EP1673344A1

EP1673344A1 - 1-(quinoline amino) and 1-(isoquinoline amino)-substituted pentan-2-ols, method for their production and their use as anti-inflammatories

Info

Publication number: EP1673344A1
Application number: EP04787047A
Authority: EP
Inventors: Stefan Jaroch; Stefan BÄURLE; Markus Berger; Konrad Krolikiewicz; Duy Nguyen; Hartmut Rehwinkel; Norbert Schmees; Werner Skuballa; Heike Schäcke
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 2003-10-06
Filing date: 2004-09-24
Publication date: 2006-06-28
Also published as: MXPA06003895A; WO2005035502A1; CN1863775A; NO20062022L; ZA200603601B; AU2004279544A1; BRPI0415084A; KR20060121894A; DE10346940B3; JP2007507450A; CA2539572A1; IL174433A0

Abstract

The invention relates to substituted pentanols, to a method for their production and to their use as anti-inflammatories.

Description

1- (CHINOLIN-AMINO) AND 1- (ISOCHINOLIN-AMINO) SUBSTITUTED PENTANE-2-0LE, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS AN INFLAMMATORY INHIBITOR

The invention relates to quinoline and isoquinoline derivatives, a process for their preparation and their use as anti-inflammatories.

Anti-inflammatory agents of the general formula are from the prior art DE 100 38 639 and WO02 / 10143

is known, the Ar radical comprising phthalides, thiophthalides, benzoxazinones or phthalazinones. In the experiment, these compounds show dissociations of effects between anti-inflammatory and undesirable metabolic effects and are superior to the non-steroidal glucocorticoids described hitherto or at least have an equally good effect.

However, the selectivity of the compounds of the prior art over the other steroid receptors is still in need of improvement. It was therefore an object of the present invention to provide compounds whose selectivity compared to the other steroid receptors is improved. This object is achieved by the connections according to the claims.

The present invention therefore relates to compounds of the general formula I.

wherein A represents an aryl, a benzyl or a phenethyl group, where the aryl, benzyl or phenethyl group can optionally be substituted by one or more radicals from the group -C-C ₅ alkyl, CC ₅ -alkoxy, d-Cs -Alkylthio, CC ₅ - perfluoroalkyl, halogen, hydroxy, cyano, nitro, -0- (CH ₂ ) _n -0-, -0- (CH ₂ ) _n -CH ₂ -, -0-CH = CH-, - (CH ₂ ) _{n + 2} - where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms, or NR ⁴ R ⁵ , where R ⁴ and R ⁵ independently of one another are hydrogen, Cι- Can be C ₅ alkyl or (CO) -C 1 -C ₅ alkyl,

R ¹ and R ² independently of one another are a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the chain, a C ₃ -C ₆ cycloalkyl ring,

R ^{3 is} an optionally substituted group selected from C ₄ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₇ heterocyclyl, aryl, Heteroaryl, (C Cβ-alkyl Cs-Cβ-cycloalkyl, (CC ₈ -alkyl) aryl, or (d-Cs-alkyl heteroaryl B) a methylene group or a carbonyl group which is optionally substituted by a methyl or ethyl group, and Q is any position means associated quinolinyl or isoquinolinyl which may be optionally substituted by one or more radicals from the group Cι-C ₅ alkyl, C ₁ -C ₅ alkoxy, -C ₅ alkylthio, CRCS perfluoroalkyl, halogen, hydroxy, cyano, Nitro, or NR ⁴ R ⁵ , where R ⁴ and R ^{5 can be,} independently of one another, hydrogen, C 1 -C 4 -alkyl or (CO) -CrC ₅ -alkyl, as well as their racemates or separately present stereoisomers, and, if appropriate, their physiologically tolerable salts ,

An aryl group includes phenyl and naphthyl. Phenyl is preferred. The substituted aryl, benzyl or phenethyl groups have 1-3 substituents, preferably 2 substituents, on the ring.

The following substitution patterns on ring A are a particular subject of the invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted phenyl derivatives.

The CC ₅ alkyl groups in A, R ⁴ , and R ⁵ can be straight-chain or branched and for a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl - or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl or ethyl group is preferred.

The C ₄ -Cs alkyl group R ³ can be straight-chain or branched and, for example, butyl, isobutyl, tert. Butyl, pentyl, isopentyl mean.

The C ₂ -C ₆ alkenyl group is straight-chain or branched, for example vinyl, propenyl, isopropenyl, butenyl, isobutenyl are suitable.

The C ₂ -C ₆ alkynyl group is straight-chain or branched, for example ethynyl, propynyl, butynyl can be used.

For a cycloalkyl group, for example cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl are suitable.

The heterocyclyl group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine.

The C ₈ -C ₈ alkyl (C ₃ -C ₈ ) cycloalkyl group can be, for example, cyclobutyl methyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl. The chain is linked via the alkyl group. Phenyl and naphthyl are suitable for an aryl group, and benzyl and homobenzyl are suitable for (C 1 -C ₈ ) alkylaryl.

Heteroaryl includes furanyl, thienyl, thiazolyl, oxazolyl, imidazoyl, triazolyl, pyridyl and pyrimidyl;

(-CC ₈ alkyl) heteroaryl includes all combinations of the above definition of alkyl with monocyclic aromatic heterocycles. The chain is linked via the alkyl group, which in turn is linked at any chemically possible position of the heterocycle.

The substituents of the groups in R ³ can be C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - Ce alkynyl, CC ₆ alkoxy, halogen, hydroxy, NR ⁴ R ⁵ .

The alkyl radicals R ¹ and R ² can form a 3 to 6-membered ring together with the carbon atom of the chain.

The C ₅ -C ₅ alkoxy groups in A and Q can be straight-chain or branched and 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.

The -CC alkylthio groups in A and Q can be straight-chain or branched and 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 or halogen means a fluorine, chlorine, bromine or iodine atom. A fluorine, chlorine or bromine atom is preferred.

The NR ⁴ R ⁵ group can, for example, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , N (H) (CO) CH ₃ , N (CH ₃ ) (CO) CH ₃ , N [( CO) CH ₃ ] ₂ , N (H) CO ₂ CH ₃ , N (CH ₃ ) CO ₂ CH ₃ , N (CO ₂ CH ₃ ) ₂₎ . As alkyl radicals R ⁴ and R ⁵ , C ₁ -C ₃ -alkyl are preferred. Preferred acyl radicals R ⁴ and R ⁵ are (CO) -CC ₃ -alkyl.

For the radical B, the unsubstituted methylene group and the carbonyl group are preferred.

The radical Q can be linked to the (NH) group of the chain via any ring carbon atom. The 4-, 5-, and 8-positions are preferred for the quinoline ring and the 1-position for the isoquinoline ring.

The compounds of general formula I according to the invention can exist as different stereoisomers due to the presence of asymmetry centers. Both the racemates and the separately present stereoisomers belong to the subject of the present invention.

A particular subject of the present invention are the separately present stereoisomers, i.e. (+) - enantiomers and (-) - enantiomers.

The invention further relates to compounds in which A represents an aryl, a benzyl or a phenethyl group, where the aryl, benzyl or phenethyl group may optionally be substituted by one or more radicals from the group CrC ₅ -alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, CC ₅ perfluoroalkyl, halogen, hydroxy, cyano, nitro, or NR ⁴ R ⁵ , where R ⁴ and R ⁵ independently of one another are hydrogen, C ₅ -C ₅ alkyl or can be (CO) -CC ₅ -alkyl,

The invention further relates to compounds of the general formula I ## STR1 ## in which A is -0- (CH ₂ ) _n -0-, -0- (CH ₂ ) _n -CH ₂ -, -0-CH = CH-, - (CH ₂ ) _n + 2-, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms. The invention further relates to compounds according to claim 1, in which R ^{3 is} an optionally substituted group selected from C ₄ -C ₈ alkyl, O

C ₃ -C ₈ cycloalkyl, C ₃ -C ₇ heterocyclyl, aryl, heteroaryl, (C Cs-alkyl Cs-Cs cycloalkyl, (CC _8- alkyl)) aryl, or (d-Cs-alkyl heteroaryl).

The invention further relates to compounds according to Claim 1, in which R ^{3 is} an optionally substituted group selected from C ₃ -C ₆ cycloalkyl, C ₃ -C ₇ heterocyclyl, phenyl, heteroaryl, (CC ₃ alkyl) C ₃ -C ₆ - Cycloalkyl, (CC ₃ alkyl) phenyl, or (CC ₃ alkyl) heteroaryl.

The invention further relates to compounds of the general formula I in which A is an unsubstituted phenyl group, R ¹ and R ^{2 is} methyl, R ^{3 is} a cyclopentyl group, a methylcyclohexyl group or a phenyl group, B is a methylene group and Q is a quinoline or isoquinoline group.

The invention further relates to compounds of the general formula I in which A is an unsubstituted phenyl group, R ¹ and R ^{2 are} a methyl group, R ^{3 is} a cyclopentyl group, a methylcyclohexyl group or a phenyl group, B is a methylene group and Q is a quinoline group.

The invention furthermore relates to the use of the compounds according to claim 1 for the production of medicaments, the use of the compounds according to claim 1 to the production of a medicament for the treatment of inflammatory diseases, and pharmaceutical preparations containing at least one compound according to claim 1 or mixtures thereof and pharmaceutically acceptable Carrier.

A preferred subject of the invention are compounds of the general formula I in which R ^{3 is} C ₃ -C ₈ -cycloalkyl, (CrC ₈ alkyl) C ₃ -C ₈ -cycloalkyl, benzyl or phenyl.

A particularly preferred object of the invention are compounds of the general formula I in which R ^{3 is} C ₃ -C ₈ -cycloalkyl, (-C-C ₈ alkyl) C ₃ -C ₈ -cycloalkyl or phenyl, very particularly preferred are compounds of the general formula I. wherein wherein R ^{3 is} cyclopentyl, methylcyclohexyl or phenyl, as described in the examples. The processes for the preparation of the compounds from WO98 / 54159 (51488), WO00 / 32584 (51642) and WO02 / 10143 (51877) can also be used for the preparation of the compounds according to the invention can be used. The following process steps can be carried out to link the quinαlin or isoquinoline group which is characteristic of the compounds according to the invention:

A1) for B = CO

An α-keto acid of the general formula (II), in which A, R ¹ and R ^{2 have} the meanings given for formula (I), is reacted with an aminoquinoline, an aminoisoquinoline or a (partially) hydrogenated quinoline or isoquinoline derivative (Q-NH ₂ ) into α-ketoamide (III), where A, R ¹ and R ^{2 have} the meaning given above, in the manner known to those skilled in the art. For example, the α-ketoamide (III) is used using dehydrating coupling reagents, such as are known from peptide chemistry, for example dicyclohexylcarbodiimide, or by converting the acid into an acid chloride, for example with thionyl chloride or POCI ₃ and subsequent reaction with Q-NH _2. receive.

Compound (III) is reacted either with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, or by reaction with compound (IV),

(R ⁶ ) ₃ Si-R ³ (IV)

wherein R ^{3 has} the meaning given above and R ⁶ denotes a -C ₅ alkyl group, in the presence of a catalyst, for example fluoride salts or bases, such as alkali carbonates (J. Am. Chem. Soc. 1989, 111, 393), to give the title compound (I).

A2) for B = CO

(II) (VI) (i)

Alternatively, α-keto acids (II) to compounds (V),

(V)

wherein A, R ¹ and R ² are defined as described above and R ^{7 is} C 1 -C 4 -alkyl, are esterified by the customary methods, for example with thionyl chloride in methanol or ethanol or with methyl iodide and alkali metal carbonate and in analogy to reaction sequence A1) from (III) to (I) in compound (VI).

(VI)

The ester is saponified to the acid (VI; R ⁷ = H) under standard conditions, for example an aqueous alkali metal hydroxide solution. This is used for coupling with an aminoquinoline or aminoisoquinoline or a (partially) hydrogenated quinoline or isoquinoline derivative (Q-NH ₂ ) using a common activation reagent, e.g. thionyl chloride, optionally in the presence of a catalyst such as dimethylaminopyridine, to give the title compound ( I) implemented. B)

The title compound (I) can also be synthesized by reductive amination of a compound of the formula (XII) with Q-NH ₂ , where, for example, sodium cyanoborohydride or sodium triacetoxyborohydride are suitable as reducing agents.

R represents methyl or ethyl according to the substituents defined for the methylene group in B.

In the event that the compounds of the general formula I are present as salts, this can be, for example, in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.

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 familiar to the person skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a self-optically active carrier material (CHIRALPAK AD®). It is also possible to esterify the free hydroxyl group in a racemic compound of the general formula I with an optically active acid and to separate the diastereoisomeric esters obtained by fractional crystallization or chromatographically and the to saponify separate esters to give the optically pure isomers. For example, mandelic acid, camphorsulfonic acid or tartaric acid can be used as the optically active acid.

Otherwise, the methods used in the experimental part for the preparation of the compounds according to the invention are also part of the disclosure on the manufacturability of the claimed compounds.

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 checked with the help of recombinantly produced receptors. Cytosol preparations from Sf9 cells which had been infected with recombinant baculoviruses which code for the GR are used for the binding studies. Compared to the reference substance [ ³ H] -dexamethasone, the substances show a high to very high affinity for GR.

In addition, the quinolines and isoquinolines of the formula (I) described here show a high selectivity for the glucocorticoid receptor.

The GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is regarded as an essential molecular mechanism for the anti-inflammatory effect of glucocorticoids. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa- B, effects (for an overview see Cato, AGB and Wade E, BioEssays 18, 371-378 1996).

The compounds of the general formula I according to the invention inhibit the secretion of the cytokine IL-8 triggered by lipopolysacchard (LPS) in the human monocyte cell line THP-1. The concentration of the cytokines in the supernatant was determined using commercially available ELISA kits. The anti-inflammatory activity of the compounds of the general formula I were tested in animal experiments by testing in croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108). For this purpose, croton oil was applied topically to the ears in ethanolic solution. 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 measure of the inflammatory edema, the peroxidase activity as a measure of the immigration of granulocytes and the elastase activity as a measure of the immigration of neutrophilic granulocytes. The compounds of the general formula I inhibit the three above-mentioned inflammation parameters in this test both after topical and after systemic application.

One of the most common undesirable effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Basic Immunology, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible for this and by free amino acids that result from the breakdown of proteins (catabolic effect of the glucocorticoids). A key enzyme of the catabolic metabolism in the liver is tyrosine aminotranferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measure of the undesirable metabolic effects of the glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after the administration of the test substances, the liver is removed and the TAT activity in the Homogenate measured. In this test, the compounds of the general formula I do not induce the tyrosine aminotransferase, or do so only to a small extent, in which they are anti-inflammatory.

Because of their anti-inflammatory and additional anti-allergic, immunosuppressive and anti-proliferative action, the compounds of general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans: The term "DISEASE" stands for the following indications:

(i) Lung diseases that are associated with inflammatory, allergic and / or proliferative processes: - Chronic obstructive lung diseases of any genesis, especially bronchial asthma - Bronchitis of different origins - All forms of restrictive lung diseases, especially allergic alveolitis, - All forms of pulmonary edema, especially toxic pulmonary edema - sarcoidosis and granulomatosis, especially Boeck's disease (ii) rheumatic diseases / autoimmune diseases / joint diseases that are associated with inflammatory, allergic and / or proliferative processes: - all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia - Reactive arthritis - Inflammatory soft tissue diseases of other genesis - Arthritic symptoms in degenerative joint diseases (arthrosis) - Traumatic arthritis - Collagenosis of any genesis, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Still's syndrome, felty syndrome

(iii) Allergies associated with inflammatory and / or proliferative processes:

- All forms of allergic reactions, e.g. Quincke's edema, hay fever, insect bite, allergic reactions to medicines, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis (iv) vascular inflammation (vasculitis)

- Panarteritis nodosa, temporal arteritis, erythema nodosum (v) Dermatological diseases that are associated with inflammatory, allergic and / or proliferative processes: - Atopic dermatitis (especially in children) - Psoriasis - Pityriasis rubra pilaris - Erythematous diseases caused by different noxious substances, e.g. radiation, chemicals, burns etc. - Bullous dermatoses - Diseases of the lichenoid form, - Pruritus (e.g. allergic genesis) - Seborrheic eczema - Rosacea - Pemphigus vulgaris - Erythema exudative multiforme - Balanitis - Vulvitis - Hair loss like alopecia areata - Cutane T - Zeil - Lymphoma

(vi) Kidney diseases that are associated with inflammatory, allergic and / or proliferative processes: - Neph rot syndrome - All nephritis

(vii) Liver diseases that are associated with inflammatory, allergic and / or proliferative processes: - acute liver cell disintegration, acute hepatitis of different origins, e.g. viral, toxic, drug-induced - chronically aggressive and / or chronic intermittent hepatitis (viii) gastrointestinal diseases, which are associated with inflammatory, allergic and / or proliferative processes are associated: - regional enteritis (Crohn's disease) - ulcerative colitis - gastritis - Refluxoesophagitis - Gastroenteritis of another genesis, e.g. indigenous sprue (ix) proctological diseases that are associated with inflammatory, allergic and / or proliferative processes: - anal eczema - fissures - hemorrhoids - idiopathic proctitis (x) eye diseases that are associated with inflammatory, allergic and / or proliferative processes are associated: - allergic keratitis, uveitis, iritis, - conjunctivitis - blepharitis - neuritis nervi optici - chorioditis - ophtalmia sympathica (xi) diseases of the ear, nose and throat area, which are associated with inflammatory, allergic and / or proliferative processes:

- allergic rhinitis, hay fever

Otitis externa, e.g. due to contact x, infection etc.

- Otitis media (xii) Neurological diseases associated with inflammatory, allergic and / or proliferative processes: - cerebral edema, especially tumor-related cerebral edema - multiple sclerosis - acute encephalomyelitis - meningitis - various forms of seizures, e.g. BNS convulsions (xiii ) Blood disorders that are associated with inflammatory, allergic and / or proliferative processes: - Acquired hemolytic anemia - Idopathic thrombocytopenia (xiv) Tumor diseases that are associated with inflammatory, allergic and / or proliferative processes: - Acute lymphoblastic leukemia - Malignant lymphomas - Lymphogranulomatoses - Lymphosarcomas - Extensive metastases, especially in breast, bronchial and prostate cancer

(xv) Endocrine diseases associated with inflammatory, allergic and / or proliferative processes: - Endocrine orbitopathy - Thyrotoxic crisis - Thyroiditis de Quervain - Hashimoto thyroiditis - Graves' disease

(xvi) organ and tissue transplantation, graft-versus-host disease (xvii) severe shock conditions, e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS) (xviii) substitution therapy for: congenital primary adrenal insufficiency, e.g. congenital adrenogenital syndrome - acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, post-infectious, tumors, metastases etc. congenital secondary adrenal insufficiency, e.g. congenital hypopitutitarianism - acquired secondary adrenal insufficiency, e.g. post-infectious, tumors etc.

(xix) emesis associated with inflammatory, allergic and / or proliferative processes: - eg in combination with a 5-HT3 antagonist for cytostatic agents - vomiting. (xx) Pain in inflammatory genesis, eg lumbago In addition, the compounds of general formula I according to the invention can be used for the therapy and prophylaxis of further disease states not mentioned above, for which synthetic glucocorticoids are used today (see also Hatz, HJ, glucocorticoids: immunological bases, pharmacology and therapy guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart , 1998).

All of the above indications (i) to (xx) are described in detail in Hatz, HJ, Glucocorticoide: Immunological basics, pharmacology and therapy guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998.

The suitable dose for the therapeutic effects in the abovementioned disease states is different and depends, for example, on the potency of the compound of the general formula I, the host, the mode of administration and the type and severity of the conditions to be treated, and the use as a prophylactic or therapeutic agent.

The invention further provides

(i) the use of a compound of the formula I according to the invention or a mixture thereof for the manufacture of a medicament for the treatment of a DISEASE;

(ii) a method of treating a DISEASE, the method comprising administering an amount of compound according to the invention, the amount suppressing the disease, and the amount of compound being given to a patient in need of such a medicament;

(iii) a pharmaceutical composition for the treatment of a DISEASE, which treatment comprises one of the compounds according to the invention or their mixture and at least one pharmaceutical auxiliary and / or carrier. In general, satisfactory results can be expected in animals if the daily doses comprise a range from 1 μg to 100,000 μg of the compound according to the invention per kg of body weight. For larger mammals, such as humans, a recommended daily dose is in the range of 1 μg to 100,000 μg per kg body weight. A dose of 10 to 30,000 μg per kg body weight is preferred, more preferably a dose of 10 to 10,000 μg per kg body weight. For example, this dose is conveniently administered several times a day. For the treatment of acute shock (e.g. anaphylactic shock), single doses can be given that are clearly above the doses mentioned above.

The formulation of the pharmaceutical preparations based on the new compounds is carried out in a manner known per se by processing the active ingredient with the carrier substances, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, taste-correcting agents, colorants, etc. customary in galenics and converted into the desired application form. Reference should be made to Remington ^'s Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

Tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions are particularly suitable for oral administration.

Injection and infusion preparations are possible for parenteral administration.

Appropriately prepared crystal suspensions can be used for intra-articular injection.

Aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used for intramuscular injection. For rectal administration, the new compounds in the form of suppositories, capsules, solutions (for example in the form of clysms) and ointments can be used both for systemic and for local therapy.

The pulmonary application of the new compounds can be used in the form of aerosols and inhalants.

The new compounds can be used as drops, ointments and tinctures in corresponding pharmaceutical preparations for local use on the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses.

For topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powder, milk and tinctures are possible. The dosage of the compounds of the general formula I should be 0.01% to 20% in these preparations in order to achieve a sufficient pharmacological effect.

The invention also encompasses the compounds of the general formula I according to the invention as a therapeutic active ingredient. The invention furthermore relates to the compounds of the general formula I according to the invention as a therapeutic active ingredient together with pharmaceutically acceptable and acceptable excipients and carriers.

The invention also comprises a pharmaceutical composition which contains one of the pharmaceutically active compounds according to the invention or their mixture or their pharmaceutically acceptable salt and a pharmaceutically acceptable salt or pharmaceutically acceptable adjuvants and carriers.

The examples below serve to explain the invention in more detail without wishing to restrict it thereto. The syntheses of important precursors, which are not disclosed in the experimental part, are already state of the art and can be found, for example, in WO 98/54159 and WO 02/10143. Experimental part

example 1

1- (Quinolin-5-ylamino) -2-cyclopentyl-4-methyl-4-p enylpentan-2-ol

4-methyl-4-phenyl-2-oxo-pentanoic acid ethyl ester

10.0 g of 2-phenyl-2-propanoI and 30.4 g of ethyl 2- (trimethylsilyloxy) acrylic acid

(Bull. Chem. Soc. Jpn. 1992, 65, 3209) are placed in 386 ml of CH ₂ CI ₂ and treated at -70 ° C. with 11.5 ml of tin tetrachloride. After 15 min at -70 ° C, the mixture is introduced into semi-concentrated potassium carbonate solution, extracted with CH ₂ CI ₂ , dried (Na ₂ S0 ₄ ) and i. Vak. concentrated. Column chromatography on silica gel with ethyl acetate-cyclohexane provides 4.64 g of the product as colorless

Oil.

'H NMR (CDCI ₃ ); δ = 1.23 (t, 3H), 1.45 (s, 6H), 3.16 (s, 2H), 4.09 (q, 2H), 7.14 -

7.40 (m, 5H).

2-Cvclopentyl-2-hvdroxy-4-methyl-4-phenylpentanoic acid, ethyl ester To a solution of 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid, ethyl ester in 20 mL THF, 2.13 mL of a 2nd M ethereal cyclopentyl magnesium chloride solution was added dropwise. After 3 h at -70 ° C the mixture is brought to cold sat. Poured NH CI solution and extracted with ethyl acetate. The extracts are dried (Na ₂ S0 ₄ ) and concentrated. Column chromatography on silica gel with ethyl acetate-cyclohexane provides 320 mg of the product. Η NMR (CDCI ₃ ); δ = 0.90 - 1.80 (m, 8H), 1.15 (t, 3H), 1.34 (s, 3H), 1.43 (s, 3H), 2.09 (m, 1 H), 2.14 (d, 1 H), 2.26 ( d, 1 H), 2.84 (s, 1 H), 3.50 (dt, 1H), 3.87 (dt, 1H), 7.13 (m, 1 H), 7.20 - 7.48 (m, 4H).

2-Cvclopentyl-4-methyl-4-phenyl-1, 2-pentanediol 320 mg of ethyl 2-cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanoate are converted into 185 mg of product with 92 mg of lithium aluminum hydride. Η NMR (CDCI ₃ ); δ = 1.10 - 1.70 (m, 8H), 1.40 (s, 3H), 1.49 (s, 3H), 2.00 (AB system, 2H), 2.08 (m, 1H), 3.18 (AB system, 2H), 7.20 (t, 1H), 7.32 (t, 2H), 7.45 (d, 2H).

2-Cvclopentyl-2-Hydroxy-4-methyl-4-phenylpentanal

185 mg of 2-cyclopentyl-4-methyl-4-phenyl-1, 2-pentanediol are mixed with 438 mg

Pyridine-sulfur trioxide complex, 2.5 mL DMSO and 0.5 mL triethylamine transferred to 160 mg aldehyde.

Η NMR (CDCI3); δ = 0.70 - 1.70 (m, 9H), 1.30 (s, 3H), 1.40 (s, 3H), 2.11 (d,

1 H), 2.29 (d, 1 H), 3.02 (s, 1 H), 7.20 (m, 1 H), 7.30 (m, 4H), 8.85 (s, 1H).

1- (quinolin-5-ylamino) -2-cvclopentyl-4-methyl-4-phenylpentan-2-ol

160 mg 2-cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanal, 106 mg 5-

Aminoquinoline and 405 mg sodium triacetoxyborohydride in 6.3 mL acetic acid are converted to imine.

Η NMR (CDCI3); δ = 0.80 - 1.70 (m, 15H), 2.75 (d, 1H), 3.01 (d, 1H), 3.87 (,

1 H), 4.81 (d, 1 H), 6.12 (d, 1H), 7.15 - 7.50 (m, 8H), 8.20 (d, 1 H), 8.88 (dd, 1 H).

MS (ESI), 387.

Column chromatography on silica gel with ethyl acetate-cyclohexane provides 70 mg of the imine, which is reduced with 21 mg of sodium borohydride in THF (2 ml) and methanol (0.5 ml). Column chromatography provides 30 mg of product.

Η NMR (CDCI ₃ ); δ = 0.80 - 2.00 (m, 17H), 3.30 (m, 1H), 3.73 (m, 1H), 5.90 (d,

1 H), 7.25 - 7.40 (m, 8H), 8.10 (d, 1 H), 8.77 (dd, 1 H).

MS (ESI), 389.

Example 2

1- (quinolin-5-ylamino) -2-cyclohexylmethyl-4-methyl-4-phenylpentan-2-ol

2-Cvclohexylmethyl-2-hvdroxy-4-methyl-4-phenylpentanoic acid ethyl ester Analogously to Example 1, 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid ethyl ester is obtained with Grignard reagent prepared from 1 mL cyclohexylmethyl bromide and 174 mg magnesium transferred into 290 mg product.

Η NMR (CDCI ₃ ); δ = 0.70 - 1.75 (m, 13H), 1.25 (t, 3H), 1.31 (s, 3H), 1.40 (s, 3H), 2.03 (d, 1 H), 2.26 (d, 1 H), 3.50 ( dt, 1H), 3.90 (dt, 1 H), 7.15 (t, 1 H), 7.22 - 7.36 (m, 4H).

2-Cvclohexylmethyl-4-methyl-4-phenyl-1, 2-pentanediol

Analogously to Example 1, 290 mg of 2-cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanoic acid ethyl ester with 76 mg of lithium aluminum hydride in 160 mg

Product transferred.

Η NMR (CDCI ₃ ); δ = 0.90 (m, 3H), 1.10 - 1.80 (m, 10H), 1.40 (s, 3H), 1.43 (s,

3H), 1.94 (d, 1 H), 2.10 (d, 1 H), 3.12 (AB system, 2H), 7.20 (t, 1 H), 7.32 (t, 2H),

7.43 (d, 2H).

1- (Quinolin-5-ylamino) -2-cvclohexylmethyl-4-methyl-4-phenylpentan-2-ol Analogously to Example 1, 160 mg of 2-cyclohexlmethyl-4-methyl-4-phenyl-1,2-pentanediol are also used 342 mg pyridine-sulfur trioxide complex, 1.95 mL DMSO and 0.39 mL triethylamine to 2-cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanal (Η-NMR (CDCI ₃ ); δ = 0.90 - 1.60 (m, 10H) , 1.30 (s, 3H), 1.41 (s, 3H), 1.76 (m, 2H), 1.95 (m, 1 H), 2.20 (d, 1 H), 2.35 (d, 1 H), 2.97 (s, 1 H), 7.20 (m, 1 H), 7.30 (m, 4H), 8.76 (s, 1H)). The crude product is combined with 137 mg of 5-aminoquinoline and 524 mg of sodium triacetoxyborohydride to give the lmin (180 mg; 'H NMR (CDCI3); δ = 0.90 - 1.90 (m, 18H), 2.25 (m, 1 H), 2.80 (d, 1 H), 3.00 (d, 1 H), 3.76 (t, 1 H), 5.06 (d, 1 H), 6.25 (d, 1 H), 7.10 - 7.55 (m, 8H), 8.25 (d, 1 H), 8.87 (dd, 1H); MS (ESI), 415). Reductive amination with 49 mg sodium borohydride gives 130 mg end product after column chromatography. Η NMR (CDCI ₃ ); δ = 1.10 - 1.90 (m, 20H), 2.12 (m, 1 H), 3.41 (m, 1 H), 3.70 (m, 1H), 4.31 (m, 1H), 6.47 (dd, 1 H), 7.20 - 7.45 (m, 8H), 8.07 (d, 1 H), 8.82 (dd, 1 H). MS (ESI), 417.

Example 3

1- (quinolin-5-ylamino) -2,4-diphenyl-4-methyl pentan-2-ol

2,4-diphenyl-2-Hydroxy-4-methylpentanoic acid ethyl ester

Analogously to Example 1, 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid ethyl ester is transferred to 2.14 mL of a 2 M phenylmagnesium chloride-THF solution in 980 mg of product.

2,4-diphenyl-4-methyl-1,2-pentanediol

Analogously to Example 1, 980 mg of diphenyl-2-hydroxy-4-methylpentanoic acid ethyl ester are converted into 450 mg of product with 289 mg of lithium aluminum hydride. Η NMR (CDCI ₃ ); δ = 1.10 (s, 3H), 1.25 (s, 3H), 2.23 (d, 1 H), 2.61 (d, 1 H), 3.41 (AB system, 2H), 7.15 - 7.37 (m, 10H).

2,4-diphenyl-2-hydroxy-4-methylpentanal

Analogously to Example 1, 445 mg of 2,4-diphenyl-4-methyl-1,2-pentanediol are added

1.02 g pyridine-sulfur trioxide complex, 5.85 mL DMSO and 1.16 mL

Triethylamine converted to 390 mg aldehyde.

Η NMR (CDCI3); δ = 1.36 (s, 3H), 1.51 (s, 3H), 2.49 (d, 1 H), 2.82 (d, 1 H), 3.60

(s, 1H), 7.20 - 7.42 (m, 10H), 8.98 (s, 1H).

1 - (Quinolin-5-ylamino) -2,4-diphenyl-4-methylpentan-2-ol Analogously to Example 1, 190 mg of 2,4-diphenyl-2-hydroxy-4-methylpentanal and 122 mg of 5-aminoquinoline via the imine (Η-NMR (CDCI3); δ = 1.37 (d, 3H), 1.42 (s, 3H), 2.70 (d, 1 H), 2.94 (d, 1 H), 4.67 (s, 1 H) , 6.14 (d, 1H), 6.22 (br., 1H), 7.12-7.40 (m, 13H), 8.34 (d, 1H), 8.85 (dd, 1H)) 40 mg product obtained.

Η NMR ([Del-DMSO); δ = 1.24 (s, 3H), 1.35 (s, 3H), 1.50 & 1.78 (dd, 1H), 2.00

(m, 1H), 3.59 & 3.80 (m, 1H), 4.18 & 4.30 (m, 1H), 4.86 (m, 1H), 6.13 -6.30 (m,

2H), 7.09-7.33 (m, 10H), 7.39 (d, 1H), 7.54 (dd, 1H), 8.68 (d, 1H), 8.81 (d, 1H).

Claims

claims

1. Compounds of the general formula I

wherein

A represents an aryl, a benzyl or a phenethyl group, where the aryl, benzyl or phenethyl group may optionally be substituted by one or more radicals from the group CC ₅ -alkyl, d-Cs-alkoxy, Cι-C ₅ -Alkyl thio, d-Cs-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -0- (CH ₂ ) _n -0-, -0- (CH ₂ ) _n -CH ₂ -, -0-CH = CH-, - (CH ₂ ) _{n + 2} - where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms, or NR ⁴ R ⁵ , where R ⁴ and R ⁵ independently of one another are hydrogen, Ci -Cs-alkyl or (COH Cs-alkyl can be

R ^{3 is} an optionally substituted group selected from C ₈ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₇ heterocyclyl, aryl, heteroaryl , (-C ₈ -C ₈ alkyl) C ₃ -C ₈ cycloalkyl, (-C ₈ alkyl) aryl, or (CC ₈ - alkyl) heteroaryl B an optionally substituted by a methyl or ethyl group or a methylene group and a carbonyl group and Q represents a quinolinyl or isoquinolinyl group linked via any position, which may optionally be substituted by one or more radicals from the group -C-C ₅ -alkyl, C1-C ₅ -alkoxy, CC ₅ -alkylthio, C Cs-perfluoroalkyl, Halogen, hydroxy, cyano, nitro, or NR ⁴ R ⁵ , where R ⁴ and R ^{5 can be,} independently of one another, hydrogen, C 1 -C ₅ alkyl or (CO) -C ₅ C ₅ alkyl, as well as their racemates or separately present stereoisomers, and optionally their physiologically tolerable salts.

2. Compounds of general formula I according to claim 1, wherein A represents an aryl group.

3. Compounds according to claim 1 or 2, wherein A -0- (CH ₂ ) _n -0-, -O- (CH ₂ ) _n -CH ₂ -, -0-CH = CH-, - (CH ₂ ) _{n +} 2- where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms.

4. Compounds according to claim 1 or 2, wherein R ^{3 is} an optionally substituted group selected from C -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ - C ₇ heterocyclyl, aryl, heteroaryl, (d-C8- means alkyl) aryl, or (dC ₈ alkyl) heteroaryl - alkyl) C ₃ -C ₈ cycloalkyl, (dC. ₈

5. Compounds according to claim 1 or 2 wherein R ^{3 is} an optionally substituted group selected from C ₃ -C ₆ cycloalkyl, C ₃ -C - heterocyclyl, phenyl, heteroaryl, (d-Cs-alky d-Cs-cycloaikyl, (dC ₃ - alkyl) phenyl, or (dC ₃ alkyl) heteroaryl.

6. Use of the compounds according to claim 1 for the manufacture of medicaments.

7. Use of the compounds according to claim 1 for the manufacture of a medicament for the treatment of inflammatory diseases.

8. Pharmaceutical preparations containing at least one compound according to claim 1 or mixtures thereof and pharmaceutically acceptable carriers.