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(21)Application Number:    KE/P/2010/ 001087   
   
(22) Filing Date' 08/11/2008   
   
(30) Priority data: 07076019.4 22/11/2007    EP
   
(86)  PCT data    PCT/EP08/009440    08/11/2008 WO  2009/065503    28/05/2009

(73) Owner: Bayer Schering Pharma Aktiengesellschaft of 13353, Berlin, Germany

(72) Inventors: BERGER, Markus ofMalplaquetstrasse 35, 13347 Berlin, Gennany; REHWINKEL, Hartmut of BIUcherstr. 13, 10961 Berlin, Germany; ZOLLNER, Thomas of Holsteinische Str. 36, 12161 Berlin, Germany; HASSFELD, Jorma ofDunckcrstrasse 29 A, 10439 Berlin,Germany; MAY, Ekkehard ofKarmcliterstr. 57, 13465 Berlin, Germany and SCHACKE, Heike of Gartcnstr. 105-106, 10115 Berlin, Germany

(74) AgenUaddress for correspondence Kaplan & Stratton Advocates, P.O. Box 40111~00100 Nairobi

(54) Title: 5-[(3,3,3-TRIFLUOR0-2-HYDROXY-1-ARYLPROPYL)AMINOJ-IH-QUINOLIN-2-0NES, A  PROCESS FOR THEIR PRODUCTION AND THEIR USE AS ANTI-INFLAMMATORY AGENTS

(57) Abstract: The present invention relates to compounds of formula (I), processes for their production and their use as anti-inflammatory agents.
 
5-[(3,3,3-Trifluoro-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-ones, A

Process for Their Production and Their Use as Anti~inflammatory Agents

The present invention relates to compounds offonnula I, a process for their

production and their use as anti-innammatory agents.

5 The most common anti-inflammatory agents are still the glucocorticoids (GCs) which are small molecules having a steroidal structure that interact with the glucocorticoid receptor (GR), whether endogenous, like cortisol, or synthetic, like dexamethasone and others. However, the application of highly potent GCs, especially over long treatment pertods, led to the occurrence of undesired effects. A

10    number of these effects, are severe and sometimes irreversible such as e.g. diabetes, osteoporosis, skin and muscle atrophy, glaucoma (Schiicke et al., 2002 Pharmacal. & Therapeutics (2002) 96(1 ):23-43., Miner et al., 2005 Expert Opin. lnvestig. Drugs (2005) 14(12):1527-1545.)The GCs potently inhibit pro-inflammatory cytokines and chemokines at the site of administration, whereas they elicit only

15    limited systemic effects (O'Connell,2003 Clin. Ther. (2003) 2S(Suppl. C):C42-60; Welker et al. tnt. Arch. Allergy tmmunol. (1996) 1 09(2):11 0-115, 1996, Gunther et al., 1998. Skin Pharmacal. App/. Skin Physiol. (1998) 11(1):35-42). Although locally active GCs appeared to be the ideal anti-inflammatory drugs, their application is limited due to local side effects and to insufficient efficacy in severe disease states.

20 Therefore, there is a great medical need for new compounds that have anti-inflammatory I immunomodulatory activity similar to the marketed GCs, an"il are less likely to produce undesired effects.

From the prtorart of DE 100 38 639 and WO 02110143, anti-inflammatory agents of the following general formula
are known, wherein the Ar radical comprises phthalides, thiophthalides,

benzoxazinones or phthalazinones. In the experiment, these compounds show

dissociations of action between anti-inflammatory and undesirable metabolic actions
 
and are superior to the previously described nonsteroidal glucocorticoids or exhibit at

least just as good an action.

Compounds structurally related to those described in this patent application

are disclosed in WO 2005/035518 .

. ?f->ioH
c'    R'

R1    NH
 

5
 
~2
 

Due to the manufacturing process these compound always do contain a group

wherein the bond between a and b or between band c may be unsaturated

and which thus must contain a group selected from -CH2-CH(CH3),,  a -CH=C(CH3 ),

10    or a -CH,-C(CH3)=CH 2). Compounds of such a composition are specifically disclaimed in the present application.

Despite all efforts, the selectivity of the compounds of the prior art towards the glucocorticoid receptor (GR) compared to the other steroid receptors as well as their
efficacy or potency still requires improvement.

15    It was therefore the object of this invention to make compounds available

showing improvements of at least one aspect mentioned above.

This object has been achieved by the compounds according to the claims.
 This invention therefore relates to compounds of general formula I
wherein

5 R1and R2 independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-C,o)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-pertluoroalkyl group, a cyano group, a nitro group, orR1 and R2

10    together mean a group that is selected from the groups -O-(CH2),-0-, - O-(CH2),-CH2-, -0-CH=CH-, -(CH2),.2-, -NH-(CH2),.1, -N(C,-C,-alkyl)-(CH2),., and -NH-N=CH-,

whereby p = 1 or 2, and the terminal oxygen atoms and/or

carbon atoms and/or nitrogen atoms are linked to directly

15 adjacent ring-carbon atoms, orNR6 R7 ,

whereby R6 and R7, independently of one another, mean hydrogen, C1-Cs-alkyl or (CO)-(C1-Cs)-alkyl,

RJ    means a hydrogen atom, a hydroxy group, a halogen atom, a

20    cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-Cs)-peliluoroalkyl group,

R'    means a hydrogen, halogen, hydroxy, (C1-Cs)-alkyl, (C,-Cs)alkoxy, (C,-

Cs)-alkylthio, (C1-C5)-pertluoroalkyl, cyano, nitro, NR6R7,  COOR9,

25    (CO)NR6R7 or a (C,-Cs-alkylene)-0-(CO)-(C1_Cs)alkyl group
 R5    means a group selected from
    -(C1-C1o)alkyl,    which may be optionally partially or completely
    halogenated,   
    -(C2-C1o)alkenyl,   
    -(C2-C1o)alkynyl,   
    (C3-C7)cycloalkyi-(C1-C8)alkyl, • -
    (C3-C7 )cycloalkyi-(C1-C8)alkyenyl,
    (C3-C,)cycloalkyi-(C,-Ca)alkynyl,
    heterocyclyi-(C1-C8)alkyl,
    heterocyclyi-(C1-Ca)alkenyl,
    heterocyclyi-(C2-Ca)alkynyl,
    -R',       
    R8-(C1-C8)alkyl,   
    R8-(C2-Ca)alkenyl,   
    R8-(C2•Ca)alkynyl,   
    -S-(C1-C10)-alkyl,   
    -802-(C,-C,o)-alkyl   
    -S-R8,       
    -SOrR8    ,   
    -CN       
    -Hal,       
    -O-(C1-C10)-alkyl,   
    -NR6R7    wherein R6 , R7 have the meaning defined above
    -O-R8,       
    -OH       
    with the exception of -CH(CH,)2, or -C(CH,)=CH2
R'    means an aryl group which may optionally be substituted by 1-3
    hydroxy, halogen, C,-C,-alkyl, C,-C,-alkoxy, cyano, CF,, nitro, COO(C,-
    C5-alkyl) or C(O)OCH2-phenyl or a heteroaryl group
 

30    whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen, cyano or c,-c,-alkoxy groups.

and their salts, solvates or salts of solvates.
 
One aspect of the invention relates to compounds of formula I wherein

R1and R2 independently of one another, mean a hydrogen atom, a hydroxy
group, a halogen atom, an optionally substituted (C1-C1o)-alkyl group, an
optionally substituted (C,-C,o)-alkoxy group, a (C,-C10)-alkylthio group, a
5    (C1-C5)-perfuoroalkyt group, a cyano group, a nitro group, or-

R1 and R2 together mean a group that is selected from the groups -O-(CH2),-0-, -O-(CH2),-CH2-, -0-CH=CH-, -(CH2),.,-, -NH-(CH2),.,, -N(C,-

C:r-alkyi)-(CH2)p•1• and -NH-N=CH-,

10    whereby p = 1 or 2, and

the tenninal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms,
orNR6R7,

        whereby R6 and R7,    independently of one another mean
15        hydrogen, C1-C5-alkyl or (CO)-(C1-Cs)-alkyl,
    R'    means a hydrogen atom, a hydroxy group, a halogen atom, a
        cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-
        alkoxy group, a {C,-C10)-alkylthio group, or a {C1-C5}-perfuoroalkyl group,
    R4    means a hydrogen atom, a hydroxy group, a halogen atom,
20    R'    means a group selected from
        -{C1-C1o)alkyl,    which may be optionally partially or completely
        halogenated   
-(C2-C1o)alkenyl, -(C,-C10)alkynyl,

25    (C3-C7)cycloalkyi-{C1-Cs)alkyl, (C3-C7)cycloalkyi-(C2-Cs-)alkenyl, (C,-C7)cycloalkyi-(C2-Cs-)alkynyl,

heterocyclyi-(C,-Ca)alkyl, heterocyclyi-(C2-Ca)alkenyl,

30    heterocyclyi-(C2-Ca)alkynyl,

-R',

R8-(C1-C8)alkyl, R8-(C2-Ca)alkenyl,
 
    R8-(C,-C8)alkynyl,
    -S-(C,-C10)-alkyl,
    -S-R8 ,
    -SO,-R8,
    -S02-(C1-C10)-alkyl,
    -CN,
    -Hal,
    -O-(C,-C,0)-alkyl,
    -NR6R7     wherein R6,  R7 have the meaning indicated above
10    -0-R8,
    -OH
    wilh the exception of -CH(CH,),,  or -C(CH3)=CH,
R8    means an aryl which may optionally be substituted with 1-3 alkyl, hydroxy,
    halogen, cyano or c,-C5-alkoxygroups or

15    a heteroarylgroup wherein the heteroarylgroup may contain 1-3 heteroatoms which may optionally be substituted with 1-3 alkyl, hydroxy, halogen, cyano or C,-C,-alkoxygroups,

means an integer selected from 1, 2, 3, 4, 5 and their salts, solvates or salts of

solvates.

20

Another aspect of the invention are compounds of general fonnula I according to claim 1, wherein R1and R2 independenlly of one another, mean a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C,-C1o)-alkoxy group, a (C1-C5)-

25    perfluoroalkyl group, a cyano group, or NR6R7, whereby R6 and R7, independenlly of one another, mean hydrogen, c,-Cs-alkyl or(CO)-(C1-C5)-alkyl, R3 means a hydrogen

atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C,-C,o)-alkoxy group, or a (C1-C5)-perfluoroalkyl group, R' means hydrogen, c,-c,-alkyl, c,-C3-alkoxy, hydroxy, halogen, R5 means a group
30    selected from -(C1-C10)-alkyl, which may be optionally partially or completely

halogenated -(C,-C,o)-alkenyl, -(C,-C,o)-alkynyl, -(C3-C7)cycloalkyi-(C1-C8)alkyl, -(C3-C,)cycloalkyi-(C,-C,)alkenyl, -S-(C,-C10)-alkyl, -S02-(C1-C10)-alkyl, -CN, -Hal,

-0-(C1-C1o)-alkyl, -NR6R7 wherein R6, R7 have the meaning defined above, -OH with
 the exception of -CH(CH3)2 , or -C(CH3)=CH, and their salts, solvates or salts of solvates.A further aspect of the invention are compounds of general formula I according to claim 1, wherein R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy group, R'is hydrogen, C,-C,-alkyl, halogen, R5 is hydroxyl group, chlorine, -S-CH3, -S-CH2-CH,, -S-CH2-CH2-CH3, -O-CH3 or -O-CH2-CH3,

-O-CH,.-CH2-CH3, -N-(CH3) 2• -N-(CH2-CH3), and their salts, solvates or salts of solvates.A further aspect of the invention are compounds of general formula I

according to claim 1, wherein R1,  R2 and R3 are independently of one another

10    hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy

group, a hydroxyl group, R'is hydrogen, C,-C,-alkyl, halogen, R5 is a hydroxyl group, chlorine, -S-CH3 , -S-CH,-CH,, -S-CH2-CH2-CH,, -O-CH3 , -O-CH2-CH3 ,

-O-CH,.-CH2-CH, or N(CH,), and their salts, solvates or salts of solvates.

Still another aspect of the invention are compounds of general formula I

15    according to claim 1, wherein R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy
group, a hydroxyl group, R4 is hydrogen, C,-C,-alkyl, halogen, R5 is a hydroxyl group, chlorine, -S-CH,, -S-CH,.-CH,, -S-CH2-CH,-CH,, -O-CH3 or -0-CH2-CH3,

-0-CH2-CH2-CH, and their salts, solvates or sails of solvates.

20    One aspect of the invention are compounds of general formula I according to claim 1,

wherein R1 and R2 are independently of one another hydrogen, fluorine, chlorine, a methoxy group, a hydroxyl group, R3 is hydrogen, fluorine, chlorine or a methoxy
group, R'is hydrogen or fluorine, R5 is a hydroxy group, a chlorine atom, -S-CH,, -S-CH2-CH3, -0-CH3, -O-CH,-CH3 or N(CH3), and their salts, solvates or salts of

25    solvates.A further aspect of the invention are compounds of general formula I

according to claim 1, wherein R1 and R2 are independently of one another hydrogen, fluorine, chlorine, a methoxy group, R3 is hydrogen, fluorine, chlorine or a methoxy
group, R4 is hydrogen or fluorine, R5    is a hydroxyl group, a chlorine atom, -S-CH3 ,

-S-CH2-CH3, -O-CH3 , or -O-CH,-CH3 and their salts, solvates or salts of solvates.

30    Another aspect of the invention are compounds according to at least one of claims 1-

4 in enantiomerically pure form and their salts, solvates or salts of solvates.Another aspect of the invention are compounds according to claim 1 selected from the list consisting of
 

5-{[1-(2-Fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyljmethyl)propyl]amino}-1 H-quinolin-2-one

5-{[2-([Ethylsulfanyl] methyl )-1-(2-fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-one

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyljme!hyl)propyl]amino}-1H-quinolin-2-one

5-{[1-(2-Chloro-3-fiuoro-4-methoxyphen;1)-2-([ethy!sulfanyljmethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one

5-{[1-(2-Chloro-3-fiuoro-4-methoxyphenyl}-3,3,3-triftuoro-2-hydroxy-2-10 (methoxymethyl)propyl]amino}-7-fiuoro-1 H-quinolin-2-one
5-{[1-(2-Chloro-3-fiuoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7 -fluoro-1 H-quinolin-2-one

5-{[1-(2-Chloro-J-fluoro-4-methoxyphenyl}-3,3,3-trifluoro-2-hydroxy-2-(hyd roxymethyl)propyl]amino J-7 -fluoro-1 H-quinolin-2-one

15 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluoro-1 H-quinolin-2-one

5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one

5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropyl]amino}-20 1H-quinolin-1-one

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino J-7 -fluoro-1 H-quinolin-2-one

5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fiuoro-1 H-quinolin-2-one

25 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7 -fluoro-1 H-quinolin-2-one

5-{[1-(2-Chloro-3-fluoro-4-hydrmcyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyljamino J-7-fiuoro-1 H-quinolin-2-one

and their salts, solvates or salts of solvates.

30

Still another aspect of the invention are enantiomerically pure compounds

according to claim 1 selected from the list consisting of5-{[1-(2-Fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1 H-quinolin-2-one
 




5-{[2-([Ethylsulfanyl]melhyl)-1-(2-fluoro-4-methoxyphenyl)-3,3,3-tlifluoro-2-hydroxypropyl]amino)-1 H-quinolin-2-<Jne

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3 ,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino]-1H-quinolin-2-one

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino)-7-fluoro-1 H-quinolin-2-one

5-([1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-10 trifluoro-2-hydroxypropyl]amino}-7 -fluoro-1 H-quinolin-2-<Jne

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3 ,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl)amino}-7 -fluoro-1 H-quinolin-2-one

5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluoro-1 H-quinolin-2-one

15 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino )-7-fluoro-1 H-quinolin-2-<Jne

5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropyl]amino]-1H-quinolin-1-one and their salts, solvates or salts of solvates.

Another aspect of the invention are enantiomerically pure compounds according to

20    claim 1 selected from the list consisting of

5-{(rs, 2R)[1-(2-Fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl)methyl)propyl]amino }-1 H-quinolin-2-one

5-{( 1S, 2R)[2-([Ethylsulfanyl)methyl)-1-(2-fluoro-4-methoxyphenyl)-3,3,3-tlifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-<Jne
25 5-{(1S, 2R)[1-{2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1 H-quinolin-2-one

5-{(1S, 2R)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2- ([ethylsulfanyl)methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-<Jne

5-{( 1S, 2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-

30 hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-<Jne 5-{( 1s, 2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-

3,3,3-trifluoro-2-hydroxypropyl]amino)-7-fluoro-1H-quinolin-2-one

5-{(1S, 2S)[1-(2-Chloro-3-ftuoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino)-7-fluoro-1 H-quinolin-2-one
 



10

5-{( 1S, 2S)[1-{5-Chloro-3-fiuoro-2-methoxypheny\)-3,3,3-trifiuoro-2-hydroxy-2-{hydroxymethy\)propy\]amino}-7 -fiuoro-1 H-quino\in-2-one

5-{( 1S, 2R)[1-(5-Chloro-3-fiuoro-2-methoxyphenyl}-2-{ch\oromethy\)-3,3,3-trifiuoro-2-hydroxypropy\]amino}-7 -fiuoro-1 H-quino\in-2-one

5-{( 1S, 2S)[3,3,3-trifiuoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropy\]amino }-1 H-quino\in-1-one
5-{[(1S, 2R)[1-(2-Ch\oro-3-fiuoro-4-methoxypheny\)-2-{diaminomethyl)-3,3,3-trifiuoro-2-hydroxypropyl]amino)-7 -fiuoro-1 H-quino\in-2-one
5-{( 1S, 2S)[1-{2-Ch\oro-3-fiuoro-4-hydroxypheny\)-3,3, 3-trifiuoro-2-hydroxy-2-10 (hydroxymethyl)propyl]amino)-7-fiuoro-1 H-quinolin-2-one
and their salts, solvates or salts of solvates.

A further aspect of the invention are enantiomerically pure compounds according to

claim 1 selected from the Jist consisting of

5-{( 1S, 2R)[1-(2-F\uoro-4-methoxyphenyl)-3,3,3-trifiuoro-2-hydroxy-2-15 ([methylsu\fanyl]methy\}propy\]amino}-1H-quinolin-2-one

5-{(1S, 2R)[2-([Ethylsu\fanyl]methy\)-1-(2-fiuoro-4-methoxyphenyl)-3,3,3-trifiuoro-2-hydroxypropy\]amino}-1 H-quino\in-2-one

5-((1S, 2R)[1-(2-Chloro-3-fiuoro-4-methoxypheny\)-3,3,3-trifiuoro-2-hydroxy-2-([methylsulfanyl]methy\)propyl]amino)-1 H-quino\in-2-one

20 5-{(1S, 2R)[1-(2-Ch\oro-3-fiuoro-4-methoxypheny\)-2- ([ethy\su\fany\]methy\)-3,3,3-trifiuoro-2-hydroxypropy\]amino)-7-fiuoro-1 H-quinolin-2-one

5-{( 1S, 2S)[1-{2-Ch\oro-3-fiuoro-4-methoxyphenyl)-3,3,3-trifiuoro-2-hydroxy-2-(methoxymelhy\}propyl]amino}-7-fiuoro-1 H-quino\in-2-one
5-{( 1S, 2S)[1-(2-Ch\oro-3-fiuoro-4-melhoxyphenyl)-2-( elhoxymethy\)-25 3,3,3-lrifiuoro-2-hydroxypropy\]amino)-7-fiuoro-1 H-quinolin-2-one

5-{( 1S, 2S)[1-(2-Chloro-3-fiuoro-4-methoxyphenyl)-3,3,3-trifiuoro-2-hydroxy-2-{hydroxymethyl)propy\]amino}-7-fiuoro-1H-quinolin-2-one

5-{(1S, 2S)[1-{5-Chloro-3-fiuoro-2-methoxyphenyl)-3,3,3-lrifiuoro-2-hydroxy-2-(hydroxymelhy\)propyl]amino}-7-fiuoro-1 H-quino\in-2-one

30 5-{(1S, 2R)[1-(5-Ch\oro-3-fiuoro-2-methoxypheny\)-2-{ch\oromethyl}-3,3,3-trifiuoro-2-hydroxypropy\]amino }-7-fiuoro-1 H-quino\in-2-one

5-{( 1S, 2S)[3,3,3-trifiuoro-2-hydroxy-2-([methoxymethyl)-1-pheny\propyl]amino}-1H-quinolin-1-one and their salts, solvates or salts of

solvates.
 



II

Compounds of general fomnula I, wherein at least one of R1 , R2 or R3 are different from hydrogen are one preferred embodiment of the invention.

Compounds of general fomnula I according to claims 1-7, wherein at least one of R1 , R2 or R3 is different from hydrogen are one preferred embodiment of the
5    invention.

In another embodiment two of R1, R2 or R3 according to claim 1 or claims 1-7 are different from hydrogen.

In yet a further embodiment all three R\ R2 or R3 according to claim 1 or claims 1-7 are different from hydrogen.

10    In one aspect of the invention the alkyl groups of the compounds of formula (I)

have 1-5 carbon atoms.

In another aspect the alkyl groups of the compounds of formula (I) have 1-3

carbon atoms.

The qui nolan ring of formula I can be substituted by a radical R4 selected from

15    the group consisting of halogen, hydroxy, (C,-C5)-alkyl, (C1-C5)alkoxy, (C1-C5)-alkylthio, (C1-C5)-perfluoroalkyJ, cyano, nitro, NR7R8 COOR8 (CO)NR7R8 or a (C,-G,;-

alkylene)•O-(CO)•(C,.C5)alkylgroup, preferably R4 is selected from the group C1-C,-alkyl, C1-C3-alkoxy, hydroxy, halogen. In another aspect of the invention R4 is selected from the group hydrogen, c,-c,-alkyl, halogen, hydroxy, preferably from

20    hydrogen or halogen, more preferably from hydrogen, chlorine or fluorine.

Another subject of the invention are compounds according to formula 1

wherein R4 is hydrogen or fluorine.

Yet another subject of the invention are compounds according to fomnula 1

wherein R4 is fluorine.

25 More particularly compounds according to fomnula I wherein R4 is a 7-fluoro-substituent or hydrogen and at least one of R1, R2 and R3 is selected from chlorine, fluorine, methoxy, hydroxy, R5 is selected from S-CH,-CH,, -0-CHrCH3, -S-CH3, -O-CH3 -, N(CH,)2, -OH and -CL
 



12

Another aspect of the invention are compounds according to formula I wherein

R4 is a 7-fluoro-substituent or hydrogen and at least one of R1 , R2 and R'is selected from chlorine, fluorine, methoxy, R5 is selected from S-CH,-CH,, -O-CH2-CH3,

-S-CH3 , -0-CH, -, -OH and -CI.A preferred aspect of the invention are the 5 subcombinations of all the residues as disclosed in the examples.

One aspect of the invention are compounds of general formula I, wherein the

phenyl group is substituted with 1-3 of the same or different substituents R1, R2 and R'.R1 and R2 are independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally

10    substituted (C,-C1o)-alkoxy group, a (C,-C,o)-alkylthio group, a (C,-C,)-perfluoroalkyl group, a cyano group, a nitro group, or R1 and R2 together mean a group that is

selected from the groups -0-(CH,),-0-, -0-(CH,),-CH,-, -0-CH~CH-, -(CH,),,,-, -NH-(CH2),,1, -N(C1-C3-alkyi)-(CH2),,1, and -NH-N~CH-, whereby p = 1 or 2, and the

terminal oxygen atoms and/or carbon atoms andtor nitrogen atoms are linked to

15    directly adjacent ring-carbon atoms, or R1 and R2 are NR6R7 , whereby R6 and R7 , independently of one another, mean hydrogen, C1-C5-alkyl or (CO)-(C1-C5)-alkyl.

The third substituent R3 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C,-C,o)-alkyl group, a (C,-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-Cs)-perfluoroalkyl group.

20 In another aspect any other phenyl group may be substituted by a group selected from ,C,-C,-alkoxy, hydroxy, and halogen, in particular methoxy, hydroxy,
fluorine, chlorine, or bromine.

In another aspect of the invention R5 of compounds of claim 1-6 selected from -(C1-C10)-alkyl, which may be optionally partially or completely halogenated,

25    -(C,.-C10)-alkenyl, -(C2-C")-alkynyl, (C,-C,)cycloalkyi-(C1-Ca)alkyl, (C3-C7)cycloalkyi-(C,-C,)alkenyl, (C3-C,)cycloalkyi-(C1-Ca)alkynyl, heterocyclyi-(C,-C,)alkyl, heterocyclyi-(C,-C,)alkenyl, heterocyclyi-(C2-Ca)alkynyl -R',
R'-(C-Ca)alkyl, R8-(C,-C,)alkenyl, R8-(C,-C,)alkynyl,
1

-S-(C1-C10)alkyl, -SO,-(C,-C,o)alkyi-S-R',- SO,-R',- CN, -Hal, -0-(C1-C,o)alkyl,

30    -NR'R'{wherein R6, R7 have the meaning defined above), -O-R'and -OH with the exception of -CH(CH,),, or -C(CH,)~CH,. In yet another aspect R5 is selected from the group consisting of -(C,-C,o)-alkyl, which may be optionally partially or completely halogenated, -(C,-C10)-alkenyl, -(C,-C10)-alkynyl,
 



13

-(C3-C7)cycloalkyi-(C1-Ca)alkyl, -(C,-C,)cycloalkyi-(C,-Ca)alkenyl, -8-(C,-C,o)-alkyl, -802-(C1-C10)-alkyl, -CN, -Hal, -O-(C,-C1o)•alkyl, -NR6 R7 (wherein R6, R7 have the meaning defined above), -OH with the exception of -CH(CH,),, or-C(CH,)=CH,., preferably R5 is -OH, Cl, -8-CH,, -8-CH,-CH,, -8-CH,-CH,-CH,, -0-CH,,

5    -O-CH,-CH3, -0-CH,-CH,-CH,, N(CH,), , NHCH3 with the exception of -CH(CH,), or -C(CH3)=CH2, R5 is most preferably is -OH, -8-CH3, -8-CH,-CH,, -O-CH3 , -O-CH2-CH3 or N(CH3),.

In another aspect of the invention R5 of compounds of claim 1-6 selected from
(C3-C7)cycloalkyi-(C1-C8)alkyl, (C3-C7)cycloalkyi-(C,-C8)alkenyl,

10    (C3-C7 )cycloalkyi-(C1-Ca)alkynyl, heterocyclyi-(C,-C8)alkyl, heterocyclyi-(C2-C8)alkenyl, heterocyclyi-(C,-C,)alkynyi-R8, R8-(C1-C8)alkyl, R8-(C2-C8)alkenyl, R8-(C2-C8)alkynyl, -8-(C,-C,o)alkyl, -802-(C1-C,o)alkyi-8-R8, -802-R8, -CN, -Hal, -O-(C1-C10)alkyl, -NR6R7 (wherein R6, R7 have the meaning defined above), -O-R8 and -OH.

15 In yet another aspect R5 of compounds of claim 1-6 is selected from lhe group consisting of -(C3-C7)cycloalkyi-(C1-C8)alkyl, -(C,-C,)cycloalkyi-(C,-C8)alkenyl, -8-(C1-C10)-alkyl, -80,-(C,-C,o)-alkyl, -CN, -Hal, -0-(C,-C,o)-alkyl, -NR6R7 (wherein R6 , R7 have the meaning defined above), -OH; preferably R5 is -OH, Cl, -8-CH3 ,
-8-CH2-CH,, -8-CH,-CH,-CH,, -0-CH,, -0-CH,-CH,, -0-CH,-CH,-CH,, N(CH,), ,

20    NHCH,, R5 is most preferably is -OH, -s-CH3, -8-CH2 -CH3, -0-CH3, -O-CH,-CH3 or N(CH,),.

Another aspect of the invention relates to compounds according to claims 1-6 wherein R5 selected from -R',- 8-(C,-C,o)-alkyl, -80,-(C,-C,o)-alkyl, -8-R8, -80,-R'. -CN, -Hal, -O-(C1-C10)-alkyl, -NR6R7, wherein R6, R7 have the meaning defined in
25    claim 1, -O-R8 or-OH.

Another aspect of the invention relates to compounds according to claims 1-6 wherein R5 selected from -8-(C,-C10)-alkyl, -80,-(C,-C1o)-alkyl,

-CN, -Hal, -O-(C,-C1o)-alkyl, -NR6R7, wherein R6, R7 have the meaning defined in claim 1, or-OH.
 




Another aspect of the invention relates to compounds according to claims 1-6

wherein R5 selected from -S-(C,-C10)-alkyl, -O-(C1-C10)-alkyl, -NR6 R7 , wherein R6, R7

have the meaning defined in claim 1, or-OH.

One aspect of the invention are compounds according to claims 1-7, wherein

5    R5 is not -(C1-C10)-alkyl or -(C,-C10)-alkenyL

Another aspect of the present invention are compounds of general formula I

according to claims 1-7, wherein R5 is not -(C1-C10)-alkyl or -(C,-C10)-alkenyl and from R1/R2/R3 at least two are different from hydrogen or R1/R2/R3 all are different from hydrogen and R4 is halogen. in addition, the invention relates to the use of the

10    compounds of general formula I for the production of pharmaceutical agents as well as their use for the production of pharmaceutical agents for treating inflammatory diseases.


Unless otherwise notifed the term "alkyl" refers to a straight or branched,

15    substituted or unsubstituted chain. For example, the term propyl comprises "-propyl and 1"-propyl, the term butyl comprises "-butyl, 1"'-butyland ''"•-butyl.

The alkyl groups can be straight-chain or branched and stand e.g. for a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or n-pentyl group, or a 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl or ethyl group is

20    preferred. They can optionally be substituted by 1-3 hydroxy groups, cyano groups, halogen, 1-3 C,-C5-alkoxy groups, and/or 1-3 COO(C,-C,-alkyl or benzyl) groups. Preferred are hydroxy groups. The total number of substituents depends on the number of carbon atoms of the chain. Usually the number of substituents does not exceed the number of carbon atoms except for halogen which leads at a maximum

25    number of substituents to e.g. perfluorated alkyl groups.

For a partially or completely fluorinated C,-C3-alkyl group, the following partially or completely fluorinated groups are considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1, 1-difluoroethyl, 1 ,2-difluoroethyl, 1,1, 1-trifluoroethyl, tetrafluoroethyl, and pentafluoroethyl. Of the latter, the trifluoromethyl

30    group or the pentafluoroethyl group is preferred.
 



JS

The C1-C5-alkoxy groups in R'.R2, R3 and R5 can be straight-chain or branched and stand for a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. A methoxy or ethoxy group is preferred. They can optionally be substituted by C,-C5-alkyl groups, cyano groups or halogen

The C1-Cs-alkylthio groups can be straight-chain or branched and stand for a methylthio, ethylthio, n-propylthio. iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. A methylthio or ethylthio group is preferred.

10    The tenn halogen atom, Hal or halogen means a fluorine, chlorine, bromine or

iodine atom. Preferred is a fluorine, chlorine or bromine atom.

The NR6R7 group includes, for example, NH2, N(H)CH3, N(CH3)2, N(H)(CO)CH,, N(CH,)(CO)CH,, N[(CO)CH,]2, N(H)C02CH,, N(CH,)C02CH,, or N(C02CH,)2.

15 The term C2-C8-alkenyl is a straight or branched, substituted or unsubstituted, chain including isomers having an E- or Z-configurated double bond such as e.g. vinyl, propen-1-yl, propen-2-yl (Allyl), but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl. If the alkenyl residue is placed between two other moieties the term alkenyl means

20    alkenylene such as e.g. vinylene, propen-1-ylene, propen-2-ylene (AIIylen), but-1-en-1-ylene, but-1-en-2-ylene, but-2-en-1-ylene, but-2-en-2-ylene, 2-methyl-prop-2-en-1-ylene, 2-methyl-prop-1-en-1-ylene, but-1-en-3-ylen, but-3-en-1-ylene.

The term C,-C8-alkynyl stands for a straight or branched chain e,g, -C=CH,
-CH2-C=CH, -C=C-CH,, -CH(CH,)-C=CH, -C=C-CH2(CH,),
25    -C(CH3)2-C=CH, -C=C-CH(CH,)2, -CH(CH,)-C=C-CH3, , -CH,-C=C-CH2(CH,) or, if the alkynyl residue is placed between two other moieties the term alkynyl means alkynylene such as e.g. -C=C-, -CH2-C=C-, -C=C-CHr, -CH(CH,)-C=C-, -C=C-CH(CH3)-, -C(CH,J,-C=C-, -C=C-C-(CH,)2-, -CH(CH,)-C=C-CH2-,

-CH2-C=C-CH (CH,)-.
 



16

The term C3-Crcycloalkyl means a substituted or unsubstituted group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The possible substitutents may be selected from hydroxy, halogen, (C,-Cs)-alkyl, (C1-C5)-alkoxy, NR4R5, COO(C,-Cs)-alkyl, CHO, cyano.

The term C3-Crcycloalkyi-(C,-C10)-alkyl- means e.g. -(CH,)-cycloalkyl,

-(C2H4)-cycloalkyl, -(C,Hs)-cycloalkyl, -(C,Ha)-cycloalkyl, -(CsH,o)-cycloalkyl whereby the cycloylkyl stand for e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

The term C3-Crcycloalkyi-(C,-C8)-alkenyl means e.g. -(CH=CH)-cycloalkyl,

10    -[C(CH3)=CH]-cycloalkyl, -[CH=C(CH,)]-cycloalkyl, -(CH=CH-CH 2)-cycloalkyl, -(CH,-CH=CH)-cycloalkyl, -(CH=CH-CH,-CH,)-cycloalkyl,
-(CH2-CH=CH-CH2)-cycloalkyl, -( CH,-CH,-CH=CH)-cycloalkyl, -(C(CH3)=CH-CH2)-cycloalkyl,

-(CH=C(CH3)-CH2)-cycloalkyl whereby the term cycloalkyl is defined above..

15 The term heterocyclyl means e.g. piperidinyl-, morpholinyl-, thiomorpholinyl-, piperazinyl-, tetrahydrofuranyl-, tetrahydrothienyl-, imidazolidinyl- or pyrrolidinyl-whereby the heterocyclyl group may be bound via any possible rtng atom ..

The heterocyclyl group may be substituted by C,-Cs-alkyl (optionally substituted), hydroxy-, C1-Cs-alkoxy-, NR4R5-, halogen, cyano-, COOR8-, CHO-. If possible these

20    substitutens may also be bound to one of the free nitrogen atoms if any. N-oxides are also included in the definition.
The term heterocyclyi-(C,-C10)-alkenyl- means an alkylene group as defined above which is connected to the heterocyclyl group which also is already defined

above.

25 The term heterocyclyi-(C,-Ca)-alkenyl- means an alkylenylene group as defined above which is connected to the heterocyclyl group which also is already
defined above.

The tenn aryl in the sense of the invention means aromatic or partially

aromatic carbocyclic rings having 6 to 14 carbon atoms, e.g. phenyl and which may
 



17

also may have a condensed a second or third ring such as e.g. napthyl or anthranyl.

Further examples are phenyl, naphthyl, tetralinyl, anthranyl, benzoxazinone,

dihydroindolone, indanyl, and indenyl.

The aryl groups may be substituted at any position leading to a ~table molecule by

5    one or several substitutents, e.g. 1-3 substitutents, such as e.g. hydroxy, halogen, C1-C5-alkyl, c,-C5-alkoxy, cyano, CF,, nitro, COO(C,-C.-alkyl or benzyl) or a heteroaryl group'preferably by 1-3 c,-c,-alkyl groups, hydroxyl, halogen, cyano or

c,-c,-alkoxy.

The optionally substituted phenyl group is one aspect of the invention. Yet another 10 aspect are the compounds of fonmula I whereby R8 is not phenyl.

The tenm heteroaryl means an aromatic ring system having 1-3 heteroatoms

selected from nitrogen, oxygen or sulfur, for five membered rings the maximum

number of heteroatoms is three whereby only two oxygen or sulfur atoms are allowed

provided that these two are not directly bound to each other.

15    Possible heteroaryl rings are e.g. thienyl, !uranyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, benzothiazol, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azaindolizinyl-,benzopyridyl, benzopyridazinyl, benzopyrimidinyl, benzopyrazinyl, benzotriazinyl,

20    quinolyl, isoquinolyl, phthalidyl-, thiophthalidyl, indolonyl-, dihydroindolonyl-, isoindolonyl-, dihydroisoindolonyl-, benzofuranyl- or benzimidazolyl.

The compounds of the present invention can exist in stereoisomeric forms such

as enantiomers of diastereoisomers depending on their structure and residues as

defined in fonnula I. In one aspect of the invention therefore all these enantiomers,

25    diastereoisomers or mixtures thereof are encompassed. The isolation of enantiomerically or diastereomerically pure isomern can be done by methods of the stale of the art, e.g. using column chromatography with a chiral solid phase.

Should it be possible that the compounds of the invention also exist in tautomeric

fonns these are also an aspect of the present invention.

30 In one aspect of the invention all compounds defined in fonmula I as well as their salts, solvates and solvates of salts are encompassed,. especially the salts,

sotvates and salts of sotvates of the compounds disclosed in the examples are one
 



18

aspect of the invention as long as the disclosed compounds themselves are not

already salts, solvates or solvates of the salts.

Salts in the sense of the present invention are not only physiologically unobjectable salts but also salts which might be objectable for pharmaceutical use but which are useful e.g. during the process of isol_ation or purification.

The term physiologically unobjec!able salts includes addition salts of mineral acids, carbonic acids, sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,

sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,

toh.iolsulfonic acid, benzenesulfonic acid, naphthalinesulfonic acid, acetic acid,

10    trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, pivalic acid, maleic acid, succinic acid and benzoic acid.

In addition the term physiologically unobjectable salts includes salts of commonly suitable bases, e.g. salts of alkalimetall (e.g .. sodium- and potassium salts), alkaline earth salts (e.g. calcium- and magnesium salts) and ammonium salts, derivatized from

15    NH3 or organic amines with 1 to 16 carbon atoms, e.g. ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, prokaine, dibenzylamine, N-methylmorpholin, arginin, lysin, ethylendiamine and N-methylpiperidin.

Solvates in the sense of the invention are such forms of the compounds of the

20    present combinations which build complexes by coordination of solvent molecules in a liquid or a solid phase. Hydrates are special fonns of a solvate wherein water molecules are coordinated.

Salts in the sense of the present invention are not only physiologically unobjeclable salts but also salts which might be objectable for pharmaceutical use but
25    which are useful e.g. during the process of isolation or purification.
 



19

The compounds can be produced by the two processes that are described below (a-b).

Process a)

step a)

~
R~~NAO

(III)H

TI(OR)4 and/or acid

(II)    (IV)


Benzaldehydes of type (II) can be condensed with substituted aminoquinolones of type (Ill) to imines of type (IV) using Lewis acids, preferably titanium alcoholates
10    Ti(OR)4 wherein R is c,-C,-alkyl, such as e.g. tetraethyl orthotitanate or tetra tert. butyl orthotitanate and/or acidic co~ditions, e.g. organic acids such as acetic acid as reagents. Suitable solvents are e.g. toluene, 1 ,4-dioxane or mixtures thereof.

Step b)

<lCF
3

(V)



15

(IV)    (VI)

Step c)
 



20

R'
CF3

1
NH
R:  Rroo
H

{VI)    {I)

Imines of type {IV) are treated at low temperatures of -BO'to-1 OO'Cwith the lithiated epoxide (V) to yield compounds of type (VI). Suitable solvents are e.g.

5    tetrahydrofurane, hexane, diethylether or mixtures thereof. The epoxides (VI) can be opened by nucleophiles of type R5-Met to deliver compound (I). Met means metal and includes alkalimetals e.g. sodium or lithium, alkaline earth metals such as e.g.

magnesium, caesium; aluminium, copper, silicon or tin (Sn) which bind the

nucleophilic residue R5 of R5-Met depending on their valence and according to the

10    knowledge of a person with ordinary skill. The resulting possible nucleophilic

reagents R5-Met are e.g. alkylcuprates, vinylcuprates, thioles, allylsilanes, vinylsilanes, vinylstannanes, grignard compounds whereby R5 is defined as in claim
1, which react in the presence of Lewis acids like e.g. BF3 or AIMe3, AICI,. Suitable

solvents are e.g. diethylether, dimethylfonnamide, tetrahydrofurane. The epoxides

15    {VI) can also be opened directly by cyanides, amines, alcoholates, thioalcoholates, halogen ides and even water or Cs2COJiH20 in the presence of bases or strong protic

acids.

Suitable bases in the sense of the invention are e.g. Cs2C03• K2C03 or NaOH Suitable strong protic acids are e.g. HCIO,, HCI or HBr.

20    Process b) step a)

<lCF
3
(V)

nBuLI, -BO" to-1oo•c
 



21

(VII)    (VIII)

Methoxymethylamides of type (VII) are treated at low temperatures of -80oto -1 oooc with the lithiated epoxide (V) to yield compounds of type (VIII). Compounds of formula (VII) are commercially available or can be synthesized according to Branca

5    et al, Chimia 49, 10; 1995, 381-385. step b)





(VIII)    (IX)

The epoxides (VIII) can be opened by nucleophils of type R5-Met to deliver

10    compound (IX). Possible nucleophiles are alkylcuprates, vinylcuprates, thioles, allylsilanes, vinylsilanes, vinylstannanes, glignard compounds, in the presence of Lewis acids like BF, or AI Me,, AlGI,, or directly by cyanides, amines, alcohols, thioalcohols, halogen ides and water in the presence of bases or strong protic acids.

15    stepc)
roc
(III)H

1. Ti(OR)4 /   HOAc

2. reduction


(IX)    (I)
 



22

Ketones of type (IX) can be condensed with substituted aminoquinolones of type (Ill) to imines and subsequently or simultaneously reduced to the aminoalcoholl by a reductive amination using complex hydrides like e.g. NaB H. or LiAIH• (Katritzky eta/. J.Org.Chem. 1995, 60, 7631-7640) or hydrogen in the presence of catalytic amounts

5    of palladium or platinum or by application of an asymmetric organocatlytic transfer hydrogenation (List et al. Angew. Chem. 2005, 117, 7590-7593).

This processes described above can be perfomed enantioselectively by use of enantiopure epoxide of fonmula (V) to yield enantiopure compounds of fonmula (VI), (VIII), (IX) and (1). The last reductive step of b) can be perfonmed in a
10    diastereoselective manner to yield enantiopure compound I when enantiopure compound IX is used as starting material.

Alternatively during the process of the production of the compounds offonmula I at different stages purification for obtaining enantiomerically or diastereomerically pure intenmediates may be perfonmed e.g. intenmediates offonmula VI, VIII, IX can be

15    purified at the step when they are obtained or compounds of fonmula I can be purified to obtain enantiomerically or diastereomerically pure end products after the complete reaction cascade. Examples for methods for obtaining enantiopure (enantiomerically pure) compounds are described below. The separation of optical isomers can be

perfonmed by separation of one or more of the intenmediates and/or separation of the

20    end products. Usually separation of intenmediates and separation of end products are alternatives as long as no racemisation had taken place during the production process.

If the compounds according to the invention are present as racemic mixtures,

they can be separated into pure, optically active fonms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the

25    racemic mixtures can be separated by chromatography on an even optically active carrier material (CHIRALPAK AD®) into the pure isomers. It is also possible to use chiral auxiliary agents as optically pure acids. For that purpose the free hydroxy group is esterified to yield a racemic compound of general fonmula I with an optically
active acid and to separate the diastereoisomeric esters that are obtained by

30    fractionated crystallization or by chromatography, and to saponify the separated esters in each case to the optically pure isomers. As an optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
 



23

Thus one aspect of the invention is the process of obtaining compounds of

formula I in diastereomerically pure form, optionally using chromatography with

columns containing chiral material or using chiral auxiliary agents.

Each of the intermediates of the synthesis of the compounds of formula I are

5    one aspect of the present invention as well as especially their use for the synthesis of the compounds of formula I. A specific aspect of the invention are the concrete intermediates as used for the synthesis of the compounds of the examples, either as racemate or in their enantiomerically (having one chiral center) or diastereomerically

(having two chiral centers) pure form.

10 The binding of the substances to the glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is examined with the aid of recombinantly produced receptors. Cytosol preparations of Sf9 cells, which had been infected with

recombinant baculoviruses, which code for the GR, are used for the binding studies.

15    In comparison to reference substance (3H]-dexamethasone, the substances show a

high to very high affinity to GR. IC50(GR) = 6.8 nM, IC50(GR) = 5.7 nM and IC50(GR) = 3.1 nM and IC50(GR) =7.1 nM was thus measured for the compound from Examples 1, 4, 5 and 7 respectively.

As an essential, molecular mechanism for the anti-inflammatory action of

20    glucocorticoids, the GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is considered. This inhibition is produced by an interaction of the GR with other transcription factors, e.g., AP-1 and NF-kappa-B (fora survey, see Cato, A. C. B., and Wade, E., BioEssays 18,371-378, 1996).

25 The compounds of general formula I according to the invention inhibit the secretion of cytokine IL-8 into the human monocyte cell line THP-1 that is triggered by lipopolysaccharide (LPS). The concentration of the cytokines was determined in the supernatant by means of commercially available ELISA kits. The compound from Examples 4, 5, 7 and 8 showed an inhibition 1Cso(IL8) = 0.61 nmol, IC50(1L8) = 0.19

30    nmol, IC50(1L8) = 0.44 nmol and 1Cso(IL8) = 3.1nmol with efficacies of 97%, 98%, 98% and 80% respectively in comparison with dexamethasone as reference.
 



2'

The anti-inflammatory action of the compounds of general formula I was

tested in the animal experiment by tests in the croton oil-induced inflammation in rats

and mice (J. Exp. Med. 1995, 182, 99-108). To this end, croton oil in ethanolic

solution was applied topically to the animals'ears.  The test substances were also

5    applied topically or systemically at the same time or two hours before the croton oil. After 16-24 hours, the ear weight was measured as a yardstick for inflammatory edema, the peroxidase activity as a yardstick for the invasions of granulocytes, and the elastase activity as a yardstick for the invasion of neutrophilic granulocytes. In this test, the compounds of general formula I inhibit the three above-mentioned

10    inflammation parameters both after topical administration and after systemic administration.

One of the most frequent undesirable actions of a glucocorticoid therapy is the

so-called "steroid diabetes" [cf., Hatz, H. J., Glucocorticoide: lmmunologische

Grundlagen, Pharmakologie und Therapierichtlinien [Giucocorticoids:  Immunological

15    Bases, Pharmacology and Therapy Guidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible in this respect and by free amino acids, which are produced from the degradation of proteins

(catabolic action of glucocorticoids).  A key enzyme of the catabolic metabolism in

20    the liver is tyrosinamino transferase (TAT). The activity of this enzyme can be determined from liver homogenates by photometry and represents a good measurement of the undesirable metabolic actions of glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after the test substances are administered, the livers are removed, and the TAT activity is measured in the

25    homogenate. In this test, at doses wherein they have an anti•inflammatoryaction, the compounds of general formula I induce little or no tyrosinamino transferase.

Because of their anti-inflammatory and, in addition, anti-allergic, immunosuppressive and anti proliferative action, the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of

30    the following pathologic conditions in mammals and humans: In this case, the term "DISEASE" stands for the following indications:
 



25

(i) Lung diseases, which ccincide with infiammatory, allergic and/or proliferative

processes:

-    Chronic, obstructive lung diseases of any origin, primarily bronchial asthma

5    Bronchitis of different origins

Adult respiratory distress syndrome (ARDS), acute respiratory distress syndrome
Bronchiectases

All fonns of restrictive lung diseases, primarily allergic alveolitis,

10    All forms of pulmonary edema, primarily toxic pulmonary edema: e.g., radiogenic pneumonitis
Sarcoidoses and granulomatoses, especially Boeck'sdisease

(ii)    Rheumatic diseases/autoimmune diseases/joint diseases, which coincide with infiammatory, allergic and/or proliferative processes:

15    All fonns of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, Beh9et'sdisease

Reactive arthritis

Inflammatory soft-tissue diseases of other origins

Arthritic symptoms in the case of degenerative joint diseases

20    (arthroses)

Traumatic arthritides

Vitiligo
 



26

Collagenoses of any oligln, e.g., systemic lupus erythematodes,

sclerodermia, polymyositis, dermatomyositis, Sjogren'ssyndrome,

Still'ssyndrome, Felty'ssyndrome

Sarcoidoses and granulomatoses

Soft-tissue rheumatism

(iii)    Allergies or pseudoallergic diseases, which coincide with inflammatory and/or proliferative processes:

All forms of allergic reactions, e.g., Quincke'sedema, hay fever, insect

bites, allergic reactions to phannaceutical agents, blood derivatives,

10    contrast media, etc., anaphylactic shock, urticana, allergic and irritative contact dennatitis, allergic vascular diseases

Allergic vasculitis

(iv)  Vascular Inflammations (vasculitides)

Panarteritis nodosa, temporal arteritis, erythema nodosum

15    Polyarteris nodosa Wegnefs granulomatosis Giant-cell artelitis

(v)    Dermatological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

20    Atopic dermatitis (primarily in children)

All forms of eczema, such as, e.g., atopic eczema (primarily in children)

Rashes of any origin or dermatoses Psoriasis and parapsoriasis groups
 



27

Pityriasis rubra pilaris

Erythematous diseases, triggered by different noxae, e.g., radiation,

chemicals, burns, etc.

Bullous dermatoses, such as, e.g., autoimmune pemphigus vulgaris,

bullous pemphigoid

Diseases of the lichenoid group,

Pruritis (e.g., of allergic origin)

Seborrhea! eczema

Rosacea group

10    Erythema exudativum multiforme Balanitis

Vulvitis

Manifestation of vascular diseases

Hair loss such as alopecia areata

15    Cutaneous lymphoma

(vi)    Kidney diseases, which coincide with inflammatory, allergic and/or proliferative processes:

Nephrotic syndrome

All nephritides, e.g., glomerulonephritis

20    (vii) Liver diseases, which coincide with inflammatory, allergic and/or proliferative processes:

Acute liver cell decomposition

-    Acute hepatitis of different origins, e.g., viral, toxic, pharmaceutical agent-induced
 



28

Chronic aggressive hepatitis and/or chronic intermittent hepatitis

(viii)  Gastrointestinal diseases, which coincide with inflammatory, allergic and/or

proliferative processes:

Regional enteritis (Crohn'sdisease')

5    Colitis ulcerosa Gastritis
Reflux esophagitis

Ulcerative colitis of other origins, e.g., native sprue

(ix)  Proctologic diseases, which coincide with inflammatory, allergic and/or

10    proliferative processes:

-    Anal eczema Fissures Hemorrhoids

Idiopathic proctitis

15    (x)  Eye diseases, which coincide with inflammatory, allergic and/or proliferative

processes:

Allergic keratitis, uveitis, iritis

Conjunctivitis

Blepharitis

20    Optic neuritis Chorioiditis Sympathetic ophthalmia
 




29

(xi)    Diseases of the ear-nose-throat area, which coincide with inflammatory, allergic and/or proliferative processes:

Allergic rhinitis, hay fever

Otitis extema, e.g., caused by contact denmatitis, infection, etc.

Otitis media

(xii)    Neurological diseases, which coincide with inflammatory, allergic and/or proliferative processes:

Cerebral edema, pnmartly tumor-induced cerebral edema

Multiple sclerosis

10    Acute encephalomyelitis

Meningitis

Various forms of convulsions, e.g., infantile nodding spasms

Acute spinal cord injury Stroke

15    (xiii) Blood diseases, which coincide with inflammatory, allergic and/or proliferative processes, such as, e.g.: M. Hodgkins or Non-Hodgkins lymphomas, thrombocythemias, erythrocytoses

Acquired hemolytic anemia

Idiopathic thrombocytopenia

20    (xiv) Tumor diseases, which coincide with inflammatory, allergic and/or proliferative processes, such as, e.g.: carcinomas or sarcomas

Acute lymphatic leukemia

Malignant lymphoma
 



30

Lymphogranulomatoses

Lymphosarcoma

Extensive metastases, mainly in breast, bronchial and prostate cancers

(xv) Endocrine diseases, which coincide with infla~matory, allergic and/or

5    proliferative processes, such as, e.g.:

Endocrine orbitopathy

Thyreotoxic crisis

De Quervain'sthyroiditis

Hashimoto'sthyroiditis

10    Basedow'sdisease Granulomatous thyroiditis
Lymphadenoid goiter

(xvi)    Organ and tissue transplants, graft-versus-host disease

(xvii)    Severe shock conditions, e.g., anaphylactic shock, systemic inflammatory 15 response syndrome (SIRS)

(xviii)    Substitution therapy in:

Innate primary suprarenal insufficiency, e.g., congenital adrenogenital

syndrome

Acquired primary suprarenal insufficiency, e.g., Addison'sdisease,

20    autoimmune adrenalitis, meta-infective tumors, metastases, etc. Innate secondary suprarenal insufficiency, e.g., congenital hypopituitarism
 



31

Acquired secondary suprarenal insufficiency, e.g., meta-infective

tumors, etc.

(xix)    Emesis, which coincide with inflammatory, allergic and/or proliferative processes:

5    e.g., in combination with a 5-HT3 antagonist in cytostatic-agent-induced vomiting

(xx)    Pains of inflammatory origins, e.g., lumbago

(xxi)    Other different stages of disease including diabetes type I (insulin-dependent

diabetes), osteoarthritis, Guillain-Barre syndrome, restenoses after percutaneous

10    transluminal angioplasty, Alzheimer'sdisease, acute and chronic pain, arteriosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, acute purulent meningitis, necrotizing enterocolitis and syndromes associated with hemodialysis,

leukopheresis, and granulocyte transfusion.

15 Moreover, the compounds of general formula I according to the invention can be used for treatment and prophylaxis of additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this respect Hatz, H. J., Glucocorticoide: lmmunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998).

20 All previously mentioned indications (i) to (xx) are described in more detail in Hatz, H. J., Glucocorticoide: lmmunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaflliche Verlagsgesellschafl mbH, Stuttgart, 1998.

All of the diseases mentioned above do have in common that they are thought to

be caused by inflammatory, allergic, immunosuppressive or antiproliferative

25    processes. Thus the invention also relates to methods for treatment of inflammatory, allergic, immunosuppressive or antiproliferative diseases and the use of the compounds of formula I or a pharmaceutically acceptable salt thereof for the
 



32

manufacture of a medicament for the treatment thereof. One special aspect is the treatment of inflammatory diseases.

The glucocorticoid receptor is known to be involved in the process of inflammation Thus another aspect of the invention is a method of treating a

5    glucocorticoid receptor mediated disease state in a mammal, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof and the use of a compound or formula (I), or a Pharmaceutically acceptable salt thereof, as claimed

in claim 1-6, for the manufacture of a medicament for use in the treatment of a

10    glucocorticoid receptor mediated disease state.

Another aspect of the invention are compounds of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1-6 for use in therapy.

For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose vanes and depends on, for example, the active strength of the compound

15    of general formula I, the host, the type of administration, and the type and seventy of the conditions that are to be treated, as well as the use as a prophylactic agent or therapeutic agent.

In addition, the invention provides:

(i)    The use of one of the compounds of formula I according to the invention

20    or mixture thereof for the production of a medication for treating a

DISEASE;

(ii)    A process for treating a DISEASE, said process compnses an

administration of an amount of the compound according to the invention,

wherein the amount suppresses the disease and wherein the amount of

25    compound is given to a patient who requires such a medication;

(iii)    A pharmaceutical composition for treating a DISEASE, said treatment comprises one of the compounds according to the invention or mixture thereof and at least one pharmaceutical adjuvant and/or vehicle.

In general, satisfactory results can be expected in animals when the daily

30    doses compnse a range of 1 ~g to 100,000 ~g of the compound according to the
 



33

invention per kg of body weight. In the case of larger mammals, for example the human, a reccmmended daily dose lies in the range of 1 ~g to 100,000 ~g per kg of body weight. Preferred is a dose of 10 to 30,000 pg per kg of body weight, and more preferred is a dose of 10 to 10,000 ~g per kg of body weight. For example, this dose is suitably administered several times daily. For treating acute shock (e.g., anaphylactic shock}, individual doses can be given that are significantly above the

above~menfioned doses.

The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art by the active ingredient

10    being processed with the vehicles that are commonly used in galenicals, fillers, substances that influence decomposition, binding agents, moisturizers, lubn"cants, absorbents, diluents, flavoring correctives, coloring agents, etc., and converted into the desired fonn of administration. In this case, reference is made to Remington's
Pharmaceutical Science, 15th Edition, Mack Publishing Company, East Pennsylvania

15    (1980).

For oral administration, especially tablets, coated tablets, capsules, pills,

powders, granulates, lozenges, suspensions, emulsions or solutions are suitable.

For parenteral administration, injection and infusion preparations are possible.

For intra~articular injection, correspondingly prepared crystal suspensions can

20    be used.

For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments both

25    for systemic and for local treatment.

For pulmonary administration of the new compounds, the latter can be used in the form of aerosols and inhalants.

For local application to eyes, outer ear channels, middle ears, nasal cavities,

and paranasal sinuses, the new compounds can be used as drops, ointments and

30    tinctures in corresponding phannaceutical preparations.
 




For topical application, formulations in gels, ointments, fatty ointments,

creams, pastes, powders, milk and tinctures are possible.  The dosage of the

compounds of general formula I should be 0.01%-20% in these preparations to

achieve a sufficient pharmacological action.

5    The invention also comprises the compounds of general formula I according to_

the invention as therapeutic active ingredients.

In addition, the compounds of general fonnula I according to the invention are

part of the invention as therapeutic active ingredients together with pharmaceutically

compatible and acceptable adjuvants and vehicles.

10    The invention also comprises a pharmaceutical composition that contains one

of the pharmaceutically active compounds according to the invention or mixtures

thereof or a pharmaceutically compatible salt thereof and a pharmaceutically compatible salt or pharmaceutically compatible adjuvants and vehicles.

The compounds of general formula (I) according to the invention can optionally 15 also be formulated and/or administered in combination with other active ingredients.

The invention therefore also relates to combination therapies or combined compositions, wherein a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that contains a compound of general formula (I) or a pharmaceutically acceptable salt thereof, is administered either

20    simultaneously (optionally in the same composition) or in succession together with one or more pharmaceutical agents for treating one of the above-mentioned pathologic conditions. For example, for treatment of rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive lung disease), asthma or allergic rhinitis, a compound of general formula (I) of this invention can be combined with one or more pharmaceutical agents

25    for treating such a condition. When such a combination is administered by inhalation, the pharmaceutical agent that is to be combined can be selected from the following list:

A PDE4 inhibitor including an inhibitor of the PDE4D isoform,

A selective ~.sub2.adrenoceptor agonist, such as, for example,

metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol,
 



35

forrnoterol, salmeterol, terbutatine, orcipresnaline, bitolterol mesylate,

pirbuterol or indacaterol;

A muscarine receptor antagonist (for example, an M1, M2 or M3

antagonist, such as, for example, a more selective M3 antagonist), such

5    as, for example, ipratropium bromide1 tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;

A modulator of the chemokine receptor function (such as, for example, a CCR1 receptor antagonist); or

An inhibitor of the p38 kinase function.

10 For another subject of this invention, such a combination with a compound of general formula (I) or a pharmaceutically acceptable salt thereof is used for treatment of COPD, asthma or allergic rhinitis and can be administered by inhalation or orally in combination with xanthine (such as, for example, aminophylline or thyeophylline), which also can be administered by inhalation or orally.

15
 



36

Experimental Part:

The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
5

Example 1




5-{[1-(2-Fluoro-4-methoxyphenyll-3.3 3-trifluoro-2-hydroxy-2-([methylsulfanyllmethyllpropyllamino\-1H-quinolin-2-<Jne
5-{[{2-Fiuoro-4-methoxypheny/){2-trifluoromethyl-oxiranyl)methyl]amino}-1H-quino/in-

10    2-one

To 600 mg (3.9 mmol) 5-Amino-7-ftuoro-1H-quinolin-2-<Jne and 624 mg (3.9 mmol) 2-

ftuoro-4-methoxybenzaldehyde in 12 ml toluene are added 18 ~I acetic acid and 2 g molecular sieve. The mixture is heated over 25 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is

15    two times azeotrophed with small portions of toluene to obtain 5-{{1-(2-ftuoro-4-me!hoxyphenyl)-methylidene]amino}-1H-quinolin-2-one are quantitatively. 0.81 ml

(11.6 mmol) 1, 1, 1-trifluoroepoxypropane in 12 ml THF and 3.5 ml hexane are cooled

to -100'Cand 3.75 ml of a 2.5 M n-butyllithium solution (9.4 mmol) in hexane are

added over 10 minutes while the temperature does not exceed -95'C.10 Minutes

20    after complete addition 1.11 g (12 mmol) 5-{[1-(2-ftuoro-4-methoxyphenyl)-methylidene]amino}-1 H-quinolin-2-one in 10 ml THF are added over 15 minutes while the temperature does not exceed -95'C.After tree hours at -100'C3 .75 ml diethyl

ether are added and the reaction mixture is warmed to -1 ooc over one hour. The

reaction is quenched by addition of saturated ammonium chloride solution. The

25    phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 80%) yields 410 mg of 5-{[(2-Fiuoro-4-methoxyphenyl)(2-trifiuoromethyl-oxiranyl}methyl]amino}-1 H-quinolin-2-one.
 



37

1 H-NMR (CDCI3); 8 ~ 2.59 (dq, 1H), 3.15 (d,1H), 3.78 (s, 3H), 4.93 (d,1H), 5.53 (d, 1H), 6.21 (d,1H), 6.67 (m, 3H), 6.77 (d,1H), 7.13 (t,1H), 7.22 (t,1H), 7.96 (d,1H).

To 50 mg (0.12 mmol) 5-{[(2-Fiuoro-4-methoxyphenyl)(2-trifluoromethyl-

5    oxiranyl)methyl]amino}-1H-quinolin-2-one and 80 mg Cs2CO, in 0.5 ml DMF are added 0.18 ml of a 1M solution of methyl mercaptan in DMF. The mixture is stirred vigorously for 4 hours and water is added. The aqueous layer is extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After

removal of the solvent thin layer chromatography on silica gel (acetone in hexane

10    50%) yields 27 mg of the title compound.

1H-NMR (CDC I,); 8 ~ 2.09 (s, 3H), 2.87 (d, 1H), 3.06 (d, 1 H), 3.81 (s, 3H), 5.24 (d, 1H), 5.88 (d,1H), 6.22 (d,1H), 6.68 (m, 4H), 7.23 (t, 1H), 7.38 (t, 1H), 7.97 (d,1H).

Example 2




15

5-U2-([Ethylsulfanyl]methyll-1-(2-fluoro-4-methoxyphenyll-3,3,3-trifluoro-2-

hydroxypropyllaminol-1 H-guinolin-2-one

To 50 mg (0.12 mmol) 5-{[(2-Fiuoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-1 H-quinolin-2-<>ne and 80 mg CszCO, in 0.5 ml DMF are

20    added 14 ~I (0.18 mmol) of ethyl mercaptan in DMF. The mixture is stirred vigorously for 4 hours and water is added. The aqueous layer is extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (acetone in hexane 50%) yields 20 mg of the title compound.

25 1H-NMR (CDC!,); 8 ~ 1.18 (t, 3H), 2.45 (dq, 2H), 2.85 (d, 1H), 3.09 (d,1H), 3.81 (s, 3H), 5.19 (d,1H), 5.82 (d,1H), 6.21 (d, 1H), 6.68 (m, 4H), 7.23 (t,1H), 7.38 (t, 1H), 7.98 (d, 1 H).
 



38

Example 3






5-{[1-(2-Chloro-3-fluoro-4-methoxvphenyll-3. 3.3-trifluoro-2-hydroxv-2-

5    ([methylsulfanyllmethyllpropyllaminol-1 H-guinolin-2-one

2-Ch/oro-3-fluoro-4-methoxybenza/dehyde

1g (6.2 mmol) 3-Chloro-2-fluoroanisole in 20 ml THF are cooled to -7o•c and 2.7 ml of a 2.5 M n-butyllithium solution in hexane are added. Afler one hour at -7o• 3.93 ml

DMF in 7 ml THF are added at -7o•c and the mixture is stirred another hour at -7o•c.

10    15 ml of a 1 M aqueous HCI are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel to yield 0.25 g 2-chloro-3-fluoro-4-
15    methoxybenzaldehyde. 1H-NMR (CDC!,); B = 3.98 (s, 3H), 6.98 (dd, 1H), 7.75 (dd, 1H), 10.30 (s, 1H).

5-Amino-7-fluoro-1H-quinofin-2-one

To a solution of 2-bromo-'1-fluoroaniline(6.5 g, 34.17 mmol) and pyridine (2.7 g,

20    34.17 mmol) in 20 ml of CH,CI,, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH,CI2 are added dropwise and mixture was refluxed for 30 min. The reaction

mixture is diluted with CH,CJ,, the organic layer washed with diluted HCI , saturated Na2C03 solution, water, and dried (Na2SO,). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-'1-fluorophenyl)-3-phenylacrylamide.To a solution of N-(2-

25    bromo-3-fluorophenyl)-3-phenylacrylamide (1 0.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130 •c AlGI, (21 .9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76 %). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1 H-quinolin-2-

one are refluxed in 30 mL of POCI3 during 2 h, then poured on ice, extracted with 30 benzene. the benzene extract dried (Na2SO•) to yield 6.1 g B-bromo-2-chloro-7-
 



39

fluoroquinoline after solvent removal. To a mixture of 10 ml1 Oo/o-oleum and 1.4 g

(22.2 mmol) of fuming HN03 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is

added portionwise. The mixture is heated at 100 •c for 2 h. Additional HN03 (0.17 g)

is added and stirred for additional1 h. The reaction mixture is poured in ice-water,

5    extracted with EtOAc, filtered through silica gel, and crystallized from heptane-

toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100 •c for 5 h in a

solution containing 16 ml of CH3COOH, 3.2 ml of H,O and 5 ml of cone. HCI. The

mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and

10    filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-<me. To a suspension

1.7    g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-<me and 2.3 g (35.5 mmol) ofHCOONH4 in 10 ml of ethanol 0.1 g 10% Pd-C are added, and stirred for

2h at 60 •c. A solid disappeared and then formed again. The precipitate is fittered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to
15    the eluate, the precipitate is filtered off and dried to yield 0.5 g (47 %) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-ds); B = 6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).

5-{[(2-Ch/oro-3-f/uoro-4-methoxypheny/)(2-trifluoromethy/-oxirany/)methy/]amino}-7-

20    fluoro-1 H-quino/in-2-one

To 1.6 g (9 mmol) 5-amino-7-fluoro-1H-quinolin-2-one and 1.69 g (9 mmol) 2-chloro-3-fluoro-4-methoxybenzaldehyde in 27 ml toluene and 8 ml 1 ,4-dioxane are added

1.96 ml acetic acid and 7 ml tetra butyl orthotitanate. The mixture is heated over 20 hours to 11 ooc, cooled to room temperature and poured into aqueous ammonium

25    fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 1 hour. Phases are separated and addition of ethylacetate is repeated two times while stirring is done under reflux and phases are separated while they are still hot. The combined organic phases are concentrated and the residue is purified by flash

chromatography on silica gel (ethyl acetate, then methanol in dichloromethane 15%

30    to 20%) to yield 2.17 g of 5-([1-(2chloro-3-fluoro-4-methoxyphenyl)methylidene]-amino}-7-fluoro-1H-quinolin-2-<me. 465 mg NaH (55% in mineraloil, 9.7 mmol} were washed with dry THF and suspended together with 2.6 g (7.5 mmol) of 5-([1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino }-7- fluoro-1 H-quinolin-2-one in 90 ml THF. 1-Butyldimethylsilyl chloride is added as solid and the mixture is stirred for
 




3.5 hours while it becomes a clear solution. In parallel 0.96 ml1 ,1 ,1-trifluoro-2,3-epoxypropane in 24 ml THF and 7 ml hexane are cooled to -100°C and 4.5 ml of a 2.5 M n•butyllithium solution in hexane are added over 10 minutes while the temperature does not exceed -95°C. 10 Minutes after complete addition the

5    previously prepared 1-{l-butyldimethylsilyl}-5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoroquinolin-2-one solution in THF is added over 30 minutes while the temperature does not exceed ~95°C. After 3 hours at

-1 00°C 7.5 ml diethyl ether are added and the reaction mixture is warmed to room

temperature over one hour. The reaction is quenched by addition of saturated

10    ammonium chloride solution. After stirring for 30 minutes the phases are separated and the aqueous layer is extracted with dichloromethan, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 50 to 100%) yields 2.14 g of 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]amino}-

15    7 -fluoro-1 H-quinolin-2-<me which is used for some of the following examples for opening of the oxirane ring with different nucleophiles.

1H-NMR (DMSO-d6); 8 = 2.62 (m, 1 H), 3.29 {d, 1 H), 3.87 (s, 3H), 5.49 (d, 1 H), 5.83 (d, 1 H), 6.34 {d, 1 H), 6.37 (d, 1 H), 7.04 {d, 1 H), 7.22 {dd, 1 H), 7.44 (d, 1 H), 8.31 {d, 1H), 11.63 (s, 1H).

20

To 65 mg (0.14 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1 H-quinolin-2-on and 92 mg (0.28 mmol) Cs2C03 in 0.5 ml DMF are added 0.21 ml of a 1M solution of methyl mercaptan in DMF. The mixture is stirred vigorously for 20 hours and water is added. The aqueous layer is

25    extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (ethyl acetate) yields 22 mg of the title compound.

1H-NMR (CDCJ,); 8 =1.91 (s, 3H), 2.68 (d, 1H), 3.04 {d, 1H), 3.87 (s, 3H), 5.21 (d, 1H), 5.80 (dd, 1H), 5.94 {d, 1 H), 6.38 (dd, 1H), 6.57 {d, 1H), 6.87 (dd, 1H), 7.24 (dd,

30    1 H), 7.84 (d, 1 H).
 




Example 4





5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyll-2-([ethylsulfanyllmethyll-3 3.3-trifluoro-2-

hydroxvpropyllamino1-7 -fluoro-1 H-quinolin-2-one

To 66 mg (0.14 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino)-7-fluoro-1H-quinolin-2-<Jn obtained in example 3 and 93 mg (0.29 mmol) Cs2C03 in 0.6 ml DMF are added 16 ~I (0.22 mmol) of ethyl mercaptan in DMF. The mixture is stirred vigorously for 20 hours and water is added. The aqueous layer is extracted with ethyl acetate, the organic phases washed with brine

10    and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (ethyl acetate) yields 14 mg of the title compound.

1H-NMR (CDCI3); 5; 1.07 (t, 3H), 2.27 (dq, 2H), 2.69 (d, 1 H), 3.06 (d, 1 H), 3.88 (s, 3H), 5.20 (d, 1 H), 5.79 (dd, 1 H), 5.92 (d, 1 H), 6.37 (dd, 1 H), 6.57 (d, 1 H), 6.87 (dd, 1H), 7.24 (dd, 1H), 7.84 (d, 1H).

15

Example 5





5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxvmethyllpropyl]amino\-7-fluoro-1 H-guinolin-2-<Jne

20    2.14 g (4.64 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 are stirred with 2.57 g (7.9 mmol) Caesium carbonate in 37 ml methanol. After 3 days water is

added and the aqueous phase is extracted with ethyl acetate. The combined organic

phases are washed with brine and dried over sodium sulphate. After removal of the

25    solvent flash chromatography on silica gel (methanol in dichloromethan 0 to 5 %) yields 0.98 g of the title compound.
 




1H-NMR (CD30D); 5 = 3.07 (d, 1 H), 3.23 (s, 3H), 3.50 (d, 1 H), 3.84 (s, 3H), 5.33 (s, 1H), 6.02 (dd,1H), 6.29 (dd,1H), 6.43 (d, 1H), 7.05 (dd, 1H), 7.47 (dd, 1H), 8.04 (d, 1H).

5    Example 6





5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyll-2-(ethoxvmethyll-3 3 3-trifluoro-2-

hydroxypropy\lamino l-7 -fluoro-1 H-quinolin-2-one

70 mg (0.15 mmol) 5-([(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-

10    oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-<>n obtained in example 3 are stirred with 84 mg (0.26 mmol) Caesium carbonate in 0.67 ml ethanol. Alter 40 hours water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl

15    acetate) yields 22 mg of the title compound.

1H-NMR (CDC!,); 5 = 1.15 (t, 3H), 3.39 (dq, 1H), 3.42 (d, 1H), 3.51 (dq, 1H), 3.69 (d, 1H), 3.87 (s, 3H), 5.26 (d,1H), 5.86 (dd, 1H), 6.18 (d,1H), 6.33 (dd,1H), 6.54 (d, 1H), 6.87 (dd,1H), 7.25 (dd,1H), 7.80 (d,1H).

20    Example 7





5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3 3 3-trifluoro-2-hydroxv-2-(hydroxymethyll-propyiJamino )-7-fluoro-1 H-ouinolin-2-one
250 mg (0.54 mmol) 5-([(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-

25    oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on are stirred with 353 mg (1.1 mmol) Caesium carbonate in 3 ml DMF, 1.9 ml water and 0.5 ml DMSO. Water is added
 




and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent fiash chromatography on silica gel (methanol in dichloromethan 0 to 5 %) yields 0.98 g of the title compound.
1H-NMR (CD30D); 8 ~ 3.60 (d, 1H), 3.71 (d, 1H), 3.85 (s, 3H), 5.34 (s, 1H), 5.96 (dd, 1H), 6.29 (dd,1H), 6.45 (d,1H), 7.06 (dd,1H), 7.51 (dd,1H), 8.04(d,1H).

Example 8





10    5-![1-(5-Chloro-3-fiuoro-2-methoxyohenyll-3 3 3-trifluoro-2-hydroxy-2-(hydroxymethyll-propyllamino1-7 -fiuoro-1 H-quinolin-2-one

5-Ch/oro-3-fluoro-2-methoxybenza/dehyde

To 5 g (34 mmol) 4-Chloro-2-fiuorophenol and 416 mg (3.41 mmol) 4-

dimethylaminopyridine in 18 ml THF are added 3.7 ml  (37 .5 mmol) isopropyl

15    isocyanate and the mixture is heated for 20 hours at60'CAfter. cooling down to room temperature 2 M HCI is added and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield 7.2 g isopropylcarbamic acid 4-chloro-2-fiuorophenyl

ester as the crude product. To 7.2 g (31 mmol) isopropylcarbamic acid 4-chloro-2-

20    fiuorophenyl ester and 5.1 mltetramethylene diamine in 300 ml diethyl ether are added 5.9 ml (32.5 mmol) (trimethylsilyl)(trifiuoromethan)sulfonate at room temperature. After 30 minutes the mixture is cooled to -70'C,10.2 mltetramethylene diamine and 27 ml of a 2.5 M n-BuLi solution are added successively. After one hour at-70'24 ml DMF in are added at-70'Cand the mixture is stirred another hour at-

25    70'C.130 ml ethanol and 36 ml of a 2 M aqueous NaOH are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is set acidic by addition of 100 ml 2 M aqueous HCI and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic

phases are washed with brine, dried over sodium sulphate and evaporated. The

30    crude product is purified by chromatography on silica gel to yield 1.1 g 5-chloro-3-
 




fiuoro-2-hydroxybenzaldehyde. 1.1 g (6.1 mmol) 5-chloro-3-fiuoro-2-hydroxybenzaldehyde and 1.56 g (11.3 mmol) potassium carbonate are stirred vigorously in 11 ml DMF while 0.7 ml methyliodide are added. Stirring is continued for 18 hours and water is added. The aqueous phase is extracted with diethyl ether, the

combined organic phases are dried over sodium sulfate and evaporated. The crude

product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 1 0%) to yield 570 mg 5-chloro-3-fiuoro-2-methoxybenzaldehyde. 1H-NMR (CDC!,); 8 ~

4.10 (d, 3H), 7.35 (dd, 1H), 7.59 (m, 1H), 10.35 (s, 1H).

10    5-{[(5-Ch/oro-3-fluoro-2-methoxypheny/)(2-trifluoromethy/-oxirany/)methy/]amino}-7-fluoro-1H-quinolin-2-one
To 0.54 g (3 mmol) 5-amino-7-fiuoro-1H-quinolin-2-one and 0.57 g (3 mmol) 5-chloro-3-fluoro-2-methoxybenzaldehyde in 9 ml toluene and 2.6 ml1 ,4-dioxane are

added 0.65 ml acetic acid and 2.4 ml tetrabutyl orthotitanate. The mixture is heated

15    over 17 hours to 11 0°C, cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 1 hour. Phases are separated and addition of ethylacetate is repeated two times while stirring is done under reflux and phases are separated while they are

still hot. The combined organic phases are concentrated and the residue is purified

20    by flash chromatography on silica gel (ethyl acetate, then methanol in dichloromethane 10% to 20%) to yield 0.63 g of 5-{[1-(5chloro-3-fluoro-2-methoxyphenyl)methylidene]-amino}-7-fiuoro-1H-quinolin-2-one. 57 mg NaH (55% in mineraloil, 1.4 mmol) were washed with dry THF and suspended together with 0.63 g (1.8 mmol} of 5-([1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]amino}-7- fluoro-

25    1H-quinolin-2-one in 22 ml THF. t-Butyldimethylsilyl chloride is added as solid and the mixture is stirred for 2.5 hours while it becomes a clear solution. In parallel 0.24 ml1, 1, 1-trifluoro-2,3-epoxypropane in 6 ml THF and 2 ml hexane are cooled to

-1 oo•c and 1.1 ml of a 2.5 M n-butyllithium solution in hexane are added over 1 o minutes while the temperature does not exceed -95•c. 10 Minutes after complete
30    addition the previously prepared 1-{t-butyldimethylsilyl}-5-{[1-(5-chloro-3-fiuoro-2-methoxyphenyl}methylidene]amino}-7-fluoroquinolin-2-one solution in THF is added over 20 minutes while the temperature does not exceed -95•c. After 3.5 hours at -1 oo•c2 ml diethyl ether are added and the reaction mixture is warmed to room temperature over one hour. The reaction is quenched by addition of saturated
 




ammonium chloride solution. After stirring for 30 minutes the phases are separated

and the aqueous layer is extracted with dichloromethan, the combined organic

phases are washed with brine, dried over sodium sulphate and then evaporated.

Flash chromatography on silica gel (ethyl acetate in hexane 0 to 100%) yields 152

5    mg of 5-{[(5-chloro-3-fluoro-2-methoxyphenyl)(2-trifiuoromethyloxiranyl)methyl]-amino)-7 -fluoro-1 H-quinolin-2-one

1H-NMR (CDC!,); 5 = 2.48 (m, 1H), 3.18 (d, 1H), 4.11 (s, 3H), 5.13 (d, 1H), 5.54 (d, 1H), 5.86 (dd, 1H), 6.53 (dd, 1H), 6.64(d, 1H), 6.94(m, 1H), 7.14(d, 1H), 7.88 (d, 1H) and 87 mg at 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-

10    trifluoro-2-hydroxypropyl]amino)-7-fluoro-1 H-quinolin-2-one

50 mg (0.11 mmol) 5-{[(5-chloro-3-fluoro-2-methoxyphenyl)(2-trifiuoromethyl-oxiranyl)methyl]amino)-7-fiuoro-1 H-quinolin-2-on are stirred with 67 ~I perchloric acid

(70%) in 0.55 ml DMF for 24 hours at 40'C.Additional with 67 ~I perchloric acid

15    (70%) are added and the mixture is stirred for further 48 hours at 40'C.Saturated aqueous NH,CI solution is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (ethyl acetate) yields 39 mg of the title compound.
20 1H-NMR (CD30D); 5 = 3.49 (d, 1H), 3.78 (d, 1H), 4.14 (d, 3H), 5.48 (s, 1H), 6.12 (dd, 1H), 6.34(d, 1H), 6.47(d, 1H), 7.20(dd, 1H), 7.52(m, 1H), 8.10(d, 1H).

Example 9





25    5-{[1-15-Chloro-3-fluoro-2-methoxyphenyll-2-lchloromethyll-3,3,3-trifluoro-2-hydroxypropyllamino}-7-fluoro-1 H-guinolin-2-one
Can be isolated as a product in the epoxide synthesis of example 8 after aqueous

ammonia chloride work up.

1H-NMR (DMSO-d6); 5 = 3.88 (d, 1H), 4.00 (d, 3H), 4.19 (d, 1H), 5.49 (d, 1H), 6.12

30    (d, 1H), 6.37 (d, 2H), 6.51 (d, 1H), 7.42 (d, 1H), 7,66 (s, 1H), 8.24 (d, 1H).
 



46

Example 10




5-{[3 3,3-trifluoro-2-hyd roxv-2-([methoxymethyll-1-phenylpropyllamino l -1 H-quinolin-

1-one

3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one

2.3 ml (26 mmol} 1,1,1-trifluoro-2,3-epoxypropane in 30 ml THF and 8 ml hexane are cooled to -1 oo•cand 6.3 ml of a 2.5 M n-butyllithium solution (16 mmol} in hexane are added over 15 minutes while the temperature does not exceed -95•c. 10 Minutes after complete addition 2.0 (12 mmol} g N-methoxy-N-methylbenzamid in 38 ml THF

10    are added over 15 minutes while the temperature does not exceed -95•c. After 5 hours at-1oo•c 12 ml diethyl ether are added and the reaction mixture is warmed to room temperature over 14 hours. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is

extracted twice with ethyl acetate, the combined organic phases washed with brine,

15    dried over sodium sulphate and then evaporated to yield 2.59 g of Phenyl-[2-(trifluoromethyl}oxiranyl]methanone. 1H-NMR (CDC!,}; 5; 3.07 (dq, 1 H), 3.38 (d, 1 H),

7.50 (t, 2H}, 7.65 (tt, 1 H), 8.07 (d, 2H}.

2.59 g (12 mmol} Phenyl-[2-(trifluoromethyl}oxiranyl]methanone are stirred with 8.8 g

(27 mmol} Caesium carbonate in 94 ml methanol. The reaction is quenched by

20    addition of water after 3 days. The aqueous layer is extracted with ethyl acetate, the combined organfc phases are washed with brine, dried over sodium sulphate and then evaporated to yield 2.87 g 3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-
one. 1H-NMR (CDC!,); 5; 3.42 (s, 3H}, 3.89 (d, 1H}, 4.23 (d, 1 H), 4.55 (s, 1 H), 7.47 (t, 2H}, 7.60 (t, 1H}, 8.01 (d, 2H}.

25

To 194 mg (1.2 mmol} 5-amino-1H-quinolin-2-one and 300 mg (1.2 mmol} 3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one in 4 ml toluene and 1 mit ,4-dioxane are added 0.26 ml acetic acid and 1 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 11 o•c,cooled to room temperature and poured into

30    aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is
 



47

stirred vigorously for 30 minutes. Phases are separated and two times extracted with

ethylacetate. The combined organic phases are concentrated to yield quantitatively 5-[(3,3,3-trifluoro-2-hydroxy-2-methoxymethyl-1-phenylpropylidene )amino ]-1 H-quinolin-2-one. 396 mg (1 mmol) imine in 22 ml methanol is cooled to 5•c and 700 mg sodium boron hydride are added in multiple portions over the period of 24 hours. The reaction is quenched by addition of saturated ammonium chloride solution•and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on

10    silica gel (ethyl acetate in hexane 0 to 80%) yields 53 mg of the title compound.

1H-NMR (CD30D); B; 3.45 (s, 3H), 3.47 (d, 1H), 3.64 (d, 1H), 4.97 (s, 1H), 6.19 (d, 1H), 6.58 (t, 2H), 7.16 (t,1H), 7.30 (m, 3H), 7.50 (d, 2H), 8.05 (d,1H).

Example 11




15

5-1[1-(2-Chloro-3-fluoro-4-methoxvphenyl)-2-( diaminomethyll-3,3 3-trifluoro-2-

hyc!roxypropyllaminol-7-nuoro-1 H-quinolin-2-one

150 mg (0.33 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifiuoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 are stirred

20    with 69 mg lithium perchlorate and molcular sieve in 3.25 ml (6.5 mmol) of a 2 M THF solution of dimethyamine in a pressure vessel at 60°C. After 20 hers the reaction mixture was filtered from solids which and washed with ethyl acetate. After removal of the solvent flash chromatography on silica gel (ethyl acetate in hexane 0 to100%) yields 129 mg of the title compound.

25    1H-NMR (CDC!,); B; 1.68 (br, 3H), 2.30 (d, 1 H), 2.36 (br, 3H), 2.77 (br, 1 H), 3.87 (s, 3H), 5.09 (d,1H), 5.81 (d,1H), 5.98 (d,1H), 6.35 (d,1H), 6.56 (d, 1H), 6.88 (dd,1H), 7.32 (d,1H), 7.85(d,1H).
 



48

Example 12





5.{[1-(4-Chloro-3-fluoro-2-methoxyohenyll-3 3.3-trinuoro-2-hydroxy-2-

(methoxymethyl)propyllaminol-7-fluoro-1 H-auinolin-2-one

(4-ch/oro-3-ffuoro-2-methoxypheny/)[2-(triffuoromethy/)oxirany/]methanone.

1g (6.2 mmol) 3-Chloro-2-fluoroanisole in 10 ml THF are cooled to -70'Cand 2.7 ml of a 2.5 M n-butyllithium solution in hexane are added. After 1.5 hours at -70'1 g

(6.9 mmol) N,N'-dimethoxy-N,N'-dimethylurea in 6 ml THF are added at-70'Cand the mixture is stirred another hour at -70'C.7.5 ml of a 2M aqueous HCI are added and the
10    reaction is wanned to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 30%) to yield 0.59 g 4-chloro-3-fluoro-2,N-dimethoxy-N-

15    methylbenzamid. 1H-NMR (CDC!,); o= 3.35 (br, 3H), 3.49 (br, 3H), 3.98 (s, 3H), 6.99 (dd, 1H), 7.13(dd, 1H).

0.44 ml (5.1 mmol) 1,1, 1-trifluoro-2,3-t>poxypropane in 7.5 ml THF and 2.2 ml hexane are cooled to -100'Cand 2.03 ml of a 2.5 M n-butyllithium solution (5. 1 mmol) in

hexane are added over 15 minutes while the temperature does not exceed -95'C.10

20    minutes after complete addition 0.57g (2.3 mmol) 4-chloro-3-fluoro-2,N-dimethoxy-N-methylbenzamid in 10 ml THF are added over 15 minutes while the temperature does

not exceed -95'C.After 3 hours at -100'C2 .3 ml diethyl ether is added and the reaction

mixture is wanned to room temperature over 14 hours. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the
25    aqueous layer is extracted twice with diethyl ether, the combined organic phases

washed with brine, dried over sodium sulphate and then evaporated to yield 570 mg of

(4-chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone. 1H-NMR (CDC!,); o=2.99 (dq, 1H), 3.37 (d, 1H), 4.14 (d, 3H), 7.18 (m, 1H), 7.19 (m, 1H).
 




285 mg (0.95 mmol) (4-Chloro-3-fiuoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone are stirred with 622 mg (1.9 mmol) caesium carbonate in 6.7 ml methanol. The reaction is quenched by addition of water after one day. The aqueous layer is extracted with ethyl acetate, the combined organic phases

5    are washed with brine, dried over sodium sulphate and then evaporated to yield 262 mg 1-(4-<:hloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifiuoro-2-hydroxy-2-methoxymethypropan-1-one. To 27 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-chloro-3-fiuoro-2-methoxyphenyl)-3,3,3-trifluoro-2-

hydroxy-2-methoxymethypropan-1-one in 0.45 ml toluene and 0.13 ml1,4-dioxane are

10    added 33 ~I acetic acid and 0.12 ml tetra butyl orthotitanate. The mixture is heated over

20 hours to 11 0°C, cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethyl acetate. The combined organic phases are concentrated to yield quan!Ratively 5-{[1-(4-<:hloro-3-

15    fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino }-7-fluoro-1H-quinolin-2-one. The raw imine in 4.2 ml methanol is cooled to 5"C and 120 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution

and diluted with water and ethyl acetate. The phases are separated, the aqueous

20    layer is extracted with ethyl acetate, the combined organic phases are washed with

brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silic~ gel (acetone in methylene chloride, 30%) yields 9.5

mg of the title compound.

1H-NMR (CD30D); 6 = 3.44 (s, 3H), 3.65 (m, 1H), 3.69 (d, 1 H), 4.05 (d, 3H), 5.44 (s,

25    1H), 6.03 (dd, 1H), 6.30 (dd,1H), 6.45 (d, 1H), 7.12 (dd, 1H), 7.35 (dd, 1H), 7.94 (d, 1H).
 



50

Example 13





5-/[1-( 4-Chloro-3-ftuoro-2-methoxyphenyll-2-( ethoxymethyl)-3,3 3-triftuoro-2-

hydroxypropyllaminol-7 -fluoro-1 H-guinolin-2-one

5    1-(4-Ch/oro-3-fluoro-2-methoxypheny/)- 3,3,3-trifluoro-2-ethoxymethy-2-hydroxypropan-1-one

285 mg (0.95 mmol) (4-Ch/oro-3-1/uoro-2-melhoxypheny/)[2-(trifluoromethyl)-oxiranyl]methanone obtained in example 12 are stirred with 622 mg (1 .9 mmol) Caesium carbonate in 8 ml ethanol. The reaction is quenched by addition of water

10    after 1 day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 173 mg 1-(4-Chloro-3-fiuoro-2-methoxyphenyl )-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxy propan-1-<>ne. 1H-NMR (CDC!,); B = 1.20 (t, 3H), 3.60 (dq, 1 H), 3.62 (dq,

1H), 3.79 (d, 1H), 3.97 (d, 3H), 4.09(d, 1H), 4.72 (s, 1H), 7.11 (dd, 1H), 7.18 (dd, 1H).

15    To 26 mg (0.15 mmol) 5-Amino-7-fiuoro-1H-quinolin-2-<>ne and 50 mg (0.15 mmol) 1-(4-Chloro-3-fiuoro-2-methoxyphenyl )•3,3,3-trifiuoro-2-ethoxymethyl-2-hydroxy
propan-1-one in 0.44 ml toluene and 0.13 ml1 ,4-dioxane are added 30 ~I acetic acid and 0.11 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 11 o•c,

cooled to room temperature and poured into aqueous ammonium fluoride solution.

20    Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethylacetate. The combined organic phases are concentrated to yield quantitatively 5-{(1-(4-Chloro-3-fiuoro-2-methoxyphenyl)- 3,3,3-triftuoro-2-ethoxymethyl-2-hydroxypropylidene]amino)-7-
fiuoro-1H-quinolin-2-one. The raw imine in 4.7 ml methanol is cooled to s•c and 180

25    mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer
 



51

chromatography on silica gel (acetone in methylene chloride 30%) yields 3.2 mg of the title compound.
1H-NMR (CD,OD); li ~ 1.25 (t, 3H), 3.58 (dq, 1H), 3.59 (dq, 1H), 3.68 (dq,1H), 3.74 (d, 1H), 4.05 (d, 3H), 5.47 (s, 1H), 6.02 (dd,1H), 6.30 (dd, 1H), 6.43 (d, 1H), 7.13 (dd, 1H),
5    7.34 (dd, 1H), 7.93 (d, 1 H).


Example 14





10    5-{[1-(2-Chloro-3-fluoro-4-hydroxyphenyll-3,3 3-trifluoro-2-hydroxv-2-(hydroxymethyl)-propyl]amino}-7 -fluoro-1 H-quinolin-2-one

To 100 mg (0.20 mmol) of 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-

2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one of example 5

in 8.6 dichloromethane at -so•c are added 1.6 ml of a 1 M solution of boron

15    tribromide in dichloromethane under argon. The reaction mixture is stirred for 16

hours in a temperature range of between O'"Cand 25°C. The reaction mixture is mixed at o•c with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and

phases are separated. The aqueous phase is acidified with 4 M HCI and extracted

20    with 10 % methanol in dichloromethane. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate I methanol4: 1) yields 16 mg of the

title compound.

1H-NMR (CD30D); li ~ 3.62 (d, 1H), 3.71 (d, 1H), 5.32 (s, 1H), 5.99 (dd, 1H), 6.30

(dd,1H), 6.45 (d,1H), 6.87 (dd,1H), 7.38 (dd, 1H), 8.05 (d,1H).

25
 


-1-

Claims

1.  Compounds of general formula I









(I)

wherein R'is a 7-fluoro-substituent and at least one of R1, R2 and R3 is selected from chlorine, fluorine, methoxy,

R5 is selected from S-CH2-CH3, -O-CH2-CH3, -S-CH3, -O-CH3, -OH and -CI, and their salts, solvates or salts of solvates.

2. Compounds of general formula I according to claim 1, selected from the list consisting of

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-7-fluoro-1H-quinolin-2-one

5-([1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7 -fluoro-1 H-quinolin-2-one

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7 -fluoro-1 H-q uinolin-2-one

5-([1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7 -fluoro-1 H-quinolin-2-one

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7 -fluoro-1 H-quinolin-2-one 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7 -fluoro-1 H-quinolin-2-one

5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7 -fluoro-1 H-quinolin-2-one
 


-2-

5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2-hyd roxypropyl]amino }-7-fluoro-1 H-quinolin-2-one
5-{[1-(4-Chloro-3-f/uoro-2-methoxyphenyl)-3,3,3-trif/uoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-f/uoro-1H-quinolin-2-one

5-{[1-(2-Ch/o~o-3-fluoro-4-methoxypheny/)-2-( ethoxymethy/)-3,3 ,3-trif/uoro-2-hydroxypropy/]amino }-7-f/uoro-1 H-q uinolin-2-one
5-{[1-(2-Ch/oro-3-fluoro-4-hydroxypheny/)-3,3,3-trifluoro-2-hyd roxy-2-(hydroxymethyl)propy/]amino}-7 -fluoro-1 H-quino/in-2-one

and their salts, so/vales or salts of so/vales.

3.    Enantiomerical/y pure compounds according to claim 1 selected from the Jist

consisting of

5-{( 1S, 2R)[1-(2-C hloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfany/]methyl)propy/]amino}-7-fluoro-1H-quinolin-2-one
5-{(1S, 2R)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2- ([ethy/sulfany/]methyl)-3,3,3-trifluoro-2-hydroxypropy/]amino}-7-fluoro-1H-quinolin-2-one
5-{(1 S, 2S)[1-(2-Ch/oro-3-f/uoro-4-methoxyphenyl)-3,3,3-trifluoro-2-

hyd roxy-2-(methoxymethy/)propy/]amino }-7-f/uoro-1 H-quinolin-2-one 5-{(1S, 2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-
3,3,3-trifluoro-2-hydroxypropy/]amino}-7-fluoro-1H-quinolin-2-one 5-{(1S, 2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-

hydroxy-2-(hydroxymethyl)propy/]amino}-7-fluoro-1H-quinolin-2-one 5-{(1S, 2S)[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trif/uoro-2-

hyd roxy-2-(hyd roxymethyl)propyl]amino }-7-fluoro-1 H-q uinolin-2-one 5-{(1S, 2R)[1-(5-Chloro-3-f/uoro-2-methoxyphenyl)-2-(ch/oromethy/)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 5-{(1S, 2R)[ [1-(2-Ch/oro-3-fluoro-4-methoxypheny/)-2-(diaminomethy/)-3,3,3-

trifluoro-2-hydroxypropyl]amino }-7-fluoro-1 H-quinolin-2-one

5-{[( 1S, 2S)[1-(2-Ch/oro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethy/)propy/]amino}-7 -f/uoro-1 H-quinolin-2-one
and their salts, so/vales or salts of so/vales.

4.    Use of the compounds according to fonmula I of at least one of claims 1-3 for the manufacture of pharmaceutical agents.
 


-3-

5.    Use of the compounds according to formula I of at least one of claims 1-3 for the manufacture of pharmaceutical agents for treating inflammatory diseases.

6.    A pharmaceutical composition comprising a compound or formula {I) or a pharmaceutically acceptable salt thereof ~s defined in claim 1-3 and a phanmaceutically acceptable adjuvant, diluent or carrier.

7.    Process for the manufacture of the compounds of general formula I according to claim 1, wherein the following steps are performed: step a):

~
R4.!LANAO
(III)H

Ti(OR)4 andlor acid

(II)    (IV)

step b):

<lCF
3
M

nBuU,-80" to-100"C



(IV)    (VI)

step c):
 


-4-

    R'   
    CF3   
    1   
RR2    NH   
    RroO   
    H   
(VI)    {I)   

wherein all residues have the definitions as given in claim 1 and R is C1-C4-alkyl and Met means alkali metals, alkaline earth metals, aluminium, copper, silicon or tin.

B. Process step a) according to claim 7 for the manufacture of intermediates of general formula IV, characterized in that benzaldehydes of general formula II are reacted with substituted quinolone amines of formula Ill to imines of general formula IV in the presence of Lewis acids and/or under acidic conditions,

~
R4~NAO
{Ill) H

Ti(OR)4 and/or acid

(II)

wherein R1, R2 , R3and R4 have the meanings that are defined in claim 1 and R is c,-c.-alkyl.

9. Process step b) according to claim 7 for the manufacture of intermediates of general formula VI, characterized in that metallated trifluoroepoxipropane V, optionally being in its enantiomerically pure form, is reacted with imines of formula IV at low temperatures to yield epoxides of general formula VI
 


-5-

    H    ~R'    <t_CF2    :d'OCF,
R~ ~ I    (V)    R'"""    NH
R~    N    ~ NH    nBuLi, -BO'C-(-100)'C   R'  _,;    ~
R'        O            R~N---LO
                    H
    (IV)                (VI)

wherein R1, R2, R3and R4 have the meanings that are defined in claim 1 and optionally subsequently a separation of diastereoisomers is performed.

1 0. Process step c) according to claim 7 for the manufacture of compounds of general formula I, characterized in that epoxides of general formula VI optionally in its enantiomerically pure form
are reacted with compounds of general formula R5-Met

whereby Met means alkalimetals, alkaline earth metals, aluminium, copper, silicon or tin and R5 has the definitions as defined in claim 1,

in the presence of Lewis acids, or

are opened directly by cyanides, amines, alcohols, thioalcoholes, halogen ides and/or water in the presence of bases or strong protic acids. to yield compounds of general formula I

R'

CF2

1
R~ RrooNH
H

(VI)    (I)

wherein R1, R2, R3, R4 and R5 have the meanings that are defined in claim 1 and optionally subsequently a separation of diastereoisomers is performed.

11.    Compounds of general formula VI according to claim 9,
 


-6-








(VI)

in form of a racemic mixture or as enantiomerically pure isomer.

12. Process for the manufacture of the compounds of general formula I according to claim 1, wherein the following steps are performed:
step a):

<lCF,
M

nBuLi, -ao•c- (-100tc

(VII)    (VIII)

step b):







(VIII)    (IX)

step c):
 


-7-










(IX)    (I)

wherein all residues have the meaning as defined in claim 1, Met means alkalimetals, alkaline earth metals, aluminium, copper, silicon or tin and R is C1-C4-alkyl.

13. Process step c) according to claim 12 for the manufacture of compounds of general formula I, characterized in that ketones of type (IX) optionally in its enantiomerically pure form can be condensed with substituted amino quinolones of type (Ill) to imines and subsequently or simultaneously reduced to yield compounds formula I









(IX)    (I)

wherein R1, R2, R3 , R4 and R5 have the meanings that are indicated in claim 1 and R as defined in claim 8 and optionally subsequently a separation of diastereoisomers may be performed.

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