WO2010049073A1 - 1,1,1-trifluoro-3-amino-3-heteroaryl-2-propanoles, a process for their production and their use as anti-inflammatory agents - Google Patents

Abstract

The present invention relates to the compounds of formula (I), processes for their production and their use as anti-inflammatory agents.

Description

1,1,1-Trifluoro-3-amino-3-heteroaryl-2-propanoles, A Process for Their Production and Their Use as Anti-inflammatory Agents

The present invention relates to compounds of formula I, a process for their production and their use as anti-inflammatory agents.

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 periods, led to the occurrence of undesired effects. A number of these effects, are severe and sometimes irreversible (Schacke et al., 2002 Pharmacol. & Therapeutics (2002) 96(1 ):23- 43, Miner et al., 2005 Expert Opin. Investig. Drugs (2005) 14(12):1527-1545) The GCs potently inhibit pro-inflammatory cytokines and chemokines at the site of administration, whereas they elicit only limited systemic effects

(O'Connell, 2003 CHn. Ther. (2003) 25(Suppl. C):C42-60; Welker et al. Int. Arch. Allergy Immunol. (1996) 109(2):110-115, 1996; Gϋnther et al., 1998. Skin Pharmacol. Appl. 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.

Therefore, there is a great medical need for new compounds that have anti-inflammatory / immunomodulatory activity similar to the marketed GCs, and superior physico chemical properties. Desired physico chemical properties for example are a good solubility and/or a suitable partition coefficient log P.

This object has been achieved by the compounds according to the claims.

From the prior art of WO 2008/006627, anti-inflammatory agents of the following general formula

are known.

The compounds of the present invention are different with regard to the substituent

which is now a heterocyclic group (R¹ in formula I)

The present invention therefore relates to compounds of general formula I

in which

R¹ is a group

in which

# denotes the point of attachment of the R¹ group via a single bond, X¹, X², X³, X⁴, X⁵ independently of one another are nitrogen, or a group C- R⁴ and the R¹ group contains a minimum of 1 and a maximum of 3 nitrogen atoms in the ring

in which R⁴ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, (Ci-C₅)-alkoxy, (Ci-C₅)-alkyl, (CrC₅)- halo-alkyl and COOR⁵,

in which R⁵ is selected from the group consisting of hydrogen and Ci-C₅-alkyl group,

R² means a monocyclic, or bicyclic, aromatic, partially aromatic, or non-aromatic ring system, which optionally contains 1-4 nitrogen atoms,

1-2 oxygen atoms and/or 1-2 sulfur atoms and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (CrC₅)-alkyl, partially fluorinated (CrC₅)- alkyl, (Ci-C₅)-perfluoroalkyl, (CrC₅)-alkoxy, (CrC₅)-alkylthio, COOR5, cyano or nitro,

R³ means a group selected from

-(CrC₅)-alkyl, which may be optionally partially or completely halogenated,

-(C₂-C₅)-alkenyl -(C₂-C₅)-alkynyl,

R⁶-(CrC₅)-alkyl,

R⁶-(C₂-C₅)-alkenyl,

R⁶-(C₂-C₅)-alkynyl,

-S-(CrC₅)-alkyl, -SO-(Ci-C₅)-alkyl,

-SO₂-(Ci-C₅)-alkyl

-S-R⁶,

-SO-R⁶,

-SO₂-R⁶, -CN,

-Hal, -NR⁷R⁸, -OH,

-O-Cd-CsJ-alkyl or -O-R⁶, in which R⁶ means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (d-CsJ-alkyl, (Ci-C₅)-alkoxy, cyano, CF₃, nitro, COO(Ci-C₅-alkyl) or C(O)OCH₂-phenyl or a heteroaryl group whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, and in which R⁷ and R⁸, independently of one another, can be hydrogen, (Ci-C₅)-alkyl or (CO)-(Ci-C₅)-alkyl.

In another aspect the invention relates to compounds of general formula I in which

R¹ is a group

, in which

# denotes the point of attachment of the R¹ group via a single bond, and the R¹ group contains 1 or 2 nitrogen atoms in the ring,

X¹, X², X³, X⁴, X⁵ independently of one another are nitrogen, or a group C-R⁴

in which R⁴ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, (CrC₅)-alkoxy, (Ci-C₅)-alkyl, (d-CsJ-halo-alkyl and COOR⁵,

in which R⁵ is selected from the group consisting of hydrogen and Ci-C₅- alkyl group,

R² means a monocyclic or bicyclic, aromatic, partially aromatic, or non- aromatic ring system, which optionally contains 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (Ci-CsJ-alkyl, partially fluorinated (Ci-C₅)-alkyl, (Ci-C₅)- perfluoroalkyl, (d-CsJ-alkoxy, (Ci-C₅)-alkylthio or, cyano,

R³ means a group selected from -(Ci-CsJ-alkyl, which may be optionally partially or completely halogenated, -(C₂-C₅)-alkenyl R⁶-(Ci-C₅)-alkyl, R⁶-(C₂-C₅)-alkenyl, -S-(CrC₅)-alkyl,

-SO₂-(Ci-C₅)-alkyl, -SO₂-R⁶, -CN, -Hal, -NR⁷R⁸,

-OH, or -O-(CrC₅)-alkyl, in which R⁶ means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (Ci-C₅)-alkyl, (Ci-C₅)-alkoxy, cyano, CF₃, nitro, COOCd-Cs-alkyl) or C(O)OCH₂-phenyl or a heteroaryl group whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, and in which R⁷ and R⁸, independently of one another, can be hydrogen, (d-CsJ-alkyl or (CO)-(C_rC₅)-alkyl.

In another aspect the invention relates to compounds of general formula I in which

R is a group , in which # denotes the point of attachment of the R¹ group via a single bond, and the R¹ group contains 1 or 2 nitrogen atoms in the ring,

X¹, X², X³, X⁴, X⁵ independently of one another are nitrogen, or a group C- R⁴

in which R⁴ is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (Ci-C₅)-alkoxy, and (C-i-CsJ-alkyl,

R² means a monocyclic, or bicyclic, aromatic, partially aromatic, or non- aromatic ring system, which optionally contains 1-3 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (Ci-C₅)-alkyl, (Ci-C₅)-perfluoroalkyl or (Ci-C₅)-alkoxy,

R³ means a group selected from

-(Ci-C₅)-alkyl, which may be optionally partially or completely halogenated, -(C₂-C₅)-alkenyl,

-S-Cd-C^-alkyl, -SOa-tCrCsJ-alkyl, -CN, -Hal, -NR⁷R⁸ in which R⁷ and R⁸, independently of one another, can be hydrogen, (Ci-C₅)-alkyl or (COHCrCsJ-alkyl, -OH, or -O-Cd-CsJ-alkyl.

In another aspect the invention relates to compounds of general formula I according to the claims in which the R¹ group contains a minimum of 1 or 2 nitrogen atoms in the ring.

In another aspect the invention relates to compounds of general formula I according to the claims in which R³ means a group selected from -(C_rC₅)-alkyl, which may be optionally partially or completely halogenated, -(C₂-C₅)-alkenyl -(C₂-C₅)-alkynyl,

R⁶-(CrC₅)-alkyl,

R⁶-(C₂-C₅)-alkenyl,

R⁶-(C₂-C₅)-alkynyl, -S-(CrC₅)-alkyl,

-SO-td-CsJ-alkyl,

-SO₂-(CrC₅)-alkyl,

-S-R⁶,

-SO-R⁶, -SO₂-R⁶,

-CN,

-Hal,

-NR⁷R⁸,

-OH, -O-(Ci-C₅)-alkyl, or

-O-R⁶.

In another aspect the invention relates to compounds of general formula I

according to the claims in which R is a group

, in which # denotes the point of attachment of the R¹ group via a single bond, and the R¹ group contains 1 or 2 nitrogen atoms in the ring, and

R³ means a group selected from

-(Ci-C₅)-alkyl, which may be optionally partially or completely halogenated,

-(C₂-C₅)-alkenyl -(C₂-C₅)-alkynyl,

R⁶-(C₁-C₅)-alkyl,

R⁶-(C₂-C₅)-alkenyl,

R⁶-(C₂-C₅)-alkynyl,

-S-(Ci-C₅)-alkyl, -SO-(Ci-C₅)-alkyl,

-SO₂-(C_rC₅)-alkyl, -S-R⁶,

-SO-R⁶,

-SO₂-R⁶,

-CN, -Hal,

-NR⁷R⁸,

-OH,

-O-(CrC₅)-alkyl, or

-O-R⁶, in which R⁶ means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (Ci-C₅)-alkyl, (d-C₅)-alkoxy, cyano, CF₃, nitro,

COO(Ci-C₅-alkyl) or C(O)OCH₂-phenyl or a heteroaryl group whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, in which R⁷ and R⁸, independently of one another, can be hydrogen, (Ci-C₅)-alkyl or (CO)-(CrC₅)-alkyl, and the other residues not mentioned above may be defined according to any of the claims.

Another object of the invention are compounds of general formula I, in which R² means an optionally substituted phthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydroquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1 ,7- or 1 ,8-naphthyridinyl, indolonyl, isoindolonyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole, coumarinyl, isocoumarinyl, pyrazolopyrimidinyl or indolyl group that is linked via any position. They are another object of the invention if these heterocyclic systems are substituted. They are another object of the invention if if they are substituted with 1 to 3 of the same or different radicals from the group (CrC₅)- alkyl, hydroxy, carbonyl or halogen, especially if they are substituted with methyl, chlorine or fluorine.

Another object of the invention are compounds of general formula I wherein R² means phenyl, naphthyl, quinolin-5-yl, phthalazinyl, quinazolinyl which can be optionally substituted independently with 1-3 radicals selected from the group carbonyl, (Ci-C₅)-alkyl, chlorine or fluorine. Preferably there is only one carbonyl group in R².

Another object of the invention are compounds of general formula I wherein R² means, quinolin-5-yl, phthalazinyl, quinazolinyl which can be optionally substituted independently with 1-3 radicals selected from the group carbonyl, (CrCsJ-alkyl, chlorine or fluorine.

Another object of the invention are compounds of general formula I wherein R² means phenyl, naphthyl, quinolin-5-yl, phthalazinyl, quinazolinyl which can be optionally substituted independently one or two times by carbonyl, methyl or halogen.

Another object of the invention are compounds of general formula I wherein R² means quinolin-5-yl, which can be substituted independently one or two times by carbonyl, methyl or fluorine.

One group of compounds of general formula I is that in which R² is a heterocycle containing one or more nitrogen atoms , such as pyridine, pyrimidine, indolizine, indol or isoindol, pyrazole, imidazole, triazole, quinoline, isoquinoline, cinnoline, phthalazine, or quinazoline. Another group of compounds of general formula I is that in which R² is an oxygen containing heterocycle, such as coumaron (benzofurane) or chromane. A further group of compounds of general formula I is that in which R² is a heterocycle, containing two or more different heteroatoms, such as thiazole, isothiazole, oxazole or benzothiazole.

R² can be substituted in one or more positions with a radical selected from the group carbonyl, halogen, hydroxy, (Ci-C₅)-alkyl, (d-C₅)-alkoxy, (Ci-C₅)- alkylthio, (Ci-C₅)-perfluoroalkyl, cyano, nitro, COOR⁵, NR⁷R⁸ ,(CO)NR⁷R⁸ or a (Ci-C₅-alkylene)-O-(CO)-(Ci.C₅)alkyl group, preferably hydroxy, halogen, or carbonyl; preferably with methyl, chlorine or fluorine. The substituents can be the same or different.

The substituent carbonyl for a group R² is to be defined such that the carbonyl carbon atom is a ring carbon atom, to which an oxygen atom is double-bound. Compounds of general formula I, in which radical R² is substituted with none, one or several of the same or different radicals from the group (CrC₅)-alkyl, (C-i-CsJ-alkoxy, hydroxy, halogen, or carbonyl, preferably with none or one or several of the same or different radicals from the group (Ci-CsJ-alkyl, hydroxy, carbonyl or halogen, in particular by one or more of the same or different radicals from the group methyl, chlorine or fluorine, especially by methyl, chlorine or fluorine, are an object of the invention.

Optionally the nitrogen atom of radical R² of general claim 1 (such as in in the indazole, quinolone, isoquinolone and phthalazine) can also be alkylated with a (Ci-C₅)-alkyl group.

Compounds of general formula I, in which R² means a monocyclic 5- or 6- membered heterocyclic ring system that is linked via any position, such as, e.g., furan or thiophene, are another object of the invention.

Compounds of general formula I, in which R² means an substituted phenyl ring or an substituted naphthyl ring are another object of the invention.

Most preferred embodiments are those wherein:

I) at least one of the substituents for rings contained in R¹ is selected from methoxy or fluoro,

II) R² is quinolin-5-yl which can be substituted independently one or two times by carbonyl, methyl or fluoro,

III) R³ is selected from methylsulfanyl, ethylsulfanyl, dimethylamino, hydroxy, methoxy, ethoxy,

and all subcombinations of l-lll.

One aspect of the invention are compounds of formula I Structure

5-{[2-({Ethylsulfanyl}methyl-1-(6-methoxypyridin-3-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-1H-quinolin-2-one 5-{[3,3,3-Trifluoro-2-hydroxy-2-(methoxymethyl)-1-(6- methoxypyridin-3-yl)-propyl]amino}-1 H-quinolin-2-one 5-{[2-(Ethoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-(6-methoxypyridin- 3-yl)propyl]amino}-1 H-quinolin-2-one 5-{[3,3,3-Trifluoro-2-hydroxy-2-(hydroxymethyl)-1-(6- methoxypyridin-3-yl)-propyl]amino}-1 H-quinolin-2-one 1 ,1 ,1 -Trifluoro-2-(methoxymethyl)-3-(6-methoxypyridin-3-yl)-3-(2- methylquinolin-5-amino)propan-2-ol

2-(Ethoxymethyl)-1 ,1 ,1 -trifluoro-3-(6-methoxypyridin-3-yl)-3-(2- methylquinolin-5-amino)propan-2-ol

2-[(Ethylsulfanyl)methyl]-1 ,1 ,1-trifluoro-3-(6-methoxypyridin-3-yl)-3- (2-methylquinolin-5-amino)propan-2-ol 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-{[2-({Ethylsulfanyl}methyl-1-(2-methoxypyridin-4-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one 7-Fluoro-5-{[2-methoxymethyl-1-(2-methoxypyridin-4-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-one 5-{[2-Ethoxymethyl-1-(2-methoxypyridin-4-yl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one 7-Fluoro-5-{[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-1-(2- methoxypyridin-4-yl)propyl]amino}-1H-quinolin-2-one 5-{[2-({Dimethylamino}methyl)-1-(6-methoxypyridin-3-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-one 5-{[1 -(2-Methoxypy rim id i n-3-yl))-3, 3 , 3-trif I uoro-2-hyd roxy-2- (methoxymethyl)propyl]amino}-1 H-quinolin-2-one 5-{[1-(6-Fluoropyridin-3-yl))-3,3,3-trifluoro-2-hydroxy-2- (ethoxymethyl)propyl]amino}-1 H-quinolin-2-one 5-{[1-((2-Fluoropyridin-4-yl))-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl]amino}-1 H-quinolin-2-one and/or their salts, solvates or salts of solvates. In addition, the invention relates to the use of the 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.

Definitions:

Unless otherwise notifed the term "alkyl" refers to a straight or branched, substituted or unsubstituted chain. For example, the term propyl comprises "- propyl and ^/so-propyl, the term butyl comprises "-butyl, ^/so-butyl and ^fert-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. One aspect are (C₁- C₅)alkyl groups. A methyl or ethyl group is preferred. They can optionally be substituted by 1-3 hydroxy groups, cyano groups, halogen, 1-3 Ci-Cs-alkoxy groups, and/or 1-3 COO(Ci-C₁₀-alkyl or benzyl) 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 number of substituents to e.g. perfluorated alkyl groups.

For a partially or completely fluorinated CrCs-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 group or the pentafluoroethyl group is preferred.

The CrC₅-alkoxy groups 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 CrC₅-alkyl groups, cyano groups or halogen

The Ci-C₅-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.

The term halogen atom, Hal or halogen means a fluorine, chlorine, bromine or iodine atom. Preferred is a fluorine, chlorine or bromine atom.

The term "haloalkyl" is to be understood as preferably meaning branched and unbranched alkyl, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen. Particularly preferably, said haloalkyl is, e.g. chloromethyl, fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof.

The NR⁷R⁸ group includes, for example, NH₂, N(H)CH₃, N(CH₃)₂, N(H)(CO)CH₃, N(CH₃)(CO)CH₃, N[(CO)CH₃]₂.

The term C₂-C₅-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 (AIIyI), 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 alkenylene such as e.g. vinylene, propen-1- ylene, propen-2-ylene (Allylen), 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 C₂-C₅-alkynyl stands for a straight or branched chain e,g, -C≡CH, -CH₂-C=CH, -C=C-CH₃, -CH(CH₃)-C≡CH, -C=C-CH₂(CH₃), -C(CH₃)₂-C≡CH, -C≡C-CH(CH₃)₂, -CH(CH₃)-C≡C-CH₃, , -CH₂-C≡C-CH₂(CH₃) 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-CH₂-, -CH(CH₃)-C≡C- , -C=C-CH(CH₃)-, -C(CH₃)₂-C≡C-, -CsC-C-(CH₃J₂-, -CH(CH₃)-C≡C-CH₂-, -CH₂-C=C-CH (CH₃)-.

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 ring atom.

The heterocyclyl group may be substituted by Ci-Cs-alkyl (optionally substituted), hydroxy-, C_rC₅-alkoxy-, NR⁷R⁸-, halogen, cyano-, COOR⁵-, CHO-. If possible these substitutens may also be bound to one of the free nitrogen atoms if any. N-oxides are also included in the definition.

The term 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 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 stable molecule by one or several substitutents, e.g. 1-3 substitutents, such as e.g. hydroxy, halogen, Ci-C₅-alkyl, Ci-C₅-alkoxy, cyano, CF₃, nitro, COO(C₁-Cs- alkyl or benzyl) or a heteroaryl group, preferably by 1-3 Ci-C₅-alkyl groups, hydroxyl, halogen, cyano or Ci-C₅-alkoxy.

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

The term 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. Possible heteroaryl rings are e.g. thienyl, furanyl, 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, quinolyl, isoquinolyl, phthalidyl-, thiophthalidyl, indolonyl-, dihydroindolonyl-, isoindolonyl-, dihydroisoindolonyl-, benzofuranyl- or benzimidazolyl.

The term or "moncyclic or bicyclic, aromatic or partially aromatic or non- aromatic ring system which optionally contains 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms" includes the definitions of aryl, heteroaryl and heterocyclyl. The preferred number of heteroatoms is 1-5, more preferred 1-3. As for one aspect the heteroatoms are 1-2 nitrogen atoms. For the purposes of the term "partially aromatic or non-aromatic" the ring systems are to be understood as the ring systems as disclosed under the definitions for these three terms having a partially or completely hydrogenated ring and in case of bicyclic systems one or two rings being partially or completely hydrogenated. Should the substituents exemplified under the definition section differ from the group as defined in the claims both groups are one aspect of the invention, preferred the group as shown in the claims.

The substituent carbonyl for a group R² is to be defined such that the carbonyl carbon atom is a ring carbon atom, which is bound to an oxygen atom via a double bond.

Generally as substituents for R² are preferred halogen or carbonyl.

The term "partially aromatic ring system", refers to bicyclic systems that contain an aromatic ring and a non-aromatic ring, such as, e.g., benzoxazinones or dihydroindolone.

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 formula I. In one aspect of the invention therefore all these enantiomers, diastereoisomers or mixtures thereof are encompassed. The isolation of enantiomerically or diastereomerically pure isomers can be done by methods of the state 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 forms these are also an aspect of the present invention.

In one aspect of the invention all compounds defined in formula I as well as their salts, solvates and solvates of salts are encompassed, especially the salts, solvates and salts of solvates of the compounds disclosed in the examples are one 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 isolation or purification.

The term physiologically unobjectable 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, toluolsulfonic acid, benzenesulfonic acid, naphthalinesulfonic acid, acetic acid, 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 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 present combinations which build complexes by coordination of solvent molecules in a liquid or a solid phase. Hydrates are special forms of a solvate wherein water molecules are coordinated. The compounds can be produced by the various processes that are described below (a-b). a)

(H) (III)

(III) (IV)

(IV) (V)

(V) (I) Ketones of the general formula (II) can be aminated under use of LDA (=Lithiumdiisopropylamid ) or (L)- or (D)-proline catalysis at the α-position with azadicarboxylates (B. List, J.Am.Chem.Soc. 2002, 124, 5656-5657; N. Kumaragurubaran et al. J.Am.Chem.Soc. 2002, 124,6254-6255). The hydrazino ketones of formula (III) can be reacted with Grignard, organo-lithium reagents or organo-indium reagents of type R³-CH₂-Met to yield hydrazino alcohols of type (IV). Catalytic hydrogenation reduces the hydrazino carboxylates (IV) to amines of type (V) which can be substrates for aromatic amination with arylhalogens R²HaI under copper, nickel or palladium catalysis to yield compound (I). ( F.Y.Kwong, S.L. Buchwald, Org. Lett. 2003, 5, 793- 796; C.Desmarets, R. Schneider, Y. Fort, J.Org. Chem. 2002, 67, 3029-3036; S.R. Stauffer, S. Le, JP. Stambuli, S.I. Hauck, J. F. Hartwig, Org. Lett. 2000 2, 1423-1426; Nat.Prot. 2007, 2, 2881-2887)

In the formulae provided above Cbz has the meaning of a Carboxybenzyl group.

b)

*

(Vl) (VII)

(VII) (IX)

(IX) (I)

In b) described aldehydes of type (Vl) are treated with amines of type R₂-NH₂ to yield imines of type (VII). lmines of type (VII) are treated at low temperatures of -80°to -100⁰C with the lithiated epoxide (VIII) to yield compounds of type (IX). The epoxides (IX) can be opened by nucleophils of type R³-Met to deliver compound (I). Possible nucleophiles are alkylcuprates, vinylcuprates, thioles, allylsilanes, vinylsilanes, vinylstannanes, grignard compounds, in the presence of Lewis acids like BF₃ or AIMe₃, AICI₃, cyanides, amines, alcoholes and thioalcoholes.

This process described above can be performed enantioselectively by use of enantio pure epoxides of formula (VIII) to yield enantiopure compounds of formula (IX) and (I). (Y.Yamauchi, T. Katagiri, K. Uneyama, Org. Lett. 2002, 4, 173-176)

A further object of the invention are compounds of general formulae V, VII and IX,

(V) (VII) (IX)

in which R¹, R² and R³ have the meanings described in the claims, especially the intermediates used in the examples, and their use for the manufacture of compounds If the various compounds according to the invention are present as racemic mixtures, they can be separated into pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the 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 esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereoisomeric esters that are obtained by 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.

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. In comparison to reference substance [³H]- dexamethasone, the substances show a high to very high affinity to GR. IC₅₀(GR) = 76 nM and IC₅o(GR) = 26 nM was thus measured for the compound from examples 7 and 8 respectively.

As an molecular mechanism for the anti-inflammatory action of 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 (for a survey, see Cato, A. C. B., and Wade, E., BioEssays 18, 371-378, 1996).

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 Example 1 showed an inhibition IC₅o(IL8) = 112 nmol with efficacy of 36% in comparison with dexamethasone as reference. 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 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 inflammation parameters both after topical administration and after systemic administration.

The compounds of general formula I possess superior physico chemical properties. The compounds described in Examples 4 and 8 for example showed a water solubility of 136 mg per liter. For the compounds of Examples 4 and 8 a low partition coefficient log P of 0.5 and 1.8, respectively, was determined.

Methods for the determination of the solubility and log P values, which are to be preferred in the context of the present invention, are described below.

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 [Glucocorticoids: Immunological 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 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 homogenate. In this test, at doses in which they have an anti-inflammatory action, the compounds of general formula I induce little or no tyrosinamino transferase.

Because of their anti-inflammatory and, in addition, anti-allergic, immunosuppressive and antiproliferative action, the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans: In this case, the term "DISEASE" stands for the following indications: (i) Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes:

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

- Bronchitis of different origins - Adult respiratory distress syndrome (ARDS), acute respiratory distress syndrome

- Bronchiectases

- All forms of restrictive lung diseases, primarily allergic alveolitis,

- All forms of pulmonary edema, primarily toxic pulmonary edema; e.g., radiogenic pneumonitis

- Sarcoidoses and granulomatoses, especially Boeck's disease

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

- All forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, Behget's disease

- Reactive arthritis

- Inflammatory soft-tissue diseases of other origins

- Arthritic symptoms in the case of degenerative joint diseases (arthroses) - Traumatic arthritides

- Vitiligo - Collagenoses of any origin, e.g., systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, Sjogren's syndrome, Still's syndrome, Felty's syndrome

- Sarcoidoses and granulomatoses - Soft-tissue rheumatism

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

- All forms of allergic reactions, e.g., Quincke's edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular diseases

- Allergic vasculitis

(iv) Vascular inflammations (vasculitides)

- Panarteritis nodosa, temporal arteritis, erythema nodosum - Polyarteris nodosa

- Wegner's granulomatosis

- Giant-cell arteritis

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

- 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 - 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)

- Seborrheal eczema

- Rosacea group

- Erythema exudativum multiforme - Balanitis

- Vulvitis

- Manifestation of vascular diseases

- Hair loss such as alopecia areata

- Cutaneous lymphoma

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

- Nephrotic syndrome

- All nephritides, e.g., glomerulonephritis

(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

- Chronic aggressive hepatitis and/or chronic intermittent hepatitis

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

- Regional enteritis (Crohn's disease)

- Colitis ulcerosa

- Gastritis - Reflux esophagitis

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

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

- Anal eczema - Fissures

- Hemorrhoids

- Idiopathic proctitis

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

- Allergic keratitis, uveitis, iritis

- Conjunctivitis

- Blepharitis

- Optic neuritis - Chorioiditis

- Sympathetic ophthalmia

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

- Allergic rhinitis, hay fever - Otitis externa, e.g., caused by contact dermatitis, infection, etc.

- Otitis media

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

- Cerebral edema, primarily tumor-induced cerebral edema - Multiple sclerosis

- Acute encephalomyelitis

- Meningitis

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

- Acute spinal cord injury - Stroke

(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

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

- Acute lymphatic leukemia - Malignant lymphoma

- Lymphogranulomatoses

- Lymphosarcoma

- Extensive metastases, mainly in breast, bronchial and prostate cancers

(xv) Endocrine diseases, which coincide with inflammatory, allergic and/or proliferative processes, such as, e.g.:

- Endocrine orbitopathy

- Thyreotoxic crisis

- De Quervain's thyroiditis - Hashimoto's thyroiditis

- Basedow's disease

- Granulomatous thyroiditis

- Lymphadenoid goiter

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

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

(xviii) Substitution therapy in:

- Innate primary suprarenal insufficiency, e.g., congenital adrenogenital syndrome - Acquired primary suprarenal insufficiency, e.g., Addison's disease, autoimmune adrenalitis, meta-infective tumors, metastases, etc.

- Innate secondary suprarenal insufficiency, e.g., congenital hypopituitarism - Acquired secondary suprarenal insufficiency, e.g., meta-infective tumors, etc.

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

- 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 transluminal angioplasty, Alzheimer's disease, 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.

Without prejudice to the foregoing, the compounds of formula (I) can also be used to treat disorders such as: Conies Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's Syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, oesophageal varicies, muscle weakness, increased melanin pigmentation of the skin, weight loss, hypotension, hypoglycemia, Cushing's Syndrome, obesity, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, tissue rejection associated with organ transplant, malignancies such as leukemias and lymphomas, rheumatic fever, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Thl/Th2 cytokine balance, chronic kidney disease, hypercalcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, Little's syndrome, systemic inflammation, inflammatory bowel disease, Wegener's granulomatosis, giant cell arthritis, osteoarthritis, angioneurotic edema, tendonitis, bursitis, autoimmune chronic active hepatitis, hepatitis, cinhosis, panniculitis, inflamed cysts, pyoderma gangrenosum, eosinophilic fasciitis, relapsing polychondritis, sarcoidosis Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, lichen planus, erythema nodosum acne, hirsutism, toxic epidermal necrolysis, erythema multiform, psychoses, cognitive disorders (such as memory disturbances) mood disorders (such as depression and bipolar disorder), anxiety disorders and personality disorders.

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).

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

For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose varies and depends on, for example, the active strength of the compound of general formula I, the host, the type of administration, and the type and severity 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 or mixture thereof for the production of a medication for treating a DISEASE; (ii) A process for treating a DISEASE, said process comprises an administration of an amount of the compound according to the invention, in which the amount suppresses the disease and in which the amount of 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 doses comprise a range of 1 μg to 100,000 μg of the compound according to the invention per kg of body weight. In the case of larger mammals, for example the human, a recommended daily dose lies in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg of body weight, and more preferred is a dose of 10 to 10,000 μg 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-mentioned 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 being processed with the vehicles that are commonly used in galenicals, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, coloring agents, etc., and converted into the desired form of administration. In this case, reference is made to Remington's Pharmaceutical Science, 15^th Edition, Mack Publishing Company, East Pennsylvania (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 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 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 tinctures in corresponding pharmaceutical 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.

The invention also comprises the compounds of general formula I according to the invention as therapeutic active ingredients.

In addition, the compounds of general formula I according to the invention are part of the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles.

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 also be formulated and/or administered in combination with other active inqredients. The invention further relates to combination therapies or compositions wherein a GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with one or more agents for the treatment of any of the above disease states.

For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD, asthma or allergic rhinitis a GR agonist of the invention can be combined with one or more agents for the treatment of such a condition. Where such a combination is to be administered by inhalation, then the one or more agents is selected from the list comprising:

• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;

• a selective β.sub2. adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;

• a muscarinic receptor antagonist (for example a M1 , M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;

• a modulator of chemokine receptor function (such as a CCR1 receptor antagonist);

• an inhibitor of p38 kinase function;

• an inhibitor of matrix metalloproteases, most preferably targeting MMP- 2, MMP-9 or MMP-12, or

• An inhibitor of neutrophil serine proteases, most preferably neutrophil elastase or proteinase 3.

In another aspect of the invention where such a combination is for the treatment of COPD, asthma or allergic rhinitis the GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, can be administered by inhalation or by the oral route and this is in combination with a xanthine (such as aminophylline or theophylline) which can be administered by inhalation or by the oral route.

Experimental Part:

Methods

1. Determination of the water solubility of a compound Solubility was determined by laser nephelometry. Laser nephelometry is the measurement of forward scattered light, when a laser beam is directed through a solution. The more particulate there is in the solution, the greater the amount of forward scattered light. The assay used 10 mM DMSO stock solutions in 96 well plate format, eight compounds per 96 well plate. The measured solubility assay ranged between 1 mg/L (L=liter) -150 mg/L approximately. Used instrumentation were a Hamilton STAR liquid handling system (Hamilton Robotics GmbH, Fraunhoferstr. 17, DE-82152 Martinsried), a Labsystems Nepheloskan Ascent nephelometer (Part of Thermo Fisher Scientific lnc.81 Wyman Street Waltham, MA 02454, USA) and in house developed evaluation software. 150 μl of a 10 mM DMSO stock solution was pipetted in a deep-well plate. The stock solution was diluted with DMSO to decreasing molarity across the plate resulting in a new micro titer plate (Greiner bio-one, PS, V-Form, Greiner Bio-One GmbH, Rosenkamper Strasse 6, DE-42719 Solingen-Wald) with eight concentrations: 10/5/2.5/1.25/0.625/0.313/0.156 and 0.078 mM. 261 μl phosphate buffer (9.71 g di-sodium hydrogenphosphate dihydrate and 1.65 g pottassium dihydrogen phosphate solved in 1 liter water) was transferred to a cliniplate (UB Thermo Electron Corporation, part of Thermo Fisher Scientific lnc.81 Wyman Street Waltham, MA 02454, USA) and 9 μl diluted DMSO stock was added. The concentration of DMSO cosolvent was kept constant at 3%. The cliniplates were read in the nephelometer. Raw data were processed using inhouse software "Solubility", which fits concentration versus measured nephelometric scan to an ideal curve for determination of solubility in the point of gradient change.

2. Determination of logP by HPLC

HPLC was performed on analytical columns packed with a commercially available solid phase containing long hydrocarbon chains (C₁₈) chemically bound onto silica. Compounds injected onto such a column move along it by partitioning between the mobile solvent phase and the hydrocarbon stationary phase. The compounds are retained in proportion to their hydrocarbon-water partition coefficient, with water-soluble compounds eluted first and oil-soluble compounds last. This enables the relationship between the retention time on a reverse-phase column and the n-octa no I/water partition coefficient to be established. The partition coefficient P is deduced from the capacity factor K, given by the expression

with tR as the retention time of the test substance and t₀ as the dead-time, i.e. the average time a solvent molecule needs to pass the column.

In order to correlate the measured capacity factor K of a compound with its P, a calibration graph was established. The following calibration compounds and their P values available from literature were used:

The calibration graph plots logK versus logP. The partition coefficients P of the test compound was obtained by interpolation of the calculated capacity factor K on the calibration graph.

Used Instrumentation were a Knick pH-Meter 766, a Waters Alliance HT 2790, DAD Waters 996, MS Micromass ZQ HPLC devices with a Spherisorb ODS 3 μm 4.6 x 60 mm HPLC column (Mobile phase: 1.54 g NH4OAc solved in 500 ml Water. Addition of 1500 ml MeOH, pH adjusted to pH 7.0 with cone. Acetic acid, Flow: 1 ml/min) and MassLynx V4.1 SCN562 software for HPLC (Waters GmbH, Helfmann-Park 10, DE-65760 Eschborn) and in house developed POW determination software for logP evaluation by interpolation of determined logK to logP. Stock solution of reference compounds were solved in methanol (s. table above). 100 μl of each stock solution and 450 μl methanol and 550 μl water are combined in a HPLC vial.

A stock solution of 7 mg formamide (dead time compound) solved in 10 ml methanol was prepared. 100 μl of this stock solution was mixed with 1250 μl methanol and 550 μl water.

Test compounds in 10 mM DMSO stock solutions were diluted 1 :10 with methanol/water 75:25. The following injection scheme was used: formamide, reference mixture, test compound, test compound, formamide, reference mixture (injection volume: formamide 5 μl, references 5 μl, test compounds 15 μl). Retention times of samples and references were analysed by HPLC with diode-array detection (200-400nm). MS was used as verification of compound identity. The logP value was calculated automatically by the POW determination software by interpolation of determined logK to logP.

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.

Example 1

5-(f2-αEthylsulfanyl)methyl-1-(6-methoxypyridin-3-yl)-3.3.3-trifluoro-2- hvdroxypropyllamino)-1/-/-quinolin-2-one

5-{[(6-methoxypyridin-3-yl){(2-trifluoromethyl}oxiran-2-yl)methyl]amino}-1H- quinolin-2-one To 2.45 g (15.3 mmol) 5-Amino-7-fluoro-1 H-quinolin-2-one and 2.0 g (14.6 mmol) 6-methoxypyridin-3-ylcarboxaldehyde in 58 ml toluene and15 ml DMSO were added 0.83 ml acetic acid and 11 ml titanium tert.-butoxide. The mixture was heated over 25 hours to 100⁰C and filtrated through a path of cellites after cooling and addition of water.

The solid residue was washed extensively with warm methanol, dichloromethan was added, the phases were separated and the aqueous layer was extracted with dichloromethan containing 10% methanol, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. The residue was two times azeotrophed with small portions of toluene to obtain 2.7 g crude 5-{[1-(6-methoxypyridin-3-yl)methylidene]amino}- 1/-/-quinolin-2-one. 0.6 g sodium hydride (55% in mineraloil, 12.6 mmol) were washed with dry THF and suspended together with 2.7 g (7.5 mmol) of 5-{[1 - (6-methoxypyridin-3-yl)methylidene]amino}-1/-/-quinolin-2-one in 80 ml THF. t- Butyldimethylsilyl chloride was added as solid and the mixture was stirred for 3.5 hours while it became a clear solution. In parallel 1.25 ml (14.5 mmol) 1 ,1 ,1-trifluoroepoxypropane in 32 ml THF and 9 ml hexane were cooled to - 100⁰C and 5.8 ml of a 2.5 M n-butyl lithium solution in hexane were added over 10 minutes while the temperature does not exceed -95°C. 10 Minutes after complete addition the previously prepared 1-{f-butyldimethylsilyl}-5-{[1-(6- methoxypyridin-3-yl)methylidene]amino}-1H-quinolin-2-one in 10 ml THF was added over 20 minutes while the temperature did not exceed -90⁰C. After tree hours at -100°C 10 ml diethyl ether were added and the reaction mixture was warmed to room temperature over night. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with dichloromethane, 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%) yielded 320 mg of 5-{[(6-methoxypyridine-3-yl)(2-tπfluoromethyl- oxiranyl)methyl]amino}-1/-/-quinolin-2-one.

¹H-NMR (CD₃OD); δ = 2.71 (dq, 1 H), 3.16 (d, 1 H), 3.87 (s, 3H), 5.29 (s, 1 H), 6.40 (d, 1 H), 6.50 (d, 1 H), 6.59 (d, 1 H), 6.77 (d, 1 H), 7.23 (t, 1 H), 7.80 (dd, 1 H), 8.22 (d, 1 H), 8.31 (d, 1 H).

To 45 mg (0.11 mmol) of 5-{[(6-methoxypyridine-3-yl)(2-trifluoromethyloxiran-2- yl)methyl]amino}-1H-quinolin-2-one and 75 mg caesium carbonate in 1 ml DMF were added 10.2 μl of ethyl mercaptan. The mixture was stirred vigorously for 16 hours and saturated ammonium chloride solution was added. The aqueous layer was 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 in hexane 66%) yielded 10 mg of the title compound.

¹H-NMR (CDCI₃); δ = 1.19 (t, 3H), 2.51 (q, 2H), 2.84 (d, 1 H), 2.94 (d, 1 H), 3.91 (s, 3H), 4.84 (d, 1 H), 5.85 (d, 1 H), 6.14 (d, 1 H), 6.62 (m, 2H), 6.71 (d, 1 H), 7.15 (t, 1 H), 7.67 (dd, 1 H), 7.93 (d, 1 H), 8.21 (d, 1 H).

Example 2

5-([3.3,3-Trifluoro-2-hvdroxy-2-(methoxymethyl)-1-(6-methoxypyridin-3-yl)- propyl]amino)-1 /-/-quinolin-2-one

45 mg (0.11 mmol) 5-{[(6-methoxypyridine-3-yl)(2-trifluoromethyloxiran-2- yl)methyl]amino}-1H-quinolin-2-one and 75 mg caesium carbonate were stirred in 1.1 ml methanol. After 18 hours saturated ammonium chloride solution is added and the aqueous phase is extracted with ethyl acetate. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate in hexane 66%) yielded 13 mg of the title compound. 1H-NMR (CDCI₃); δ = 3.47 (d, 1 H), 3.49 (s, 3H), 3.69 (d, 1 H), 3.90 (s, 3H), 4.97

(d, 1 H), 5.32 (br, 1 H), 6.18 (d, 1 H), 6.57 (m, 2H), 6.70 (d, 1 H), 7.14 (t, 1 H),

7.64 (d, 1 H) 7.87 (d, 1 H), 8.22 (d, 1 H).

Example 3

5-(r2-(Ethoxymethyl)-3.3,3-trifluoro-2-hvdroxy-1-(6-methoxypyridin-3- yl)propyllamino)-1/-/-quinolin-2-one

Analogously to example 2 the title compound can be prepared by treating 5- {[(6-methoxypyridine-3-yl)(2-trifluoromethyloxiran-2-yl)methyl]amino}-1/-/- quinolin-2-one with caesium carbonate in ethanol.

Example 4

5-(f3,3.3-Trifluoro-2-hvdroxy-2-(hvdroxymethyl)-1-(6-methoxypyridin-3-yl)- propyl]amino}-1 H-quinolin-2-one

45 mg (0.11 mmol) 5-{[(6-methoxypyridine-3-yl)(2-trifluoromethyloxiran-2- yl)methyl]amino}-1 /-/-quinolin-2-one were stirred with 110 μl perchloric acid (70%) in 0.97 ml DMF for 72 hours at 40⁰C. Saturated aqueous ammonium chloride solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (ethyl acetate in hexane 50% to 100% ) yielded 6 mg of the title compound. ¹H-NMR (CD₃OD); δ = 3.28 (d, 1 H), 3.84 (d, 1 H), 3.91 (s, 3H), 5.14 (s, 1 H), 6.32 (d, 1 H), 6.57 (d, 1 H), 6.63 (d, 1 H), 6.80 (d, 1 H), 7.24 (t, 1 H), 7.91(dd, 1 H), 8.22 (d, 1 H), 8.33 (d, 1 H).

Example 5

1.1.1 -Trifluoro-2-(methoxymethyl)-3-(6-methoxypyridin-3-yl)-3-(2- methvlquinolin-5-amino)propan-2-ol {[6-Methoxypyπdin-3-yl][2-(trifluoromethyl)oxiran-2-yl]methyl}-2-methylquinolin- 5-amine

To 2.31 g (14.6 mmol) 5-amino-2-methylquinolin and 2.0 g (13,6 mmol) 6- methoxypyridin-3-ylcarboxadehyde in 44 ml toluene were added 4.4 ml acetic acid and 14 ml titanium tert.-butoxide. The mixture was heated over 5 hours to 110⁰C then additional 4.4 ml acetic acid and 5 ml titanium tert.-butoxide were added. Heating was continued for 5 hours and the mixture was filtrated through a path of cellites after cooling. After removal of the solvent flash chromatography on silica gel (ethyl acetate in hexane 0 to 50% ) yielded 2.4 g of [(6-Methoxypyridin-3-yl)methylidene][2-methylquinolin-5-yl]amine. 0.89 ml (10.3 mmol) 1 ,1 ,1-trifluoroepoxypropane in 22 ml THF and 6.5 ml hexane were cooled to -100⁰C and 4.1 ml of a 1 ,6 M n-butyl lithium solution in hexane were added over 1 hour while the temperature did not exceed -90⁰C. 10 Minutes after complete addition 2.4 g (8.6 mmol) [(6-Methoxypyridin-3- yl)methylidene][2-methylquinolin-5-yl]amine in 82 ml THF were added over 30 minutes while the temperature did not exceed -90⁰C. After 3 hours at -100⁰C 7 ml diethyl ether were added and the reaction mixture was warmed to room temperature over one hour. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with dichloromethane, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 0 to 100%) yielded 1.6 g of {[6-methoxypyridin-3-yl][2-(trifluoromethyl)oxiran-2- yl]methyl}-2-methylquinolin-5-amine. 1H-NMR (CDCI₃); δ = 2.72 (s, 3H)₁ 2.79 (m, 1 H), 3.19 (d, 1 H), 3.92 (s, 3H), 5.02 (d, 1 H), 5.19 (d, 1 H), 6.39 (d, 1 H), 6.72 (d, 1 H), 7.28 (d, 1 H)₁ 7.36 (t, 1 H)₁ 7.42 (d, 1 H)₁ 7.57 (dd, 1 H), 8.15 (d, 1 H), 8.22 (d, 1 H). 100 mg (0.26 mmol) {[6-Methoxypyridin-3-yl][2-(trifluoromethyl)oxiran-2- yl]methyl}-2-methylquinolin-5-arnine were stirred with 142 mg (0.44 mmol) caesium carbonate in 2 ml methanol. After 18 hours saturated ammonium chloride solution was added and the aqueous phase was extracted with ethyl acetate. After removal of the solvent flash chromatography on silica gel (ethyl acetate in hexane 75%) yielded 29 mg of the title compound. ¹H-NMR (CDCI₃); δ = 2.71 (s, 3H), 3.51 (s, 3H), 3.54 (d, 1 H), 3.71 (d, 1 H), 3.90 (s, 3H), 4.99 (d, 1 H)₁ 6.02 (d, 1 H), 6.41 (d, 1 H)₁ 6.69 (d, 1 H)₁ 7.27 (d, 1 H)₁ 7.34 (t, 1 H), 7.40 (d, 1 H)₁ 7.64 (dd, 1 H)₁ 8.10 (d, 1 H)₁ 8.24 (d. 1 H).

Example 6

2-(Ethoxymethyl)-1 ,1 ,1-trifluoro-3-(6-methoxypyridin-3-yl)-3-(2-methylquinolin-

5-amino)propan-2-ol

100 mg (0.26 mmol) {[6-Methoxypyridin-3-yl][2-(trifluoromethyl)oxiran-2- yl]methyl}-2-methylquinolin-5-amine were stirred with 167 mg (0.51 mmol) caesium carbonate in ethanol. After 18 hours saturated ammonium chloride solution was added and the aqueous phase is extracted with ethyl acetate.

After removal of the solvent flash chromatography on silica gel (ethyl acetate in hexane 75%) yielded 31 mg of the title compound.

¹H-NMR (CDCI₃); δ = 1.39 (t, 3H)₁ 2.71 (s, 3H), 3.63 (d, 1 H), 3.66 (dq, 1 H)₁ 3.78 (d, 1 H), 3.90 (s, 3H), 5.00 (d, 1 H), 6.19 (d, 1 H)₁ 6.42 (d, 1 H)₁ 6.69 (d, 1 H)₁

7.27 (d, 1 H), 7.34 (t, 1 H)₁ 7.41 (d, 1 H), 7.63 (dd, 1 H), 8.12 (d, 1 H)₁ 8.23 (d,

1 H).

Example 7

2-r(Ethylsulfanvnmethvn-1.1.1-trifluoro-3-(6-methoxypyridin-3-yl)-3-(2- methylquinolin-5-amino)propan-2-ol

To 100 mg (0.26 mmol) {[6-Methoxypyridin-3-yl][2-(trifluoromethyl)oxiran-2- yl]methyl}-2-methylquinolin-5-amine and 167 mg (0.51 mmol) caesium carbonate in 1 ml DMF were added 28 μl (0.4 mmol) of ethyl mercaptan. The mixture was stirred vigorously for 16 hours and water was added. The aqueous layer was extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (ethyl acetate in hexane 0 to 75%) yielded 35 mg of the title compound.

> ¹H-NMR (CDCI₃); δ = 1.18 (t, 3H), 2.49 (q, 3H), 2.71 (s, 3H), 2.88 (d, 1 H), 3.02 (d, 1 H), 3.91 (s, 3H), 4.89 (d, 1 H), 5.79 (d, 1 H), 6.36 (d, 1 H), 6.70 (d, 1 H), 7.27 (d, 1 H), 7.36 (t, 1 H), 7.38 (d, 1 H), 7.67 (dd, 1 H), 8.17 (d, 1 H), 8.25 (d, 1 H).

Example 8

5-([1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3.3.3-thfluoro-2-hvdroxy-2-

(hvdroxymethyl)-propyHamino}-7-fluoro-1H-quinolin-2-one

200 mg (0.52 mmol) {[6-Methoxypyridin-3-yl][2-(trifluoromethyl)oxiran-2- yl]methyl}-2-methylquinolin-5-amine were stirred with 257 μl perchloric acid (70%) in 2.1 ml DMF at 40⁰C. The addition of 257 μl perchloric acid (70%) was repeated after 24 and 72 hours. After additional 48 hours saturated aqueous ammonium chloride solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (acetone in hexane 0% to 40% ) yielded 35 mg of the title compound.

¹H-NMR (CDCI₃); δ = 2.71 (s, 3H), 3.89 (d, 1 H), 3.90 (s, 3H), 3.94 (d, 1 H), 4.98 (br, 1 H), 6.25 (br, 1 H), 6.37 (d, 1 H), 6.68 (d, 1 H), 7.19 (d, 1 H), 7.33 (t, 1 H), 7.38 (d, 1 H), 7.71 (dd, 1 H), 8.14 (d, 1 H), 8.26 (d, 1 H).

The following examples can be prepared from 5-amino-2H-quinolin-1-ones or qinolines and pyridinylcarboxadehydes or pyrimidinylcarboxadehydes analogously:

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

5-{[1-(2-Methoxypyrimidin-3-yl))-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propyl]amino}-1 H-quinolin-2-one

5-{[ 1 -(6-Fluoropyrid i n-3-y l))-3, 3 , 3-trif luoro-2-hyd roxy-2- (ethoxymethyl)propyl]amino}-7/-/-quinolin-2-one

5-{[1-((2-Fluoropyridin-4-yl))-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl]amino}-tH-quinolin-2-one

Claims

Claims

1. Compounds of general formula I

in which

R¹ is a group

, in which

# denotes the point of attachment of the R¹ group via a single bond,

X¹, X², X³, X⁴, X⁵ independently of one another are nitrogen, or a group C- R⁴ and the R¹ group contains a minimum of 1 and a maximum of 3 nitrogen atoms in the ring

in which R⁴ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, (C-i-CsJ-alkoxy, (Ci-C₅)-alkyl, (Ci-C₅)-halo-alkyl and COOR⁵,

in which R⁵ is selected from the group consisting of hydrogen and Ci-C₅-alkyl group,

R² means a monocyclic, or bicyclic, aromatic, partially aromatic, or non-aromatic ring system, which optionally contains 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (Ci-C₅)- alkyl, partially fluorinated (C_rC₅)-alkyl, (C1-C5)-perfluoroalkyl, (Ci- C₅)-alkoxy, (d-C₅)-alkylthio, COOR⁵, cyano or nitro, R³ means a group selected from

-(Ci-C₅)-alkyl, which may be optionally partially or completely halogenated,

-(C₂-C₅)-alkenyl -(C₂-C₅)-alkynyl,

R⁶-(Ci-C₅)-alkyl,

R⁶-(C₂-C₅)-alkenyl,

R⁶-(C₂-C₅)-alkynyl,

-S-(CrC₅)-alkyl, -SO-(Ci-C₅)-alkyl,

-SO₂-(Ci-C₅)-alkyl,

-S-R⁶,

-SO-R⁶,

-SO₂-R⁶, -CN,

-Hal,

-NR⁷R⁸,

-OH,

-O-(Ci-C₅)-alkyl, or -O-R⁶, in which R⁶ means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (Ci-C₅)-alkyl, (Ci-C₅)-alkoxy, cyano, CF₃, nitro, COO(d-C₅-alkyl) or C(O)OCH₂-phenyl or a heteroaryl group, whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, and in which R⁷ and R⁸, independently of one another, can be hydrogen, (Ci-C₅)-alkyl or (COHCi-C₅)-alkyl,

2. Compounds of general formula I according to claim 1 , in which R is a group

, in which

# denotes the point of attachment of the R¹ group via a single bond, and the R¹ group contains 1 or 2 nitrogen atoms in the ring,

X¹, X², X³, X⁴, X⁵ independently of one another are nitrogen, or a group C- R⁴

in which R⁴ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, (Ci-C₅)-alkoxy, (d-CsJ-alkyl, (Ci- C₅)-halo-alkyl and COOR⁵,

in which R⁵ is selected from the group consisting of hydrogen and CrCs-alkyl group,

R² means a monocyclic, or bicyclic, aromatic, partially aromatic, or non-aromatic ring system, which optionally contains 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (Ci-C₅)-aIkyl, partially fluorinated (C_rC₅)-alkyl, (C₁-C₅)-perfluoroalkyl, (C_rC₅)- alkoxy, (CrC₅)-alkylthio or, cyano,

R³ means a group selected from

-(Ci-C₅)-alkyl, which may be optionally partially or completely halogenated,

-(C₂-C₅)-alkenyl,

R⁶-(Ci-C₅)-alkyl,

R⁶-(C₂-C₅)-alkenyl,

-S-Cd-CsJ-alkyl, -SO₂-(Ci-C₅)-alkyl,

-SO₂-R⁶,

-CN,

-Hal, -NR⁷R⁸ , -OH, or -O-(Ci-C₅)-alkyl,

in which R⁶ means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (C_rC₅)-alkyl, (Ci-C₅)- alkoxy, cyano, CF₃, nitro, COO(CrC₅-alkyl) or C(O)OCH₂-phenyl or a heteroaryl group, whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, and in which R⁷ and R⁸, independently of one another, can be hydrogen, (Ci-C₅)-alkyl or (CO)-(C_rC₅)-alkyl.

3. Compounds of general formula I according to claim 1 to 2, in which

R¹ is a group

, in which

# denotes the point of attachment of the R¹ group via a single bond, and the R¹ group contains 1 or 2 nitrogen atoms in the ring,

X¹, X², X³, X⁴, X⁵ independently of one another are nitrogen, or a group C- R⁴

in which R⁴ is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (Ci-C₅)-alkoxy, and (Ci-C₅)-alkyl,

R² means a monocyclic, or bicyclic, aromatic, partially aromatic, or non-aromatic ring system, which optionally contains 1-3 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom and optionally is substituted in one or more places by a radical that is selected from the group carbonyl, halogen, hydroxy, (Ci-C₅)-alkyl, (Ci-C₅)- perfluoroalkyl or (Ci-C₅)-alkoxy,

R³ means a group selected from

-(Ci-C₅)-alkyl, which may be optionally partially or completely halogenated,

-(C₂-C₅)-alkenyl, -S-(Ci-C₅)-alkyl, -Sθ2-(Ci-C₅)-alkyl, -CN, -Hal,

-NR⁷R⁸ in which R⁷ and R⁸, independently of one another, can be hydrogen, (CrC₅)-alkyl or (CO)-(Ci-C₅)-alkyl, -OH, or -O-(C₁-C₅)-alkyl,

4. Compounds of general formula I according to claim 1 to 3 selected from the list consisting of:

5-{[2-({Ethylsulfanyl}methyl-1-(6-methoxypyridin-3-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-one

5-{[3,3,3-Trifluoro-2-hydroxy-2-(methoxymethyl)-1-(6- methoxypyridin-3-yl)-propyl]amino}-1 H-quinolin-2-one

5-{[2-(Ethoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-(6-methoxypyridin-

3-yl)propyl]amino}-1 H-quinolin-2-one

5-{[3, 3 , 3-Trif luoro-2-hyd roxy-2-(hyd roxy methyl)- 1 -(6- methoxypyridin-3-yl)-propyl]amino}-1H-quinolin-2-one

1 ,1 ,1 -Trifluoro-2-(methoxymethyl)-3-(6-methoxypyridin-3-yl)-3-(2- methylquinolin-5-amino)propan-2-ol

2-(Ethoxymethyl)-1 ,1 ,1 -trifluoro-3-(6-methoxypyridin-3-yl)-3-(2- methylquinolin-5-amino)propan-2-ol

2-[(Ethylsulfanyl)methyl]-1 ,1 ,1-trifluoro-3-(6-methoxypyridin-3-yl)-3-

(2-methylquinolin-5-amino)propan-2-ol

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-{[2-({Ethylsulfanyl}methyl-1-(2-methoxypyridin-4-yl)-3,3,3- trifIuoro-2-hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one

7-Fluoro-5-{[2-methoxymethyl-1-(2-methoxypyridin-4-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-one

5-{[2-Ethoxymethyl-1-(2-methoxypyridin-4-yl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-7-fluoro-1 H-quinolin-2-one

7-Fluoro-5-{[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-1-(2- methoxypyridin-4-yl)propyl]amino}-1 H-quinolin-2-one

5-{[2-({Dimethylamino}methyl)-1-(6-methoxypyridin-3-yl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-1 H-quinolin-2-one

5-{[1-(2-Methoxypyrimidin-3-yl))-3,3,3-trifluoro-2-hydroxy-2-

(methoxymethyl)propyl]amino}-1 H-quinolin-2-one

5-{[1-(6-Fluoropyridin-3-yl))-3,3,3-trifluoro-2-hydroxy-2-

(ethoxymethyl)propyl]amino}-1 H-quinolin-2-one

5-{[1-((2-Fluoropyridin-4-yl))-3,3,3-trifluoro-2-hydroxy-2-

(hydroxymethyl)propyl]amino}-1 H-quinolin-2-one

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

6. Use of the compounds according to formula I of at least one of claims 1-4 for the manufacture of pharmaceutical agents for treating inflammatory diseases.

7. Process for the manufacture of compounds of general formula I, characterized in that amines of general formula V are reacted under aromatic amination conditions with arylhalogens of formula R²-Hal

(V) (D wherein R¹, R² and R³ have the meanings that are indicated in claim 1 and Hal has the meaning of iodine, bromine or chlorine.

8. Process for the manufacture of intermediates of general formula V, in a process for the manufacture of compounds of general formula I characterized in that ketones of general formula Il are reacted with azadicarboxylates under use of LDA or (L) or (D)-proline catalysis to compounds of formula III

(II) (III)

further reaction of compounds of formula III with Grignard, organo- lithium- or organo-indium reagents of formula R³-Met to yield hydrazino alcohols of formula (IV)

(III) (IV)

and subsequent catalytic hydrogenation of compound of formula IV to yield a compound of formula V

(IV) (V) wherein R¹, R² and R³ have the meanings that are indicated in claim 1 ,

Met has the meaning of Mg-HaI, Li, InR³HaI or InHa^, Hal has the meaning of chlorine, bromine or iodine and Cbz has the meaning of a Carboxybenzyl group.

9. Process for the manufacture of compounds of general formula I, characterized in that epoxides of general formula IX are reacted with compounds of general formula R3-Met

(IX) (I)

wherein R¹, R² and R³ have the meanings that are indicated in claim 1 and in which Met has the meaning of an alkalimetal e.g. caesium, potassium, sodium or lithium, alkaline earth metal such as e.g. magnesium and calcium, or aluminium, copper, silicon or tin (Sn).

10. Process for the manufacture of intermediates of general formula IX, in a process for the manufacture of compounds of general formula I characterized in that imines of general formula VII are reacted with epoxides of formula IX that have been reacted with organolithium (R⁹-Li) compounds at temperatures below -80⁰C to yield epoxides of formula X

(VII) (IX) wherein R¹ and R² have the meanings that are indicated in claim 1 and R⁹ has the meaning of a Ci-C₄-alkyl group.

11. Compounds of general formula V and IX

(V) (IX)

wherein R¹, R² and R³ have the meanings that are indicated in claim 1

12. Use of compounds of general formulae V and IX, according to at least one of claims 5-11 for the manufacture of a compound of general formula I.

13. A pharmaceutical composition comprising a compound or formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1-4, and a pharmaceutically acceptable adjuvant, diluent or carrier.

14. A compound or formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1-4 for use in therapy.

15. The use of a compound or formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1-4, in the manufacture of a medicament for use in the treatment of a glucocorticoid receptor mediated disease state.

16. A method of treating a 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.

17. A combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more agents selected from the list comprising:

• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;

• a selective β.sub2. adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;

• a muscarinic receptor antagonist (for example a M1 , M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;

• a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); or,

• an inhibitor of p38 kinase function.