,4-tetrahydro-4-methyl-6-(trifluoromethyl)-8-pyridone[5,6-g] quinoline (compound 426); 1,2,2-trimethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 427); (R/S)-1,2,3,4-tetrahydro-4-propyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 428); 1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-9-thiopyran-8-ono[5,6-g] quinoline (compound 429); 1,2-dihydro shall rmeil-8-pyridone[5,6-g] quinoline (compound 431); 1,2,3,4-tetrahydro-1-methyl-4-propyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 432); 1,2,3,4-tetrahydro-10-hydroxymethyl-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g]quinoline (compound 433); 1,2,3,4-tetrahydro-1,2,2,4-tetramethyl-6-trifluoromethyl-9-thiopyran-8-ono[5,6-g] quinoline (compound 434); 1,2,3,4-tetrahydro-2,2,9-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 435); (R/S)-1,2,3,4-tetrahydro-3-methyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 436); 1,2,3,4-tetrahydro-3,3-dimethyl-6-trifluoromethyl-8-pyridone-[5,6-g] quinoline (compound 437); (R/S)-1,2,3,4-tetrahydro-2,2,3-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 438); (R/S-21,4 u)-1,2,3,4-tetrahydro-2,4-dimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 439); (R/S-21,4 u)-4-ethyl-1,2,3,4-tetrahydro-2-methyl-6-trifluoromethyl-8-pyranone[5,6-g] quinoline (compound 440); (R/S-21,3 u)-1,2,3,4-tetrahydro-2,3-dimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 441); (R/S-21,31)-1,2,3,4-tetrahydro-2,3-dimethyl-6-trifluoromethyl-8-pyridone-[5,6-g]quinoline (compound 442); (R/S)-1,2,3,4-tetrahydro-2,3,3-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g] the quinoline (compound 443); (R/S)-1,2,3,4-tetrahydro-2-methyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 444); (R/S)-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridone-[5,6-g] quinoline (compound 445); (R/S-21,3 u)-1,2,3,4-tetrahydro-2,3,9-the Dono[5,6-g] quinoline (compound 447); (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline (compound 448); (R/S)-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-3-propyl-8-pyridone[5,6-g] quinoline (compound 449); and 1-methyl-5-trifluoromethyl-7-pyridone[5,6-f]indoline (compound 450).

12. Connection on p. 2, where the connection comprises an agonist or antagonist of the estrogen receptor.

13. Connection on p. 2, where the connection comprises an agonist or antagonist of the glucocorticoid receptor.

14. Connection on p. 2, where the connection comprises an agonist or antagonist mineralocorticoid receptor.

15. Pharmaceutical composition comprising an effective amount of modulating steroid receptor, the compounds of formulas I-XVIII (see graphic part).

where R1- 5 - or 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted C1-C4-alkyl, F, Cl, Br, NO2, CO2N, CO2R2CHO, CN, CF3CH2HE or PINES3where R2is hydrogen, C1-C4is alkyl or perfluoroalkyl, and where specified R1-heterocycle is attached to compounds of formulas I and X on carbon atom or nitrogen;

R3is hydrogen, C1-C4-alkyl or first>2R2, COR2CN, CF3CH2HE1-C4is alkyl or perfluoroalkyl, or phenyl;

R9and R10each independently is hydrogen or C1-C6-alkyl;

R11-R15each independently is hydrogen, F, Cl, Br, I, NO2, COR2, CF3CH2OH, OR2, SR2, SO2R2WITH1-C4-alkyl, or perfluoroalkyl or phenyl, where R2is hydrogen, C1-C4-alkyl or CF3;

W IS O, NH, NR7CH2, CHOH, C=O, OS=O, where R7has the values specified above, except that when W is NH, CH2or in compounds of formula III, then R11R14and R4can't all be hydrogen when R3, R9and R10all are CH3and they can't be one Deputy F, Cl or Br, and all other substituents are hydrogen, when R3, R9and R10all - CH3and further except that when W is O or NH in the compounds of formula IV, then R5-R6and R11-R14can't all be hydrogen when R3, R9and R10all - CH3;

X - CH2, O, S or NR7where R7has the meaning indicated above;

R16is hydrogen, C1-C6-alkyl, C13WITH1-C4-alkyl, C1-C4-alkoxyl or CH2HE; pyridyl, optionally substituted with halogen or C1-C10-alkyl, or thienyl, optionally substituted C1-C4-alkyl;

R18and R19each independently is hydrogen or C1-C6-alkyl;

R20- C1-C6-alkyl or phenyl, optionally substituted by 1 or 2 substituents which are the same or different and selected from halogen, C1-C4-alkyl or C1-C4-alkoxyl;

R21and R22each independently is hydrogen or C1-C4-alkyl;

R23is hydrogen, C1 or Br;

R24is hydrogen, C1-C4-alkyl, 3-furyl, CF3except that R24cannot be CH3when Z Is Oh, R22, R23, R26and R29everything is hydrogen and R3, R27and R28all - CH3;

R26is hydrogen;

R27-R29each independently is hydrogen or C1-C4-alkyl;

R30and R31each independently is hydrogen, C1-C4-alkyl or were, neoba the Z - O, S or NH;

the wavy line in the compounds of formula VII, XII, XIII and

XVI indicates olefinic bond or in CIS-or in transconfiguration;

the dashed lines in the structures represent an optional double bond,

and pharmaceutically acceptable carrier.

16. The composition according to p. 15, where the compounds of formulas I-XVIII include connection-modulators of steroid receptors.

17. The composition according to p. 16, where the compounds of formulas I-IV, X and XI include antagonists ETC.

18. The composition according to p. 16, where the compounds of formulas V and VI include modulators, ETC.

19. The composition according to p. 16, where the compounds of formulas VII, VIII, XII-XVI include agonists, ETC.

20. The composition according to p. 16 where the compound of formula IX, XVII and XVIII include modulators of AR.

21. The composition according to p. 20, where the compounds of formulas IX and XVII include antagonists of AR.

22. The composition according to p. 15, where the connection comprises an agonist or antagonist of the estrogen receptor.

23. The composition according to p. 15, where the connection comprises an agonist or antagonist of the glucocorticoid receptor.

24. The composition according to p. 15, where the connection comprises an agonist or antagonist mineralocorticoid receptor.

25. The composition according to p. 15, intended for peroral rednaznachena for introduction to the patient in a standard dosage form from about 1 μg/kg body weight to about 500 mg/kg body weight.

27. The composition according to p. 15, intended for administration to the patient in a standard dosage form from about 10 to about 250 mg/kg body weight.

28. The composition according to p. 15, intended for administration to the patient in a standard dosage form from about 20 μg/kg body weight to about 100 mg/kg body weight.

29. The composition according to p. 15, effective for the treatment and/or modulation of human fertility, hormone replacement therapy women, dysfunctional uterine bleeding, endometriosis, leiomyoma, acne, baldness in men, osteoporosis, prostatic hyperplasia, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, disorders of carbohydrate, protein and lipid metabolism, salt and water balance and functioning of the cardiovascular, renal, Central nervous, immune, and musculoskeletal systems.

30. The connection formulas

< / BR>
or

< / BR>
or

< / BR>
or

< / BR>
where Z Is O, S, or NR1where R1is hydrogen, R2C=O, R2C=S, R3OC=O, R3SC=O, R3OC=S, RCSC=S or R3R4NC=O, where R2is hydrogen, C1-C6is alkyl or perfluoroalkyl, optionally substituted allyl-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R5is hydrogen, R2C=O, R2C=S, R3OC=O, R3SC=O, R3OC=S, RCSC=S or R3R4NC=O, where R2, R3and R4have the values specified above;

R6is hydrogen, C1-C6-alkyl, R3O HOCH2, R3OCH2, F, C1, Br, I, cyano or perfluoroalkyl, where R3has the values listed above;

R7-R9each independently is hydrogen or C1-C6-alkyl, or R8and R9taken together form a three-semiline carbocyclic or heterocyclic ring;

R10is hydrogen, C1-C6-alkyl, R2C=O, R2C=S, R3OC=O, R3SC=O, RCOC=S, RCSC=S or R3R4NC=O, where R2-R4have the values specified above;

R11and R12each independently is hydrogen, C1-C6-alkyl, R3O, NON2, RCOCH2, F, Cl, Br, I, cyano or perfluoroalkyl, where R3has the values listed above;

R13is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, alkenyl, quinil, aryl, heteroaryl, R3O, NON2, R3OCH2, R3R4N, CF/SUP> is hydrogen, C1-C6-alkyl, R3O, NON2, R3OCH2, F, Cl, Br, I, cyano or perfluoroalkyl, where R3has the values listed above;

R15Is Cl, Br, I, (OR16)2, SnR17R18R19or OSO2R20where R16is hydrogen or C1-C6-alkyl, R17-R19each independently - C1-C6-alkyl, R2O or heteroaryl, R20- C1-C6-alkyl, perfluoroalkyl, aryl or heteroaryl and R2has the meaning specified above.

31. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline, including (a) carried out in one reaction vessel replacement 6-halogen-1,2-dihydro N-1 protected quinoline formula

< / BR>
in the presence of alkylate or in the presence of the reactive metal with the subsequent addition of organoborate or organosolv and treatment with an acid to obtain the corresponding 6-boron(or stannyl)-1,2-dihydro N-1 protected quinoline;

(b) binding of the obtained 6-boron(or stannyl)-1,2-dihydro N-1 protected quinoline with the compound of the formula R9Y in the presence of a palladium catalyst and a base to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline formula

< / BR>
where R1- Bob>4
is alkyl, aryl or heteroaryl;

R4-R6each independently is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, alkenyl, quinil, aryl, heteroaryl, R7O, NON2, R7OCH2, F, Cl, Br, I, cyano, R7R8N or perfluoroalkyl, where R7and R8each independently is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R9- aryl or heteroaryl;

X is Br, Cl or I;

Y is Cl, Br, I or OSO2CF3;

R is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R10C=O, R10C=S, R11OC=O, R11SC=O, R11OC=S, R11SC=S or R11R12NC= O, where R10is hydrogen, C1-C6is alkyl or perfluoroalkyl, optionally substituted allyl or arylmethylidene, quinil, aryl or heteroaryl, R11and R12each independently is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.

32. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline by p. 31, where stage a) is carried out in the presence of alkylate with the addition of organoborate and treatment with acid and obtaining 6-Bo is taking 6-substituted-1,2-dihydro N-1 protected quinoline by p. 32, additionally comprising removing the protection of the 6-substituted-1,2-dihydro N-1 protected quinoline to obtain the corresponding 6-substituted-1,2-dihydroquinoline.

34. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline by p. 31, where stage a) is carried out in the presence of the reactive metal with the subsequent addition of organoborate and treatment with acid and obtain the corresponding 6-Bor-1,2-dihydro N-1 protected quinoline, which is the original product at the stage b).

35. The way to obtain a 6-substituted-1,2-dihydro-N-1-substituted quinoline by p. 34, where the reactive metal selected from the group comprising magnesium, zinc and their combinations.

36. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline under item 34 or 35, further comprising removing the protection of the 6-substituted-1,2-dihydro-H-1 protected quinoline to obtain the corresponding 6-substituted-1,2-dihydroquinoline.

37. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline by p. 31, where stage a) is carried out in the presence of alkylate then adding derived organic tin and obtain the corresponding 6-stannyl-1,2-dihydro N-1 protected quinoline, which was the ina by p. 36, additionally comprising removing the protection of the 6-substituted-1,2-dihydro N-1 protected quinoline to obtain the corresponding 6-substituted-1,2-dihydroquinoline.

39. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline by p. 31, where stage a) is carried out in the presence of reaction of the active metal and then adding derived organic tin and obtain the corresponding 6-stannyl-1,2-dihydro N-1 protected quinoline, which is the original product at the stage b).

40. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline on p. 39, where the reactive metal selected from the group comprising magnesium, zinc and their combinations.

41. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline under item 39 or 40, further comprising removing the protection of the 6-substituted-1,2-dihydro N-1 protected quinoline to obtain the corresponding 6-substituted-1,2-dihydroquinoline.

42. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline, including the binding of 6-halo-1,2-dihydro N-1 protected quinoline with the compound of the formula R9Y in the presence of a palladium catalyst and a base to obtain a 6-substituted-1,2-dihydro-N-l-protected SUP> and R3each independently - C1-C4is alkyl, aryl or heteroaryl;

R4-R6each independently is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, alkenyl, quinil, aryl, heteroaryl, R7O HOCH2, R7OCH2, F, Cl, Br, I, cyano, R7RBN or perfluoroalkyl, where R7and R8nesasio is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R9- aryl or heteroaryl;

X is Br, Cl or I;

Y - (OR10)2or SnR11R12R13where R10is hydrogen or C1-C4-alkyl, R11-R13each independently - C1-C4-alkyl;

R is hydrogen, C1-C6-alkyl, R14C=O, R14C=S, R15OC=O, R15SC=O, R15OC=S, R15SC= S or R15R16NC= O, where R14is hydrogen, C1-C6is alkyl or perfluoroalkyl, optionally substituted allyl or arylmethylidene, quinil, aryl or heteroaryl, R15and R16each independently is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.

43. The way to obtain a 6-substituted-1,2-dihydro N-1 protected quinoline by p. 42, additionally the displaced-1,2-dihydroquinoline.

44. The method of producing nitrobenzamide includes (a) linking the derived 2-halogen-5-nitrobenzoic acid with 2-methoxyflavone acid formula

< / BR>
in the presence of a palladium catalyst and a base to obtain Giallorossi formula

< / BR>
and (b) carried out in one reaction vessel sequential cyclization of diarylpyrimidine with the corresponding nitrobenzamide by removing the protection of diarylpyrimidine and get djarikatsebi acid, conversion of this djarikatsebi acid into the corresponding chloride dilloway acid followed by cyclization of the chloride dilloway acid in the presence of a Lewis acid with getting nitrobenzamide formula

< / BR>
where R1-R6each independently is hydrogen, F, Cl, Br, CN, CF3WITH1-C4-alkyl or or7where R7is hydrogen or C1-C4-alkyl;

X - OR8or NR8R9where R8and R9each independently is hydrogen, C1-C4is alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl.

45. The way of getting p. 44, further comprising restoring nitrobenzamide to the appropriate aminobutyl formula

< / BR>
to aminobenzoylamino with getting cumarine[3,4-f]quinoline of formula

< / BR>
where R1-R9have the values listed in paragraph 44;

R10is hydrogen, C1-C4is alkyl, aryl or heteroaryl;

R11and R12each C1-C4is alkyl, aryl or heteroaryl.

47. The method according to p. 46, additionally comprising the sequential addition of metalloorganic to cumarine[3,4-f]quinoline with subsequent restoration to 5H-chromeno[3,4-f]quinoline of formula

< / BR>
where R1-R12have the values listed in paragraph 46;

R13is hydrogen, C1-C12-alkyl, HE, OR14or SR14where R14- C1-C10-alkyl, CF3, five-membered heteroaryl, optionally substituted by F, C1, Br, CH3or CF3, the six-membered heteroaryl, optionally substituted by F, C1, Br or CH3or aryl, optionally substituted with hydrogen, F, C1, Br, OR15or NR215where R15is hydrogen or C1-C4-alkyl.

48. The method of obtaining 5H-chromeno[3,4-f]quinoline, including sequential addition of metalloorganic to cumarine[3,4-f]quinoline, followed by dehydration and receiving 5H-chromeno[3,4-f]quinoline of formula

< / BR>
where R1-R1-C4-alkyl;

X - OR8or NR8R9where R8and R9each independently is hydrogen, C1-C4alkyl or optionally substituted allyl, arylmethyl, aryl or heteroaryl;

R10is hydrogen, C1-C4is alkyl, aryl or heteroaryl;

R11and R12each independently - C1-C4is alkyl, aryl or heteroaryl;

R13is hydrogen, C1-C12-alkyl, HE, OR14or SR14where R14- C1-C10-alkyl, CF3, five-membered heteroaryl, optionally substituted by F, C1, Br, CH3or CF3, the six-membered heteroaryl, optionally substituted by F, C1, Br or CH3or aryl, optionally substituted with hydrogen, F, C1, Br, OR15or NR215where R15is hydrogen or C1-C4-alkyl;

the wavy line in the structure when R13means olefinic bond or a CIS-or TRANS-configuration.

49. A method of obtaining a non-branched tricyclic 1,2-dihydroquinoline, including (a) the acylation of a 3-nitroarene formula

< / BR>
allermuir agent of the formula

< / BR>
to obtain the corresponding 5-protected 3-nitrourea and restore this 5-protected 3-nitroarene to soo the stimulating agent formula

< / BR>
in the presence of a base to obtain the corresponding 5-protected 3-aminoaryl (b) adding to the specified 5-protected 3-aminoaryl optionally substituted allyl formula

< / BR>
obtaining 5-protected 1,2-dihydroquinoline formula

< / BR>
and (C) the cyclization of 5-protected 1,2-dihydroquinoline by first removing protection with Z-group and subsequent cyclization in the presence of the ether - acid formula

< / BR>
and Lewis acid with obtaining non-branched tricyclic 1,2-dihydroquinoline selected from the group including

< / BR>
< / BR>
< / BR>
< / BR>
where R1and R2each independently is hydrogen, C1-C4-alkyl, hydroxymethyl, F, C1, Br, I or CN;

R3is hydrogen, C1-C4alkyl, aryl or heteroaryl;

R4and R5each independently - C1-C4is alkyl, aryl or heteroaryl;

R6is hydrogen, C1-C4-alkyl, CF3, five-membered heteroaryl, optionally substituted by F, Cl, Br, CH3or CF3, the six-membered heteroaryl, optionally substituted by F, Cl, Br or CH3or aryl, optionally substituted with hydrogen, F, Cl, Br, OR7or NR7R8where R7and R8each independently - vodor the UB>OR10CH2OR10or or10where R10- C1-C4-alkyl; R11and R12each independently is hydrogen or C1-C4-alkyl;

Z is O, N or S;

X is F, Cl, Br, I, CN, or6where R6has the values listed above;

R is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl, R13C=O, R13C=S, R14OS=O, R14SC=O, R14OC=S, R14SC=S or R14R15NC= O, where R13is hydrogen, C1-C6is alkyl or perfluoroalkyl, optionally substituted allyl or arylmethylidene, quinil, aryl or heteroaryl, R14and R15each independently is hydrogen, C1-C6-alkyl, optionally substituted allyl, arylmethyl, aryl or heteroaryl.

Priority points and features:

22.12.1994 on PP.1-49;

05.06.1995 on PP.1-49 varieties radicals.

 

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< / BR>
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< / BR>
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The invention relates to a new process for the preparation of 2,3-pyridinecarboxamide formula (I), where R is hydrogen, C1-C6alkyl or C1-C6alkoxymethyl, R1means hydrogen, C1-C6alkyl, C(O)R2, phenyl, benzyl, R2means C1-C6alkyl, benzyl or phenyl, which is that the compound of formula (II), where R has the above meaning, R6means C1-C6alkyl, R7means OR8or NR9R10, R8means hydrogen, C1-C6alkyl, C(O)R11, phenyl, benzyl, R11means C1-C6alkyl, OR12, NR12, R13, benzyl or phenyl, R12and R13denote hydrogen, C1-C6alkyl, benzyl or phenyl, R9and R10denote hydrogen, C1-C6alkyl, benzyl or phenyl, is subjected to the interaction with the imide of maleic acid of the formula (III), where R1have the above values

The invention relates to compounds of General formula (I) in which X represents hydrogen or halogen or alkyl, CNS, triptorelin or phenylmethoxy, R1represents hydrogen or alkyl, cyclopropyl or phenylmethylene group, R2represents either an alkyl group, possibly substituted, or phenylalkyl group, possibly substituted, or cyclohexylmethyl group, or thienylmethyl group, or pyridinylmethyl group, or phenyl group, possibly substituted, or pyridinyl group, or 5-methyl-1,2-oxazolidinyl group, or 5-methyl-1,3,4-thiadiazolyl group, or naphthalenyloxy group, R3and R4each represents hydrogen or alkyl, 2-methoxyaniline, hydroxyalkyl, carboxialkilnuyu, alkoxycarbonylmethyl or phenylalkyl group, or together with the nitrogen atom which carries them, form or pyrrolidinyloxy group, possibly substituted, or piperidinyl group, or morpholinyl group, or 4-methylpiperidino group, or azetidinol group, or thiazolidinedione group, and the bond between carbon atoms at positions 3 and 4 is a simple or double

The invention relates to an inhibitor semipretioase - derived imidazo [1,5-a] pyridine, containing containing structural unit (link) of General formula (I), where R1and R2represent hydrogen, R3and R4independently represent hydrogen, (1-6C) alkyl or together form =CH-NR5R6and R5and R6represent (1-6C) alkyl; X is hydrogen, R7, acetyl, PMC, R7-SO2N-protecting group, where R7is (1-12C) alkyl or (1-14C) aryl; R3represents a bond, D-Tig, Atc, D - amino acid with a hydrophobic side chain; R2is Pro, Gly, Val, Jle, 2,4-Me P2O, 3,3-Dmp, Jlc, Thr, Hyp, 2,2-Dmt or 5,5-Dmt; or R2is the link in case when R3is a bond, and X is R7-SO2-; or R2and R3together represent a structure similar to a dipeptide having the formula (II), in which the positions marked with asterisks may be condensed with a benzene ring and in which R9is hydrogen; or its pharmaceutically acceptable salt

The invention relates to new bicyclic pyrimidine derivative or its pharmaceutically acceptable salts, methods of inhibiting tyrosine kinase receptor, epidermal growth factor, in particular in the treatment of cancer, the pharmaceutical composition having inhibitory to tyrosinekinase factor receptor epidermal growth activity, as well as composition having contraceptive action

The invention relates to methods of reducing the level of TNFin mammals and connections that are applicable for this purpose
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