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(11) Patent Number: KE 460

(45) Date of grant: 09/08/2011
           
(51) Int.CI.7:    A 61K 31/4184, 31/4245, 31/444, A       

(73) Owner:Sanofi Aventis Deutschland GmbH of 65929 Frankfurt 61P 29/00    am Main, Germany

(21)Application Number:    KJE/P/2003/000295

(72) Inventors:RITZELER, OlafofHubertushohe 6, 65812 Bad Soden,Germany; MICHAELIS, Martin of Savignystr. 22, 60325 Frankfurt, Germany; JAEHNE, Gerhard of Seebachstrasse 22, 65929 Frankfurt, Germany RUDOLPH!, Karl ofKapuziner Strasse 19, 55116 Mainz,

(22) Filing Date:05/08/2003

(30) Priority data:10237723.5  17/08/2002            Germany; GEISSLINGER, Gerd ofDrei Linden Strasse
  DE        31, 65812 Bad Soden, Germany and SCHAIBLE, Hans-
            Georg ofDombluthweg 18,07743 Jena, Germany
(86)  PCT data    PCT/EP03/008628    05/08/2003       

(74) Agent/address for correspondence:        Kaplan & Stratton Advocates, P.O. Box 40111-00100,
wo 2004/022057    18/03/2004        Nairobi
   
(54)Title:USE OF IKB KINASE INHIBITORS FOR THE TREATMENT OF PAIN

(57) Abstract:The invention relates to the use of IKB kinase inhibitors that are suitable for producing medicaments for the treatment of pain. Suitable inhibitors are produced from compounds of formulas (I) and (Ia).
 
Aventis Pharma Deutschland GmbH    DEAV2002/0064    Dr. TH

Description

5    Use of IKB-kinase inhibitors in pain therapy

The invention relates to the use of IKB-kinase inhibitors for treating pain. Patent applications WO 01/00610, WO 01/30774 and WO 01/68648

10    describe compounds which are able to modulate NFKB.

NFKB is a heterodimeric transcription factor which is able to activate a large number of genes which encode, inter alia, proinflammatory cytokines such as IL-1, IL-2, TN Fa or IL-6. NFKB is present in the cytosol of cells, where it is complexed with its naturally occurring inhibitor IKB. Stimulation of the

15    cells, for example by cytokines, leads to the IKB being phosphorylated and subsequently broken down proteolytically. This proteolytic breakdown leads to the activation of NFKB, which then migrates into the nucleus of the cell,

where it activates a large number of proinflammatory genes.

In diseases such as rheumatoid arthritis (in connection with inflammation),

20    osteoarthritis, asthma, cardiac infarction, Alzheimer's diseases or atherosclerosis, NFKB is activated to beyond the normal extent. The inhibition of NFKB is also of value in the treatment of cancer since it is used in such treatment to augment the cytostatic therapy. It has been

demonstrated that pharmaceuticals such as glucocorticoids, salicylates or

25    gold salts, which are used in the therapy of rheumatism, inhibit the NFKB-activating signal chain at various points or interfere directly with the transcription of the genes.
The first step in said signal cascade is the breakdown of IKB. This phosphorylation is regulated by the specific IKB kinase.

30

Pharmaceuticals belonging to a large number of different substance groups are employed in treating acute and chronic pain. Despite this, the therapy of pain has still not been satisfactorily solved even today. This is due, in particular, to the fact that the analgesics which are on the market do not

35    have a sufficiently powerful effect.

In an endeavor to obtain active compounds for treating pain, it has now been found that it is possible to use IKB-kinase inhibitors for this purpose.

In particular, it has been possible to demonstrate, in the models employed, a strength of effect which is clearly superior to that of classical nonsteroidal anti-inflammatory agents.

5    The invention relates, therefore, to the use of lKB-kinase inhibitors for producing pharmaceuticals for treating pain.

The term "pain" is understood as meaning acute pains and chronic pains. The following are examples of chronic pains:
10    chronic musculoskeletal diseases, such as back pains, pains associated with menstrual bleeding,

pains associated with osteoarthritis or rheumatoid arthritis, pains associated with intestinal inflammation,

pains associated with cardiac muscle inflammation,

15    pains associated with multiple sclerosis, pains associated with neuritis,

pains associated with carcinomas and sarcomas, pains associated with AIDS,
pains associated with chemotherapy,

20    amputation pain, trigeminus neuralgia,

headaches, such as migraine cephalalgia, or neuropathic pains, such as post-herpes zoster neuralgia.

25    The following are examples of acute pains: pains following injuries,
post-operative pains,

pains in association with an acute attack of gout, or acute pains following jaw-bone surgery interventions.

30

Examples of lKB-kinase inhibitors are indole derivatives or benzimidazole derivatives as are described in the patent applications WO 01/00610 and wo 01/30774.

35    The invention furthermore relates to the use of compounds of the formula l

and/or a stereoisomeric form of the compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I,

5    for producing pharmaceuticals for treating pains, where E is N atom or the radicai-C(R19)-,

where R19 is hydrogen atom or the radical R9,

one of the substituents R1, R2, R3 and R4 is a radical of the formula II,

(II)
in which  D is -C(O)-, -S(O)- or -S(O)z-,
R8 is  hydrogen atom or -(C1-C4)-alkyl,
R9 is  1.  characteristic radical of an amino acid,
2.    aryl, in which aryl is unsubstituted or substituted,

3.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted,
4.    heterocycle having from 5 to 12 ring members, in which heterocycle is unsubstituted or substituted,

5.    -(C1-Cs}-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or substituted, once, twice or three times, independently of each other, by

5.1    aryl, in which aryl is unsubstituted or substituted,

5.2    heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted,

5.3    heterocycle having from 5 to 12 ring members, in which heterocycle is unsubstituted or substituted,

5.4    -O-R11 ,

5.5    =0,
 

5.6    halogen,

5.7    -CN,

5.8    -CFa,
35    5.9    -S(O)x-R11 , in which xis the integer zero, 1 or 2,
        4       
    5.10    -C(O}-O-R11 ,       
    5.11    -C(O)-N(R11 )2,       
    5.12    -C(O)-R,,,       
    5.13    -N(R11)2.       
5    5.14    -( C3-Cs)-cycloalkyl,       
    5.15    radical of the formula       
        R11       
        y(R11       
        or       
10    5.16    radical of the formula    R11   
               

a)    hydrogen atom,

b)    (C1-C6 }-alkyl, in which alkyl is unsubstituted or substituted once, twice or three times

1.  aryl,   in   which   aryl   is   unsubstituted   or

15    substituted,
2.  heteroaryl having from 5 to 14 ring members,
3.    heterocycle having from 5 to 12 ring members,
4.    halogen,
5.    -N-(C,-Cs)n-alkyl, in which n is the integer zero,
20    1 or 2 and alkyl is unsubstituted or substituted
    once,  twice  or  three  times,  independently  of
    each other, by halogen or by -C(O)-OH,
6.    -0-(C,-Cs)-alkyl or

7.  -C(O)-OH,

25    c)  aryl, in which aryl is unsubstituted or substituted,

d)    heteroaryl having from 5 to 14 ring members, or

e)    heterocycle having from 5 to 12 ring members, and, in the case of (R11 }2, R11 has, independently of each other, the meanings of a) to e),

30    Z is    1.    aryl, in which aryl is unsubstituted or substituted,
        2.    heteroaryl having from 5 to 14 ring members, in
            which heteroaryl is unsubstituted or substituted,
        3.    heterocycle having from 5 to 12 ring members, in
            which heterocycle is unsubstituted or substituted,
35        4.    -(C1-C6 )-alkyl,  in  which  alkyl  is  substituted  or
            unsubstituted
 




5
5.    -C(O)-R1\

6.    -C(O)-O-R11 or
7    -C(O)-N(R11 )2, or
R8 and R9 form, together with the nitrogen atom and carbon atom to which 5 they are in each case bonded, a heterocyclic ring of the formula II a,

"'D-..N,....IY Z    (lla)
~ B
X,~

in which  D and Z are defined as in formula II,
A is    nitrogen atom or the radical -CH2-,
8 is    oxygen atom, sulfur atom, nitrogen atom or the  radical
    -CHz-,
X is    oxygen atom, sulfur atom, nitrogen atom or the radical
    -CH2-.
Y is    absent or is oxygen atom, sulfur atom, nitrogen atom or

the radical -CH;z-, or

X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or 1 ,4-diazine radical,

where the ring system which is formed by N, A, X, Y; 8 and carbon atom
 

20    does not contain more than one oxygen atom, X is not oxygen atom, sulfur atom or nitrogen atom when A is nitrogen atom, does not contain more than one sulfur atom, and contains 1, 2, 3 or 4 nitrogen atoms, and where an oxygen atom and a sulfur atom are not present simultaneously,

where the ring system which is formed by N, A, X, Y, 8 and carbon atom is

25    unsubstituted or is substituted, once, twice or three times, independently of each other, by (C1-Cs)-alkyl, in which alkyl is unsubstituted or substituted, once or two times, by

1.1.    -OH,

1.2.    -(C1-Cs)-alkoxy,

30    1.3.   halogen,

1.4.    -N02,

1.5.    -NHz,

1.6.    -CF3,

1.7.    methylenedioxyl,

35    1.8   -C(O),

1.9.   -C(O)-CH3,
 




6

1.10.    -(C,-C4)-alkoxycarbonyl,

1.11.    -CN,

1.12.    -C(O)-OH,

1.13.    -C(O)-NH2,

5    1.14.  tetrazolyl,

1.15.    phenyl,

1.16.    phenoxy,

1.17.    benzyl or

1.18.    benzyloxy or

10

R9 and Z form, together with the carbon atoms to which they are in each case bonded, a heterocyclic ring of the formula lie,

    ;N0/R11   
'D-...    N(lie)   
I        I   
R8           
    T,  ,w   
v

15

in which  D, R8 and R11 are defined as in formula II,

T is   oxygen atom, sulfur atom, nitrogen atom or the radical

-CH2-,

W is  oxygen atom, sulfur atom, nitrogen atom or the  radical

20    -CHr,

V is   absent or is oxygen atom, sulfur atom, nitrogen atom or

the radical -CHr, or

T and V or V and W together form a phenyl, 1 ,2-diazine, 1,3-diazine or 1,4-diazine radical,

25    where the ring system which is formed by N, T, V, Wand two carbon atoms does not contain more than one oxygen atom, does not contain more than one sulfur atom and contains 1, 2, 3 or 4 nitrogen atoms, where an oxygen atom and a sulfur atom are not present simultaneously, and where the ring system which is formed by N, T,

30    V, Wand two carbon atoms is unsubstituted or is substituted, once, twice or three times, independently of each other, by the substituents which are defined above under 1.1. to 1.18., and
the other substituents R\ R2, R3 and R4 in each case are, independently of
each other,


2.    halogen,

3.    -(C1-Cs)-alkyl,

4.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted,

5    5. heterocycle having from 5 to 12 ring members, in which heterocycle is unsubstituted or substituted,

6.    -N02,

7.    -CN,

8.    -O-(Co-C4)-alkylaryl,

10 9 -O-(C1-C4)-alkyl, 10.-0-R1\
11.-N(R11)2,
12.-S(O)r"R1\ in which r is the integer zero, 1 or 2, or 13.-CF3,

15    R5 is  1.  hydrogen atom,
2.    -OH or

3.    =0, and

R6 is 1. aryl, in which aryl is unsubstituted or substituted, 2. phenyl which is substituted once or twice by

20    2.1 -CN,

2.2    -N02,

2.3    -O-(C1-C4)-alkyl,

2.4    -N(R11)2,

2.5    -NH-C(O)-R11 ,
25    2.6    -S(O)s-R11 , in which s is the integer zero, 1 or 2,
2.7    -C(O)-R11 or
2.8    -(C1-C4)-alkyi-NH2,

3.    heteroaryl having from 5 to 14 ring members, is unsubstituted or

is substituted once, twice or three times, or

30    4. heterocycle having from 5 to 12 ring members, is unsubstituted or is substituted once, twice or three times.

The invention furthermore relates to the use, according to the invention, of

the compound of the formula I, where 35 E is N atom or the radicai-C(R19)-,
where R19 is hydrogen atom or the radical R9,
one of the substituents R\ R2, R3  and R4 is a radical of the formula II, in
which

D is   -C(O)-, -S(O)- or -S(0)2-,

R8 is  hydrogen atom or -(C1-C4)-alkyl,

R9 is 1. a characteristic radical of an amino acid which is derived from a naturally occurring a-amino acid of the group alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine,

5    threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid,

2.    a characteristic radical of an amino acid which is derived from an

amino acid which is not naturally occurring, such as 2-amino-

adipic    acid,   2-aminobutyric   acid,   2-aminoisobutyric  acid,

10    2,4-diaminobutyric acid, 2,3-diaminopropionic acid, 1 ,2,3,4,-tetrahydroisoquinoline-1-carboxylic acid, 1 ,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 3-(2-

thienyl)alanine,  3-(3-thienyl)alanine,  sarcosine,  pipecolic  acid,

2-aminoheptanoic acid, hydroxylysine, N-methylisoleucine, 6-N-

15    methyllysine, norleucine, N-methylvaline, norvaline, ornithine, allo-isoleucine, 4-hydroxyproline, allo-hydroxylysine, alia-threonine, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homocysteine, homophenylalanine, homo-

cysteic    acid,    2-amino-3-phenylaminoethylpropionic    acid,

20    2-amino-3-phenylaminopropionic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)-alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluoro-phenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, cyclohexylalanine, 4-aminophenylalanine,
25    citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide or -NH-NR11-CON(R11 )2, in which R11 is defined as below,
3.  aryl,   from   the   group   anthryl,   biphenylyl,   2-biphenylyl, 3-biphenylyl,   4-biphenylyl,   fluorenyl,   naphthyl,   1-naphthyl, 30            2-naphthyl or phenyl, in which aryl is unsubstituted or substituted once, twice or three times by identical or different radicals from

the series -C(O)-(C1-C4)-alkyl, -C(O}, =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(C1-C8)-alkyl, -(C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-

35    alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl,

methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 in which x is the


integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O}-OH, -C(O}-O-(C,-C4)-alkyl, -NH-C(O}-(C,-C4)-alkyl or tetrazolyl,
4.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted and, as a radical, is derived from

5    the group azepine, azetidine, benzimidazole, benzodioxolane, 2-benzofuran, benzothiazole, benzothiophene, 2-benzo-

thiophene, 2-benzoxazole, ~-carboline, quinoxaline, quinazoline,

quinoline,    2-quinoxaline,   cyclohepta[b]-5-pyrrole,   diazepine,

dihydropyridine,    3-hydroxypyrro-2,4-dione,    imidazole,

10    4-imidazole, imidazolidine, imidazoline, indazole, indole, isoquinoline, isoindole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone, methylimidazole, 3-(N-methylpyrrolidine}, morpholine, oxazole, 1 ,3,4-oxadiazole,

    oxadiazolidinedione,    oxadiazolone,    5-oxo-4,5-dihydro-
15    [1 ,3,4]oxadiazole,    5-oxo-1 ,2,4-thiadiazole,    1,2,3,5-oxathia-
    diazole-2-oxide,   1-oxo-1 ,2-dihydro-3-isoquinol,   phenylpyrrole,
    5-phenyl-2-pyrrole, phthalazine, piperazine, piperidine, pyrazine,
    pyrazole,   pyrazoline,   pyrazolidine,   pyrazoline,   pyridazine,
    pyrimidine,   pyridine,   pyridyi-N-oxide,   2-pyrrole,   3-pyrrole,
20    pyrrolidine,  pyrroline,  4,5,6,7-tetrahydro-2-indole,  tetrahydro-
    thienyl,    tetrazole,    thiadiazole,    thiazole,    thiomorpholine,

thiophene, triazole, triazolone or triazole,

in which heteroaryl is unsubstituted or substituted once, twice or three times by identical or different radicals which are derived

25    from the series -C(O}-(C,-C4)-alkyl, ~C(O}, =0, -NH-(C,-C4)-alkyl, -NH-((C,-C4)-alkyl)2, -(C,-Cs)-alkyl, -(C,-Cs)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CFa, hydroxy-(C,-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or

2-hydroxyethyl,  methylenedioxy,  ethylenedioxy,  formyl,  acetyl,

30    cyano, hydroxycarbonyl, aminocarbonyl, -(C,-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 , in which x is the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C,-C4)-alkyl, -NH-C(O}-(C,-C4)-alkyl or tetrazolyl,

5.  -(C1-C6)-alkyl in which alkyl is straight-chain or branched and is

35    unsubstituted or substituted once, twice or three times, independently of each other, by

5.1    aryl, in which aryl is defined as above,

5.2    heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above,


5.3    -(C3-Cs)-cycloalkyl,

5.4    -O-R1\

5.5    =0,

5.6    halogen,

5    5.7    -CN,

5.8    -CF3,

5.9    -S(O)xR11 , in which xis the integer zero, 1 or 2,
5.10    -C(O)-O-R11 ,
5.11    -C(O)-N(R11 )2,
10    5.12    -C(O}-R1\               
    5.13    -N(R11 )2,               
    5.14   a radical of the formula       
            R11       
        8.11    ~1           
        ~R11       
        or            R11   
    5.15                   
15        a radical of the formula       
               
        in which               
    R11 is    a)  hydrogen atom,       
        b)  (C1-C6)-alkyl  in  which  alkyl  is  unsubstituted  or   
        substituted once, twice or three times by   
20        1.  aryl, in which aryl is defined as above,   
        2.  heteroaryl  having  5  to  14  ring  members,  in   
        which heteroaryl is defined as above,   
        3.  halogen,       
        4.  -N-(C,-Cs)n-alkyl, in which n is the integer zero,   
25        1 or 2 and alkyl is unsubstituted or substituted   
        once,  twice  or three  times,  independently of   
        each other, by halogen or by -C(O)-OH,   
        5.  -0-(C,-Cs)-alkyl or       
        6.  -C(O)-OH,       
30        c)  aryl, in which aryl is defined as above, or   
        d)  heteroaryl having from 5 to  14 ring members, in   
        which heteroaryl is defined as above, and   
        in the case of (R11 )2 ,  the radical R11  has, independent of   
        each other, the meaning of a) to d),       
35    Z is   1.  aryl in which aryl is defined as above,       
2.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above,
3.    -(C1-C6)-alkyl, in which alkyl is straight-chain or branched and is

substituted once or twice by phenyl or -OH, 5 4. -C(O)-O-R11 , or
5.  -C(O)-N(R11 )2, and
the other substituents R\ R2, R3 and R4 in each case are, independently of
each other,

1.  hydrogen atom,

10    2.  halogen,

3.    -(C1-C4)-alkyl,

4.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is as defined above,

5.    -(C1-Cs)-alkyl,

15    6.  -N02,

7.    -CN,

8.    -O-(Co-C4)-alkyl-aryl, in which aryl is defined as above,

9.    -O-(C1-C4)-alkyl,
10.-0R1\
20    11.-N(R11)2,

12.-S(O)x-R11 , in which xis the integer zero, 1 or 2, or
    13.-CF3.
R5 is    1.    hydrogen atom,
    2.    -OH, or
25    3.    =0, and
R6 is    1.  aryl, from  the  group naphthyl,  1-naphthyl, 2-naphthyl,  phenyl,
        biphenylyl,  2-biphenylyl,  3-biphenylyl,  4-biphenylyl,  anthryl  or

fluorenyl,

in which aryl is unsubstituted or substituted, once, twice or three

30    times, by identical or different radicals from the series -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(C1-Ca)-alkyl, -(C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl such as hydroxymethyl or

1-hydroxyethyl  or  2-hydroxyethyl,  methylenedioxy,  ethylenedioxy,

35    formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R1\ in which x is the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl, or


2.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above and
in which heteroaryl is unsubstituted or substituted, once, twice or

three  times,  by identical or different radicals from  the  series

5    -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(C1-C8)-alkyl, -(C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl such as

hydroxymethyl    or    1-hydroxyethyl    or    2-hydroxyethyl,

methylenedioxy,    ethylenedioxy,    formyl,    acetyl,    cyano,

10    hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 , in which x is the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl.

15    The invention furthermore relates to the use, according to the invention, of

the compound of the formula I, where E is N atom or the radicai-C(R19)-,
in which R19 is hydrogen atom,
one of the substituents R\ R2, R3  and R4 is a radical of the formula II, in
20    which

R8 is  hydrogen atom,
R9 is 1. a characteristic radical of an amino acid from the group histidine, serine, tryptophan, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid, or

25    2. -(C1-C6)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or substituted, once or twice, by

a)    phenyl,

b)    a radical from the group azepine, azetidine, benzimidazole,

benzothiazole,    benzothiophene,    benzoxazole,    diazepine,

30    imidazole, indole, isothiazole, isoxazole, morpholine, 1,3,4-oxa-diazole, 5-oxo-4,5-dihydro-[1,3,4)oxadiazole, oxazole piperidine, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, thiazole, thiomorpholine, thiophene or triazole,

c)    -NH(R11 ),
35    d) -C(O)-R12, in which
R12   is naphthyl, phenyl, morpholinyl or pyrimidinyl,
e)    -O-R1\
f)    -N(R12)-phenyl, in which R12 is defined as above,
g)    -S(O)x-R12, in which xis zero, 1 or 2, and
 


h)    -CN, or

i)    -(C3-Cs)-cycloalkyl,

and the radicals defined above by a), b), d) and i) and R12 are unsubstituted or are substituted, once or twice, by -OH, -(C1-C4)-

5    alkyl, -CF3, halogen, -O-(C1-C4}-alkyl, -COOH, -C(O)-O-(C1-C4)-alkyl, -NH2 or -NH-C(O)-(C1-C4)-alkyl,

Z is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole, isothiazole,

10    isothiazolidine, isoxazole, isoxazolidine, 2-isoxazolidine, isoxazolone, morpholine, 1,3,4-oxadiazole, oxadiazolidinedione, oxadiazolone, 1 ,2,3,5-oxathiadiazole-2-oxide, oxazole, 5-oxo-4,5-dihydro-[1 ,3,4]oxadiazole, 5-oxo-1 ,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine,

15    tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazolone, and
the heteroaryl radical is unsubstituted or substituted, once, twice or three times, independently of each other, by
1.1    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,
20    1.2   -(C1-C4)-alkyl,

1.3    -O-R15, in which R15 is hydrogen atom or -(C1-C4}-alkyl,

1.4    -N(R15)-R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,

1.5    halogen, or

25    1.6   keto radical,

2.    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,

3.    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or
4.    -C(O)-N(R15)-R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,
30    R11 is    1.    -(C1-C4)-alkyl,
2.    R13 or,
3.    -N(R13}2,
in which R13 is, independently of each other,
a)    hydrogen atom,

35    b)    -(C1-C6)-alkyl,

c)    -(C1-C4)-alkyl-O-(C1-C4)-alkyl,

d)    -(C1-C6)-alkyi-N(R15)2, in which R15 is defined as above, or

e)    -(Co-C4}-alkyl which is substituted, once or twice, by imidazolyl, morpholinyl or phenyl, or
 




14

R8 and R9 form, together with the nitrogen atom and carbon atom to which they are in each case bonded, a ring of the formula lla from the group pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole,

5    pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione, triazole, which are

substituted by F, CN, CF3 or COO-(C1-C4)-alkyl, 3-hydroxypyrro-2,4-

10 diones, 5-oxo-1 ,2,4-thiadiazoles, 1 ,3,4-oxadiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline and isoquinoline, or

15 R9 and Z form, together with the carbon atoms to which they are in each case bonded, a ring of the formula lie from the group pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole,

20    2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine,
pteridine,    indole,   tetrahydroquinoline,   tetrahydroisoquinoline,

isoquinoline,    tetrazole,    1,2,3,5-oxathiadiazole-2-oxides,

25    oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione, triazole, which are substituted by F, CN, CF3 or COO-(C1-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 1,3,4-oxadiazole and 5-oxo-1 ,2,4-

thiadiazole and
the other substituents R1, R2,  R3 and R4 in each case are, independently of
30    each other,

1.    hydrogen atom,

2.    halogen,

3.    -(C1-C4)-alkyl,

4.    -CN,

35    5.  -N02,

6.    -O-(Co-C4)-alkyl-phenyl,

7.    -O-(C1-C4)-alkyl,

8.    -N-(Co-C4)-alkyl-phenyl,

9.    -N-(C1-C4)-alkyl or
 
10.-CF3,

R5 is  1.  hydrogen atom,

2.    -OH, or

3.    =0, and

5    R6 is  1.  phenyl, substituted, once or twice, by

1.1    -CN,

1.2    -N02,

1.3    -O-(C1-C4)-alkyl, or

1.4    -NH2, or

10    2.  is pyridine or pyrimidine,

where pyridine or pyrimidine is unsubstituted or substituted, once,

twice or three times, by identical or different radicals from the series -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-
alkyl)2,    -(C1-Ca)-alkyl,   -(C1-C6)-alkoxy,   halogen,   nitro,   amino,
15    trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,

aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 , in which x is the integer zero, 1 or 2,

20    -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to the invention, of

the compound of the formula I,
25    where E is the radicai-C(R19)-,
in which R19 is hydrogen atom or R9,
one of the substituents R\ R2, R3 and R4 is a radical of the formula II in
which

Dis    -C(O)-,

30    R8 is  hydrogen atom,

Z is   5-oxo-4,5-dihydro-[1 ,3,4]oxadiazole, -C(O)-OH or -C(O)-NH2,
R9 is 1. -(C1-C4)-alkyl, in which alkyl is straight-chain or branched and is substituted once or twice, independently of each other, by

1.1    -S(O)-R1\  where R11 is defined as below,

35    1.2 -N(R11 )2, where R11 is defined as below, or 1.3 pyrrole, or

2.    the characteristic radical of an amino acid from the group histidine, tryptophan, serine, threonine, cysteine, methionine,


asparagine,  glutamine,  lysine,  arginine,  glutamic  acid  and

aspartic acid, R11 is a) hydrogen atom,
b)  -(C1-C6 )-alkyl, in which alkyl is unsubstituted or substituted, once

5    or three times, independently of each other, by halogen, or

c)    phenyl, in which phenyl is unsubstituted or substituted, once to three times, independently of each other, by halogen or -(C1-C4 )-

alkyl,

the other substituents R\ R2 , R3 and R4 are in each case hydrogen atom,
10    R5 is  hydrogen atom, and
R6 is  phenyl, pyridine or pyrimidine,

where phenyl, pyridine or pyrimidine is unsubstituted or substituted, once, twice or three times, by identical or different radicals from the series -C(O)-(C,-C4)-alkyl, -C(O), =0, -NH-(C,-C4)-alkyl,
15    -NH-((C1-C4)-alkyl)2 , -(C1-C8)-alkyl, -(C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3 , hydroxy-(C1-C4 )-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,
aminocarbonyl,  -(C1-C4 )-alkoxycarbonyl,  phenyl,  phenoxy,  benzyl,

20    benzyloxy, -S(O)x-R11 , in which x is the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C,-C4)-alkyl, -NH-C(O)-(C,-C4)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to the invention, of 25 the compound of the formula Ia

~R21

"f:R24
/N    ~O                   
W        E,    ;='7(    R31       
/' . N-...;::::                (Ia)   
R22    1    ~ •  N       
    0        11           
        N\    M~           
                       
        H    /N-H       
            R23       

and/or a stereoisomeric form of the compound of the formula Ia and/or a 30 physiologically tolerated salt of the compound of the formula Ia, where
 

E and M are identical or different and are, independently of each other N

atom or CH

R21  and  R31  are identical or different and are, independently of each

other,

5    1.  hydrogen atom,

2.    halogen,

3.    -(C1-C4)-alkyl,

4.    -CN,

5.    -CF3,
10    6.  -OR15, in which R15 is hydrogen atom or-(C1-C4)-alkyl,
7.    -N(R15)-R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,
8.    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or
9. :.S(O)x-R15, in which x is the integer zero, 1 or 2, and R15 is 15 hydrogen atom or -(C1-C4)-alkyl,

R22 is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone, morpholine, oxazole, 1,3,4-oxadiazole,

20 oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide, 5-oxo-4,5-dihydro-[1 ,3,4)oxadiazole, 5-oxo-1 ,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazolone, and

25    the heteroaryl radical is unsubstituted or is substituted once, twice or three times, independently of each other, by

1.1    -C(O}-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,

1.2    -(C1-C4)-alkyl,
30    1.3   -O-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,
1.7    -N(R15)-R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,

1.8    halogen, or

1.9    keto radical,
35    2.  -C(O}-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,

3.    -C(O)-OR15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or
4.    -C(O)-N(R17)-R18, in which R17 and R18 are, independently of each other, hydrogen atom, -(C1-C4)-alkyi-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl,
 
18
R23 is hydrogen atom or -(C1-C4)-alkyl,
R24 is 1. a heteroaryl radical from the group pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxa-

5    diazolones, isoxazolones, oxadiazolidinediones, triazoles, 3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,

f3-carboline and benzo fused cyclopenta derivatives or cyclohexa

10    derivatives of these heteroaryl radicals,

where the heteroaryl radical is unsubstituted or is substituted,

once, twice or three times, independently of each other, by -(C1-C5)-alkyl, -(C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy,

15    ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, amino-carbonyl or -(C,-C4)-alkoxycarbonyl, or
2.    an aryl radical from the group phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl and
4-biphenylyl, anthryl or fluorenyl, and

20    the aryl radical is unsubstituted or substituted, once, twice or three times, independently of each other, by -(C1-C5)-alkyl, -(C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C,.C4)-

25    alkoxycarbonyl.

The invention furthermore relates to the use, according to the invention, of the compound of the formula Ia, where

E and M are identical or different and are, independently of each other, N

30    atom or CH,

R21 and R31 are identical or different and, independently of each other, are defined as above under 1. to 9.,

R22 is 1.  a  heteroaryl  radical  from  the  group  imidazole,  isothiazole,

isoxazole,    2-isoxazolidine,    isoxazolone,   1,3,4-oxadiazole,

35    oxadiazolidinedione, 1,2,3,5-oxadiazolone, oxazole, 5-oxo-4,5-dihydro-[1 ,3,4]oxadiazole, tetrazole, thiadiazole, thiazole, triazole or triazolone, and the heteroaryl radical is unsubstituted or is substituted once, twice or three times, independently of each other, by


1.1    keto radical,

1.2    halogen or

1.3    -(C1-C2)-alkyl, or

2. -C(O)-N(R17)-R18, in which R17 and R18 are, independently of 5 each other, hydrogen atom, -(C1-C4}-alkyi-OH, -O-(C1-C4}-alkyl,

or -(C1-C4)-alkyl,
R23 is hydrogen atom, methyl or ethyl,
R24 is 1. a heteroaryl radical from the group of the unsaturated, partially saturated or completely saturated rings which are derived from

10    pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole or isothiazole,

where the heteroaryl radical is unsubstituted or substituted, once, twice or three times, independently of each other, by -(C1-C4)-

15    alkyl, -(C1-C4)-alkoxy, F, Cl, J, Br, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy,

formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4)-alkoxycarbonyl, or

2.  phenyl and phenyl is unsubstituted or is substituted once, twice

20    or three times, independently of each other, by F, Cl, I, Br, CF3, -OH, -(C1-C4)-alkyl or -(C1-C4)-alkoxy.

The invention furthermore relates to the use, according to the invention, of the compound N-[( S)-2-diphenylamino-1-(5-oxo-4,5-dihydro-

25    [1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide or N-( (S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methyl-aminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide.

The term "halogen" is understood as meaning fluorine, chlorine, bromine or

30    iodine. The terms "-(C1-Ca}-alkyl", "-(C1-C6)-alkyl" and "-(C1-C4)-alkyl" are understood as meaning hydrocarbon radicals whose carbon chain is

straight-chain or branched and contains from 1 to 8, from 1 to 6 and from 1 to 4 carbon atoms, respectively, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, heptyl or cetyl. The term "-(Co)-alkyl" is understood as

35    meaning a covalent bond. Examples of cyclic alkyl radicals are 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The phrase "R8 and R9 form, together with the nitrogen atom and carbon atom to which they are in each case bonded, a heterocyclic ring of the formula lla" is understood as meaning radicals which are derived from pyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole, isoxazole,

5    tetrazole, isoxazoline, isoxazolidine, morpholine, thiazole, isothiazole, isothiazoline, purine, isothiazolidine, thiomorpholine, pyridine, piperidine,

pyrazine,  piperazine,  pyrimidine,  pyridazine,  indole,  isoindole,  indazole, benzimidazole,    phthalazine,   quinoline,   isoquinoline,   quinoxaline, quinazoline,  cinnoline,  pteridine,  triazolones,  tetrazole,  1 ,2,3,5-oxathia-10   diazole-2-oxides,   oxadiazolones,   isoxazolones,   oxadiazolidinediones, triazoles, which are substituted by F, -CN, -CF3 or -C(O)-O-(C1-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 5-oxo-1 ,2,4-thiadiazoles, imidazolidine, carboline

and benzofused derivatives of these heterocycles.

15    The phrase "R9 and Z form, together with the carbon atoms to which they are in each case bonded, a heterocyclic ring of the formula lie" is understood as meaning radicals which [lacuna] from the group pyrrole,

pyrroline,    pyrrolidine,   pyridine,   piperidine,   piperylene,   pyridazine,

pyrimidine,    pyrazine,   piperazine,   pyrazole,   imidazole,   pyrazoline,

20    imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole,

phthalazine,   quinazoline,   quinoxaline,   purine,   pteridine,   indole, tetrahydroquinoline, tetrahydroisoquinoline, isoquinoline, tetrazole, 1 ,2,3,5-25   oxathiadiazole-2-oxides,     oxadiazolone,     isoxazolone,     triazolone, 3-hydroxypyrro-2,4-diones,  1,3,4-oxadiazole  and  5-oxo-1 ,2,4-thiadiazole, oxadiazolidinedione, triazole, which are unsubstituted or substituted by F,

CN, CF3 or C(O)-O-(C1-C4)-alkyl.

30    The phrase "heteroaryl radical from the group of the unsaturated, partially saturated or completely saturated rings which are derived from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole,
pyrazole, oxazole, isoxazole, thiazole and isothiazole", is understood as

meaning,  for  example,  compounds  such  as  piperazine,  pyrazoline,

35    imidazoline, pyrazolidine, imidazolidine, tetrahydropyridine, isoxazoline, isoxazolidine, morpholine, isothiazoline, isothiazolidine, tetrahydro-1 ,4-thiazine and piperidine.
The term "aryl" is understood as meaning aromatic hydrocarbon radicals having from 6 to 14 carbon atoms in the ring. Examples of -(C5-C14)-aryl
 




21

radicals are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl and fluorenyl. Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals. Aryl radicals, in particular phenyl

5    radicals, can be substituted once or more than once, preferably once, twice

or three times, by identical or different radicals, preferably by radicals from the series -(C1-Ca)-alkyl, in particular -(C1-C4)-alkyl, -(C1-C8)-alkoxy, in

particular -(C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl,

hydroxy-(C1-C4)-alkyl,  such  as  hydroxymethyl  or  1-hydroxyethyl  or

10    2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl. The same applies, in a

corresponding  manner,  for  example,  for  radicals  such  as  arylalkyl  or

arylcarbonyl. Arylalkyl radicals are, in particular, benzyl and also 1- and

15    2-naphthylmethyl, 2-, . 3- and 4-biphenylylmethyl and 9-fluorenylmethyl. Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals which are substituted, in the aryl moiety, by one or more -(C1-Ca)-alkyl radicals, in particular -(C1-C4)-alkyl radicals, for

example 2-,  3- and  4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl,

20    4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7-and 8-methyl-1-naphthylmethyl, and 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, benzyl radicals and naphthylmethyl radicals which are
substituted, in the aryl moiety, by one or more -(C1-Cs)-alkoxy radicals, in particular   -(C1-C4)-alkoxy   radicals,   for   example   4-methoxybenzyl, 25   4-neopentyloxybenzyl,   3,5-dimethoxybenzyl,   3,4-methylenedioxybenzyl and 2,3,4-trimethoxybenzyl, nitrobenzyl radicals, for example 2-, 3- and 4-nitrobenzyl, halobenzyl radicals, for example 2-, 3- and 4-chlorobenzyl, 2-, 3-   and   4-fluorobenzyl,   3,4-dichlorobenzyl,   pentafluorobenzyl   and trifluoromethylbenzyl radicals, for example 3- and 4-trifluoromethylbenzyl

30    and 3,5-bis(trifluoromethyl)benzyl.

In monosubstituted phenyl radicals, the substituent can be located in the 2 position, the 3 position or the 4 position. Doubly substituted phenyl can be

substituted in the 2,3 position, the 2,4 position, the 2,5 position, the 2,6

35    position, the 3,4 position or the 3,5 position. In triply substituted phenyl radicals, the substituents can be located in the 2,3,4 position, the 2,3,5 position, the 2,4,5 position, the 2,4,6 position, the 2,3,6 position or the 3,4,5 position.
 




22

The comments made with regard to the aryl radicals apply, in a corresponding manner, to divalent arylene radicals, for example to phenylene radicals, which can be present, for example, as 1,4-phenylene or as 1 ,3-phenylene. Phenylene-(C1-Ce)-alkyl is, in particular,

5 phenylenemethyl (-CeH4-CH2-) and phenyleneethyl, (C1-Ce}-alkylenephenyl, in particular methylenephenyl (-CH2-CeH4-). Phenylene-(C2-C6)-alkenyl is, in particular, phenyleneethenyl and phenylenepropenyl.

The phrase "heteroaryl having from 5 to 14 ring members" means a radical

10    of a monocyclic or polycyclic aromatic system having from 5 to 14 ring members which contains 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are N, 0 and S. If several heteroatoms are present, they may be identical or different. Heteroaryl radicals can also be substituted, once or more than once, preferably once, twice or three times,

15    by identical or different radicals from the series ---(C1-Cs)-alkyl, in particular -(C1-C4)-alkyl, -(C1-C8)-alkoxy, in particular -(C1-C4)-alkoxy, halogen, nitro, -N(R10)2, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl,

acetyl,  cyano,  hydroxycarbonyl,  aminocarbonyl,  -(C1-C4)-alkoxycarbonyl,

20    phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl. Heteroaryl having from 5 to 14 ring members is"preferably a monocyclic or bicyclic aromatic radical which contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or different heteroatoms from the series N, 0 and S, and which can be substituted by

1, 2, 3 or 4, in particular 1 to 3, identical or different substituents from the

25    series -(C1-C6)-alkyl, -(C1-C6)-alkoxy, fluorine, chlorine, nitro, -N(R10)2, trifluoromethyl, hydroxyl, hydroxy-(C1-C4}-alkyl, -(C1-C4)-alkoxycarbonyl,

phenyl, phenoxy, benzyloxy and benzyl. Particularly preferably, heteroaryl

is a monocyclic or bicyclic  aromatic radical  having  from  5  to .1 0  ring

members, in particular a 5-membered to 6-membered monocyclic aromatic

30    radical which contains 1, 2 or 3, in particular 1 or 2, identical or different heteroatoms from the series N, 0 and S and which can be substituted by 1

or 2 identical or different substituents from the series -(C1-C4)-alkyl, halogen, hydroxyl, -N(R10)2, -(C1-C4)-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.

35

The term "heterocycle having from 5 to 12 ring members" means a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which is partially saturated or completely saturated. Examples of heteroatoms are N, 0 and S. The heterocycle is unsubstituted or is


substituted by identical or different substituents at one or more carbon atoms or at one or more heteroatoms. These substituents have been defined above in connection with the heteroaryl radical. In particular, the heterocyclic ring is substituted at carbon atoms, once or more than once,

5    for example once, twice, three times or four times, by identical or different radicals from the series -(C1-Ca)-alkyl, for example -(C1-C4)-alkyl, -(C1-C8)-alkoxy, for example -(C1-C4)-alkoxy, such as methoxy, phenyi-(C1-C4)-alkoxy, for example benzyloxy, hydroxyl, oxo, halogen, nitro, amino or

trifluoromethyl  and/or is substituted  at the  ring  nitrogen  atom(s) in  the
10    heterocyclic ring by -(C1-C8)-alkyl, for example -(C1-C4)-alkyl such as methyl or ethyl, by optionally substituted phenyl or phenyi-(C1-C4)-alkyl, for example benzyl. Nitrogen heterocycles can also be present as N-oxides or as quaternary salts.

15    Examples of the terms heteroaryl having from 5 to 14 ring members and heterocycle having from 5 to 12 ring members are radicals which are derived from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1 ,2,3,5-oxathiadiazole-2-oxides,

triazolones,  oxadiazolones,  isoxazolone,  oxadiazolidinedione,  triazole,

20    which are substituted by F, -CN, -CF3 or -C(O)-O-(C1-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 5-oxo-1 ,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline,

quinoxaline, quinazoline, cinnoline, -carboline and benzo fused, cyclopenta

fused,    cyclohexa  fused  or  cyclohepta  fused  derivatives  of  these

25    heterocycles. Particular preference is given to the radicals 2- or 3-pyrrolyl, phenylpyrrolyl, such as 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or 4-pyridyi-N-oxide,

2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl,

1.16.    for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1 ,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzo-thienyl, 2-benzoxazolyl or benzothiazolyl or dihydropyridinyl, pyrrolidinyl, for

35    example 2- or 3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and benzodioxolanyl.

The general structural formula of a-amino acids is as follows:
 
The a-amino acids differ from each other in the radical R which, within the context of the present application, is designated the "characteristic radical"
5    of an amino acid. When R9 denotes the characteristic radical of amino acid, use is preferably made of the characteristic radicals of the following naturally occurring a-amino acids: glycine, alanine, valine, leucine,

isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine,

methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid

10    and aspartic acid. Particular preference is given to histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid. In addition, amino acids which do not occur naturally, such as 2-aminoadipic acid, 2-aminobutyric acid,

2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 15   1,2,3,4-tetrahydroisoquinoline-1-carboxylic   acid,   1,2,3,4-tetrahydroiso-quinoline-3-carboxylic  acid,  2-aminopimellic  acid,  phenylglycine,  3-(2• thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid,  pipecolic acid,  hydroxylysine,  sarcosine,  N-methylisoleucine,  6-N-methyllysine,    N-methylvaline,    norvaline,    norleucine,    ornithine, 20   alloisoleucine,    allothreonine,    allohydroxylysine,    4-hydroxyproline, 3-hydroxyproline,       3-(2-naphthyl)alanine,       3-(1-naphthylalanine ), homophenylalanine,  homocysteine,  homocysteic  acid,  homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, 2-amino-3-phenylaminopropionic    acid,    2-amino-3-phenylaminoethyl-

25    propionic acid, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenyl-alanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenyl-alanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenyl-alanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluoro-

tryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide

30    or -NH-NR11-C(O)N(R11 )2 , which are also substituted, where appropriate, are also preferred characteristic radicals of amino acid which are employed as the radical R8• When amino acids which occur naturally, and also amino acids which do not occur naturally, possess a functional group such as

amino, hydroxyl, carboxyl, mercapto, guanidyl, imidazolyl or indolyl, this

35    group can also be protected.

The N-protecting groups which are customary in peptide chemistry, for example protecting groups of the urethane type, benzyloxycarbonyl (Z), t-butyloxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl (Aloe), or of the acid amide type, in particular formyl, acetyl or

5    trifluoroacetyl, and also of the alkyl type, for example benzyl, are preferably

used as suitable protecting groups for this purpose. When an imidazole radical is present in R8 , the sulfonic acid derivative of the formula IV, which is employed for the sulfonamide formation, serves, for example, as the

group for protecting the imidazole nitrogen, which group can be eliminated

10    once again in the presence of bases such as sodium hydroxide.

The compounds of the formulae I, Ia and lb are prepared as described in

patent    applications  WO 01/00610  and  WO 01/30774.  The  starting

compounds  for  the  chemical  reactions  are  known  or  can  be  readily

15    prepared using methods known from the literature.

Due to the pharmacological properties, which are evident in the models employed, of the IKB-kinase inhibitors which are used in accordance with
the invention, said inhibitors are suitable for being employed in all forms of

20    pain, in particular in association with pains in which inflammatory processes play a role.

The pharmaceuticals according to the invention can be administered orally, by  inhalation,  rectally  or transdermally  or by  means of subcutaneous, 25   intraarticul~r, intraperitoneal or intravenous injection. Oral or intraarticular

administration is preferred.

The invention also relates to a process for producing a pharmaceutical which comprises bringing at least one compound of the formulae I or Ia,
30    together with a pharmaceutically suitable and physiologically tolerated excipient and, where appropriate, other suitable active compounds, additives or auxiliary substances, into a suitable form for administration.

Examples  of suitable  solid  or  galenic  preparation  forms  are  granules,

35    powders, sugar-coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and also preparations with protracted active compound release, in the preparation of which customary auxiliary substances, such as carrier substances, disintegrants, binders, coating agents, swelling agents,
glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently employed auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives,

5    animal and vegetable oils, such as cod liver oil, sunflower oil, groundnut oil ~ or sesame oil, polyethylene glycol and solvents, such as sterile water and monohydric or polyhydric alcohols, such as glycerol. The pharmaceutical

preparations are preferably produced and administered in dosage units,

with each unit containing as the active constituent a particular dose of the

10    compound of the formula I according to the invention. In the case of solid dosage units, such as tablets, capsules, sugar-coated tablets or suppositories, this dose can be up to about 1000 mg, preferably from about 50 mg to 300 mg, and, in the case of injection solutions in ampoule form, up to about 300 mg, preferably from about 10 mg to 100 mg. Depending on

15    the activity of the compound according to the formulae I or Ia, daily doses of from about 20 mg to 1000 mg of active compound, preferably of from about 100 mg to 500 mg, are indicated for treating an adult patient of about 70 kg in weight. However, higher or lower daily doses may also possibly be

appropriate. The daily dose can be administered  either by means of a

20    once-only administration in the form of a single dosage unit, or of several smaller dosage units, or by means of the multiple administration of subdivided doses at predetermined intervals.

As a rule, mass-spectroscopic methods (FAB-MS, ESI-MS) are used for

25    determining end products. Temperatures are given in degrees centigrade; RT denotes room temperature (from 22cc to 26°C). Abbreviations which are used are either explained or correspond to the customary conventions. The invention is explained in more detail below with the aid of examples.
 
Preparation Examples

A.1.) Synthesis of the amino acid (methyl (S)-2-amino-3-diphenylaminopropionate (5))
5


    (OH        DEADfTPP,        Diphenylamine   
                       
O~NHZ    CH3CNfTHF,        100"C   
    -35"C               
OH    1            2       
                       
                    H2,Pd(OH)C   
SOCI2 1MeOH            MeOH       


5


N-Benzyloxycarbonyi-L-serine-~-lactone (2)

54.8 g (0.209 mol) of triphenylphosphine  were  suspended  in  600 ml  of

10    acetonitrile and the mixture was cooled down to -35"C to -45"C while excluding moisture. 36.4 g (0.209 mol) of diethyl azodicarboxylate were added dropwise at this temperature within the space of 50 minutes. The mixture was subsequently stirred at -35"C for 15 minutes. A solution of

50 g  (0.209 mol)  of  N-benzyloxycarbonyi-L-serine  (1)  in  500 ml  of

15    acetonitrile was then slowly added dropwise to this mixture such that the temperature did not rise above -35"C. The mixture was then stirred at 5"C for 12 h. In order to terminate the reaction, the reaction solution was freed from the solvent under reduced pressure and the crude product was

purified  by  means  of  medium-pressure  chromatography  on  silica  gel.

20    (DCM/AcCN: 25/1 ). 20.8 g of N-benzyloxycarbonyi-L-serine-~-lactone (2) were obtained after the solvent had been removed; yield 45%; (see also
Org. Synth. 1991 (70) 1ff.) in fine needles.

Empirical formula  C11H 11 N04;  M.W. = 221.2;  MS  (M+H) 222.1; 1H NMR

(DMSO-d5) 4.30 (m, 1H), 4.45 (m, 1H), 5.10 (s, 2H), 5.22 (m, 2H), 7.45 (m,

25    5H), 8.20 (d, J = 9.8 Hz, 1H). ( S)-2-Benzyloxycarbonylamino-3-diphenylaminopropionic acid (3)
 

5.0 g (22.6 mmol) of serine lactone (2) were mixed by stirring with 20 g (118.2 mmol) of diphenylamine, and the mixture was heated at 100°C for 2 h. The crude product was purified by means of medium-pressure chromatography on silica gel. (DCM/methanol: 9/1, then EA/n-heptane:

5 4/1). 3.65 g (yield 42%) of pure 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (3) were obtained after the solvent had been removed.

Empirical formula C23HzzNz04; M.W. = 390.44; MS (M+H) 391.2;
1H NMR (DMSO-ds) 3.85 (m, 1H), 4.18 (m, 1H), 4.3 (m, 1H), 4.9 (m, 2H), 10 6.9 (m, 5H), 7.25 (m, 10H).

Methyl (S)-benzyloxycarbonylamino-3-diphenyla minopropionate (4)

6.5 ml (89.1 mmol) of thionyl chloride were added dropwise, at -5°C, to 75 ml of methanol and the mixture was stirred for 15 min. 3.6 g (9.22 mmol)

15    of 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (3), dissolved in 75 ml of methanol, were then added and the mixture was stirred at room temperature for a further 3 hours (h). After the solvents had been evaporated, the residue was taken up in ethyl acetate and extracted with

sodium    carbonate  solution.   The   purification   by  means  of  flash

20    chromatography (n-heptane/ethyl acetate 7:3) yielded 2.76 g (50% yield) of methyl 2-benzyloxycarbonylamino-3-diphenylaminopropionate (4).
Empirical formula Cz4H24N204; M.W. =404.47; MS (M+H) 405.2;
1H NMR (DMSO-d6) 3.58 (s, 3H), 3.95 (m, 1H), 4.18 (m, 1H), 4.4 (m, 1H), 4.95 (m, 2H), 6.9 (m, 6H), 7.3 (m, 9H), 7.85 (d, J = 9.8 Hz, 1H).

25

Methyl (S)-2-amino-3-diphenylaminopropionate (5)

In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of the Z-protected derivative (4) were dissolved in 500 ml of methanol, and 100 mg of catalyst (1 0% Pd(OH)2-C) were supplied under a protective atmosphere
30    of nitrogen. The inert gas was subsequently displaced with a large excess of hydrogen and the mixture was shaken for 2 h in the hydrogen atmosphere. In order to terminate the reaction, the catalyst was filtered off

and the filtrate was concentrated. 1.65 g (yield: 91 %) of methyl 2-amino-3-diphenylaminopropionate (5) were obtained.

35    Empirical formula C1sH1sN202; M.W. = 270.32; MS (M+H) 271.2;

1H NMR (DMSO-ds) 3.45 (s, 3H), 3.58 (m, 1H), 3.8 (m, 1H), 3.95 (m, 1 H), 6.9 (m, 6H), 7.3 (m, 4H).
 

A.2.) Synthesis of the heterocyclic parent substance (2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid {1 0))
Methylguanidine    I6I.
Hydrochlride    0
NaOEIIEtOH,
S.Sh, reflux

~ ~
'NJl,r
H    9

4-Hydrazlno-
benzoic acid.
-~-~~-•~-ge_H_zS_O_.,_HO,Cm--Q

H    NH
10.    I

5    1-Dimethylamino-4,4-dimethoxypent-1-en-3-one (8)

100 g (0.76 mol) of 3,3-dimethoxy-2-butanone were stirred, at 12o•c for 48 h, with 90.2 g of N,N-dimethylformamide dimethylacetal (0.76 mol). The methanol which was formed during the reaction was continuously removed from the reaction solution by distillation. When the solution was cooled,

10    spontaneous crystallization occurred, with this crystallization being brought to completion by adding a little heptane. This resulted in 128.24 g of crude product 8 (yield 90%), which was subjected to reaction without any further purification.
Empirical formula C9H17N03; M.W. = 187.24; MS (M+H) 188.2;

15    1H NMR (DMSO-ds)  1.22 (s,  3H),  2.80  {s,  3H),  3.10  {s,  9H),  5.39  (d,

J =15Hz, 1H), 7.59 (d, J =15Hz, 1H).

[4-(1, 1-Dimethoxyethyl)pyrimidin-2-yl]methylamine (9)

1.22 g (53 mmol) of sodium were dissolved in 100 ml of absolute ethanol.

20    5.8 g (53 mmol) of methylguanidine hydrochloride and 10 g (53 mmol) of 1-dimethylamino-4,4-dimethoxypent-1-en-3-one (8) were added, with stirring, to this solution, which was heated at boiling heat for 4 h. In order to

terminate the reaction, the ethanol was evaporated. The product 9, which was obtained in this way, was used for the subsequent reaction without any

25    further purification. Yield 11.5 g (58 mmol, quantitative). Empirical formula CsH1sN302; M.W. = 197.24; MS (M+H) 198.2;
1H NMR (DMSO-de)  1.45 {s,  3H),  2.78  {s,  3H),  3.10  {s,  6H),  6.75  {d,

J =3Hz, 1H), 7.0-7.1 (s(b), 1H), 8.30 (d, J =3Hz, 1H).
 
2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid (1 0)

5 g (25 mmol) of [4-(1, 1-dimethoxyethyl)pyrimidin-2-yl]methylamine (9) and 3.85 g of 4-hydrazinobenzoic acid were added, while stirring, to 150 ml of 50% sulfuric acid, and the mixture was heated at 130°C for 4 h. The

5    methanol Which was formed during the reaction was removed continuously

from the reaction solution by distillation. After it had been cooled down to 1ooc, the reaction mixture was poured onto 200 ml of ice, and the pH was adjusted to about 5.5 using concentrated sodium hydroxide solution. The

precipitate of sodium sulfate and product mixture which was formed in this

10    connection was filtered off and the filter residue was extracted several times with methanol. The combined methanol extracts were concentrated and the product was purified by means of flash chromatography (DCM/methanol9:1). Yield: 0.76 g (11%).
Empirical formula C14H13N402; M.W. = 268.28; MS (M+H) 405.2; 1H NMR

15    (DMSO-d6 ) 2.95 (s, 3H), 6.90-7.10 (s(b), 1H), 7.18 (d, J =3Hz, 1H), 7.4 (s, 1H), 7.58 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 4.5 Hz, 1H), 8.30 (s, 1H), 7.80 (d, J=4.5Hz, 1H), 8.38 (d, J=3Hz, 1H), 11.85 (s, 1H), 12.40-12.60 (s(b), 1H).


20    A.3.) Bringing the building blocks together and synthesizing N-[(S)-2-diphenylam ino~ 1-(5-oxo-4 ,5-dihydro-[1 ,3 ,4]oxadiazol-2-yl )ethyl]-(2•(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (13))




TOTU, OlEA.
+    DMF,RT

Phosgene In toluene, DCM,
RT


3-Diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-

carbonyl]-( S)-amino}propionic acid (11)

5.0 g (18.64 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid (1 0) were dissolved in 1.2 I of DMF, after which 7.9 g
5    (24.08 mmol) of TOTU and 7.9 ml (46.45 mmol) of ethyldiisopropylamine were added consecutively. The mixture was stirred at soc for 20 min, after

which 0.73 g (3.28 mmol) of (S)-2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (5) was added to the solution. After 15 h of stirring, the mixture was concentrated under reduced pressure, after which
10    the residue was taken up in n-butanol and the organic phase was extracted with a saturated solution of sodium hydrogen carbonate in order to
separate off byproducts. After the organic phase had been dried with MgS04 and concentrated, the methyl ester of the title compound was isolated by means of flash chromatography on silica gel (DCM:MeOH =

15    19:1). Yield: 4.3 g (98%)

Empirical formula CaoH28N60a; M.W. = 520.22; MS (M+H) 521.3;

1H NMR (DMSO-d6 )  2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4.58 (m, 2H), 4.85

(q, 1H), 6.90-7.10 (m, 7H), 7.18 (d, J =3Hz, 1H), 7.25-7.40 (m, SH), 7.50 (d, J = 4.5 Hz, 1H), 7.65 (d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 8.35 (d, J =3Hz,

20    1H), 8.70 (d, J = 3.75 Hz, 1H), 11.85 (s, 1H).

N-( ( S)-2-Diphenylamino-1-hyd razinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (12)

1.0    g (1.92 mmol) of 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-25 1H-indole-5-carbonyi]-(S)-amino}propionic acid (11) was dissolved in 10 ml

of methanol,  after which  0.48 g (9.95 mmol)  of hydrazine  hydrate  was

added  and the mixture was  stirred  at room  temperature for  15 h. The

precipitate of the product (0.3 g) was separated off from the mother liquor

by  filtration.  Further  hydrazone  12  (0.1 g)  was  isolated  from  the

30    concentrated mother liquor by flash chromatography on silica gel (DCM:MeOH = 19:1). Yield: 0.4 g (40%)

Empirical formula C29H2aNa02; M.W. = 520.6; MS (M+H) 521.4;

1H NMR (DMSO-d6) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.4 (s, 2H), 4.85 (q, 1H), 6.90-7.10 (m, 7H), 7.18 (d, J =3Hz, 1H), 7.20-7.45 (m, 5H), 7.50 (d,

35    J =4.5 Hz, 1H), 7.62 (d, J =4.5 Hz, 1H), 7.99 (s, 1H), 8.25 (d, J =3Hz, 1H), 8.35 (s(b ), 1H), 9.30 (s, 1H), 11.70 (s, 1H).

N-[ ( S)-2-Diphenylamino-1-( 5-oxo-4 ,5-dihydro-[1 ,3 ,4 ]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (13)
 




32

200 mg (0.384 mmol) of N-((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopydmidin-4-yl)-1 H-indole-5-carboxamide (12) were suspended in 20 ml of methylene chloride, and a 20% solution of phosgene in toluene (0.398 mmol) was added dropwise at ooc and while stirring. The

5    mixture was stirred at room temperature for a further 15 h and the solvent was concentrated. The oxadiazolone 13 was subsequently isolated by flash

chromatography on silica gel (DCM:MeOH = 9:1). Yield: 160 mg (76%)
Empirical formula C3oH26N80 3; M.W. = 546.6; MS (M+H) 547.3;
1H NMR (DMSO-d6 )  2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.85 (q, 1H), 6.90-

10    7.10 (m, 7H), 7.15 (d, J =3Hz, 1H), 7.20-7.40 (m, 6H), 7.52 (d, J = 4.5 Hz, 1H), 7.68 (d, J = 4.5 Hz, 1H), 8.10 (s, 1H), 8.92 (d, J =3Hz, 1H), 11.78 (s, 1H), 12.15-12.40 (s(b), 1H).

B.) Example benzimidazole lxB-kinase inhibitor

15    8.1.) Synthesis of the amino acid (methyl (S)-2-amino-3-diphenylaminopropionate (5)) as described under A.1.

8.2.) Synthesis   of   the    heterocyclic   parent   substance    (2-(2-

methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid ( 19))

20

......_            ,                '-            Methylguanldine    1    1   
                                    I    Hydrochloride    0        0   
o        .    1100    C    0    ~        NaOEt/EtOH,        ~   
                            .)__   .-.-....            3h, reflux               
...... 0        + 'o1 f" -        '-o-  If ~ N, -----    N    "'-'::   
14    O        15            O   16                'NAN-"'   
                                            H        17   
                I    I                                       
                            3,4-Diamino-                               
                ON~O        benzok: acid,    H02C'O:N" F\       
    2N H2SO.,                Nitrobenzene,           
    eo•c,    3h    .....        150"C            I    ~liN   
            'NJl,r        ----            .b    N    N~   
                                    H        I    NH   
                H    18                        19               
                                                           



4-Dimethylamino-1,1-dimethoxybut-3-en-2-one (16)

25    300 g (307 ml, 2.54 mol) of methylglyoxal dimethylacetal were stirred, at 11 ooc for 4 hours (h), with 303 g (337 ml, 2.54 mol) of N,N-dimethylformamide dimethylacetal. The methanol which was formed during the reaction was removed continuously from the reaction solution by distillation. After having been cooled down, the solution was extracted with
 
heptane and the solvents were evaporated. This resulted in 303 g of crude product 16 (yield 70%), which was reacted without any further purification. Empirical formula CsH15N03; M.W. = 173.21; MS (M+H) 174.1;
1H NMR (DMSO-d6)  2.10 (s, 1 H), 2.80 (s, 3H), 3.10 (s, 3H), 3.25 (s, 3H),
5    3.3 (s, 3H), 4.42 (s, 1H), 5.19 (d(b), J = 12.8 Hz, 1H), 7.60 (d, J =15Hz, 1H).


(4-Dimethoxymethylpyrimidin-2-yl)methylamine (17)

0.33 g (14.4 mmol) of sodium was dissolved in 50 ml of absolute ethanol.

10    1.57 g (14.4 mmol) of methylguanidine hydrochloride and 2.48 g (14.4 mmol) of 4-dimethylamino-1,1-dimethoxybut-3-en-2-one (16) were added, while stirring, to the solution, which was heated at boiling heat for 3 h. In order to terminate the reaction, the ethanol was evaporated. The resulting product 17 was used without any further purification. Yield: 2.6 g

15    (quantitative).

Empirical formula CsH13N30 2; M.W. = 183.21; MS (M+H) 184.1;

1H NMR (DMSO-ds) 2.78 (s,  6H),  3.10 (s,  3H),  5.02  (s,  1H),  6.62  (d,
J =3Hz, 1H), 8.30 (d, J =3Hz, 1H).

20    2-Methylaminopyrimidine-4-carbaldehyde (18)

10 g (54 mmol) of (4-dimethoxymethylpyrimidin-2-yl)methylamine (17) were dissolved in 54 ml of 2N sulfuric acid and the solution was heated at 80°C

for 3 h while being stirred. After the reaction had cooled down, the reaction
solution was carefully brought to a pH of about 9 using solid Na2C03 and

25    extracted 3 times with ethanol. After the solvent had been evaporated, the combined dried extracts yielded the title aldehyde 18 in 60% yield (4.47 g)
Empirical formula CsH1N30; M.W. = 137.12; MS (M+H) 138.2;

1H NMR (DMSO-ds) 2.60-2.80 (s(b), 3H), 6.95 (d, J =3Hz, 1H), 7.40-7.60
(s(b), 1H), 8.55 (d, J =3Hz, 1H).

30

2-(2-Methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid (19) 4.3 g (31.3 mmol) of methylaminopyrimidine-4-carbaldehyde (18) and 4.8 g (31.1 mmol) of 3,4-diaminobenzoic acid were heated at 150°C for 2 h in 300 ml of nitrobenzene. After the mixture had been cooled down to ooc, the

35    precipitate of the benzimidazole was separated off from the nitrobenzene by filtration and the product was purified by flash chromatography (DCM/methanol4:1). Yield: 2.66 g (32%)

Empirical formula C13H11Ns02; M.W. = 269.28; MS (M+H) 270.2;

1H NMR  (DMSO-d5)  2.95  (s,  3H),  7.50  (d,  J =3Hz,  1H),  7.75  (d,
J = 4.5 Hz, 1H), 7.90 (d, J = 4.5 Hz, 1H), 8.35 (s, 1H), 8.55 (d, J =3 Hz,

1 H), 8.70-9.05 (s{b), 1H).

5    .3.) Bringing the building blocks together and synthesizing N-{(S)-1-carbamoyl-2-diphenylaminoethyl)-2-{2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (22)


3-0 iphenylamino-2-{[2 -{2-methylam inopyrimidin-4-yl)-1 H-benzimidazole-5-carbonyi]-(S)-amino}propionic acid {21)

2.6 g (9.6 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid {20) were dissolved in 300 ml of DMF, after which 3.17 g

15    {9.6 mmol) of TOTU and 1.6 ml (11.6 mmol) of ethyldiisopropylamine were added consecutively. The solution was stirred at 5°C for 20 min, after which 2.6 g {9.6 mmol) of (S)-2-benzyloxycarbonylamino-3-diphenylamino-propionic acid (5) were added to it. After 16 h of stirring, the mixture was concentrated under reduced pressure, after which the methyl ester 21 was

20    isolated by means of flash chromatography on silica gel {DCM:MeOH = 9:1 ). Yield: 1.61 g (32%)

Empirical formula C2sH21N103; M.W. = 521.58; MS (M+H) 522.3;

1 H NMR (DMSO-d5) 2.95 {s{b ), 3H), 3.60 (s, 3H), 4.19-4.40 (m, 2H), 4.90 (q, 1H), 6.90-7.10 {m, 6H), 7.25-7.35 (m, 6H), 7.40 (d, J =4.5 Hz, 1H),

25    7.60-7.80 (d{b) 1H), 8.05-8.25 {d{b), 1H), 8.45 {d, J =3Hz, 1H), 8.90 (s(b), 1H), 11.85 (s(b ), 1H).

N-((S)-1-Carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (22)
50 ml of (absolute) methanol were saturated with ammonia at 0°C. 0.5 g (0.959 mmol) of 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-
5    benzimidazole-5-carbonyi]-(S)-amino}propionic acid (21) was added to this mixture and the whole was stirred at room temperature for 24 h. After the solvent and excess ammonia had been evaporated, the amide 22 was
isolated  by  flash  chromatography  on  silica  gel  (DCM:MeOH  = 19:1).

Yield: 0.43 g (89%)
10    Empirical formula CzsHz8N80 2; M.W. = 506.57; MS (M+H) 507.2;

1H NMR (DMSO-ds) 2.95 (s(b), 3H), 4.02-4.35 (m, 2H), 4.85 (q, 1H), 6.80-

7.10    (m, 6H), 7.15-7.25 (m, 5H), 7.40 (d, J=4.5Hz, 1H), 7.58 (s(b), 1H),

7.68    (s(b), 1H), 8.06-8.19 (d(b), 1H), 8.40-8.58 (m, 2H), 13.10 (s, 1H).

15    Pharmacological examples IKB-kinase ELISA:

The activity of the IKB-kinase was determined using an ELISA which comprised a biotinylated substrate peptide, which contained the amino acid

sequence in the IKB protein from serine 32 to 36, and a specific polyclonal

20    or monoclonal antibody (e.g. from New England Biolabs, Beverly, MA, USA, Cat.: 9240), which only bound to the phosphorylated form of the IKB peptide. This complex was immobilized on an antibody-binding (protein A-

coated) plate and detected using a conjugate composed of a biotin-binding protein and HRP (e.g. streptavidin-HRP). The activity was quantified with

25    the aid of a standard curve constructed using substrate phosphopeptide.

Implementation:

In order to obtain the kinase complex, 10 ml of Hela S3 cell extract S100

were diluted with 40 ml of 50 mM HEPES, pH 7.5, brought to 40% with

30    respect to ammonium sulfate and incubated on ice for 30 minutes. The precipitated pellet was dissolved in 5 ml of SEC buffer (50 mM HEPES, pH 7.5, 1 mM DTI, 0.5 mM EDTA, 10 mM 2-glycerophosphate), centrifuged at 20 000 g for 15 minutes and filtered through a 0.22 11m filter. The sample was loaded onto a 320 ml Superose-6 FPLC column

35    (Amersham Pharmacia Biotech AB, Uppsala, Sweden) which had been equilibrated with SEC buffer and which was operated at 4°C with a flow rate of 2 mllmin. The fractions which were located at the migration time of the 670 kDa molecular weight standard were combined for the activation. Activation was achieved by means of a 45-minute incubation with 100 nM
 




36

MEKK1~. 250 J.!M MgATP, 10 mM MgCI2, 5 mM dithiothreitol (OTT), 10 mM 2-glycerophosphate and 2.5 J.!M microcystin-LR at 3rC. The activated enzyme was stored at -80"C. The test substances (2 J.LI), which were dissolved in DMSO, were preincubated, at 25"C for 30 minutes, with 43 J.!l

5    of activated enzyme (diluted 1:25 in reaction buffer 50 mM HEPES, pH 7.5,

10 mM MgCI2, 5 mM OTT, 10 mM p-glycerophosphate, 2.5 1-1M microcystin-LR). 5 1-11 of substrate peptide (biotin-(CH2)6-DRHDSGLDSMKD-CONH2) (200 1-1M) were then added, after which the mixture was incubated for one hour and the reaction was stopped with

10    1501-11  of  50 mM  HEPES,  pH 7.5,  0.1%  BSA,  50 mM  EDTA,  antibody

[1 :200]. 100 1-11 of the stopped reaction mixture or of a standard phosphopeptide dilution series (biotin-(CH2)6-DRHDS[P03]GLDSMKD-CONH2) were then transferred to a protein A plate (Pierce Chemical Co., Rockford, IL, USA), after which the plate was incubated for 2 hours while

15    being shaken. After 3 washing steps with PBS, 100 1-11 of 0.5 1-1g/ml streptavidin-HRP (horseradish peroxidase) (diluted in 50 mM HEPES/0.1% BSA) were added for 30 minutes. After 5 washing steps with PBS, 100 1-1L of TMB substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD,

USA) were  added  and  the  color development was stopped  by adding

20    100 1-1L of 0.18 M sulfuric acid. The absorption was measured at 450 nm. The standard curve was produced by linear regression corresponding to a 4-parameter dose-effect relationship. This standard curve was used to quantify the enzyme activity or its inhibition by the test substances.

25    The IC50 for N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide was 0.050 1-1M.

The    IC50    for    N-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-
30   methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide    was
0.045 J.LM.           

Pain assay

The  analgesic  and  antinociceptive  activity  of  the  compound  N-[( S)-2-

35    diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4 ]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide, termed compound 13 in that which follows, was demonstrated in the two following models:
1st model: Zymosan-induced paw inflammation in the rat;

    Parameter: paw withdrawal time or paw withdrawal threshold during
    thermal or mechanical stimulation of the hind paw.
    2"d model: Kaolin/carrageenan-induced knee joint inflammation in the rat;
    Parameter: reaction of spinal neurons during pressure stimulation of
5    the knee.

Model1

Experimental ~mplementation: in short-term anesthesia using isoflurane, 1 mg of Zymosan (as a suspension in 100 Ill of PBS (phosphate-buffered

10    salt solution)) was injected subcutaneously into the middle of the plantar side of one of the experimental animal'shind paws. After that, two different

behavioral tests were used to quantitatively determine the development of

a    hyperalgesia.

a)    Determining  the  paw  withdrawal  time  during  thermal  stimulation

15    (Hargreaves test).

The experimental animal was placed in a transparent plastic chamber having a glass floor. As soon as the experimental animal was no longer moving, following the reconnaissance phase (about 5 min), an infrared light

source was positioned directly below the hind paw to be stimulated and

20    switched on. The lamp emitted focused infrared light of increasing intensity, such that the skin temperature of the hind paw increased almost linearly. As soon as the animal withdrew the paw, the lamp switched itself off. The temperature of the paw at the time it is withdrawn has just become unpleasant for the animal; this is referred to as the thermal pain threshold.

25

b)    Determining  the  paw  withdrawal  threshold  during  mechanical

stimulation (von Frey test)

The  experimental  animal  was  placed  in  a transparent  plastic  chamber

whose floor consisted of wire-gauze. Punctate pressure of defined strength

30    was produced using calibrated nylon fibers, what are termed von Frey hairs. The weakest pressure stimulation during which the animal withdrew its paw determines the mechanical pain threshold.

About  half  an  hour  before,  and  at  various  times  after,  the  Zymosan

35    injection, the thermal and mechanical pain thresholds were determined on the right hind paw and on the left hind paw (see Tables 1, 2). The decrease in the ipsilateral pain threshold, expressed in % of the contralateral pain threshold, was then calculated (see Tables 1, 2). The degree of hvoeralaesia is directlv proportional to the maonitude of this decrease.
 




38

In a control group, the Zymosan injection induced pronounced mechanical and thermal hyperalgesia (see control data in Tabs. 1 and 2). In another group of animals, which were under short-term isoflurane anesthesia, the abovementioned compound 13 was injected intraperitoneally (i.p.) (in each

5    case 30 mg/kg in polyethylene glycol/water mixture (PEG/water 1:1) about 15 minutes before, and 2.5 and 5.5 hours after Zymosan injection. From two hours after Zymosan injection onward, the thermal hyperalgesia was

less pronounced in these animals than it was in the control group; after the

third administration of the substance, it was no longer possible to observe

10    any side difference at all in the paw withdrawal time (Tab. 1). In addition, this effect still persisted for 18 hrs after the last administration of the

substance.

Compound 13 also significantly reduced the mechanical hyperalgesia. The effect set in 1 hour after Zymosan injection and also still persisted 18 hrs

15    after the last administration of the substance (see Tab. 2).

The activity of compound 13 is very strong in both test models. Comparative data from a study which was carried out previously show that

compound 13 reduces the thermal hyperalgesia considerably more 20 powerfully than does the NSAIO diclofenac.

Table 1: Change in the paw withdrawal time (%)       
Time (h)    Mean value    SO compound    Mean value   
after Zymosan    Compound 13    13    control    SO control
injection (0)               
Baseline -0.5    0.0    0.0    0.0    0.0
0.5    -16.6    6.6    -21.4    6.3
1    -31.3    14.1    -28.8    11.6
2    -30.2    15.4    -44.8    19.1
3    -15.3    5.3    -49.2    17.9
4    -16.0    11.5    -50.6    23.0
5    -9.7    18.6    -46.6    24.8
6    5.0    2.6    -38.4    17.6
7    3.4    5.8    -29.9    22.1
24    -3.8    7.0    -46.1    18.4
 




        39       
Table 2:               
Change in the paw withdrawal threshold (%)       
Time (h)        so       
after Zymosan    Mean value    compound    Mean value    SO control
injection (0)    Compound 13    13    control   
Baseline -0.5    0.0    0.0    0.0    0.0
0.5    -37.4    6.6    -48.9    31.3
1    -43.1    20.5    -66.0    23.2
2    -36.0    17.8    -71.8    26.0
3    -35.1    13.1    -60.5    20.2
4    -46.7    11.9    -64.3    18.2
5    -40.6    14.0    -55.5    25.8
6    -33.1    23.3    -57.3    18.0
7    -44.7    21.5    -47.1    23.9
24    -9.7    26.6    -41.5    17.3

Model2,

5    Experimental implementation: In rats which were under sodium thiopental anesthesia, the spinal canal was opened and spinal medullary neurons which processed the "pain impulses" from the knee-joint were identified. Following identification, a long-term recording, in which the activity of the

nerve cell was recorded before and during the development of an acute

10    inflammation in the knee-joint, was carried out. For this, the responses to non-noxious and noxious stimulation at the knee-joint were measured in a control period before inducing the inflammation and for several hours after

inducing the inflammation.

The acute inflammation was induced by the intraarticular injection of a

15    suspension (about 150 Ill) of kaolin and carrageenan. In controlled experiments, only the vehicle was applied to the spinal medullary surface in order to represent the development of the hyperexcitability under control conditions. As a rule, this development of hyperexcitability took place within

2 to 4 hours and was expressed in a marked increase in the responses to

20    non-noxious and noxious stimulation of the knee-joint (Tab. 3). In the experiments in which the abovementioned compound 13 was applied, the

substance was added (about 30 1-11 of a 10 1-1M solution) to the spinal medulla about 30 minutes before inducing the inflammation. The responses of the cell to non-noxious and noxious stimulation were then subsequently

25    monitored as in the control experiments.
 




40

Comparison of the changes in the responses in the two groups shows that, as compared with the controls, compound 13 almost completely suppressed the development of spinal hyperexcitability (Tab. 3). Taken overall, the effect of compound 13 on the responses to noxious knee-joint

5    stimulation was more strongly expressed than was the effect of indomethacin, as was shown by a comparison with published data from an earlier study.

Table 3: Neuronal responses before and during knee-joint inflammation 10 (imp/15s)

    Noxious stimulation at the knee-joint   
Time (min)               
after KIC    Mean value    SEM    Mean value    SEM
injection    Compound 13    compound 13    control    control
Baseline    0.8    29.9    0    0
30-60    62.3    49.3    161.6    43.7
60-120    26.9    35    458.1    125.4
120-180    8.5    58.9    544.2    140.0
180-240    19.5    59.9    616.3    174.7
    Non-noxious stimulation at the knee-joint
Time (min)               
after K/C    Mean value    SEM    Mean value    SEM
injection    Compound 13    compound 13    control    control
Baseline    0.92    16.90    0    0
30-60    8.66    23.76    21.4    11.9
60-120    2.71    25.94    74.6    38.3
120-180    11.16    24.22    105.7    39.0
180-240    39.78    25.09    149.7    44.3

The    effect    of    N-( ( S)-1-ca rba moyl-2-diphenylaminoethyl)-2-(2-
15   methylaminopyrimidin-4-yl)-11 ~-benzimidazole-5-carboxamide,    termed
compound 22 below, was also tested in model 2.   
 




41
 

Control data: see Table 3 Table 4: Neuronal responses (imp/15s)

Time (min) after K/C injection Baseline 30-60 60-120 120-180 180-240

5

Time (min) after K!C injection 0 Baseline 30-60 60-120 120-180 180-240
 


before  and  during  knee-joint inflammatio

Noxious stimulation at the knee-joint

Compound 22    Compound 22
Experiment 1    Experiment 2
0    0
-109.1    -9.2
-101.1   
-37.8    60
    96.7



Non-noxious stimulation at the knee-joint

Compound 22    Compound 22
Experiment 1    Experiment 2
0    0
-34.1    -30.6
-37.2   
-32.1    50.3
    68.7
 

The data verify the good effect of compound 22 in model 2.

3rd model: Zymosan-induced paw inflammation in the mouse;

Parameter: paw withdrawal time during thermal stimulation of the

hind paw.

Experimental implementation:    In short-term anesthesia using isoflurane,

5    25 J.ll of a suspension containing 50 mg of zymosan/ml were injected into the right hind paw of the experimental animal. The development of a hyperalgesia was then determined quantitatively as follows:
Determining the paw withdrawal time during thermal stimulation (Hargreave'stest; see above).

10    The experimental animal was placed in a transparent plastic chamber having a glass floor. As soon as the experimental animal was no longer moving, following the reconnaissance phase (about 5 min), an infrared light source was positioned directly below the hind paw to be stimulated and switched on. The lamp emitted focused infrared light of increasing intensity

15    such that the skin temperature of the hind paw increased almost linearly. As soon as the animal withdrew the paw, the lamp switched itself off. The temperature of the paw at the time it is withdrawn has just become unpleasant for the animal; this is referred to as the thermal pain threshold.

20    Shortly before the zymosan injection, and for from 7 to 14 days after the injection, the thermal pain threshold was determined once daily on the right hind paw and left hind paw. Subsequently, the integral of the area which was formed from the curves •for the paw withdrawal times of the inflamed

paw  and  the  noninflamed  paw  (AUC,  area  between  the  curves,  see

25    tables 5 and 6) was determined as a measure of the hyperalgesia. The larger this value is, the more pronounced is the hyperalgesia, and the smaller the value is in animals which are being given the substance, the greater is the success of the therapy.

30    In a 7-day study, the zymosan injection induced pronounced thermal hyperalgesia in a control group (see vehicle, tab. 5). In the other groups, the substance was administered for the first time one day after the zymosan injection, after marked thermal hyperalgesia had already developed. Compound 13 was then administered orally twice daily for 7

35    days, in each case at the rate of 25 or 75 mg/kg in HEC!Iipofundin (1% HEC in lipofundin). Analysis of the paw withdrawal times during the entire period of the study (7 days) showed that, when the substance was


administered, the AUC decreased in a dose-dependent manner. At single doses of from 8.3 mg/kg and upwards, a significant therapeutic effect was achieved as compared with the vehicle group (tab. 5). Compound 13 exhibits very strong activity in the test model. A very high dose of

5    paracetamol was likewise administered twice daily to another group of animals which was taken through the experiment in parallel. Compound 13 reduced the thermal hyperalgesia to a greater extent than did paracetamol (tab. 5).

10    Table 5  Thermal hyperalgesia during the seven days following zymosan
. . t' lnJec 10n

                       
        AUC    Standard error    Number of    Statistical   
        mean value    of the arithmetic    animals per    difference as   
        [measure of    mean (SEM)    group    compared with   
        hyperalgesia]            the vehicle   
                       
                       
    Vehicle    45.1    1.5    8       
                       
                       
    Paracetamol, 200 mg/kg    24.6    4.1    8    [yes   
                       
    Compound 13, 2.8 mg/kg    40.4    2.4    8    no   
                       
    Com_Qound 13, 8.3 mg/kq    32.3    2.2    8    [yes   
                       
    Compound 13, 25 mg/kg    19.4    2.9    8    [yes   
                       
    Compound 13, 75 mglkg    17.4    2.6    8    [yes   

In another study carried out on mice, the activity of compound 13 was compared with that of the specific COX-2 inhibitor Celecoxib. The scheme

15    for zymosan injection and dosing was identical to that in the previously described study. The only difference was that this additional study ran for 14 days.

Once again, compound 13 was able to reduce thermal hyperalgesia in a dose-dependent manner (tab. 6). In the experiment, compound 13 and

20    Celecoxib had equally strong effects at the high dosage (tab. 6).

Table  6   Thermal  hyperalgesia during the  14 days following  zymosan

.. f tn]eC IOn

                   
    AUC    Standard error    Number of    Statistical   
    mean value    of the arithmetic    animals per    difference as   
                   
                   
    [measure of    mean (SEM)    group    compared with   
    hyperalgesia]            the vehicle   
                   
                   
Vehicle    90.0    5.1    8       
Celecoxib, 8.3 mg/kg_    79.9    5.9    5    no   
                   
Celecoxib, 25 mg/kg    51.5    3.7    9    no   
                   
Compound 13, 8.3 mg/kg    64.5    5.0    5    yes   
                   
                   
Compound 13, 25 mglkg    47.6    4.4    9    Iyes   
                   

4th model: Zymosan-induced paw inflammation in the mouse;

5    Parameter: spontaneous running performance in a running wheel.

In the cage in which it is kept, the experimental animal has access to a running wheel, the revolutions of which are recorded electronically. During the night hours, the C57/86 mice use the running wheel voluntarily and, after a one-week phase of acclimatization, cover on average

10    4 100 meters/night. After zymosan has been injected, the distance run each night is reduced. This reduction in running performance is a valid parameter for a restriction in function which is due to inflammation pain.
Experimental implementation: After an acclimatization phase of one week, the distance run/24 hours was measured in order to determine the

15    base line. 25 J.JI of a suspension containing 50 mg of zymosan/ml were then injected into the right hind paw of the experimental animal during short-term anesthesia using isoflurane. The distance run/24 hours was then

determined during the following seven days. In the analysis, the area under

the curve for the values for the distance run was determined (AUC, tab. 7):

20    the lower the AUC, the lower was the running performance during the week following injection of the zymosan. Compound 13 was administered twice daily for 7 days, with the dose in each case being 25 or 75 mg/kg in HEC/Iipofundin (1% HEC in lipofundin). The substance was administered for the first time on day 1 after injection of the zymosan.

25

In one study, the effect of compound 13 on running performance following zymosan injection was compared with that of paracetamol. A dose-dependent increase in the distance run, which was significant as compared with the vehicle group, was found in the case of both the higher doses

30    (tab. 7) .. By contrast, no improvement as compared with the vehicle group
 




45

was achieved when paracetamol was used at an extremely high dose (also 2 x daily) (tab. 7).

Table 7  Running wheel activity during the seven days following zymosan
5    ..   f
JnjeC IOn

                   
    AUC    Standard error    Number of    Statistical   
    mean value    of the arithmetic    animals per    difference as   
                   
        mean (SEM)    group    compared with   
                the vehicle   
                   
Vehicle    108.8    12.5    8       
Paracetamol, 200 mQ!kQ    187.2    42.7    8    no   
Compound 13, 2.8 mg/kg    131.1    23.3    8    no   
                   
Compound 13, 8.3 mg/kQ    142.1    29.1    8    no   
Compound 13, 25 mg/kg    216.7    58.5    8    Iyes   
                   
                   
Compound 13, 75 mQ/kQ    251.7    41.9    8    Iyes   
 

Patent claims:

1.    The use of IKB-kinase inhibitors for producing pharmaceuticals for treating pains.
5

2.    The use of the compound of the formula I

10    and/or a stereoisomeric form of the compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I,

for producing pharmaceuticals for treating pains, where

E is N atom or the radical -C(R19)-,
15    where R19 is hydrogen atom or the radical R9 ,
one of the substituents R1,  R2,  R3 and R4  is a radical of the formula

            (II)
    in which    D is -C(O)-. -S(O)- or -S(O}z-,
R8 is    hydrogen atom or -(C,-C4)-alkyl,
R9 is    1.    characteristic radical of an amino acid,
    2.    aryl, in which aryl is unsubstituted or substituted,
    3.    heteroaryl having from 5 to 14 ring members, in which
        heteroaryl is unsubstituted or substituted,
    4.    heterocycle  having  from  5 to  12  ring  members,  in
        which heterocycle is unsubstituted or substituted, or
    5.    (C,-C6}-alkyl,  in  which  alkyl  is  straight-chain  or
        branched and is unsubstituted or is substituted, once,
        twice or three times, independently of each other, by
        5.1    aryl,   in   which   aryl   is   unsubstituted   or
            substituted,


5.2    heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted,

5.3    heterocycle having from 5 to 12 ring members, in which heterocycle is unsubstituted or
5    substituted,

4.    -O-R11,

5.    =0,

6.    halogen,

7.    -CN,

10    5.8    -CF3,
5.9    -S(O)x-R11 , in which xis the integer zero, 1 or 2,
5.10    -C(O)-O-R11 ,

5.11    -C(O)-N(R11)2,
5.12    -C(O)-R11,

15    5.13   -N(R11)2.

5.14    -( C3-C6)-cycloalkyl,

5.15    radical of the formula

or
5.16 radical of the formula --===--- R11 in which
R11 is a)    hydrogen atom,
25 b) -(C1-C6)-alkyl, in which alkyl is unsubstituted or is substituted once, twice or three times,

1.    aryl,  in  which  aryl  is  unsubstituted  or
    substituted,
2.    heteroaryl  having  from  5  to  14  ring
30    members,
3.    heterocycle  having  from  5  to  12  ring
    members,
4.    halogen,
5.    -N-(C1-C6)n-alkyl, in which n is the integer
35    zero, 1 or 2 and alkyl is unsubstituted or
    is substituted once, twice or three times,


independently of each other, by halogen or by -C(O)-OH,
6.    -O-(C,-C6)-alkyl or

7.    -C(O)-OH,

5 c) aryl, in which aryl is unsubstituted or substituted,

d)    heteroaryl having from 5 to 14 ring members, or

e)    heterocycle having from 5 to 12 ring members, and,

10    in the case of (R11 )2, R11 has, independently of each other, the meanings of a) to d),

Z is   1. aryl, in which aryl is unsubstituted or substituted,

2. heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted,

15 3. heterocycle having from 5 to 12 ring members, in which heterocycle is unsubstituted or substituted,

4.    -(C1-C5)-alkyl, in which alkyl is substituted or unsubstituted,
5.    -C(O)-R1\
20    6.    -C(O)-O-R11 or
7.    -C(O)-N(R11)2, or

R8 and R9 form, together with the nitrogen atom and carbon atom to which they are bonded, a heterocyclic ring of the formula lla,

        .........  _...    N'-...    /Z   
        D    I  \    (lla)   
            '\ B       
25            x... ~       
                   
    in which  D and Z are defined as in formula II,   
    A is    nitrogen atom or the radical -CH;z-,   
    B is    oxygen  atom,  sulfur atom,  nitrogen  atom  or the   
30        radical -CH2-,       
    X is    oxygen atom, sulfur atom, nitrogen or the radical   
        -CH;z-,           
    Y is    absent or is  oxygen  atom,  sulfur atom,  nitrogen   
        atom or the radical -CH2-, or   
35    X and Y together form a phenyl, 1,2-diazine, 1 ,3-diazine,   
        or 1,4-diazine radical,   
 




49

where the ring system which is formed by N, A, X, Y, 8 and carbon atom does not contain more than one oxygen atom, X is not oxygen atom, sulfur atom or nitrogen atom when A is nitrogen atom, does not contain more than one sulfur atom, and contains 1, 2, 3 or 4

5    nitrogen atoms, and where an oxygen atom and a sulfur atom are not present simultaneously,

where the ring system which is formed by N, A, X, Y, 8 and carbon atom is unsubstituted or is substituted, once, twice or three times, independently of each other, by -(C1-C8)-alkyl, in which alkyl is

10    unsubstituted or is substituted, once or two times, by

1.1.    -OH,

1.2.    -(C1-Cs)-alkoxy,

1.3.    halogen,

1.4.    -N02,

15    1.5.    -NH2,

1.6.    -CF3,

1.7.    methylenedioxyl,

1.8.    -C(O),

1.9.    -C(O}-CH3,

20    1.1 0.  -(C1-C4)-alkoxycarbonyl,

1.11.    -CN,

1.12.    -C(O}-OH,

1.13.    -C(O}-NH2,

1.14.    tetrazolyl,

25    1.15.  phenyl,

1.17.    phenoxy,

1.18.    benzyl or

1.19.    benzyloxy or

R9 and Z form, together with the carbon atoms to which they are in 30 each case bonded, a heterocyclic ring of the formula lie,
........._ D....-    N0 N/R11 (lie)   
    I    I   
    RB       
    T,    /w   
v
 

in which  D, R8 and R11 are defined as in formula II,

    Tis    oxygen  atom,  sulfur atom,  nitrogen  atom  or the
            radical -CHz-,
    Wis  oxygen  atom,  sulfur atom,  nitrogen  atom  o•r the
            radical -CHz-,
5    V is        absent or is  oxygen  atom,  sulfur atom,  nitrogen
            atom or the radical -CH2-. or
    T and V or V and W together form a phenyl, 1,2-diazine,
    1,3-diazine or 1,4-diazine radical,
    where the ring system which is formed by N, T, V, Wand
10    two carbon atoms does not contain more than one oxygen
    atom, does not contain more than one sulfur atom and
    contains 1, 2, 3 or 4 nitrogen atoms, where an oxygen
    atom and a sulfur atom are not present simultaneously,
    and where the ring system which is formed by N, T, V, W
15    and two carbon atoms is unsubstituted or is substituted,
    once to three times, independently of each other, by the
    substituents which are defined above under 1.1. to 1.18.,
    and       
    the other substituents R\ R2 ,  R3 and R4 in each case are,
20    independently of each other,
    1.    hydrogen atom,
    2.    halogen,
    3.  -(C1-Cs)-alkyl,
    4.  heteroaryl having from 5 to 14 ring members, in which
25        heteroaryl is unsubstituted or substituted,
    5.  heterocycle  having  from  5  to  12  ring  members,  in
        which heterocycle is unsubstituted or substituted,
    6.    -N02,   
    7.    -CN,   
30    8.  -O-(Co-C4)-alkylaryl,
    9.  -O-(C1-C4)-alkyl,
    10.-0R1\   
    11.-N(R11 )2,
    12.-S(O)r-R1\  in which r is the integer zero, 1 or 2, or
35    13.-CF3,   
    R5 is    1.    hydrogen atom,
            2.    -OH or
            3.    =0, and
 
        51
R6 is    1.    aryl,   in   which   aryl   is   unsubstituted   or
    substituted,
    2.  phenyl which is substituted once or twice by
    2.1 -CN,
5    2.2 -N02,
    2.3 -O-(C1-C4)-alkyl,
    2.4    -N(R11)2,
    2.5    -NH-C(O)-R11 ,
    2.6    -S(O)s-R11 , in which sis the integer zero, 1 or 2,
10    2.7    -C(O)-R11 or
    2.8 -(C1-C4)-alkyi-NH2,
    3.  heteroaryl having from 5 to 14 ring members, is
    unsubstituted or is substituted once, twice or three
    times, or
15    4.    heterocycle having from 5 to 12 ring members,
    is  unsubstituted  or is  substituted  once,  twice  or
    three times.

3.    The use of the compound of formula I as claimed in claim 2, wherein
20    E is N atom or the radicai-C(R19)-,

in which R19 is hydrogen atom or the radical R9,
one of the substituents R\ R2, R3 and R4 is a radical of the formula II, in which

D is   -C(O)-, -S(O)- or -S(O)z-,

25    R8 is  hydrogen atom or (C1-C4)-alkyl,
R9 is 1. a characteristic radical of an amino acid which is derived from a naturally occurring a-amino acids of the group alanine, valine, leucine, isoleucine, phenylalanine, tyrosine,

tryptophan, serine, threonine, cysteine, methionine, 30 asparagine, glutamine, lysine, histidine, arginine, glutamic

acid and aspartic acid,

2. a characteristic radical of an amino acid which is derived from an amino acid which is not naturally occurring, such as 2-aminoadipic acid, 2-aminobutyric acid, 2-

35 aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid, 1,2,3,4,-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, sarcosine, pipecolic acid, 2-aminoheptanoic
 
acid, hydroxylysine, N-methylisoleucine, 6-N-methyllysine, norleucine, N-methylvaline, norvaline, ornithine, aile-isoleucine, 4-hydroxyproline, allo-hydroxylysine, aile-threonine, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homocysteine, homophenylalanine, homocysteic acid, 2-amino-3-phenylaminoethylpropionic acid, 2-amino-3-phenylaminopropionic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, cyclohexylalanine, 4-aminophenylalanine, citrulline, 5-fluorotryptophan, 5-

methoxytryptophan, methionine sulfone, methionine sulfoxide or -NH-NR11-CON(R11)2, in which R11 is defined as below,

3. aryl, from the group anthryl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, fluorenyl, naphthyl, 1-naphthyl, 2-naphthyl or phenyl, in which aryl is unsubstituted or substituted once, twice or three times by identical or different radicals from the series -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(C1-Cs)-alkyl, -(C1-Cs)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 in which x is the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl,

4. heteroaryl having from 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted and, as a radical, is derived from the group azepine, azetidine, benzimidazole, benzodioxolane, 2-benzofuran, benzothiazole, benzothiophene, 2-benzothiophene, 2-benzoxazole, J3-carboline, quinoxaline, quinazoline, quinoline, 2-quinoxaline, cyclohepta[b)-5-pyrrole, diazepine, dihydropyridine, 3-hydroxypyrro-2,4-dione, imidazole, 4-imidazole, imidazolidine, imidazoline, indazole, indole, isoquinoline, isoindole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone, methylimidazole, 3-(N-
 
methylpyrrolidine ), morpholine, oxazole, 1,3,4-oxadiazole, oxadiazolidinedione, oxadiazolone, 5~oxo-4,5-dihydro-
[1 ,3,4]oxadiazole, 5-oxo-1 ,2,4-thiadiazole, 1,2,3,5-oxathiadiazole-2-oxide, 1-oxo-1 ,2-dihydro-3-isoquinol, phenylpyrrole, 5-phenyl-2-pyrrole, phthalazine, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyrazoline, pyridazine, pyrimidine, pyridine, pyridyi-N-oxide, 2-pyrrole, 3-pyrrole, pyrrolidine, pyrroline, 4,5,6,7-tetrahydro-2-indole, tetrahydrothienyl, tetrazole, thiadiazole, thiazole, thiomorpholine, thiophene, triazole, triazolone or triazole,

in which heteroaryl is unsubstituted or substituted once, twice or three times by identical or different radicals which are derived from the series -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C,-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(C1-C6)-alkyl, -(C 1-C6)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 , in which xis the integer zero, 1 or 2, -O-(C,-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C,-C4)-alkyl or tetrazolyl,

5. -(C,-C6)-alkyl in which alkyl is straight-chain or branched and is unsubstituted or substituted once, twice or three times, independently of each other, by

5.1    aryl, in which aryl is defined as above,

5.2    heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above,

5.3    -(C3-C6)-cycloalkyl,
 

30    5.4    -O-R1\

5.5    =0,

5.6    halogen,

5.7    -CN,

5.8    -CF3,

35    5.9    -S(O)xR11 , in which xis the integer zero, 1 or 2,
5.10    -C(O)-O-R1\
5.11    -C(O)-N(R11 )2,

5.12    -C(O)-R1\
5.13    -N(R11 )2.

5.14    a radical of the formula

R11 ylR11

or

5.15    a radical of the formula R'1 in which
R11 is a)    hydrogen atom,
b)    (C,-C6)-alkyl in which alkyl is unsubstituted or substituted once, twice or three times by

1.    aryl, in which aryl is defined as above,

2.    heteroaryl having 5 to 14 ring members, in which heteroaryl is defined as above,

3.    halogen,

4.    -N-(C1-C6)n-alkyl, in which n is the integer zero, 1 or 2 and alkyl is unsubstituted or substituted once, twice or three times, independently of each other, by halogen or by -C(O)-OH,
5.    -O-(C,-C6)-alkyl or

6.    -C(O)-OH,

c)    aryl, in which aryl is defined as above, or

d)    heteroaryl having from 5 to 14 ring members, in

which heteroaryl is defined as above, and
in the case of (R11)2 , the radical R11 has, independently of each another, the meaning of a) to d),

Z is   1.    aryl in which aryl is defined as above,

2.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above,

3.    -(C1-C6)-alkyl,  in  which  alkyl  is  straight-chain  or

branched and is substituted once or twice by phenyl or -OH,
4.    -C(O)-O-R11 , or

5.    -C(O)-N(R11)2, and
the  other  substituents  R\  R2,   R3  and  R4 are  in  each  case,
independently of each other,

1.    hydrogen atom,

2.    halogen,

3.    -(C1-C4)-alkyl,


8.    heteroaryl having from 5 to 14 ring members, in which heteroaryl is defined as above,

9.    -(C1-Cs)-alkyl,

10.    -N02,

5    7. -CN,

8.    -O-(Co-C4)-alkyl-aryl, in which aryl is defined as above,

9.    -O-(C1-C4)-alkyl,

10.    -OR1\
11.    -N{R11 }2,
10    12.    -S(O)x-R1\  in which xis the integer zero, 1 or 2, or
13.    -CF3,

R5 is  1.    hydrogen atom,
2.    -OH, or

3.    =0, and

15    R6 is 1. aryl, from the group naphthyl, 1-naphthyl, 2-naphthyl, phenyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl or fluorenyl,

in which aryl is unsubstituted or substituted, once, twice or three times, by identical or different radicals from the series

20    -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2. -(C1-Ca)-alkyl, -(C1-Ca}-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl such as

hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,

ethylenedioxy,    formyl,    acetyl,    cyano,    hydroxycarbonyl,

25    aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O}x-R1\ in which x is the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl, or

2.    heteroaryl having from 5 to 14 ring members, in which

30    heteroaryl is defined as above and

in which heteroaryl is unsubstituted or substituted, once, twice or three times, by identical or different radicals from the series -C(O)-(C1-C4)-alkyl, -C(O}, =0, -NH-(C1-C4)-alkyl, -NH-((C1-C4)-alkyl)2, -(C1-C8 }-alkyl, -(C1-Ca)-alkoxy, halogen, nitro, amino,

35    trifluoromethyl, hydroxyl, -CF3, hydroxy-(C1-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,

aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R11 , in which x is the integer zero, 1 or 2,


-O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl.
 
4.    The use of the compound of the formula I as claimed in claim 2,

wherein

E is N atom or the radical -C(R19)-, in which R19 is hydrogen atom,

one of the substituents R1, R2, R3 and R4 is a radical of the formula II, in which

R8 is  hydrogen atom,

R9 is 1. a characteristic radical of an amino acid from the group histidine, serine, tryptophan, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid, or
2.    -(C1-C6 )-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or substituted, once or twice, by

a)    phenyl,

b)    a radical from the group azepine, azetidine, benzimidazole, benzothiazole, benzothiophene, benzoxazole, diazepine, imidazole, indole, isothiazole, isoxazole, morpholine, 1,3,4-oxadiazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, oxazole piperidine, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, thiazole,

thiomorpholine, thiophene or triazole,
c)    -NH(R11 ),
d)    -C(O)-R12, in which
R12   is naphthyl, phenyl, morpholinyl or pyrimidinyl,
e)    -O-R11 ,

f)    -N(R12)-phenyl, in which R12 is defined as above,
g)    -S(O)x-R12, in which xis zero, 1 or 2, and

h)    -CN, or

i)    -(C3-Cs)-cycloalkyl,

and the radicals defined above by a), b), d) and i) and R12 are unsubstituted or are substituted, once or twice, by -OH, -(C,-C4)-alkyl, -CF3, halogen, -O-(C1-C4)-alkyl, -COOH, -C(O)-O-(C,-C4)-alkyl, -NH2 or -NH-C(O)-(C,-C4)-alkyl,

Z is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole,
 
isothiazole, isothiazolidine, isoxazole, isoxazolidine, 2-isoxazolidine, isoxazolone, morpholine, 1,3,4-oxadiazole, oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide, oxazole, 5-oxo-4,5-dihydro-[1,3,4)oxadiazole, 5-oxo-

5 1,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazolone, and

the heteroaryl radical is unsubstituted or substituted, once, twice or three times, independently of each other, by

10 1.1 -C(O)-R15 , in which R15 is hydrogen atom or -(C,-C4)-alkyl,

1.2    -(C,-C4)-alkyl,

1.3    -O-R15, in which R15 is hydrogen atom or -(C,-C4)-alkyl,

1.4    -N(R15)-R16 ,  in which R15 and R16 are, independently of

15    each other, hydrogen atom or -(C,-C4)-alkyl,

1.5    halogen, or

1.6    keto radical,

2.    -C(O)-R15, in which R15 is hydrogen atom or -(C,-C4)-alkyl,

20    3.    -C(O)-R15,  in which R15  is hydrogen atom or -(C,-C4)-

alkyl, or

4.    -C(O)-N(R15)R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C,-C4)-alkyl,
25    R11  is 1. -(C,-C4)-alkyl,
2.    R13 or,

3.    -N(R13)z,
in which R13 is, independently of each other,

a)    hydrogen atom,

30    b)    -(C,-Cs)-alkyl,

c)    -( C,-C4 )-alkyi-O-(C,-C4 )-alkyl,

d)    -(C,-Cs)-alkyi-N(R15)2 , in which R15 is defined as above, or

e)    -(Co-C4)-alkyl which is substituted, once or twice, by

35        imidazolyl, morpholinyl or phenyl, or
    R8 and R9 form, together with the nitrogen atom and carbon atom to
    which they are in each case bonded, a ring of the formula lla from
    the  group    pyrrole,  pyrroline,  pyrrolidine,  pyridine,  piperidine,
    piperylene,    pyridazine,  pyrimidine,  pyrazine,  piperazine,  pyrazole,
 


imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, tetrazole, 1 ,2,3,5-oxathiadiazole-2-oxides, oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione,

5    triazole, which are substituted by F, CN, CF3 or COO-(C,-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 5-oxo-1 ,2,4-thiadiazoles, 1,3,4-oxadiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, tetrahydroquinoline,

10    tetrahydroisoquinoline and isoquinoline, or

R9 and Z form, together with the carbon atoms to which they are in each case bonded, a ring of the formula lie from the group pyrrole,

pyrroline,  pyrrolidine,  pyridine,. piperidine,  piperylene,  pyridazine,

pyrimidine,  pyrazine,  piperazine,  pyrazole,  imidazole,  pyrazoline,

15    imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine,

pteridine,    indole,   tetrahydroquinoline,   tetrahydroisoquinoline,

20    isoquinoline, tetrazole, 1 ,2,3,5-oxathiadiazole-2-oxides, oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione,
triazole, which are substituted by F, CN, CF3 or COO-(C,-C4)-alkyl,

3-hydroxypyrro-2,4-diones,   1 ,3,4-oxadiazole   and   5-oxo-1 ,2,4-

thiadiazole and

25    the other substituents R\ R2, R3 and R4 in each case are, independently of each other,

1.    hydrogen atom,

2.    halogen,

3.    -(C,-C4)-alkyl,

30    4. -CN,

5.    -N02,

6.    -O-(Co-C4)-alkyl-phenyl,

7.    -O-(C1-C4)-alkyl,

8.    -N-(Co-C4)-alkyl-phenyl,

35    9. -N-(C,-C4)-alkyl or 10. -CF3,
R5 is  1.    hydrogen atom,
2.    -OH, or

3.    =0, and
 
R6 is  1.    phenyl, substituted, once or twice, by

1.1    -CN,

1.2    -N02,

1.3    -O-(C,-C4)-alkyl, or

1.4    -NH2. or

2.    is pyridine or pyrimidine,

where pyridine or pyrimidine is unsubstituted or substituted, once, twice or three times, by identical or different radicals from the series -C(O)-(C,-C4}-alkyl, -C(O}, =0, -NH-(C,-C4}-alkyl, -NH-((C,-C4}-alkyl)2, -(C1-C8}-alkyl, -(C1-Ca)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3 , hydroxy-(C1-C4}-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -(C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, -S(O)x-R1 \ in which xis the integer zero, 1 or 2, -O-(C,-C4)-alkyl, -C(O)-OH, -C(O)-O-(C,-C4}-alkyl, -NH-C(O)-(C,-C4)-alkyl or tetrazolyl.
 

20    5. The use of the compound of formula I as claimed in claim 2, wherein

E is the radical -C(R19}-.
in which R19 is hydrogen atom or R9 ,
one of the substituents R1, R2, R3 and R4 is a radical of the formula II
in which

25    D is   -C(O)-,

R8 is  hydrogen atom,

Z is   5-oxo-4,5-dihydro-[1,3,4]oxadiazole, -C(O}-OH or -C(O}-NH2,

R9 is 1. -(C,-C4}-alkyl, in which alkyl is straight-chain or branched and is substituted once or twice, independently of

30    each other, by

1.1    -S(O}-R11 , where R11 is defined as below,

1.2    -N(R11 )2, where R11 is defined as below, or

1.3    pyrrole, or

2.    the  characteristic radical of an amino acid  from the

35    group histidine, tryptophan, serine, threonine, cysteine,

methionine,  asparagine,  glutamine,  lysine,  arginine,

glutamic acid and aspartic acid,

R11  is a)    hydrogen atom,

b)    -(C1-Cs)-alkyl, in which alkyl is unsubstituted or substituted, once to three times, independently of each other, by halogen, or

c)    phenyl, in which phenyl is unsubstituted or substituted,

5    once to three times, independently of each other, by
halogen or -(C1-C4)-alkyl,
the other substituents R1, R2, R3 and R4 are in each case hydrogen atom,

R5 is  hydrogen atom, and
10    R6 is  phenyl, pyridine or pyrimidine,

where phenyl, pyridine or pyrimidine is unsubstituted or substituted, once, twice or three times, by identical or different radicals from the series -C(O)-(C1-C4)-alkyl, -C(O), =0, -NH-(C1-C4)-

alkyl,    -NH-((C1-C4)-alkyl)2,   -(C1-Cs)-alkyl,  -(C1-Cs)-alkoxy,

15 halogen, nitro, amino, trifluoromethyl, hydroxyl, -CF3 , hydroxy-(C1-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, -{C1-C4)-alkoxycarbonyl, phenyl, phenoxy,

20 benzyl, benzyloxy, -S(O)x-R1\ in which xis the integer zero, 1 or 2, -O-(C1-C4)-alkyl, -C(O)-OH, -C(O)-O-(C1-C4)-alkyl, -NH-C(O)-(C1-C4)-alkyl or tetrazolyl.

6.    The use of the compound of the formula Ia as claimed in claim 2

25

~R21

'CR24
(N~        R31       
/""'---N    ~    E,    r- ==7(       
R22    1    ~ •  //N    (Ia)   
    0    N\    M~       
                   
        H    /N-H       
            R23       

and/or a stereoisomeric form of the compound of the formula Ia and/or a physiologically tolerated salt of the compound of the
30    formula Ia, where

E and M are identical or different and are, independently of each other, N atom or CH,
R21 and R31 are identical or different and are, independently of each other,
5    1. hydrogen atom,

2.    halogen,

3.    -(C1-C4)-alkyl,

4.    -CN,

5.    -CFa,
10    6. -OR15, in which R15 is hydrogen atom or-(C1-C4)-alkyl,

7.    -N(R15)-R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,

8.    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or
9.    -S(O)x-R15, in which x is the integer zero, 1 or 2, and R15 is
 
hydrogen atom or -(C1-C4)-alkyl,

R22 is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone, morpholine, oxazole, 1,3,4-oxa-diazole, oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathia-diazole-2-oxide, 5-oxo-4,5-dihydro-[1 ,3,4]oxadiazole, 5-oxo-1 ,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazolone, and

the heteroaryl radical is unsubstituted or substituted once, twice or three times, independently of each other, by

1.1    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,

1.2    -(C1-C4)-alkyl,

1.3    -O-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,

1.4    -N(R15)-R16, in which R15 and R16 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,

1.5    halogen, or

1.6    keto radical,

2.    -C(O)-R15, in which R15 is hydrogen atom or -(C1-C4)-alkyl,

3.    -C(O)-OR15, in which R15 is hydrogen atom or -(C1-C4)-alkyl, or


62

4.    -C(O)-N(R17)-R18, in which R17 and R18 are, independently of each other, hydrogen atom, -(C1-C4)-alkyi-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl,
R23 is hydrogen atom or -(C1-C4)-alkyl,

R24 is 1. a heteroaryl radical from the group pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxide, triazolones, oxadiazolones, isoxazolones, oxadiazolidine-dione, triazole, 3-hydroxypyrro-2,4-dione, 5-oxo-1 ,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, ~-carboline and benzo fused cyclopenta derivatives or cyclohexa derivatives of these heteroaryl radicals,

where the heteroaryl radical is unsubstituted or substituted, once, twice or three times, independently of each other, by -(C1-Cs)-alkyl, -(C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylene-dioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4)-alkoxycarbonyl, or

2. an aryl radical from the group phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, and

the aryl radical is unsubstituted or is substituted, once, twice or three times, independently of each other, by -(C1-C5)-alkyl, -(C1-Cs)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1.C4)-alkoxycarbonyl.

7.    The use of the compound of the formula Ia as claimed in claim 6, wherein

E and M are identical or different and are, independently of each

other, N atom or CH,

R21 and R31 are identical or different and are, independently of each other, as defined as above under 1. to 9.,
R22 is 1. a heteroaryl radical from the group imidazole, isothiazole, isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone, 1,3,4-oxadiazole, oxadiazolidinedione, 1 ,2,3,5-
 

oxadiazolone, oxazole, 5-oxo-4,5-dihydro[1 ,3,4]oxadiazole, tetrazole, thiadiazole, thiazole, triazole or triazolone, and the heteroaryl radical is unsubstituted or is substituted once, twice or three times, independently of each other, by
1.4    keto radical,

1.5    halogen or

1.6    -(C,-C2)-alkyl, or

2.    -C(O)-N(R17)-R18,     in   which   R17    and   R18    are,
independently of each other, hydrogen atom, -(C1-C2)-alkyi-OH, -O-(C,-C2)-alkyl or -(C,-C4)-alkyl,

R23 is hydrogen atom, methyl or ethyl,

R24 is 1. a heteroaryl radical from the group of the unsaturated, partially saturated or completely saturated rings which are derived from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole or isothiazole,

where the heteroaryl radical is unsubstituted or is substituted, once, twice or three times, independently of each other, by -(C1-C4)-alkyl, -(C1-C4)-alkoxy, F, Cl, I, Br, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylene-dioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C,-C4)-alkoxycarbonyl, or

2. phenyl and phenyl is unsubstituted or is substituted once, twice or three times, independently of each other, by F, Cl, I, Br, CF3, -OH, -(C,-C4)-alkyl or -(C,-C4)-alkoxy.

8.    The use of the compound of the formula I or Ia as claimed in claim 2 or 6, wherein the compound N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-
 

30    1H-indole-5-carboxamide or N-((S)-1-carbamoyl-2-diphenylamino-ethyl)-2-(2-methylaminopyrimidin-4-yl)"1 H-benzimidazole-5-carboxamide is employed.

9.    The use of the compound of the formula I or Ia as claimed in one or

35    more of claims 1 to 8 for producing pharmaceuticals for the prophylaxis and therapy of acute pains or chronic pains.

10.    The use as claimed in claim 9, wherein the chronic pains are chronic pains from the group chronic musculoskeletal diseases, such as
 

back pains, pains associated with menstruation, pains associated with osteoarthritis or rheumatoid arthritis, pains associated with intestinal inflammation, pains associated with cardiac muscle inflammation, pains associated with multiple sclerosis, pains
5    associated with neuritis, pains associated with carcinomas and sarcomas, pains associated with AIDS, pains associated with chemotherapy, amputation pain, trigeminus neuralgia, headaches, for example migraine cephalalgia, or neuropathic pains, such as post-herpes zoster neuralgia.

10

11.    The use as claimed in claim 9, wherein the acute pains are acute pains from the group pains following injuries, post-operative pains, pains associated with an acute attack of gout, or acute pains following jaw-bone surgical interventions.

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