Substituted 4-phenyltetrahydroisoquinolines, preparation method, application as medicinal agents, and also medicinal agents containing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

 

The invention relates to substituted 4-vinyltetrahydrofuran. Drugs, containing compounds of this type are useful for prevention or treatment of various diseases. So join in, among other things, can be used at diseases of kidneys, acute or chronic renal failure, disorders of the gall bladder function and disorders of respiration, as snore or stop breathing during sleep.

The invention relates to compounds of formula I

where

R1, R2, R3 and R4

independently of one another denote hydrogen, F, Cl, Br, I, CN, NO2or R11-(CmH2m)-An-;

m represents zero, 1, 2, 3 or 4;

n denotes zero or 1;

R11 denotes hydrogen, methyl or CpF2p+1;

A represents oxygen, NH, N(CH3) or S(O)q;

p denotes 1, 2 or 3;

q represents zero, 1 or 2;

R5 denotes hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

R6 denotes hydrogen, OH, F, CF3, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

R7 and R8

independently of one another denote hydrogen, F, Cl, Br, CN, CO2R12, NR13R14or R16-(CmmH2mm)-Bnn-;

R12 denotes hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

R13 and R14

regardless of the Rog from each other denote hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

or

R13 and R14

form together with the nitrogen atom to which they relate, 4-, 5-, 6 - or 7-membered cycle in which one CH2group can be substituted NR15, S, or oxygen;

R15 denotes hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

mm denotes zero, 1, 2, 3 or 4;

nn denotes zero or 1;

R16 denotes hydrogen, methyl or CppF2pp+1;

B denotes an oxygen or S(O)qq;

pp denotes 1, 2 or 3;

qq denotes zero, 1 or 2;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

r denotes 1, 2, 3, 4, 5, 6, 7 or 8;

s denotes 2, 3, 4, 5, 6, 7 or 8;

X denotes-C(O)- or-S(O)2-;

Z represents-C(O)- or a bond;

and their pharmaceutically acceptable salts and triptoreline.

In the form of carrying out the invention preferred compounds of formula I, where R1, R2, R3 and R4

independently of one another denote hydrogen, F, Cl, Br, CN or R11-(CmH2m)-An-;

m represents zero or 1;

n denotes zero or 1;

R11 denotes hydrogen, methyl or CpF2p+1;

Oboznachaemogo, NCH3or S(O)q;

p denotes 1 or 2;

q represents zero, 1 or 2;

R5 denotes hydrogen, methyl, ethyl or cyclopropyl;

R6 denotes hydrogen or methyl;

R7 and R8

independently of one another denote hydrogen, F, Cl, CN, CO2R12, NR13R14 or R16-(CmmH2mm)-Bnn-;

R12 denotes hydrogen, methyl or ethyl;

R13 and R14

independently of one another denote hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

or

R13 and R14

form together with the nitrogen atom to which they are linked, 5-, 6 - or 7-membered cycle in which one CH2group can be substituted NR15, S, or oxygen;

R15 denotes hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

mm represents zero, 1 or 2;

nn denotes zero or 1;

R16 denotes hydrogen, methyl or CppF2pp+1;

B denotes an oxygen or S(O)qq;

pp denotes 1 or 2;

qq denotes zero, 1 or 2;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

r denotes 2, 3, 4, 5, 6, 7 or 8;

s denotes 2, 3, 4, 5, 6, 7 or 8;

X denotes-C(O)- or-S(O)2-;

Z represents-C(O)-;

as well as their pharmaceutically acceptable salts and triptoreline.

Especially preferred compounds of formula I, where

R1 and R3

represent hydrogen;

R2 and R4

independently of one another denote hydrogen, F, Cl, Br, NH2, NHCH3or N(CH3)2;

R5 denotes hydrogen, methyl, ethyl or cyclopropyl;

R6 denotes hydrogen or methyl;

R7 and R8

represent hydrogen;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen or methyl;

r denotes 2, 3, 4, 5 or 6;

s is 2, 3, 4, 5 or 6;

X denotes-C(O)- or-S(O)2-;

Z represents-C(O)-;

and their pharmaceutically acceptable salts and triptoreline.

The following form of the preferred compounds of formula I, where

R1 and R3

represent hydrogen;

R2 and R4

independently of one another denote hydrogen, F, Cl, NH2, NHCH3or N(CH3)2;

R5 denotes hydrogen, methyl, ethyl or cyclopropyl;

R6 denotes hydrogen or methyl;

R7 and R8

represent hydrogen;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen or methyl;

r denotes 2, 3, 4, 5 or 6;

<> s is 2, 3, 4, 5 or 6;

X denotes-C(O)- or-S(O)2-;

Z represents-C(O)-;

and their pharmaceutically acceptable salts and triptoreline.

Very particularly preferred compounds of formula I selected from the group:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dio is,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethylpiperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-dimethylpiperidin-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrothieno is n-4-yl)phenyl]imidazolidin-2,4-dione,

3-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-methylimidazolidine-2,4-dione,

(3R,4S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,4-dimethylpiperidin-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

1-[2-((R)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-isopropylimidazole-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-isobutylthiazole-2,4-dione,

(R and S)-3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-(2-methylsulfonylamino)imidazolidin-2,4-dione,

3-[2-((R-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5,5-dimethylimidazolidin-2,4-dione,

1-[2-((R)-6,8-dichloro-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,

1-[2-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((S)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3,4,4-tetramethylpyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4,4-dimethylpiperidine-2,6-dione,

and 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,

and their pharmaceutically acceptable salts and triptoreline.

Especially preferred compounds of formula I, selected from the group:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-di the ENT-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethylpiperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-dimethylpiperidin-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-methylimidazolidine-2,4-dione,

(3R,4S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,4-dimethylpiperidin-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidin-2,6-dione

and

3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

and their pharmaceutically acceptable salts and triptoreline.

Particularly preferred compounds of formula I, selected from the group:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-is ion,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethylpiperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-dimethylpiperidin-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrothieno is n-4-yl)phenyl]imidazolidin-2,4-dione,

3-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,

3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione

and

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,

and their pharmaceutically acceptable salts and triptoreline.

The following form of execution includes the compounds of formula I, where:

R1, R2, R3 and R4

independently of one another denote hydrogen, F, Cl, Br, CN or R11-(CmH2m)-An-;

m represents zero or 1;

n denotes zero or 1;

R11 denotes hydrogen, methyl or CpF2p+1;

A stands for oxygen, NCH3or S(O)q;

p denotes 1 or 2;

q represents zero, 1 or 2;

R5 denotes hydrogen, methyl, ethyl or cyclopropyl;

R6 denotes hydrogen or methyl;

R7 and R8

independently of one another denote hydrogen, F, Cl, CN, CO2R12, NR13R14 or R16-(CmmH2mm)-Bnn-;

R12 denotes hydrogen, methyl or ethyl;

R13, R14 independently of one another denote hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

or

R13 and R14

form together with the nitrogen atom to which they are linked, 5-, 6 - or 7-membered cycle in which one CH2group can be substituted NR15, or oxygen;

R15 denotes hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

mm represents zero, 1 or 2;

nn denotes zero or 1;

R16 denotes hydrogen, methyl or CppF2pp+1;

B denotes an oxygen or S(O)qq;

pp denotes 1 or 2;

qq denotes zero, 1 or 2;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5, or 6 atoms;

r denotes 1, 2, 3, 4, 5, 6, 7 or 8;

s denotes 2, 3, 4, 5, 6, 7 or 8;

X denotes-C(O)- or-S(O)2-;

Z represents a bond;

and their pharmaceutically acceptable salts and triptoreline.

Especially preferred are the compounds of formula I, where

R1 and R3

represent hydrogen;

R2 and R4

independently of one another denote hydrogen, F, Cl, Br, NH2, NHCH3or N(CH3)2;

R5 denotes hydrogen, methyl, ethyl or cyclopropyl;

R6 denotes hydrogen or methyl;

R7 and R8

represent hydrogen;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen or m is Teal;

r denotes 1, 2, 3, 4, 5 or 6;

s is 2, 3, 4, 5 or 6;

X denotes-C(O)- or-S(O)2-;

Z represents a bond;

and their pharmaceutically acceptable salts and triptoreline.

Particularly preferred are the compounds of formula I, where

R1 and R3

represent hydrogen;

R2 and R4

independently of one another denote hydrogen, F, Cl, NH2, NHCH3or N(CH3)2;

R5 denotes hydrogen, methyl, ethyl or cyclopropyl;

R6 denotes hydrogen or methyl;

R7 and R8

represent hydrogen;

W represents CrH2ror CsH2s-2;

moreover, one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S;

R17 represents hydrogen, methyl;

r denotes 1, 2, 3, 4, 5 or 6;

s is 2, 3, 4, 5 or 6;

X denotes-C(O)- or-S(O)2-;

Z represents a bond;

and their pharmaceutically acceptable salts and triptoreline.

Very particularly preferred compounds of formula I selected from the group:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methyl-1,3-dihydroimidazole-2-it,

(R)-6,8-dichloro-4-[2-(1,1-dioxo-1-λ6-isothiazolin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahed ozkinay-4-yl)phenyl]oxazolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2-it,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-he

and

6,8-dichloro-4-[4-(1,1-dioxo-1-λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,

and their pharmaceutically acceptable salts and triptoreline.

Specifically preferred compounds of formula I, selected from the group:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methyl-1,3-dihydroimidazole-2-it,

(R)-6,8-dichloro-4-[2-(1,1-dioxo-1-λ6-isothiazolin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-the l)phenyl]imidazolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2-it,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he

and

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-it,

and their pharmaceutically acceptable salts and triptoreline.

Particularly preferred are the compounds of formula I, selected from the group:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methyl-1,3-dihydroimidazole-2-it,

(R)-6,8-dichloro-4-[2-(1,1-dioxo-1-λ6-isothiazolin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2-it,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,

and their pharmaceutically acceptable salts and triptoreline.

p> The following form of the preferred compounds of formula I, in which the residues R1, R2, R3 and R4 independently of one another denote hydrogen, F, Cl, Br, CN or R11-(CmH2m)-An-where m and n are independently from each other denote zero or 1, R11 denotes hydrogen, methyl or CpF2p+1and A stands for oxygen, NCH3or S(O)qand p denotes 1 or 2 and q represents zero, 1 or 2; especially preferred compounds of formula I in which R1 and R3 represent hydrogen, and R2 and R4 independently of one another denote hydrogen, F, Cl, Br, NH2, NHCH3or N(CH3)2such as Cl or Br. In one form of the preferred compounds of formula I in which R1 and R3 represent hydrogen, and R2 and R4 independently of one another denote F, Cl, NH2, NHCH3or N(CH3)2for example Cl.

The following form of the preferred compounds of formula I, in which R5 denotes hydrogen, methyl, ethyl or cyclopropyl; especially preferred compounds of formula I, in which R5 denotes hydrogen, methyl or cyclopropyl, for example, methyl.

The following form of the preferred compounds of formula I, in which R6 denotes hydrogen or methyl, for example hydrogen.

The following form of the preferred compounds of formula I, in which the residues R7 and R8 independently of one another denote water is od F, Cl, CN, CO2R12, NR13R14 or R16-(CmmH2mm)-Bnn-, and R12 denotes hydrogen, methyl or ethyl, R13 and R14 independently of one another denote hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5 or 6 atoms, or R13 and R14 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle in which one CH2group can be substituted NR15, S, or oxygen, and R15 denotes hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5 or 6 C atoms, and where mm represents zero, 1 or 2, nn denotes zero or 1, and R16 denotes hydrogen, methyl or CppF2pp+1and B denotes an oxygen or S(O)qqand pp denotes 1 or 2 and qq denotes zero, 1 or 2; especially preferred compounds of formula I in which R7 and R8 are hydrogen.

The following form of the preferred compounds of formula I in which W represents CrH2ror CsH2s-2moreover , one or more CH2group CrH2rand CsH2s-2can be replaced with NR17, oxygen or S, and R17 represents hydrogen, alkyl with 1, 2, 3 or 4 atoms or cycloalkyl with 3, 4, 5 or 6 C atoms, in particular hydrogen or methyl, for example hydrogen, and where r denotes 2, 3, 4, 5, 6, 7 or 8, in particular 2, 3, 4, 5 or 6, and s denotes the 2, 3, 4, 5, 6, 7 or 8, in particular 2, 3, 4, 5 or 6.

In the following form bipolarization the compounds of formula I, in which X represents-C(O)- or-S(O)2-.

The following form of the preferred compounds of formula I in which Z represents-C(O)-.

In another form of the preferred compounds of formula I in which Z denotes a connection.

If the compounds of formula I contain one or more centers of asymmetry, they may independently from each other exist in the form as S and R configuration. The compounds can exist as optical isomers, diastereomers, racemates or as mixtures thereof in all ratios. Further, the compounds of formula I can exist in the form of a rotary isomers.

This invention relates to all possible tautomeric forms of the compounds of formula I.

Further, the invention relates to derivatives of compounds of formula I, for example, a solvate, a hydrate and products attach alcohols, esters, prodrugs and other physiologically acceptable derivatives of compounds of formula I, as well as active metabolites of compounds of formula I. the invention Also relates to all crystal modifications of the compounds of formula I.

Alkyl residues can be unbranched and branched. This is also the case if they have substituents or occur as substituents of other residues, such as alkyl fluoride residues or as koksilah residues. Examples for alkyl residues are methyl, ethyl, n-propyl, isopropyl (=1-methylethyl), n-butyl, isobutyl (=2-methylpropyl), verbatim (=1-methylpropyl), tert-butyl (=1,1-dimethylethyl), n-pentyl, isopentyl, trepetin, neopentyl and hexyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl and n-butyl. In the alkyl residues of one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, of the hydrogen atoms may be substituted by fluorine atoms. Examples of such alkyl fluoride residues are trifluoromethyl, 2,2,2-triptorelin, pentafluoroethyl, heptafluoroisopropyl. Substituted alkyl residues can be substituted in any positions.

Alkylene residues, such as, for example, CmH2mCmmH2mmor CrH2rcan be unbranched or branched. This also applies when they have substituents or occur as substituents of other residues, for example in Forellenbach residues, such as, for example, CpF2pand CppF2pp. Examples for alkilinity residues are methylene, ethylene, 1-METROTILE, propylene, 1-mutilation, butylene, 1-propylethylene, 1-ethyl-1-METROTILE, 1,2-dimethylethylene, 1,1-dimethylmethylene, 1-ethylethylene, 1-methylpropyl, 2-methylpropyl, pentile, 1-butylamine, 1-propylethylene, 1-methyl-2-ethylethylene, 1,2-dimethylpropylene, 1,3-dimethy is propylene, 2.2-dimethylpropylene, hexylen and 1-methylpentyl. In alkilinity one or more residues, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, of the hydrogen atoms may be substituted by fluorine atoms. Substituted alkylene residues can be substituted in any positions. In alkilinity residues, one or more CH2-groups may be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl. As in unbranched and branched alkilinity circuits CH2-groups can be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl, for example, as a 1-hydroxyethylene the rest.

Alkenylamine residues, such as, for example, CsH2s-2can be unbranched or branched. This also applies when they are substituents, for example in Forellenbach residues. Alkenylamine residues can be ninasimone in various positions. Examples for alkenylamine residues are ethenylene, 1-methyladenine, propylen, but-1-Anilin, but-2-Anilin, 1-methylprop-1-Anilin, 1,2-dimethylethylene, penttinen or hexarelin. In alkenylamine one or more residues, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hydrogen atoms may be substituted by fluorine atoms. Substituted alkanolamine residues can be substituted in any positions. In alkenylamine residues, one or more CH2-groups may be replaced by oxygen is, S, NH, N-alkyl or N-cycloalkyl. As in unbranched and branched alkenylamine circuits CH2-groups can be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl.

Examples cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In cycloalkyl one or more residues, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, of the hydrogen atoms may be substituted by fluorine atoms. Substituted cycloalkyl residues can be substituted in any positions. Cycloalkyl residues can also be branched, as alkylsilanes or cycloalkenyl, such as methylcyclohexyl or cyclohexylmethyl.

Examples of cycles of NR13R14, and R13 and R14 form together with the nitrogen atom to which they relate, 4, 5, 6 or 7-membered cycle, are morpholine, pyrrolidine, piperidine, piperazine and N-methylpiperazine.

As CH2-links also have the power of CH3group, located at the end of the alkyl residue, which in this context are perceived as CH2-H group. This is also valid in the branched alkilinity residues, such as, for example, CmH2mCmmH2mmor CrH2r.

If a variable, such as cycloalkyl or R1, is found as a component more than once, then set a variable for each case are independent of each other.

If the compounds of formula I contain one or more acidic or basic groups or one or more basic heterocycles, by the invention include physiologically and toxicologically acceptable salts, in particular pharmaceutically acceptable salts. Thus the compounds of formula I can be deprotonirovannym one acidic group and be used, for example, as alkali metal salts, preferably sodium salts or potassium, or ammonium salts, for example as salts with ammonia or organic amines or amino acids. Since the compounds of formula (I always contain at least one alkaline group, they can also be obtained in the form of their physiologically acceptable salts accession acids, for example with the following acids: mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as, for example, acetic acid, citric acid, tartaric acid, lactic acid, malonic acid, methanesulfonate, fumaric acid. At the same time as salts accession acids take into account all salts of pharmacologically acceptable acids, for example halides, in particular chlorides, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, p-toluensulfonate, adipinate, fumarate, glucona is s, glutamate, glycerophosphate, maleates and pamoate (this group is also physiologically acceptable anions), as well as trifenatate.

The object of the invention also include methods of making compounds of formula I, described below.

Described herein the compounds of formula I can be obtained, for example, by analogy with the known literature methods based on the aniline derivatives of the formula VIII.

Aniline of formula VIII, for example, by heating with the appropriate acid of formula XXII in polyphosphoric acid (PPA) can be converted to compound of formula Ia (Tetrahedron Letters 2003, 44, 2133), and R1 to R8 and W are defined as described above

and

X and Z correspond to the-C(O)-.

Alternatively, the compounds of formula Ia can be obtained by the fact that anilines of formula VIII is subjected to transformation in an aprotic solvent like dichloromethane with anhydrides type XXIX to the intermediate amides of the acids. Then get the desired imides of the formula Ia, the fact that the intermediates cyclist in an aprotic solvent like dichloromethane with a suitable reagent cyclization as EDC in the presence of a base as the basis Hunya (Hünig''s base). Alternatively, the intermediates can also be heated in a high boiling solvent as a simple diphenyl ether or no solvent, so that when amaswazi the years of the formation of a closed loop, moreover, the residues R1-R8 and W are defined as above

and

X and Z correspond to the-C(O)-.

The compounds of formula Ib can be obtained, for example, in a two-step reaction based on esters isocyanatobenzene acids of the formula XII. In this first intermediate by reaction of the nitrogen of aniline with an isocyanate group to form a urea before then there is acid catalyzed cyclization, and R1-R8 are defined as above,

X and Z correspond to the-C(O)-,

R22 represents alkyl with 1, 2, 3 or 4 C atoms, for example methyl or ethyl,

-VN-NH denotes the remainder of W, in which the end of CH2group substituted NH,

and

-V'-NCO denotes the remainder of W, in which the end of CH2group substituted by an isocyanate group.

The variation of the balance R17 can be achieved then by alkylation of compounds of formula Ib in the presence of a base, such as sitedisability or lithium - or sodium-hexamethyldisilazide with an alkylating agent of the formula XIII

and R1-R8 and R17 are defined as described above

X and Z correspond to the-C(O)-,

-VN-NH denotes the remainder of W, in which the end of CH2group substituted NH,

-VN-NR17 - denotes the remainder of W, in which the end of CH2group substituted NR17,

and

LG stands at alkylation on vignau detachable group as for example, bromide, chloride, tosylate or mesilate.

Alternatively, the cycle can also be synthesized in a three step sequence. To do this, first on the aniline nitrogen is transferred carbonyl group. This occurs, for example, by using derivatives of Harborview acid of the formula XIV or carbonyldiimidazole. Subsequent transformation with complex amino esters of formula XV due to cyclization catalyzed by acids or bases, preferably with hydrochloric acid or matrikelstyrelsen, leads to the formation of the compounds of formula Ic,

and R1 to R8, R17, and-VN-NR17 - defined, as described above,

R23 denotes alkyl with 1, 2, 3 or 4 C atoms, for example methyl or ethyl,

and

R24 denotes optional substituted phenyl residue, for example phenyl or 4-nitrophenyl.

Cyclic urea of formula Id can be obtained from the product of aniline of formula VIII using derivatives of Harborview acid of formula XIV to the fact that educated carbamate subjected to transformation with amines of formula XVI, as a result of the cyclization stage in the presence of a base such as sodium hydride, potassium carbonate or nutregisterdevice,

and

R1-R8, R17, R24, -VN-NR17 - and-VN-NHR17 determined as described above

and

Y appears the t detachable group, for example chlorine, or a preliminary stage for split groups, for example hydroxy, which is then transferred to a detachable group, for example, using methylchloride.

The lactam of formula Ie can be obtained by transformation of aniline of the formula VIII with the lactones of formula XVII (Synlett 2001, 1485) the fact that the intermediate formed hydroxyamide of the hydroxyl group by transformation, for example, sulfochlorides, anhydride or a strong acid are doing well-detachable group, which is then replaced through the nitrogen of aniline, preferably in the presence of a base, such as sodium hydride, potassium carbonate or nutregisterdevice,

and R1-R8 and W are defined as above,

X is-C(O)-

and

Z denotes the connection.

Alternative, you may also direct transformation halogenating compounds of formula XVIII with a lactam of the formula XIX in the presence of catalysts, such as copper iodide, to compounds of formula Ie (J. Am. Chem. Soc. 2001, 7727, ibid. 2002, 7421),

and R1-R8 and W are defined as above,

X is-C(O)-,

Z denotes the link

and

Hal denotes Cl, Br, I or-O-triflate.

You can get halogenating compounds of formula XVIII is based on carbonyl the s derivative of the formula VI, similarly with the synthesis of aniline derivatives of the formula VIII, which is further described below.

The next alternative is the conversion of anilines of the formula VIII with anhydrides of the acids of formula XXV to form compounds of formula Ie. Intermediate amides obtained are then subjected to cyclization in the presence of a base like sodium hydride, potassium carbonate or nutregisterdevice in solvents like THF, DMSO and DMF. Thus R1-R8, LG and W are defined as above,

Z corresponds to communication and

X denotes-C(O)-.

The sulfonamides of formula If can be derived from anilines of formula VIII by transformation with globalcirculation formula XX (Tetrahedron Letters 44, 5483 (2003)),

moreover, R1-R8, R17, and-VN-NR17 - defined, as described above,

T denotes Cl or Br,

X is-SO2-

and

Z denotes the connection.

The compounds of formula Ig can be synthesized by the cyclization reaction catalyzed by acids. Based on ureas of formula XXI, which can be received by one of the above methods in the presence of acids, for example hydrochloric acid or formic acid at the cleavage Catala or acetal obtain the compounds of formula Ig,

and R1-R8 and R17 are defined as described above

X is-C(O)-,

Z denotes the link

-NR17-V-CV*HCV"'(ORa)2corresponds to the remainder of W with the designation CrH2rin which end CH2group substituted NR17, the following CH2group substituted acetal group/ketal and V* and V"' indicate the possible ramifications alkalinous balance, and Ra denotes alkyl with 1, 2, 3 or 4 C atoms, for example methyl or ethyl, or both residue Ra together form an ethylene residue

and

-NR17-V-CV*=CV"'denotes the residue of W with the designation CsH2s-2in which end CH2group substituted NR17, and V* and V"' indicate the possible ramifications alkenilovyh balance.

The compounds of formula Ih can be obtained in that first aniline VIII is subjected to transformation with chlorothioformate formula XXVI as familiarities, and then, the obtained intermediate THIOCARBAMATE after treatment with a solution of sodium methylate may react with the acid chloride of the acid of type XXVII. At the same time balances R1-R8, R24 and LG are defined as above.

VKrefers to a group W, which is shortened to one group CH2,

VS-S - denotes the group of W, in which one CH2group substituted sulphur and

X and Z correspond to the-C(O)-.

The compounds of formula Ii can be synthesized in a three-stage sequence, as indicated. First anilines of type VII is subjected to transformation in an aprotic solvent, as THF, in the presence of a base, as nutregisterdevice, with anhydrides of acids of the type XXVIII with the formation of the intermediate amides. Then in the presence of nucleophiles and bases like potassium carbonate in methanol to separate the protective group P from oxygen. Finally, the obtained alcohol in an aprotic solvent like THF, is subjected to transformation with the equivalent of carbonyl as 1,1-carbonyldiimidazole or phosgene, in the presence of a base, as nutregisterdevice.

Residues R1-R8 are defined as above,

VO-O - corresponds to the group W in which one CH2group is replaced by oxygen,

P corresponds to a protective group as acetyl, benzoyl, menthoxycarbonyl or trityl, and

X and Z correspond to the-C(O)-.

The compounds of formula Ij can be obtained by the fact that anilines of formula VIII is subjected to transformation with chloroformate formula XXX in an aprotic solvent like THF, and then the intermediate carbamate is subjected to cyclization in an aprotic solvent like THF, in the presence of a base like sodium hydride. At the same time balances R1-R8, LG and VO-O are defined as above, and

Z corresponds to the connection, and

X denotes-C(O)-.

The compounds of formula Ik can be obtained by the fact that anilines of formula VIII is subjected to transformation with solfanelli the house of formula XXXI in an aprotic solvent, as THF, in the presence of a base, as nutregisterdevice. At the same time balances R1-R2, T and W are defined as above, and

Z corresponds to the connection, and

X denotes-SO2-.

Compounds of formulas XII, XIII, XIV, XV, XVI, XVII, XIX, XX, XXII, XXV, XXVI, XXVII, XXVIII, XXIX, XXX and XXXI are commercially available or can be obtained by analogy with the described in the literature methods known to the expert.

The initial compounds of formula VIII can be obtained as follows.

By reduction of the carbonyl group in compounds of formula VI and the subsequent cyclization of the corresponding alcohols of formula VII, acid-catalyzed (see Tetrahedron Lett. 1989, 30, 5837; Org. Prep. Proced. Int. 1995, 27, 513), in a known manner can be obtained tetrahydroisoquinoline formula VIIIa, and R1-R8 are defined as above, and

R20 denotes a well-known specialist protective group for nitrogen, such as acetyl residue.

To compounds of formula VIII are then delivered a famous professional way, based on compounds of the type formula VIIIa, that removes the protective group R20. This occurs in proton solvent such as water or lower alcohols, preferably under acid catalysis, for example, hydrochloric acid or triperoxonane acid or alkaline catalysis, for example, in the presence of methylate or ethylate sodium.

p> Alternatively, after the recent restoration of the protective group R20 may be split before cyclization, which is preferably possible in the presence of strong bases, such as methylate or ethylate sodium in methanol or ethanol. As well as a group R20 may be preferably removed using acids as hydrochloric acid in the presence of alcohols as methanol or ethanol. Prior removal of R20 is especially recommended in case orthoaminophenol. So directly receive unprotected anilines of formula VIII.

To obtain alternativley compounds of the formula I, in which R6 is not hydrogen, the corresponding complex diphenylalanine esters of the formula IX in alpha-position to R6 can be alkylated with known methods. Thus preferably replaces a hydrogen atom of aniline protective R21 group, such as allyl or benzyl. The compounds of formula X can be converted by standard methods into the corresponding amides of formula XI, which is transferred to the desired tetrahydroisoquinoline formula VIIIb for similar reactions Pictet-Spengler (cf. Tetrahedron 1987, 43, 439; Chem. Pharm. Bull. 1985, 33, 340),

and R1-R8 and R20 is defined as above,

R21 denotes a protective group, such as allyl or benzyl,

and

LG corresponds to the movable detachable group when alkiline the years as for example, bromide, chloride, tosylate or mesilate.

Unprotect compounds of formula VIIIb with well-known specialist methods gives free aniline of formula VIII. However, depending on the type of protective group of carbonyl protective group as acetyl, preferably separated by acid (e.g., aqueous HCl) or basic catalysis (for example, using methylate or ethylate sodium), while the benzyl or allyl protective group best hatshepsuts by hydrogenation.

The compounds of formula IX are commercially available or can be obtained by analogy with the described in the literature methods known to the expert.

Used above, the compounds of formula VI preferably get well-known expert in the ways of benzylamino formula IV and the corresponding aminosilane compounds alpha-bromoacetophenone formula V,

and R1-R8 and R20 is defined as above.

Join alpha bromoacetophenone formula V can be obtained by known literature methods from the corresponding precursors of acetophenone by synthesized.

Predecessors of benzylamine formula IV, if they are not commercially available, can be synthesized by well-known specialist standartisation from the corresponding benzylchloride or bromide of the formula III and the corresponding amines,

and R1-R5 are defined as described above

and

X denotes F, Cl, Br or I, in particular Cl or Br.

Alternatively, the compounds of formula IV can be obtained by reductive amination of the aldehyde of formula IIIa well-known specialist in standard ways,

and R1-R5 are defined as described above.

Compounds of formulas III and IIIa, and R5-NH2are commercially available or can be obtained by analogy with the described in the literature methods known to the expert.

Processing and, optionally, purification of the products and/or intermediates occurs using conventional techniques, such as extraction, chromatography or crystallization and normal drying.

It was shown that the compounds of formula I are exclusive inhibitors of the sodium-hydrogen exchange (NHE), in particular the sodium-hydrogen exchange subtype 3 (NHE3).

Still known inhibitors of NHE3 was, for example, from compounds of the type arylguanidines (EP 825178), type norbornanamine (WO 0144164), type 2-guanidinylation (WO 0179186) or type of benzamidine (WO 0121582, WO 0172742). Squalamine, also described as an inhibitor of NHE3 (M. Donowitz et al., Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144), acts on the modern level of knowledge not directly, as the compounds of formula I, and through nepra the second mechanism, and, thus, its maximum power of action can only be achieved in an hour.

Tetrahydroisoquinoline as inhibitors nutrition exchange subtype 3 (NHE3) is already described in the patent applications WO 03048129, WO 2004085404 and Germany application No. 102004046492.8. In the patent application WO 03055880 describes compounds of the class of salts of tetrahydroisoquinoline as inhibitors of NHE3. It has been unexpectedly found that these compounds of formula I are also effective inhibitors of NHE3 and thus possess a preferred pharmacological and pharmacokinetic properties.

NHE3 is in different species, preferably in the gall bladder, intestine and kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735-741, 1998), and also detected in the brain (E. Ma et al., Neuroscience 79: 591-603).

Thanks to its properties, inhibiting NHE, the compounds of formula I are suitable for the prevention and treatment of diseases caused by activation or activated NHE, as well as diseases caused by secondary violations, due to the NHE. The compounds of formula I can also be used for the treatment and prevention of diseases and inhibit NHE only partially, for example when using reduced doses.

The use of compounds according to the invention relates to the prevention and treatment of acute and chronic diseases in veterinary medicine is e and the medicine man.

Because of their pharmacological action of the compounds of formula I are suitable to improve the impulse to breathe. Therefore, they can be used for the treatment of disturbed States of breath, which may occur, for example, under the following clinical conditions and diseases: disorders of the Central pulse respiration (for example, the Central stop breathing during sleep, sudden infant death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term mechanical ventilation, respiratory disorders during adaptation in the highlands, obstructive and mixed forms stop breathing during sleep, acute and chronic lung disease with hypoxia and hypercapnia.

Additional connection improves muscle tone of the upper respiratory tract, so that snoring is suppressed. Therefore, these compounds are preferred by the application to obtain drugs for prevention and treatment of respiratory arrest during sleep and muscle-related breathing disorders and to obtain drugs for prevention and treatment of snoring.

The combination of an NHE inhibitor of the formula I with a carbonic anhydrase inhibitor (eg, acetazolamide) may be preferred, the latter leads to metabolic acidosis and thus increases dehat the optimum activity so what can be achieved with increased action and reduced the introduction of biologically active substances.

Compounds according to the invention due to its inhibitory NHE3 action conserve cellular energy reserves, which are toxic and pathogenic situations quickly and thus cause damage or cell death. While energy-intensive resorption of sodium, consuming ATP in the proximal tubules under the influence of NHE3 inhibitors temporarily calm down (calm down) and the cell is thus able to transfer acute pathogenic, ischemic or toxic situation. Therefore, the compounds are suitable, for example, as pharmaceuticals for the treatment of ischemic harmful factors, such as acute renal failure.

Further, the compounds are also suitable for the treatment of all chronic diseases of the kidneys and forms of nephritis, which is due to an increased excretion of protein lead to chronic renal failure. Accordingly, the compounds of formula I suitable for the production of medicines for the treatment of diabetic late damage, diabetic nephropathy and chronic kidney disease, especially all inflammations of the kidneys (nephritis) (Nephritiden)that are associated with increased secretion of the protein/albumin.

It was shown that using the e according to the invention compounds have soft bowel cleansing effect and consequently also preferably can be used as a laxative or threatening constipation.

Further compounds according to the invention preferably can be used for the prevention and treatment of acute and chronic diseases of the intestinal tract caused by, for example, ischemic conditions in the intestinal area and/or subsequent reperfusion, or inflammatory conditions and situations. Such complications can occur when insufficient peristalsis of the intestine, for example, often after surgery, with constipation or with greatly reduced activity of the intestine.

Using the compounds according to the invention it becomes possible to prevent the formation of gallstones.

The NHE inhibitors according to the invention is universally suitable for the treatment of diseases caused by ischemia and reperfusion.

Compounds according to the invention due to its pharmacological properties suitable as antiarrhythmic drugs.

Thanks cardiostim components of NHE inhibitors especially suitable for the prophylaxis and treatment of infarction and for the treatment of angina, and they also preventively inhibit or greatly reduce the pathophysiological processes in the occurrence of ischemia-induced disorders, especially when the occurrence of ischemia-induced cardiac arrhythmias. Due to their protective action against patologicheskim hypoxic and ischemic situations, the compounds of formula I, used according to the invention, by inhibiting the cellular mechanism of Na+/H+the ion exchange can be used as medicines for the treatment of all acute or chronic damage caused by ischemia, or primary or secondary induced diseases.

This also applies to their use as pharmaceuticals for surgical interventions. Thus the compounds according to the invention can be used for the transplantation of organs, and connections can be used to protect the organs of the donor before and during removal, for the protection of removed organs, for example in the treatment or storage in saline solution, and also the introduction into the organism of the recipient being treated by the compounds of formula I.

Compounds are also valuable drugs with protective action when conducting angioplasticheskih operations, for example on the heart and peripheral organs and blood vessels.

Further compounds according to the invention can be used for blending bypass, such as imposition of bypass in coronary vessels and the coronary arteries (Coronary Artery Bypass Graft) (CABG).

In accordance with its action against violations caused by ischemia, the compounds of formula I can also be used in owani for resuscitation after cardiac arrest.

In accordance with its protective effect against ischemia-induced damage, the compounds according to the invention are also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, especially the Central nervous system (CNS), and they are, for example, is suitable for treatment of a stroke or cerebral edema.

As NHE inhibitors not only effectively protect tissues and organs from damage caused by ischemia and reperfusion, but also from the cytotoxic effects of drugs, particularly used in the treatment of cancer and autoimmune diseases, and they combined use of compounds of the formula I, which may reduce or suppress the cytotoxic effect of therapy. By reducing cytotoxic effect, particularly cardiotoxicity due to additional prescription drugs with NHE inhibitors, in addition, the dose of cytotoxic therapeutic agents may be increased and/or doctor's order such medicines extended. therapeutic benefit of such cytotoxic therapy may be significantly increased by combination with NHE inhibitors.

The compounds of formula I is particularly suitable for improving treatment with medicines that contain unwanted cardiotoxic to the components.

In General described here NHE inhibitors favorable image can be combined with other compounds that regulate intracellular pH, and are meant inhibitors enzyme groups carbohydrates inhibitors systems, transporting bicarbonate ions as inhibitors of the sodium-bicarbonate joint Transporter (NBC) or dependent sodium chloridebicarbonate exchanger (NCBE), as well as with other NHE inhibitors with inhibitory action on other NHE subtypes as components for the combination, as their support is essential pharmacological regulating pH effect described here NHE inhibitors can be amplified or modulated.

In accordance with its protective effect against ischemia-induced damage, the compounds according to the invention are also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, especially the Central nervous system, and they are, for example, is suitable for treatment of a stroke or cerebral edema.

The compounds of formula I are also suitable for the treatment and prevention of diseases and disorders caused by increased excitability of the Central nervous system, in particular for the treatment of diseases falling within the scope of epileptic induced clonic and tonic spasms of the Central nervous system, mental depression, States and fear psychosis. While the NHE inhibitors according to the invention can be used alone or in combination with other anti-epileptic current antipsychotic substances or biologically active substances or inhibitors carbohydrates, for example, acetazolamide, and other inhibitors of NHE or the sodium-dependent chloridecontaining the ion exchanger (NCBE).

In addition, the compounds of formula I according to the invention is also suitable for the treatment of diseases in the form of shock, as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of formula I can also be used for the prevention and treatment of thrombotic diseases, as they are as NHE inhibitors and can inhibit the aggregation of platelets. In addition, they can inhibit or prevent the release of mediators of inflammation and coagulation abundant after ischemia and reperfusion, in particular the von Willebrand factor and thrombogenic selective proteins. Thereby can be reduced and eliminated pathogenic action thrombogenic and significant inflammatory factors. Therefore, the NHE inhibitors according to this invention is combined with other anticoagulant and/or thrombolytics the mi biologically active substances, as, for example, plasminogen activators of recombinant or natural fabrics, streptokinase, urokinase, acetylsalicylic acid, antagonists of thrombin, factor Xa antagonists, fibrinoliticeski existing drugs, antagonists of thromboxane receptor, inhibitors of phosphodiesterase antagonists of factor VIIa, clopidogrel (Clopidogrel), ticlopidine, etc. Combined use of these inhibitors of NHE with NCBE inhibitors and/or inhibitors carbohydrates, for example, acetazolamide, particularly preferably.

In addition, the NHE inhibitors according to the invention are characterized by a strong inhibitory effect on the proliferation of cells, for example, the proliferation of fibroblasts and proliferation of smooth muscle cells of blood vessels. So we are talking about the compounds of formula I as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause, and therefore they can be used as anti-atherosclerosis, anti-chronic renal failure, cancer. Thus, they can be used for the treatment of hypertrophy and hyperplasia of organs such as the heart and prostate. Therefore, the compounds of formula I are suitable for the prevention and treatment of heart failure (damage zakupie what happened to the heart (congestive heart failure = CHF), and also for the treatment and prevention of prostate hyperplasia or hypertrophy of the prostate.

The NHE inhibitors further characterized by the slowing or prevention of diseases caused by fibrosis. Thus, they are suitable as an excellent means for the treatment of fibrosis of the heart and lung fibrosis, liver fibrosis, kidney fibrosis and other fibrotic diseases.

Since NHE in essential hypertensive patients is significantly increased, the compounds of formula I are suitable for the prevention and treatment of high blood pressure and cardiovascular disease. However, they can be used separately or in conjunction with suitable components for combinations for the treatment of high blood pressure and cardiovascular disease. For example, one or more casinomodule acting diuretics, loop diuretics, aldosterone antagonists and pseudoaldosteronism as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eperon, can be combined with compounds of formula I. Further, the NHE inhibitors of the present invention can be used in combination with calcium antagonists, as verapamil, diltiazem, amlodipine or nifedipine, as well as with ACE inhibitors, such as ramipril, enalapril, lisinopril fosinopril or captopril. Other favorable components for combinations are also β-blockers like metoprolol, albuterol etc., receptor antagonists angiotensin and subtypes of its receptor, as losartan, irbesartan, valsartan, omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, agonists of the adenosine receptor, inhibitors and activators of potassium channels as glibenclamide, glimepiride, diazoxide, cromakalim, Minoxidil and derivatives thereof, activators of mitochondrial sensitive to ATP (ATP) potassium channel (mitoK(ATP) channel), inhibitors of other potassium channels, as Kv1.5, etc.

Due to its anti-inflammatory action, the NHE inhibitors according to the invention can be used as anti-inflammatory drugs. Mechanically this attention inhibitors of release of mediators of inflammation. Thus, the compounds can be used individually or in combination with anti-inflammatory agent for the prevention or treatment of chronic and acute inflammatory diseases. As components for combinations of preferable use of steroidal and non-steroidal anti-inflammatory agents.

In addition, it was found that NHE inhibitors have a favorable effect on serum lipoproteins. Therefore, they can be used to prof the prevention and regression of atherosclerotic changes, they exclude a causal risk factor. These include not only the primary hyperlipidemia, but also known secondary hyperlipidemia, which occur, for example, diabetes. In addition, the NHE inhibitors lead to a clear reduction of heart attacks caused by metabolic disorders, and in particular to a significant reduction in induced scale of a heart attack and its severity. Therefore, the NHE inhibitors of the formula I preferably are used for getting medicines for the treatment of hypercholesterinemia to obtain drugs for the prevention of atherogenesis, to obtain drugs for prevention and treatment of atherosclerosis, for obtaining a medicinal product for the prevention and treatment of diseases caused by high cholesterol levels, to obtain drugs for prevention and treatment of diseases caused by endothelial dysfunction, to obtain drugs for prevention and treatment of hypertension-induced atherosclerosis, to obtain drugs for prevention and treatment of thrombosis induced by atherosclerosis, to obtain drugs for prevention and treatment of ischemic disorders and post-ischemic reperfusion disorders, induced hypercholest what inemia and endothelial dysfunction, to obtain drugs for prevention and treatment of cardiac hypertrophy and cardiomyopathy and congestive heart failure (CHF), to obtain drugs for prevention and treatment of coronary vascular spasm and myocardial infarction induced by hypercholesterinemia and endothelial dysfunction, to obtain drugs for the treatment of the mentioned diseases in combination with substances that reduce blood pressure, preferably inhibitors of the enzyme that converts angiotensin (Angiotensin Converting Enzyme) (ACE) and antagonists of the angiotensin receptor. The combination of an NHE inhibitor of the formula I with biologically active substances that reduce the level of fat in the blood, preferably an inhibitor of HMG-CoA reductase inhibitors (eg, lovastatin or pravastatin), the latter leads to lipid-lowering action, and consequently, the hypolipidemic properties of the NHE inhibitor of the formula I increase is a favorable combination with intensified action and reduced use of biologically active substances.

Thus, the NHE inhibitors lead to effective protection against damage to the endothelium of various origins. With this protection of the vessels against the syndrome of endothelial dysfunction NHE inhibitors are valuable drugs for the por is the prevention and treatment of spasms of the coronary vessels, diseases of the peripheral vessels, particularly intermittent claudication (claudicatio intermittens), atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic diseases.

In addition, the NHE inhibitors suitable for treating ainsliezubaida mellitus (NIDDM), and, for example, insulin resistance is suppressed. The strengthening of the anti-diabetic effect and action of the compounds according to the invention can contribute to their combination with biguanides as Metformin, with antidiabetic sulfonylurea as glibenclamide (Glyburid), glimepiride, tolbutamide, etc., a glucosidase inhibitor, a PPAR agonist, as rosiglitazone, pioglitazone, etc. with insulin preparations of various forms of application, with inhibitor DB4 with insulin sensitizer or meglitinides.

In addition to acute antidiabetic effects of NHE inhibitors counteract the occurrence of diabetic late complications and can therefore be used as pharmaceuticals for the prevention and treatment of diabetic late disorders like diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and other diseases that arise as a consequence of diabetes. However, they may preferably be combined with antidiab the practical drugs described above in the treatment of NIDDM. Combination with favorable forms of applying insulin if this can be of particular value.

The NHE inhibitors in addition to protective effect against acute ischemic situations and also subsequent acute burdened reperfusion situations also find a direct therapeutic effect against diseases and disorders of the whole organism mammals that are closely associated with symptoms of chronic aging process and which are also available independently from acute conditions of insufficient blood supply and can also meet at a normal, pesemistic conditions. Under these pathological arising after prolonged aging age-related manifestations, such as malaise, hiloti and death, which in recent years has been able to make available to treatment with inhibitors of NHE, we are talking about diseases and disorders, largely due to age-related changes in vital organs and their functions, acquiring in the aging body of growing importance.

Diseases associated with functional age-related disorders with age symptoms of wear bodies are, for example, the lack of contact and the ability of blood vessels to the reaction with respect to contractions and responses re is axali. This is due to the age of the weakening of the ability of the reaction vessels by squeezing and relaxing the excitation, which is an essential process of the cardiovascular system and thereby life and health, can be substantially eliminated or reduced by using the NHE inhibitors. An important function and a measure to maintain the ability of the vessels to the reaction is a blockade or retardation of age-related progressive endothelial dysfunction, which can be reduced considerably by NHE inhibitors. Thus, inhibitors of NHE especially suitable for the treatment and prevention of age-progressive endothelial dysfunction, in particular intermittent claudication. In addition, therefore, the NHE inhibitors especially suitable for the treatment and prevention of heart failure, congestive heart failure (CHF), as well as for treatment and, in particular, for the prevention of age-related cancers.

Thus take into account the combination with lower blood pressure drugs such as ACE inhibitors, receptor antagonists angiotensin, diuretics, antagonists of Ca2+and so on, or with drugs, normalizerbase metabolism as substance reduce cholesterol. Thus, the compounds of formula I are suitable for p is opractice age-related changes in tissues and to prolong life while maintaining a high quality of life.

Compounds according to the invention are effective inhibitors of the cellular antiporta sodium/proton (the agreed transfer of the two solutions through the membrane in opposite directions) (ion exchanger Na/H), which in numerous diseases (essential hypertension, atherosclerosis, diabetes etc), these cells also increased, measurements are readily available, as, for example, in erythrocytes, platelets or leukocytes. So used according to the invention compound suitable as an exceptional and simple scientific tools, for example, in their use as diagnostics for the detection and identification of certain forms of hypertension, but also of atherosclerosis, diabetes and late diabetic complications, proliferative diseases, etc.

Further, the NHE inhibitors are suitable for the treatment of diseases (human and animal), caused by bacteria and protozoa. Among the diseases caused by protozoa, in particular, can be called malaria in humans and chicken coccidiosis.

In addition, compounds suitable as means to control sucking parasites in human medicine and veterinary medicine and plant protection. Thus preferably used as tools against blood-sucking parasites in human medicine and veterinary medicine.

So the name is nnye compounds are used individually or in combination with other drugs or biologically active substances to obtain drugs for treatment or prevention of disorders pulse, breathing, breathing, breathing disorders during sleep, stop breathing during sleep, snoring, acute and chronic kidney disease, acute renal failure and chronic renal failure, disorders of bowel function, high blood pressure, essential hypertension, diseases of the Central nervous system, diseases resulting from hyperexcitability of the Central nervous system (ZNS), epilepsy and seizures or state of fear, depression and psychosis caused by Central nervous system ischemic conditions of the peripheral or Central nervous system or stroke, acute and chronic disorders and diseases of the organs and extremities caused by situations of ischemia or reperfusion, atherosclerosis, disorders of lipid metabolism, thrombosis, impaired function of the gall bladder, lesion parasites, diseases caused by endothelial dysfunction, diseases caused by protozoa, malaria, preservation and storage of transplants for surgical interventions, for use in surgical operations and organ transplantation or for the treatment of shock or diabetes and late violations resulting from diabetes, or diseases, primary or secondary cause of which is the proliferation of the cells, and for the preservation of health, and so the duration of life.

Further, the invention concerns the use of compounds of the formula I and their pharmaceutically acceptable salts for use as pharmaceuticals.

Further, the invention also applies to medicinal products for use in human medicine, veterinary, or plant protection agents containing an effective amount of the compounds of formula I and/or pharmaceutically acceptable salts, as well as drugs for use in human medicine, veterinary, or plant protection agents containing an effective amount of the compounds of formula I and/or pharmaceutically acceptable salts alone or in combination with one or more other biologically active pharmacological substances or drugs.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt, can be administered, for example, oral, parenteral, intramuscular, intravenous, rectal, nasal, by inhalation, subcutaneously, or by suitable percutaneous forms of application, and the preferred application depends on the appropriate form of the disease. The compounds of formula I can be used separately or together with galenovye auxiliary substances in veterinary medicine and in human medicine, and to protect plants is. Medicines contain biologically active substances of the formula I and/or their pharmaceutically acceptable salts in General in amounts of from 0.01 mg to 1 g per unit dose.

What excipients suitable for the desired pharmaceutical finished forms, is known to the specialist because of his special knowledge. In addition to solvents, geleobrazovanie, suppositories, excipients for tablets and other carriers of biologically active substances can be used, for example, antioxidants, dispersants, emulsifiers, antispyware, substances that improve the taste, preservatives, agents, dissolution or dyes.

For oral forms of receiving active compound is mixed with suitable additives, as carriers, stabilizers or inert diluents, and using conventional methods lead to suitable forms of applications, such as tablets, pills, investing capsules (Steckkapseln), aqueous, alcoholic or oily solutions. As inert carriers may be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Thus the composition may be in the form of dry or moist granules. As oily carriers or solvents are used, for example,vegetable or animal oils, for example, sunflower oil or fish oil.

For subcutaneous, percutaneous or intravenous use use the active connection request accepted for this substances as agents dissolving, emulsifying agents or other excipients in the solution, suspension or emulsion. As solvents mean, for example, water, physiological saline solution or alcohols, for example ethanol, propanol, glycerin, along with this also solutions of sugars, as glucose or mannitol, or a mixture of various of the aforementioned solvents.

As pharmaceutical preparative ready-made forms for admission in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of biologically active substances of formula I in a pharmaceutically harmless solvent, especially ethanol, or water, or mixtures of such solvents.

Preparative ready form can optionally contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as the propellant. One such preparative ready form usually contains a biologically active substance in a concentration of from about 0.1 to 10, especially from about 0.3 to 3 wt%.

Dosage accepted biologically active substances of the formula I and astate receive depend on the efficiency and time of exposure used compounds; in addition, also influence the type and intensity of the disease being treated, as well as gender, age, weight and individual predisposition of the mammal being treated.

The average daily dose of the compounds of formula I with a weight of about 75 kg is at least 0.001 mg/kg, preferably 0.1 mg/kg up to maximum of 30 mg/kg, preferably 1 mg/kg of body weight. In acute situations, such as immediately after the transfer condition stop breathing in the high altitude areas, you may need an even higher dose. Especially when administered intravenously, for example, in patients with infarction in the intensive care unit may be necessary dose up to 300 mg/kg / day. The daily dose can be divided into one or more, for example up to 4 single doses.

Description of the TESTS AND EXAMPLES

Abbreviations

TFA (TFA)Triperoxonane acid
HPLC (HPLC)High performance liquid chromatography
LCMSLiquid chromatography-mass spectrometry (Liquid Chromatography-Mass Spectrometry)
RtTime is I'm holding
THF (THF)Tetrahydrofuran
DMSO (DMSO)The sulfoxide
abs.Absolute
DMF (DMF)Dimethylformamide
ACN (atsn)Acetonitrile
min.Minutes
hHour(s)
EDCN-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
AiBN2,2'-Azobis(2-methylpropionitrile)
NBSN-Bromosuccinimide
CIChemical ionization
ESIIonization scattered electrons (Electrospray ionization)
mMultiplet
dDoublet
sThe singlet

Total

From epimeres C-4 of the formula I one epimer often OK is called active, than others.

So used enantiomers ortho-, meta - and paraamino (2-, 3 - or 4-(1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine, for example 2-, 3 - or 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine), was isolated from the chiral phase as described in WO 2004085404.

Racemic amines of the formula VIII can represent, as described in WO 2004085404, for example: racemic paramin: 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 1, intermediate product 6); meta-amine: 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 2, the intermediate product 1), artemin: 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 3, intermediate 5) and subsequently separated into its enantiomers, as described in the application WO 2004085404, for example, a pure enantiomer pair-amine: (S)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 42, the intermediate product 1, enantiomer B); meta-amine: (S)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 20, the intermediate product, enantiomer B); ortho-amine: (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 41, the intermediate product 1, enantiomer B).

2-(6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine and the corresponding (R)- and (S)-enantiomers can be obtained from this ka is described in example 41 b.

Describes the syntheses carried out, if not mentioned else known to the expert way in a protective gas atmosphere, e.g. argon, in standard reaction vessels, as one -, two-or three-neck flask that was equipped with a stirrer, a refrigerator, a device for addition, and the like. Solvents drove, unless otherwise stated, on a rotary evaporator with a suitable vacuum and at a suitable temperature.

Conditions

Preparative HPLC

Preparative HPLC was performed under the following conditions:

Stationary phase:Merck Purospher RP18 (10 μm) 250×25 mm
Mobile phase:90% H2O (0.05% of TFA)→90% acetonitrile in 40 min; 25 ml/min

Analytical HPLC/MS

Methods HPLC

Method A:

Stationary phase:YMC J ' sphere ODS H80 20×2.1 mm
Mobile phase:90% H2O (0.05% of TFA)→95% acetonitrile 1.9 min; 95% acetonitrile 0.5 min→10% acetonitrile 0.05 min; 1 ml/min

Method B:

The hospital is the first phase: YMC J ' sphere ODS H80 20×2.1 mm
Mobile phase:96% H2O (0.05% of TFA)→95% acetonitrile for 2.0 min; 95% acetonitrile and 0.4 min→4% acetonitrile in 0.05 min; 1 ml/min

Mass spectrometry

The mass spectrometer was directly connected to HPLC (LCMS). As a method of ionization, unless otherwise stated, used the scattered electrons (ESI+). The specified retention time belonged to the maximum ion current signal corresponding connections, as they did in connection LCMS using the above HPLC.

Example 1

3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione

a){3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ureido}ethylacetoacetate;

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (95 mg; obtained as described in WO 2004085404) was dissolved in acetonitrile (2 ml) and stirring was bury utilizationfocused (30 mg). After four hours, the solution was concentrated, and the residue was purified by preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with potassium carbonate and three times were extracted is by ethyl acetate. After drying over magnesium sulfate passed for drying. The residue was absorbed in an aqueous solution of hydrochloric acid and dried by freezing. Received 107 mg of the desired compound.

LCMS-Rt (A): 1,14 min;

[M+H+]: 436,5

b)3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione

Took {3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ureido}ethylacetoacetate (30 mg). Was added water (3 ml) and 10%hydrochloric acid (231 μl) and then with stirring for three hours, was heated with reverse flow. After cooling and freeze-drying the reaction solution was obtained white solid.

LCMS-Rt (A): 0,98 min;

[M+H+]: RUR 390.4

Example 2

3-[4-(-((S)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-digidroid

Example 2 was synthesized analogously to example 1. Needed for this, (S)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining described in WO 2004085404) was obtained from the racemate by separation on a chiral phase.

LCMS-Rt (B): 0,89 min;

[M+H+]: 390,1

Example 3

3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione

Example 3 was synthesized analogously to example 1. The necessary 3-(6,8-dichlo the-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine was obtained, as described in WO 2004085404.

LCMS-Rt (A): 0,96 min;

[M+H+]: 390,3

Example 4

3-[3-((S)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-digidroid

Example 4 was synthesized analogously to example 1. Needed for this, (S)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining described in WO 2004085404) was obtained from the racemate by separation on a chiral phase.

LCMS-Rt (B): 0,90 min;

[M+H+]: 390,0

Example 5

3-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-digidroid

Example 5 was synthesized analogously to example 1. The necessary 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine prepared as described in WO 2004085404.

LCMS-Rt (A): 1,04 min;

[M+H+]: RUR 390.4

Example 6

3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-digidroid

Example 6 was synthesized analogously to example 1. The necessary (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining, as described in WO 2004085404) was obtained from the racemate by separation on a chiral phase.

LCMS-Rt (B): 0,98 min;

[M+H+]: 390,0

Example 7

1-[2-((R)-6,8-Di the ENT-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-digidroid

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (100 mg; enantiomer B, a receipt, as described in WO 2004085404) was placed in a flask together with succinic acid (58 mg). To this was added polyphosphoric acid (about 2 ml). Then the reaction mixture was stirred at 135°C. After 4 hours, added a little more of succinic acid (~9 mg). After another 2 hours at 135°C and left overnight at room temperature. For handling poured on ice water, the acidic phase was set to pH 10 with potassium carbonate solution and then three times were extracted with ethyl acetate. Purified organic phase once washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with potassium carbonate and three times were extracted with ethyl acetate. After drying over magnesium sulfate was filtered and passed for drying. The residue was absorbed aqueous hydrochloric acid and dried by freezing.

LCMS-Rt (B): 1,03 min;

[M+H+]: 389,0

Example 8

6,8-Dichloro-4-[4-(1,1-dioxo-1-λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline

2-Chloroethylnitrosourea (75 mg) was stirred for the eyes with sulfurylchloride (0,32 ml) in acetonitrile (10 ml) at 75-80°C. Cooled to room temperature, the mixture was concentrated, and the residue was absorbed absolute diethyl ether (1 ml). The ether phase containing chlorosulfonated, bury to a solution of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (110 mg, obtaining, as described in WO 2004085404), absolute diethyl ether (1 ml) and triethylamine (85 ml) at -70°C. After the end of the additives, the reaction mixture was left at room temperature and was stirred for 2.5 hours. Then mixed with a mixture of water and saturated sodium hydrogen carbonate solution (3:1) and added a little ether. The phases were separated, and the aqueous phase twice more was extracted with diethyl ether. The combined ether phases were dried over magnesium sulfate, filtered and concentrated.

The crude product was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with potassium carbonate and three times was extracted with dichloromethane. After drying over magnesium sulfate was filtered and passed for drying. Part of the thus obtained product (20 mg) was dissolved in DMSO (0.5 ml), mixed with potassium carbonate (6.2 mg) and six hours was stirred at room temperature. After storage in a Cabinet-freezer over night under high vacuum drove DMSO, and the residue was mixed with a small the quantity of water, a saturated solution of sodium bicarbonate and diethyl ether. The phases were separated, and the aqueous phase twice more was extracted with diethyl ether. The combined ether phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with potassium carbonate and three times was extracted with dichloromethane. After drying over magnesium sulfate was filtered and passed for drying. The residue was absorbed aqueous hydrochloric acid and dried by freezing.

LCMS-Rt (B): 1,02 min;

[M+H+]: 412,1

On the basis of the corresponding amines, which, if necessary, used in enantiomerically pure form, and the corresponding dicarboxylic acids, similarly, were obtained the following compounds.

ExampleStructureSolSimilar,
example
MS
[M+H+]
LCMS
Rt [min]
9HCl7389,0 (ESI+) of 1.03 (B)
10HCl7387,0 (ESI+)1,05 (B)
11HCl7403,0 (ESI+)1,06 (B)
12HCl7403,0 (ESI+)1,04 (B)
13HCl7389,0 (ESI+)0,97 (B)
14HCl7389,0 (ESI+)0,96 (B)
15HCl7403,1 (ESI+),97 (B)
16HCl7403,1 (ESI+)0,96 (B)
17HCl7389,1 (ESI+)0,97 (B)
18HCl7403,1 (ESI+)0,98 (B)
19HCl7387,0 (ESI+)1,05 (B)
20HCl7387,0 (ESI+)1,12 (B)
21HCl7431,1 (ESI+)1,20 (B)
22HCl7415,0 (ESI+)1,19 (B)
23HCl7443,1 (ESI+)1,31 (B)
24TFA7375,0 (ESI+)1,04 (B)
25TFA7417,0
(ESI+)
1,15 (B)
26TFA7445,1
(ESI+)
1,24 (B)
27HCl7403,0 (ESI+)1,07 (B)
28TFA7417,0 (ESI+)of 1.16 (B)
29TFA7431,1 (ESI+)1,19 (B)
30TFA7417,0 (ESI+)1,15 (B)
31TFA7417,0 (ESI+)1,13 (B)
32HCl7415,0 (ESI+)1,21 B)
33HCl7415,0 (ESI+)1,21 (B)
34HCl7389,0 (ESI+)1,06 (B)

Example 35

1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he-triptorelin

a)N-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-hydroxybutyrate

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (100 mg, enantiomer B, obtaining, as described in WO 2004085404) downloaded from γ-butyrolactone (84 mg) in absolute THF (8 ml) and then bury for 15 min at 0°C sodium hexamethyldisilazide (NaHMDS; 2M/THF; 0,65 ml). After 10 min stirring at 0°C, the bath was removed with ice and then stirred for 2 hours. To the reaction was added a saturated solution of ammonium chloride (0.6 ml), ethyl acetate and water. The phases were separated, and the aqueous phase is twice were extracted with ethyl acetate. The combined organic phases are once washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized to what rebonato potassium and three times was extracted with dichloromethane. After drying the combined dichloromethane phase over magnesium sulfate filtered and passed for drying.

LCMS-Rt (B): 0,98 min;

[M+H+]: 393,1

b)1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he-triptorelin

N-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-hydroxybutyrate (100 mg) was dissolved in absolute THF (4 ml) and bury the triethylamine (77 μl) and a solution of methanesulfonamide (44 μl) in THF (0.5 ml). After six hours of stirring at room temperature drove THF, and the residue was mixed with saturated solution of sodium bicarbonate. After three times of extraction with ethyl acetate, combined organic phase was dried over magnesium sulfate, filtered and concentrated. Part of the remainder (44 mg) was dissolved in absolute THF (2 ml)and the reaction mixture was cooled to 0°C. At this temperature for 10 min bury nutregisterdevice (96 μl). Then another 10 min was stirred at 0°C until removed bath with ice. After 1.5 hours was added in the reaction of a saturated solution of ammonium chloride (0.2 ml) and water. Then three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile drove on ro is ornam evaporator, the aqueous residue was neutralized with potassium carbonate and three times was extracted with dichloromethane. After drying the combined dichloromethane phase over magnesium sulfate filtered and passed for drying.

LCMS-Rt (B): 1,04 min;

[M+H+]: 375,1

Example 36

1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-anhydrobiotic

a)4-Chloro-N-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide

2-((R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (250 mg) was dissolved in absolute THF (20 ml). 4-chlorobutyrate (115 mg) and triethylamine (208 μl) was added with stirring. 3 hours and stirred at room temperature. After standing overnight the reaction mixture was concentrated, and the residue was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. Received 290 mg of oily product.

LCMS-Rt (B): 1,14 min;

[M+H+]: 411,0

b)1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-anhydrobiotic

4-Chloro-N-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide (249 mg) was dissolved in absolute DMSO (10 ml) and added fine powder and dried potassium carbonate (250 mg). With the exclusion of moisture for 4 hours was strongly stirred at room temperature. After standing overnight the reaction mixture was diluted with water (50 ml) and then three times were extracted with ethyl acetate. The combined extract was dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was dissolved in water/acetonitrile and using 0.1 n HCl was established pH 2. After freeze-drying during the night he obtained the desired product (116 mg) as a white powder.

LCMS-Rt (B): 1,06 min;

[M+H+]: 375,1

Example 37

1-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he

The title compound was synthesized based on 2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 41b) analogously to example 36.

LCMS-Rt (B): 1,12 min;

[M+H+]: 401,0

Example 38

1-[3-((S)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2-he

On the basis of (S)-3-(6,8-dichlor-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining, as described in WO 2004085404) and δ-valerolactone was synthesized 1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2-it analogously to example 35.

LCMS-Rt (B): 1,05 min;

[M+H+]: 389,1

Example 39

1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2-anhydrobiotic

a)1-(2-Chloroethyl)-3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]urea

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (100 mg, enantiomer B, obtaining, as described in WO 2004085404) was dissolved in absolute dichloromethane (5 ml) and with stirring was added 4-nitrophenylphosphate (79 mg). After 4 hours stirring at room temperature, left to stand overnight. The next day was added 4-nitrophenylphosphate (10 mg) and 1 hour and stirred at room temperature. The reaction mixture was transferred to drying in vacuum, and the residue was dissolved in absolute dichloromethane (5 ml). After adding triethylamine (180 μl) was bury a solution of 2-chloroethylnitrosourea (61 mg) in absolute dichloromethane (3 ml), and four hours was stirred at room temperature. Then mixed with the next portion of methylene chloride and diluted with a solution of potassium carbonate, and the organic phase three times were extracted dilute the second solution of potassium carbonate. After drying over magnesium sulfate and filtering, the organic phase was concentrated and purified by preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. There was obtained 50 mg of the desired product.

LCMS-Rt (B): 1,05 min;

[M+H+]: 412,1

b)1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2-anhydrobiotic

1-(2-Chloroethyl)-3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]urea (40 mg) was dissolved in absolute DMSO (1 ml) and with stirring was added potassium carbonate (14 mg). After four hours of stirring at room temperature was added a little potassium carbonate (7 mg). After standing over night drove in vacuum DMSO, the residue was mixed with a small amount of water and saturated sodium hydrogen carbonate solution, and then formed the mixture three times was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC, however, the mixture could not be separated, so spent chromium is tography on kieselgel (dichloromethane/methanol 100/0 to 88/12 within 80 min). Pure fractions were combined, transferred to the drying, and then the residue with water and a small amount of hydrochloric acid was dried by freezing.

LCMS-Rt (B): 1,00 min;

[M+H+]: 376,0

Example 40

1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-anhydrobiotic

a)1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2,2-diatexite)urea

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (75 mg, enantiomer B, obtaining, as described in WO2004085404) analogously to example 25a) was subjected to transformation with 4-nitrophenylphosphate (64 mg) and then with 2,2-diethoxyaniline (46 mg).

LCMS-Rt (B): 1,14 min;

[M+H+]: 466,1

b)1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-anhydrobiotic

1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl-3-(2,2-diatexite)urea (65 mg) was dissolved in formic acid (0.4 ml) and 2 hours and stirred at room temperature. Then mixed with water and neutralized with a saturated solution of sodium bicarbonate. After three times of extraction with ethyl acetate the combined organic phases were dried over magnesium sulfate, filtered, concentrated and purified by preparative HPLC. The fractions containing the product, badinelli, acetonitrile drove on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was absorbed aqueous HCl and dried by freezing.

LCMS-Rt (B): 1,05 min;

[M+H+]: 374,0

Example 41

3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-

4-yl)phenyl]thiazolidin-2,4-dione

a)1-(2-AMINOPHENYL)-2-[cyclopropyl-(2,4-dichlorobenzyl)amino]ethanol and 2-{2-[cyclopropyl-(2,4-dichlorobenzyl)amino]-1-methoxyethyl}phenylamine

N-2-{2-[Cyclopropyl-(2,4-dichlorobenzyl)amino]-1-hydroxyethyl}phenyl)ndimethylacetamide (46 g, obtained analogously to example 15 in WO 0348129) was dissolved in methanol (250 ml). To this with stirring was added a 30%solution of sodium methylate and the mixture is then 10 hours boiled with reverse flow. For a more complete reaction was added solid sodium methylate (10 g) and boiled with reverse flow for another 4 hours. For processing and then to the reaction mixture was added 1.5 l of ice water and three times was suirable with ethyl acetate. United an ethyl acetate phase once washed with saturated saline, then was dried over magnesium sulfate, filtered and concentrated. P the following chromatographic purification on kieselgel were obtained:

14 g of 1-(2-AMINOPHENYL)-2-[cyclopropyl-(2,4-dichlorobenzyl)amino]ethanol

LCMS-Rt (B): 1,03 min;

[M+H+]: 351,0,

13.8 g of 2-{2-[Cyclopropyl-(2,4-dichlorobenzyl)amino]-1-methoxyethyl}phenylamine

LCMS-Rt (B): 1,18 min;

[M+H+]: 365,0

and 5.5 g of fraction a mixture of both.

Three fractions can be subjected to cyclization, as described below for 1-(2-AMINOPHENYL-2-[cyclopropyl-(2,4-dichlorobenzyl)amino]ethanol under paragraph (b) under the action of sulphuric acid with the formation of 2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine.

b)2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine and 2-((S)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine

1-(2-AMINOPHENYL)-2-[cyclopropyl-(2,4-dichlorobenzyl)amino]ethanol (14 g) was dissolved in dichloromethane (250 ml) and with stirring, cooled to 0°C. To the cold mixture was bury concentrated sulfuric acid (50 ml). After the addition was stirred for about 7 hours at room temperature and then 2 hours at 45°C, and dichloromethane is slowly evaporated. After keeping overnight at room temperature to complete the reaction again was added sulfuric acid (5 ml), and within 12 hours maintained the temperature of 65°C. Then the reaction mixture was filed on ice water and with a solution of sodium hydroxide (10h) condition is enableval pH 11. The aqueous phase was three times washed with dichloromethane. The combined extract was dried over magnesium sulfate, filtered and concentrated. The crude product (12.3 g) was subjected to chromatography on kieselgel (ethyl acetate/n-heptane 1:1 to 4:1). Purified racemic product (10.7 g) then, using chiral HPLC (Chiralpak ADH/45, eluent: heptane/isopropanol/methanol 20:1:1 +0.1% of TFA) was separated into its enantiomers.

There was obtained 7 g primarily lirovannomu 2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine P1 and 6 g more slowly lirovannomu 2-((S)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine P2 in the form of their double salts TFA (TFA).

Chiral HPLC:

Column: Chiralpak ADH/45, 250×4.6 mm

Eluent: heptane/isopropanol/methanol: 20/1/1+0,1% TFA

Flow rate: 1 ml/min at 30°C

P1: Rt: 7,27 min

P2: Rt: 12,81 min

c) Phenyl ester [2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiocarbamides acid

2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (300 mg) was dissolved in absolute THF (5 ml) and bury familiarities (75 ml), dissolved in absolute THF (1 ml). The reaction mixture was stirred 4 hours at room temperature and left overnight. The solvent is then drove away, and the residue was purified using preparative HPLC. Fractions containing the product, combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying.

LCMS-Rt (B): 1,87 min;

[M+H+]: 469,0

d)3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione

Phenyl ether [2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiocarbamides acid (50 mg) was dissolved in 30%solution of sodium methylate in methanol (5 ml). For the dissolution of slightly heated by the dryer with stirring. A clear solution was stirred for about 3 hours at room temperature and left overnight. Then the reaction mixture was diluted with water and three times were extracted with ethyl acetate. The combined extract was dried over magnesium sulfate, filtered and concentrated. Thus obtained crude product (45 mg) was dissolved in absolute methylene chloride (3.5 ml) was added bromocatechol (16.5 mg). At room temperature was stirred for 3 hours without access to water. After standing over night in the closet-freezer drove the solvent and excess acid chloride acid, and the residue was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile drove is on a rotary evaporator, the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. Part (12 mg) of the resulting sludge (15 mg) was dissolved in water/acetonitrile, add a little hydrochloric acid and the clear solution throughout the night was dried by freezing.

LCMS-Rt (B): 1,40 min;

[M+H+]: 433,0

Example 42

3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione

Analogously to example 41 was subjected to transformation of (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining, as described in WO 2004085404). The crude product was characterized by a double peak is identical masses in the LCMS, so that both products were separated using preparative HPLC and then identified. Along with the contaminated fraction was found to be both rotary isomer P1 and P2.

P1:

LCMS Rt (B): 1,09 min;

[M+H+]: 407,0

1H NMR (500 MHz, DMSO-d6): 7,51-7,28 (m, 4H), 7,11 (m, 1H), 6,72 (s, 1H), 4,51 (d, 15 Hz, 1H), 4,34 (d, 15 Hz, 1H), 4,18 (m, 1H), 3,64 (d, 15 Hz, 1H), 3,50 (d, 15 Hz, 1H), 2,70 (m, 1H), 2.49 USD (m, DMSO), of 2.33 (s, 3H) [ppm]

P2:

LCMS-Rt (B): 1,14 min;

[M+H+]: 407,0

1H NMR (500 MHz, DMSO-d6): 7,52-7,26 (m, 4H), 7,19-to 7.09 (m, 1H), 6,72 (s, 1H), 4,49 (d, 15 Hz, 1H), 4,35 (d, 15 Hz, 1H), 4,12 (m, 1H), 3,65 (d, 15 Hz, 1), 3,50 (d, 15 Hz, 1H), 2,72 (m, 1H), 2,48 (m, DMSO), of 2.33 (s, 3H) [ppm]

Alternative synthesis

Used instead of bromoacetanilide chlorocatechol thus received mostly P2, which, after preparative HPLC was contaminated P1 only to a small extent (<10% in accordance with1H NMR).

Example 43

3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione

a)[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylcarbamoyl]acetate

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (300 mg, enantiomer B, obtaining, as described in WO 2004085404) was dissolved in absolute THF (10 ml) and at room temperature with stirring solution was added nutregisterdevice (0.5 ml; 2M in THF). After 30 min was added acetoxyacetyl (77 μl) and 2 hours and stirred at room temperature. Then the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water, was installed in an alkaline medium with a solution of sodium bicarbonate and separated phases. The aqueous phase three times were extracted with ethyl acetate. The combined extract was dried over magnesium sulfate, filtered and concentrated. Received 380 mg of the desired product. 40 mg was dissolved in acetonitrile/water, padcal is whether 0,1N hydrochloric acid and dried by freezing.

LCMS-Rt (B): 1,02 min;

[M+H+]: 407,0

b)N-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-hydroxyacetamido

[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylcarbamoyl]acetate (180 mg) was dissolved in methanol (5 ml). With stirring, was added potassium carbonate (305 mg, in the form of a fine powder) and then 4 hours the well was stirred at room temperature. The solvent is then drove away, the residue was absorbed by ethyl acetate and three times washed with water. An ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. There was obtained 160 mg of the desired product.

LCMS-Rt (B): 0,94 min;

[M+H+]: 365,0

c)3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione

N-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-hydroxyacetate (20 mg) was dissolved in absolute THF (2 ml)at room temperature under stirring was subjected to transformation with a solution nutregisterdevice (0.5 ml; 2M in THF). Then was added 1,1-carbonyldiimidazole (13 mg) and 2 hours and stirred at room temperature. After standing overnight the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water, was installed in an alkaline medium with a solution of sodium bicarbonate and separated phases. The aqueous phase three times ex who was regionali with ethyl acetate. The combined extract was dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was dissolved in water/acetonitrile, and the clear solution throughout the night was dried by freezing. Received 10 mg of the desired product.

LCMS-Rt (B): 1,09 min;

[M+H+]: 391,0

Example 43a

3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-

4-yl)phenyl]oxazolidin-2,4-digidroid

Similarly, the sequence in example 43 was synthesized 25 mg of the title compound. In the cyclization stage instead of 1,1-carbonyldiimidazole used trichlorochloroform, and drying by freezing was carried out in the presence of hydrochloric acid.

LCMS-Rt (B): 1,31 min;

[M+H+]: 417,0

Example 44

Salt triperoxonane acid 4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione

a)Salt triperoxonane acid 4-{[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-yl)phenylcarbamoyl]methoxy}acetic acid

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (70 mg, enantiomer B, obtaining, as described in WO 2004085404) was dissolved with stirring in absolute dichloromethane (5 ml) and mixed with the anhydride diglycolic acid (27 mg). A few hours was stirred at room temperature and left overnight. After adding the following amounts of anhydride diglycolic acid (26 mg) was stirred for 10 hours and left overnight. After removal of the solvent the residue was purified using preparative HPLC. The fractions containing the product were combined, the acetonitrile was off on a rotary evaporator and the aqueous residue was dried by freezing.

LCMS-Rt (B): 0,93 min;

[M+H+]: 423,1

b)Salt triperoxonane acid 4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione

Salt triperoxonane acid 4-{[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylcarbamoyl]methoxy}acetic acid (50 mg) was dissolved with stirring in absolute dichloromethane (2 ml) and mixed with the base Hunya (46 μl). Then was added EDC (22 mg) and was stirred for several hours at room temperature. After standing overnight was added the next portion of the EDC (22 mg) and base Hunya (46 μl). After 24 hours, drove away the solvent, and the residue was purified using preparative In the LC. The fractions containing the product were combined, drove acetonitrile and dried by freezing.

LCMS-Rt (B)with 1.07 min;

[M+H+]: 405,0

Example 45

3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-he

a)2-Chloroethyl-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate

2-((R)-(6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (400 mg) was dissolved in absolute THF (25 ml), was added with stirring 2-chloroethylphosphonic (102 mg). After 3 hours stirring at room temperature the mixture was left overnight. Then drove the solvent, and the residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. Received 380 mg of the desired product.

LCMS-Rt (B): of 1.66 min;

[M+H+]: 439,0

b)3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-he

2-Chloroethyl-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate (320 mg) was dissolved in absolute the m THF (20 ml). With stirring, was added sodium hydride (35 mg). After 2 hours stirring at room temperature the reaction mixture was concentrated, the residue was dissolved in ethyl acetate and twice washed with water. An ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was dissolved in acetonitrile/water, acidified 0.1 n hydrochloric acid and dried by freezing. Received 176 mg of the desired product as hydrochloride.

LCMS-Rt (B): 1,16 min;

[M+H+]: 403,0

Example 46

3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-he

a)2-Chloroethyl-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate

Analogously to example 45a) (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (300 mg, enantiomer B, obtaining, as described in WO 2004085404) were subjected to transformation with 2 claritinclaritin (140 mg). Received 400 mg of the desired product is KTA.

LCMS-Rt (B): 1,15 min;

[M+H+]: 413,0

b)3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-he

Analogously to example 45b) 2-chloroethyl-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate (340 mg) was subjected to transformation with sodium hydride (39 mg). Was obtained 230 mg of the desired product as hydrochloride.

LCMS-Rt (B): 1,01 min;

[M+H+]: 377,0

Example 47

(S)-1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione

Download ((S)-5-oxo-2-trichloromethyl[1,3]dioxolane-4-yl)acetic acid (171 mg, see Synthesis 2002, 2165) and thionyl chloride (2 ml) and stirring for 4 hours was heated with reverse flow. Then drove the excess thionyl chloride on a rotary evaporator (the rotavapor), the residue was dissolved in absolute toluene (14 ml), was added (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine and triethylamine (of 0.91 ml), and the mixture of 2 hours was heated with reverse flow. After standing overnight the reaction mixture was concentrated, the residue was mixed with ethyl acetate/water, was set to pH 8 with sodium hydrogen carbonate solution and three times washed with a saturated solution of salt. An ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate/HepB is Ana. Received 65 mg of the desired compound, which was characterized by a turning isomerism. However, LCMS showed only weak, not quantitative separation.

LCMS-Rt (B): 1,02 min;

[M+H+]: 405,0

Example 48

(R)-1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione

Download ((R)-5-oxo-2-trichloromethyl[1,3]dioxolane-4-yl)acetic acid (214 mg, see Synthesis 2002, 2165) and thionyl chloride (2.5 ml) and with stirring for 4 hours was heated with reverse flow. Then drove the excess thionyl chloride on a rotary evaporator, the residue was dissolved in absolute toluene (18 ml), was added (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (250 mg) and triethylamine (1.13 ml)and the mixture is 2 hours was heated with reverse flow. Then the reaction mixture was concentrated, the residue was mixed with ethyl acetate/water, was set to pH 8 with sodium hydrogen carbonate solution and three times washed with a saturated solution of salt. An ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. Subsequent crystallization from ethyl acetate/n-heptane was obtained 240 mg of the desired product which was characterized by a turning isomerism, so LCMS showed two signals of identical mass.

LCMS-Rt (B): 0,99 and 1.04 min;

[M+H+]: 405,0

Example 49

(R)-1-[2-((R)-,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione

Download ((R)-5-oxo-2-trichloromethyl[1,3]dioxolane-4-yl)-acetic acid (94 mg, see Synthesis 2002, 2165) and thionyl chloride (2 ml) and stirring for 4 hours was heated with reverse flow. Drove the excess thionyl chloride on a rotary evaporator, and the residue was dissolved in absolute toluene (15 ml). Added solid salt triperoxonane acid 2-((R)-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (200 mg), followed by triethylamine (0.5 ml). Then the mixture was stirred 2 hours at room temperature, then for 1 hour at 60°C followed by 2 hours at 80°C and finally 6 hours at 100°C. After cooling and removal of solvent was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was dried by freezing. Then, for further purification used kieselgel (dichloromethane/methanol 100:0 to 90:10). Purified fractions were combined and solvent was removed. The result of freeze-drying from water/acetonitrile was obtained 20 mg of the desired product.

LCMS-Rt (B): 1,15 min;

[M+H+]: 431,0

Example 50

(S)-1-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione

Analogously to example 49 was subjected to transformation ((R)-5-oxo-2-trichloromethyl[1,3]dioxolane-4-yl)UKS who scurry acid (94 mg, see Synthesis 2002, 2165), thionyl chloride (2 ml) and salt triperoxonane acid 2-((R)-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (200 mg). The result of freeze-drying from water/acetonitrile was obtained 31 mg of the desired product.

LCMS-Rt (B): 1,13 min;

[M+H+]: 413,0

Example 51

(R)-6,8-Dichloro-4-[2-(1,1-dioxo-1-λ6-isothiazolin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinolinium

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (100 mg) was dissolved in absolute THF (8 ml) and at room temperature was bury 3-chloropropanesulfonyl (116 mg, dissolved in absolute THF (1.5 ml), and then the reaction mixture was heated for 16 hours with reverse flow. For a more complete reaction again was added chloropropanesulfonyl (8 mg), then the solution nutregisterdevice (0.2 ml; 2M in THF). After 30 minutes stirring at room temperature and subsequent heating with reverse flow for a more complete reaction was added the following equivalent solution nutregisterdevice and again heated with reverse flow. Then mixed with water at room temperature and three times were extracted with ethyl acetate. United an ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. Then the STATCOM was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was absorbed water/hydrochloric acid and dried by freezing. Received 12 mg of the title compound.

LCMS-Rt (B): 1,05 min;

[M+H+]: 411,0

Example 52

Salt triperoxonane acid 1-[2-((R)-6,8-dichloro-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione

a)N-{2-[2-(2,4-Dichloraniline)-1-hydroxyethyl]phenyl}ndimethylacetamide

2,4-Dichloraniline (2.1 ml) was dissolved in absolute ethanol (20 ml) and with stirring at room temperature was bury N-[2-(2-bromoacetyl)phenyl]ndimethylacetamide (2 g), dissolved in absolute ethanol (50 ml). After 30 min was added sodium borohydride (600 mg) under ice cooling and stirred for further 1.5 hours. Then drove the solvent, and the residue was absorbed with a mixture of ethyl acetate/water. The phases were separated, and the aqueous phase three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative chromatography. Fracc and, containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was podslushivaet potassium carbonate and three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Received 720 mg of the title compound.

LCMS-Rt (B): 0,93 min;

[M+H+]: 353,0

b) 1-(2-AMINOPHENYL)-2-(2,4-dichloraniline)ethanol

N-{2-[2-(2,4-Dichloraniline)-1-hydroxyethyl]phenyl}ndimethylacetamide (100 mg) was dissolved in methanol (5 ml) and mixed with a solution of sodium methylate (0.3 ml; 30% in methanol). After 6 hours of heating with reverse flow of the reaction mixture was filed in ice water, neutralized 2n hydrochloric acid and three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with saturated potassium carbonate solution and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. Received 34 mg of the desired compound, which is then directly subjected to the transformation.

LCMS-Rt (B): 0,90 min;

[M+H+

c)2-((R)-6,8-Dichloro-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine

1-(2-AMINOPHENYL)-2-(2,4-dichloraniline)ethanol (34 mg) was dissolved in dichloromethane (1 ml) and was mixed with concentrated sulfuric acid under ice cooling and stirring. Then deleted the bath with ice and upon evaporation of the dichloromethane and the mixture was stirred for 10 hours at 80°C. After cooling, the reaction mixture while cooling with ice was mixed with ice water and set in an alkaline medium with 10M sodium hydroxide solution. The aqueous phase three times was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified on kieselgel. Received 22 mg of the desired compound.

LCMS Rt (B): 0,99 min;

[M+H+]: 293,0

d)Salt triperoxonane acid 1-[2-((R)-6,8-dichloro-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione

2-((R)-(6,8-Dichloro-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (22 mg) was heated with succinic acid (10 mg) and polyphosphoric acid (2 ml) in a laboratory glass vessel with screw cap for 3 hours to 150°C. For processing the still hot reaction mixture was filed in ice water and set alkaline with saturated potassium carbonate solution. The aqueous phase three times were extracted with ethyl acetate, and the joint organic phase was dried over magnesium sulfate, was filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator, and the residue was dried by freezing. Received 7 mg of the title compound.

LCMS-Rt (B): 1,04 min;

[M+H+]: 375,0

Example 53

3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-digidroid

39 mg of the title compound was obtained analogously to example 1 from 2-((R)-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 41b) and ethylisothiocyanate.

LCMS-Rt (B): 1,14 min;

[M+H+]: 416,0

Example 54

3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-digidroid

a)4-Nitrophenyl-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (200 mg, enantiomer B, obtaining, as described in WO 2004085404) was dissolved in absolute dichloromethane (6 ml) and with stirring was added 4-nitrophenylphosphate (157 mg). After 4 hours was added 0.1 equivalent of 4-nitrophenylphosphate. After keeping overnight drove dichloromethane, and the residue was directly used in the next stage.

LCMS-Rt (B): 1,29 min;

[M+H+]: 472.0 M.

b)3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-digidroid

4-Nitrophenyl-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate (125 mg) was dissolved in absolute THF (5 ml), and stirring was bury hydrochloride sarasinorum (complex) ether and triethylamine. After 5 hours stirring, the reaction mixture was freed from solvent, the residue was mixed with water and 2n hydrochloric acid and 2 hours was heated with reverse flow. After standing overnight the reaction mixture was concentrated and mixed with ethyl acetate, water and a saturated solution of potassium carbonate. After phase separation the organic phase is washed five times with saturated potassium carbonate solution and twice with a saturated solution of salt. After drying over magnesium sulfate and filtration was concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with saturated potassium carbonate solution and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was absorbed water/hydrochloric acid and dried by freezing. There was obtained 60 the g of the title compound.

LCMS-Rt (B): 1,02 min;

[M+H+]: 404,0

Example 55

3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-digidroid

Based on 2-((R)-2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 41b), synthesized the title compound analogously to example 54 and received 55 mg of the title compound as hydrochloride.

LCMS-Rt (B): 1,17 min;

[M+H+]: 430,0

Example 56

3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5,5-dimethylimidazolidin-2,4-digidroid

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (50 mg, enantiomer B, obtaining, as described in WO 2004085404) was dissolved in absolute dichloromethane (5 ml) and stirring was bury methyl ester of 2-isocyanate-2-methylpropionic acid. After 3 hours of mixing and incubation over night mixed with water, the phases were separated and the aqueous phase twice more was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with saturated potassium carbonate solution and three RA is and was extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. The residue was dissolved in acetonitrile (1 ml) and mixed with 10%hydrochloric acid. After 2 hours of stirring was diluted with water (3 ml) and was dried by freezing. Received 68 mg of the title compound.

LCMS-Rt (B): 1,08 min;

[M+H+]: 418,0

Example 57

Salt triperoxonane acid (R and S)-3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-(2-methylsulfonylamino)imidazolidin-2,4-dione

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (50 mg, enantiomer B, obtaining, as described in WO 2004085404) were subjected to transformation analogously to example 56 ethyl-2-isocyanate-4-(methylthio)butyrate (33 mg) in methylene chloride, purified and subjected to cyclization. Thus obtained crude product is then purified by HPLC and could be divided into its diastereoisomers, polar P1 and nonpolar P2.

P1:

LCMS-Rt (B): 1,11 min;

[M+H+]: 464,0

P2:

LCMS-Rt (B): 1,16 min;

[M+H+]: 464,0

On the basis of (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining, as described in WO 2004085404) and the appropriate isocyanate as in example 56 were obtained the following products in the form of a mixture of diastereomers:

tr>
ExampleStructureSolAnalogously to exampleMS
[M+H+]
LCMS-Rt [min]
58HCl56446,1 (ESI+)1,25 (B)
59HCl56432,0 (ESI+)1.13 and 1,21 (B)
60-56404,0 (ESI+)the 1.04 and 1.12 (B)

Example 61

1-[2-((R)-2-Methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-digidroid

In hydrogenator to a solution of 1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione (68 mg, example 7) in methanol (15 ml) was added at the tip of a spatula palladium on charcoal (5%) and after creating the atmosphere of hydrogen was shaking for 2 hours. After removal the hydrogen apparatus was left overnight under argon, and then the catalyst was filtered and washed with methanol. The filtrate is passed for drying. 10 mg of the crude product was absorbed water and 10%hydrochloric acid and dried by freezing. Received 10 mg of the title compound.

LCMS-Rt (B): 0,87 min;

[M+H+]: 312,1

Example 62

1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methyl-1,3-dihydroimidazole-2-anhydrobiotic

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (enantiomer B, obtaining, as described in WO 2004085404), 4-nitrophenylphosphate and methylaminoacetaldehyde was subjected to transformation analogously to example 40, and then the obtained intermediate product (85 mg) was subjected to cyclization with a mixture of water (1 ml) and 10%hydrochloric acid (3.2 ml). Processing and purification took place analogously to example 40. Was allocated 65 mg of the title compound.

LCMS-Rt (B): 1,02 min;

[M+H+]: 388,0

Example 63

1-[2-(8-Bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-digidroid

a)2-Bromo-1-methyl bromide-4-chlorobenzene

2-Bromo-4-chlorotoluene (5 g) were placed in carbon tetrachloride (120 ml), and then one after another was introduced under stirring AIBN (400 mg) and NBS (4.8 g). Then the reaction mixture with stirring, heating and reverse flow for 6 hours, and then added the following portion of NBS (0.6 g) at room temperature. Even after two hours of heating with reverse flow heating was switched off and left to stand overnight. After filtering off the precipitate washed with carbon tetrachloride, and then the filtrate three times were extracted 0,5N solution of sodium bicarbonate, washed several times with water until neutral pH of the washing solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. After chromatography on kieselgel got 3.57 g of the title compound.

LCMS-Rt (B): 1,85 min;

[M+H+]: 202,6 (Cl+)

b)(2-Bromo-4-chlorbenzyl)methylamine

Took a 33% ethanolic solution of methylamine (13 ml) and stirring for 30 min bury 2-bromo-1-methyl bromide-4-chlorobenzene (3 g)dissolved in absolute ethanol (20 ml). After 4 hours stirring at room temperature, left to stand overnight. After removal of the solvent the residue was absorbed by ethyl acetate and once was extracted with 1N hydrochloric acid. With 10h of sodium hydroxide solution was set to pH 11 aqueous phase and then three times were extracted with ethyl acetate. United an ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. There was obtained 1.7 g of the desired compound.

LCMS-Rt (B): 0,76 min;

[M+H+]: 33,9

c)N-(2-{2-[(2-Bromo-4-chlorbenzyl)methylamino]acetyl}phenyl)ndimethylacetamide

(2-Bromo-4-chlorbenzyl)methylamine (1.7 g) were placed in absolute ethanol (5 ml). After adding sodium hydrogen carbonate (1.2 g) under stirring was bury N-[2-(2-bromoacetyl)phenyl]ndimethylacetamide (2 g)dissolved in ethanol (80 ml). After stirring for 4 hours at room temperature, leaving the mixture overnight. To process the solvent is kept off, the residue was mixed with ethyl acetate/water, the aqueous phase twice more were extracted with ethyl acetate and then the combined an ethyl acetate fraction was dried over magnesium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. There was obtained 1.5 g of the desired product.

LCMS-Rt (B)with 1.07 min;

[M+H+]: 409,0

d)N-(2-{2-[(2-Bromo-4-chlorbenzyl)methylamino]-1-hydroxyethyl}phenyl)ndimethylacetamide

N-(2-{2-[(2-Bromo-4-chlorbenzyl)methylamino]acetyl}phenyl)ndimethylacetamide (1.5 g) was placed in methanol (45 ml) and cooled to 0°C using a water b is neither. After this batch was made detribalized (266 mg), brought to room temperature and then stirred for another 2 hours. The solvent is kept off, the residue was mixed with ethyl acetate/water, three times were extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. Was obtained 1.44 g of the title compound.

LCMS-Rt (B): 0,94 min;

[M+H+]: 411,0

e) 1-(2-AMINOPHENYL)-2-[(2-bromo-4-chlorbenzyl)methylamino]ethanol

N-(2-{2-[(2-Bromo-4-chlorbenzyl)methylamino]-1-hydroxyethyl}phenyl)ndimethylacetamide (1.4 g) was dissolved in absolute methanol (50 ml), was mixed with a solution of sodium methylate (3.5 ml) and was heated for 8 hours with reverse flow. Next add a solution of sodium methylate (1.5 ml), and again 4 hours was heated with reverse flow. The reaction mixture was filed in the icy water, three times were extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with saturated potassium carbonate solution and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and conveyed to the ears. Was obtained 801 mg of the title compound.

LCMS-Rt (B): 0,92 min;

[M+H+]: 369,0

f)2-(8-Bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine

1-(2-AMINOPHENYL)-2-[(2-bromo-4-chlorbenzyl)methylamino]ethanol (800 mg) was dissolved in dichloromethane (1 ml) and cooled with ice was mixed with concentrated sulfuric acid (8 ml). Then was stirred at 60°C for 7 hours. For processing the reaction mixture was filed in the icy water, was installed in an alkaline medium with 10h of sodium hydroxide solution and three times washed with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative HPLC. The fractions containing the product were combined, drove acetonitrile on a rotary evaporator and the aqueous residue was neutralized with a saturated solution of sodium bicarbonate and three times were extracted with ethyl acetate. After drying the combined an ethyl acetate phase over magnesium sulfate filtered and passed for drying. Received 438 mg of the desired compound.

LCMS-Rt (B): 1,03 min;

[M+H+]: 351,0

g)1-[2-(8-Bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-digidroid

2-(8-Bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (60 mg) was mixed with succinic acid (22 mg) and subjected to pravr is the conversion in polyphosphoric acid analogously to example 7. Received 47 mg of the title compound.

LCMS-Rt (B): 1,04 min;

[M+H+]: 433,0

Example 64

1-[2-(8-Bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he

Analogously to example 36 was subjected to transformation of 2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (80 mg) with the acid chloride of 4-harpalani acid (35 mg)and the resulting amide is then subjected to cyclization in DMSO with potassium carbonate.

LCMS-Rt (B): 1,05 min;

[M+H+]: 419,0

PHARMACOLOGICAL DATA

Test description

In this test, determine the recovery of intracellular pH (pHi) LAP1-cells, which stably will expriment ion-exchange the sodium/proton subtype 3 (NHE3), after acidification. This recovery occurs when a normally functioning NHE3 in the absence of bicarbonate. To do this, define pHiusing pH-sensitive fluorescent dye BCECF (Molecular Probes, Eugene, OR, USA, using a preliminary stage (Vorstufe) BCECF-AM). Cells are first incubated with BCECF (5 μm BCECF-AM) in the buffer NH4Cl (buffer NH4Cl: 115 mm CholinCl, 20 mm NH4Cl, 5 mm KCl, 1 mm CaCl2, 1 mm MgCl2, 20 mm Hepes, 5 mm glucose, through 1M KOH establish a pH of 7.4). Intracellular acidification induce washing the cells, incubated in the buffer NH4Cl, buffer not containing NH 4Cl (133,8 mm holdingarea, of 4.7 mm KCl, 1.25 mm CaCl2, 1.25 mm MgCl2, 0,97 mm K2HPO4, 0.23 mm KH2PO4, 5 mm Hepes, 5 mm glucose; using 1M KOH establish a pH of 7.4). After the washing process is limited to 90 ál of buffer not containing NH4Cl, on the cells. Restoring pH to cause the addition of 90 μl of Na+-containing buffer (133,8 mm NaCl, of 4.7 mm KCl, 1.25 mm CaCl2, 1.25 mm MgCl2, 0,97 mm Na2HPO4, 0.23 mm NaH2PO4, 10 mm Hepes, 5 mm glucose, by 1M NaOH establish a pH of 7.4) in the measuring device (FLIPR, "Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, Ca., USA). The fluorescence of BCECF is determined at a wavelength of 498 nm excitation and emission filter FLIPR 1 (band-pass filter from 510 to 570 nm). Subsequent changes in fluorescence recorded as a measure of recovery pH two minutes. To calculate inhibiting NHE3 abilities of the tested substances first, the cells are examined in the buffer, which is fully or largely not observed any restore pH. For full recovery of pH (100%) of cells incubated in Na+-containing buffer (see above)to determine a value of 0% in the buffer does not contain Na+(see above). They are added to the test compounds in Na+-containing buffer. Recovery of intracellular pHs for each tested concentration of a substance expressed in percent of the maximum of no the of. Of the percentage recovery of pH using XLFit (idbs, Surrey, UK) calculate the value of the IC50a suitable substance for NHE3.

Inhibiting activity (the value of the IC50various examples of compounds on NHE3 in the following table:

ExampleIC50[µm]
40,129
70,039
82,59
100,047
140,119
160,222
291,2
3429,2
350,082
380,461
400,131
420,069
430,049
440,22
46 0,22
510,141
5212,3
550,12
571,4
587,4
640,25

1. The compounds of formula I

where
R1, R2, R3 and R4 independently of one another denote hydrogen, F, Cl, Br, I;
R5 denotes hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 atoms, or cycloalkyl with 3, 4, 5, or 6 atoms;
R6 denotes hydrogen;
R7 and R8 independently of one another denote hydrogen,
W denotes CrH2ror CsH2s-2;
moreover, one or more CH2-groups WithrH2rand CsH2s-2can be replaced with NR17, oxygen or S;
R17 represents hydrogen, alkyl with 1, 2, 3 or 4 atoms;
r denotes 1, 2, 3, 4, 5 or 6;
s denotes 2, 3 or 4;
X denotes-C(O)- or-S(O)2-;
Z represents-C(O)- or a bond;
and their pharmaceutically acceptable salts and triptoreline.

2. The compounds of formula I according to claim 1, where R1 and R3 denote hydrogen;
R2 and R4 independently of one another denote hydrogen, F, Cl or Br;
R5 denotes hydrogen, methyl, ethyl or cyclepro the sludge;
R6 denotes hydrogen;
R7 and R8 represent hydrogen;
W represents CrH2ror CsH2s-2;
moreover, one or more CH2-groups WithrH2rand CsH2s-2can be replaced with NR17, oxygen or S;
R17 represents hydrogen;
r denotes 2, 3, 4, 5 or 6;
s denotes 2, 3 or 4;
X denotes-C(O)- or-S(O)2-;
Z represents-C(O)-;
and their pharmaceutically acceptable salts and triptoreline.

3. The compounds of formula I according to claim 1, selected from the group
1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione,
3-[2-((R)-6,8-ALOR-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,
1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,
(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethylpiperidine-2,6-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpyrrolidine-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-dimethylpiperidin-2,5-dione,
1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole the in-2,5-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-methylimidazolidine-2,4-dione,
(3R,4S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,4-dimethylpiperidin-2,5-dione,
1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,
1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
1-[2-((R)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-isopropylimidazole-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-isobutylene solidin-2,4-dione,
(R and S)-3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-(2-methylsulfonylamino)imidazolidin-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5,5-dimethylimidazolidin-2,4-dione,
1-[2-((R)-6,8-dichloro-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,
1-[2-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[2-((S)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3,4,4-tetramethylpyrrolidine-2,5-dione,
(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4,4-dimethylpiperidine-2,6-dione,
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,
and their pharmaceutically acceptable salts and triptoreline.

4. The compounds of formula I according to claim 1, selected from the group
1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydro the isoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-3,5-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]thiazolidin-2,4-dione,
1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,
(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpiperidine-2,6-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethylpiperidine-2,6-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylpyrrolidine-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-dimethylpiperidin-2,5-dione,
1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,-dione,
1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-2,6-dione,
1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrole-2,5-dione,
1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2,5-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2,4-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2,4-dione,
and their pharmaceutically acceptable salts and triptoreline.

5. The compounds of formula I according to claim 1, where
R1, R2, R3 and R4 independently of one another denote hydrogen, F, Cl or Br;
R5 denotes hydrogen, methyl, ethyl or cyclopropyl;
R6 denotes hydrogen;
R7 and R8 independently of the other is from another denote hydrogen;
W denotes CrH2ror CsH2s-2;
moreover, one or more CH2-groups WithrH2rand CsH2s-2can be replaced with NR17, oxygen or S;
R17 represents hydrogen, alkyl with 1, 2, 3 or 4 atoms;
r denotes 1, 2, 3, 4, 5 or 6;
s denotes 2, 3 or 4;
X denotes-C(O)- or-S(O)2-;
Z represents a bond;
and their pharmaceutically acceptable salts and triptoreline.

6. The compounds of formula I according to claim 1 and/or 5, where
R1 and R3 represent hydrogen;
R2 and R4 independently of one another denote hydrogen, F, Cl or Br;
R5 denotes hydrogen, methyl, ethyl or cyclopropyl;
R6 denotes hydrogen;
R7 and R8 represent hydrogen;
W represents CrH2ror CsH2s-2;
moreover, one or more CH2-groups WithrH2rand CsH2s-2can be replaced with NR17, oxygen or S;
R17 represents hydrogen or methyl;
r denotes 1, 2, 3, 4, 5 or 6;
s denotes 2, 3 or 4;
X denotes-C(O)- or-S(O)2-;
Z represents a bond;
and their pharmaceutically acceptable salts and triptoreline.

7. The compounds of formula I according to claim 1 or 5, selected from the group
1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methyl-1,3-dihydroimidazole-2-it,
(R)-6,8-dichloro-4-[2-(1,1-dioxo-1-λ6-isothiazol the one-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,
1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)fennel]piperidine-2-it,
1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]oxazolidin-2-it,
6,8-dichloro-4-[4-(1,1-dioxo-1-λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,
and their pharmaceutically acceptable salts and triptoreline.

8. The compounds of formula I according to claim 1 or 5, selected from the group
1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] pyrrolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methyl-1,3-dihydroimidazole-2-it,
(R)-6,8-dichloro-4-[2-(1,1-dioxo-1-λ6-isothiazolin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline,
3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] oxazolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dihydroimidazole-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-is tetrahydroisoquinoline-4-yl)phenyl]imidazolidin-2-it,
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-he
and
1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-2-it,
and their pharmaceutically acceptable salts and triptoreline.

9. The compounds of formula I and their pharmaceutically acceptable salts according to one or more of claims 1 or 5 for use as medicines, which have inhibitory activity of NHE3.

10. The compounds of formula I and their pharmaceutically acceptable salts according to one or more of claims 1 or 5 to obtain drugs for treatment or prevention of disorders of impulse breathing, breathing, breathing disorders during sleep, stop breathing during sleep, snoring, acute and chronic kidney disease, acute renal failure and chronic renal failure, disorders of bowel function, disorders of the gall bladder function.

11. The use of compounds of the formula I and their pharmaceutically acceptable salts according to one or more of claims 1 to 8 to obtain drugs for treatment or prevention of disorders of impulse breathing, breathing, breathing disorders during sleep, stop breathing during sleep, snoring, acute and chronic kidney disease, acute renal failure and chronic renal failure, disorders of bowel function, impaired function of bile is wow bubble.

12. The application of paragraph 11 of the compounds of the formula I and/or their pharmaceutically acceptable salts according to one or more of claims 1 to 8 to obtain drugs for treatment or prevention of disorders of impulse breathing and/or breathing disorders during sleep as stopping of breathing during sleep.

13. The application of paragraph 11 of the compounds of the formula I and/or their pharmaceutically acceptable salts according to one or more of claims 1 to 8 to obtain drugs for treatment or prevention of snoring.

14. The application of paragraph 11 of the compounds of the formula I and/or their pharmaceutically acceptable salts according to one or more of claims 1 to 8 to obtain drugs for treatment or prevention of acute or chronic kidney disease, acute renal failure or chronic renal failure.

15. The application of paragraph 11 of the compounds of the formula I and/or their pharmaceutically acceptable salts according to one or more of claims 1 to 8 to obtain drugs for treatment or prevention of disorders of bowel function.

16. Pharmaceutical composition having inhibitory activity of NHE3, for use in human or veterinary medicine, containing an effective amount of the compounds of formula I and/or pharmaceutically acceptable salts, one or more of claims 1 to 8.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , where R1 is -O-X, where X is -(CH2)m-(CR9R10)p-(CH2)n-Z-(CH2)q-W, where m, n and q are independently equal to zero or assume values from 1 to 5; p equals 0 or 1; R9 and R10 are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or R9 and R10 together represent alkylene, which together with the carbon atom to which the are bonded, form an aryl; Z is a bond or O, W is aryl; R2 is hydrogen; L is a bond; R3 is hydrogen; R4 is hydrogen; R5 and R6 are independently hydrogen; R7 is hydrogen, halogen, hydroxy, trifluromethyl, lower alkyl, lower alkoxy, alkanoyl, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, carboxy, alkoxycarbonyl; or R5 and R6 together represent -(CH2)1-2-; Y is -(CH2)r-, -O-(CH2)r, -(CH2)r-O-, where r equals zero or assumes values from 1 to 3; Q together with atoms to which it is bonded form an aryl, pyridyl, pyrimidinyl, thienyl, furyl, pyrroliyl or indolyl ring; or to its pharmaceutically acceptable salts. The invention also relates to a method of inhibiting rennin activity in mammals, to a pharmaceutical composition, as well as to application.

EFFECT: obtaining new biologically active compounds with inhibitory activity towards renin.

23 cl, 52 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: in derivatives of 1,2-di(cyclo)substituted benzole of general formula I, their salts and hydrates , R10 is 5-10 member cycloalkyl, optionally substituted, or 5-10 member cycloalkenyl, optionally substituted, n=0, 1 or 2; XI is CH or nitrogen.

EFFECT: inhibiting activity with respect to cell adhesion or cell infiltration and application as therapeutic or preventive agent for inflammatory and autoimmune diseases, connected with adhesion and infiltration of leucocytes.

22 cl, 3 tbl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivative 4-aminomethyl-5-hydroxyindole-3-carboxylate of the general formula I: where; R indicates cyclohexyl, cycloheptyl; R1 indicates C1-C3-alkyl, -CH2-X-phenyl; X indicates NH, O, S; R2 indicates C1-C5-alkyl, R3, R4 have identical value and are selected from C1-C3-alkyl, predominantly, CH3, or R3 and R4 together with a nitrogen atom form -5-10- member heterocycle, which contains 1-2- heteroatom selected from N, O, S or their pharmaceutically acceptable salts, with the exception of 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-(piperidinomethyl)-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-(pirrolidinemethyl)-1-cyclohexyl-3-ethoxycarbonylindole and methyl-1-cyclohexyl-4-piperidinomethyl-6-bromine-5-hydroxy-2-methyl-indole-3-carboxylate. The methods of obtaining compound I are described.

EFFECT: exhibit antiviral activity and can be used for treating influenza of the type A.

5 cl, 2 dwg, 2 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of dihydrobenzodiazepin-2-one represented by the formula (I): wherein X means a simple bond or ethynediyl group; if X means a simple bond then R1 means hydrogen atom, halogen atom, (lower)-alkyl, (lower)-alkoxy-group, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxy-group, pyrrol-1-yl or unsubstituted phenyl or phenyl substituted with one or two substitutes chosen from group comprising halogen atom, (lower)-alkyl; if X means ethynediyl group then R1 means unsubstituted phenyl, phenyl substituted with one or two substitutes chosen from group comprising halogen atom, (lower)-alkyl or fluoro-(lower)-alkyl; R2 means hydrogen atom, (lower)-alkyl, (lower)-alkenyl, (lower)-alkoxy-group, -NR'R'', pyrrolidin-1-yl, morpholin-4-yl, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxy-group, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(lower)-alkoxy-group, hydroxy-(lower)-alkyl or (lower)-alkoxy-(ethoxy)m-group wherein m = 1, 2, 3 or 4; R' means hydrogen atom, (lower)-alkyl or (C3-C6)-cycloalkyl; R'' means hydrogen atom, (lower)-alkyl or (C3-C6)-cycloalkyl; Y means -CH= or =N-; R3 means six-membered aromatic heterocycle comprising from 1 to 3 nitrogen atoms or pyridine-N-oxide wherein indicated cycles are unsubstituted or substituted with one or two substitutes chosen from group comprising fluoro-(lower)-alkyl, amino-, (lower)-alkylamino-, (lower)-alkoxy-(lower)-alkylamino- (lower)-hydroxy-(lower)-alkylamino-, hydroxy-, (lower)-alkoxy-group, (C3-C6)-cycloalkyl, morpholin-4-yl and (lower)-alkyl that is substituted optionally with fluorine atom, -NR'R'', hydroxy-, (lower)-alkoxy-group, pyrrolidin-1-yl, azethidin-1-yl wherein R' and R'' have values given above; n = 0, 1, 2, 3 or 4, and to their pharmaceutically acceptable additive salts possessing antagonistic activity with respect to metabotropic glutamate receptor (mGluR). Also, invention describes a medicinal agent comprising indicated compounds. Invention provides synthesis of novel compounds possessing useful biological properties, and a medicinal agent based on thereof.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

28 cl, 1 tbl, 417 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

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