HK1112243B - 5-substituted quinoline and isoquinoline derivatives, a method for the production thereof and their use as antiphlogistics - Google Patents

Description

5-substituted quinoline and isoquinoline derivatives, process for their preparation and their use as anti-inflammatory agents

The present invention relates to 5-substituted quinoline and isoquinoline derivatives, processes for their preparation and their use as anti-inflammatory agents.

Anti-inflammatory agents of the general formula (I) are known from the prior art document WO03/082827

Wherein Q-group includes quinoline and isoquinoline derivatives. In experiments, these compounds show anti-inflammatory effects without undesirable metabolic effects and are superior to or have at least comparable effects to the previously described non-steroidal glucocorticoids. Furthermore, these compounds have improved selectivity compared to other steroid receptors.

It has now been found quite surprisingly that the compounds of formulae (IIa) and (IIb) are particularly effective without side effects, preferably they are suitable for topical administration.

The invention therefore relates to compounds of the general formulae (IIa) and (IIb) and racemates or independently occurring stereoisomers thereof and optionally to their physiologically compatible salts or prodrugs thereof,

wherein

R¹And R²Can be independently of one another a hydrogen atom, C_1-3Alkyl, halogen atom, cyano, C_1-3Alkoxy or hydroxy.

The designation halogen atom or halogen denotes a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine atoms are preferred.

Said C is₁-C₃Alkyl and said C₁-C₅Alkyl may be straight-chain or branched and represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl.

Methyl or ethyl is preferred.

Radical R¹And R²Preferably represents hydrogen, C_1-3Alkyl, halogen or hydroxy. Particularly preferred are hydrogen, methyl, chlorine and hydroxyl.

A particular subject of the invention is therefore compounds of the formulae IIa and IIb in which R is¹And R²Independently of one another preferably represent hydrogen, C_1-3Alkyl, halogen or hydroxy.

Wherein R is¹And R²Compounds of the formulae I and IIb which, independently of one another, represent hydrogen, methyl, chlorine or hydroxyl are particularly preferred.

A particular aspect of the invention is a compound of formula IIa.

The term "topical" includes any possible administration of the compounds according to the invention, which makes it possible for the active ingredient to penetrate directly at the site of action.

Because of the presence of asymmetric centers, the compounds of the general formulae (IIa) and (IIb) according to the invention can exist as different stereoisomers. Both the racemate and the independently present stereoisomers are subject matter of the present invention.

In particular, the independent stereoisomers of examples 1, 2, 3, 4, 5, 11 and 12, namely the (+) -enantiomer and the (-) -enantiomer, are particular subject matter of the present invention.

If the compounds according to the invention contain a hydroxyl group in the alpha-position to the quinolyl or isoquinolyl nitrogen atom, they are also distinguished by the presence of keto-enol tautomerism. According to the invention, even if, for example, only one of the two tautomeric forms is mentioned in the experimental part, both forms are part of the subject matter of the invention.

In particular, the subject of the invention is:

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -1-methylisoquinoline),

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinolin-1 (2H) -one,

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2, 6-dimethylquinoline,

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -6-chloro-2-methylquinoline,

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinoline,

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinoline,

5- [4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinolin-2 [1H ] -one,

6-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

8-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylisoquinoli-n-1 (2H) -one, and its individual enantiomers:

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline),

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -1-methylisoquinoline,

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinolin-1 (2H) -one,

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2, 6-dimethylquinoline,

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -6-chloro-2-methylquinoline,

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinoline,

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinoline,

2(R) -5- [4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinolin-2 [1H ] -one,

2(R) -6-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

2(R) -8-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

2(R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinolin-1 (2H) -one,

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline),

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -1-methylisoquinoline),

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinolin-1 (2H) -one,

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2, 6-dimethylquinoline,

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -6-chloro-2-methylquinoline,

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinoline,

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinoline,

2(S) -5- [4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinolin-2 [1H ] -one,

2(S) -6-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

2(S) -8-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline,

2(S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylisoquinol-1 (2H) -one.

Particularly preferred are 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline and its independently present enantiomers 2- (R) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline and 2- (S) -5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline Quinoline.

The processes used for the preparation of the compounds of WO98/54159, WO00/32584 and WO02/10143 may also be used for the preparation of the compounds according to the invention. For bonding the quinoline or isoquinoline group, which is a feature of the compounds according to the invention, the following method steps may be performed:

the title compounds (IIa) and (IIb) can be synthesized, for example, by reductive amination of compounds of formula (III) with 5-aminoquinoline or 5-aminoisoquinoline, where, for example, sodium borohydride or sodium cyanoborohydride is considered a reducing agent in the presence of an acid.

The synthesis of aldehydes starts, for example, from compound (IV) (WO0032584) and is carried out by the following method: cleavage of methyl ether, allylation of the resulting phenol (V), rearrangement of allyl ether (VI) to (VII), dihydroxylation and diol cleavage of the double bond and formation of lactitol (VIII), reduction of lactitol to diol (IX), ring closure to dihydrobenzofuran (X), reduction of the ester to alcohol (XI), which is finally oxidized to aldehyde (III).

The above ester is preferably ethyl ester, but may be-COOR³Esters of the type wherein R³Is represented by C₁-C₅An alkyl group.

A particular subject of the invention is the formation of compounds of the general formulae (IIa) and (IIb) by reaction of the aldehyde (III) with a 5-aminoquinoline derivative or a 5-aminoisoquinoline derivative under reductive amination conditions, optionally in two stages

Wherein R is¹And R²Have the meanings indicated in claim 1 for the compounds of the formulae IIa and IIb.

Another subject of the present invention is the preparation of the aldehyde (III), which can be obtained by: reduction of R, wherein R is used as chiral compound or as racemate, according to methods known to the person skilled in the art³Is represented by C₁-C₅Alkyl compounds of the general formula X, form alcohols (XI), which are subsequently oxidized according to methods also known to the person skilled in the art to form aldehydes, or the esters X are reduced directly in a simplified manner to aldehydes according to methods known to the person skilled in the art.

Another subject of the invention is a process for the preparation of compounds of the general formula X, which can be obtained by alkylation of 5-fluoro-2, 3-dihydrobenzofuran by Friedel-crafts, followed by enantiomeric separation.

Another method for preparing compounds of the formulae IIa and IIb is carried out as follows:

with the use of Lewis acid catalysts, e.g. TiCl₄、Ti(OR³)₄、TiCl₂(OR³)₂、TiBr₂(OR³)₂、PdCl₄、Pd(OR³)₄、PdCl₂(OR³)₂、PdBr₂(OR³)₂、ZnCl₂、ZnBr₂、AlCl₃、AlBr₃、AlEtCl₂、AlMe₂Cl, Cu salts such as Cu (OTf)₂、CuCl₂、CuBr₂、Yb(OTf)₃Chiral catalysts such as (BINOL)₂TiCl₂、(BINAP)₂TiCl₂、(BINOL)₂PdCl₂、(BINAP)₂PdCl₂、(BINOL)₂TiBr₂、(BINAP)₂TiBr₂、(BINOL)₂PdBr₂、(BINAP)₂PdBr₂Preferably FeCl₃Wherein R is³Is represented by C₁-C₅Alkyl, reacting isobutylene with trifluoroethylpyruvate to form 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester XII. Then, in another reaction step, the reaction product is reacted with 5-fluoro-2, 3-dihydrobenzofuran to obtain the compound of formula (X). The esters are reduced to the alcohol (XI) and subsequently oxidized to the aldehyde (III) or the esters (X) are reduced to the aldehyde (III) according to methods known to the person skilled in the art, giving the direct precursor aldehydes of the compounds of the formulae IIa and IIb, which can then be obtained by reacting the aldehyde (III) with the corresponding quinolinamine or isoquinolinamine under reductive amination conditions, as has been described in the prior art. In the stage of the ester (XII) or ester (X), enantiomeric separation can be carried out. Furthermore, the alcohols (XI) are suitable for enantiomeric separations. Then, the insertion of the chiral ester alone yields enantiomerically pure compounds of the general formulae IIa and IIb.

Another subject of the invention is the preparation of R wherein³Is represented by C₁-C₅Alkyl compounds of the general formula XII: isobutene is reacted with trifluoroalkyl pyruvate using a Lewis acid catalyst and the reaction product is separated into enantiomers.

As solvents for the reaction of isobutene with trifluoroethyl pyruvate, for example CH₂Cl₂Tetrahydrofuran, dioxane and diethyl ether are suitable.

A particular aspect of the present invention is the use of a chiral lewis acid catalyst for the process according to the present invention.

One aspect of the invention is that in any stage of the synthesis, enantiomeric separation is performed on a chiral phase using column chromatography. The isolation in the stage of the compounds of the formula IIa or IIb is a particular aspect of the present invention. The separation of the enantiomers in the stage of the esters XII or X is another important aspect of the invention.

Another aspect of the invention is the isolation of suitable racemic intermediate stages of synthesis using chiral auxiliary agents. The racemic intermediate stage can be converted either to diastereomeric salts with a chiral auxiliary, e.g., a base, or to diastereomers with a chiral auxiliary, followed by separation of the diastereomers. Then, the chiral auxiliary is cracked again and can be recovered.

Suitable chiral auxiliaries are known to the person skilled in the art and can be found, for example, in the book "chiral Auxiliaries and Ligands in asymmetry Synthesis", J.Seyden-Penne, WileyVerlag, New York (1995).

Suitable intermediate stages for the separation of the racemic intermediate stage are, for example:

a) all precursors having at least one alcohol functional group; in this connection, chiral acids are suitable as auxiliaries.

b) An aldehyde precursor, such as aldehyde (II), obtained after reduction of the ester to alcohol (XI) followed by oxidation to aldehyde (III), or reduction of ester (X) to aldehyde (III); furthermore, other ester precursors can optionally also be converted into aldehydes for enantiomeric separation. In this regard, the auxiliary is a chiral diol, which then forms a diastereomeric ketal, which can be separated and then cleaved again.

c) All acids which can optionally be obtained from the ester precursors by cleavage of the ester functions present or by oxidation of the compounds of the lower oxidation stage according to methods known to the person skilled in the art; chiral alcohols or chiral amines may be used as auxiliaries here.

d) All precursors containing ester functions can be converted into diastereomeric esters by re-esterification, which can then be worked up as described in c).

If the compounds according to the invention are present as racemic mixtures, they can be separated into the pure optically active forms by methods of racemate separation well known to the person skilled in the art. For example: the racemic mixture can be chromatographed on a suitable optically active support material (CHIRALPAKAD)) The pure isomers were isolated. Suitable precursors are compounds of the formulae III, IV, V, VI, VII, VIII, IX, X and XI.

It is also possible to esterify the free hydroxyl groups in the racemic compounds of the formulae (IIa) and (IIb) or suitable precursors with optically active acids and to separate the esters of the diastereomers obtained by fractional crystallization or chromatography and to saponify the esters separated in each case into the optically pure isomers. Mandelic acid, camphorsulfonic acid or tartaric acid may be used as the optically active acid. The adjuvant may optionally be recovered as known to those skilled in the art.

A particular subject of the invention is therefore a method as represented in one of the two alternatives described above, characterized in that: the diastereomer separation is carried out in any suitable stage by esterifying the alcohol function with a chiral acid, separating the diastereomer and saponifying, with or without recovery of the chiral auxiliary.

In the case where the compounds of the general formulae (IIa) and (IIb) are present as salts, they may be, for example: in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate salt.

A prodrug is defined as a compound that is optionally only slightly altered from the claimed compound, which belongs or does not belong to the claimed equivalent, and which is cleaved into the claimed compound by metabolism in an organism or by contact with an organism. The prodrugs are subjected to at least one biotransformation (biotransformation) step until the claimed compounds are released, which then exert their pharmacological effect.

The binding of the respective substances to the Glucocorticoid Receptor (GR) and to other steroid hormone receptors (mineralocorticoid receptor (MR), Progesterone Receptor (PR) and Androgen Receptor (AR)) was examined by means of the recombinantly produced receptors. Binding experiments were performed using extracts of Sf9 cells that had been infected with baculovirus containing coding sequences for the corresponding steroid hormone receptors. And a reference product³H]These materials show high to very high affinity for GR compared to dexamethasone.

Furthermore, the quinolines and isoquinolines of formulae (IIa) and (IIb) described herein show high selectivity for the glucocorticoid receptor.

GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors (pro-inflammatory factors) is considered to be an important molecular mechanism for the anti-inflammatory action of glucocorticoids. This inhibition occurs through GR interaction with other transcription factors such as AP-1 and NF-. kappa.B (for review see Cato, A.C.B. and Wade, E., BioEssays 18, 371-.

The compounds of the general formulae (IIa) and (IIb) according to the present invention inhibit the secretion of the cytokine IL-8 induced by Lipopolysaccharide (LPS) in the human monocyte cell line THP-1. The cytokine concentration in the supernatant was determined using a commercially available ELISA kit. (efficacy of dexamethasone 100%); EXAMPLE 1IC₅₀5.9nmol (74% efficacy); example 10, IC₅₀21nmol (86% efficacy); example 11, IC₅₀8.5nmol (61% efficacy); prednisolone, IC₅₀13nmol (96% efficacy).

Compounds of general formulae (IIa) and (IIb) were tested for their anti-inflammatory effect in animal experiments by testing croton oil-induced inflammation in rats and/or mice (j.exp.med. (1995)182, 99-108). For this purpose croton oil in ethanol solution was topically applied to the animal ears. The test substance is administered topically at the same time. After 16 to 24 hours, ear weight was measured as a measure of inflammatory edema, peroxidase activity was measured as a measure of granulocyte invasion, and elastase activity was measured as a measure of neutrophil invasion. In this test, the compounds of the general formulae (IIa) and (IIb) inhibit the three inflammatory parameters mentioned above after topical administration.

One of the most common undesirable effects of glucocorticoid therapy is the so-called "steroidal diabetes" [ see Hatz, h.j., glucoorticoide: immunologische grundagen, pharmakologic und therierichrine [ gluconociticoids: immunologicalcalcalcaines, Pharmacology and Therapy Guidelines]，WissenschaftlicheVerlagsgesellschaft mbH，Stuttgart，1998]. The reason for this is the stimulation of gluconeogenesis in the liver by the induction of the enzymes responsible for this and free amino acids produced by protein degradation (catabolic action of glucocorticoids). A key enzyme in catabolism in the liver is Tyrosine Aminotransferase (TAT). The activity of the enzyme in cell cultures derived from treated rat hepatoma cells can be determined photometrically. Cells were treated with test substances for 24 hours and then assayed for TAT activity. The compounds of general formulae (IIa) and (IIb) induced tyrosine aminotransferases in this test to a minor extent (efficacy of dexamethasone-100%); example 1, EC₅₀3.7nmol (93% efficacy); example 10, EC₅₀10nmol (92% efficacy); example 11, EC₅₀4.0nmol (86% efficacy); prednisolone, EC₅₀2.6nmol (103% efficacy).

Another undesirable effect, which is present especially after topical treatment, is the induction of skin atrophy, which leads to a loss of thickness, elasticity and finally to a loss of mechanical resistance of the skin. The possibility of the substance inducing skin atrophy can be determined in rats. The animals were treated topically at equivalent doses for 18 days with daily test substance. Using skin fold thickness measurements, the reduction in skin thickness over the treatment time can be tracked.

It caused a 65% reduction in skin thickness at a concentration of 0.01% (maximum anti-inflammatory effect achieved) compared to clobetasol propionate, and in example 1, only a 41% reduction (maximum anti-inflammatory effect achieved) was measurable at a concentration of 0.1%.

This advantage can also be seen with respect to the substance from application WO 03/082827; for example, the eumer of example 36 has induced a 60% reduction in skin thickness at a concentration of 0.06% (maximal anti-inflammatory effect).

Furthermore, based on the anti-inflammatory and antiallergic, immunosuppressive and antiproliferative effects of the compounds of general formulae (IIa) and (IIb) according to the invention, they are useful as medicaments for the treatment or prevention of the following pathological conditions in mammals and humans; in particular for topical administration:

in this case, the term "disease" represents the following indications:

(i) lung diseases with inflammatory, allergic and/or proliferative processes:

chronic obstructive pulmonary disease of any origin, mainly bronchial asthma

Bronchitis of different origins

Adult Respiratory Distress Syndrome (ARDS), acute respiratory distress syndrome

Bronchiectasis

Various forms of restrictive lung disease, mainly allergic alveolitis,

various forms of pulmonary edema, mainly toxic pulmonary edema; such as pneumonia caused by radiation

Sarcoidosis and granulomatosis, mainly Boeck's disease

(ii) Rheumatic/autoimmune/arthrosis with inflammatory, allergic and/or proliferative processes:

various forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica,Disease and disorder

Reactive arthritis

Inflammatory soft tissue diseases of other origin

Arthritic symptoms (arthrosis) in relation to degenerative joint diseases

Traumatic arthritis

Vitiligo

Collagen diseases of any origin, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, Still syndrome, Filler's syndrome

Sarcoidosis and granulomatosis

Rheumatism of soft tissues

(iii) Allergic or pseudoallergic diseases (pseudoalloergicdisease) with inflammatory and/or proliferative processes

Various forms of allergic reactions, such as Kunck edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents and the like, anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular diseases

-allergic vasculitis

(iv) Vasculitis (vasculitis)

Nodose arteritis, temporal arteritis, erythema nodosum

-Polyarteris nodosa

-Wegener granulomatosis

Giant cell arteritis

(v) Skin diseases with inflammatory, allergic and/or proliferative processes:

atopic dermatitis (mainly in children)

-all forms of eczema, such as: atopic eczema (mainly in children)

Rashes or skin diseases of any origin

Psoriasis and psoriasis-like

Pityriasis rubra pilaris

Red blotch caused by different harmful effects (noxae) such as radiation, chemicals, burns, etc

Bullous skin diseases, such as: such as autoimmune pemphigus vulgaris, bullous pemphigoid

Lichen disease

Pruritus (e.g. of allergic origin)

-seborrheic eczema

-rosacea

Exudative erythema multiforme

Balanitis (balanitis)

-vulvitis

The phenomenon of vascular disease

Alopecia such as alopecia areata

Cutaneous lymphocytoma

(vi) Renal disease with inflammatory, allergic and/or proliferative processes:

nephrotic syndrome

All nephritis, e.g. glomerulonephritis

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

acute hepatocyte lysis

Acute hepatitis of different origin, e.g. viral, toxic or drug-induced

Chronic obliterative and/or chronic intermittent hepatitis

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

crohn's disease

Ulcerative colitis

-gastritis

Reflux esophagitis

Ulcerative colitis of other origin, such as: congenital stomatitis diarrhea (native speue)

(ix) Rectal diseases with inflammatory, allergic and/or proliferative processes:

-eczema of the anus

Anal fissure

Piles-hemorrhoids

-idiopathic proctitis

(x) Ocular diseases associated with inflammatory, allergic and/or proliferative processes:

allergic keratitis, uveitis, iritis

Conjunctivitis

Blepharitis marginalis

Optic neuritis

Choroiditis (choroiditis)

Sympathetic ophthalmia

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

allergic rhinitis, hay fever

Otitis externa, such as: otitis externa caused by contact dermatitis and infection

Otitis media

(xii) Neuropathy with inflammatory, allergic, and/or proliferative processes:

cerebral edema, mainly tumor-induced cerebral edema

Multiple sclerosis

-acute encephalomyelitis

Meningitis

-various convulsive forms, such as: nodulation spasm of infant

Acute spinal cord injury

-stroke

(xiii) Hematological disorders accompanied by inflammatory, allergic and/or proliferative processes, such as: hodgkin's lymphoma or non-Hodgkin's lymphoma, thrombocythemia, erythrocytosis

Acquired hemolytic anemia

Idiopathic thrombocytopenia

(xiv) Neoplastic diseases accompanied by inflammatory, allergic and/or proliferative processes, such as: cancer or sarcoma

Acute lymphatic leukemia

-malignant lymphoma

-lymphogranulomatosis

-lymphosarcoma

Extensive metastasis, mainly in breast, bronchial and prostate cancer

(xv) Endocrine diseases accompanied by inflammatory, allergic and/or proliferative processes, such as:

endocrine orbital disease (Endocrine orbitopathy)

-thyroid toxicity crisis

-De Quervain thyroiditis

Hashimoto thyroiditis

-Beauveria disease

Granulomatous thyroiditis

Goiter lymphadenoids

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

(xvii) Severe states of shock, such as: anaphylactic shock, Systemic Inflammatory Response Syndrome (SIRS)

(xviii) Alternative treatment in the following conditions:

congenital primary adrenal insufficiency, such as: congenital adrenal genital syndrome

Acquired primary adrenal insufficiency, for example: addison's disease, autoimmune adrenalitis, post-infection tumors, metastases, etc

Congenital secondary adrenal insufficiency, such as: congenital hypofunction of the pituitary

Acquired secondary adrenal insufficiency, such as: tumor after infection, etc

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

combinations with 5-HT3 antagonists, e.g. in cytostatic-induced emesis

(xx) Pain of inflammatory origin, e.g. lumbago

(xxi) Other diseases in different stages, including type I diabetes (insulin-dependent diabetes mellitus), osteoarthritis, Guillain-Barr é syndrome, restenosis 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 granulocytic metastasis.

It is preferred to administer the compounds according to the invention or mixtures thereof topically for the treatment of the diseases listed under (i), (ii), (iii), (v), (viii), (ix), (x), (xi), (xv) and (xxi).

The invention also relates to a combination therapy or combined preparation, wherein a Glucocorticoid Receptor (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 simultaneously (optionally in the same composition) or sequentially with one or more drugs for the treatment of one of the above-mentioned diseases. For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, the GR agonists of the present invention may be combined with one or more agents for the treatment of this condition. When such a combination of a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof is administered by inhalation, the agent with which it is combined may be selected from the following list:

-PDE4 inhibitors, including inhibitors of the isoform PDE 4D;

-selectivity beta₂-adrenergic receptor agonists, such as: metaproterenol, isoproterenol, albuterol, salbutamol, formoterol, salmeterol, terbutaline, metaproterenol, bitolterol mesylate, pirbuterol, or indacaterol;

-muscarinic receptor antagonists (e.g. M1, M2 or M3 antagonists, e.g. more selective M3 antagonists), such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;

modulators of chemokine receptor function (e.g. CCR)¹Receptor antagonists); or

-inhibitors of p38 kinase function.

Furthermore, the compounds of the general formulae (IIa) and (IIb) according to the invention can be used for the Treatment or prophylaxis of further pathological states not mentioned above for which synthetic Glucocorticoids are currently used (see Hatz, H.J., Glucocorticoide: immunologic Grundling, Pharmakologue und Therapirichtiens [ Glucocorticoides: immunologic reasonable principles, Pharmacology and Treatment Guidelines ], Wissenschaftlich Verlagsgeselschaft [ Scientific Publishing Co. ], Stuttgart, 1998).

All of the previously mentioned indications (i) to (xx) are found in Hatz, h.j., glucoorticoide: immunologische grundagen, pharmakologic und therierichrine [ gluconociticoids: immunological Principles, Pharmacology and treatment guidelines ], Wissenschaftliche Verlagsgesellschaft mbH [ scientific publishing Co. ], Stuttgart, 1998, are described in more detail.

For therapeutic effect in the above-mentioned pathological conditions, the appropriate dosage varies and depends, for example, on the strength of activity of the compounds of the general formulae (IIa) and (IIb), the host, the type of administration, the type and severity of the condition to be treated, and whether it is used as a prophylactic or therapeutic agent.

The present invention relates to the use of a compound according to the invention for the preparation of a medicament.

Furthermore, the present invention provides:

(i) the use of one of the compounds of formulae (IIa) and (IIb) according to the invention or of mixtures thereof for the preparation of a medicament for the treatment of "diseases";

(ii) a method of treating a "disease" comprising administering an amount of a compound according to the invention, wherein said amount inhibits said disease and said amount of said compound is administered to a patient in need thereof;

(iii) a pharmaceutical composition for the treatment of a "disease" comprising one of the compounds according to the invention or a mixture thereof and at least one pharmaceutical auxiliary and/or carrier.

In particular, the treatment of inflammatory diseases with the compounds according to the invention is a subject of the present invention.

In general, satisfactory results in animals can be expected when the daily dose of the compounds of the invention comprises a range of from 1. mu.g/kg body weight to 100,000. mu.g/kg body weight. In the case of larger mammals, such as humans, a daily dose of 1. mu.g to 100,000. mu.g/kg body weight is recommended. The preferred dose is 10 to 30,000. mu.g/kg body weight, and the more preferred dose is 10 to 10,000. mu.g/kg body weight. For example: the dose is suitable for administration several times daily.

Pharmaceutical preparations based on these novel compounds are formulated in a manner known per se and are prepared by processing the active ingredient with the carriers, fillers, substances influencing decomposition, binders, wetting agents, lubricants, absorbents, diluents, flavoring agents, colorants and the like customarily used in galenic preparations and converting them into the desired administration form. In this case, reference is made to Remington's pharmaceutical Science, 15 th edition, Mack Publishing Company, EastPennsylvania (1980). Additives suitable for topical administration are particularly preferred.

For oral administration, tablets, coated tablets, capsules, pills, powders, granules, lozenges, suspensions, emulsions and solutions are particularly suitable.

For parenteral administration, injectable formulations are suitable.

For intra-articular injection, a correspondingly prepared crystal suspension may be used.

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

For rectal administration, the novel compounds can be used in systemic and topical treatments in the form of suppositories, capsules, solutions (e.g. in the form of enemas), ointments.

For pulmonary administration of the novel compounds, the novel compounds may be used in the form of aerosols and inhalants.

For topical administration to the eye, external auditory canal, middle ear, nasal cavity and paranasal sinuses, the novel compounds can be used in corresponding pharmaceutical preparations as drops, ointments and tinctures.

For topical administration, suitable formulations are gels, ointments, fatty ointments (fat), creams, pastes, powders, emulsions, solutions and suspensions. The dosage of the compounds of the general formulae (IIa) and (IIb) in these preparations should be from 0.01% to 20% in order to obtain a sufficient pharmacological effect.

The invention also comprises compounds of the general formulae (IIa) and (IIb) according to the invention as therapeutically active ingredients. Furthermore, the compounds of the general formulae (IIa) and (IIb) according to the invention are part of the present invention as therapeutically active ingredients together with pharmaceutically compatible and acceptable auxiliaries and carriers.

The invention also encompasses pharmaceutical compositions comprising one of the pharmaceutically active compounds according to the invention or a mixture thereof or a pharmaceutically compatible salt thereof and a pharmaceutically compatible salt or a pharmaceutically compatible auxiliary agent and carrier.

The following examples are intended to illustrate the invention in more detail, but are not intended to limit the invention. The synthesis of important precursors, which have not been disclosed in the experimental context, is already state of the art and can be obtained, for example, from WO98/54159 and WO02/10143, WO 03/082280 or WO 03/082827.

Experiment of

Example 1

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline

4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

A solution of ethyl 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate (WO00/32584) (10.83g, 30.74mmol) in dichloromethane (200ml) was mixed with a 1M boron tribromide-chloroform solution (60ml) while cooling in an ice bath and stirring at 2-4 ℃ for 3 hours. The batch was poured into ice with saturated NaHCO₃The solution was stirred for 30 minutes while cooling with ice. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. The combined organic extracts were washed with saturated NaCl solution and dried (Na)₂SO₄) And concentrated by evaporation in vacuo. The residue was subjected to column chromatography (silica gel) using hexane-ethyl acetate to give 5.36g of a product. The aqueous phase was extracted with ethyl acetate to give a further 4.0g of product.

¹H-NMR(300MHz，CDCl₃)；δ＝1.22(t，3H)，1.41(s，3H)，1.47(s，3H)，2.52(d，1H)，2.87(d，1H)，3.55(br.，1H)，3.76(dq，1H)，4.11(dq，1H)，5.01(s，1H)，6.59(dd，1H)，6.77(ddd，1H)，6.90(dd，1H)。

4- (2-allyloxy-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

Potassium carbonate (4.15g, 30mmol) and allyl bromide (2.16ml, 25mmol) were added to a solution of ethyl 4- (5-fluoro-2-hydroxyphenyl) -4-methyl-2-trifluoromethylpentanoate (5.36g, 15.84mmol) in DMF (50ml) while cooling with ice. After 2 hours at 2 ℃ and 2 hours at room temperature, the batch is poured onto ice-water and extracted with hexane-ether 2: 1. Drying (Na)₂SO₄) The combined organic extracts were concentrated by evaporation in vacuo. Silica gel column chromatography with hexane-ethyl acetate afforded 5.7g of product.

¹H-NMR(300MHz，CDCl₃)；δ＝1.18(t，3H)，1.39(s，3H)，1.45(s，3H)，2.54(d，1H)，2.91(d，1H)，3.48(br.，1H)，3.65(dq，1H)，4.09(dq，1H)，4.55(dt，2H)，5.31(dq，1H)，5.45(dq，1H)，6.09(ddt，1H)，6.76(dd，1H)，6.84(ddd，1H)，6.91(dd，1H)。

4- (3-allyl-5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

Ethyl 4- (2-allyloxy-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate (5.65g, 14.93mmol) was heated in a microwave for 10 min to 230 ℃. The reaction mixture was purified by silica gel column chromatography using hexane-ethyl acetate. 3.31g of product are obtained.

¹H-NMR(300MHz，CDCl₃)；δ＝1.23(t，3H)，1.40(s，3H)，1.45(s，3H)，2.60(d，1H)，2.78(d，1H)，3.37(d，2H)，3.49(br.，1H)，3.83(dq，1H)，4.14(dq，1H)，5.09(br.，1H)，5.23(dq，1H)，5.26(dq，1H)，5.99(ddt，1H)，6.72(dd，1H)，6.83(dd，1H)。

4- (5-fluoro-2-hydroxy-3- (2-hydroxyethyl) phenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

Ethyl 4- (3-allyl-5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate (4.9g, 12.95mmol) in acetone (214ml) and water (32ml) was mixed with N-methylmorpholine oxide-hydrate (1.75g, 12.95mmol) and 0.4ml of osmium tetroxide solution (2.5 wt% in t-butanol) while cooling with ice. After 30 minutes at 2 ℃ and 16 hours at room temperature, the batch is mixed with a further 0.3ml of osmium tetroxide solution and stirred for 3 days at room temperature. For work-up, the acetone was distilled off in a rotary evaporator, the residue was taken up in ethyl acetate (200ml) and water (150ml), and the phases were separated. The aqueous phase was extracted twice more with ethyl acetate, the combined ethyl acetate extracts were washed with saturated NaCl solution and dried (Na)₂SO₄) And concentrated by evaporation. Silica gel column chromatography with hexane-ethyl acetate afforded 5.27g of ethyl 4- (3- (2, 3-dihydroxypropyl) -5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate. The latter (5.2g, 12.6mmol) was stirred under nitrogen with sodium periodate (5.39, 25.2mmol) in THF (75ml) and water (12.5ml) for 24 h. The batch is concentrated by evaporation and the aqueous residue is extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried (Na)₂SO₄) And vacuum evaporating to concentrateAnd (4) shrinking. Silica gel column chromatography with hexane-ethyl acetate afforded 4.3g of ethyl 4- (5-fluoro-2-hydroxy-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate. 4.1g (10.78mmol) of this was dissolved in methanol (150ml), the solution was mixed portionwise with sodium borohydride (586mg, 15mmol) and stirred at room temperature for 30 minutes. The pH was adjusted to 7.5 with acetic acid and the reaction mixture was concentrated by evaporation. The residue was collected in ethyl acetate (200ml) and saturated NaHCO₃In solution (75ml), the phases were separated, the organic phase was washed with saturated NaCl solution and dried (Na)₂SO₄) And concentrated by evaporation in vacuo, whereby 4.01g of the product was cumulatively obtained.

¹H-NMR(300MHz，CDCl₃)；δ＝1.23(t，3H)，1.40(s，3H)，1.47(s，3H)，2.59(d，1H)，2.76-2.92(m，2H)，2.91(d，1H)，3.85(dq，1H)，3.98(m，2H)，4.05(dq，1H)，6.67(dd，1H)，6.81(dd，1H)。

4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

Ethyl 4- (5-fluoro-2-hydroxy-3- (2-hydroxyethyl) phenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate (3.90g, 10.2mmol), triphenylphosphine (3.14g, 12mmol) and triethylamine (2.1ml, 15mmol) were dissolved in acetonitrile (150ml), mixed with carbon tetrachloride (2ml) and stirred at room temperature under nitrogen for 3 days. The solvent was distilled off on a rotary evaporator, the residue was collected in ethyl acetate (200ml) and water (75ml), and the phases were separated. The ethyl acetate phase is separated, washed with saturated NaCl solution and dried (Na)₂SO₄) And concentrated by evaporation in vacuo. Silica gel column chromatography with hexane-ethyl acetate afforded 3.31g of product.

¹H-NMR(300MHz，CDCl₃)；δ＝1.21(t，3H)，1.35(s，3H)，1.40(s，3H)，2.43(d，1H)，2.74(d，1H)，3.15(m，2H)，3.56(br.，1H)，3.73(dq，1H)，4.13(dq，1H)，4.58(t，2H)，6.68(dd，1H)，6.77(dm，1H)。

4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -4-methyl-2-trifluoromethyl-1, 2-pentanediol

A solution of ethyl 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate (3.2g, 8.78mmol) in diethyl ether (150ml) was mixed with lithium aluminum hydride (683mg, 18 mmol) while cooling with ice, stirred at 2 ℃ for 1 hour, and stirred at room temperature for 6 hours. The batch was cooled to 3 ℃ and saturated HaHCO was added dropwise thereto₃The solution (1.5ml) was stirred at 3 ℃ for 30 minutes and at room temperature for 16 hours. The colorless precipitate was aspirated and washed with ether. The combined filtrate was concentrated by evaporation and purified by silica gel column chromatography using hexane-ethyl acetate. 2.65g of product are obtained cumulatively as a colorless crystalline solid.

¹H-NMR(300MHz，CDCl₃)；δ＝1.39(s，3H)，1.47(s，3H)，2.21(d，1H)，2.46(d，1H)，2.89(br.，1H)，3.17(t，2H)，3.41(dm，1H)，3.49(d，1H)，4.57(t，2H)，6.80(d，2H)。

4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde

Pyridine-sulfur trioxide complex (3.82g, 24mmol) was added to a solution of 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -4-methyl-2-trifluoromethyl-1, 2-pentanediol (2.61g, 8.1mmol), dimethyl sulfoxide (28.6ml) and triethylamine (5.6ml, 40mmol) in dichloromethane (85ml) under a nitrogen atmosphere. The batch was stirred at room temperature for 3 hours and reacted with saturated NH₄The Cl solutions (50ml) were mixed, stirred at room temperature for 30 minutes and diluted with ether (250 ml). The phases were separated and the aqueous phase was extracted with ether. The combined organic phases were washed with saturated NaCl solution and dried (Na)₂SO₄) And concentrated by evaporation in vacuo. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate to give 2.19g of a product.

¹H-NMR(300MHz，CDCl₃)；δ＝1.35(s，3H)，1.42(s，3H)，2.20(d，1H)，3.17(t，2H)，3.28(d，1H)，3.62(s，1H)，4.59(m，2H)，6.63(dd，1H)，6.81(dm，1H)，9.08(s，1H)。

2-methyl-5-nitroquinoline

2-methylquinoline (108.3ml, 0.80mol) was added dropwise to 65% nitric acid (61ml, 0.88mol) over 45 minutes at an internal temperature of 0-10 deg.C (dry ice cooled). After 1 hour, the precipitated nitrate was aspirated off and added in portions to concentrated sulfuric acid (240ml) at an internal temperature of 0-6 ℃. After 30 minutes, potassium nitrate (6g, 60mmol) was added thereto, and stirred at room temperature for 16 hours. The batch was slowly poured onto ice/water and the pH was adjusted to 1.5 with 40% NaOH (. about.500 ml). The precipitate was aspirated, the filtrate was basified with 25% ammonia (pH 10) and filtered. The filter residue was dissolved in hot methanol (500 ml). During cooling, the 8-nitro isomer crystallizes out. The mother liquor was concentrated by evaporation and purified by column chromatography on silica gel using hexane-ethyl acetate, whereby 53g of 2-methyl-5-nitroquinoline were cumulatively obtained.

¹H-NMR(300MHz，CDCl₃)；δ＝2.79(s，3H)，7.52(d，1H)，7.76(d，1H)，8.31(d，1H)，8.32(d，1H)，8.88(d，1H)。

5-amino-2-methylquinoline

2-methyl-5-nitroquinoline (25g 132.85mmol) and palladium on carbon (2.5g) in 8ml of glacial acetic acid were stirred under normal pressure under a hydrogen atmosphereAnd (4) hours. The catalyst was aspirated and washed with ethyl acetate. The combined filtrates were concentrated by evaporation. The residue was subjected to silica gel column chromatography using methylene chloride-acetone to give 10.6g of a product.

¹H-NMR(300MHz，CDCl₃)；δ＝2.72(s，3H)，4.15(br.，2H)，6.76(dd，1H)，7.23(d，1H)，7.43-7.50(m，2H)，8.06(d，1H)。

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene ] -2-methylquinoline

A mixture consisting of 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde (320mg, 1mmol) and 5-amino-2-methylquinoline (190mg, 1.2mmol) in acetic acid (2ml) was stirred at room temperature for 16 h, diluted with 10ml of toluene and heated in a water separator for 4 h. The batch was concentrated by evaporation, in which acetic acid was removed azeotropically with toluene. The residue was purified by silica gel column chromatography using hexane-ethyl acetate: 274mg of product are obtained in the form of colorless crystals.

¹H-NMR(300MHz，CDCl₃)；δ＝1.34(s，3H)，1.54(s，3H)，2.27(d，1H)，2.66(m，1H)，2.76(s，3H)，2.94(m，1H)，3.29(d，1H)，4.47(m，2H)，4.85(s，1H)，6.28(dm，1H)，6.51(d，1H)，6.61(dd，1H)，7.33(d，1H)，7.51(t，1H)，7.63(s，1H)，7.90(d，1H)，8.18(d，1H)。

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene amino group in methanol (15ml)]-2-methylquinoline (266mg, 0.58mmol) and sodium bicarbonate (250mg) were stirred at room temperature for 15 min. Sodium borohydride (152mg, 4mmol) was added in four portions over 24 hours. After completion of the reaction (TLC monitoring), the batch was mixed with saturated NaHCO₃The solutions (10ml) were mixed and concentrated by evaporation. The residue was collected in ethyl acetate (30ml) and water (20ml), and the phases were separated. The aqueous phase was extracted with ethyl acetate. Drying (Na)₂SO₄) The combined organic phases are concentrated by evaporation. Silica gel column chromatography with hexane-ethyl acetate afforded 200mg of product.

¹H-NMR(300MHz，CDCl₃)；δ＝1.43(s，3H)，1.54(s，3H)，2.29(d，1H)，2.68(d，1H)，2.71(s，3H)，2.92-3.19(m，3H)，3.34(dd，1H)，4.26(br.，1H)，4.52(m，2H)，6.09(dm，1H)，6.81(dm，1H)，6.87(dm，1H)，7.20(d，1H)，7.39-7.47(m，2H)，7.89(d，1H)。

Of the (+) and (-) isomers, chiral HPLC was usedThe enantiomers were separated by using a column of Chiralpak AD type 20 μ and the eluent hexane (0.1% diethylamine) -ethanol. First eluting (-) -enantiomer ([ alpha ])]_D(THF) -43.2 °, c ═ 1.45), and then the (+) -enantiomer (([ α ] was eluted]_D(THF)+42.8°，c＝1.53)。

Example 2

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -1-methylisoquinoline

In analogy to the procedure of example 1, 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde was converted with 5-amino-1-methylisoquinoline into 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene-amino ] -1-methylisoquinoline which was reduced to the product with sodium borohydride.

¹H-NMR(300MHz，CDCl₃)；δ＝1.43(s，3H)，1.55(s，3H)，2.29(d，1H)，2.69(d，1H)，2.90(s，3H)，2.90-3.20(m，4H)，3.33(br.，1H)，4.35(br.，1H)，4.53(m，2H)，6.26(d，1H)，6.80(dm，1H)，6.88(dm，1H)，7.29(t，1H)，7.35(d，1H)，7.48(d，2H)，8.32(d，1H)。

The enantiomers were separated by chiral HPLC (column: Chiralpak AD 20. mu. eluent: hexane-ethanol) to obtain first the (+) -enantiomer ([ alpha.. alpha. ]]_D(MeOH) +29.8 °, c ═ 0.54), and then (-) -enantiomer ([ α [. alpha. ]) was obtained]_D(MeOH)-29.4°，c＝0.55)。

Example 3

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinolin-1 (2H) -one

In analogy to example 1, 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde was converted with 5-aminoisoquinolin-2 (1H) -one into 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene ] isoquinolin-1 (2H) -one, which was reduced to the product with sodium borohydride.

¹H-NMR(300MHz，[D]₆-DMSO)；δ＝1.33(s，3H)，1.52(s，3H)，1.98(d，1H)，2.78(d，1H)，2.84-3.10(m，4H)，4.49(t，1H)，4.80(t，1H)，6.03(s，1H)，6.21(d，1H)，6.41(d，1H)，6.80-6.87(m，2H)，7.12-7.17(m，2H)，7.47(d，1H)，11.21(br.d，1H)。

The enantiomers were separated by chiral HPLC (column: Chiralpak AS 20. mu. eluent: hexane-ethanol) to obtain first the (+) -enantiomer ([ alpha. ] -enantiomer]_D(MeOH) +29.9 °, c ═ 0.92), and then (-) -enantiomer ([ α [. alpha. ]) was obtained]_D(MeOH)-28.4°，c＝0.94)。

Example 4

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2, 6-dimethylquinoline

In analogy to example 1, 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde was converted with 5-amino-2, 6-dimethylquinoline into 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene-amino ] -2, 6-dimethylquinoline, which was reduced to the product with sodium cyanoborohydride.

¹H-NMR(300MHz，CDCl₃)；δ＝1.34(s，3H)，1.57(s，3H)，2.22(d，1H)，2.31(s，3H)，2.45(d，1H)，2.66-2.76(m，1H)，2.74(s，3H)，2.83-3.00(m，2H)， 3.10(d，1H)，3.52(br.1H)，4.20(q，1H)，4.29(s，1H)，4.38(q，1H)，6.55(d，1H)，6.77(dm，1H)，7.22(d，1H)，7.42(d，1H)，7.68(d，1H)，7.94(d，1H)。

By using chiralityThe enantiomers were separated by HPLC (column: Chiralcel OJ 5. mu. eluent: hexane-ethanol) to obtain first the (+) -enantiomer ([ alpha. ]]_D(MeOH) +55.8 °, c ═ 0.94), and then (-) -enantiomer ([ α [. alpha. ]) was obtained]_D(MeOH)-52.1°，c＝0.99)。

Example 5

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -6-chloro-2-methylquinoline

In analogy to example 1, 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde was converted with 5-amino-6-chloro-2-methylquinoline into 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene-amino ] -6-chloro-2-methylquinoline, which was reduced to the product with sodium cyanoborohydride.

¹H-NMR(300MHz，CDCl₃)；δ＝1.34(s，3H)，1.57(s，3H)，2.22(d，1H)，2.53(d，1H)，2.75(s，3H)，2.72-2.83(m，1H)，2.89-3.02(m，2H)，3.16(dd，1H)，4.04(s，1H)，4.30(q，1H)，4.42(q，1H)，6.51(dm，1H)，6.73(dd，1H)，7.26(d，1H)，7.55(d，1H)，7.66(d，1H)，7.96(d，1H)。

Enantiomers were separated by chiral HPLC (column: Chiralcel OJ 20. mu. eluent: hexane-ethanol). The (+) -enantiomer ([ alpha ] is obtained first]_D(MeOH) +41.7 °, c ═ 0.88), and then (-) -enantiomer ([ α [. alpha. ]) was obtained]_D(MeOH)-39.8°，c＝0.99)。

Example 6

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] isoquinoline

In analogy to example 1, 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde was converted with 5-aminoisoquinoline into 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene ] isoquinoline and reduced with sodium borohydride to the product.

¹H-NMR(300MHz，CDCl₃)；δ＝1.43(s，3H)，1.55(s，3H)，2.30(d，1H)，2.71(d，1H)，2.92(m，1H)，3.07(m，1H)，3.17(dd，1H)，3.35(dd，1H)，4.35(br.t，1H)，4.49(q，1H)，4.55(q，1H)，6.27(m，1H)，6.78(dm，1H)，6.88(dm，1H)，7.36(m，2H)，7.40(d，1H)，8.45(d，1H)，9.13(s，1H)。

Example 7

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinoline

In analogy to example 1, 4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanal is converted with 5-aminoquinoline into 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylidene ] quinoline, which is reduced to the product with sodium borohydride.

¹H-NMR(300MHz，CDCl₃)；δ＝1.43(s，3H)，1.54(s，3H)，2.31(d，1H)，2.68(d，1H)，2.96(m，1H)，3.08(m，1H)，3.17(dd，1H)，3.35(dd，1H)，4.32(br.t，1H)，4.52(m，2H)，6.15(d，1H)，6.80(dm，1H)，6.88(dd，1H)，7.31(dd，1H)，7.45(t，1H)，7.53(d，1H)，7.98(d，1H)，8.86(dd，1H)。

Example 8

5- [4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] quinolin-2 [1H ] -one

The corresponding imine is prepared in analogy to example 1, starting from 250mg of 4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde and 124mg of 5-aminoquinolin-2 [1H ] -one. After reaction with sodium cyanoborohydride, the title compound is obtained.

¹H-NMR(CD₃OD)：δ＝1.38(s，3H)，1.60(s，3H)，2.74-2.88(m，1H)，2.94-3.05(m，4H)，3.05-3.17(m，1H)，4.50(t，2H)，5.83(d，1H)，6.52(d，1H)，6.62-6.72(m，2H)，6.83(dd，1H)，7.22(t，1H)，7.94(d，1H)。

Example 9

6-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline

The corresponding imine was prepared in analogy to example 1, starting from 250mg of 4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde and 138mg of 5-amino-6-fluoro-2-methylquinoline. After reaction with cyanoborohydride, the title compound is obtained.

¹H-NMR(CD₃OD)：δ＝1.36(s，3H)，1.57(s，3H)，2.01(d，1H)，2.72(s，3H)，2.74-2.84(m，1H)，2.92(d，1H)，2.94-3.08(m，1H)，3.23(d，1H)，3.31(d，1H)，4.34-4.53(m，2H)，6.62(d，1H)，6.75(dd，1H)，7.34-7.49(m，3H)，8.19(d，1H)。

Example 10

8-fluoro-5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline

The corresponding imine is prepared in analogy to example 1, starting from 45mg of 4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde and 25mg of 5-amino-8-fluoro-2-methylquinoline. After reaction with cyanoborohydride, the title compound is obtained.

¹H-NMR(CD₃OD)：δ＝1.38(s，3H)，1.62(s，3H)，2.01(d，1H)，2.53(dt，1H)，2.73(s，3H)，2.84-3.22(m，4H)，4.44(dt，2H)，5.90(dd，1H)，6.66(dd，1H)，6.82(dd，1H)，7.14(dd，1H)，7.40(d，1H)，8.21(dd，1H)。

Example 11

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylisoquinol-1 (2H) -one

In analogy to example 1, 4- (2, 3-dihydro-5-fluoro-7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleraldehyde was converted with 5-amino-2-methylisoquinol-1 (2H) -one into the corresponding imine. After reaction with hydroboration, the title compound is obtained.

¹H-NMR(CDCl₃)：δ＝1.40(s，3H)，1.55(s，3H)，2.25(d，1H)，2.65 (d，1H)，2.95-3.30(m，4H)，3.60(s，3H)，4.00(br.，1H)，4.50(q，1H)，4.55(q，1H)，6.25(d，1H)，6.30(d，1H)，6.80(dm，1H)，6.90(dm，1H)，7.05(d，1H)，7.25(t，1H)，7.85(d，1H)。

The enantiomers were separated on a chiral column (Chiralpak AD-H5. mu. eluent; hexane/ethanol). The rotation angle of the enantiomers is:

[α]_D31.5 ± 0.2(c ═ 1 methanol) and [ α ═ 1 methanol]_DNot-32.4 ± 0.1(c not 0.99 methanol)

Example 12

5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl ] -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline

a) 2-hydroxy-4-methyl-2-trifluoromethyl-pent-4-enoic acid ethyl ester-

3.2g of iron (III) chloride are suspended in 1000ml of dichloromethane and cooled to-10 ℃. 100g of trifluoroethylpyruvate were added and stirred for 1 hour. About 140g of isobutene was condensed (condensation) to about-50 ℃ while cooling, and the mixture was stirred at-40 ℃ to-50 ℃ for five hours and stirring was continued overnight. After the usual aqueous work-up, the aqueous phases are combined and washed with dichloromethane, the organic phases are combined, mixed with activated carbon, stirred for 30 minutes, filtered and concentrated by evaporation. For additional purification, the product was collected in a cyclohexane (100 ml)/methanol (120ml) mixture and the phases were separated. The methanol phase containing the product is concentrated by evaporation.

Yield: 118.0 g%

¹H-NMR(600MHz，CDCl₃)：δ＝1.35(t，3H)，1.79(s，3H)，2.59(d，1H)，2.76(d，1H)，3.87(s，1H)，4.325(dq，1H)，4.365(dq，1H)，4.82(s，1H)，4.92(s，1H)。

Separation of enantiomers:

dissolving 200mg of the ester obtained in 12a) in 2ml of hexane and separating in 5cmProchrom units (Chiralpak AD) at an equilibrium pressure of 2bar (counterpressure); eluent: hexane/0.1% trifluoroacetic acid. Two fractions were obtained.

Enantiomer I(first eluted with the indicated HPLC method; Chiralpak AS250-0.46 mm: 7.58 min/Chiralpak AD-H-5. mu.: 6.8 min):

[α]_D＝-6.1°±0.2°(c＝0.944；CHCl₃)

enantiomer II(elution by the indicated HPLC method as second compound; ChiralpakAS 250-4.6. mu.: 9.17 min/Chiralpak AD-H-5. mu.: 8.2 min):

[α]_D＝+5.9°±0.5°(c＝1.072；CHCl₃)

b)4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

18.32g of 5-fluoro-2, 3-dihydrobenzofuran were added and cooled to 0 ℃. While stirring vigorously, 11.77g of aluminum (III) chloride were added in one portion. While maintaining this temperature, 10.00g of the compound prepared in example 12a) are slowly added dropwise. The batch was allowed to reach room temperature and stirring was continued for about 7 hours. 50ml of ethyl acetate and water were added thereto, and the mixture was stirred for 15 minutes. After addition of 5ml of concentrated hydrochloric acid, the phases are separated and the organic phase is precipitated absorptively with sodium bicarbonate solution. The organic phase is washed with water and saturated sodium chloride solution and concentrated by evaporation. After bulb-tube distillation at 85 ℃/1mbar and subsequent crystallization of the crude product (bottom layer) from ethanol (100 mol)/water (80ml), 13.1g of 81% of the theoretical reaction product are obtained. Furthermore, 8.51g of 5-fluoro-2, 3-dihydrobenzofuran (distillate) was recovered as a colorless liquid.

Melting point: 72.4 deg.C

¹H-NMR(600MHz，CDCl₃): δ is 1.21(t, 3H), 1.35(s, 3H), 1.40(s, 3H), 2.43(d, 1H), 2.745(d, 1H), 3.15(m, 2H), 3.56(sbr, 1H), 3.73(dq, 1H), 4.125(dq, 1H), 4.58(t, 2H), 6.68(dd, 1H), 6.77(dm, 1H). The resulting ester can then be reacted further as racemate or as pure enantiomer, as described, for example, in WO03/082827, to form compounds of the formulae IIa and IIb.

Claims (5)

1. A compound which is 5- [4- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino ] -2-methylquinoline or a physiologically compatible salt thereof.

2. Use of a compound of claim 1 for the manufacture of a medicament.

3. Use of a compound of claim 1 for the preparation of a medicament for the treatment of an inflammatory disease.

4. Use of a compound of claim 1 for the manufacture of a medicament for topical administration.

5. A pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically compatible carrier.