Substituted 4-phenyltetrahydroisoquinoline, their using as medicinal agent and medicinal agent comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

 

The invention relates to compounds of formula (I):

where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, I, CN, NO2, OH, NH2CaH2a+1CqqH2qq-1OCbH2b+1, COOR10, OCOR10, COR10 orx-(CH2)yis phenyl;

a and b in groups WithandH2A+1and OCbH2b+1independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

qq means 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

R10 denotes H or CwithH2C+1;

with means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

x is zero or 1;

I mean zero, 1, 2, 3 or 4;

with the phenyl ring to the group Aboutx-(CH2)yis phenyl unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CN, NO2, OH, NH2or CdH2d+1;

d is 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean heteroaryl, and in a loop can contain 0, 1, 2, 3 or 4 nitrogen atom, 0 or 1 oxygen atom or 0 or 1 sulphur atom;

or

R1, R2, R3 and R4, independently of one another, mean CONR11R12 or NR11R12;

R11 and R12, independently of the others is g from each other, mean H, CeH2E+1CrrH2rr-1;

e means 1, 2, 3, 4, 5, 6, 7 or 8;

rr means 3, 4, 5, 6, 7 or 8,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR13;

R13 denotes H or CfH2f+1;

f means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R13 and one CH2-a group of radical R11 or R12 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle;

or

R11 and R12, independently of one another, mean COR14, CSR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR13;

or

R1, R2, R3 and R4, independently of one another, denote-Oh-SOjR15, and

h stands for zero or 1;

j denotes zero, 1 or 2;

R15 means CkH2k+1, OH, OClH2l+1or NR17R18;

k means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

l means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced the tive F atoms;

R17 and R18, independently of one another, denote H or CmH2m+1;

m means 1, 2, 3, 4, 5, 6, 7 or 8, and in group CmH2m+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced with O, CO, CS or NR19;

R19 denotes N or CnH2n+1;

n denotes 1, 2, 3 or 4;

and CnH2n+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle;

or

R19 and CH2-a group of radical R17 or R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

moreover, however, R2 does not always have to mean N;

R5 denotes H, CpH2P+1CssH2ss-1, COR20 or SO2R20;

R means 1, 2, 3, 4, 5, 6, 7 or 8;

ss means 3, 4, 5, 6, 7 or 8;

R20 means CqH2q+1;

q means 1, 2, 3, 4, 5, 6, 7 or 8,

and in groups WithpH2P+1CssH2ss-1and CqH2q+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR21;

R21 denotes N or CrH2r+1;

r is 1, 2, 3 or 4;

and WithrH2r+1one or more H atoms may be replaced by F atoms;

R6 denotes H, F, Cl, Br, I, CsH2s+1CddH 2dd-1, OH, OCtH2t+1or OCOR22;

s and t independently of one another, mean 1, 2, 3, 4, 5, 6, 7 or 8;

dd is 3, 4, 5, 6, 7 or 8, and CsH2s+1CddH2dd-1and OCtH2t+1one or more H atoms may be replaced by F atoms;

R22 means CuH2u+1;

u mean 1, 2, 3 or 4;

and CuH2u+1one or more H atoms may be replaced by F atoms;

R7, R8 and R9, independently of one another, denote-Ov-SOw-R23;

v means zero or 1;

w stands for zero, 1 or 2;

R23 means CnnH2nn+1CmmH2mm-1, OH, OCppH2pp+1or NR25R26;

nn and PP, independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8;

mm means 3, 4, 5, 6, 7 or 8,

and CnnH2nn+1CmmH2mm-1and OCppH2pp+1one or more H atoms may be replaced by F atoms;

R25 and R26, independently of one another, denote H, CN or CzH2z+1CzzH2zz-1;

z means 1, 2, 3, 4, 5, 6, 7 or 8;

zz means 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms and

in CzH2z+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced with O, CO, CS or NR27;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and WithAAH2A+1one or more H atoms may be replaced by F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle,

or

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SObbR30;

R30 denotes H, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2group can be replaced by O or NR33;

R32 and R33, independently of one another, denote H or ChH2h+1;

bb means 2 or 3;

SS means 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5, 6, 7 or 8;

h means 1, 2, 3, 4, 5, 6, 7 or 8;

and ChH2h+1one or more H atoms may be replaced by F atoms and groupsSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2-groups can be replaced by NR31 and one CH2group can be replaced by O;

R31 denotes H, CkkH2kk+1, COR65 or SO2R65;

kk means 1, 2, 3 or 4;

moreover, one or more H atoms may be replaced by F atoms;

R65 means H, CXXH2xx+1;

XX means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R31 together with one of CH2the group is of adical R30 forms a 5-, 6 - or 7-membered cycle;

or

R30 means 5 - or 6-membered heteroaryl with 1, 2, 3 or 4 nitrogen atoms, 0 or 1 sulfur atoms and 0 or 1 oxygen atoms, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH2oo+1, NR70R71;

R70 and R71 independently from each other signify H, CuuH2uu+1and COR72;

R72 include means H, CvvH2vv+1;

oo, uu and vv, independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8;

and in groups WithGSHOO+1CuuH2uu+1or CvvH2vv+1one or more H atoms may be replaced by F atoms;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, Br, I, NO2, CN, OH, NH2CeeH2ee+1CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42;

ee and ff, independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8;

ww means 3, 4, 5, 6, 7 or 8;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR44;

R44 means N or CggH2gg+1;

gg on the means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group CggH2gg+1one or more H atoms may be replaced by F atoms and R44 together with one of CH2-a group of radical R40 or R41 and the nitrogen atom to which they are linked can form a 5 - or 6-membered cycle;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

moreover, however, two deputies from the group of R7, R8 and R9 are not simultaneously can mean HE or och3

and at least one of the residues R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30;

and their pharmaceutically acceptable salts and triftoratsetata.

Preferred compounds of formula (I), where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, I, CN, NO2, OH, NH2CaH2a+1cycloalkyl with 3, 4, 5 or 6 C-atoms, OCbH2b+1, COOR10;

a and b, independently of one another denote 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R10 denotes H or CwithH2C+1;

with mean 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently researched the Simo from each other, mean 5 - or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl;

or

R1, R2, R3 and R4, independently of one another, mean CONR11R12 or NR11R12;

R11 and R12, independently of one another, denote H, CeH2E+1CrrH2rr-1;

e means 1, 2, 3 or 4;

rr means 3, 4, 5 or 6,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms;

or

R11 and R12, independently of one another, mean hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a pyrolidine, piperidinyl, N-methylpiperazine, pieperazinove or morpholinyl cycle;

or

R11 and R12, independently of one another, mean COR14, CSR14, CONHR14, CSNHR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean OSO3H, SO3H, SO2R15, and

R15 means CkH2k+1OClH2l+1or NR17R18;

k is 1, 2, 3 or 4, where one or more H atoms may be replaced by the F-atoms;

l means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R17 and R18, independently of one another, denote H, CmH2m+1in which linked to the nitrogen atom of the first CH2group is replaced by CO and the second CH2the group replaced with NR19;

m denotes 1, 2, 3, 4 or 5, and in group CmH2m+1one or more H atoms may be replaced by F atoms;

R19 denotes N or CnH2n+1;

n denotes 1, 2, 3 or 4;

and CnH2n+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

moreover, however, R2 does not always have to mean N;

R5 denotes H, CpH2P+1;

p denotes 1, 2, 3 or 4;

and WithpH2P+1one or more H atoms may be replaced by F atoms;

R6 denotes H, CsH2s+1OCtH2t+1or OCOR22;

s and t independently of one another denote 1, 2, 3 or 4;

and CsH2s+1and OCtH2t+1one or more H atoms may be replaced by F atoms;

R22 means CuH2u+1;

u mean 1, 2, 3 or 4;

and CuH2u+1one or more H atoms may be replaced by F atoms;

R7, R8 and R9, independently of one another, mean OSO3H, SO3H or SO2R23;

R23 oz is achet C nnH2nn+1CmmH2mm-1OCppH2pp+1or NR25R26;

nn and PP, independently of one another denote 1, 2, 3, 4 or 5;

mm means 3, 4, 5 or 6,

and CnnH2nn+1CmmH2mm-1and OCppH2pp+1one or more H atoms may be replaced by F atoms;

R25 and R26, independently of one another, denote H, CN, CzH2z+1and linked to the nitrogen atom of the first CH2group is replaced by CO or CS, and the second CH2group is replaced by NR27;

z is 1, 2, 3, 4, 5 or 6;

and CzH2z+1one or more H atoms may be replaced by F atoms;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and WithAAH2A+1one or more H atoms may be replaced by F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle,

or

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SO2R30;

R30 denotes H, HE, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2group can be replaced by O or NR33;

R32 and R33, independently of one another, denote H or ChH2h+1;

SS oznacza is t 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5 or 6;

h stands for 1, 2, 3 or 4;

and ChH2h+1one or more H atoms may be replaced by F atoms and groupsSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2-groups can be replaced by NR31 and one CH2group can be replaced by O;

R31 denotes H, CkkH2kk+1, COR65 or SO2R65;

kk means 1, 2, 3 or 4;

moreover, one or more H atoms may be replaced by F atoms;

R65 means H, CXXH2xx+1;

XX means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R31 together with one of CH2-a group of radical R30 and the nitrogen atom with which they are linked, form a 5 - or 6-membered cycle;

or

R30 means 5 - or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, teinila, thiazolyl and oxazolyl, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH2oo+1, NR70R71;

R70 and R71 independently from each other signify H, CuuH2uu+1or COR72;

R72 include means H, CvvH2vv+1;

oo, uu and vv, independently of one another denote 1, 2, 3 or 4;

and the time With GSHOO+1CuuH2uu+1or CvvH2vv+1one or more H atoms may be replaced by F atoms;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, Br, I, NO2, CN, OH, NH2CeeH2ee+1CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42;

ee and ff, independently of one another denote 1, 2, 3 or 4;

ww means 3, 4, 5 or 6;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms;

or

R40 and R41 independently from each other, are selected from the group consisting of hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a cycle selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and research;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3 or 4;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

moreover, however, the two Deputy the Deputy from the group R7, R8 and R9 are not simultaneously can mean HE or och3

and with at least one of the residues R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30;

and their pharmaceutically acceptable salts and triptoreline.

Especially preferred compounds of formula (I), where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, OH, NH2CaH2a+1cycloalkyl with 3, 4, 5 or 6 C-atoms, OCbH2b+1;

a and b groups CaH2a+1and OCbH2b+1, independently of one another denote 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean NR11R12;

R11 and R12, independently of one another, denote H, CeH2E+1CrrH2rr-1;

e means 1, 2, 3 or 4;

rr means 3, 4, 5 or 6,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a cycle selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and research;

or

R11 and R12, independently of one another, mean COR14, CSR14, CONHR14, CSNHR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3 or 4, where one or a few is to H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean OSO3H, SO3H, SO2R15;

R15 means CkH2k+1or NR17R18;

k is 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R17 and R18, independently of one another, denote H or CmH2m+1;

m denotes 1, 2, 3, 4 or 5, and in group CmH2m+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

moreover, however, R2 does not always have to mean N;

R5 denotes methyl or trifluoromethyl;

R6 denotes H;

R7, R8 and R9, independently of one another, mean OSO3H, SO3H or SO2R23;

R23 means CnnH2nn+1or NR25R26;

nn is 1, 2, 3, 4 or 5;

and CnnH2nn+1one or more H atoms may be replaced by F atoms;

R25 and R26, independently of one another, denote H, CN or CzH2z+1in which linked to the nitrogen atom of the first CH2group is replaced by CO or CS, and the second CH2group is replaced by NR27;

z is 1, 2, 3, 4, 5 or 6;

and CzH2z+1one or more H atoms may be replaced by F atoms;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and WithAAH2A+1one or more H atoms may bytesarray F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle,

or

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SO2R30;

R30 denotes H, HE, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2group can be replaced by O or NR33;

R32 and R33 denote H, methyl or CF3;

SS means 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5 or 6;

and in groups WithSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2-groups can be replaced by NR31 and one CH2group can be replaced by O;

R31 denotes H, methyl, ethyl, CF3CH2CF3, acetyl, propionyl, methanesulfonyl or econsultancy;

or

R31 together with one of CH2-a group of radical R30 and the nitrogen atom with which they are linked, form a 5 - or 6-membered cycle;

or

R30 denotes pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which is unsubstituted or substituted by a maximum of three substituents selected from the group consisting of F, Cl, methyl, ethyl, trifloromethyl, NH 2, NH-acetyl;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, OH, NH2CeeH2ee+1CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42;

ee and ff, independently of one another denote 1, 2, 3 or 4;

ww means 3, 4, 5 or 6;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3 or 4;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms;

or

R40 and R41 independently from each other, means hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a pyrolidine, piperidinyl, N-methylpiperazine, pieperazinove or morpholinyl cycle;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3 or 4;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

moreover, however, two deputies from the group of R7, R8 and R9 are not simultaneously can mean HE or och3

and with at least one of the residues R7, R8 or R9 must be selected from the group consisting of CONR40R41, -O vSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30;

and their pharmaceutically acceptable salts and triptoreline.

Highly preferred compounds of formula (I), where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, OH, NH2CaH2a+1cycloalkyl with 3, 4, 5 or 6 C-atoms, OCbH2b+1;

a and b groups CaH2a+1and OCbH2b+1, independently of one another denote 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean NR11R12;

R11 and R12, independently of one another, denote H, CeH2E+1CrrH2rr-1;

e means 1, 2, 3 or 4;

rr means 3, 4, 5 or 6,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a cycle selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and research;

or

R11 and R12, independently of one another, mean COR14, CSR14, CONHR14, CSNHR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean OSO3H, SO3H, SO2R15;

R15 means CkH 2k+1or NR17R18;

k is 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R17 and R18, independently of one another, denote H or CmH2m+1;

m denotes 1, 2, 3, 4 or 5, and in group CmH2m+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

moreover, however, R2 does not always have to mean N;

R5 denotes methyl or trifluoromethyl;

R6 denotes H;

R7, R8 and R9, independently of one another, mean OSO3H, SO3H or SO2R23;

R23 means CnnH2nn+1or NR25R26;

nn is 1, 2, 3, 4 or 5;

and CnnH2nn+1one or more H atoms may be replaced by F atoms;

R25 and R26, independently of one another, denote H, CN or CzH2z+1in which linked to the nitrogen atom of the first CH2group is replaced by CO or CS, and the second CH2group is replaced by NR27;

z is 1, 2, 3, 4, 5 or 6;

and CzH2z+1one or more H atoms may be replaced by F atoms;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and WithAAH2A+1one or more H atoms may be replaced by F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle,

and the

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SO2R30;

R30 denotes H, HE, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2group can be replaced by O or NR33;

R32 and R33 denote H, methyl or CF3;

SS means 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5, 6;

and in groups WithSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2-groups can be replaced by NR31 and one CH2group can be replaced by O;

R31 denotes H, methyl, ethyl, CF3CH2CF3, acetyl, propionyl, methanesulfonyl or econsultancy;

or

R31 together with one of CH2-a group of radical R30 and the nitrogen atom with which they are linked, form a 5 - or 6-membered cycle;

or

R30 denotes pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which is unsubstituted or substituted by a maximum of three substituents selected from the group consisting of F, Cl, methyl, ethyl, trifloromethyl, NH2, NH-acetyl;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, OH, NH2CeeH2ee+1 CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42;

ee and ff, independently of one another denote 1, 2, 3 or 4;

ww means 3, 4, 5 or 6;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3 or 4;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms;

or

R40 and R41 independently from each other, means hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a pyrolidine, piperidinyl, N-methylpiperazine, pieperazinove or morpholinyl cycle;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3 or 4;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

moreover, however, two deputies from the group of R7, R8 and R9 are not simultaneously can mean HE or och3

and at least one of the residues R7, R8 or R9 must be selected from the group consisting of OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30;

and their pharmaceutically acceptable salts and triptoreline.

In you is capable of preferred connection:

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N,N-dimethylbenzenesulfonamide;

5) 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethylbenzamide;

8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzamide;

9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)benzamide;

10) 6,8-dichloro-2-methyl-4-(4-(morpholine-4-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]diethylamine;

12) 6,8-dichloro-2-methyl-4-(4-piperidine-1-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

14) 6,8-dichloro-2-methyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline;

15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

17) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-propylboronic;

18) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ylphenyl]-3-methylthiocarbamate;

19) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

20) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

21) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

22) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

24) N-[4-(8-chloro-2-methyl-6-morpholine-4-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

25) N-{4-[8-chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide;

26) N-{4-[8-chloro-6-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide;

27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid;

28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxy-N-methylbenzamide;

29) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethyl-2-hydroxybenzamide;

30) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)-2-hydroxybenzamide;

31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoyl]guanidine;

32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

35) N-[4-(6,8-DIC the PR-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

37) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

40) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

41) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

42) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-triptorelin;

44) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

47) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

48) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

51) [3-(6,8-dichlo the-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acid;

52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

54) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

55) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

56) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-triptorelin;

58) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

61) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

62) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

65) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

67) N-[2-(6,8-d is chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

68) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

69) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

70) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-triptorelin;

72) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

73) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

74) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

78) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

82) [4-(6,8-dichloro-2-methyl-1,2,3,4-Tetra Koskinen-4-yl)phenyl]amide and 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

83) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide and 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

84) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acids;

85) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acids;

86) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-bromothiophene-2-sulfonic acids;

87) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-bromothiophene-2-sulfonic acids;

88) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,s-triftormetilfullerenov;

89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,s-triftormetilfullerenov;

90) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,2,2-cryptgetuserkey;

91) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,2,2-cryptgetuserkey;

92) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulphochloramide;

93) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

94) 2-methyl-4-phenyl-6,8-bistritei-1,2,3,4-tetrahydroisoquinoline;

95) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

96) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoethanol;

97) N-[4-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

98) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

99) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

100) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

101) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-2-carboxylic acid;

102) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

103) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

104) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-2-carboxylic acid;

105) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

106) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,4-dimethyl-1H-pyrrole-2-carboxylic acid;

107) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-nitro-1H-pyrrole-2-carboxylic acid;

108) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,5-dimethyl-1H-pyrrole-3-carboxylic acid;

109) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

110) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

111) [4-(6,8-dichloro-2-methyl-1,2,3,4-those whom rehydrogenation-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

112) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

113) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;

114) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoethanol;

115) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

116) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

117) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

118) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

119) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-2-carboxylic acid;

120) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

121) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

122) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-2-carboxylic acid;

123) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

124) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,4-dimethyl-1H-pyrrole-2-carboxylic acid;

125) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-NITR what-1H-pyrrole-2-carboxylic acid;

126) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,5-dimethyl-1H-pyrrole-3-carboxylic acid;

127) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

128) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

129) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

130) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

131) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;

132) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-etildiocolmain;

133) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-etildiocolmain;

134) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-etildiocolmain;

135) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamyl;

136) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

137) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

138) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

139) [3-(6,8-dichloro-2-methyl-1,2,3,4-those whom rehydrogenation-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

140) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

141) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamyl;

142) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

143) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

144) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

145) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

146) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamic;

147) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimethylaminoethyl)-1-methylcarbamic;

148) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

149) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

150) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-3-ylcarbamate;

151) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-4-ylcarbamate;

152) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

153) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamyl;

154) 3-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamyl;

155) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

156) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

157) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

158) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

159) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

160) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

161) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

162) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamyl;

163) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamyl;

164) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

165) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

166) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

167) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

168) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

169) [4-(6,8-dichloro-2-m is Teal-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

170) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamyl;

171) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

172) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylsilane;

173) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide piperidine-1-carboxylic acid;

174) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

175) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide pyrrolidin-1-carboxylic acid;

176) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamic;

177) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamic;

178) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

179) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

180) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide pyrrolidin-1-carboxylic acid;

181) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide piperidine-1-carboxylic acid;

182) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylsilane;

183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamyl;

184) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

185) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamic;

187) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamic;

188) 2-dimethylaminoethyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

189) 2-dimethylaminoethyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

190) 2-dimethylaminoethyl ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

191) methyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

192) ethyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

193) isopropyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

194) 2,2-dimethylpropionic ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

195) methyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

196) isopropyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetr hydroisoquinoline-4-yl)phenyl]carbamino acid;

197) 2,2-dimethylpropionic ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

198) ethyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

199) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

200) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

201) (R)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

202) (S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

203) N-[3-(6,8-debtor-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

204) 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

205) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

206) ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

207) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

and their pharmaceutically acceptable salts.

Highly preferred compounds from the group:

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrothieno the Jn-4-yl)phenyl]-3-methylthiocarbamate;

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

6) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

7) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

8) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

9) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

10) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

12) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

13) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

14) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

16) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

17) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-triptorelin;

19) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

20) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-those whom rehydrogenation-4-yl)phenyl]nicotinamide;

21) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

22) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

23) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

24) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

25) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

26) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

27) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

28) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

29) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

30) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

31) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide and 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

32) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,s-triftormetilfullerenov;

33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,s-triftormetilfullerenov;

34) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulphochloramide;

35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-Tetra Koskinen-4-yl)phenyl]-2-dimethylaminoacetyl;

36) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

37) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

38) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

39) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

40) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoethanol;

42) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

43) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

44) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

45) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

46) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

47) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

48) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

49) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroxy the Olin-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

50) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

51) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamyl;

52) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

53) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

54) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

55) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

56) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

57) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamyl;

58) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

59) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

60) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

62) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamic;

63) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimetilan noetic)-1-methylcarbamic;

64) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

65) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

66) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-3-ylcarbamate;

67) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-4-ylcarbamate;

68) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

69) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamyl;

70) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

71) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

72) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamyl;

73) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamyl;

74) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

75) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

76) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

77) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

78) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)vinylformamide;

79) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylsilane;

80) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamyl;

81) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

82) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

83) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamic;

84) 2-dimethylaminoethyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

85) 2-dimethylaminoethyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

86) 2-dimethylaminoethyl ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

87) methyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

88) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

89) (R or S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

90) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

and their pharmaceutically acceptable salts.

Further, the invention relates to the use of compounds of formula (I) to receive the deposits of the medicinal product for the treatment of diseases, which can be influenced by inhibiting the sodium-proton exchange subtype III (NHE3), where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, I, CN, NO2, OH, NH2CaH2a+1CqqH2qq-1OCbH2b+1, COOR10, OCOR10, COR10 orx-(CH2)yis phenyl;

a and b in groups WithandH2A+1and OCbH2b+1independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

qq means 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

R10 denotes H or CwithH2C+1;

with means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

x is zero or 1;

I mean zero, 1, 2, 3 or 4;

with the phenyl ring to the group Aboutx-(CH2)yis phenyl unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CN, NO2, OH, NH2or CdH2d+1;

d is 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean heteroaryl, and as atoms of the cycle may contain 0, 1, 2, 3 or 4 nitrogen atom, 0 or 1 oxygen atom or 0 or 1 sulphur atom;

or

R1, R2, R3 and R4, independently of one another, mean COR11R12 or NR11R12;

R11 and R12, independently researched the performance from each other, mean H, CeH2E+1CrrH2rr-1;

e means 1, 2, 3, 4, 5, 6, 7 or 8;

rr means 3, 4, 5, 6, 7 or 8,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR13;

R13 denotes H or CfH2f+1;

f means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R13 and one CH2-a group of radical R11 or R12 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle;

or

R11 and R12, independently of one another, mean COR14, CSR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR13;

or

R1, R2, R3 and R4, independently of one another, denote-Oh-SOjR15, and

h stands for zero or 1;

j denotes zero, 1 or 2;

R15 means CkH2k+1, OH, OClH2l+1or NR17R18;

k means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms;

l means 1, 2, 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced the tive F atoms;

R17 and R18, independently of one another, denote H or CmH2m+1;

m means 1, 2, 3, 4, 5, 6, 7 or 8, and in group CmH2m+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced with O, CO, CS or NR19;

R19 denotes N or CnH2n+1;

n denotes 1, 2, 3 or 4;

and CnH2n+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle;

or

R19 and one CH2-a group of radical R17 or R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

R5 denotes H, CpH2P+1CssH2ss-1, COR20 or SO2R20;

R means 1, 2, 3, 4, 5, 6, 7 or 8;

ss means 3, 4, 5, 6, 7 or 8;

and WithpH2P+1and CssH2ss-1one or more H atoms may be replaced by F atoms;

R20 means CqH2q+1;

q means 1, 2, 3, 4, 5, 6, 7 or 8,

and in group CqH2q+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced by O or NR21;

R21 denotes N or CrH2r+1;

r is 1, 2, 3 or 4;

and WithrH2r+1one or more H atoms may be replaced by F atoms;

R6 denotes H, F, Cl, Br, I, C H2s+1CddH2dd-1, OH, OCtH2t+1or OCOR22;

s and t independently of one another, mean 1, 2, 3, 4, 5, 6, 7 or 8;

dd is 3, 4, 5, 6, 7 or 8, and CsH2s+1CddH2dd-1and OCtH2t+1one or more H atoms may be replaced by F atoms;

R22 means CuH2u+1;

u mean 1, 2, 3 or 4;

and CuH2u+1one or more H atoms may be replaced by F atoms;

R7, R8 and R9, independently of one another, denote-Ov-SOw-R23;

v means zero or 1;

w stands for zero, 1 or 2;

R23 means CnnH2nn+1CmmH2mm-1, OH, OCppH2pp+1or NR25R26;

nn and PP, independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8;

mm means 3, 4, 5, 6, 7 or 8,

and CnnH2nn+1CmmH2mm-1and OCppH2pp+1one or more H atoms may be replaced by F atoms;

R25 and R26, independently of one another, denote H, CN or CzH2z+1CzzH2zz-1;

z means 1, 2, 3, 4, 5, 6, 7 or 8;

zz means 3, 4, 5, 6, 7 or 8, and one or more H atoms may be replaced by F atoms and

in CzH2z+1one or more H atoms may be replaced by F atoms and one or more CH2-groups may be replaced with O, CO, CS or R27;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and su AAH2A+1one or more H atoms may be replaced by F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-membered cycle,

or

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SObbR30;

R30 denotes H, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2group can be replaced by O or NR33;

R32 and R33, independently of one another, denote H or ChH2h+1;

bb means 2 or 3;

SS means 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5, 6, 7 or 8;

h means 1, 2, 3, 4, 5, 6, 7 or 8;

and ChH2h+1one or more H atoms may be replaced by F atoms and groupsSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2-groups can be replaced by NR31 and one CH2group can be replaced by O;

R31 denotes H, CkkH2kk+1, COR65 or SO2R65;

kk means 1, 2, 3 or 4;

moreover, one or more H atoms may be replaced by F atoms;

R65 means H, CXXH2xx+1;

XX means 1, 2, 3 or 4, where one or more H atoms of mo is ut to be replaced by F atoms;

or

R31 together with one of CH2-a group of radical R30 forms a 5-, 6 - or 7-membered cycle;

or

R30 means 5 - or 6-membered heteroaryl with 1, 2, 3 or 4 nitrogen atoms, 0 or 1 sulfur atoms and 0 or 1 oxygen atoms, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH2oo+1, NR70R71;

R70 and R71 independently from each other signify H, CuuH2uu+1and COR72;

R72 include means H, CvvH2vv+1;

oo, uu and vv, independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8;

and in groups WithGSHOO+1CuuH2uu+1or CvvH2vv+1one or more H atoms may be replaced by F atoms;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, Br, I, NO2, CN, OH, NH2CeeH2ee+1CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42;

ee and ff, independently from each other, means 1, 2, 3, 4, 5, 6, 7 or 8;

ww means 3, 4, 5, 6, 7 or 8;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms and one or more CH2groups may be the replaced on or NR44;

R44 means N or CggH2gg+1;

gg means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group CggH2gg+1one or more H atoms may be replaced by F atoms;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

and their pharmaceutically acceptable salts.

Preferably the use of compounds of formula (I), where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, I, CN, NO2, OH, NH2CaH2a+1cycloalkyl with 3, 4, 5 or 6 C-atoms, OCbH2b+1, COOR10;

a and b, independently of one another denote 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R10 denotes H or CwithH2C+1;

with mean 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, denote a 5 - or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl;

or

R1, R2, R3 and R4, independently of one another, mean CONR11R12 or NR11R12;

R11 and R12, independently of one another, denote H, CeH2E+1C rrH2rr-1;

e means 1, 2, 3 or 4;

rr means 3, 4, 5 or 6,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms;

or

R11 and R12, independently of one another, mean hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a pyrolidine, piperidinyl, N-methylpiperazine, pieperazinove or morpholinyl cycle;

or

R11 and R12, independently of one another, mean COR14, CSR14, CONHR14, CSNHR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean OSO3H, SO3H, SO2R15, and

R15 means CkH2k+1OClH2l+1or NR17R18;

k is 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

l means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R17 and R18, independently of one another, denote H, CmH2m+1in which linked to the nitrogen atom of the first CH2group is replaced by CO and the second CH2the group replaced with NR19;

m denotes 1, 2, 3, 4 or 5, p is item in group C mH2m+1one or more H atoms may be replaced by F atoms;

R19 denotes N or CnH2n+1;

n denotes 1, 2, 3 or 4;

and CnH2n+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

R5 denotes H, CpH2P+1CssH2ss-1;

p denotes 1, 2, 3 or 4;

ss means 3, 4, 5 or 6,

and WithpH2P+1and CssH2ss-1one or more H atoms may be replaced by F atoms;

R6 denotes H, CsH2s+1OCtH2t+1or OCOR22;

s and t independently of one another denote 1, 2, 3 or 4;

and CsH2s+1and OCtH2t+1one or more H atoms may be replaced by F atoms;

R22 means CuH2u+1;

u mean 1, 2, 3 or 4;

and CuH2u+1one or more H atoms may be replaced by F atoms;

R7, R8 and R9, independently of one another, mean OSO3H, SO3H or SO2R23;

R23 means CnnH2nn+1CmmH2mm-1OCppH2pp+1or NR25R26;

nn and PP, independently of one another denote 1, 2, 3, 4 or 5;

mm means 3, 4, 5 or 6,

and CnnH2nn+1CmmH2mm-1and OCppH2pp+1one or more H atoms may be replaced by F atoms;

R25 and R26, ezavisimo from each other, mean N, CN, CzH2z+1and linked to the nitrogen atom of the first CH2group is replaced by CO or CS, and the second CH2group is replaced by NR27;

z is 1, 2, 3, 4, 5 or 6;

and CzH2z+1one or more H atoms may be replaced by F atoms;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and WithAAH2A+1one or more H atoms may be replaced by F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle,

or

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SO2R30;

R30 denotes H, HE, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2group can be replaced by O or NR33;

R32 and R33, independently of one another, denote H or ChH2h+1;

SS means 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5 or 6;

h stands for 1, 2, 3 or 4;

and ChH2h+1one or more H atoms may be replaced by F atoms and groupsSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2groups mouthbut replaced by NR31 and one CH 2group can be replaced by O;

NR31 means H, CkkH2kk+1, COR65 or SO2R65;

kk means 1, 2, 3 or 4;

moreover, one or more H atoms may be replaced by F atoms;

R65 means H, CXXH2xx+1;

XX means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R31 together with one of CH2-a group of radical R30 and the nitrogen atom with which they are linked, form a 5 - or 6-membered cycle;

or

R30 means 5 - or 6-membered heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, teinila, thiazolyl and oxazolyl, which is unsubstituted or substituted by up to three substituents selected from the group consisting of F, Cl, Br, I, CooH2oo+1, NR70R71;

R70 and R71 independently from each other signify H, CuuH2uu+1or COR72;

R72 include means H, CvvH2vv+1;

oo, uu and vv, independently of one another denote 1, 2, 3 or 4;

and in groups WithGSHOO+1CuuH2uu+1or CvvH2vv+1one or more H atoms may be replaced by F atoms;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, Br, I, NO2, CN, OH, NH2CeeH2ee+1CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42;

ee and ff, independently of one another denote 1, 2, 3, or 4;

ww means 3, 4, 5 or 6;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3, 4, 5, 6, 7 or 8;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms;

or

R40 and R41 independently from each other, are selected from the group consisting of hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a cycle selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and research;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3 or 4;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

and their pharmaceutically acceptable salts.

Especially preferred is the use of compounds of formula (I), where:

R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, OH, NH2CaH2a+1cycloalkyl with 3, 4, 5 or 6 C-atoms, OCbH2b+1;

a and b groups CaH2a+1and OCbH2b+1, independently of one another denote 1, 2, 3 or 4, with the Ying or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean NR11R12;

R11 and R12, independently of one another, denote H, CeH2E+1CrrH2rr-1;

e means 1, 2, 3 or 4;

rr means 3, 4, 5 or 6,

and in groups WitheH2E+1and CrrH2rr-1one or more H atoms may be replaced by F atoms;

or

R11 and R12 together with the nitrogen atom to which they are bound, form a cycle selected from the group consisting of pyrrolidine, piperidine, N-methylpiperazine, piperazine and research;

or

R11 and R12, independently of one another, mean COR14, CSR14, CONHR14, CSNHR14 or SO2R14;

R14 means CgH2g+1;

g means 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

or

R1, R2, R3 and R4, independently of one another, mean OSO3H, SO3H, SO2R15;

R15 means CkH2k+1or NR17R18;

k is 1, 2, 3 or 4, where one or more H atoms may be replaced by F atoms;

R17 and R18, independently of one another, denote H or CmH2m+1;

m denotes 1, 2, 3, 4 or 5, and in group CmH2m+1one or more H atoms may be replaced by F atoms;

or

R17 and R18 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

R5 denotes H, CpH2p+1CssH2ss-1;

p is 1, 2, 3 or 4;

ss Osnach the et 3, 4, 5 or 6,

and WithpH2P+1and CssH2SS-1one or more H atoms may be replaced by F atoms;

R6 denotes N, CH3;

R7, R8 and R9, independently of one another, mean OSO3H, SO3H or SO2R23;

R23 means CnnH2nn+1or NR25R26;

nn is 1, 2, 3, 4 or 5;

and CnnH2nn+1one or more H atoms may be replaced by F atoms;

R25 and R26, independently of one another, denote H, CN or CzH2z+1in which linked to the nitrogen atom of the first CH2group is replaced by CO or CS, and the second CH2group is replaced by NR27;

z is 1, 2, 3, 4, 5 or 6;

and CzH2z+1one or more H atoms may be replaced by F atoms;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

and WithAAH2A+1one or more H atoms may be replaced by F atoms;

or

R25 and R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle,

or

R27 and one CH2-a group of radical R25 or R26 together with the nitrogen atom to which they are bound, form a 5 - or 6-membered cycle;

or

R7, R8 and R9, independently of one another, mean NR32COR30, NR32CSR30 or NR32SO2R30;

R30 denotes H, HE, CSSH2cc+1WithsuHUu-1pyrrolidinyl or piperidinyl, in cycles where one CH2-GRU the PA can be replaced by O or NR33;

R32 and R33 mean N, CH3or CF3;

SS means 1, 2, 3, 4, 5, 6, 7 or 8;

su means 3, 4, 5 or 6;

and in groups WithSSH2cc+1and CsuHUu-1one or more H atoms may be replaced by F atoms and one or more CH2-groups can be replaced by NR31 and one CH2group can be replaced by O;

R31 denotes H, methyl, ethyl, CF3CH2CF3, acetyl, propionyl, methanesulfonyl or econsultancy;

or

R31 together with one of CH2-a group of radical R30 and the nitrogen atom with which they are linked, form a 5 - or 6-membered cycle;

or

R30 denotes pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which is unsubstituted or substituted by a maximum of three substituents selected from the group consisting of F, Cl, methyl, ethyl, trifloromethyl, NH2, NH-acetyl;

or

R7, R8 and R9, independently of one another, denote H, F, Cl, OH, NH2CeeH2ee+1CwwH2ww-1OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42;

ee and ff, independently of one another denote 1, 2, 3 or 4;

ww means 3, 4, 5 or 6;

in groups CeeH2ee+1CwwH2ww-1and OCffH2ff+1one or more H atoms may be replaced by F atoms;

R40 and R41 mean H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, or 4;

and in group CttH2tt+1one or more H atoms may be replaced by F atoms;

or

R40 and R41 independently from each other, means hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinyl, N-methylpiperazine, piperidinoethyl, morpholinoethyl or piperidinoethyl;

or

R40 and R41 together with the nitrogen atom to which they are bound, form a pyrolidine, piperidinyl, N-methylpiperazine, pieperazinove or morpholinyl cycle;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3 or 4;

and in group ChhH2hh+1one or more H atoms may be replaced by F atoms;

and their pharmaceutically acceptable salts.

Highly preferably the use of compounds selected from the group consisting of

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N,N-dimethylbenzenesulfonamide;

5) 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethylbenzamide;

8) 4-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzamide;

9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)benzamide;

10) 6,8-dichloro-2-methyl-4-(4-(morpholine-4-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]diethylamine;

12) 6,8-dichloro-2-methyl-4-(4-piperidine-1-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

14) 6,8-dichloro-2-methyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline;

15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

17) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-propylbromide;

18) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

19) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

20) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

21) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

22) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

24) N-[4-(8-chloro-2-methyl-6-morpholine-4-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

25) N-{4-[8-chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahedrite the Olin-4-yl]phenyl}ndimethylacetamide;

26) N-{4-[8-chloro-6-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide;

27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid;

28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxy-N-methylbenzamide;

29) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethyl-2-hydroxybenzamide;

30) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)-2-hydroxybenzamide;

31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoyl]guanidine;

32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

37) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

40) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

41) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide is clubusacasino acid;

42) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

44) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

47) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

48) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

51) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

54) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

55) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

56) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide the Cyclops is tankerenemy acid;

57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

58) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

61) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

62) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

65) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

68) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

69) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

70) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-triflora is etamide;

72) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

73) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

74) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

78) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

82) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

83) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

84) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acids;

85) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-chloro-1,3-dimethy what-1H-pyrazole-4-sulfonic acids;

86) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-bromothiophene-2-sulfonic acids;

87) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-bromothiophene-2-sulfonic acids;

88) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,-triftoratsetofenona;

89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,-triftoratsetofenona;

90) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,2,2-cryptgetuserkey;

91) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,2,2-cryptgetuserkey;

92) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

93) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

94) 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

95) 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

96) 4-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenol;

97) 8-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

98) 2-(8-amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenol;

99) 2-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenol;

100) 5-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methoxyphenol;

101) 2-methyl-8-nitro-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

102) 4-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzene-1,2-diol;

10) 2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

104) 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

105) 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

106) 4-(2,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

107) 4-(3-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

109) 2-butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ndimethylacetamide;

111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

115) 6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

117) 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

118) 6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

119) 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

120) 2-methyl-4-phenyl-6,8-bistritei-1,2,3,4-tetrahydroisoquinoline;

121) 6,8-dichloro-2-isopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

122) 5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

123) 6,8-dichloro-4-(4-forfinal)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

124) 6,8-dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline;

125) 5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline is;

126) of 6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

128) 6,8-dichloro-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

129) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

130) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

131) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

132) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

133) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

134) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

135) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

136) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-2-carboxylic acid;

137) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

138) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

139) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-2-carboxylic acid;

140) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

141) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ylphenyl]amide 1,4-dimethyl-1H-pyrrole-2-carboxylic acid;

142) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-nitro-1H-pyrrole-2-carboxylic acid;

143) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,5-dimethyl-1H-pyrrole-3-carboxylic acid;

144) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

145) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

146) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

147) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

148) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;

149) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

150) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

151) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

152) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

153) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

154) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-2-carboxylic acid;

155) N-[3-(6,8-ALOR-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

156) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

157) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-2-carboxylic acid;

158) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

159) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,4-dimethyl-1H-pyrrole-2-carboxylic acid;

160) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-nitro-1H-pyrrole-2-carboxylic acid;

161) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,5-dimethyl-1H-pyrrole-3-carboxylic acid;

162) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

163) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

164) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

165) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

166) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;

167) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

168) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ylphenyl]-3-ethylthiourea;

169) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

170) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

171) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

172) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

173) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

174) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

175) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

176) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

177) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

178) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

179) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

180) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

181) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamate;

182) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-Dima is iluminati)-1-methylcarbamate;

183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

184) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

185) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-3-ylcarbamate;

186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-4-ylcarbamate;

187) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

188) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

189) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

190) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

191) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

192) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

193) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

194) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

195) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

196) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carbon is th acid;

197) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

198) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

199) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

200) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

201) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

202) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

203) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

204) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

205) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

206) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

207) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

208) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide piperidine-1-carboxylic acid;

209) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

210) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide pyrrolidin-1-carboxylic acid;

211) 1-[4-(6,8-dichlo the-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

212) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamate;

213) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

214) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

215) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide pyrrolidin-1-carboxylic acid;

216) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide piperidine-1-carboxylic acid;

217) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

218) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

219) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

220) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

221) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

222) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamate;

223) 2-dimethylaminoethanol ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

224) 2-dimethylaminoethanol ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

225) 2-dimethylaminoethanol ether [2-(6,8-dichlo the-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid;

226) methyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

227) ethyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

228) isopropyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

229) 2,2-dimethylpropyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

230) methyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

231) isopropyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

232) 2,2-dimethylpropyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

233) ethyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

234) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

235) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

236) (R)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

237) (S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

238) N-[3-(6,8-debtor-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

239) 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro the quinoline;

240) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

241) ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

242) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

and their pharmaceutically acceptable salts.

Highly preferably the use of compounds selected from the group consisting of

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

5) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethylbenzamide;

6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzamide;

7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)benzamide;

8) 6,8-dichloro-2-methyl-4-(4-(morpholine-4-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

10) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

11) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

12) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]azeta the IDA;

13) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid;

14) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)-2-hydroxybenzamide;

15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

16) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

17) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

18) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

19) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

20) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

21) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

22) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

23) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

24) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

25) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

26) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

27) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahedrite inolin-4-yl)phenyl]-2,2,2-trifurcated;

29) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

30) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

32) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

33) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

34) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

35) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

36) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

37) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

38) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

39) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

40) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

41) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,-triftoratsetofenona;

43) N-[3-(6,8-dichloro-2-meth is l-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-s,-triftoratsetofenona;

44) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

46) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

47) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

48) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

49) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

50) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

53) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

54) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

55) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

56) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

57) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-shall midazol-4-carboxylic acid;

58) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

59) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

60) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

62) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

63) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

64) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

65) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

66) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

67) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

68) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

69) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

70) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

71) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahedrite inolin-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

72) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamate;

73) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimethylaminoethyl)-1-methylcarbamate;

74) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

75) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-3-ylcarbamate;

77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-4-ylcarbamate;

78) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

80) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

81) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

82) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

83) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

84) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

85) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

86) [4-(6,8-d is chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

87) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

88) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

90) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

91) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

92) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

93) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

94) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

95) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

96) 2-dimethylaminoethanol ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

97) 2-dimethylaminoethanol ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

98) 2-dimethylaminoethanol ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

99) methyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

100) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]metasolv is named;

101) (R or S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

102) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

103) ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

104) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

and their pharmaceutically acceptable salts.

If the compounds of formula (I) contain one or more asymmetric centers, they may be located in the S-and R-configuration. Connections can be in the form of optical isomers, diastereomers, racemates or mixtures thereof.

These alkyl residues, respectively, partially or fully fluorinated alkyl residues may be both linear and branched. Group CandH2A-1and their counterparts untilsuHUu-1mean either alkenyl, cycloalkyl, cycloalkenyl or alkylcyclohexane.

To heteroaryl in features include 2 - or 3-thienyl, 2 - or 3-furyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl; 1,2,3-triazole-1-, -4 - or-5-yl; 1,2,4-triazole-1-, -3 - or-5-yl; 1 - or 5-tetrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-oxadiazol-2-yl or-5-yl, 2-, 4 - or 5-thiazo the sludge, 3-, 4 - or 5-isothiazole, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 3 - or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-indazole, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic, 2-, 4-, 5-, 6-, 7 - or 8-hintline, 3-, 4-, 5-, 6-, 7 - or 8-indolinyl, 2-, 3-, 5-, 6-, 7 - or 8-honokalani, 1-, 4-, 5-, 6-, 7 - or 8-phthalazine. Further, it includes the corresponding N-oxides of these compounds, for example, 1-hydroxy-2-, -3 - or 4-pyridyl.

While the preferred 5 - or 6-membered heterocycles. Particularly preferably imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl.

For CH2groups also include end of CH3groups in the alkyl chain, which are considered as CH2-N-group.

Describes how to get the used connections.

So described, in this case, the substance may be based on benzylamino formula (IV) as precursors. In turn, it is possible to synthesize, if they are not commercially available, standard methods from the corresponding benzylchloride or bromide of formula (III):

Thus obtained benzylamine formula (IV) is known to the specialist way alkylate through the Yu appropriate substituted alpha-bromoacetophenone formula (V).

alpha Bromoacetophenone formula (V) can be obtained well-known from the literature by means of appropriate acetophenones as precursors synthesized by. By restoring the carbonyl group in the compound of formula (VI) and subsequent catalyzed by acid cyclization of the corresponding alcohols of the formula (VII) (see Tetrahedron Lett.,30, 5837 (1989); Org. Prep. Proced. Int.,27, 513 (1995)) by known methods, you can get tetrahydroisoquinoline formula (I).

In the case of R6, not meaning N, the desired compounds of formula (I) can be obtained, for example, from the iodides of the formula (VIII) by reaction of the exchange of the halogen-metal and subsequent nucleophilic impact intermediate organolithium compounds to carbonyl group (see Chem. Pharm. Bull.,43, 1543 (1995)).

Synthesized at tertiary alcohols by known methods can be converted to other derivatives.

To obtain branched alkyl analogs of formula (I) corresponding esters diphenyloxazole acid of formula (X) by known methods alkylate in the alpha position. The desired products of the formula (XI) standard methods can be translated into the corresponding amides of formula (XII), which according to the reaction similar to the reaction Pictet-Spengler, accepts amauta in desirable tetrahydroisoquinoline formula (I) (see Tetrahedron,43, 439 (1987); Chem. Pharm. Bull.,33, 340 (1985)).

In the descriptions of the applications WO 01/32624 and WO 01/32625 describes compounds of type (I) as inhibitors of reuptake of norepinephrine, dopamine and serotonin. However, in these patent applications are protected exclusively compounds in which R1 and R2 can only mean N. In the case of proposed according to the invention compounds, however, indicates that at least R2 does not mean N. Next, using one of the provided according to the invention compounds were not able to detect any inhibitory properties described receptors, so that the described compounds as structure and their pharmacological properties distinctly different from those described in these patent applications connections.

Further, the compounds of type (I) as described in application EP 1113007 describes as agonists and antagonists of estrogen. Found that the proposed according to the invention compounds show activity against these receptors, so the consequence of structural differences proposed according to the invention compounds are clearly other pharmacological properties.

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

Due to these properties, the compounds are suitable for treating diseases due to oxygen deficiency. Due to their pharmacological properties, the compounds especially suitable as antiarrhythmic drugs with cardiotoxin component for the prophylaxis and treatment of infarction and for the treatment of angina, and they preventively inhibit or greatly reduce the pathophysiological processes in the occurrence of ischemia-induced damage, in particular in the case of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological and ischemic conditions used according to the invention the compounds of formula (I), by inhibiting the cellular mechanism of Na+/H+-can be used as medicines for the treatment of all acute and chronic ischemia caused by damage or induced due to this primary or secondary disease. This applies to their use as medicines in the case of surgical interventions, for example, transplant organs, and connections can be used to protect the organs in the donor before and during removal, for the protection of removed organs, for the example, when processing using physiological electrolyte solutions, or in the case of storage in them, and when moving in the recipient's organism. Compounds are also valuable, protective current medicines when angioplasticheskih operational interventions, for example, in the case of the heart, and in the case of peripheral vessels. Due to their protective effects against ischemia-induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, especially the Central nervous system, for example for the treatment of stroke or of cerebral edema. Moreover, used according to the invention the compounds of formula (I) are also suitable for the treatment of various forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

Further, the compounds induce improvement in respiratory pulse, and therefore they are used to treat conditions of the respiratory system in case of the following clinical conditions and disorders: impaired Central respiratory pulse (for example, the Central stop breathing during sleep, sudden death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term mechanical ventilation, respiratory failure when adapt the AI to the highlands, obstructive and mixed form stop breathing during sleep, acute and chronic lung disease with hypoxia and hypercapnia. Additional connection improves muscle tone of the upper respiratory tract, so suppressed snoring.

The combination of an NHE inhibitor with a carbonic anhydrase inhibitor (eg, acetazolamide), the latter leads to metabolic acidosis and already due to this increasing respiratory activity, is preferred due to the enhanced impact and reduced the introduction of biologically active substances.

It is shown that the applied according to the invention compounds have a mild laxative effect and as a consequence they can be used as laxatives or threatening constipation, and especially preferred is the prevention of ischemic damage caused by obdurately in the gut.

Further, it becomes possible to prevent the formation of gallstones.

Moreover, used according to the invention the compounds of formula (I) have strong inhibitory activity against the proliferation of cells, such as fibroblasts and proliferation of smooth muscle cells. Therefore, the compounds of formula (I) are regarded as a valuable therapeutic agents in the case of diseases in which the s cell proliferation is a primary or secondary cause, and because of this they can be used as antiatherosclerotic funds funds against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, hypertension syndrome and hyperplasia of bodies, particularly in prostate hyperplasia or hypertrophy of the prostate.

Used according to the invention compounds are effective inhibitors of the cellular sodium-proton antiport (Na/H exchange), which in the case of numerous diseases (essential hypertension, atherosclerosis, diabetes etc) increased in cells that are available for measurements, as, for example, in erythrocytes, platelets or leukocytes. Used according to the invention the compounds are therefore suitable as an exceptional and simple scientific tools, for example, as diagnostic tools for the detection and identification of certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. moreover, the compounds of formula (I) are suitable for preventive therapy to prevent the Genesis of high blood pressure, for example of essential hypertension.

In addition, we discovered that NHE inhibitors have a favorable effect on serum lipoproteins. It is well known that for the occurrence of atherosclerotic vascular changes, osobennosti coronary heart disease, significant risk factor is too high concentrations of lipoproteins in the blood, the so-called hyperlipoproteinemias. For the prevention and regression of atherosclerotic changes of the extraordinary importance attached to the reduction of high content of serum lipoproteins. Used according to the invention the connection so you can use for the prevention and regression of atherosclerotic changes, because they exclude a causal risk factor. Due to this protection of the vessels against the syndrome of endothelial dysfunction of the compounds of formula (I) are valuable drugs for the prevention and treatment of coronary vascular spasm, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic diseases.

These compounds therefore are mainly used to produce medicines for the prevention and treatment of apnoea during sleep and muscle-related breathing disorders; to obtain drugs for prevention and treatment of snoring; to get medicines to reduce blood pressure; to obtain drugs for prevention and treatment of diseases that are provoked by ischemia and reperfusion of the Central and peripheral organs, as tra renal nedostatocnosti, stroke, endogenous shock, bowel disease, etc.; to obtain drugs for the treatment of diabetic late damage and chronic kidney disease, especially any inflammation of the kidneys (nephritis), associated with increased secretion of the protein/albumin; to obtain drugs for the treatment of lesions of parasites in human medicine and veterinary medicine; to obtain drugs for the treatment of these diseases in combination with blood pressure-lowering substances, preferably with inhibitors angiotenzinkonvertiruyuschego enzyme (ACE), with diuretics and saluretics, as furosemide, hydrochlorothiazide, antagonists pseudoaldosteronism and aldosterone antagonists; receptor modulators adenosine, in particular with the activators of the receptor adenosine (A2-agonists); and receptor antagonists angiotensin.

According to the invention proposes the introduction of inhibitors of the sodium-proton exchange of the formula (I) as a new kind of medicines to reduce elevated levels of lipids in the blood, and the combination of inhibitors of the sodium-proton exchange with blood pressure-lowering and/or gipolipidemiceski existing drugs.

Containing the compound of formula (I) medicines you can enter on the social, parenteral, intravenous, rectal, transdermal, or by inhalation, preferably the introduction depends on the appropriate clinical picture of the disease. The compounds of formula (I) can be applied individually or together with galenovye excipients, both in veterinary and in human medicine.

What excipients suitable for the desired finished shape of the medicinal product, the specialist is known on the basis of his special knowledge. Along with solvents, geleobrazovanie, the basics of suppositories, auxiliary materials for the production of tablets and other carriers of biologically active substances can be applied, for example, antioxidants, dispersants, emulsifiers, antispyware, corrective taste substances, preservatives, contributing to the dissolved substances or dyes.

For oral use, the active substance is mixed with suitable additives, as carriers, stabilizers or inert diluents, and the usual ways to bring suitable forms of administration, such as tablets, pills, detachable capsules, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn cu is hmal. This preparation can be carried out both as dry and as wet granules. As oily carriers or solvents are used, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds in the desired case, along with the usual for this purpose substances, such as contributing to the dissolved substances, emulsifiers or other auxiliaries, bring it to the form of solution, suspension or emulsion. As the solvent used, for example, water, physiological sodium chloride solution or alcohols, such as ethanol, propanol, glycerol, as well as solutions of sugars, as glucose or mannitol, or a mixture of these solvents.

As pharmaceutical compositions for use in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of biologically active substances of the formula (I) in a pharmaceutically acceptable solvent, in particular such as ethanol or water, or mixtures of such solvents.

The composition optionally may also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as the propellant. This composition sod is RIT biologically active substance in a concentration of usually from about 0.1 to 10 wt.% in particular from about 0.3 to 3 wt.%.

Dosage introduce biologically active substances of the formula (I) and the frequency of administration depend on the strength and duration of action of the compounds used; additionally, from the kind and intensity of treatable diseases, as well as gender, age, weight and individual sensitivity being treated mammal.

On average, the daily dose of the compounds of formula (I) when the weight of the patient of approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, up to at most 10 mg/kg, preferably 1 mg/kg of body weight. In acute outbreaks, for example, directly after myocardial infarction may be necessary even higher and, above all, more frequent dosing, for example, up to 4 doses per day. Especially when administered intravenously, for example, in the case of a patient with infarction in the intensive care unit may require up to 200 mg per day.

Experiences and examples:

List of abbreviations:

RtRetention time
TFOC (TFA)Triperoxonane acid
HPLCHigh performance liquid chromatography
EQ.Equivalent to
LCMSThe liquids is Naya chromatography with mass spectrometry
MS (MS)Mass spectrometry
CIChemical ionization
ES, ESIIonization electron spray
THF (THF)Tetrahydrofuran
TOTUO-[(etoxycarbonyl)cyanomethylene]-N,N,N',N'-tetramethylpropylenediamine
DMSO (DMSO)The sulfoxide
Abs.Absolute
Zers.Decomposition
DMF (DMF)Dimethylformamide

A common part

The following retention times (Rt) belong to the LCMS measurement with the following parameters:

Method a:

stationary phase:Merck Purospher; 3 micron; 2×55 mm
mobile phase:95% H2About (0.05% TFUC) → 95% acetonitrile; 4 min; 95% acetonitrile; 1.5 min → 5% acetonitrile; 1 min; 0.5 ml/min; 30°

Method:

stationary phase:Merck Purospher; 3 micron; 2×55 mm
mobile phase:0 min 90% N2About (0.05% TFUC); 2.5 minutes - 95% acetonitrile; 95% acetonitrile up to 3.3 min; 10% acetonitrile 3,4 min; 1 ml/min

With the royals B1:

stationary phase:YMC, J ' sphere ODS H80; 4 microns; 2×20 mm
the mobile phase0 min 90% N2About (0.05% TFUC); 1,9 min - 95% acetonitrile; 95% acetonitrile up to 2.4 min; 10% acetonitrile at 2.45 min; 1 ml/min

The method:

stationary phaseMerck LiChroCart 55-2 Purosper STAR RP 18e
the mobile phasesolvent A: acetonitrile/water 90:10+ 0.5% HCOOH

solvent b: acetonitrile/water 10:90+0.5% HCOOH
consumption:0.75 ml/min
time (min)the solvent [%]
0,0095,0
0,5095,0
1,755,0
4,255,0
4,5095,0
5,0095,0
stop time:6,20 min
temperature:40°

Method D

stationary phase Merck Purospher RP18 Star, 55×2 mm, the grain size of 3 microns
the mobile phasesolvent A: acetonitrile+ 0,08% HCOOH

solvent A: water + 0.1% HCOOH
consumption:of 0.45 ml/min
time (min)the solvent [%]
095
55
75
895
95
temperature:room temperature

Example 1

N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-

4-yl)phenyl]ndimethylacetamide

The intermediate product 1: 2,4-dichlorosalicylic

Get known from the literature (J. Med. Chem.,27, 1111 (1984)).

The intermediate product 2: N-[4-(2-bromoacetyl)phenyl]ndimethylacetamide

Synthesize well-known specialist way by the synthesized N-(4-acetylphenyl)ndimethylacetamide.

The original connection (0,256 mol) add 300 ml of acetic acid and at a temperature of 60°With added dropwise a solution of 39.9 g (1.0 EQ.) bromine in 60 ml of acetic acid. After 1.5 hours, allowed to cool to room temperature and p is a promotional mix make into 1 l of ice water. The precipitate is filtered under vacuum, washed with water and dried, and allocate 60 g specified in the connection header (TPL: 192°).

The intermediate product 3: N-{4-[2-(2,4-dichloraniline)acetyl]phenyl}ndimethylacetamide

of 37.1 g (of € 0.195 mol) of the intermediate product 1 bring in 400 ml of dioxane and mixed with a solution of 60 g (0,234 mol) of the intermediate product 2 in 600 ml of dioxane. Add 134 ml of triethylamine and stirred for 4 hours at room temperature. After standing overnight the precipitate is filtered off and the filtrate was concentrated in vacuo. The residue is treated with ethyl acetate, washed with a solution of NaHCO3and H2Oh, dried over magnesium sulfate and concentrated. The resulting oily residue triturated with a mixture of ethyl acetate and diethyl ether, and obtain 36 g of the intermediate product 3 in the form of a crystalline solid (TPL: 115-117°).

The intermediate product 4: N-{4-[2-(2,4-dichloraniline)-1-hydroxyethyl]phenyl}ndimethylacetamide

36 g (0,099 mol) of the intermediate product 3 was dissolved in 500 ml of methanol and at a temperature of 0°mixed With 7.8 g (2 EQ.) sodium borohydride. Additionally stirred for 30 minutes at a temperature of 0°and in the next hour at room temperature. For processing, the reaction mixture was concentrated and the residue partitioned between 1N. HCl and this is lacerata. The aqueous phase is separated, set to pH 9 and extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. The thus obtained crude product without further purification can be further subjected to transformation.

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

20 g (0,054 mol) of intermediate compound 4 is dissolved in 250 ml dichloromethane and at a temperature of 0°With dropwise mixed with 250 ml of concentrated H2SO4. Stirred for 2 hours at a temperature of 0°and for 1 hour at room temperature. For processing, the reaction mixture make iced water and the precipitate is filtered off under vacuum. By drying the organic phase and concentration get the crude product, which was triturated with diisopropyl ether, and allocate 11,7 g specified in the title compound as crystalline solid (TPL: 205-206°).

1A: N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acetamidomalonate

The sample (100 mg) specified in the title compound from example 1 are suspended in 10 ml of 2n. HCl and mixed with the same amount of tetrahydrofuran to form a clear solution. Concentrated in vacuo, the residue triturated with diethyl ether and outfilter who agree in vacuum, then get listed in the title compound as crystalline solid (Rt=3,807 min (method A); TPL: 125°With decomposition).

Example 2

2A: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulfonamidelor

2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulfonamidelor

2C: (-)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide

2d: (-)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide

2A/2C2b/2d

The intermediate product 1: 2,4-dichlorosalicylic

Get known from the literature (J. Med. Chem.,27, 1111 (1984)).

The intermediate product 2: 2-[(2,4-dichlorobenzyl)methylamino]-1-phenylethanone

The intermediate product 1 is injected into the interaction with 2-bromo-1-phenylethanone as described in example 1 for the intermediate product 3 methods. Processing in a similar way and purification on silica gel lead to the target alkylation product with a good yield in the form of a yellowish oil (Rt=4,188 min (method A); MS (CI+)=308,2/310,2).

The intermediate product 3: 2-[(2,4-dichlorobenzyl)methylamino]-1-phenylethanol

The intermediate product 2 according to described the example 1 for the intermediate product 4 methodology restore using sodium borohydride. After monitoring the reaction shows a complete transformation, concentrated and the residue is treated with ethyl acetate. Washed twice with water, dried over magnesium sulfate and the solvent is removed. Obtained kolichestvennymi yield the crude product without further purification can be further subjected to transformation (Rt=4,149 min (method A); MS (CI+)=310,2/312,2).

The intermediate product 4: 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline

20 g (64,5 mmol) of intermediate 3 was dissolved in 55 ml of dichloromethane and cooled to a temperature of 0°C. This solution was added dropwise to 55 ml of pre-cooled concentrated H2SO4and then stirred for two hours at room temperature. To be processed, placed on ice and much alkalinized with 6N. NaOH solution. Extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. The oily crude product is purified on silica gel, and get the intermediate product 4 with the release of 53% (Rt=4,444 min (method A); MS (CI+)=292,2/294,2).

4A: (-)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium

4b: (+)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium

The intermediate product 4 is divided into hyral the Noi phase by HPLC for both enantiomers.

Column with a chiral phase Chiralpak OD, 250×4.6;

solvent: n-heptane/isopropanol 7:3+0.1 TPUK;

volumetric flow rate: 1 ml/min;

Rt((-)-enantiomer/4A)=9,340 min;

Rt((+)-enantiomer/4b)=20,327 minutes

2A: (+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulfonamidelor

2b: (+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulfonamidelor

A suspension of 500 mg (1.7 mmol) of the intermediate product 4A in 10 ml of dichloromethane at a temperature of 0°bring in 1.2 ml of chlorosulfonic. Stirred for 1 hour at a temperature of 0°and in the next hour at room temperature. Add 5 ml of chlorosulfonic and stirred for another hour at room temperature. To be processed, placed on ice and with NaHCO3establish a pH value of 8. Extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The thus obtained crude product in 20 ml of concentrated solution of NH3heated at a temperature of 90°C for three hours. After complete conversion of the reaction solution was concentrated and the residue partitioned between water and ethyl acetate. The organic phase is separated and the aqueous phase extracted again with ethyl acetate. The combined organic phases are dried over sulfate NAT the Oia and the solvent is removed in vacuum. Subsequent chromatography on silica gel get 335 mg of the mixture of the compounds of examples 2A and 2b in the form of a yellowish amorphous solid. By further purification by preparative HPLC obtain 212 mg specified in the header of the para-substituted compounds 2A and 58 mg of meta-isomer 2b.

Conditions preparative HPLC:

column with a chiral phase Chiralpak AS, 250×4.6 mm;

solvent: n-heptane/ethanol/methanol/acetonitrile in the ratio 20:1,5:0,5:0,5;

volumetric flow rate: 1 ml/min;

Rt(basic fraction) = 14,145 min (→2A);

Rt(by faction) = 11,623 min (→2b).

Both fractions are dissolved in mixtures of methanol and 2n. HCl and subjected to drying by freezing, and listed in the connection header 2A and 2b can be obtained as crystalline solids.

(Rt(2a)=3,630 min (method A); MS(2A),(ES+)=371,3/373,3 (M++N)/412,3/414,3 (M++CH3CN); Rt(2b)=3,668 min (method A); MS(2b),(ES+)=371,3/373,3 (M++N)/412,3/414,3 (M++CH3CN)).

2C: (-)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide

2d: (-)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide

Synthesis specified in the connection header carried out as described in the case of 2A/2b methods, and as a starting compound used, the intermediate product 4b. The sight of the weave and the separation from the target meta-isomer is carried out in the following conditions:

column with a chiral phase Chiralpak AS, 250×4,6/12 mm;

solvent: acetonitrile;

volumetric flow rate: 1 ml/min;

Rt(basic fraction) = 4,394 min (→2C);

Rt(by faction) = 4,130 min (→2d).

Refined products treated with 10%solution of acetic acid and subjected to drying by freezing, and get the target acetates in the form of a slightly yellowish solid substances. (Rt(2c)=of $ 3,656 min (method A); MS(ES+)=371,1/373,1 (M++N)/412,1/414,1 (M++CH3CN); Rt(2d)=1,562 min (method C); MS(ES+)=371,1/373,1 (M++N)/412,1/414,1 (M++CH3CN)).

Example 3

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N,N-dimethylbenzenesulfonamide

6.6 ml of chlorosulfonic portions contribute 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (intermediate 4, example 2). Then stirred for one hour at a temperature of 40°C. After that the reaction mixture is cooled to room temperature and mixed with water and ice. Dropped when this precipitate is filtered under vacuum and treated with ethyl acetate, obtained an ethyl acetate phase after washing with saturated sodium chloride solution, dried over magnesium sulfate. By further concentrating receive a 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)be solargorilla in the form of a solid crude product, part of which (150 mg) portions contribute directly cooled to a temperature of 10°With a solution of dimethylamine (5 ml; about 40%in water). The resulting slurry is then stirred at this temperature for 1.5 hours. After that is mixed with water and ice, extracted three times with ethyl acetate, combined an ethyl acetate phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. The residue is treated with water, mixed with 2n. HCl and subjected to drying by freezing. The thus obtained crude product is then purified by preparative HPLC.

Conditions:

stationary phase: Merck Purospher RP18 (10 μm), 250×25 mm;

mobile phase: 90% N2About (0.05% TFUC) → 90% acetonitrile; 40 min; volumetric flow rate: 25 ml/min

Containing the product fractions are combined, the acetonitrile removed in a rotary evaporator, the aqueous phase is washed with saturated potassium carbonate solution and then extracted three times with ethyl acetate. United an ethyl acetate phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is treated with water, mixed with 2n. HCl and subjected to drying by freezing. Receive 80 mg of bright solids, approximately 80% consisting of the target compounds along with about 20% of regioisomer (Rt=4,000 min (method A); MS(CI+)=399,1).

Example 4

4A: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-benzensulfonamidelor

The intermediate product 1: 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulphochloride

At a temperature of 0°1 mmol 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (intermediate 4, example 2) add 1 ml of chlorosulfonyl and stirred for 3 hours at room temperature. For processing, the reaction mixture is placed on ice, using a 1H. NaOH solution set to pH 7-8 and extracted twice with ethyl acetate. United an ethyl acetate phase is dried over sodium sulfate and concentrated in a rotary evaporator. The thus obtained crude product without further purification further subjected to transformation.

The intermediate product 2: 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide

319 mg of the intermediate product 1 is suspended in 6 ml of 25%ammonia solution and heated to a temperature of 90°C. After 3 hours, diluted with water and extracted with ethyl acetate. The organic phase is separated and dried over sodium sulfate, and get 165 mg specified in the connection header.

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-benzensulfonamidelor

145 mg of the intermediate product 2 is suspended the 15 ml of diethyl ether and mixed with 1 ml of a solution of HCl in diethyl ether. After stirring for 30 minutes at room temperature the precipitate is filtered under vacuum and dried, thus obtain 136 mg of the hydrochloride as a yellowish solid.

4b: 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide

255 mg of the intermediate product 2, example 8, is mixed with 5 ml of glacial acetic acid and add 50 ml of water. After filtering off insoluble component parts subjected to drying by freezing, you get a 250 mg specified in the connection header.

Example 5

4-(4-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolinium

The intermediate product 1: 1-(4-bromophenyl)-1-[(2,4-dichlorobenzyl)methylamino]alanon

(2,4-Dichlorobenzyl)methylamine (see example 1, intermediate 1) and 2-bromo-1-(4-bromophenyl)Etalon enter into an interaction similar to that described in example 1 for the intermediate product 3 methods. After similar treatment and chromatography on silica gel can be allocated to the product of alkylation with 69%yield.

The intermediate product 2: 1-(4-bromophenyl)-2-[(2,4-dichlorobenzyl)methylamino]ethanol

Similar to that described in example 1 for the intermediate product 4 the method of intermediate 1, using 2 equivalents NaBH4Vosstania liveout to the corresponding alcohol, which can be identified with the yield of 86%.

The intermediate product 3: 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

the 5.45 g (14.0 mmol) of 1-(4-bromophenyl)-2-[(2,4-dichlorobenzyl)-methylamino]make ethanol in 15 ml dichloromethane and at a temperature of 0°mixed with 15 ml of concentrated H2SO4. After stirring for 2 hours at room temperature the reaction mixture is placed on ice and alkalinized with 6N. NaOH solution. Extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. For further purification the residue chromatographic on silica gel, thus obtain 2.6 g specified in the title compound as yellowish oil.

4-(4-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolinium

300 mg of 4-(4-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline in 2H. HCl was stirred at room temperature. The precipitation is filtered under vacuum and dried.

Example 6

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid

to 5.57 g (15 mmol) of 4-(4-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate product 3) was dissolved in 150 ml of a mixture of absolute dimethylformamide and benzene (1:1 ratio). After Degas the purpose of the solution in an argon atmosphere added 1.18 g (4.5 mmol) of triphenylphosphine and of 1.17 g (9 mmol) of CA(HCO 3)2. After the new purging with argon add 867 mg (0.75 mmol) of Pd[P(C6H5)3]4and the solution is injected carbon monoxide. Stirred at a temperature of 120°C. six hours at a temperature of 120°and incubation overnight in an argon atmosphere add again 867 mg (0.75 mmol) of Pd[P(C6H5)3]4and stirred for eight hours at a temperature of 120°and the solution is injected carbon monoxide. After the new bear in the night added 135 mg PdCl2and in the same conditions left to react. For processing, the solvent is removed in vacuo and the residue treated with ethyl acetate. Extracted three times with 2n. NaOH solution. In the combined aqueous phases using 6N. HCl set to pH 6 and extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed. The residue is purified on silica gel using a mixture of dichloromethane and methanol, thus obtain 420 mg specified in the connection header (Rt=4,025 min (method A); MS(CI+)=336,1/338,1).

Example 7

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-etilendiamintetraatsetat

146 mg (0.43 mmol) of 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid (see example 6) dissolved in 5 ml digitiform the foreign Ministry and mixed with 1.0 equivalent of triethylamine. At a temperature of 0°add a solution of 141 mg (0.43 mmol) of TOTU in 3 ml of dimethylformamide. Stirred for 30 minutes at a temperature of 0°and for 30 minutes at room temperature. This solution is then at 0°add to the solution of 0.28 ml of a 2M solution of ethylamine and 0.06 ml (0,043 mmol) of triethylamine in 5 ml of dimethylformamide and the reaction mixture is stirred for three hours at room temperature. For processing, the solvent is distilled off in vacuum, the residue is treated with ethyl acetate and washed twice 1H. the KOH solution and once with water. The organic phase is dried over sodium sulfate and concentrated. For further purification carry out chromatography on silica gel (dichloromethane/methanol in the ratio 95:5). By further purification by preparative HPLC (acetonitrile/water/triperoxonane acid) get the target amide carboxylic acid in the form of triptoreline. (Rt=4,169 min (method A); MS(CI+)=363,3/365,3).

Example 8

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzenesulfonyl

On the basis of n-Propylamine and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid (see example 6) can be obtained specified in the header of the connection described in example 7 method (Rt=1,881 min (method C); MS(CI+)=37,3/379,3).

Example 9

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)benzamidopiperidine

Get similar to the method of example 7, on the basis of the compounds of example 6 and N1,N1-dimethylated-1,2-diamine, mediated by TOTU reaction combinations (Rt=1,449 min (method C); MS(CI+)=406,3/408,3).

Example 10

6,8-Dichloro-2-methyl-4-(4-(morpholine-4-ylphenyl)-1,2,3,4-tetrahydroisoquinolinium

456 mg (1.4 mmol) Cs2CO3, 6.75 mg (0.03 mmol) of palladium acetate and 28 mg (0.045 mmol) of 2,2-bis(diphenylphosphino)-1,1-binaphthyl bring in 5 ml of absolute toluene. In the atmosphere of argon is added a solution of 0.104 g ml (1.2 mmol) of the research in 2.5 ml of absolute dimethylformamide, and a solution of 371 mg (1.0 mmol) of 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline in 2.5 ml of absolute toluene and stirred for 9 hours at a temperature of 100°C. To handle, remove the solvent, the residue is treated with dichloromethane and filtered from the insoluble part. After concentration of the filtrate by chromatography of the selected residue on silica gel (dichloromethane/methanol in the ratio 95:5) to obtain 350 mg of the target derivative research. After further purification by preparative HPLC can be distinguished 160 mg of the corresponding three is taratata in the form of a colorless solid.

Example 11

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

Based on diethylamine and 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetraethylene (example 5, intermediate product 3) are similar to those described in example 10 method. The duration of reaction is 2 days at a temperature of 100°use three times the amount of palladium catalyst and phosphine ligand. By preparative HPLC can be allocated target triptorelin in the form of a colorless solid.

Example 12

6,8-Dichloro-2-methyl-4-(4-piperidine-1-ylphenyl)-1,2,3,4-tetrahydroisoquinolinium

Similar to that described in example 10 method, the target piperidine derivative can be obtained on the basis of piperidine and 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate product 3).

Example 13

6,8-Dichloro-2-methyl-4-(4-pyrrolidin-4-ylphenyl)-1,2,3,4-tetrahydroisoquinolinium

The reaction is performed in analogy with the procedure outlined in example 10 method based on pyrrolidine and 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate product 3). After chromatographic purification of the resulting product of srabatyvayut a mixture of dimethyl sulfoxide and acetonitrile, and precipitation, which is filtered off, dissolved in 2n. HCl and subjected to drying by freezing, it is mentioned in the title compound as a colourless solid.

Example 14

6,8-Dichloro-2-methyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1,2,3,4-tetrahydroisoquinolinium

By introducing into the interaction of N-methylpiperazine and 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate product 3) as described in example 10 method get mentioned in the title compound as a colourless solid.

Example 15

6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium

The intermediate product 1: cyclopropyl-(2,4-dichlorobenzyl)Amin

the 5.25 g (30 mmol) of 2,4-dichlorobenzaldehyde contribute in 140 ml of methanol and, at room temperature add a solution 1,71 g (30 mmol) of cyclopropylamine. Stirred at room temperature for 40 minutes and then portions mixed with 1.42 g (37.5 mmol) NaBH4. After standing overnight the solvent is removed and the residue is treated with 2n. HCl. Extracted twice with ethyl acetate. The aqueous phase is alkalinized with NaOH and again extracted twice with ethyl acetate. The organic phase drying is over magnesium sulfate and concentrated. The thus obtained crude product in the form of a slightly yellow oil without further purification can be further subjected to transformation.

The intermediate product 2: 2-[cyclopropyl-(2,4-dichlorobenzyl)amino]-1-phenylethanone

The intermediate product 1 in the presence of triethylamine in dioxane enter into interaction with alpha bromoacetophenone as described in example 1 for the intermediate product 3 methods. For processing, the solvent is distilled off and the residue is treated with ethyl acetate. Washed twice with water and twice with 2n. HCl, dried over magnesium sulfate and concentrated. The thus obtained crude product without further purification can be further subjected to transformation.

The intermediate product 3: 2-[cyclopropyl-(2,4-dichlorobenzyl)amino]-1-phenylethanol

The intermediate product 2, similar to that described in example 1 for the intermediate product 4 methodology restore using NaBH4. For processing, concentrated and the residue partitioned between 1N. HCl and ethyl acetate. The aqueous phase is separated and again extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed in vacuum.

6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium

The intermediate product 3 (1.9 grams) without further purification was dissolved in 10 ml dichloromethane and described in example 1 is yodice cyclist with concentrated H 2SO4. For processing the reaction mixture is placed on ice. The organic phase is separated, and the aqueous phase is again extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and the solvent is removed. Chromatography on silica gel (n-heptane/ethyl acetate in a ratio of 5:1 → 3:1) receive 200 mg of a yellowish oil, which is subjected to further purification by preparative HPLC. Thus obtain 184 mg specified in the connection header in the form of triptoreline.

Example 16

16A: (-)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

16b: (+)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

500 mg specified in the header of the example 1 compound separated on chiral phase, and get about 250 mg of both enantiomeric of acetamido 16A and 16b.

Column with a chiral phase Chiralpak OD, 250×4.6 mm;

solvent: acetonitrile;

volumetric flow rate: 1 ml/min;

Rt((-)-enantiomer/16A)=5,856 min;

Rt((+)-enantiomer/16b)=8,613 minutes

Example 17

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylaminopropane

The intermediate product 1: 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine

3.0 g (8.6 mmol) of N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro skinoren-4-yl)phenyl]ndimethylacetamide (example 1) are dissolved in 100 ml of 20%aqueous solution of sodium methylate and refluxed for four hours. Add the following 2.0 g (29.4 mmol) of solid sodium methylate and refluxed for three hours. To process the solvent is removed in vacuum, the residue is treated with 200 ml of water and extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. For further cleaning implement chromatography on silica gel (ethyl acetate/heptane 1:1), and receive aniline with a quantitative yield in the form of a yellowish oil.

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylaminopropane

200 mg (of 0.65 mmol) of 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine dissolved in 30 ml of a solution of HCl in ethanol. The clear solution was concentrated in vacuo. The residue is triturated in diethyl ether, filtered under vacuum and dried, and can be distinguished 208 mg of the desired hydrochloride.

Example 18

N-Ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzensulfonamidelor

1.0 mmol of 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide (example 4, the intermediate product 2) in 15 ml anhydrous acetone is mixed with 350 mg (2.5 EQ.) To2CO3and stirred at room temperature for 1.5 hours. At room temperature when apiwat solution of 2.5 equiv. utilizationof in acetone and the solution is heated to the boiling temperature under reflux. For processing, concentrated in vacuo, the residue is treated with water and extracted twice with ethyl acetate. The aqueous phase is acidified using 6N. HCl and the precipitated precipitate is filtered off under vacuum. By washing with ethyl acetate and drying in vacuo get mentioned in the title compound in good yield.

Example 19

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

To a solution of 500 mg (1,63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (see example 17) in 15 ml of toluene under stirring was added dropwise a solution of 0.17 g (2.0 mmol) n-propositionthe in toluene. After standing for one hour at a temperature of 40°add the following 0.17 g of n-propositionthe and stirred for one hour at a temperature of 80°C. To handle, remove the solvent and the residue triturated with water and diethyl ether. After drying obtain 503 mg of the target n-propylbromide.

19a: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-profilereminder.exe

450 mg of 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-propylbromide dissolved in a mixture of 2n. HCl and tetrahydrofur the Ana. The clear solution was concentrated in vacuo, the residue triturated with diethyl ether and filtered under vacuum. After drying receive 473 mg target hydrochloride.

Example 20

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

From 500 mg (1,63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (see example 17) and 220 mg (3.0 mmol) methylisothiocyanate similar to that described in example 19, the method can distinguish 245 mg of the target thiocarbamide.

Example 21

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

Get similar to that described in example 19 method, on the basis of 500 mg (1,63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine and 284 mg (4 mmol) utilizationof.

21A: 1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbazole

The transfer into the corresponding hydrochloride is carried out as described in example 19a method.

Example 22

N-[4-(6-Methanesulfonyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

The intermediate product 1: (4-methanesulfonylaminoethyl)methylamine

Synthesize well-known specialist of the way, on the basis of 1-methyl bromide-4-methanesulfonate and methylamine.

Specified in the header of the connection get analogously to example 1, from (4-methanesulfonylaminoethyl)methylamine (intermediate 1) and N-[4-(2-bromoacetyl)phenyl]ndimethylacetamide (example 1, intermediate 2).

Example 23

N-[4-(2,6,8-Trimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

On the basis of (2,4-dimethylbenzyl)methylamine, which can be obtained from 1-methyl bromide-2,4-xylene and methylamine well-known specialist way, and N-[4-(2-bromoacetyl)phenyl]ndimethylacetamide (example 1, intermediate 2) conduct the synthesis analogously to example 1.

Example 24

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

On the basis of (4-bromo-2-Chlorobenzyl)methylamine, which can be obtained well-known specialist of 4-bromo-1-methyl bromide-2-chlorobenzene and methylamine, and N-[4-(2-bromoacetyl)phenyl]ndimethylacetamide (example 1, intermediate 2) conduct the synthesis analogously to example 1.

Example 25

N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

1,02 g (3,12 mmol) Cs2CO3, 8,8 mg (0.04 mmol) of palladium acetate, and the 36.1 mg (0.06 mmol) of 2,2-bis(diphenylphosphino)-1,1-binaphthyl in almost the re argon contribute 6.5 ml of absolute toluene. At room temperature add a solution of 512 mg (1.3 mmol) of N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide (example 24) in 4 ml of absolute dimethylformamide, and a solution of 111 mg (1.56 mmol) of pyrrolidine in 4 ml of dimethylformamide and heated for 7 hours at a temperature of 100°C. For processing, the solvent is removed in vacuo and the residue treated with dichloromethane. Filtered from insoluble components and the filtrate concentrated. From the residue by chromatography on silica gel using a mixture of dichloromethane and methanol, can be selected 360 mg specified in the header of the example compounds.

25A: N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acetamidomalonate

320 mg of N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide dissolved in 20 ml of HCl solution in ethanol, stirred for 30 minutes at room temperature and concentrate. The residue is treated with water and subjected to drying by freezing.

Example 26

N-[4-(8-Chloro-2-methyl-6-morpholine-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acetamidomalonate

Get similar to that described in example 25, from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide (p is emer 24) and the research. After chromatographic separation on silica gel carry out further purification by preparative HPLC.

Example 27

N-{4-[8-Chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide

Get similar to that described in example 25 method based on N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide (example 24) and N-methylpiperazine.

27A: N-{4-[8-Chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}acetamidomalonate

220 mg of N-{4-[8-Chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide dissolve in a small amount of methanol, diluted with 2n. HCl and subjected to drying by freezing, and obtain 226 mg target hydrochloride.

Example 28

N-{4-[8-Chloro-6-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}acetamidomalonate

Get similar to that described in example 25 method based on N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide (example 24) and C-cyclopropanemethylamine. After chromatographic separation on silica gel carry out further purification by preparative HPLC. The purified compound was dissolved in 1N. HCl, Rabaul the Ute water and subjected to drying by freezing.

Example 29

5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid

The intermediate product 1: ethyl ester of 5-acetyl-2-hydroxybenzoic acid

Get well-known specialist of 5-acetyl-2-hydroxybenzoic acid by the acid catalyzed esterification reaction.

The intermediate product 2: ethyl ester of 5-(2-bromoacetyl)-2-hydroxybenzoic acid

Receive by known methods from the ethyl ester of 5-acetyl-2-hydroxybenzoic acid as described in example 1 for the intermediate product 2 method.

The intermediate product 3: ethyl ester of 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid

On the basis of the ethyl ester of 5-(2-bromoacetyl)-2-hydroxybenzoic acid and 2,4-dichlorobenzyltoluene (see example 1, intermediate 1) synthesize specified in the header of the connection as described in example 1 method.

5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid

6.8 g (18 mmol) ethyl ester 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid is known to the specialist way omelet in a mixture of ethanol and 2n. the KOH solution, while getting to 5.4 g of the free acid.

29A: Sodium salt of 5-(6,8-dichloro-2-methyl-1,2,3,4-Tetra is hydroisoquinoline-4-yl)-2-hydroxybenzoic acid

352 mg (1 mmol) 5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid dissolved in 10 ml of 0.1 m NaOH solution, diluted with water and subjected to drying by freezing, while getting 375 mg specified in the connection header.

Example 30

5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxy-N-methylbenzeneethanamine

On the basis of 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid can be obtained is specified in the header connection mediated by TOTU reaction with methylamine as described in example 7 method.

Example 31

5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethyl-2-hydroxybenzenesulfonate

On the basis of 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid can be obtained is specified in the header connection mediated by TOTU reaction with ethylamine as described in example 7 method.

Example 32

5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-

(2-dimethylaminoethyl)-2-hydroxybenzenesulfonate

On the basis of 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid to monopolizing specified in the header connection mediated by TOTU reaction with N1,N1-dimethylated-1,2-diamine as described in example 7 method.

Example 33

N-[5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoyl]guanidine

To a solution 2,39 g (25 mmol) of guanidine hydrochloride in 15 ml of absolute dimethylformamide add 2,52 g of potassium tert-butylate and stirred for 45 minutes at room temperature. Add a solution of 950 mg (2.5 mmol) ethyl ester 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid (example 29, intermediate product 3) in 10 ml of absolute dimethylformamide and stirred for four hours at room temperature. Once more unable to install any increase conversions, the precipitate is filtered off under vacuum and the solvent is removed in vacuum. The residue is treated with 2n. HCl and extracted 2 times with dichloromethane. In the aqueous phase set to about pH 10 with KOH, and the target acylhalides falls in the form of a colorless precipitate. By filtration under vacuum and drying receive 793 mg specified in the connection header.

Example 34

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

The target meta-acetanilide get similar to that described in example 1 synthesis from N-(3-acetylphenyl)ndimethylacetamide and 2,4-dichlorobenzyltoluene (example 1, intermediate 1), according to the four similar stages.

Example 35

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

The removal of acetyl groups from N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide (example 34) carried out as described in example 17 for the intermediate product 1 method in the presence of sodium methylate.

Example 36

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

The intermediate product 1: N-[2-(2-bromoacetyl)phenyl]ndimethylacetamide

31 g (0,175 mol) of N-(2-acetylphenyl)ndimethylacetamide (obtained by acylation of 2-aminoacetophenone using acetylchloride according to Alois Fuerstner, Jumbam Denis N., Tetrahedron,48, 29, 5991-6010 (1992)) are dissolved in 200 ml of glacial acetic acid. Add 127 ml of 33%solution of HBr in glacial acetic acid and then at room temperature is added slowly is 8.75 ml (0,175 mol) of bromine. The mixture is stirred over night at room temperature and with stirring, bring in 1.5 l of ice water, the precipitated precipitated product is filtered off under vacuum, additionally well washed with ice water and dried in vacuum. According to HPLC and NMR of the crude product contains a small amount of substance and dibromononane product, however, for further transformation is the fast clean enough (about 85%purity). Output: 43,

The intermediate product 2: N-(2-{2-[(2,4-dichlorobenzyl)methylamino]acetyl}phenyl)ndimethylacetamide

12.4 g (65,24 mmol) of 2,4-dichloro-N-methylbenzylamine (example 1, intermediate 1) was dissolved in 200 ml of dioxane. To the resulting solution was added 19,96 g crude product of the previous synthesized, also dissolved in 200 ml of dioxane, and 45 ml of triethylamine. The mixture is stirred over night at room temperature and then filtered. The filtrate is evaporated, the residue treated with ethyl acetate and washed with saturated sodium hydrogen carbonate solution and sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator. The crude product (20.4 g) according to NMR is pure enough for further transformations.

The intermediate product 3: N-(2-{2-[(2,4-dichlorobenzyl)methylamino]-1-hydroxyethyl}phenyl)ndimethylacetamide

20 g (50 mmol) obtained in the previous phase of the crude product is dissolved in 200 ml of methanol and cooled in a bath with ice to a temperature of <5°C. To the resulting solution with good stirring portions added 4.3 g (109 mmol) of sodium borohydride, so that the internal temperature did not exceed 10°C. Then further stirred for 30 minutes in a bath with ice and for 1 hour at room temperature. After standing overnight the mixture is evaporated, the residue treatment is primarily with ethyl acetate, washed 3 times with water and 1 time with a solution of sodium chloride, dried over sodium sulfate and concentrated in a rotary evaporator. The crude product (19,4 g) without further purification further subjected to transformation.

The intermediate product 4: 1-(2-AMINOPHENYL)-2-[(2,4-dichlorobenzyl)methylamino]ethanol

10 g of the obtained in the previous phase of the crude product is dissolved in 300 ml of methanol. Add 200 ml of concentrated hydrochloric acid and stirred for 10 hours at a temperature of 50°C. Leave to cool, the reaction mixture was poured into water and using a 20%NaOH solution set to a pH of 10-12. The product is extracted with ethyl acetate, the combined extracts washed with sodium chloride solution, dried over sodium sulfate and evaporated. The crude product (9,9 g) contains little sodium chloride, which, however, does not prevent further turning.

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

to 9.9 g of the obtained in the previous phase of the crude product is dissolved in 350 ml of chloroform. When the cooling bath was added dropwise with ice 123 ml of concentrated sulfuric acid. Additionally stirred for 2 hours in a bath with ice, and then the temperature is slowly increased to room and, finally, during the night is heated at a temperature of 50°C. the Cooled mixture was poured on ice and alkalinized with a solution guide is sodium oxide (pH> 10). The organic phase is separated, the aqueous phase is additionally extracted 2 times with dichloromethane, the combined organic phases are washed with water and NaCl solution, dried over sodium sulfate and evaporated.

A General method of preparing compounds of examples 37-77

154 mg (0.5 mmol) of the target compounds from example 35 and example 36 and example 17, the intermediate product 1, bring in 5 ml dichloromethane and mixed with 0,076 ml (0.55 mmol) of triethylamine. At a temperature of 0°add a solution of 1.1 equivalents (0.55 mmol) of the carboxylic acid in 5 ml dichloromethane and stirred overnight at thawing. For processing, filter and remove the solvent. The residue is dissolved in 20 ml of ethyl acetate and washed once with 5%aqueous solution of NaHCO3and 5%NaCl solution, and dried. After removal of the solvent make final purification by preparative HPLC.

Example 78

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

0,355 m the ol compound of example 35 was dissolved in 5 ml of anhydrous acetonitrile and mixed with 0,39 mmol utilizationof. After keeping overnight with exclusion of moisture, the solvent is removed and the crude product purified by preparative HPLC, it is mentioned in the title compound as a colourless solid.

Example 79

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

Proceeding from the compound of example 35 and methylisothiocyanate as described in example 78 methodology synthesize specified in the header of the connection.

Example 80

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

Proceeding from the compound of example 36 and utilizationof followed by the method similar to example 78. For processing, the precipitate is filtered under vacuum and washed with acetonitrile, you get a target ethylcarbamate in the form of a colorless solid.

Example 81

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

The compound of example 36 and methylisothiocyanate enter into an interaction similar to that described in example 78 method.

Example 82

Hydrochloride [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultancy

to 307.1 mg (1 mmol) of the compound of example 35 was dissolved in 10 ml of pyridine and at a temperature of 0°With a mix from 0.19 g (1.5 mmol) of acanaloniidae, and with a catalytic amount of 4-dimethylaminopyridine (DMAP). Stirred at room temperature. For processing, the solvent is removed in vacuum, the residue is treated with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate and concentrated. The crude product chromatographic on silica gel. Thus the resulting sulfonamide is dissolved in a mixture of tetrahydrofuran and 2n. HCl and again concentrated in vacuo, thus obtain 208 mg target hydrochloride.

Example 83

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

Proceeding from the compound of example 35 and methanesulfonanilide followed similar to that described in example 82 method.

Example 84

Hydrochloride [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultancy

Proceeding from compounds of example 17, the intermediate product 1, and acanaloniidae follow the same way as described in example 82 method.

Example 85

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

Proceeding from compounds of example 17, the intermediate product 1, and methanesulfonanilide follow the same way as described in example 82 method.

Example 86

86a: (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

86b: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide

2.0 g specified in the header of example 34 compound separated on chiral phase, and receive approximately 1.0 g of both enantiomeric of acetamido 86a and 86b.

Column with a chiral phase Chiralpak ADH/31; 250×4.6 mm;

solvent: acetonitrile;

volumetric flow rate: 1 ml/min;

Rt((-)-enantiomer/86a)=5,541 min;

Rt((+)-enantiomer/86b)=7,033 minutes

A General method of preparing compounds of examples 87-98

1.0 mmol of 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 17, the intermediate product 1), respectively, 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 35) add 10 ml of pyridine and at a temperature of 0°With added dropwise a solution of 1.2 equivalents of the appropriate acid chloride of acid (see table 2) in 5 ml of dichloromethane. Stirred at room temperature. Depending on the development of the reaction add a catalytic amount of DMAP and, if necessary, raise the reaction temperature to 50°With, should not be more than is becoming no increase in conversion. For processing, concentrated and the residue distributed between ethyl acetate and a saturated solution of NaHCO3. The organic phase is separated and again washed with a saturated solution of NaHCO3and water, dried over sodium sulfate and concentrated. For further purification the crude product is chromatographic on silica gel. For transferring the products obtained in the respective hydrochloride substances dissolved in 2n. HCl or ethanol solution of HCl and the solvent is removed, you get a target HCl-salt.

When purification by preparative HPLC receive the correct products in the form of trifurcation.

General methods of synthesis of compounds of examples 99-110

Getting amine component

4.0 mmol of aromatic aldehyde (see table 3) with 8.0 mmol aliphatic amine (see table 3) in methanol is stirred for 2 hours at room temperature and then, depending on the progress of the reaction, mix portions from 0.67 to 2.0 equivalents NaBH4. After keeping overnight at room temperature to remove solvent and the residue is treated with 1N. HCl. Extracted with dichloromethane. In the aqueous phase set the pH value of 11 to 12 using NaOH and again extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator. Further purification is carried out by chromatography on silica gel or by preparative HPLC.

Getting bromatologia component

Bracketology synthesize components known from the literature methods, based on commercially available acetophenones by treatment with bromine in glacial acetic acid analogously to the method of example 1 to intermediate 2.

Based on table 3 amine and bracketology connection components examples 100-111 can be obtained by analogy with the procedure outlined in example 1 synthesis of (alkylation of amine component using bromatologia component, then restore using NaBH4and subsequent mediated H2SO4cyclization).

The resulting tetrahydroisoquinoline known to the specialist, you can translate into the corresponding salt.

A General method of preparing compounds of examples 111-124

0,358 mmol listed in table 4 acid dissolved in 1 ml of dimethylformamide and add 0,221 ml (1,30 mmol) diisopropylethylamine. At a temperature of 0°With added dropwise a solution of 128 mg (0,390 mmol) of TOTU in 1 ml of dimethylformamide. After mixing with a solution of 100 mg (0,325 mmol) specified is in table 4 amine component in 2 ml of dimethylformamide is stirred at room temperature overnight. For processing, filtered from insoluble components and optionally washed with 20 ml of ethyl acetate. The filtrate is washed twice with a saturated solution of NaHCO3and once with 5%aqueous NaCl solution, dried and concentrated.

From raw foods, which contain more of the BOC-protective group, without further purification to remove the protective group (see below: General method of removal of the BOC-protective groups). If not protected BOC-groups of components, after highlighting spend preparative HPLC, thus obtain the target compounds of examples in the form of trifurcation.

A General method of preparing compounds of examples 125-147

0,358 mmol listed in table 4 acid dissolved in 1 ml of dimethylformamide and add 0,221 ml (1,30 mmol) diisopropylethylamine. At a temperature of 0°mixed with 151 mg (0,975 mmol) diethylcarbamazine, a solution of 132 mg (0,975 mmol) N-hydroxybenzotriazole (HOBt) in 1 ml of dimethylformamide and 20 mg (rate £ 0.162 mmol) of 4-dimethylaminopyridine (DMAP). After addition of the solution specified in table 4 amine component in 2 ml of dimethylformamide is stirred at room temperature overnight. For processing, filtered from insoluble components and optionally washed with 20 ml of ethyl acetate. The filtrate is washed twice with a saturated solution of NaHCO and 1 time with 5%aqueous NaCl solution, dried and concentrated.

From raw foods, which contain more of the BOC-protective group, without further purification to remove the protective group (see below: General method of removal of the BOC-protective groups). If not protected BOC-groups of components, after highlighting spend preparative HPLC, thus obtain the target compounds of examples in the form of trifurcation.

A General method of removal of the BOC-protective groups

The resulting crude products in 5 ml of 10%aqueous solution triperoxonane acid in dichloromethane is stirred for one hour at room temperature. Then concentrated in vacuo and the residue purified by preparative HPLC, and get the target compounds of examples in the form of trifurcation.

Example 148

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

95 mg of 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 36) add 4 ml of acetonitrile and added with stirring 27 mg ethylisothiocyanate. After the UDERZhIVANIYa for 15 hours at room temperature the solvent is removed in vacuo and the residue purified by preparative HPLC. Thus obtained triptorelin process water and alkalinized with help from2CO3. The aqueous phase is extracted with ethyl acetate. The organic phase is separated, dried over magnesium sulfate and concentrated. The residue is treated with diluted hydrochloric acid and subjected to drying by freezing, and get 36 mg specified in the connection header.

Example 149

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

50 mg of 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 17, the intermediate product 1) add 4 ml of tetrahydrofuran and mixed with 14 mg ethylisothiocyanate. After boiling under reflux for 2 hours, the reaction solution is concentrated and heated for 2 hours at a temperature of 85°C. the Thus obtained crude product is purified by preparative HPLC. Further processing of the thus obtained trifenatate as described in example 148, after freeze-drying give 33 mg of the target hydrochloride.

Example 150

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

50 mg of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound Primera) dissolved in 3 ml of tetrahydrofuran, and with stirring, mixed with 14 mg ethylisothiocyanate. After boiling under reflux for 2 hours, the reaction solution is concentrated and heated for 2 hours at a temperature of 85°C. the Thus obtained crude product is purified by preparative HPLC, and get 66 mg specified in the connection header.

Example 151

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

The intermediate product 1: hydrochloride 4-nitrophenylthio ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid

350 mg of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 35) was dissolved in 17.5 ml of dichloromethane and mixed under stirring with 230 mg of 4-nitrophenylamino ether Harborview acid. After 4.5 hours add the following to 0.1 equivalent (23 mg), 4-nitrophenylamino ether Harborview acid and the solution is stirred over night. For processing, the precipitation is filtered off and washed with dichloromethane. The thus obtained indicated in the title compound without further purification can be further subjected to transformation.

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

35 mg of the hydrochloride of 4-nitrophenylthio ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]to raminosoa acid (intermediate 1) suspended in 3.5 ml of dichloromethane and was added dropwise with stirring a solution of 3.7 mg of dimethylamine in 1 ml dichloromethane. After 1 hour, diluted with dichloromethane and washed with an aqueous solution To a2CO3. The organic phase is separated and washed twice with a saturated solution of K2CO3, dried over magnesium sulfate and concentrated. The residue is treated with diluted hydrochloric acid and subjected to drying by freezing, and obtain 29 mg specified in the connection header.

Compounds of the following examples get similar to that described in example 151 methodology on the basis of the intermediate product 1 and the corresponding amine components:

Compounds of the following examples get similar to that described in example 151 methodology. The solvent is tetrahydrofuran, the reaction is carried out in a closed reaction vessel. In the case of examples 159-166 was necessary reaction temperature 85°C. Compound of example 167 purified by preparative HPLC.

Example 168

Hydrochloride [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid

The intermediate product 1: hydrochloride 4-nitrophenylamino ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid

200 mg of 2-(6,8-dichloro-2-meth is l-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 36) was dissolved in 10 ml dichloromethane and mixed under stirring with 131 mg of 4-nitrophenylamino ether Harborview acid. After 3.5 hours the precipitation is filtered under vacuum and washed with dichloromethane. The thus obtained crude product is recrystallized from dichloromethane, thus obtain 159 mg specified in the connection header.

Hydrochloride [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid

15 mg of the hydrochloride of 4-nitrophenylamino ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid are suspended in 2 ml of dichloromethane and mixed with a solution of 3.2 mg of 1-methylpiperazine in 1 ml dichloromethane. After 1 hour, diluted with dichloromethane and washed with an aqueous solution To a2CO3. The organic phase is separated and washed twice with a saturated solution of K2CO3, dried over magnesium sulfate and concentrated. The residue is treated with diluted hydrochloric acid and subjected to drying by freezing, while 13 mg specified in the connection header.

Compounds of the following examples get similar to that described in example 168 to the method.

Example 176

Hydrochloride [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic Kislots

The intermediate product 1: hydrochloride 4-nitrophenylamino ether [4(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid

200 mg of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 17, the intermediate product 1) dissolved in 10 ml dichloromethane and mixed under stirring with 131 mg of 4-nitrophenylamino ether Harborview acid. After 4.5 hours the precipitation is filtered under vacuum and washed with dichloromethane. The thus obtained crude product is recrystallized twice from dichloromethane, and obtain 254 mg specified in the connection header.

Hydrochloride [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid

15 mg of the hydrochloride of 4-nitrophenylthio ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid are suspended in 2 ml of dichloromethane and mixed with a solution of 3.2 mg of 1-methylpiperazine in 1 ml dichloromethane. After stirring for 5 hours and standing overnight, diluted with dichloromethane and washed with an aqueous solution To a2CO3. The organic phase is separated and washed twice with a saturated solution of K2CO3, dried over magnesium sulfate and concentrated. The residue is treated with diluted hydrochloric acid and subjected to drying by freezing, and 13 mg specified in the connection header.

Compounds of the following examples get similar to that described in the example is 176 method.

Example 184

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

200 mg of 4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 17, the intermediate product 1) was dissolved in 1 ml of formic acid and refluxed for 15 minutes. After standing overnight the mixture contribute to the mixture of ice water and extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. The residue is treated with dichloromethane and washed with saturated solution of NaHCO3. The phases are separated and the aqueous phase is extracted three times with dichloromethane. By drying of the organic phases (MgSO4and removal of the solvent obtain 167 mg of crude product. 10 mg of the product is dissolved in dilute HCl and subjected to drying by freezing, and get 11 mg specified in the connection header.

Example 185

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

150 mg of N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide (compound of example 184) dissolved in 2.5 ml of tetrahydrofuran and at a temperature of 50°in argon atmosphere etc is capiat to a solution of 0.45 ml of a 1M solution of sociallyengaged in tetrahydrofuran, 2.5 ml of tetrahydrofuran. Refluxed for 1 hour. After standing over night added at a temperature of 50°the following is 0.22 ml of a 1M solution of sociallyengaged and refluxed in the next hour. To handle, remove the solvent and the residue partitioned between dichloromethane and aqueous solution of HCl. The phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. Further purification is carried out by preparative HPLC. The thus obtained product is treated with a solution of NaHCO3and extracted with dichloromethane. Drying the organic phase over magnesium sulfate receive 80 mg of free base. 10 mg base is treated with diluted aqueous HCl and subjected to drying by freezing, and receive 10 mg specified in the connection header.

Example 186

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

Specified in the header of the connection get described in example 151 methodology, based on [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine (example 185), 4-nitrophenylphosphate and methylamine (20 ml, 2M solution in tetrahydrofuran), and receive 9 mg of the target hydrochloride is.

Similarly to the method of example 186 on the basis of [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine (example 185), 4-nitrophenylphosphate and the appropriate amine components, receive the following connections:

Example 194

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

600 mg of 3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (compound of example 35) was dissolved in 2.4 ml of formic acid and refluxed for 15 minutes. After standing overnight the reaction mixture contribute in a mixture of ice water and a saturated solution of NaHCO3and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated, and receive 588 mg specified in the connection header.

Example 195

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

588 mg of N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide (compound of example 194) dissolved in 10 ml of tetrahydrofuran and at a temperature of 50°C in an atmosphere of argon added to a solution of 1.8 ml of 1M solution of sociallyengaged in tetrahydrofuran. Boil with education is the principal refrigerator for 1 hour. After standing over night added at a temperature of 50°With the following 2 ml of 1M solution of sociallyengaged and refluxed for 30 minutes. For processing, mixed with ice and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. Further purification is carried out by preparative HPLC. The thus obtained product is treated with a solution of NaHCO3and extracted with ethyl acetate. Drying the organic phase over magnesium sulfate give 270 mg of the free base. 45 mg of the base is treated with diluted aqueous HCl and subjected to drying by freezing, and receive 45 mg specified in the connection header.

As described in example 151 methodology based on [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine (example 195), 4-nitroformate and the appropriate amine components receive the following connections:

Example 204

Hydrochloride 2-dimethylaminoethanol ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid

Under stirring and argon atmosphere 15 mg of the hydrochloride of 4-nitrophenylthio ester [3-(6,8-dichloro-2-methyl,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid (see example 151, the intermediate product 1) are suspended in 1.5 ml dichloromethane and mixed with a solution of 3 mg of 2-dimethylaminoethanol in 0.5 ml dichloromethane and stirred for 6 hours. After standing overnight, water is added, dichloromethane and a saturated solution of NaHCO3and the organic phase is separated. The dichloromethane phase is washed three times with saturated solution of NaHCO3, dried over magnesium sulfate and the solvent is removed in vacuum. The thus obtained crude product is purified by preparative HPLC. Containing the product fractions are concentrated and distributed between ethyl acetate and a saturated solution of NaHCO3. The organic phase is separated, dried over magnesium sulfate and concentrated. The residue is treated with diluted hydrochloric acid and subjected to drying by freezing, and receive 5 mg specified in the connection header.

Similarly, on the basis of the hydrochloride of 4-nitrophenylthio ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid hydrochloride and 4-nitrophenylamino ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino receive appropriate acid isomers: hydrochloride 2-dimethylaminoethanol ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid hydrochloride and 2-dimethylaminoethanol ether [2-(6,8-dihl the p-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid.

Example 207

Hydrochloride methyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid

In an argon atmosphere and with stirring, 15 mg of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine (example 35) add 1.5 ml dichloromethane and mixed with a solution of 4.6 mg methylcarbamate in 0.5 ml of dichloromethane. After stirring for 6 hours and incubation over night add the following to 2.3 mg methylcarbamate and stirred for 5 hours. To handle, remove the solvent, the residue is treated with diluted hydrochloric acid and subjected to drying by freezing, while receiving 20 mg specified in the connection header.

Similarly, on the basis of the corresponding anilines - 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine, 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine you can obtain the following carbamates:

Example 215

A: (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide

215b: (-)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide

96 mg is semichasnoho N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide (see example 83) is separated into the enantiomers by preparative HPLC on a chiral phase.

Column with a chiral phase Chiralpak AD 20 μm; 250×50 mm;

solvent: heptane:ethanol:methanol in the ratio of 10:1:1;

volumetric flow rate: 50 ml/min

The resulting enantiomers dissolved in diluted hydrochloric acid and subjected to drying by freezing, and get listed in the connection header a and 215b. The purity of the enantiomers was determined by HPLC on a chiral phase.

Column with a chiral phase Chiralpak AD-H/31; 250×4.6 mm;

solvent: heptane:ethanol:methanol in the ratio of 10:1:1;

volumetric flow rate: 1 ml/min;

Rt(first eluruumis enantiomer)= 6,84 min, 100%excess enantiomer;

Rt(second eluruumis enantiomer)= 8,02 min, 100%enantiomer excess.

Example 216

A: (+)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbazole

216b: (-)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbazole

316 mg of racemic 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate (the compound of example 80) is separated into the enantiomers by preparative HPLC on a chiral phase.

Column with a chiral phase Chiralpak OD, 20 μm; 250×50 mm;

solvent: heptane:ethanol:isoprop the ol in the ratio of 50:2:1; 0.3% diethylamine;

volumetric flow rate: 50 ml/min

The enantiomers separately subjected to further purification by preparative HPLC. These products are partitioned between a saturated solution of NaHCO3and ethyl acetate, the organic phase is separated, dried over magnesium sulfate and the solvent is removed. By dissolving the residue in dilute hydrochloric acid and freeze-drying obtain 37 mg aliremove first and 58 mg aliremove the second enantiomer. The purity of the enantiomers determined by analytical HPLC.

Column with a chiral phase Chiralpak OD-20; 250×4.6 mm;

solvent: heptane:ethanol:isopropanol in a ratio of 50:2:1 (0.3% diethylamine);

volumetric flow rate: 1 ml/min;

Rt(first eluruumis enantiomer)=which 9.22 min, 100%excess enantiomer;

Rt(second eluruumis enantiomer)=9,96 min, 98%enantiomer excess.

Example 217

N-[3-(6,8-Debtor-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acetamidomalonate

The intermediate product 1: 2,4-diftorbenzofenon

Based on 2,4-diferentialglea can be obtained 2,4-diftorbenzofenon known to the expert (see example 1, the intermediate product 1).

N-[3-(6,8-Debtor-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acetamidomalonate

Proceeding from N-(3-acetylphenyl)ndimethylacetamide and 2,4-diftormetilirovaniya (intermediate 1) can be obtained specified in the header of the connection described in example 1 synthesis pathway.

Example 218

4-(3-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolinium

Based on 2,4-dichlorobenzyltoluene (see example 1) and 2-bromo-1-(3-bromophenyl)ethanone as alkylating tools can be accessed is specified in the header of the connection described in example 1 synthesis.

Example 219

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

509 mg (1 mmol) of the hydrochloride of 4-nitrophenylthio ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acid (compound of example 151, the intermediate product 1) is dissolved in 15 ml of absolute dimethylformamide and at a temperature of 0°mixed with a solution of 67.2 per mg (1.1 mmol) of 2-aminoethanol in 10 ml of dimethylformamide. Stirred for three hours at room temperature and then the solvent is removed in vacuum. The residue is distributed between ethyl acetate and saturated NaCl solution. The organic phase is separated, and the aqueous phase is extracted two more times with ethyl acetate. The combined organic phases are washed with a saturated solution of NaHCO3, dried over magnesium sulfate and concentrated. Chromatography on silica gel (dichloromethane/methanol) to obtain 265 mg specified in the connection header.

Example 220

Ethyl e is Il-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid

The intermediate product 1: 3-acetylbenzoic acid

Get well-known specialist of 3-acetylbenzoate by saponification of nitrile groups.

The intermediate product 2: ethyl ester of 3-acetylbenzoic acid

Get known to the specialist by way of the intermediate product 1.

The intermediate product 3: ethyl ester of 3-(2-bromoacetyl)benzoic acid

Synthesized from ethyl ester of 3-acetylbenzoic acid (intermediate 2) similar to that described in example 1 for the intermediate product 2 method.

Ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid

You can follow the procedures in example 1 synthesis on the basis of the ethyl ester of 3-(2-bromoacetyl)benzoic acid (intermediate 3) and 2,4-dichlorobenzyltoluene (example 1, intermediate 1), after the reaction of alkylation, reduction and cyclization reaction receive the ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid.

Example 221

3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid

500 mg of ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid are dissolved in 15 ml of methanol and mixed with 10 ml of 2n. the solution of KOH. P the following aging for one hour at a temperature of 50° With concentrated in vacuo and the residue partitioned between water and diethyl ether. In the aqueous phase set to about pH 6 with 2n. HCl and the resulting precipitate is filtered under vacuum. After drying receive 304 mg specified in the title compound as a colourless solid.

Analytical data for the compounds of examples 1-221:

Pharmacological data

Description of the test

In this test, installed the recovery of intracellular pH (pHiafter acidification, which is used in the case of normal functioning of the sodium-hydrogen exchange (NHE), and in the absence of bicarbonate. This was determined by pHiusing pH-sensitive fluorescent dye BCECF (2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein) (Calbiochem; use predecessor BCECF-AM). Cells were first loaded with BCECF. The BCECF fluorescence was determined using a spectrometer "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 nm and 440 nm and the wavelength of emission of 535 nm and using the calibration curves were calculated at pHi. Cells already at a load of BCECF were incubated in NH4Cl-buffer (pH 7.4) (NH4Cl-buffer: 115 mm NaCl, 20 mm NH4Cl, 5 mm KCl, 1 mm CaCl2, 1 mm MgSO4, 20 mm Hepes, 5 mm glucose, 1 mg/ml bovine serum albumin; using 1M NaOH solution octanal what happens is rn,4). Intracellular acidification induced by adding 975 µl containing NH4Cl buffer (see below) aliquot 25 ál incubated in NH4Cl-buffer cells. The subsequent rate of recovery of pH were recorded at NHE1 two minutes when NHE2 five minutes and NHE3 three minutes. To calculate the inhibitory capacity of the tested substance cells was investigated primarily in the buffers, in which there was complete recovery of LV or not was no recovery of pH. For full recovery of pH (100%) cells were incubated in 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, 5 mm Hepes, 5 mm glucose; using 1M NaOH solution set pH=7,0). To determine the value 0% of cells incubated in not containing Na+ions buffer (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 NaOH solution set pH=7,0). The test substance was administered in Na+-containing buffer. Recovery of intracellular pH in the case of each tested concentration of a substance expressed as a percentage of maximum recovery. Of the percentages of recovery values of pH using Sigma-Plot Russ is itively the value of the IC 50(the concentration that causes 50%inhibition) of the substance concerned for the individual NHE subtypes.

Results

1. 4-Vinyltetrahydrofuran formula (I)

where R1, R2, R3 and R4, independently of one another, denote H, F, Cl, Br, CandH2a+1where one or more atoms of N replaced by F, NR11R12 or SOjR15;

and means 1, 2, 3, 4, 5, 6, 7 or 8;

R11 and R12, independently of one another, denote H, CeH2E+1or CrrH2rr-1;

E. means 1, 2, 3, 4;

rr means 3, 4;

or together with the nitrogen atom to which they are bound, form a cycle selected from the group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazine, piperazinil or morpholinyl;

j is 1 or 2;

R15 means CkH2k+1;

k means 1, 2, 3, 4, 5, 6, 7 or 8;

R5 means CpH2p+1or CssH2ss-1;

R means 1, 2, 3, 4, 5, 6, 7 or 8;

ss means 3, 4, 5, 6, 7 or 8;

R6 denotes H;

R7, R8 and R9, independently of one another, mean SOwR23, NR32COR30, NR32CSR30, NR32SObbR30, H, F, Cl, Br, HE, NH2CeeH2ee+1, NR40R41, CONR40R41 or COOR42;

w is 0, 1 or 2;

bb means 2 or 3;

R23 means NR25R26;

R25 and R26, independently of each is, mean N or CzH2z+1CzzH2zz-1;

z means 1, 2, 3, 4, 5, 6, 7 or 8;

zz means 3, 4, 5, 6, 7 or 8, where CzH2z+1CzzH2zz-1one or more atoms of N substituted by fluorine atom and one or more CH2group substituted at the C(=O) or NR27;

R27 denotes N or CAAH2A+1,

AA means 1, 2, 3 or 4;

or R25 and R26 together with the nitrogen atom to which they are bound, form a 5-, 6-or 7-membered cycle,

R30 denotes H, CccH2cc+1CyyH2yy-1pyrrolidinyl, piperidinyl, in cycles in which the group CH2- may be replaced by O or NR33;

R32 and R33, independently of one another, denote H or ChH2h+1;

cc means 1, 2, 3, 4, 5, 6, 7 or 8;

yy means 3, 4, 5, 6, 7 or 8;

h means 1, 2, 3, 4, 5, 6, 7 or 8;

where ChH2h+1one or more hydrogen atoms substituted with fluorine atom, and groups CccH2cc+1and CyyH2yy-1one or more hydrogen atoms may be substituted by fluorine atoms and the group CH2may be substituted by Oh or NR31;

R31 denotes H, methyl, ethyl, acetyl or SO2CH3;

or R30 means 6-membered heteroaryl with 1, 2, 3 or 4 nitrogen atoms, zero or 1 S atom or zero or 1 O atom, which is unsubstituted or substituted by up to three substituents selected from the gr is PPI, consisting of F, Cl, Br, I, CooH2oo+1where one or more hydrogen atoms may be substituted by a fluorine atom, NO2or NR70R71;

oo means 1, 2, 3, 4, 5, 6, 7 or 8;

R70 and R71 independently from each other signify H, CuuH2uu+1or COR72;

uu means 1, 2, 3, 4, 5, 6, 7 or 8;

R72 include means H, CvvH2vv+1;

vv means 1, 2, 3, 4, 5, 6, 7 or 8;

it means 1, 2, 3, 4, 5, 6, 7 or 8;

R40 and R41 represent independently of one another, H, CttH2tt+1or C(NH)NH2;

tt means 1, 2, 3, 4, 5, 6, 7 or 8;

where a group of CttH2tt+1one or more groups of CH2can be substituted for NR44;

R44 means CggH2gg+1;

gg means 1, 2, 3, 4, 5, 6, 7 or 8;

R42 denotes N or ChhH2hh+1;

hh means 1, 2, 3, 4, 5, 6, 7 or 8;

moreover, however, two deputies from the group of R7, R8 and R9 are not simultaneously can mean HE, and at least one of the residues R7, R8 or R9 must be selected from the group consisting of CONR40R41, -OvSOwR23, NR32COR30, NR32CSR30 and NR32SObbR30;

and their pharmaceutically acceptable salts and triptoreline.

2. The compounds of formula (I) according to claim 1, selected from the group consisting of

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4 and is)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N,N-dimethylbenzenesulfonamide;

5) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethylbenzamide;

6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzamide;

7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)benzamide;

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

9) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

10) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

6,8-dichloro-2-methyl-4-(4-(morpholine-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;

11) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

12) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

13) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

14) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] ndimethylacetamide;

15) N-[4-(8-chloro-2-methyl-6-morpholine-4-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] ndimethylacetamide;

16) N-{4-[8-chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide;

17) N-{4-[8-the ENT-6-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide;

18) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxy-N-methylbenzamide;

19) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethyl-2-hydroxybenzamide;

20) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)-2-hydroxybenzamide;

21) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoyl]guanidine;

22) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

23) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

24) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

25) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pentanolide;

26) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

27) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

28) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopropanecarboxamide;

29) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclobutanecarboxylic;

30) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopentanecarboxylic;

31) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

32) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrothieno the-4-yl)phenyl]-1-acetylpiperidine-4-carboxamide;

33) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

34) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acanalonia;

36) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

37) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] propionamide;

38) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] butyramide;

39) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pentanolide;

40) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

42) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopropanecarboxamide;

43) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclobutanecarboxylic;

44) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopentanecarboxylic;

45) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

46) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-acetylpiperidine-4-carboxamide;

47) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahedrite inolin-4-yl)phenyl]nicotinamide;

48) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acanalonia;

50) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

51) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] propionamide;

52) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

53) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pentanolide;

54) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

55) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

56) N-[2-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopropanecarboxamide;

57) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclobutanecarboxylic;

58) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopentanecarboxylic;

59) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

60) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-acetylpiperidine-4-carboxamide;

61) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

62) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro the isoquinoline-4-yl)phenyl]acanalonia;

63) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

64) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

65) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

66) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

67) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

68) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

69) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

70) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]1,2-dimethyl-1H-imidazol-4-sulfonamida;

71) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]1,2-dimethyl-1H-imidazol-4-sulfonamida;

72) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamida;

73) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamida;

74) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-bromothiophene-2-sulfonamida;

75) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-5-bromothiophene-2-sulfonamida;

7) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

77) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

78) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-cryptgethashparam;

79) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-cryptgethashparam;

80) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

81) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

82) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

83) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

84) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

85) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

86) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]hexanamide;

87) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-pyrrolidin-2-carboxamide;

88) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

89) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrrole-3-carboxamide;

90) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrrole-2-carboxamide;

91) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]1-methylpiperidin-4-carboxamide;

92) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,4-dimethyl-1H-pyrrole-2-carboxamide;

93) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-nitro-1H-pyrrole-2-carboxamide;

94) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide;

95) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-imidazole-4-carboxamide;

96) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methanesulfonamido-4-carboxamide;

97) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethyl-1H-pyrazole-4-carboxamide;

98) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrazole-4-carboxamide;

99) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-trifluoromethyl-1H-pyrazole-4-carboxamide;

100) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

101) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

102) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

103) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

104) 2,6-diamino-N-[3(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]hexanamide;

105) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] pyrrolidin-2-carboxamide;

106) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

107) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrrole-3-carboxamide;

108) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrrole-2-carboxamide;

109) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylpiperidin-4-carboxamide;

110) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,4-dimethyl-1H-pyrrole-2-carboxamide;

111) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-nitro-1H-pyrrole-2-carboxamide;

112) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxamide;

113) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-imidazole-4-carboxamide;

114) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methanesulfonamido-4-carboxamide;

115) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethyl-1H-pyrazole-4-carboxamide;

116) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrazole-4-carboxamide;

117) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-trifluoromethyl-1H-pyrazole-4-carboxamide;

118) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

119) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

120) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

121) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

122) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]4-methylpiperazin-1-carboxamide;

123) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-piperidine-1-carboxamide;

124) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-morpholine-4-carboxamide;

125) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-1-carboxamide;

126) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

127) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

128) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

129) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

130) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

131) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-metile ridin-4-yl)urea;

132) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamate;

133) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimethylaminoethyl)-1-methylcarbamate;

134) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

135) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

136) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-methylpiperazin-1-carboxamide;

137) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

138) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

139) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

140) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-piperidin-1-carboxamide;

141) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-morpholine-4-carboxamide;

142) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-pyrrolidin-1-carboxamide;

143) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

144) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-methylpiperazin-1-carboxamide;

145) N-[4-(6,8-dichloro-2-IU the Il-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-pyrrolidin-1-carboxamide;

146) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

147) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

148) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

149) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

150) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-piperidine-1-carboxamide;

151) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-morpholine-4-carboxamide;

152) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

153) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

154) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methyl-4-methylpiperazin-1-carboxamide;

155) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylsilane;

156) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylpiperidin-1-carboxamide;

157) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylmorpholin-4-carboxamide;

158) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylpyrrolidine-1-carboxamide;

159) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethy aminoethyl)-1-methylcarbamate;

160) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamate;

161) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

162) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylpyrrolidine-1-carboxamide;

163) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylpiperidin-1-carboxamide;

164) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

165) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

166) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylmorpholin-4-carboxamide;

167) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methyl-4-methylpiperazin-1-carboxamide;

168) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

169) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamate;

170) 2-dimethylaminoethyl[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

171) 2-dimethylaminoethyl[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

172) 2-dimethylaminoethyl[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

173) methyl[3-(6,8-dichloro-2-methyl-1,2,3,4-is tetrahydroisoquinoline-4-yl)phenyl]carbamate;

174) ethyl[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

175) isopropyl[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

176) 2,2-dimethylpropyl[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

177) methyl[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

178) isopropyl[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

179) 2.2-dimethylpropyl[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

180) ethyl[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

181) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

182) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

183) (R)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

184) (S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

185) N-[3-(6,8-debtor-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

and their pharmaceutically acceptable salts.

3. The compound of formula (I) according to claim 1, selected from the group consisting of

1) N-[4-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

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

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

6) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

7) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

8) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

9) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-acetylpiperidine-4-carboxamide;

10) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

11) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acanalonia;

12) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

13) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

14) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

16) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids is;

17) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-cyclobutanecarboxylic;

18) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

19) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-acetylpiperidine-4-carboxamide;

20) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

21) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

22) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]acanalonia;

23) N',N'-dimethylamino-H-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

24) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]cyclopropanecarboxamide;

25) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-acetylpiperidine-4-carboxamide;

26) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

27) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

28) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

29) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

30) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,2-dimethyl-1H-imidazol-4-sulfonamida;

32) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

33) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

34) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

36) 2,6-diamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]hexanamide;

37) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrrole-3-carboxamide;

38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylpiperidin-4-carboxamide;

39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methanesulfonamido-4-carboxamide

40) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrazolecarboxylate;

41) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

42) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

43) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

44) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro skinoren-4-yl)phenyl]butyramide;

45) 2,6-diamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]hexanamide;

46) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methylpiperidin-4-carboxamide;

47) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-imidazole-4-carboxamide;

48) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methanesulfonamido-4-carboxamide;

49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] - for 3,5-dimethyl-1H-pyrazole-4-carboxamide;

50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1H-pyrazolecarboxylate;

51) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-methylpiperazin-1-carboxamide;

53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]piperidine-1-carboxamide;

54) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-4-carboxamide;

55) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]pyrrolidin-1-carboxamide;

56) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

57) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

58) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline--yl)phenyl]-3-(2-dimethylaminoethyl)urea;

59) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

60) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

62) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamate;

63) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimethylaminoethyl)-1-methylcarbamate;

64) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-diethylaminopropyl)urea;

65) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-methylpiperazin-1-carboxyamide;

67) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

68) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

69) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-4-methylpiperazin-1-carboxyamide;

70) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

71) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

7) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

73) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

74) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]morpholine-4-carboxamide;

75) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

76) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

78) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

79) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylmorpholin-4-carboxamide;

80) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methyl-4-methylpiperazin-1-carboxamide;

81) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

82) 2-dimethylaminoethyl[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

83) 2-dimethylaminoethyl[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

84) 2-dimethylaminoethyl[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

85) methyl[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamate;

86) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]meanswhen the foreign Ministry;

87) (R or S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

88) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

and their pharmaceutically acceptable salts.

4. The use of the compounds of formula (I)and its pharmaceutically acceptable salts to obtain drugs for the treatment of diseases which can be influenced by inhibiting the sodium-proton exchange subtype III (NHE3).

5. The use according to claim 4, characterized in that the applied compounds of formula (I) selected from the group consisting of

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N,N-dimethylbenzenesulfonamide;

5) 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethylbenzamide;

8) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzamide;

9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylamino the Teal)benzamide;

10) 6,8-dichloro-2-methyl-4-(4-(morpholine-4-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

11) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]diethylamine;

12) 6,8-dichloro-2-methyl-4-(4-piperidine-1-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

13) 6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

14) 6,8-dichloro-2-methyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline;

15) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

16) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

17) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-propylbromide;

18) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

19) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

20) N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

21) N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

22) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

23) N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

24) N-[4-(8-chloro-2-methyl-6-morpholine-4-yl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

25) N-{4-[8-chloro-2-methyl-6-(4-methylpiperazin-1-yl)-1,2,3,4-Tetra Koskinen-4-yl]phenyl}ndimethylacetamide;

26) N-{4-[8-chloro-6-(cyclopropylamino)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl}ndimethylacetamide;

27) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid;

28) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxy-N-methylbenzamide;

29) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-ethyl-2-hydroxybenzamide;

30) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)-2-hydroxybenzamide;

31) N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoyl]guanidine;

32) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

33) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

34) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

35) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

36) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

37) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

38) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

39) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

40) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclepro inkarbaeva acid;

41) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

42) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

43) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

44) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

46) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

47) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

48) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

49) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

50) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

51) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide;

53) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

54) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl to the slots;

55) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

56) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

57) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

58) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

59) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

60) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

61) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] amide of econsultation;

62) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

63) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

64) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

65) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pentanol acids;

66) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] isobutyramide;

67) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2-dimethylpropanamide;

68) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl the acid;

69) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

70) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopentanecarbonyl acids;

71) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

72) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

73) N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

74) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

75) N',N'-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

78) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

80) N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

81) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

82) [4-(6,8-dichloro-2-methyl-1,2,3,4-then it is carbonated shall raiskinen-4-yl)phenyl]amide 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

83) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

84) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acids;

85) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acids;

86) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-bromothiophene-2-sulfonic acids;

87) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 5-bromothiophene-2-sulfonic acids;

88) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

90) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,2,2-cryptgetuserkey;

91) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,2,2-cryptgetuserkey;

92) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

93) 2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

94) 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

95) 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

96) 4-(8-amino-2-methyl-1,2,3,4-Tetra is hydroisoquinoline-4-yl)phenol;

97) 8-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

98) 2-(8-amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenol;

99) 2-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenol;

100) 5-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)2-methoxyphenol;

101) 2-methyl-8-nitro-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

102) 4-(8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzene-1,2-diol;

103) 2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

104) 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

105) 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

106) 4-(2,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

107) 4-(3-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

109) 2-butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-8-ylamine;

110) N-(2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ndimethylacetamide;

111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

115) 6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

117) 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

118) 6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

119) 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

120) 2-methyl-4-phenyl-6,8-bistritei-1,2,3,4-tetrahydroisoquinoline;

121) 6,8-dichloro-2-isopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

122) 5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

123) 6,8-dichloro-4-(4-forfinal)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

124) 6,8-dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline;

125) 5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

126) of 6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

128) 6,8-dichloro-4-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

129) 6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;

130) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] ndimethylacetamide;

131) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

132) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

133) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

134) 2-amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)Fe is Il]butyramide;

135) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

136) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-2-carboxylic acid;

137) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

138) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

139) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-2-carboxylic acid;

140) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

141) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,4-dimethyl-1H-pyrrole-2-carboxylic acid;

142) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-nitro-1H-pyrrole-2-carboxylic acid;

143) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,5-dimethyl-1H-pyrrole-3-carboxylic acid;

144) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

145) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

146) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

p num="2309"> 147) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

148) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;

149) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

150) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

151) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

152) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

153) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

154) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-2-carboxylic acid;

155) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isonicotinamide;

156) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

157) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-2-carboxylic acid;

158) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

159) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1,4-dimethyl-1H-pyrrole-2-carboxylic to the slots;

160) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-nitro-1H-pyrrole-2-carboxylic acid;

161) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 2,5-dimethyl-1H-pyrrole-3-carboxylic acid;

162) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

163) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

164) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

165) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

166) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;

167) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

168) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

169) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylthiourea;

170) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

171) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

172) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetr hydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

173) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

174) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

175) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

176) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

177) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

178) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

179) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

180) 3-[3 -(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

181) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamate;

182) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimethylaminoethyl)-1-methylcarbamate;

183) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

184) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

185) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-3-yl is carbamide;

186) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-4-ylcarbamate;

187) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

188) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

189) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

190) 3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

191) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

192) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

193) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

194) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

195) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

196) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

197) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

198) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

199) 3-[4-(6,8-d is chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

200) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

201) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

202) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

203) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

204) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

205) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

206) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

207) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

208) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide piperidine-1-carboxylic acid;

209) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

210) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide pyrrolidin-1-carboxylic acid;

211) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

212) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-metalcarbon is Yes;

213) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

214) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

215) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide pyrrolidin-1-carboxylic acid;

216) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide piperidine-1-carboxylic acid;

217) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

218) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

219) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

220) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

221) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

222) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3,3-diethyl-1-methylcarbamate;

223) 2-dimethylaminoethanol ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

224) 2-dimethylaminoethanol ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

225) 2-dimethylaminoethanol ether [2-(6,8-dichloro-2-methyl-1,2,3,tetrahydroisoquinoline-4-yl)phenyl]carbamino acid;

226) methyl ester[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

227) ethyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

228) isopropyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

229) 2,2-dimethylpropyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

230) methyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

231) isopropyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

232) 2,2-dimethylpropyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

233) ethyl ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

234) (R)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

235) (S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

236) (R)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

237) (S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

238) N-[3-(6,8-debtor-2-methyl-1,2,3,4-tetrahydrothieno the-4-yl)phenyl]ndimethylacetamide;

239) 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;

240) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

241) ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

242) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

and their pharmaceutically acceptable salts.

6. The use according to claim 4, characterized in that the applied compounds of formula (I)selected from the group consisting of

1) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl] ndimethylacetamide;

2) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

3) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

4) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

5) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-]-N-ethylbenzamide;

6) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-propylbenzamide;

7) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)benzamide;

8) 6,8-dichloro-2-methyl-4-(4-(morpholine-4-ylphenyl)-1,2,3,4-tetrahydroisoquinoline;

9) 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

10) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)Hairdryer is l]-3-methylthiocarbamate;

11) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

12) N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

13) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-hydroxybenzoic acid;

14) 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(2-dimethylaminoethyl)-2-hydroxybenzamide;

15) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]ndimethylacetamide;

16) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

17) 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamine;

18) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

19) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

20) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

21) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

22) N',N'-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

23) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

24) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

25) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]isobutyramide is;

26) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

27) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclobutanecarbonyl acids;

28) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2,2,2-trifurcated;

29) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

30) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]nicotinamide;

31) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

32) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of econsultation;

33) N',N'-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulphonamide;

34) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide cyclopropanecarbonyl acids;

35) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-acetylpiperidine-4-carboxylic acid;

36) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

37) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylthiocarbamate;

38) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

39) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroit the nolin-4-yl)phenyl]-3-methylthiocarbamate;

40) N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonyl]-4-methylthiazole-2-yl}ndimethylacetamide;

41) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-phenyl]amide 1,2-dimethyl-1H-imidazole-4-sulfonic acids;

42) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

43) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-C,C,C-triftoratsetofenona;

44) N-ethyl-N'-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzosulfimide;

45) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-dimethylaminoacetyl;

46) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

47) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrrole-3-carboxylic acid;

48) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

49) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

50) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

51) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-2-methylaminoacetaldehyde;

52) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrothieno the-4-yl)phenyl]-2-dimethylaminoacetyl;

53) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]propionamide;

54) 2-amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]butyramide;

55) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 2,6-diaminohexanoic acids;

56) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methylpiperidin-4-carboxylic acid;

57) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-imidazole-4-carboxylic acid;

58) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 1-methanesulfonamido-4-carboxylic acid;

59) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;

60) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide of 1H-pyrazole-4-carboxylic acid;

61) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

62) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

63) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide piperidine-1-carboxylic acid;

64) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

65) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydrothieno is n-4-yl)phenyl]amide pyrrolidin-1-carboxylic acid;

66) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

67) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

68) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

69) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydrofuran-3-yl)urea;

70) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(tetrahydropyran-4-yl)urea;

71) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-methyl-1-(1-methylpiperidin-4-yl)urea;

72) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(3-dimethylaminopropyl)-1-methylcarbamate;

73) 3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1-(2-dimethylaminoethyl)-1-methylcarbamate;

74) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(3-dimethylaminopropyl)urea;

75) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-methoxyethyl)urea;

76) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-3-ylcarbamate;

77) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-pyridin-4-ylcarbamate;

78) [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

79) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

80) 1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

81) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide 4-methylpiperazin-1-carboxylic acid;

82) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-methylcarbamate;

83) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-dimethylcarbamate;

84) 3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,1-diethylcarbamyl;

85) 1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)urea;

86) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]amide morpholine-4-carboxylic acid;

87) N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

88) [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

89) N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]formamide;

90) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamine;

91) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3,3-trimethylbutyramide;

92) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-1,3-dimethylcarbamate;

93) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro the quinoline-4-yl)phenyl]methylamide morpholine-4-carboxylic acid;

94) [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methylamide 4-methylpiperazin-1-carboxylic acid;

95) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-dimethylaminoethyl)-1-methylcarbamate;

96) 2-dimethylaminoethanol ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

97) 2-dimethylaminoethanol ester [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

98) 2-dimethylaminoethanol ether [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

99) methyl ester [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]carbamino acids;

100) (R or S)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]methanesulfonamide;

101) (R or S)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-ethylcarbamate;

102) 1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]-3-(2-hydroxyethyl)urea;

103) ethyl ester of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzoic acid;

104) 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)benzoic acid;

and their pharmaceutically acceptable salts.

7. The use of the compounds of formula (I) according to claim 4 to obtain drugs for the treatment of the Oia or the prevention of disorders of the respiratory pulse.

8. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prophylaxis of respiratory disorders, in particular caused by sleep breathing disorders, such as stopping of breathing during sleep.

9. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prevention of snoring.

10. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prevention of acute and chronic kidney diseases, especially acute renal failure and chronic renal failure.

11. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prevention of disorders of bowel function.

12. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prevention of disorders of biliary function.

13. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and stroke.

14. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

15. The use of the compounds of formula (I) according to claim 4 to obtain the drug with the estva for the treatment of shock.

16. The use of the compounds of formula (I) according to claim 4 to obtain drugs for use in surgical operations and organ transplants.

17. The use of the compounds of formula (I) according to claim 4 to obtain medicines for preservation and storage of transplants for surgical measures.

18. The use of the compounds of formula (I) according to claim 4 to obtain drugs for the treatment of diseases, primary or secondary cause of which is cell proliferation.

19. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prevention of disorders of lipid metabolism.

20. The use of the compounds of formula (I) according to claim 4 to obtain drugs for treatment or prevention of lesions parasites.

21. The drug, which is the inhibitor of sodium-proton exchange subtype III (NHE3), containing an effective amount of the compounds of formula (I) according to claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes novel derivatives of thiazole that able for effective binding and activating PPARα and/or PPARγ simultaneously and, respectively, combine antiglycemic effect caused by activation of PPARγ with anti-dyslipidemic effect caused by activation of PPARα. Also, the claim describes compounds of the formula (I): wherein substitutes from R1 to R10 as well as X and Y are determined in the description and invention claim, and their pharmaceutically acceptable salts and esters also. Also, the proposed invention describes pharmaceutical compositions possessing antagonistic activity with respect to PPARα and/or PPARγ comprising compound of the formula (I) as an active component and pharmaceutically acceptable carrier and/or additive. Except for, the invention proposes claimed compounds as therapeutically active substances for treatment and/or prophylaxis of diseases mediated by agonists of PPARα and/or PPARγ, such as diabetes mellitus, non-insulin dependent diabetes mellitus, elevated blood pressure, increased level of lipids and cholesterol, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, ovary polycystic syndrome, inflammatory or proliferative diseases.

EFFECT: valuable medicinal properties of compounds.

27 cl, 140 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzothiazole of the general formula (I): and their pharmaceutically acceptable acid-additive salts used as ligands of adenosine receptors and to a medicinal agent based on thereof. In compound of the general formula (I) R means phenyl, pyridine-2-yl, -C(O)-O-(lower)-alkyl, -C(O)-(lower)-alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2 or -(CH2)n-O-(lower)-alkyl; R' means hydrogen atom or (lower)-alkyl. Compounds can be used in treatment and prophylaxis of diseases mediated by adenosine receptors A2A and A1, for example, in Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 sch, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to using compounds represented by the general formula (II): wherein Ra and Rb are chosen independently from hydrogen atom, alkyl, cycloalkyl, aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)n-aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)nC(O)OR3; Z is chosen independently from -C(R3)(R4)-; R3 and R4 are chosen independently from hydrogen atom, alkyl and 6-membered cycle with nitrogen atom as a heteroatom; n has values 0, 1 or 2; X and Y are chosen independently from =O, =S and =N(R3). These compounds are active component in preparing a pharmaceutical composition designated in treatment of diseases wherein glycogen synthase-kinase 3-beta (GSK-3) is involved. Also, invention relates to compounds represented by the general formula (II) wherein Ra is chosen from -CH2Ph, -CH2CO2Et, 4-OMePh, 4-MePh and 4-BrPh; Rb is chosen from Me and -CH2CO2Et; X and Y represent =O. Also, invention relates to a pharmaceutical composition possessing GSK-3-inhibitory activity and containing compound of the general formula (II) as an active component. Invention provides using heterocyclic inhibitors of glycogen synthase-kinase-3β.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

17 cl, 5 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, technology of organic compounds.

SUBSTANCE: invention relates to heterocyclic o-dicarbonitriles. Invention describes heterocyclic o-dicarbonitriles of the general formula: wherein R means the following compounds: . Heterocyclic o-dicarbonitriles can be used for preparing hexazocyclanes-fluorophores as a donor-fragment used for preparing hexazocyclanes-bifluorophores and hexazocyclanes-trifluorophores. Invention provides preparing new compounds possessing valuable properties.

EFFECT: valuable properties of compounds.

2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to a derivative of 1,2,4-thiadiazole, substituted in the 5-position of General formula I, in which X Is N; R1- C1-6alkyl; R2is hydrogen, R3, R4and R5each independently selected from hydrogen; trifloromethyl;is Ar2, Ar2CH2or Het2; AG2is phenyl; Het2is a monocyclic heterocycle selected from thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl, their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

Up!