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(11) Patent Number: KE 397   

(45) Date of grant: 15/07/2010   

(73) Owner:    SANOFI AVENTIS of,  174AvenueDeFrance, F-75013 Paris,France   
                   
(21)  Application Number:2007/ 00061l       

(72) Inventor:    HOFMEISTER. Armin; HEINELT, Uwe; WIRTH, Klaus; LANG,Hans-Jochen and LICHER. Thomas   
                               
(22) Filing Date:06/07/2007           
                   
(74) Agent/address for correspondence:    Kaplan& Stratton Advocates,  , P.O. Box40111-00100, Nairobi
                   
(30) Priority data:10l00l001411.9  12/01/200l  DE                               
           
(86) PCT data    PCT/EP200l/0141    30/12/200lwo 2006/074813    20/07/2006                                       

(54)  Title: SUBSTI11JTED 4-PHENYL TETRAHYDROISOQUINOL!NES, METHODS FOR PRODUCING THEM, THEIR USE AS DRUG, AND DRUG CONTAINING THEM.

(57) Abstract: The invention relates to the compounds of formula Q), wherein Rl to R8, W, X and Z are defined as in the claims. Drugs that contain compounds of this type are suitable for use in the prevention or treatment of various diseases. The inventive compounds can be used, inter alia, for renal diseases such as acute or chronic renal failure, for biliary dysfunction and for respinrtory disorders such as snoring or sleep apnoea
 
SUBSTITUTED 4-PHENYL TETRAHYDROISOQUINOLINES, METHODS FOR PRODUCING THEM, THEIR USE AS DRUG, AND DRUG CONTAINING THEM

The invention relates to substituted 4-phenyltetrahydroisoquinolines. Medicaments

which comprise compounds of this type are useful in the prevention or treatment of various disorders. For instance, the compounds can be used, inter alia, in the event of renal disorders such as acute or chronic kidney failure, in the event of disorders of biliary function and in the event of respiratory disorders such as snoring or sleep

10    apneas.

The invention relates to compounds of the formula I
R2

R3

R4

in which:

15    R1,R2,R3andR4

are each independently hydrogen, F, Cl, Br, I, CN, N02 or R11-(CmH2mrAn-;

    m    is zero, 1, 2, 3 or4;
        is zero or 1;   
    R11    is hydrogen, methyl or CpF2p+1;
20    A    is oxygen, NH, N(CH3) or S(O)q;
        p    is1,2or3;
        q    is zero, 1 or 2;

R5    is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3,

4, 5 or 6 carbon atoms;

25    R6    is hydrogen, OH, F, CF3, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl

having 3, 4, 5 or 6 carbon atoms;

R7 and RB

are each independently hydrugen, F, Cl, Br, CN, C02R12, NR13R14 or R16-(CmmH2mm>-Bnn-;

R12    is hydrugen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

R13 and R14

are each independently hydrogen, alkyl having 1, 2, 3 or 4

carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms:

or

R13 and R14,

with the nitrogen atom to which they are bonded; fonm a 4-, 5-, 6- or 7-membered ring in which one CH2 group may be replaced by NR15, S or oxygen;

R15 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4,
5 or 6 carbon atoms;

qq    is zero, 1 or 2;
w    is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced by NR17, oxygen or S;
R17 is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
is 1, 2, 3, 4, 5, 6, 7 or B; is 2, 3, 4, 5, 6, 7 or B;
X    is -C(O)- or -S(0)2-;

Z    is -C(O)- or a bond;

and also their pharmaceutically acceptable salts and trifluoroacetates.

In one embodiment, preference is given to compounds of the formula I in which

R1, R2, R3 and R4

are each independently hydrogen, F, Cl, Br, CN or R11-(CmHzml-An-;

    m    is zero or 1;
        is zero or 1;
    R11    is hydrogen, methyl or CpF2p+1;
10    A    is oxygen, NCH3 or S(O)q;
        p    is 1 or2;
            is zero, 1 or 2;

R5    is hydrogen, methyl, ethyl or cyclopropyl;

R6    is hydrogen or methyl;

15    R7 and RS

are each independently hydrogen, F, Cl, CN, C02R12, NR13R14 or R 16-(CmmH2mml-Bnn-;
R12    is hydrogen, methyl or ethyl;
R13 and R14
20    are each independently hydrogen, alkyl having 1, 2, 3 or 4
    carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

with the nitrogen atom to which they are bonded, fonm a 5-, 6- or 7-membered ring in which one CH2 group may be replaced by NR15, S or oxygen;

R15    "15 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon
atoms;

R16    is hydrogen, methyl or CppF2pp+1;

B    is oxygen or S(O)qq;

pp    is 1 or 2;

qq    is zero, 1 or 2;

is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced by NR17, oxygen or S;

R17 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
is 2, 3, 4, 5, 6, 7 or 8; is 2, 3, 4, 5, 6, 7 or 8;
 
X    is -C(O)- or -S(0)2-;

Z    is-C(O)-;

and also their pharmaceutically acceptable salts and trifluoroacetates.

15

Particular preference is given to compounds of the formula I in which

R1 and R3

are each hydrogen;

R2 and R4

20    are each independently hydrogen, F, Cl, Br, NH2. NHCH3 or N(CH3)2;

R5    is hydrogen, methyl, ethyl or cyclopropyl;

R6    is hydrogen or methyl;

R7 and R8

are each hydrogen;

25    w   is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced

by NR17, oxygen or S;

R17  is hydrogen or methyl;

is 2, 3, 4, 5 or 6;

30    is 2, 3, 4, 5 or 6;

X    is -C(O)- or -S(0)2-;
 





5

Z    is-C(O)-;

and also their pharmaceutically acceptable salts and tr~luoroacetates.

In a further embodiment, preference is given to compounds of the formula I in which R1 and R3

are each hydrogen;

R2 and R4

are each independently hydrogen, F, Cl, NH2, NHCH3 or N(CH3)2; R5 is hydrogen, methyl, ethyl or cyclopropyl;
10    R6 is hydrogen or methyl;

R7 and R8

are each hydrogen;

W is CrH2r or CsH2s-2:

where one or more CH2 groups in CrH2r and C8 H2s-2 may be replaced
 

15



X

20    z
 

by NR17, oxygen or S;

R17    is hydrogen or methyl; is 2, 3, 4, 5 or 6;

is 2, 3, 4, 5 or 6;

is -C(O)- or -S(0)2-; is-C(O)-;
 
and also their pharmaceutically acceptable salts and trifluoroacetates.

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

1-[2-(8-bromo-6-chloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

25    2,5-dione,

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

imidazolidine-2,4-dione

30    3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidine-2,4-dione
 






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

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

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

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

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

10    3,5-dione, 3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}oxazolidine-2,4-dione, 3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]thiazolidine-

2,4-dione,

15    1-[2-((R)-6,8-dichloro-2-ctclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}-pyrrolidine-2,5-dione,

(S)-1-[2-( (R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}-3-methyl-piperidine-2,6-dione,

(R)-1-[2-( (R)-6,8-dichloro-2-methyl-1 ,2, 3,4-tetrahydroisoquinolin-4-yl)phenyl}-3-methyl-

20    piperidine-2,6-dione, 1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}-3,5-dimethyl-piperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}-3-methyl-

pyrrolidine-2,5-dione,

25    1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}-3,3-dimethyl-pyrrolidine-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4;YI)phenyl]pyrrolidine-2,5-dione, 1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}piperidine-2,6-

30    diane,

1-[4-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl}pyrrolidine-2,5-dione,
 






1-[4-(6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]pyrralidine-2,5-

dione,

1-[2-((R)-6,8-dichlara-2-methyl-1 ,2,3,4-tetrahydroisaquinalin-4-yl)phenyl]piperidine-2,6-

dione,

1-[2-(6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]piperidine-2,6-

dione,

1-[3-((S)-6,8-dichlaro-2-methyl-1 ,2 ,3,4-tetrahydroisaquinalin-4-yl)phenyl]pyrrale-2,5-

dione,

1-[2-(6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydroisaquinalin-4-yl)phenyl] pyrralidine-2,5-

10    diane,

1-[2-((R)-6,8-dichlara-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]pyrralidine-2,5-diane,
3-[2-((R)-6,8-dichlara-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]imidazalidine-

2,4-diane,

15    3-[2-(6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]imidazalidine-2,4-dione,
3-[3-((S)-6,8-dichlara-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]imidazalidine-

2,4-diane,

3-[4-((S)-6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]imidazalidine-

20    2,4-diane,

3-[4-(6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydroisaquinalin-4-yl)phenyl]imidazalidine-2,4-dione,
3-[2-((R)-6,8-dichlaro-2-cyclaprapyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]-

oxazolidine-2,4-dione,

25    3-[2-((R)-6,8-<Jichlaro-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]-5-methyl-imidazalidine-2,4-diane,

(3R,4S )-1-[2-( (R)-6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydraisaquinalin-4-yl)phenyl]-3,4-dimethylpyrralidine-2,5-diane,

1-[4-((S)-6,8-dichlaro-2-methyl-1 ,2,3,4-tetrahydroisaquinalin-4-yl)phenyl]-pyrrale-2,5-

10    diane,

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

evaporator, and the aqueous residue was neutralized with saturated sodium

hydrogencarbonate solution and extracted three times with ethyl acetate. After the

combined ethyl acetate phases had been dried over magnesium sulfate, the mixture

was fittered and concentrated to dryness. 1.5 g of the desired product were obtained.

5    LC-MS Rt (B): 1.07 min; [M+H+j: 409.0

d) N-(2-{2-[(2-Bromo-4-chlorobenzyl)methylamino]-1-hydroxyethyl)phenyl)acetamide

"If)  ~Xl-

~ OH Br

10    N-(2-{2-[(2-Bromo-4-chlorobenzyl)methylamino]acetyl)phenyl)acetamide (1.5 g) was initially charged in methanol (45 ml) and cooled to ooc with an ice bath. After sodium borohydride (266 mg) had been introduced in portions, the mixture was allowed to come to room temperature and then stirred further for 2 h. The solvent was removed

and the residue admixed with ethyl acetate/water and extracted three times with ethyl

15    acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 1.44 g of the title compound were obtained.
LC-MS Rt (B): 0.94 min; [M+H+]: 411.0

20    e) 1-(2-Aminophenyl)-2-[(2-bromo-4-chlorobenzyl)methylamino]ethanol

a~(('",

Br

N-(2-{2-[(2-Bromo-4-chlorobenzyl)methylamino]-1-hydroxyethyl)phenyl)acetamide

(1.4 g) was dissolved in absolute methanol (50 ml) and admixed with sodium
methoxide solution (3.5 ml) and heated to reflux for 8 h. After sodium methoxide solution had been added again (1.5 ml), the mixture was heated to reflux for a further 4 h. The reaction mixture was added to ice-water and extracted three limes with ethyl

acetate, and the combined organic phases were dried over magnesium sulfate, filtered

5    and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed or\ a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined

ethyl acetate phases had been dried over magnesium sulfate, they were filtered and

1o concentrated to dryness. 801 mg of the title compound were obtained. LC-MS Rt (B): 0.92 min;

[M+H+j: 369.0

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

~~

Br
15

1-(2-Aminophenyl)-2-[{2-bromo-4-chlorobenzyl)methylamino]ethanol (BOO mg) was dissolved in dichloromethane (1 ml) and admixed with concentrated su~uric acid (8 ml) with ice cooling. Subsequently, the mixture was stirred at 60"C for 7 h. For workup, the
reaction mixture was added to ice-water, alkalized with 10 N sodium hydroxide solution

20    and washed three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The tractions oomprising product were combined, the acetonitrile

was removed on a rotary evaporator, and the aqueous residue was neutralized with

saturated sodium hydrngencarbonate solution and extracted three times with ethyl

25    acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. 438 mg of the desired compound were obtained.
 





101

LC-MS Rt (B): 1.03 min; [M+W]: 351.0

g) 1-[2-(8-Bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

5    pyrrolidine-2,5-dione hydrochloride

2-(8-Bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (60 mg) was admixed with succinic acid (22 mg) and reacted in polyphosphoric acid analogously to example 7. 47 mg of the title compound were obtained.

10    LC-MS Rt (B): 1.04 min; [M+W]: 433.0

Example 64: 1-[2-(8-Bromo-6-chloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl}-phenyl]pyrrolidin-2-one


Cl

Br
15

Analogously to example 36, 2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (80 mg) was reacted with 4-<:hlorobutyryl chloride (35 mg) and the resulting amide was subsequently ring-<:losed with potassium carbonate in DMSO.

20    LC-MS Rt (B): 1.05 min; [M+H+:\: 419.0

Pharmacological data:

25    Test description:

In this test, the recovery in the intracellular pH (pH;) of LAP1 cells, which stably
 

express the sodium-proton exchanger subtype 3 (NHE3), after an acidification was

determined. This recovery sets in even under bicarbonate-free conditions in the case

offunctioning NHE3. To this end, the pH; was determined with the pH-sensitive

fluorescent dye BCECF (Molecular Probes, Eugene, OR, USA; the precursor

5    BCECF-AM is used). The cells were first incubated with BCECF (5 pM BCECF-AM) in NH4Cl buffer (NH4Cl buffer: 115 mM cholineCI, 20 mM NH4CI, 5 mM KCI, 1 mM CaCI2, 1 mM MgCI2. 20 mM Hepes, 5 mM glucose; a pH of 7.4 is established with 1 M

KOH). The intracellular acid~ication was induced by washing the cells incubated in
NH4CI buffer with NH4CI-free buffer (133.8 mM choline chloride, 4.7 mM KCI, 1.25 mM

10    CaCI2,1.25 mM MgCI2. 0.97 mM K2HP04, 023 mM KH2P04, 5 mM Hepes, 5 mM glucose; a pH of 7.4 is established with 1 M KOH). After the washing operation, 90 pi of the NH4CI-free buffer were Iefton the cells. The pH recovery was started by the

addition of 90 pi of Na+-containing buffer (133.8 mM NaCI, 4.7 mM KCI, 1.25 mM CaCI2, 125 mM MgCI2. 0.97 mM Na2HP04, 0.23 mM NaH2P04, 10 mM Hepes,

15    5 mM glucose; a pH of 7.4 is established with 1M NaOH) in the analytical instrument (FLIPR, "Fiuorometric Imaging Plate Reader", Molecular Devices, Sunnyvale, Ca., USA). The BCECF fluorescence was determined at an excitation wavelength of
498 nm and the FLIPR emission filter 1 (band gap from 510 to 570 nm). The

subsequent changes in fluorescence were registered for two minutes as a measure of

20    the pH recovery. For the calculation of the NHE3-inhb~ory potential of the tested substances, the cells were tested first in buffers in which full pH recovery, or none at all, took place. For full pH recovery (100%), the cells were incubated in Na•-containing buffer (see above), and Na+-free buffer for the determination of the 0% value (see

above). The substances to be tested were made up in Na+-containing buffer. The

25    recovery in the intracellular pH at each tested concentration of a substance was expressed in percent of the maximum recovery. From the percentages of the pH recovery, the IC5o value of the particular substance for the NHE3 was calculated by means of the program XL Fit (idbs, Surrey, UK).

30    The inhibitory action (IC50 values) of various example compounds on the NHE3 is
 

What is claimed is:

1.    A compound of the formula I




R2

R3

R4

in which:

R1, R2, R3 and R4

are each independently hydrogen, F, Cl, Br, I, CN, NOz or R11-(CmH2m)-An-;

m    is zero, 1, 2, 3 or4; is zero or 1;

10    R11 is hydrogen, methyl or CpF2p+1; A is oxygen, NH, N(CH3) or S(O)q;

is 1, 2 or3;

q    is zero, 1 or 2;

R5 is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cyc\oa\ky! having 3, 15 4, 5 or 6 carbon atoms;

R6 is hydrogen, OH, F, CF3, alkyl having 1, 2, 3 or 4 carbon atoms or cycloa\ky\ having 3, 4, 5 or 6 carbon atoms;
R7 and RB

are each independently hydrogen, F, CJ, Br, CN, COzR12, NR13R14 or 20 R16-(CmmH2mml-Bnn•;
R12 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloa\ky\ having 3, 4, 5 or 6 carbon atoms;
R13 and R14

are each independently hydrogen, alkyl having 1, 2, 3 or4
 











5




10




15




20
 






106

carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

or

R13 and R14,

with the nitrogen atom to which they are bonded, form a 4-,

5-, 6- or 7-membered ring in which one CH2 group may be replaced by NR15, S or oxygen;
R15    is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms or cycloalkyl having 3, 4,
5 or 6 carbon atoms;

mm    is zero, 1, 2, 3 or 4;

nn    iszeroor1;

R16    is hydrogen, methyl or CppF2pp+1;

B    is oxygen or S(O)qq;

pp    is 1, 2 or 3;

qq    is zero, 1 or 2;

W    is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced by NR17, oxygen or S;

R17 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

is 1, 2, 3, 4, 5, 6, 7 orB; is 2, 3, 4, 5, 6, 7 or 8;
 

X    is -C(O)- or -S(0)2-;
Z    is -C(O)- or a bond;

25    and also its phallllaceuticatly acceptable salts and trifluoroacetates.

2. A compound of the formula I as claimed in claim 1 in which R1, R2, R3 and R4
are each independently hydrogen, F, Cl, Br, CN or R11-(CmH2mrAn-;
30    m    is zero or 1;

is zero or 1;
 





107

R11    is hydrogen, methyl or CpF2p+1;

A    is oxygen, NCH3 or S(O)q;

p    is 1 or2;

q    is zero, 1 or 2;

5    R5    is hydrogen, methyl, ethyl or cyclopropyl;

R6 is hydrogen or methyl;

R7 and RB

are each independently hydrogen, F, Cl, CN, C02R12, NR13R14 or
 

10




15




20




25
 

R16-(CmmH2mml-Bnn-;

R12    is hydrogen, methyl or ethyl;

R13 and R14

are each independently hydrogen, alkyl having 1, 2, 3 or 4

carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

or

R13 and R14,

with the nttrogen atom to which they are bonded, form a 5-, 6- or 7-membered ring in which one CH2 group may be replaced by NR15, S or oxygen;

R15    is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon

atoms;

mm    is zero, 1 or 2;

nn    is zero or 1;

R16    is hydrogen, methyl or CppF2pp+1;

B    is oxygen or S(O)qq;

pp    is 1 or2;

qq    is zero, 1 or 2;
 

W    is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced
30    by NR17, oxygen or S;

R17  is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or
 






108

cycloalkyl having 3, 4, 5 or 6 carbon atoms;

is 2, 3, 4, 5, 6, 7 or 8;

is 2, 3, 4, 5, 6, 7 or 8;

X    is -C(O)- or -S(0)2-;

5    Z is -C(O)-;

and also its pharmaceutically acceptable salts and trifluoroacetates.

3.    A compound of the formula I as claimed in claim 1 and/or 2, in which

R1 and R3

10    are each hydrogen;

R2 and R4

are each independenHy hydrogen, F, Cl, Br, NHz, NHCH3 or N(CH3)2;

R5    is hydrogen, methyl, ethyl or cyclopropyl;

R6    is hydrogen or methyl;

15    R7 and R8

are each hydrogen;
w    is CrH2r or CsH2s-2:

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced

by NR17, oxygen or S;
20    R17  is hydrogen .or methyl;

is 2, 3, 4, 5 or 6;

is 2, 3, 4, 5 or 6;

X    is -C(O)- or -S(O)z-;

Z    is-C(O)-;

25    and also its pharmaceutically acceptable salts and trifluoroacetates.

4.    A compound of the formula I as claimed in one or more of claims 1 to 3, selected

from the group of:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyljpyrrolidine-

30    2,5-dione,

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





8

1-[3-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-dione,

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

dione,

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

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

3-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-isopropyl-

imidazolidine-2,4-dione,

1o  3-[2-( (R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-isobutyl-

imidazolidine-2,4-dione,

(R und S}-3-[2-( (R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-(2-methylsulfanylethyl)imidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5,5-dimethyl-

15    imidazolidine-2,4-dione,

1-[2-((R)-6,8-dichloro-1 ,2,3 ,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione, 3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-thiazolidine-2,4-dione,
1-[2-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

20    2,5-dione,

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

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

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

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

and1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrole-2,5-

30    diane,

and also its pharmaceutically acceptable salts and triftuoroacetates.
 





109

methylimidazolidine-2,4-dione,

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

imidazolidine-2,4-dione

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

(S)-1-[2-( (R)-6,8-<lichloro-2-cyclopropyl-1,2,3,4-tetrahydroisochinolin-4-yl)p henyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,
1o (R)-1-[2-( (R)-6,8-<lichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

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

15    3,5-dione, 3-[2-((R)-6,8-<lichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidine-

2,4-<lione,

3-[2-(( R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]thiazolidine-

2,4-<lione,

20    1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione,
(S )-1-[2-( (R)-6,8-<lichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-piperidine-2,6-dione,
(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-

25    piperidine-2,6-dione, 1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,5-<limethyl-piperidine-2,6-<lione, 1-[2-((R)-6,8-<lichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-

pyrrolidine-2,5-<lione,

30    1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3-dimethyl-pyrrolidine-2,5-dione, 1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-
 






110

2,5-dione,

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

dione,

1-[4-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

5    2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-

dione,

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

dione,

10    1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-telrahydroisoquinolin-4-yl)phenyl]piperidine-2 ,6-

dione,

1-[3-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny~pyrrole-2,5-

dione,

1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny~pyrrolidine-2,5-

15    diane,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-letrahydroisoquinolin-4-yl)pheny~imidazolidine-

2,4-dione,

20    3-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-

dione,

3-[3-((S)-6,8-dichloro-2-melhyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

2,4-dione,

3-[4-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

25    2,4-dione,

3-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-

dione,

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

oxazolidine-2,4-dione,

30    3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-methyl-

imidazolidine-2,4-dione,

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





111

dimethylpyrrolidine-2,5-dione,

1-[4-((S)-6,8-<Iichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrole-2,5-

dione,

1-[3-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyijpiperid ine-2,6-

5    dione,

1-[3-((S)-6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-dione,

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

dione,

1o  3-[3-(6,8-<lichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-

dione,

1-[2-((R)-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-<lione, 3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-isopropyl-

imidazolidine-2,4-dione,

15    3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-isobutyl-imidazolidine-2,4-dione,
(R und S)-3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-(2-methylsulfanylethyl)imidazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5,5-dimethyl-

20    imidazolidine-2,4-<lione,

1-[2-((R)-6,8-dichloro-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-<lione, 3-[2-((R)-6,8-dichloro-2-qclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-thiazolidine-2,4-dione,
1-[2-((S)-6,8-<Iichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

25    2,5-<lione,

1-[2-((S)-6,8-<Iichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-pyrrolidine-2,5-<lione,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3,4,4-tetra-

methylpyrrolidine-2,5-dione,

30    (S}-1-[2-((R)-6,8-<Iichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methylpiperidine-2,6-<lione,
1-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-4 ,4-dimethyl-
 






112

piperidine-2,6-<lione

and1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]pyrrole-2,5-

dione,

and also its pharmaceutically acceptable salts and trifluoroacetates.

5

s.    A compound of the formula I as claimed in one or more of claims 1 to 4, selected

from the group of:

1-[2-(8-bromo-6-chloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,
1o  3-[2-((R}-6,8-dich loro-2-cyclopropyl-1 ,2,3,4-tetrahydroisochinolin-4-yl}phenyl]-1-methyl-

imidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyij-1-methyl-

imidazolidine-2,4-dione

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

15    imidazolidine-2,4-dione

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

hydroxypyrrolidine-2,5-<lione,

20    (R)-1-[2-((R)-6,8-<Iichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyij-3-hydroxypyrrolidine-2,5-dione,
(S )-1-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidin-2,5-dione,
4-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]morpholine-

25    3,5-<lione,

3-[2-((R)-6,8-dichloro-2-methy~ 1,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]oxazolidine-2,4-dione,

3-[2-((R)-6,8-<Iichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]thiazolidine-

2,4-dione,

30    1-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]-pyrrolidine-2,5-dione,
(S}-1-[2-((R)-6,8-<Iichloro-2-methy~ 1,2,3,4-tetrahydroisoq uinolin-4-yl)phenyl]-3-methyl-
 





113

piperidine-2,6-dione,

(R}-1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-piperidine-2,6-dione,
1-[2-( (R }-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,5-dimethyl-

5    piperldine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny~-3-methyl­ pyrrolidine-2,5-dione,
1-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3-dimethyl-

pyrrolidine-2,5-dione,

10    1-[2-(6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-dione,

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

dione,

1-[4-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

15    2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-

dione,

1-[2-( (R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny~piperidine-2,6-

dione,

20    1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-

dione,

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

dione,

1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-

25    diane,

1-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

2,4-dione,

30    3-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-

dione,

3-[3-((S)-6,8-dichlora-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-
 
















10




15
 






114

2,4-<lione,

3-[4-((S}-6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-<lione,
3-[4-(6,8-<lichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]imidazolidine-2,4-

dione

and

3-[2-((R)-6,8-<Iichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl}phenyl]-

oxazolidine-2,4-dione,

and also its phanmaceutically acceptable salts and trlftuoroacetates.

6.    A compound of the formula I as claimed in claim 1, in which

R1, R2, R3 and R4

are each independently F, Cl, Br, CN or R11-(CmH2ml-An-:

m    is zero or 1;

is zero or 1;

R11    is hydrogen, methyl or CpF2p+1;

A    is oxygen, NCH3 or S(O)q;

is 1 or2;

is zero, 1 or 2;
 

20    R5 is hydrogen, methyl, ethyl or cyclopropyl;

R6 is hydrogen or methyl;

R7 and R8

are each independently hydrogen, F, Cl, CN, C02R12, NR13R14 or
 

25




30
 

R16-(CmmH2mm)-Bnn-:

R12    is hydrogen, methyl or ethyl;

R13, R14 are each independently hydrogen, alkyl having 1, 2, 3 or4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

or

R13 and R14,

with the nitrogen atom to which they are bonded, fonm a 5-, 6- or 7-membered ring in which one CH2 group may be
 





115

replaced by NR15, S or oxygen;

R15 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon

atoms;

5    mm is zero, 1 or 2; nn is zero or 1;
 



10




15
 

R16    is hydrogen, methyl orCppF2pp+1;

B    is oxygen or S(O)qq;

pp    is 1 or 2;

qq    is zero, 1 or 2;

W    is CrH2r or CsH2s-2;

where one or more CHz groups in CrHzr and C5 Hzs-2 may be replaced by NR17, oxygen or S;

R17 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

is 1, 2, 3, 4, 5, 6, 7 or 8; is 2. 3, 4, 5, 6, 7 or 8;

X    is -C(O)- or -S(0)2-;

Z    is a bond;
 

20    and also its pharmaceutically acceptable salts and trifluoroacetates.

7.    A compound of the fonnula I as claimed in claim 1 and/or 6, in which

R1 and R3

are each hydrogen; 25 R2 and R4

are each independently hydrogen, F, Cl, Br, NH2. NHCH3 or N(CH3)z; R5 is hydrogen, methyl, ethyl orcyclopropyl;
R6    is hydrogen or methyl;

R7 and R8

30 are each hydrogen; w is CrH2r or CsHzs-2;
 






116

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced

by NR17, oxygen or S;

R17    is hydrogen or methyl;

is 1, 2, 3, 4, 5 or 6;
5    s    is 2, 3, 4, 5 or6;

X    is -C(O)- or -S(0)2-;

Z    is a bond;

and also its pharmaceutically acceptable salts and trifluoroacetates.

10    8. A compound of the formula I as claimed in one or more of claims 1, 6 and 7, selected from the group of: 1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolln-4-yl)phenyl]pyrrolidin-2-

one,

1-[2-((R)-6,8-<lichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-1,3-

15    dihydroimidazol-2-one,

(R )-6,8-dichloro-4-[2-(1,1-<lioxo-1-l. 6-isothiazolldin-2-yl)phenyl]-2-methyl-1,2,3,4-tetra-hydroisoquinoline,
3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidin-2-

one,

20    1-[2-((R)-6,8-<lichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1,3-dihydro-imidazol-2-one,
1-[2-((R)-6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidin-2-

one,

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

25    one,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-one,
1-[3-((S)-6,8-<lichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidin-2-

one,

30    1-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3, 4-tetrahydroisoquinolin-4-yf)phenyl]-pyrrolidin-2-one,
 





117

3-[2-((R)-6.8-dichloro-2-cyclopropyl-1 ,2,3 ,4-tetrahydroisoquinolin-4-yl)phenyl]-

oxazolidin-2-one

and

6,8-<Jichloro-4-[4-( 1, 1-<Jioxo-1-l. 6_[1 ,2,5]thiadiazolidin-2-yl)phenyl]-2-methyl-1 ,2,3,4-

tetrahydroisoquinolines,

and also its pharmaceutically acceptable salts and trifluoroacetates.

9.    A compound of the formula I as claimed in one or more of claims 1, 6, 7 and 8,

selected from the group of:

10    1-[2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-one,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-1 ,3-dihydroimidazol-2-one,

(R)-6,8-dichloro-4-[2-(1 , 1-<Jioxo-1-l.6-isothiazolidin-2-yl)phenyl]-2-methyl-1 ,2,3,4-tetra-

15    hydroisoquinoline,

3-[2-( (R)-6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidin-2-

one,

1-[2-((R)-6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1 ,3-dihydro-

imidazol-2-one,

20    1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisochinolin-4-yl)phenyijimidazolidin-2-one,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyijpyrrolidin-2-one
and

25    1-[2-((R)-6,8-<Jichloro-2-methyl-1 ,2,3, 4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-one,
and also its pharmaceutically acceptable salts and trifluoroacetates.

10.    A compound of the formula I and its pharmaceutically acceptable salts as

30    claimed in one or more of claims 1 to 9 for use as a medicament.

11.   A compound of the formula I and its pharmaceutically acceptable salts as
 






118

claimed in one or more of claims 1 to 9 for preparing a medicament for the treatment or

prophylaxis of disorders of respiratory drive, of respiratory disorders, sleep-related

respiratory disorders, sleep apneas, of snoring, of acute and chronic renal disorders, of

acute kidney failure and of chronic kidney failure, of disorders of intestinal function, of high blood pressure, of essenfial hypertension, of disorders of the central nervous system, of disorders resulting from CNS overexcltability, epilepsy and centrally induced

convulsions or of states of anxiety, depressions and psychoses, of ischemic states of the peripheral or central nervous system or of stroke, of acute and chronic damage to and disorders of peripheral organs or limbs caused by ischemic events or by
10    reperfusion events, of atherosclerosis, of disorders of lipid metabolism, of thromboses, of disorders of biliary function, of infestation by ectoparasites, of disorders caused by endothelial dysfuncfion, of protozoal disorders, of malaria, for the preservation and storage of transplants for surgical procedures, for use in surgical operations and organ transplants, for use in bypass operations, in resuscitation after cardiac arrest, or for the

15    treatment of states of shock or of diabetes and late damage from diabetes, or of diseases in which cellular proliferation constitutes a primary or secondary cause, and for maintaining health and prolonging life.

12.    The use of a compound of the formula I and its pharmaceutically acceptable salts

20    as claimed •In one or more of claims 1 to 9 in combination with other medicaments or ac«ve ingredients for preparing a medicament for the treatment or prophylaxis of disorders of respiratory drive, of respiratory disorders, sleep-related respiratory disorders, sleep apneas, of snoring, of acute and chronic renal disorders, of acute kidney failure and of chronic kidney failure, of disorders of intestinal func«on, of high

25    blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resul~ng from CNS overexcitability, epilepsy and centrally induced convulsions or of states of anxiety, depressions and psychoses, of ischemic states of the peripheral or central nervous system or of stroke, of acute and chronic damage to
and disorders of peripheral organs or limbs caused by ischemic events or by

30    reperfusion events, of atherosclerosis, of disorders of lipid metabolism, of thromboses, of disorders of biliary function, of infestation by ectoparasites, of disorders caused by endothelial dysfunction, of protozoal disorders, of malaria, for the preservation and
 





9

Especially preferred are compounds of the formula I selected from the group of 1-[2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny~-1-methyl-imidazolidine-2,4-dione,
3-[2-( (R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methyl-

imidazolidine-2,4-dione

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

10    imidazolidine-2,4-dione

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

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

hydroxypyrrolidine-2,5-dione,

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

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

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

20    3,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]thiazolidine-

2,4-dione,

25    1-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione,
(S )-1-[2-((R)-6,8-dichloro-2-methyl-1 ,2, 3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-

piperidine-2,6-dione,

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

30    piperidine-2, 6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,5-dimethyl-piperidine-2,6-dione,
 





119

storage of transplants for surgical procedures, for use in surgical operations and organ transplants, for use in bypass operations, in resuscitation after cardiac arrest, or tor the
treatment of states of shock or of diabetes and late damage from diabetes, or of

diseases in which cellular proliferation constitutes a primary or secondary cause, and

for maintaining health and prolonging life.

13.    The use of a ccmpound of the fonnula I and/or its phannaceutically acceptable

salts as claimed in one or more of claims 1 to 9 alone or in combination with other medicaments or active ingredients for preparing a medicament for the treatment or
1o    prophylaxis of disorders of respiratory drive and/or of sleep-related respiratory

disorders such as sleep apneas.

14.    The use of a ccmpound of the fonnula I and/or its pharmaceutically acceptable

salts as claimed in one or more of claims 1 to 9 alone or In combination with other

15    medicaments or active ingredients for preparing a medicament for the treatment or prophylaxis of snoring.

15.    The use of a compound of the fonnula I and/or its pharmaceutically acceptable

salts as claimed in one or more of claims 1 to 9 alone or in combination with other

20    medicaments or active ingredients for preparing a medicament for the treatment or prophylaxis of acute or chronic renal disorders, of acute kidney failure or of chronic kidney failure.

16.  The use of a ccmpound of the fonnula I and/or its pharmaceutically acceptable

25    saHs as claimed in one or more of claims 1 to 9 alone or in combination with other medicaments or active ingredients for preparing a medicament for the treatment or prophylaxis of disorders of intestinal function.

17.    A phannaceutical preparation for human, veterinary or phytoprotective use,

30    comprising an effective amount of a ccmpound of the fonnula I and/or of a pharmaceutically acceptable salt thereof as claimed in one or more of claims 1 to 9.
 





120

18. A pharmaceutical preparation for human, veterinary or phytoprotective use, comprising an effective amount of a compound of the formula I and/or of a pharmaceutically acceptable salt thereof as claimed in one or more of claims 1 to 9, in
combination with other pharmacological active ingredients or medicaments.

5
 
 





10

1-[2-((R)-6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-m ethyl-pyrrolidine-2,5-dione,

1-[2-((R)-6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3-dimethyl-pyrrolidine-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,
1-[4-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-

dione,

1-[4-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

10    2,5-dione,

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

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

dione,

15    1-[2-(6, 8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

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

dione,

1-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-

20    diane,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,
3-[2-( (R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

2,4-<Jione,

25    3-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

3-[3-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,
3-[4-((S)-6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

30    2,4-dione,

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





11 3-[2-((R)-6,8-<Iichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

oxazolidine-2,4-dione,

3-[2-((R)-6,8-dichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl)-phenyl]-5-methyl-

imidazolidine-2,4-dione,

(3R,4S)-1-[2-( (R)-6,8-dichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl}-phenyl]-3,4-dimethyl-pyrrolidine-2,5-dione,
1-[4-((S)-6,8-<Iichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl)-phenyl]-pyrrole-2,5-

dione,

1-[3-((S}-6,8-<Iichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl)-phenyl]-piperidine-2,6-

10    dione,

1-[3-((S}-6,8-dichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl)-phenyl]-pyrrolidine-2,5-dione,
1-[4-(6,8-dichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl}-phenyl]-piperidine-2,6-dione

and

15    3-[3-(6,8-<lichlor-2-methyl-1 ,2,3,4-tetrahydroquinolin-4-yl)-phenyl]-imidazolidine-2,4-dione,

and also their pharmaceutically acceptable salts and trifluoroacetates.

20    Particularly preferred are compounds of the formula I selected from the group of: 1-[2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-

methylimidazolidine-2,4-<lione,

25    3-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methyl-imidazolidine-2,4-dione
3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

imidazolidine-2,4-dione

(S}-1-[2-((R}-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-

30    hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-<Iichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-<lione,
 





12

(R)-1-[2-((R)-6 ,8-d ichloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

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

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

3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidine-2,4-dione,
3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]thiazolidine-

10    2,4-dione,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-<Jione,
(S)-1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-

piperidine-2,6-dione,

15    (R)-1-[2-((R)-6 ,8-dichloro-2-methyl-1 ,2,3 ,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-piperidine-2,6-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,5-dimethyl-piperidine-2,6-dione,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-

20    pyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3-dimethyl-pyrrolidine-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-<Jione,

25    1-[4-((S)-6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

1-[4-((S )-6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,
1-[4-(6 ,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-

30    diane,

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





13

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

dione,

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

dione,

1-[2-(6 ,8-dichloro-2-methyl-1 ,2, 3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-

dione,

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,
3-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

10    2,4-dione,

3-[2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,
3-[3-((S}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-

2,4-dione,

15    3-[4-((S)-6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,
3-[4-(6,8-dichloro-2-methyl-1 ,2, 3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione
and

20    3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-oxazolidine-2,4-dione,
and also their pharmaceutically acceptable salts and trifluoroacetates.

A further embodiment encompasses compounds of the formula I in which 25 R1, R2, R3 and R4
are each independently hydrogen, F, Cl, Br, CN or R11-(CmH2ml-An-;

    m    iszeroor1;   
        is zero or 1;   
    R11    is hydrogen, methyl or CpF2p+1;
30    A    is oxygen, NCH3 or S(O)q;
        p    is 1 or2;
            is zero, 1 or 2;
 











5




10




15
 





14

R5    is hydrogen, methyl, ethyl or cyclopropyl;

R6    is hydrogen or methyl;

R7 and RB

are each independently hydrogen, F, Cl, CN, C02R12, NR13R14 or R16-(CmmH2mm)-Bnn-:
R12    is hydrogen, methyl or ethyl;

R13, R14 are each independently hydrogen, alkyl having 1, 2, 3 or4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

or

R13 and R14,

with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered ring in which one CH2 group may be replaced by NR15, S or oxygen;

R15    is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
 
mm    is zero, 1 or 2;

nn    is zero or 1;

R16    is hydrogen, methyl or CppF2pp+1;

20    B is oxygen or S(O)qq:

pp    is1or2;

qq    is zero, 1 or 2;

W    is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and C5 H2s-2 may be replaced 25 by NR17, oxygen or S;
R17 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
is 1, 2, 3, 4, 5, 6, 7 orB; is 2, 3, 4, 5, 6, 7 or 8;

30    X is -C(O)- or -S(0)2-; z is a bond;
 





15

and also their pharmaceutically acceptable salts and trifluoroacetates.

Preference is given to compounds of the formula I in which

R1 and R3

are each hydrogen; R2 and R4
are each independently hydrogen, F, Cl, Br, NH2, NHCH3 or N(CH3)2; R5 is hydrogen, methyl, ethyl or cyclopropyl;
R6    is hydrogen or methyl;

10    R7 and R8

are each hydrogen;

W    is CrH2r or CsH2s-2;

where one or more CH2 groups in CrH2r and C5 H2s-2 may be replaced

by NR17, oxygen or S;

15 R17 is hydrogen or methyl; is 1, 2, 3, 4, 5 or 6;

is 2, 3, 4, 5 or 6;

X    is -C(O)- or -S(0)2-;

Z    is a bond;

20    and also their pharmaceutically acceptable salts and trifluoroacetates. Particular preference is given to compounds of the formula I in which
R1 and R3

are each hydrogen; 25 R2 and R4

are each independently hydrogen, F, Cl, NH2, NHCH3 or N(CH3)2; R5 is hydrogen, methyl, ethyl or cyclopropyl;
R6    is hydrogen or methyl;

R7 and R8

30    are each hydrogen;

w
 





16

where one or more CH2 groups in CrH2r and CsH2s-2 may be replaced by NR17, oxygen or S;

R17 is hydrogen, methyl; is 1, 2, 3, 4, 5 or6; is 2, 3, 4, 5 or6;

X    is -C(O)- or -S(0)2-:

Z    is a bond;

and also their pharmaceutically acceptable salts and trifluoroacetates.

1o Very particular preference is given to compounds of the formula I selected from the group of:
1-[2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-

one,

1-[2-((R)-6,8-<lichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-1 ,3-

15    dihydroimidazol-2-one,

(R)-6,8-dichloro-4-[2-( 1 , 1-dioxo-1-:\.6-isothiazolidin-2-yl)phenyl]-2-methyl-1 ,2,3,4-tetrahydroisoquinoline,
3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyi]-{)Xazolidin-2-

one,

20    1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1 ,3-dihydro-imidazol-2-one,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidin-2-

one,

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

25    one,

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

one,

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

one,

30    1-[2-( (R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-

2-one,
 





17

3-(2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

oxazolidin-2-one

and

6,8-dichloro-4-[4-(1 , 1-dioxo-1-;>..6-[1 ,2,5]thiadiazolidin-2-yl)phenyl]-2-methyl-1 ,2,3,4-

5    tetrahydroisoquinoline,

and also their pharmaceutically acceptable salts and tr~luoroacetates.

Especially preferred are compounds of the formula I selected from the group of: 1-[2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-

10    one,

1-[2-((R)-6 ,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-1 ,3-dihydroimidazol-2-one,

(R)-6 ,8-dichloro-4-[2-( 1, 1-dioxo-1-1..6-isothiazolidin-2-yl)phenyl]-2-methyl-1 ,2, 3,4-

tetrahydroisoquinoline,

15    3-(2-((R)-6, 8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidin-2-one,
1-(2-((R}-6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1 ,3-dihydro-imidazol-2-one,
1-(2-((R}-6, 8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidin-2-

20    one,

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

1-(2-( (R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-

one,

25    1-[3-((S)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidin-2-one,
1-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-

2-one

and

30    3-[2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-oxazolidin-2--one,
and also their pharmaceutically acceptable salts and triftuoroacetates.
 





18

Particularly preferred are ccmpounds of the formula I selected from the group of: 1-[2-(8-bromo-6-chloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-

one,

1-[2-((R}-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-1 ,3-dihydroimidazol-2-one,

(R)-6,8-d ichloro-4-[2-( 1 , 1-dioxo-1-l.6-isothiazolidin-2-yl)phenyl]-2-methyl-1 ,2,3 ,4-tetra-

hydroisoquinoline,

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

10    one,

1-[2-( (R)-6,8-dich loro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1 ,3-dihydro-imidazol-2-one,
1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidin-2-

one,

15    1-[2-((R)-6,8-dichloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-one
and

1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolid in-2-

one,

20    and also their pharmaceutically acceptable salts and triftuoroacetates.

In a further embodiment, preference is given to compounds of the formula I in which the R1, R2, R3 and R4 radicals are each independently described by hydrogen, F, Cl, Br, CN or R11-(CmH2m}-An- where m and n are each independently zero or 1, R11 is

25    hydrogen, methyl or CpF2p+1 and A is oxygen, NCH3 or S(O)q. where pis 1 or 2 and q is zero, 1 or 2; particular preference is given to compounds of the formula I in which
R1 and R3 are each hydrogen and R2 and R4 are each independently hydrogen, F, Cl, Br, NH2, NHCH3 or N(CH3)2, for example Cl or Br. In one embodiment, preference is

given to ccmpounds of the formula I in which R1 and R3 are each hydrogen and R2

30    and R4 are each independently F, Cl, NH2, NHCH3 or N(CH3)2, for example Cl.
 





19

In a further embodiment, preference is given to compounds of the formula I in which

R5 is described by hydrogen, methyl, ethyl or cyclopropyl; particular preference is

given to compounds of the formula I in which R5 is hydrogen, methyl or cyclopropyl, for

example methyl.

In a further embodiment, preference is given to compounds of the formula I in which

R6 is described by hydrogen or methyl, for example hydrogen.

In a further embodiment, preference is given to compounds of the formula I in which

10    the R7 and RB radicals are each independently described by hydrogen, F, Cl, CN, C02R12, NR13R14 or R16-(CmmH2mm)-Bnn-. where R12 is hydrogen, methyl or ethyl, R13 and R14 are each independently hydrogen, alkyl having 1, 2, 3 or 4 caribon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms, or R13 and R14, together with
the nitrogen atom to which they are bonded, fonm a 5-, 6- or 7 -membered ring in which

15    one CH2 group may be replaced by NR15, S or oxygen, and where R15 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms, and where mm is zero, 1 or 2, nn is zero or 1, and R16 is hydrogen, methyl or
Cppf2pp+1, where B is oxygen or S(O)qq. where pp is 1 or 2 and qq is zero, 1 or 2;

    particular preference is given to compounds of the formula I in which R7 and RB are
20    each hydrogen.
    In a further embodiment, preference is given to compounds of the formula I in which W
    is described by CrH2r or CsH2s-2 where one or more CH2 groups in CrH2r and
    CsH2s-2 may be replaced by NR17, oxygen or S, where R17 is hydrogen, alkyl having
25    1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 cerbon atoms, especially
    hydrogen or methyl, for example hydrogen, and where r is 2, 3, 4, 5, 6, 7 or 8, in
    particular 2, 3, 4, 5 or 6, and sis 2, 3, 4, 5, 6, 7 or 8, in particular 2, 3, 4, 5 or 6.
    In a further embodiment, preference is given to compounds of the formula I in which X
30    is -C(O)- or -8(0)2-•
 





20

In a further embodiment, preference is given to compounds of the formula I in which

Z is -C(O)-.

In another embodiment, preference is given to compounds of the formula I in which Z is a bond.

When the compounds of the formula I contain one or more centers of asymmetry, they may each independently have either S or R configuration. The compounds may be present as optical isomers, as diastereomers, as racemates or as mixtures in all ratios
thereof. The compounds of the fonnula I may also be present in the fonn of rotational

10    isomers.

The present invention encompasses all possible tautomeric forms of the compounds of the fonnula I.

15    The present invention also encompasses derivatives of the compounds of the

fonnula I, for example solvates such as hydrates and alcohol adducts, esters, prodrugs and other physiologically acceptable derivatives of the compounds of the fonnula I, and also active metabclites of the compounds of the fonnula I. The invention likewise encompasses all crystal modifications of the compounds of the formula I.

20

Alkyl radicals may be straight-chain or branched. This is also true when they bear

substituents or occur as substituents of other radicals, for example in fluoroalkyl

radicals or alkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl,

isopropyl(= 1-methylethyl), n-butyl, isobutyl(= 2-methylpropyl), sec-butyl

25    (= 1-methylpropyl), tert-butyl (= 1,1 -dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl and n-butyl. In alkyl radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, hydrogen atoms may be substituted by fluorine atoms. Examples of such

fiuoroalkyl radicals are tr~luoromethyl, 2,2,2-trifiuoroethyl, pentafluoroethyl,

30    heptafiuoroisopropyl. Substituted alkyl radicals may be substituted in any positions. Alkylene radicals, for example CmH2m• CmmH2mm or CrH2r• may be straight-chain
 




21

or branched. This is also true when they bear substituents or occur as substituents of

other radicals, for example in fluoroalkylene radicals, for example in CpF2p and

CppF 2pp• Examples of alkylene radicals are methylene, ethylene, 1-methylmethylene, propylene, 1-methylethylene, butylene, 1-propylmethylene, 1-ethyl-1-methylmethylene,
1 ,2-dimethylethylene, 1, 1-dimethylmethylene, 1-ethylethylene, 1-methylpropylene, 2-methylpropylene, pentylene, 1-butylmethylene, 1-propylethylene, 1-methyl-2-ethylethylene, 1 ,2-dimethylpropylene, 1 ,3-dimethylpropylene, 2,2-dimethylpropylene, he xylene and 1-methylpentylene. In alkylene radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, hydrogen atoms may be substituted by fluorine atoms.
1o Substituted alkylene radicals may be substituted in any positions. In the alkylene radicals, one or more CH2 groups may be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl. Both in straight-chain and in branched alkylene chains, CH2 groups may be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl, for example as a 1-hydroxy-ethylene radical.

15

Alkenylene radicals, for example CsH2s-2• may be straight-chain or branched. This is also true when they bear substituents, for example in fluoroalkenylene radicals. The
alkenylene radicals may be unsaturated in different positions. Examples of alkenylene

radicals are ethenylene, 1-methylethenylene, propenylene, but-1-enylene,

20    but-2-enylene, 1-methylprop-1-enylene, 1 ,2-dimethylethylene, pentenylene or hexenylene. In alkenylene radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, hydrogen atoms may be substituted by fluorine atoms. Substituted alkenylene radicals may be substituted in any positions. In the alkenylene radicals, one or more

CH2 groups may be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl. Both in

25    straight-chain and in branched alkenylene chains, CH2 groups may be replaced by oxygen, S, NH, N-alkyl or N-cycloalkyl.

Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In cycloalkyl radicals, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12,

30    hydrogen atoms may be substituted by fluorine atoms. Substituted cycloalkyl radicals may be substituted in any positions. Cycloalkyl radicals may also be present in
 





22

branched form as alkylcycloalkyl or cycloalkylalkyl, for example methylcyclohexyl or cyclohexylmethyl.

Examples of rings from NR13R14 where R13 and R14 with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7 -membered ring are morpholine, pyrrolidine,

piperidine, piperazine and N-methylpiperazine.

The terminal CH3 groups in an alkyl radical are also regarded as CH2 units, and are

interpreted in this context as being CHz-H moieties. This also applies in branched

10    alkylene radicals, for example CmH2m• CmmH2mm or CrH2r•

When a variable, for example cycloalkyl or R 1, occurs more than once as a component, the definitions of the variables are independent from one another at each
instance.

15

When the compounds of the fonnula I contain one or more acidic or basic groups or

one or more basic heterocycles, the ccrresponding physiologically or toxicologically

acceptable salts are also included in the invention, especially the pharmaceutically

usable salts. For instance, the ccmpounds of the formula I can be deprotonated at an

20    acidic group and be used, for example, in the form of alkali metal salts, preferably sodium or potassium salts, or in the form of ammonium salts, for example as salts with ammonia or organic amines or amino acids. Since compounds of the fonnuta 1 always

contain at least one basic group, they may also be prepared in the form of their physiologically acceptable acid addition salts, for example with the following acids:
25    from inorganic acids such as hydrochloric acid, sutfuric acid or phosphonic acid, or from organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, malonic acid, methanesutfonic acid, fumaric acid. Useful acid addition salts include salts of all pharmacclogically acceptable salts, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsu~onates, p-

30    toluenesu~onates, adipates, fumarates, gluccnates, glutamates, glycerolphosphates, maleates and pamoates (this group also corresponds to the physiologically acceptable
anions); but also trifluoroacetates.
 





23

The invention also provides the processes described below for preparing compounds

of the formula I.

5    The compounds of the formula I described here can be prepared, for example, according to or analogously to literature methods starting from aniline derivatives of the formula VIII


R2
    R2   
R3    R3   
R4       
    R4   
       
VIII       

The aniline of the formula VIII can, for example, be converted by heating with the

10    corresponding acids of the formula XXII in polyphosphoric acid (PPA) to the compounds of the formula Ia (Tetrahedron Letters 2003, 44, 2133), where R1 to RB and W are each as defined above

and

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

        NH2       
        +oywyo    PPA   
    R2        R2   
               
        OH   OH    R3   
    R3           
               
    R4        R4   
               
15    VIII    XXII    Ia   

Alternatively, it is possible to obtain compounds of the formula Ia by reacting anilines of the formula VIII in aprotic solvents such as dichloromethane with anhydrides of the XXIX type to give intermediate amide acids. The desired imides of the formula Ia are
 





24

then obtained by ring-closing the intermediates in aprotic solvents such as

dichloromethane with suitable cyclizing reagents such as EDC in the presence of bases such as HOnig'sbase. Alternatively, the intermediates may also be heated in high-boiling solvents such as diphenyl ether or entirely without solvent, so that there is
fonnation of ring closure with loss of water, where the R1-RB and W radicals are each

as defined above

and

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


        0"\W/0    2.EDC,       
R2    +        base    R2   
                   
        0    or       
R3            T>100"C    R3   
                R4   
R4                   
                   
VIII        XXIX        Ia   

10    Compounds of the formula lb may be formed, for example, in a two-stage reaction starting from isocyanatocarboxylic esters of the formula XII. In this case, the urea is formed first as an intermediate by reaction of the aniline nitrogen with the isocyanate group before there is subsequent ring closure under acid catalysis, where R1 to R8 are
each as defined above,

15    X and Z each correspond to -C(O)-,

R22 is alkyl having 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl, -VN-NH- is a W radical in which a terminal CH2 group has been replaced by NH

and

-V'-NCOis a W radical in which a terminal CH2 group has been replaced by an

20    isocyanate group.
 










R2
 






            25       
+    OCN~    V'   0            R2   
        '(               
 
    R22,.....o    2, [H']   
        R3   
R3           
        R4   
R4           
           
VIII    XII    lb   
           
           

A variation in the R17 radical can subsequently be achieved by alkylating the

compound of the formula lb in the presence of a base, for example lithium

diisopropylamide or lithium or sodium hexamethyldisilazide with an alkylating agent of the formula XIII,
where R1 to R8 and R17 are each as defined above, X and Z each correspond to -C(O)-,
-VwNH- is a W radical in which a terminal CH2 group has been replaced by NH, -VN-NR17- is a W radical in which a terminal CHz group has been replaced by NR17

10    and

LG corresponds to a leaving group common in alkylations, for example bromide, chloride, tosylate or mesylate.



,.-R17
R2    +    LG    base    R2   
                   
R3                R3   
R4                   
                R4   
                   
lb        XIII        lc   

15    Alternatively, the ring can also be formed in a three-stage sequence. To this end, a carbonyl group is first transferTSd to the anilinic nitrogen. This is done, for example, with chloroformic acid derivatives of the formula XIV or carbonyldiimidazole.
 





26

Subsequent reaction with amino esters of the formula X:V, followed by acid- or base-

catalyzed cyclization, preferably with hydrochloric acid or sodium hexamethyldisilazide, leads to compounds of the formula lc,
where R1 to R8, R17 and -VN-NR17- are each as defined above,

R23 is alkyl having 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl, and
R24 is an optionally substituted phenyl radical, for example phenyl or 4-nitrophenyl.

R7

    NH,        R17..,~ ... vNfo       
                   
    +    CIYO'R24    2.    R23 ... o    XV   
R2                       
        0            R2   
            3. [H+] or base       
                   
R3                    R3   
    R4                R4   
    VIII    XIV            lc   

11    Cyclic ureas of the formula ld can be obtained from the product of the aniline of the formula VIII with the chloroformic acid derivative of the formula XIV by reacting the carbamate formed with amines of the formula XVI, followed by a cyclization step in the presence of a base, for example sodium hydride, potassium carbonate or sodium

hexamethyldisilazide,

15    where

R1 to R8, R17, R24, -VN-NR17- and -VN-NHR17 are each as defined above,

and

y is a leaving group, for example chlorine, or else a precursor to a leaving group, for

example hydroxyl, which is then converted to a leaving group, for example with mesyl

20    chloride.
 





27



R2                R2
        3. base
R3                R3
R4                R4
VIII    XIV            ld

Lactams of the formula le may be prepared by reacting an aniline of the formula VIII with lactones of the formula XVII (Synlett 2001, 1485) by, in the hydroxy am ides

formed as an intermediate, making, from the hydroxyl group by reaction with, for example, sulfonyl chlorides, anhydrides or strong acids, a good leaving group which is then subsequently substituted by the anilinic nitrogen, preferably in the presence of base, for example sodium hydride, potassium carbonate or sodium

hexamethyldisilazide,

10    where R1 to RB and Ware each as defined above, X oorresponds to -C(O)-

and

Z is a bond.

R7
    +    oA-w    2. e.g. MesCI   
R2                R2   
                   
            3. base   
R3                R3   
                   
R4                R4   
                   
VIII        XVII        le   
                   

15    Alternatively, it is also possible to react haloaromatics ofthe formula XVIII directly with Ia clams of the formula XIX in the presence of catalysts, for example copper iodide, to give compounds of the formula le (J. Am. Chern. Soc. 2001, 7727, ibid. 2002, 7421), where R1-RB and Ware each as defined above,
 





28

X corresponds to -C(O)-,

Z is a bond

and•

Hal is Cl, Br, I or -0-triflate.
    R7            R7    j   
                       
                       
                    N-w   
        0               
R2    +    A        R2       
                       
        H,...N-W               
R3                R3       
                       
R4                R4       
                       
XVIII        XIX        Je       

The haloaromatics of the formula XVIII are prepared starting from the carbonyl

derivatives of the formula VI analogously to the formation of the aniline derivatives of

the formula VIII which is described below.

t a A further alternative is the reaction of anilines of the formula VIII with acid chlorides of •theformula XXV to give compounds of the formula Ie. The amides obtained as an intermediate are then cyclized in the presence of bases such as sodium hydride, potassium carbonate or sodium hexamethyldisilazide in solvents such as THF, DMSO and DMF. The R1 to RB, LG and W radicals are each as defined above,

15    Z corresponds to a bond and X is-C(O)-.

    NH,            R7   
                N!   
        0           
                   
    +    )l /LG    2. base   
R2                R2   
    Cl               
        W           
R3                R3   
                   
    R4            R4   
                   
    VIII    XXV        Je   
                   

Sulfonamides of the formula If can be prepared starting from the anilines of the formula
 





29

VIII by reacting with chloroalkylsulfamyl chlorides of the formula XX (Tetrahedron Letters 44, 5483 (2003)),

where R1 to RB, R17 and -VN-NR17- are each as defined above, Tis Cl or Br,
5    X corresponds to -S02-

and

Z is a bond.



R2    +    R2   
           

R3
R3
R4
R4

VIII    )()(

Compounds of the formula lg may be formed via an acid-catalyzed cyclization reaction.

1o    Starting from the ureas of the formula XXI, which can be prepared by one of the

abovementioned methods, compounds of the formula lg are prepared in the presence

of acid, for example hydrochloric acid or formic acid, with elimination of the ketal or

acetal,

where R1 to RB and R17 are each as defined above,

15    X corresponds to -C(O)-, Z is a bond,
-NR17-V"-CV.HCV"'(ORa)2corresponds to a W radical with the definition of CrH2r in which a terminal CH2 group has been replaced by NR17 and a further CH2 group by
an acetal/ketal moiety, and v• and V"'represent possible branches of the alkylene

20    radical, where Ra is alkyl having 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl, or the two Ra radicals together form an ethylene radical

and

-NR17-v"-cv•=cV"'is- a W radical with the definition of CsH2s-2 in which a terminal CH2 group has been replaced by NR17 and v• and V"'represent possible branches of
 





30

the alkenyl radical.



R2

R3
R4    R3   
       
XXI    R4   
    lg   

Compounds of the formula lh may be obtained by first reacting the aniline VIII with

chlorothioformates of the formula XXVI such as phenyl chlorothioformate and

subsequently allowing the resulting intermediate thiocarbamate, after treatment with

sodium methoxide solution, to react with an acid chloride of the type XXVII. The R1 to

R8, R24 and LG radicals are each as defined above.

VK is a W group which has been shortened by one CH2 group,

Vs-S- is a W group in which one CH2 group has been replaced by sulfur and 10 X and Z each correspond to -C(O)-.

NH,

+    CIYO'R24    2. NaOMe/MeOH    R2   
R2    s               
            3.CinVk......_LG       
                   
                R3   
R3        0       
               
R4            R4   
            XXVII       
                   
VIII    XXVI            lh   

Compounds of the formula li can be synthesized in a three-stage sequence as follows.

First, anilines of the type VIII are reacted in aprotic solvents such as THF in the

presence of bases such as sodium hexamethyldisilazide with acid chlorides of type

15    XXVIII to give intermediate amides. Subsequently, the protecting group Pis removed from the oxygen in the presence of nucleophiles and bases such as potassium carbonate in methanol. Finally, the resulting alcohol is reacted in an aprotic solvent such as THF with a carbonyl equivalent such as 1, 1-carbonyldiimidazole or phosgene
 





31

in the presence of a base such as sodium hexamethyldisilazide.

The R1-RB radicals are each as defined above,

Vo-0- corresponds to a W group in which one CHz group has been replaced by

oxygen,

5    p corresponds to a protecting group such as acetyl, benzoyl, benzoxycarbonyl or trityl and
X and Z each correspond to -C(O)-.


+    CII(Voo,P    2. 0-P cleavage       
R2    0        R2   
        3. Carbonyldiimidazole       
               
R3        or phosgene, base    R3   
               
R4            R4   
Vlll    XXVIII        li   

Compounds of the formula lj can be prepared by reacting anilines of the formula VIII

10    with chloroformates of the formula XXX in aprotic solvents such as THF, and subsequently ring-closing the intermediate carbamate formed in aprotic solvents such as THF in the presence of a base such as sodium hydride. The R1-R8, LG and Vo-0

radicals are each as defined above and

Z corresponds to a bond and 15 Xis-C(O)-.

    R7       
R2    2. base    R2   
           
R3        R3   
           
R4        R4   
VIII    XXX       

Compounds of the formula lk can be obtained by reacting anilines of the formula VIII with sulfonyl chlorides of the formula XXXI in aprotic solvents such as THF in the
 





32

presence of bases such as sodium hexamethyldisilazide. The R1-R2, T and W radicals

are each as defined above and

Z corresponds to a bond and

X is-502-•



    +    p1    base    R2   
R2        ,w-,'f::::::o           
                   
    T    0        R3   
R3                   
                R4   
    R4               
                   
    VIII    XXXI        lk   

The compounds of the formulae XII, XIII, XIV, XV, XVI, XVII, XIX, XX, XXII, XXV, XXVI, XXVII, XXVIII, XXIX, XXX and XXXI are commercially available or can be

prepared according to or analogously to processes which are described in the

literature and are known to those skilled in the art.

10

The starting compounds of the formula VIII can be prepared as follows:

Reduction of the carbonyl moiety in compounds of the formula VI and subsequent acid-catalyzed cyclization of the corresponding alcohols of the formula VII (cf.

15    Tetrahedron Lett. 1989,30, 5837; Org. Prep. Proced.lnt. 1995,27, 513) can afford tetrahydroisoquinolines of the formula Villa by known processes, where R1 to R8 are each as defined above

and

R20 is a nitrogen protecting group familiar to those skilled in the art, for example an

20    acetyl radical.

Compounds of the formula VIII are subsequently obtained in the manner known to those skilled in the art starting from compounds of the type of the formula Villa by removing the protecting group R20. This is done in protic solvents such as water or
lower alcohols, preferably under acid catalysis, for example with hydrochloric acid or

25    trtfluoroacetic acid, or under base catalysis, for example in the presence of sodium
 





34

where R 1 to R8 and R20 are each as defined above, R21 is a protecting group, for example allyl or benzyl and

LG corresponds to a leaving group common in alkylations, for example chloride, bromide, tosylate or mesylate.
 

7    121

N'-...R20

R2    R6-LG

R3

R4

IX




R21
7    I

N'-R2o

R2

R3

R4

Vlllb
 
R7    r
N'R2o

R2

R3

R4

X

R5-NH2

r
N'.R20

R2

R3

R4

XI
 

Deprotection of the compound of the fonmula Vlllb by means of the process known to those skilled in the art affords the free aniline of the formula VIII. Depending on the type of protecting group, carbonyl protecting groups such as acetyl are removed

10    advantageously under acid catalysis (e.g. aqueous HCI) or base catalysis (for example by means of sodium methoxide or ethoxide), while benzyl or allyl protecting groups are best detached by hydrogenation.

compounds of the formula IX are commercially available or can be prepared according
 





35

to or analogously to processes which are described in the literature and known to

those skilled in the art.

The compounds of the fonmula VI used above are preferably prepared from benzylam\nes of the fonmula IV in the manner known to those skilled In the art and the appropriate amino-substitutad alpha-bromoacetophenone compounds of the formula V,

where R1 to RB and R20 are each as defined above

            R8~R7 !,   
            "'R20   
R2~:I        Br   
        0       
    H    v   
               
R3    °    N,R5           
    R4               
10    IV            VI   

The alpha-bromoacetophenone compounds of the fonmula V can be obtained in

literature processes from the corresponding acetophenone precursors by bromination.

If commercially unavailable, the benzylamine precursors of the fonmula IV can be

15    synthesized by standard processes known to those skilled in the art from the corresponding benzyl chlorides or bromides of the fonmula Ill and the corresponding amines,

where R1 to R5 are each as defined above

and

20   X is F, Cl, Br or I, in particular Cl or Br.           
R5-NH    2    =~~'~R4   
R2ySX           
R3~           
R4           
Ill        IV   
 






36

Alternatively, compounds of the formula IV are also obtainable by reductive ami nation of an aldehyde of the formula Ilia by standard processes known to those skilled in the art,

where R1 to RS are each as defined above.

R2~        R5-NH    2    =~~'~R4   
        O           
R3~               
R4    H               
Ilia                IV   

The compounds of the formulae Ill and Ilia and R5-NH2 are commercially available or

can be prepared according to or analogously to processes which are described in the

literature and are known to those skilled in the art.

10

The products and/or intermediates are worked up and, if desired, pur~ied by the

customary methods such as extraction, chromatography or crystallization and the

customary drying steps.

15    It has been possible to show that compounds of the formula I are outstanding inhibitors of the sodium-hydrogen exchanger (NHE), especially the sodium-hydrogen exchanger of the subtype 3 (NHE3).

The NHE3 inhibitors known to date derive, for example, from compounds of the

20    acylguanidine type (EP825178), norbornylamine type (W00144164), 2-guanidino-quinazoline type (W00179186) or benzamidine type (W00121582, W00172742). Squalamine, which has likewise been described as an NHE3 inhibitor (M. Donowitz et a!., Am. J. Physiol. 276 (Cell Physiol. 45): C136- C144), according to the current state of knowledge, does not act immediately like the compounds of the formula 1 but rather

25    via an indirect mechanism and thus attains its maximum intensity of action only after one hour.

Tetrahydroisoquinolines as inhibitors of the sodium-hydrogen exchanger of the
 





37

subtype 3 (NHE3) have already been desclibed in the patent application W003048129, W02004085404 and German application No. 102004046492.8. The patent application W003055880 describes the related compound class of the tetrahydroisaquinolinium salts as NHE3 inhibitors. It has now been found that, surprisingly, the compounds of the formula I described here likewise constitute potent inhibitors of the NHE3 and have advantageous pharmacological and pharmacokinetic properties.

The NHE3 is found in the body of various species, preferentially in the gall bladder, the 1o intestines and in the kidneys (Lany Fliegel eta/., Biochem. Cell. Bioi. 76: 735 - 741,

1998), but has also been found in the brain {E. Ma et al., Neuroscience 79: 591 - 603 ).

Owing to their NHE-inhibitory properties, the compounds of the formula I are suitable

for the prevention and treatment of disorders which are caused by an activation of or

15    by an activated NHE, and also of disorders which have the NHE-related damage as a secondary cause,
The compounds of the formula I cen also be used for the treatment and prevention of disorders in which the NHE is only partially inhibited, tor example by use of a lower

dose.

20

The use of the inventive compounds relates to the prevention and to the treatment of

acute and chronic disorders in veterinary and in human medicine.

As a consequence of their pharmacological actions, the compounds of the formula 1

25    are especially suitable for improving the respiratory drive. They can therefore be employed for the treatment of disturbed respiratory states, as can occur, for example, in the event of the fallowing clinical states and disorders: disturbed central respiratory

drive {for example central sleep apneas, sudden infant death, postoperative hypoxia),

muscular-related respiratory disorders, respiratory disorders after long-term ventilation,

30    respiratory disorders in the course of adaptation in high mountains, obstructive and mixed forms of sleep apneas, acute and chronic pulmonary disorders with hypoxia and hypercapnea.
 






38

In addition, the compounds increase the muscle tone of the upper airways, so that

snoring is suppressed. The compounds mentioned therefore advantageously find use

for the preparation of a medicament for the prevention and treatment of sleep apneas

and muscular-related respiratory disorders, and for the preparation of a medicament

for the prevention and treatment of snoring.

A combination of an NHE inhibitor of the formula I with a carbonic anhydrase inhibitor

(for example acetazolamide) can be found to be advantageous, the latter bringing

about metabolic acidosis and thus itself increasing respiratory activity, so that 1o enhanced action and reduced use of active ingredients can be achieved.

As a consequence of their NHE3-inhibitory action, the inventive compounds protect the cellular energy reserves which are rapidly depleted in toxic and pathogenic events and
thus lead to cell damage or to cell death. The energy-intensive ATP-<:onsuming sodium

15    absorption in the proximal tubulus is temporarily shut down under the influence of NHE3 inhibitors and the cell can thus survive an acute pathogenic, ischemic or toxic situation. The compounds are therefore suitable, for example, as medicaments for the treatment of ischemic noxae, for example of acute renal failure. Moreover, the
compounds are also suitable for the treatment of all chronic renal disorders and

20    nephritis fonns which lead to chronic kidney failure as a consequence of increased protein deposition. Accordingly, the compounds of the fomnula I are suitable for preparing a medicament for the treabnent of late diabetic damage, diabetic nephropathy and chronic renal disorders, especially of all renal inflammations (nephritides) which are associated wnh increased protein/albumin deposition.

25

It has been found that the compounds used in accordance with the invention have a

mild laxative effect and can accordingly also be used advantageously as laxatives or in

the event of impending constipation.

30    Moreover, the inventive compounds may be used advantageously for the prevention and therapy of acute and chronic disorders of the intestinal tract which are induced, for example, by ischemic states in the intestinal region and/or by subsequent reperfusion
 





39

or by inflammatory states and events. Such complications may occur, for example, as a result of inadequate bowel peristalsis, as are observed, for example, frequently after

surgical interventions, in the event of constipation or greatly reduced bowel activity.

With the inventive compounds, the possibility exists of preventing gallstone formation.

The inventive NHE inhibitors are suitable generally for the treatment of disorders which

are caused by ischemia and by reperfusion.

10    As a consequence of their pharmacological properties, the inventive compounds are suitable as antiarrhythmic medicaments.
As a result of their cardioprotective component, the NHE inhibitors are outstandingly suitable tor infarction prophylaxis and infarction treatment, and also for the treatment of
angina pectoris, in which cases they also inhibit or greatly reduce the

15    pathophysiological processes in the development of ischemically induced states, especially in the triggering of ischemically induced cardiac arrhythmias. Owing to their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I used in accordance with the invention, as a consequence

of inhibition of the cellular Na+/H+ exchange mechanism, may be used as medicaments

20    for the treatment of all acute or chronic damage induced by ischemia or diseases induced primarily or secondarily thereby.

This also relates to their use as medicaments for surgical interventions. For instance, the inventive compounds may be used in organ transplants, in which case the
25    compounds may be used both for the protection of the organs in the donor before and during the removal, for the protection of removed organs, for example in the course of treatment with or their storage in physiological bath liquids, and also in the course of transfer into the recipient organism pretreated with compounds of the fonmula I.

30    The compounds are likewise valuable, protective medicaments in the performance of angioplastic surgical interventions, for example on the heart, and also on peripheral organs and vessels.


Moreover, the inventive compounds may be used in the performance of bypass operations, for example in bypass operations on coronary vessels and in coronary
artery bypass graft (CABG).

In accordance with their action against ischemically induced damage, the inventive

compounds of the formula I may also be used in resuscitation after a cardiac arrest.

In accordance with their protective action against isr;:hemically induced damage, the

10    compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the CNS, in which case they are suitable, for example, for the treatment of stroke or of cerebral edema.

Since NHE inhibitors protect human tissue and organs effectively not only against

15    damage which is caused by ischemia and reperiusion but also against the cytotoxic action of medicaments as find use especially in cancer therapy and the therapy of auto'mmunedisorders, their combined administration with compounds of the formula I
is suitable for reducing or for suppressing the cytotoxic effects of a therapy. The

reduction in the cytotoxic effects, especially in the cardiotoxicity, as a consequence of

20    co-medication with NHE inhibitors also allows the dose of the cytotoxic therapeutic agents to be increased and/or the medication with such medicaments to be prolonged. The therapeutic benefit of such a cytotoxic therapy can be considerably enhanced by the combination with NHE inhibitors. The compounds of the formula I are suitable in particular for improving the therapy with medicaments which have an undesired

25    cardiotoxic component.

Generally, the NHE inhibitors described here can be combined favorably with other compounds which likewise regulate the intracellular pH, in which case possible combination partners are inhibitors of the enzyme group of the carbonic anhydrases,

30    inhibitors of the systems transporting bicarbonate ions, such as the sodium bicarbonate cotransporter (NBC) or the sodium-dependent chloride-bicarbonate exchanger (NCBE), and also with other NHE inhibitors with inhibitory action on other
NHE subtypes, because they can enhance or modulate the phanmacologically relevant pH-regulating effects of the NHE inhibitors described here.

In accordance with their protective action against ischemically induced damage, the

inventive Compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the central nervous system, in which case they
are suitable, for example, for the treatment of stroke or of cerebral edema.

The compounds of the fonmula I are also suitable for the therapy and prophylaxis of

10    diseases and disorders which are induced by overexcitability of the central nervous system, especially for the treatment of epileptic disorders, centrally induced clonic and tonic spasms, states of psychological depression, anxiety disorders and psychoses. In these cases, the inventive NHE inhibitors may be employed alone or in combination

with other antiepileptically active substances or antipsychotic active substances, or

15    carbonic anhydrase inhibitors, for example with acetazolamide, and also with further inhibitors of the NHE or of the sodium-dependent chloride-bicarbonate exchanger (NCBE).

Furthermore, the inventive compounds of the formula l are likewise suitable for the

20    treatment of types of shock, for example of allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of the fonmula I may likewise be used for the prevention and for the

treatment of thrombotic disorders since they, as NHE inhibitors, can also inhibit platelet

25    aggregation themselves. They can also inhibit or prevent the excessive release, taking place after ischemia and reperfusion, of inflammation and coagulation mediators, especially of von Willebrand factor and of thrombogenic selectin proteins. This allows the pathogenic action of thrombogenic and inflammation-relevant factors to be reduced and eliminated. Therefore, it is possible to combine the NHE inhibitors of the present

30    invention with further anticoagulative and/or thrombolytic active ingredients, for example recombinant or natural tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists,
fibrinolytically active medicaments, thromboxane receptor antagonists,

phosphodiesterase inhibitors, factor VIla antagonists, clopidogrel, ticlopidin, etc. Combined use of the present NHE inhibitors with NCBE inhibitors and/or with inhibitors of carbonic anhydrase, for example with acetazolamide, is particularly favorable.

Furthermore, the inventive NHE inhibitors feature strong inhibiting action on the proliferations of cells, for example fibroblast cell proliferation and the proliferation of

smooth vascular muscle cells. The compounds of the formula I are therefore useful as

valuable therapeutic agents for disorders in which cell proliferation constitutes a

1o primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against chronic renal failure, cancers. They may thus be used for the treatment of
organ hypertrophies and hyperplasias, for example of the heart and of the prostate.

Compounds of the formula I are therefore suitable for the prevention and for the

treatment of heart failure (congestive heart failure= CHF) and also in the treatment

15    and prevention of prostate hyperplasia or prostate hypertrophy.

NHE inhibitors also feature a retardation or prevention of fibrotic disorders. They are thus suitable as outstanding agents for the treatment of fibroses of the heart, and also of pulmonary fibrosis, hepatic fibrosis, renal fibrosis and other fibrotic disorders.
20

Since there is significant elevation in the NHE in essential hypertensives, the

compounds of the fonmula I are suitable for the prevention and treatment of high blood

pressure and of cardiovascular disorders. In these cases, they may be used alone or

with a suitable combination partner for the treatment of high blood pressure and for the

25    treatment of cardiovascular disorders. For example, one or more diuretics with a thiazide-like action, loop diuretics, aldosterone and pseudoaldosterone antagonists, such as hydrochlorothiazide, indapamide, poly1hiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone, may be combined with compounds of the fonmula I. Moreover, the NHE inhibitors of the

30    present invention may be used in combination with calcium antagonists such as verapamil, diltiazem, amlodipine or nifedipine, and with ACE inhibitors, for example ramipril, enalapril, lisinopril, fosinopril or captopril. Further favorable combination
 
partners are also p-blockers such as metoprolol, albuterol etc., antagonists of the

angiotensin receptor and its receptor subtypes such as losartan, irbesartan, valsartan, omapatrilat, gemopatritat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and activators of potassium channels such as glibenclamide, glimepiride, diazoxide, cromakalim, minoxidil and derivatives thereof, activators of the

mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of

further potassium channels, such as Kv1.5, etc.

Owing to their antiinflammatory effect, inventive NHE inhibitors may be used as

1o antiinflammatory drugs. In mechanistic terms, inhibition of the release of mediators of inflammation is notable in this connection. The compounds can thus be used alone or in combination with an antiinflammatory drug in the prevention or treatment of chronic and acute inflammatory disorders. The combination partners used are advantageously steroidal and non-steroidal antiinflammatory drugs.

15

It has additionally been found that NHE inhibitors show a beneficial effect on serum lipoproteins. They can therefore be used for the prophylaxis and regression of
atherosclerotic lesions by eliminating a causal risk factor. These include not only the

primary hyperlipidemias but also certain secondary hyperlipidemias as occur, for

20    example, in the case of diabetes. In addition, NHE inhibitors lead to a distinct reduction in the infarctions induced by metabolic abnonnalities and especially to a significant reduction in the induced infarction size and the severity thereof. NHE inhibitors of the

formula 1therefore advantageously find use for the preparation of a medicament for the

treatment of hypercholesterolemia; for the preparation of a medicament for the

25    prevention of atherogenesis; for the preparation of a medicament for the prevention and treatment of atherosclerosis, for the preparation of a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels, for the preparation of a medicament for the prevention and treatment of diseases induced by endothelial dysfunction, for the preparation of a medicament for the prevention and
30    treatment of atherosclerosis-induced hypertension, for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced thromboses, for the preparation of a medicament for the prevention and treatment of hyper-
 

cholesterolemia-induced and endothelial dysfunction-induced ischemic damage and

post-ischemic reperfusion damage, for the preparation of a medicament for the

prevention and treatment of cardiac hypertrophies and cardiomyopathies and of congestive heart failure (CHF), for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced
coronary vasospasms and myocardial infarctions, for the preparation of a medicament

for the treatment of said disorders in combinations with hypotensive substances,

preferably with angiotensin converting enzyme (ACE) inhibitors and angiotensin

receptor antagonists. A combination of an NHE inhibitor of the formula I with an active

1o    ingredient lowering the blood fat levels, preferably with an HMG-CoA reductase

inhibitor (for example lovastatin or pravastatin), the latter bringing about a

hypolipidemic effect and thus increasing the hypolipidemic properties of the NHE

inhibitor of the fonnula I constitutes a favorable combination with enhanced effect and

reduced use of active ingredients.

15

Thus, NHE inhibitors lead to effective protection against endothelial damage of

different origins. This protection of the vessels against the syndrome of endothelial

dysfunction means that NHE inhibitors are valuable medicaments for the prevention

and treatment of coronary vasospasms, peripheral vascular diseases, in particular

20    intermittent claudication, atherogenesis and atherosclerosis, left-ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders.

It has additionally been found that NHE inhibitors are suitable in the treatment of non-

insulin-dependent diabetes (NIDDM), in which case, for example, the insulin resistance

25    is restrained. In this case, it may be favorable to enhance the antidiabetic activity and quality of the effect of the compounds of the invention by combining them with a biguanide such as metformin, with an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide etc., with a glucosidase inhibitor, with a PPAR agonist such as

rosiglitazone, pioglitazone etc., with an insulin product of different administration form,

30    with a 084 inhibitor, with an insulin sensitizer or with meglitinide.

In addition lo the acute antidiabetic effects, NHE inhibitors counteract the development
 

of late complications of diabetes and can therefore be used as medicaments for the

prevention and treatment of late damage from diabetes, such as diabetic nephropathy,

diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and other disorders

occurring as a consequence of diabetes. They may advantageously be combined with

the antidiabetic medicaments described above under NIDDM treatment. The

combination with a beneficial dosage form of. insulin may be particularly important in

this connection.

In addition to the protective effects against acute ischemic events and the subsequent

10    equally acutely stressing repertusion events, NHE inhibitors also exhibit direct therapeutically utilizable effects against diseases and disorders of the entire mammalian organism which are associated with the manifestations of the chronically progressive aging process and which can also occur independently of acute ischemic
states and under normal, non-ischemic conditions. These pathological, age-related

15    manifestations induced over the long aging period, such as illness, invalidity and death, which can now be made amenable to treatment with NHE inhibitors, are diseases and disorders which are essentially caused by age-related changes in vital organs and the function thereof and become increasingly important in the aging

organism.

20    Disorders ocnnected with an age-related functional impainnent or with age-related manifestations of wear of organs are, for example, the inadequate response and reactivity of the blood vessels to contraction and relaxation reactions. This age-related

decline in the reactivity of vessels to constricting and relaxing stimuli, which are an

essential process of the cardiovascular system and thus of life and health, can be

25    significantly eliminated or reduced by NHE inhibitors. One important function and a measure of the maintenance of the reactivity of vessels is the blockade or retardation of the age-related progression in endothelial dysfunction, which can be eliminated

highly significantly by NHE inhibitors. NHE inhibitors are thus outstandingly suitable for

the treatment and prevention of the age-related progression in endothelial dysfunction,

30    especially of intermittent claudication. The NHE inhibitors are thus also outstandingly suitable for the prevention and treatment of myocardial infarction, of congestive heart failure (CHF) and also for the treatment and especially for the prevention of age-
 

related forms of cancer.

In this context, a useful combination is that with hypotensive medicaments such as with ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca2+ antagonists, etc,

or with metabolism-normalizing medicaments such as cholesterol-lowering agents. The

compounds of the formula I are thus suitable for the prevention of age-related tissue changes and for maintaining health and prolonging life while retaining a high quality of life.

The inventive compounds are effective inhibitors of the cellular sodium-proton

10    antiporter (Na/H exchanger) which is elevated in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc), even in those cells which are readily amenable to measurements, for example in erythrocytes, thrombocytes or leukocytes. The compounds used in accordance with the invention are therefore suitable as
outstanding and simple scientific tools, for example in their use as diagnostic agents

15    for the determination and differentiation of different forms of hypertension, but also of atherosclerosis, of diabetes and of diabetic late complications, proliferative disorders, etc.

Moreover, NHE inhibitors are suitable for the treatment of disorders (human and

20    veterinary) induced by bacteria and by protozoa. The diseases induced by protozoa are in particular malarial disorders in humans and coccidiosis in poultry.
The compounds are also suitable as agents for the control of sucking parasites in human and veterinary medicine and also in crop protection. Preference is given to the use as an agent against blood-sucking parasites in human and veterinary medicine.

25

The compounds mentioned therefore advantageously find use alone or in combination with other medicaments or active ingredients for preparing a medicament for the treatment or prophylaxis of disorders of respiratory drive, of respiratory disorders, sleep-related respiratory disorders, sleep apneas, of snoring, of acute and chronic

30    renal disorders, of acute kidney failure and of chronic kidney failure, of disorders of intestinal function, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resulting from CNS overexcitability, epilepsy and
 
centrally induced convulsions or of states of anxiety, depressions and psychoses, of ischemic states of the peripheral or central nervous system or of stroke, of acute and chronic damage to and disorders of peripheral organs or limbs caused by ischemic events or by reperfusion events, of atherosclerosis, of disorders of lipid metabolism, of thromboses, of disorders of biliary function, of infestation by ectoparasites, of disorders
caused by endothelial dysfunction, of protozoal disorders, of malaria, for the

preservation and storage of transplants for surgical procedures, for use in surgical

operations and organ transplants, or for the treatment of states of shock or of diabetes

and late damage from diabetes, or of diseases in which cellular proliferation constitutes

1o    a plimary or secondary cause, and for maintaining health and prolonging life.

The invention further relates to the use of the compounds of the formula I and their

pharmaceutically acceptable salts for use as a medicament.

15    The invention also relates to medicines for human, veterinary or phytoprotective use, comprising an effective amount of a compound of the formula I and/or of a pharmaceuticafly acceptable salt thereof, and also medicines for human, veterinary or phytoprotective use, comprising an effective amount of a compound of the formula 1

and/or of a pharmaceutically acceptable salt thereof, alone or in combination with one

20    or more other pharmacological active ingredients or medicaments.

Medicaments which complise a compound of the fonnula I or its phannaceutically acceptable salts can be administered, for example, orally, parenterally, intramuscularly, intravenously, rectally, nasally, by inhalation, subcutaneously or by a
25    suitable transcutaneous administration form, the preferred administration depending on the particular charactelistics of the disorder. The compounds of the formula 1 can be used alone or together with pharmaceutical excipients, both in veterinary and in human medicine, as well as in crop protection. The medicaments comprise active ingredients
of the fonnula I and/or their pharmaceutically acceptable salts generally in an amount

30    of from 0.01 mg to 1 g per dosage unit.

The excipients which are suitable for the desired pharmaceutical formulation are
familiar to those skilled in the art on the basis of their expert knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active ingredient
carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or colorings.

For an oral administration form, the active compounds are mixed with the additives suitable for this purpose, such as carriers, stabilizers or inert diluents and converted to
the suitable dosage forms, such as tablets, coated tablets, hard gelatin capsules,

aqueous, alcoholic or oily solutions by the customary methods. Examples of useful 1o inert carriers include gum arabic, magnesia, magnesium carbonate, potassium

phosphate, lactose, glucose or starch, in particular com starch. The preparation may be either in the form of dry granules or in the form of moist granules. Examples of useful oily carriers or useful solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.

15

For subcutaneous, percutaneous or intravenous administration, the active compounds used, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or further excipients, are converted to solution, suspension or emulsion. Examples of useful solvents are: water, physiological saline or alcohols, for example

20    ethanol, propanol, glycerol and additionally also sugar solutions such as glucose or mannitol solutions, or else a mixture of the different solvents mentioned.

Examples of suitable pharmaceutical formulations for administration in the form of

aerosols or sprays are solutions, suspensions or emulsions of the active ingredient of

25    the formula I in a pharmaceutically acceptable solvent, in particular ethanol or water, or a mixture of such solvents. If required, the formulation may also comprise other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and also a propellant gas. Such a preparation typically contains the active ingredient in a concentration of from about 0.1 to 10% by weight, in particular from about 0.3 to 3% by

30    weight.

The dosage of the active ingredient of the formula I to be administered and the

frequency of administration depend on the potency and duration of action of the

compounds used; additionally also on the nature and severity of the disease to be treated, and also on the gender, age, weight and individual responsiveness of the
mammal to be treated.

On average, the daily dose of a compound of the formula I in the case of a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.1 mg/kg, up to at most 30 mg/kg, preferably 1 mg/kg, of body weight. In acute situations, for instance
immediately after suffering apnetic states in high mountains, even higher dosages may

10    be necessary. Especially in the case of i.v. administration, for instance in a heart attack patient in the intensive care unit, up to 300 mg/kg per day may be necessary. The daily dose can be divided into one or more, for example up to 4, individual doses.

Experimental descriptions and examples

15

List of abbreviations used:

TFA    Trifluoroacetic acid

HPLC    High Performance Liquid Chromatography
20    LC-MS    Liquid Chromatography-Mass Spectrometry

Rt    Retention time

THF    Tetrahydrofuran

DMSO    Dimethyl sulfoxide

abs.    absolute
25    DMF    Dimethylformamide

ACN    Acetonitrile

min.    minutes
 

EDC

30    AiBN NBS Cl
 

hour(s) N-(3-dimethylaminopropyi)-N'-ethylcarbodiimide 2,2'-Az.obis(2-methylpropionitrile)
N-bromosuccinimide

Chemical ionization
 





50

ESI    Electrospray ionization

m    multiplet doublet singlet

General:

Of the epimers at C-4 of the formula I, one epimer is often more active than the other.

R7


R2

R3

R4

Therefore, some of the enantiomers of the ortho-, meta- and para-amines used (2-, 3-

10    or 4-(1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine, for example 2-, 3- or 4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine), were separated on chiral phase, as described in W02004085404.
Racemic amines of the formula VIII can be prepared as described in W02004085404,

for example: racemic para-amine: 4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydro-

15    isoquinolin-4-yl)phenylamine (example 1, intermediate 6); meta-amine: 3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (example 2, intermediate 1), ortho-amine: 2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (example 3, intermediate 5) and subsequently separated into their enantiomers as described in W02004085404, for example: enantiomerically pure para-amine:

21    (S)-4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine

(example 42, intermediate 1, enantiomer B); meta-amine: (S)-3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (example 20, intermediate,
enantiomer B); ortho-amine: (R)-2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-

4-yl)phenylamine (example 41, intermediate 1, enantiomer B).

25    2-(6,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine and the corresponding (R)- and (S)-enantiomers thereof can be prepared as described in
 





51

example 41 b).

The syntheses described were, unless stated otheiWise, performed in the manner known to those skilled in the art under protective gas such as argon in standard reaction vessels such as one-, two- or three-neck flasks which, when required, were equipped with stirrers, coolers, dropping funnels and the like. The solvents were, unless stated otherwise, drawn off on a rotary evaporator in suitable vacuum and at suitable temperature.

10    Conditions:

Preparative HPLC:

The preparative HPLC was pertormed under the following conditions:

stationary phase:    Merck Purospher RP18 (10 ~M) 250 x 25 mm

15    mobile phase:    90% H20 (0.05% TFA)-> 90% acetonitrile in 40 min;

25 ml/min
 

Analytical HPLC/MS

HPLC methods

20    Method A: stationary phase: mobile phase:


25

Method B: stationary phase: mobile phase:

30

Mass spectrometry
 




YMC J'sphereODS HBO 20 x 2.1 mm

90% H20 (0.05% TFA)--; 95% acetonitrile in 1.9 min; 95%

acetonitrile 0.5 min~ 10% acetonitrile in 0.05 min;

1 ml/min.


YMC J'sphereODS HBO 20 x 2.1 mm

96% H20 (0.05% TFA)--; 95% acetonitrile in 2.0 min; 95%

acetonitrile 0.4 min-? 4% acetonitrile in 0.05 min; 1 ml/min.
 






52

The mass spectrometer was coupled directly to the HPLC (LC-MS). The ionization method used, unless stated otherwise, was electrospray (ESI+). The retention times reported relate to the signal maximum of the ion current of the appropriate compound, as was obtained in the LC-MS coupling with the above HPLC conditions.

5

Example 1: 3-[4-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

imidazolidine-2,4-dione

0
)-'\NH
,;--   N\\
""!    0

Cl


a) Ethyl (3-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]ureido}-10 acetate hydrochloride;




4-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (95 mg; preparation as described in W02004085404) was dissolved in acetonitrile (2 ml) and ethyl isocyanatoacetate (30 mg) was added dropwise with stirring. After 4 hours, the

15    solution was concentrated and the residue purified by means of preparative HPLC.

The tractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate
and extracted three times with ethyl acetate. Drying over magnesium suWate was

followed by concentration to dryness. The residue was taken up with aqueous

20    hydrochloric acid and freeze-dried. 107 mg of the desired compound were obtained. LC-MS Rt (A): 1.14 min;

[M+W]: 436.5


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

Ethyl {3-[4-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]ureido)-acetate hydrochloride (30 mg) was initially charged. Water (3 ml) and 10% hydrochloric acid (231 ~I) were added and subsequently refluxed with stirring for three hours. After
cooling and freeze-drying of the reaction solution, a white solid was obtained.

LC-MS Rt (A): 0.98 min;

[M+H+]: 390.4

10    Example 2: 3-[4-((S )-6,8-Dichloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidine-2,4-dione hydrochloride


Example 2 was synthesized analogously to example 1. The (S)-4-(6,8-dichloro-

2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine required for this purpose

15    (enantiomer B, preparation as described in W02004085404) was obtained from the racemate by separation on chiral phase.

LC-MS Rt (B): 0.89 min; [M+H+]: 390.1

20    Example 3: 3-[3-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidine-2,4-dione
 
Example 3 was synthesized analogously to example 1. The 3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine required for this purpose was prepared as described in W02004085404.

LC-MS Rt (A): 0.96 min; [M+W]: 390.3

Example 4: 3-[3-((S)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

imidazolidine-2,4-dione hydrochloride
on
N....,.NH
HCI    O 11
0

Cl~
~N,
Cl
10

Example 4 was synthesized analogously to example 1. The (S)-3-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine required for this purpose (enantiomer B, preparation as described in W02004085404) was obtained from the

racemate by separation on chiral phase.

15    LC-MS Rt (B): 0.90 min; [M+W]: 390.0

Example 5: 3-[2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidine-2,4-dione hydrochloride
 
Cl

Example 5 was synthesized analogously to example 1. The 2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine required for this purpose was obtained as described in W02004085404.

LC-MS Rt (A): 1.04 min; [M+W]: 390.4

Example 6: 3-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

imidazolidine-2,4-dione hydrochloride





10

Example 6 was synthesized analogously to example 1. The (R)-2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine required for this purpose (enantiomer B, preparation as described in W02004085404) was obtained from the
racemate by separation on chiral phase.

15    LC-MS Rt (B): 0.98 min; [M+H+J: 390.0

Example 7: 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione hydrochloride

Cl

(R)-2-(6 ,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine ( 100 mg; enantiomer B, preparation as described in W02004085404) was initially charged in a flask together with succinic acid (58 mg). To this was added polyphosphoric acid (approx. 2 ml). The reaction mixture was subsequently stirred at 135°C. After 4 hours, a little more succinic acid (-9 mg) was added. After a further 2 hat 135°C, the mixture

was left to stand at room temperature overnight. For workup, the mixture was poured onto ice-water, and the acidic phase was adjusted to pH 10 with saturated potassium carbonate solution and then extracted three times with ethyl acetate. The combined

10    organic phases were washed once with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and
extracted three times with ethyl acetate. It was dried over magnesium sulfate, then

15    filtered and concentrated to dryness. The residue was taken up with aqueous hydrochloric acid and freeze-dried.
LC-MS Rt (B): 1.03 min; [M+W]: 389.0

20    Example 8: 6,8-Dichloro-4-[4-(1, 1-dioxo-1-l.'-[1,2,5]thiadiazolidin-2-yl)phenyl]-2-methyl-1 ,2,3,4-tetrahydroisoquinoline
 
H o~rl

O-:;:::.S,N)
ClJN'
Cl

2-Chloroethylamine hydrochloride (75 mg) was stirred with sulfuryl chloride (0.32 ml) in acetonitrile (10 ml) at 75-aooc overnight. The mixture cooled to room temperature was ocncentrated and the residue taken up with absolute ether (1 ml). The ether phase

5    comprising the chlorosulfonamide was added dropwise to a solution of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (110 mg. preparation as described in W02004085404). absolute diethyl ether (1 ml) and triethylamine (85 ~I) at -70°C. After the addition had ended, the reaction mixture was allowed to come to room temperature and stirred for a further 2.5 h. Subsequently, it was admixed with a

1o    mixture of water and saturated sodium hydrogencarbonate solution (3: 1) and a little

more ether was added. The phases were separated and the aqueous phase was

extracted twice with diethyl ether. The combined ether phases were dried over

magnesium sutfate, filtered and concentrated.

15    The crude product was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with dichloromethane. It was dried over magnesium sulfate, then
filtered and ocncentrated to dryness. A portion of the product thus obtained (20 mg)

20    was dissolved in DMSO (0.5 ml), admixed with potassium carbonate (6.2 mg) and stirred at room temperature for six hours. After storing in a freezer cabinet overnight, the DMSO was removed under high vacuum and the residue admixed with a little water, saturated sodium hydrogencarbonate solution and ether. The phases were separated and the aqueous phase was extracted twice more with diethyl ether. The

58

combined ether phases were dried over magnesium sulfate, filtered and concentrated.

The crude product was pur~ied by means of preparative HPLC. The fractions

comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with dichloi'"omethane.It was dried over magnesium sulfate, then
filtered and concentrated to dryness. The residue was taken up with aqueous

hydrochloric acid and freeze-dried.

LC-MS Rt (B): 1.02 min;

[M+H+j: 412.1

10

Starting from the corresponding amines, some of which were used in enantiomerically pure form, and the corresponding dicarboxylic acids, the following compounds were
prepared analogously.
 
Example 35: 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

pyrrolidin-2-one trifluoroacetate

~NJ
"l(C"'~oloc
Cl    F

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

(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (1 00 mg, enantiomer B, preparation as described in W02004085404) was initially charged with y-butyrolactone (84 mg) in abs. THF (8 ml), and then sodium hexamethyldisilazide (NaHMDS; 2 MfTHF; 0.65 ml) was added dropwise at O"C within 15 min. After stirring at aoc for 10 min, the ice bath was removed and the mixture was stirred for a further

2 h. The reaction was admixed with saturated ammonium chloride solution (0.6 ml),

ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once
1o  with saturated sodium chloride solution, dried over magnesium sulfate, filtered and

concentrated. The crude product was purified by means of preparative HPLC. The

tractions comprising product were combined, the acetonitrile was removed on a rotary

evaporator, and the aqueous residue was neutralized with potassium carbonate and

extracted three times with dichloromethane. After the combined dichloromethane

15    phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness.
LC-MS Rt (B): 0.98 min; [M+H+]: 393.1

20    b) 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-one trifluoroacetate
N-[2-( (R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-4-hydroxy-butyramide (100 mg) was dissolved in absolute THF (4 ml), and triethylamine (77 ~I)

and a solution of methanesulfonyl chloride (44 ~I) in THF (0.5 ml) was added dropwise.

25    After stirring at room temperature for six hours, the THF was drawn off and the residue admixed with saturated sodium hydrogencarbonate solution. After extracting three
 
times with ethyl acetate, the combined organic phases were dried over magnesium

sulfate, filtered and concentrated. A portion of the residue (44 mg) was dissolved in absolute THF (2 ml) and the reaction mixture was cooled to ooc. At this temperature, sodium hexamethyldisilazide (96 ~I) was added dropwise within 10 min. Subsequently,

5    the mixture was stirred at ooc for another 10 min before the ice bath was removed. After 1.5 h, the reaction was admixed with saturated ammonium chloride solution
(0.2 ml) and water. The mixture was then extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC. The

10    fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with dichloromethane. After the combined dichloromethane phases had been dried over magnesium sulfate, they were filtered and concentrated to

dryness.

15    LC-MS Rt (B): 1.04 min; [M+H+]: 375.1

Example 36: 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydmisoquinolin-4-yl)phenyl]-pyrrolidin-2-one hydrochloride

HCI    ~(s

Cl~~
 

20
 

Cl
 

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

butyramide


2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (250 mg) was dissolved in abs. THF (20 ml). 4-Chlorobutyryl chloride (115 mg) and triethylamine (208 ~I) were added with stirring. The mbdure was stirred at room temperature for
approx. 3 h. After standing overnight, the reaction mixture was concentrated and the residue purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with sodium hydrogencarbonate and extracted three times
with ethyl acetate. After the oombined ethyl acetate phases had been dried over

1o magnesium sulfate, they were filtered and concentrated to dryness. 290 mg of an oily product were obtained.
LC-MS Rt (B): 1.14 min; [M+H+]: 411.0

15    b) 1-[2-((R)-6,8-Dich loro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidin-2-<>ne hydrochloride
4-Chloro-N-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

butyramide (249 mg) was dissolved in abs. DMSO (1 0 ml) and finely powdered and

dried potassium carbonate (250 mg) was added. With exclusion of moisture, the

20    mixture was stirred vigorously at room temperature for 4 h. After standing overnight, the reaction mixture was diluted with water (50 ml) and then extracted three times with ethyl acetate. The combined ex1racts were dried over magnesium sulfate, filtered and ooncentrated. The residue was purified by means of preparative HPLC. The fractions

comprising product were combined, the acetonitrile was removed on a rotary

25    evaporator, and the aqueous residue was neutralized with sodium hydrogencarbonate and ex1racted three times with ethyl acetate. After the combined ethyl acetate phases

had been dried over magnesium sulfate, they were filtered and concentrated to

dryness. The residue was dissolved in water/acetonitrile and adjusted to pH 2 with

0.1 N HCI. After freeze-drying overnight, the desired product (116 mg) was obtained as a white powder.
LC-MS Rt (B): 1.06 min; [M+H+]: 375.1

Exam pie 37: 1-[2-( (R)-6,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]pyrrolidin-2-one

The title compound was synthesized starting from 2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (example 41 b) analogously to example 36.
LC-MS Rt (B): 1.12 min;

15    [M+H+J: 401.0

Example 38: 1-[3-((S )-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-piperidin-2-one


Cll(O,
Cl

20    Starting from (S)-3-(6,8-<Jichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-

phenylamine (enantiomer B, preparation as described in W02004085404) and o-valerolactone, 1-[3-((S)-6,8-<iichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]piperidin-2-one was synthesized analogously to example 35.

LC-MS Rt (B): 1.05 min;

5    [M+W]: 389.1

Example 39: 1-[2-( (R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidin-2-one hydrochloride
0-J
Cl~ NLJNH

~N...._HCI

Cl

10    a) 1-(2-Chloroethyi)-3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]urea
~0

~)lNH

CI"QQ: (

Cl

(R)-2-(6,8-Dichloro-2-methyl-1 ,2 ,3,4-tetrahydroisoquinolin-4-yl)phenylamine (1 00 mg,

enantiomer B, preparation as described in W02004085404) was dissolved in absolute

15    dichloromethane (5 ml) and admixed with stirring with 4-nitrophenyl chloroform ate (79 mg). After stirring at room temperature for 4 h, the mixture was left to stand overnight. The next day, further 4-nitrophenyl chloroform ate (1 0 mg) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was

concentrated to dryness under reduced pressure and the residue was dissolved in

20    absolute dichloromethane (5 ml). After addition of triethylamine (1 80 ~I), a solution of 2-chloroethylamine hydrochloride (61 mg) in absolute dichloromethane (3 ml) was added dropwise and the mixture was stirred at room temperature for four hours.


Subsequently, the mixture was admixed with further methylene chloride and dilute

potassium carbonate solution and the organic phase was extracted three times with dilute potassium carbonate solution. After drying over magnesium sulfate and filtration,
the organic phase was concentrated and purified by means of preparative HPLC. The

5    fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium su~ate, they were filtered and concentrated to dryness. 50 mg of the desired product were obtained.

10    LC-MS Rt (8): 1.05 min; [M+H+]: 412.1

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

imidazolidin-2-one hydrochloride

15    1-(2-Chloroethyl)-3-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]urea (40 mg) was dissolved in absolute DMSO (1 ml) and admixed with stirring with potassium carbonate (14 mg). After stirring at room temperature for four hours, a little more potassium carbonate (7 mg) was added. After being left to stand overnight,

the DMSO was removed under reduced pressure, the residue was admixed with a little

20    water and saturated sodium hydrogencarbonate solution and the resulting mixture was subsequently extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue

was purified by means of preparative HPLC, although it was not possible to remove

one impurity, so that a further chromatography on silica gel followed (1 00/0 to 88/12

25    dichloromethane/methanol within 80 min). The clean fractions were combined and concentrated to dryness, and the residue was subsequently freeze-dried with water and a little hydrochloric acid.

LC-MS Rt (8): 1.00 min;

[M+H+]: 376.0

30

Example 40: 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

1 ,3-dihydroimidazol-2-one hydrochloride
 
Cl

a) 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-(2,2-diethoxyethyl)urea
~)'NH
c1MH    yol
~N,    (0

Cl    I

(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (75 mg, enantiomer B, preparation as described in W02004085404) was reacted analogously to example 25 a) with 4-nitrophenyl chloroformate (64 mg) and subsequently with 2,2-diethoxyethylamine (46 mg).

LC-MS Rt (B): 1.14 min;

10    [M+H+]: 466.1

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

1 ,3-dihydroimidazol-2-<me hydrochloride

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

15    3-(2,2-diethoxyethyl)urea (65 mg) was dissolved in formic acid (0.4 ml) and stirred at room temperature for 2 hours. Subsequently, the mixture was admixed with water and neutralized with saturated sodium hydrogencarbonate solution. After extracting three times with ethyl acetate, the combined organic phases were dried over magnesium
su~ate, filtered, concentrated and purified by means of preparative chromatography.

20    The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. After the

combined ethyl acetate phases had been dried over magnesium sutfate, they were

filtered and concentrated to dryness. The residue was taken up with aqueous HCI and

freeze~dried.

LC-MS Rt (B): 1.05 min; [M+H+]: 37 4.0

Example 41 : 3-[2-( (R}-6, B-Dichloro-2-cyclopropyl-1 ,2, 3 ,4-tetra hydroisoquino lin -4-yl)-phenyl]thiazolidine-2,4-dione


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

Cl~ ynNH,    CI~V1    NH,   
    ~    N       
~Jo~    X0   
    Cl    I   
Cl

N-(2-{2-[Cyclopropyl(2,4-dichlorobenzyl)amino]-1-hydroxyethyl}phenyl)acetam ide

15    (46 g, obtained analogously to example 15 in WO 03 48129) was dissolved in methanol (250 ml). 30% sodium methoxide solution was added thereto with stirring and then the mixture was refluxed for 10 h. To complete the reaction, solid sodium methoxide (10 g) was added and the mixture was refiuxed for a further 4 h. For workup, the reaction mixture was subsequently added to 1.5 I of ice-water and eluted

20    three times with ethyl acetate. The combined ethyl acetate phases were washed once with saturated sodium chloride solution, then dried with magnesium sulfate, filtered and concentrated. After chromatographic purification on silica gel, 14 g of

74 1-(2-aminophenyl)-2-[cyclopropyl(2,4-dichlorobenzyl)amino]ethanol LC-MS Rt (B): 1.03 min;

[M+W]: 351 .0,

13.8 g of 2-{2-[cyclopropyl(2,4-dichlorobenzyl)amino]-1-methoxyethyl)phenylamine LC-MS Rt (B):1.18 min;

[M+H+]: 365.0

and 5.5 g of a mixed fraction of the two products were obtained.

The three fractions can all, as described below for 1-(2-aminophenyl)-2-[cyclopropyl-(2,4-dichlorobenzyl)amino]ethanol under b), be cyclized with sulfuric acid to give
1o    2-(6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine.

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

~
~NH
Cl~ 2
~NClv

15    1-(2-Aminophenyl)-2-[cyclopropyl(2,4-dichlorobenzyl)amino]ethanol (14 g) was dissolved in dichloromethane (250 ml) and cooled to ooc with stirring. Under cold conditions, cone. su~uric acid (50 ml) was added dropwise. After the addition had ended, the mixture was stirred at room temperature for approx. 7 h and then at 45oc for 2 h, in the course of which the dichloromethane evaporated slowly. After standing

20    at room temperature overnight, the reaction was completed by again adding su~uric acid (5 ml) and keeping the temperature at 65°C for 12 h. Afterward, the reaction mixture was added to ice-water and adjusted to pH 11 with 10 N sodium hydroxide solution. The water phase was extracted three times with dichloromethane. The
combined extracts were dried over magnesium sulfate, filtered and concentrated. The

25    crude product (12.3 g) was chromatographed on silica gel (1 :1 to 4:1 ethyl acetate/n-heptane). The resulting purified racemic product (10.7 g) was subsequently separated into its enantiomers by means of chiral HPLC (Chiralpak ADH/45, eluent:
75 20:1:1 heptane/isopropanol/methanol +0.1% TFA).
7 g of the 2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenylamine P1 which elutes first and 6 g of the more slowly eluting 2-((S)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylam ine P2 were obtained in the form of their double TFA salts.

Chiral HPLC:

Column: Chiralpak ADH/45, 250 x 4.6 mm;

Eluent: 20/1/1 heptane/isopropanol/methanol+ 0.1 % TFA Flow rate: 1 ml/min at 30oC

10    P1: Rt: 7.27 min P2: Rt: 12.81 min

c) Phenyl [2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

thiocarbamate
2-((R)-6,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (300 mg) was dissolved in absolute THF (5 ml) and phenyl chlorothioformate (75 ~I) dissolved in absolute THF (1 ml) was added dropwise. The reaction mixture stirred at

room temperature for 4 h and stood overnight. The solvent was then removed and the

20    residue purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness.

25    LC-MS Rt (B): 1.87 min; [M+H+]: 469.0

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

thiazolidine-2,4-dione

Phenyl [2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

thiocarbamate (50 mg) was dissolved in 30% sodium methoxide solution in methanol

(5 ml). For dissolution, the mixture was heated gently with a hot-air gun. The clear solution was stirred at room temperature for approx. 3 h and left to stand overnight.
Subsequently, the reaction mixture was diluted with water and extracted three times

with ethyl acetate. The combined extracts were dried with magnesium su~ate, filtered

10    and concentrated. The crude product thus obtained (45 mg) was dissolved in absolute methylene chloride (3.5 ml) and bromoacetyl chloride (16.5 mg) was added. The mixture was stirred at room temperature with exclusion of moisture for 3 h. After
standing overnight in a freezer cabinet, the solvent and the excess acid chloride were

evaporated off and the residue was purified by means of preparative HPLC. The

15    fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were

filtered and concentrated to dryness. A portion (12 mg) of the resulting residue (15 mg)

20    was dissolved in water/acetonitrile, a little hydrochloric acid was added and the clear solution was freeze-dried overnight.

LC-MS Rt (8): 1.40 min; [M+H+]: 433.0

25    Example 42: 3-[2-((R}-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-thiazolidine-2,4-dione


(R)-2-( 6, 8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (enantiomer B, preparation as described in W02004085404) was reacted analogously to example 41. The crude product exhibited a double peak of identical mass in the LC-MS, so that the two products were separated by means of preparative HPLC and

5    subsequently identified. In addition to a contaminated fraction, the two rotational isomers P1 and P2 were isolated.

P1:

LC-MS Rt (B): 1.09 min;

[M+W]: 407.0

10    1 H NMR (500 MHz, DMSO-d6): 7.51-7.28 (m, 4 H), 7.11 (m, 1 H), 6.72 (s, 1 H), 4.51 (d, 15Hz,1 H),4.34(d, 15Hz, 1 H),4.18(m, 1 H),3.64(d, 15Hz, 1 H),3.50(d, 15Hz, 1 H), 2.70 (m, 1 H), 2.49 (m, with DMSO), 2.33 (s, 3H) [in ppm]

P2:

LC-MS Rt (8): 1.14 min;

15    [M+H"']:407.0

1 H NMR (500 MHz, DMSO-d6): 7.52-7.26 (m, 4 H), 7.19-7.09 (m, 1 H), 6.72 (s, 1 H), 4.49 (d, 15Hz, 1 H), 4.35 (d, 15Hz, 1 H), 4.12 (m, 1 H), 3.65 (d, 15Hz, 1 H), 3.50 (d, 15Hz, 1 H), 2.72 (m, 1 H), 2.48 (m, with DMSO), 2.33 (s, 3H) [in ppm]

20    Alternative synthesis:

When chloroacetyl chloride was used instead of bromoacetyl chloride, mainly P2 was obtained wihich, according to preparative HPLC, was only slightly contaminated with P1 (<10% according to 1H NMR).
 






78

Example 43: 3-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny~­

oxazolidine-2,4-dione
Qo
CI'Q()jJ_~
I //   N 0
'-

CI

a) [2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl-carbamoyl]methyl acetate

HCI    ~N~

Clyoj  ~0
I //   N'-0

CI

(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (300 mg, enantiomer B, preparation as described in W02004085404) was dissolved in absolute THF (1 0 ml) and admixed at room temperature with stirring with sodium hexamethyl-

10    disilazide solution (0.5 ml; 2M in THF). After 30 min, acetoxyacetyl chloride (77 ~I) was added and the mixture was stirred at room temperature for 2 h. Subsequently, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water and basified with sodium hydrogencarbonate solution, and the phases were separated.
The aqueous phase was extracted three times with ethyl acetate. The combined

15    extracts were dried over magnesium sulfate, filtered and concentrated. 380 mg of the desired product were obtained. 40 mg thereof were dissolved in acetonitrile/water, acidified with 0.1 N hydrochloric acid and freeze-dried.

LC-MS Rt (B): 1.02 min;

[M+H+]: 407.0

20

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

V~~
CI'QO'  OH
1.-?    N
    '-
CI   

[2-( (R)-6,8-Dichloro-2-methyl-1 ,2,3 ,4-tetrahydroisoquinolin-4-yl)phenyl-carbamoyl]methyl acetate (180 mg) was dissolved in methanol (5 ml). With stirring,

5    potassium carbonate (305 mg, finely powdered) was added and the mixture was then stirred efficiently at room temperature for 4 h. Subsequently, the solvent was

evaporated off, and the residue was taken up in ethyl acetate and washed three times

with water. The ethyl acetate phase was dried with magnesium su~ate, filtered and concentrated. 160 mg of the desired product were obtained.

10    LC-MS Rt (B): 0.94 min; [M+H+j: 365.0

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

oxazolidine-2,4-dione

15    N-[2-((R)-6 ,8-Dichloro-2-methyl-1 ,2,3 ,4-tetrahydroisoquinolin-4-yl)phenyl]-2-hydroxy-acetamide (20 mg) was dissolved in absolute THF (2 ml), and reacted at room temperature with sodium hexamethyldisilazide solution (0.5 ml; 2 M in THF) with stirring. Afterward, 1, 1-carbonyldiimidazole (13 mg) was added and the mixture was stirred at room temperature for 2 h. After standing overnight, the reaction mixture was

20    concentrated, the residue was dissolved in ethyl acetate/water and basified with sodium hydrogencarbonate solution, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means

of preparative HPLC. The fractions comprising product were combined, the acetonitrile

25    was removed on a rotary evaporator, and the aqueous residue was neu'b"alizedwith saturated sodium hydrogencarbonate solution and extracted three times with ethyl


acetate. After the ccmbined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and ccncentrated to dryness. The residue was dissolved in water/acetonitrile and the clear solution was freeze-dried overnight. 10 mg of the

desired product were obtained.

5    LC-MS Rt (B): 1.09 min; [M+H+]: 391.0

Example 43a: 3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-

phenyl]oxazolidine-2,4-dione hydrochloride
 

 

Analogously to the sequence in example 43, 25 mg of the title compound were synthesized. Trichloromethyl chloroformate was used in the cyclization step instead of
1, 1-carbonyldiimidazole and the freeze drying was carried out in the presence of

hydrochloric acid.LCMS-Rt (B): 1.31 min;

15    [M+W]: 417.0

Example 44: 4-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-morpholine-3,5-dione trifluoroacetic acid salt
HO~F 0   1
F F    Vl---w  I
Cl~' 0 ~0
I ""'  N'
CI

(R)-2-(6 ,8-Dich\oro-2-methy\-1 ,2 ,3,4-tetrahydroisoquino\in-4-y\)pheny\amine (70 mg,

5    enantiomer B, preparation as described in W02004085404) was dissolved in absolute dich\oromethane (5 ml) with stirring and admixed with diglyco\ic anhydride (27 mg).
The mixture was stirred at room temperature for several hours and left to stand

overnight. After addition of further diglyco\ic anhydride (26 mg), the mixture was stirred for 10 hand left to stand overnight. After the solvent had been removed, the residue

10    was purified by means of preparative HPLC. The fractions comprising product were combined and the acetonitrile was removed on a rotary evaporator and the aqueous residue was freeze-dried.
LC-MS Rt (B): 0.93 min;

[M+H+]: 423.1

15

b) 4-[2-( (R)-6 ,8-Dich\oro-2-methy\-1 ,2,3,4-tetrahydroisoquinolin-4-y\)pheny\]-

morpholine-3,5-dione trifluoroacetic acid salt

4 {[2-((R)-6,8-Dich\oro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-y\)phenylcarbamoyl]-methoxy}acetic acid trifluoroacetic acid salt (50 mg) was dissolved in absolute

20    dich\oromethane (2 ml) with stirring and admixed with HOnig'sbase (46 ~I). EDC

(22 mg) was then added and the mixture was stirred at room temperature for several hours. After standing overnight, further EDC (22 mg) and HOnig'sbase (46 ~I} were added. After 24 h, the solvent was removed and the residue purified by means of preparative HPLC. The product-containing fractions were combined, freed of

25    acetonitrile and freeze-dried. LC-MS Rt (B): 1.07 min;

[M+H+]: 405.0

Example 45: 3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-

phenyl]oxazolidin-2-one






a) 2-Chloroethyl [2-((R)-6,8-<iichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]carbamate
~NJ
'    H    ~
Cllp\7  Cl

Cl

2-((R)-6 ,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine

10    (400 mg) was dissolved in absolute THF (25 ml), and 2-chloroethyl chloroformate

(102 mg) was added with stirring. After stirring at room temperature for 3 h, the mixture was left to stand overnight. The solvent was then removed and the residue purified by means of preparative HPLC. The fractions comprising product were combined, the
acetonitrile was removed on a rotary evaporator, and the aqueous residue was

15    neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. 380 mg of the desired product were obtained.

LC-MS Rt (B): 1.66 min;

20    [M+H+]: 439.0

b) 3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-oxazolidin-2-Dne2-Chloroethyl [2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate (320 mg) was dissolved in absolute THF (20 ml). With stirring, sodium hydride (35 mg) was added. After stirring at room

temperature tor 2 h, the reaction mixture was concentrated, and the residue was

dissolved in ethyl acetate and washed twice w~h water. The ethyl acetate phase was drted over magnesium sulfate, filtered and concentrated. The residue was purtfied by
means of preparative HPLC. The fractions comprising product were combined, the

acetonintrile was removed on a rotary evaporator, and the aqueous residue was

10    neutralized with saturated sodium hydrogen carbonate solution and extracted three

times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in acetonitrtle/water, acidified with 0.1 N hydrochloric acid and freeze-dried. 176 mg of the desired product were obtained as the hydrochloride.

15    LC-MSRt(B):1.16min; [M+H+j: 403.0

Example 46: 3-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

oxazolidin-2-one
Uo
' NJZO
Cl    '    lJ
~"- HCI

Cl
20

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

Analogously to example 45a), (R}-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)phenylamine (300 mg, enantiomer 8, preparation as described in W02004085404) was reacted with 2-chloroethyl chloroformate (140 mg). 400 mg of the desired product were obtained.

5    LC-MS Rt (8): 1.15 min; [M+H'']:413.0

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

2-one

1 o Analogously to example 45b), 2-chloroethyl [2-((R)-6,8-<lichloro-2-methyl-1,2,3.4-tetra-hydroisoquinolin-4-yl)phenyl]carbamate (340 mg) was reacted with sodium hydride (39 mg). 230 mg of the desired product were obtained as the hydrochloride.

LC-MS Rt (8): 1.01 min; [M+H'']:377.0
15

Example 47: (S)-1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-

phenyl]-3-hydroxypyrrolidine-2,5-dione






((S)-5-0xo-2-trichloromethyl[1,3]dioxolan-4-yl)acetic acid (171 mg, see Synthesis

20    2002, 2165) and thionyl chloride (2 ml) were initially charged and heated to refiux w~h stirring for 4 h. Subsequently, the excess thionyl chloride was distilled off on a

Rotavapor, the residue was dissolved in absolute toluene (14 ml), (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine and triethylamine (0.91 ml) were added and the mixture was refiuxed for 2 h. After standing overnight, the reaction

25    mixture was concentrated, and the residue was admixed with ethyl acetate/water, adjusted to pH 8 with sodium hydrogencarbonate solution and washed three times with

saturated sodium chloride solution. The ethyl acetate phase was dried with magnesium

sulfate, filtered and concentrated. The residue was recrystallized from ethyl

acetate/heptane. 65 mg of the desired compound were obtained, which exhibits

rotational isomerism. However. only a weak, unquantffiable splitting was found in the

5    LC-MS.

LC-MS Rt (B): 1.02 min; [M+H"J: 405.0

Example 48: (R)-1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-10 phenyl]-3-hydroxypyrrolidine-2,5-dione
~0
Clyol p .... QH
I a     No
...._

Cl

((R)-5-0xo-2-trichloromethyl[1 ,3]dioxolan-4-yl)acetic acid (214 mg, see Synthesis 2002, 2165) and thionyl chloride (2.5 ml) were in~ially charged and heated to reflux with stirring for 4 h. Subsequently, the excess thionyl chloride was distilled off on a

15    Rotavapor, the residue was dissolved in absolute toluene (18 ml), (R)-2-(6,8-dichlor0-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (250 mg) and triethylamine (1.13 ml) were added and the mixture was refluxed for 2 h. Subsequently, the reaction mixture was concentrated, and the residue was admixed with ethyl acetate/water,

adjusted to pH 8 with sodium hydrogencarbonate solution and washed three times with

20    saturated sodium chloride solution. The ethyl acetate phase was dried w~h magnesium sulfate, fi~ered and concentrated. Subsequent crystallization from ethyl acetate/n-heptane afforded 240 mg of the desired product, which exhibits rotational isomerism, so that two signals of identical mass were round in the LC-MS.

LC-MS Rt (B): 0.99 and 1.04 min;

25    [M+H+]: 405.0

Example 49: (R)-1-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione
Qo
a~P~
~No
Cl    'v

((R)-5-0xo-2-trichloromethyl[1,3]dioxolan-4-yl)acetic acid (94 mg. see Synthesis 2002,

5    2165) and thionyl chloride (2 ml) were initially charged and heated to reflux with stirring for 4 h. The excess thionyl chloride was distilled off on a Rotavapor and the residue was dissolved in absolute toluene (15 ml). 2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine trifluoroacetic acid salt (200 mg) was added in

solid form, followed by triethylamine (0.5 ml). Subsequently, the mixture was stirred at

10    room temperature for 2 h, then at 6D'Cfor 1 h, then at 8D'Cfor 2 hand finally at 10D'C for 6 h. After cooling and removal of the solvent, the mixture was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator and the aqueous residue was freeze-dried. For

further workup, the mixture was then purified further on silica gel (1 00:0 to 90:10

15    dichloromethane/methanol). The clean fractions were combined and freed of solvent. Freeze-drying from water/acetonitrile afforded 20 mg of the desired product.

LC-MS Rt (B): 1.15 min; [M+W]: 431.0

20    Example 50: (S )-1-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-

4-yl)pheny~-3-hydroxypyrrolidine-2,5-dione
 
Analogously to example 49, ((R)-5-oxo-2-trichloromethyl[1 ,3]dioxolan-4-yl)acetic acid (94 mg, see Synthesis 2002, 2165), thionyl chloride (2 ml) and 2-((R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine trifluoroacetic acid salt (200 mg) were reacted. The freeze-<Jrying from water/acetonitrile afforded 31 mg of the desired product.

LC•MS Rt (8):1.13 min; [M+W]: 413.0

6
10    Example 51: (R)-6,8-Dichloro-4-[2-(1, 1-dioxo-1-A- -isothiazolidin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

~0
HCI    ~  \\.yO
Cl~; f)
1.0    N
'
Cl

(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine ( 100 mg)

was initially charged in absolute THF (8 ml) and 3-chloropropanesulfonyl chloride

15    (116 mg, dissolved in absolute THF (1.5 ml)) was added dropwise at room temperature and the reaction mixture was subsequently refluxed for 16 hours. To complete the reaction, chloropropanesu~onyl chloride (8 mg) was added once again, followed by sodium hexamethyldisilazide solution (0.2 ml; 2 M in THF). After stirring at room temperature for 30 min and subsequent refluxing, the reaction was completed by

20    adding a further equivalent of sodium hexamethyldisilazide solution and refluxing again. Subsequently, the mixture was admixed with water at room temperature and


extracted three times with ethyl acetate. The combined ethyl acetate phases were

dried over magnesium sulfate, filtered and concentrated. The residue was

subsequently purified by means of preparative HPLC. The fractions comprising product

were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous

residue was neutralized with saturated sodium hydrogencarbonate solution and

extracted three times with ethyl acetate. After the combined ethyl acetate phases had

been dried over magnesium sulfate, they were filtered and concentrated to dryness.

The residue was taken up with water/hydrochloric acid and freeze-dried. 12 mg of the

title compound were obtained.

10    LC-MS Rt (B): 1.05 min;

[M+W]: 411.0

Example 52: 1-[2-((R)-6,8-Dichloro-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione trifluoroacetic acid salt
m    Y-;:5
Cly::;~
15    Cl

a) N-{2-[2-(2,4-Dichlorobenzylamino)-1-hydroxyethyl]phenyl}acetamide

0
"~, o,,A_
~IN~

2,4-Dichlorobenzylamine (2.1 ml) was dissolved in absolute ethanol (20 ml) and N-[2-{2-bromoacetyl)phenyl]acetamide (2 g), dissolved in absolute ethanol (50 ml),

20    was added dropwise at room temperature with stirring. After 30 min, sodium borohydride (600 mg) was added with ice cooling and stirred for a further 1.5 h.
Subsequently, the solvent was removed and the residue taken up in an ethyl
 





89

acetate/water mixture. The phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of
preparative chromatography. The fractions comprising product were combined. the

5    acetonitrOe was removed on a rotary evaporator and the aqueous residue was basified with potassium carbonate and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 720 mg of the title compound were obtained.

LC-MS Rt (B): 0.93 min;

10    [M+H+j: 353.0

b) 1-(2-Aminophenyl)-2-(2,4-dichlorobenzylamino)ethanol

Cl~?"IH     OH   NH
:::,...    N~

Cl    ~

N-{2-[2-{2,4-Dichlorobenzylamino)-1-hydroxyethyl]phenyl}acetamide (1 00 mg) was

15    dissolved in methanol (5 ml) and admixed with sodium methoxide solution (0.3 ml;

30% in methanol). After reflux for 6 h, the reaction mixture was poured onto ice-water, neutralized with 2 N hydrochloric acid and extracted three times with ethyl acetate. The combined orga•nic phases were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by means of preparative HPLC. The fractions

20    comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. 34 mg of the desired compound were obtained, which was

25    reacted further directly. LC-MS Rt (8):0.90 min;

[M+H+j: 311.0
 
90

c) 2-((R}-6,8-Dich/oro-1 ,2,3,4-tetrahydroisoquinolin-4-YI)pheny/amine
Q
;    NH2
C/    '
~H

Cl 1-(2-Aminophenyl}-2-(2,4-dich/orobenzy/amino)ethano/ (34 mg) was dissolved in dichloromethane (1 ml) and admixed with ice cooling and stirring w~h concentrated

sulfuric acid. Subsequently, the ice bath was removed and the mixture was stirred at

80°C for 1 0 hours while evaporating off the dichloromethane. After cooling, the

reaction mixture was admixed with ice•water with ice cooling and alkalized with 10 M sodium hydroxide solution. The aqueous phase was extracted three times with

dichloromethane and the combined organic phases were dried over magnesium

10    sulfate, filtered and concentrated. The residue was purified on silica gel. 22 mg of the desired compound were obtained.

LC-MS Rt (B): 0.99 min; [M+W]: 293.0

15    d) 1-12-((R)-6,8-Dichloro-1 ,2,3,4-tetrahydroisoquinolin-4-yl)pheny/]pyrrolidine-2,5-dione trffluoroacetic acid salt
2-((R}-6,8-Dichloro-1 ,2,3,4-tetrahydroisoquino/in-4-yl)phenylamine (22 mg) was heated to 150°C together with succinic acid (10 mg) and po/yphosphoric acid (2 ml) in a

closed screwtop test tube for 3 h. For workup, the still-hot reaction mixture was added

20    to ice-water and alkalized with saturated potassium carbonate solution. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were
combined, the acetonitrile was removed on a rotary evaporator and the residue was

25    freeze-dried. 7 mg of the tifle compound were obtained. LC-MS Rt (B): 1.04 min;


[M+H"']:375.0

Example 53: 3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-

phenyl]imidazolidine-2,4-dione hydrochloride


39 mg of the title compound were obtained starting from 2-((R}-6,8-dichloro-2-cyclo-propyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (example 41 b) and ethyl
isocyanatoacetate analogously to example 1.

LC-MS Rt (B): 1.14 min;

10    [M+H+]: 416.0

Example 54: 3-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methylimidazolidine-2,4-dione hydrochloride


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

HCI    ~NJO
"'QO: ¢
Cl    N02

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (200 mg,

enantiomer B, preparation as described in W02004085404) was dissolved in absolute

dichloromethane (6 ml) and admixed with stirring with 4-nitrophenyl chloroformate

(157 mg). After 4 h, a further 0.1 equivalent of 4-nitrophenyl chloroformate was added.

After standing overnight, the dichloromethane was removed and the residue was used

directly in the next stage.

10    LC-MS Rt (8):1.29 min; [M+H+]: 4 72.0

b) 3-[2-((R )-6,8-Dichlom-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methyl-

imidazolidine-2,4-dione hydrochloride

15    4-Nitrophenyl [2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate (125 mg) was dissolved in absolute THF (5 ml), and sarcosine methyl ester hydrochloride and triethylamine were added dropwise with stirring. After stirring for 5 h, the reaction mixture was freed of the solvent, and the residue was admixed with water and 2 N hydrochloric acid and refluxed for 2 h. After standing

20    overnight, the reaction mixture was concentrated and admixed with ethyl acetate, water and saturated potassium carbonate solution. After separation of the phases, the organic phase was washed five times with saturated potassium carbonate solution and twice with saturated sodium chloride solution. Drying over magnesium sulfate and filtration were followed by concentration. The residue was purified by means of

25    preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate.

After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was taken up with water/hydrochloric acid and freeze-dried. 60 mg of the title compound were obtained.
LC-MS Rt (B): 1.02 min;

5    [M+H+]: 404.0

Example 55: 3-[2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-1-methylimidazolidine-2,4-dione hydrochloride

10    Starting from 2-( (R)-6,8-dichloro-2-cyclopropyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenylamine (example 41 b), the title compound was synthesized analogously to example 54 and 55 mg of the title compound were obtained as the hydrochloride. LC-MS Rt (B): 1.17 min;

[M+H+j: 430.0

15

Example 56: 3-[2-( (R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-

5,5-<limethylimidazolidine-2,4-dione hydrochloride

(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (50 mg,

20    enantiomer B, preparation as described in W02004085404) was dissolved in absolute dichloromethane (5 ml), and methyl 2-isocyanato-2-methylpropionate was added

dropwise with stirring. After being stirred for 3 hand left to stand overnight, the mixture was admixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of

preparative HPLC. The fractions comprising product were purFfied, the acetonitrile was

removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in acetonitrile
10    (1 ml) and admixed with 10% hydrochloric acid. After stirring for 2 h. the mixture was diluted with water (3 ml) and freeze-dried. 68 mg of the title compound were obtained. LC-MS Rt (B): 1.08 min;

[M+W]: 418.0

15    Example 57: (Rand S)-3-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-(2-methylsulfanylethyl)imidazolidine-2,4-dione tr~luoroacetic acid salt
Q  0/

Clyo'   
0 ;_HYF.
N,    FfnoH
Cl    F   0

(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (50 mg,

enantiomer B, preparation as described in W02004085404) was reacted analogously

20    to example 56 with ethyl 2-isocyanato-4-(methylthio )butyrate (33 mg) in methylene chloride, purified and ring-closed. The crude product which was then obtained was purified by means of preparative HPLC and could then be separated into its diastereomers, the more polar P1 and the less polar P2.

P1:

25    LC-MS Rt (B): 1.11 min; [M+H+j: 464.0
P2:

LC-MS Rt (B): 1.16 min;

[M+W]: 464.0

Starting from (R)-2-(6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)-phenylamine (enantiomer B, preparation as described in W02004085404) and the
corresponding isocyanates, the following products were obtained as diastereomer

mixtures analogously to example 56:

Example 61 : 1-[2-((R)-2-Methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-

2,5-dione hydrochloride

In a hydrogenation apparatus, a spatula-tip of palladium on activated carbon (5%) was

added to a solution of 1-[2-((R)-6,8-dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione (68 mg, example 7) in methanol (15 ml), and, after application of a hydrogen atmosphere, agitated for 2 h. After the hydrogen had been
removed, the apparatus was left to stand under argon overnight, and then the catalyst was filtered off and washed with methanol. The filtrate was concentrated to dryness.
1o  10 mg of the crude product were taken up with water and 10% hydrochloric acid and

freeze-dried. 10 mg of the title compound were obtained.

LC-MS Rt (B): 0.87 min;

[M+H+]: 312.1

15    Example 62: 1-[2-((R)-6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-1 ,3-dihydroimidazol-2-one hydrochloride


(R)-2-(6,8-Dichloro-2-methyl-1 ,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine

(enantiomer B, preparation as described in W02004085404), 4-nitrophenyl

20    chloroforrnate and methylaminoacetaldehyde dimethyl acetal were reacted analogously to example 40, and the resulting intermediate (85 mg) was subsequently

cyclized with a mixture of water (1 ml) and 10% hydrochloric acid (3.2 ml). Workup and

purification were analogous to example 40. 65 mg of the title compound were isolated.

LC-MS Rt (B): 1.02 min; [M+H+j: 388.0
5

Example 63: 1-[2-(8-Bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-

phenyl]pyrrolidine-2,5-<lione hydrochloride
Cl

Br

10    a) 2-Bromo-1-bromomethyl-4-chlorobenzene

CI~Br

Br

2-Bromo-4-chlorotoluene (5 g) was initially charged in carbon tetrachloride (120 ml), and then AIBN (400 mg) and NBS (4.8 g) were Introduced successively with stirring.
Subsequently, the reaction mixture was heated under reflux for 6 hand then further

15    NBS (0.6 g) was added at room temperature. After a further 2 h under refiux, the heater was removed and the mixture was left to stand overnight. After the precipitate

had been filtered off, the mixture was washed with carbon tetrachloride and then the filtrate was extracted three times with 0.5 N sodium hydrogencarbonate solution, followed by several washes with water until the pH of the wash solution was neutral.
20    The organic phase was dried over magnesium sulfate, filtered and concentrated. After chromatography on silica gel, 3.57 g of the title compound were obtained.

LC-MS Rt (B): 1.85 min; [M+H+]: 202.6 (CI+)

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