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Definitions

• the invention relates to tetrahydronaphthalene derivatives, processes for their preparation and their use as anti-inflammatory agents.
• Open-chain non-steroidal anti-inflammatory agents are known from the prior art (DE 100 38 639 and WO 02/10143). These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.
• nonsteroidal anti-inflammatory agents are provided.
• the present invention relates to compounds of the general formula (I),
• R 1 and R 2 independently of one another represent a hydrogen atom, a hydroxyl
• Alkyl group a (CrCio) alkoxy, (Ci-Cio) -alkylthio group, a (Ci-C5) - perfluoroalkyl group, a cyano group, a nitro group, or an -NR 9 R 9a group, or R 1 and R 2 together a group selected from the groups
• R 11 is a hydrogen atom, a hydroxy group, a halogen atom, a
• Cyano group an optionally substituted (Ci-Cio) alkyl group, a (CrCio) alkoxy group, a (C- ⁇ -Cio) -alkylthio group, or a
• R 12 is a hydrogen atom, a hydroxy group, a halogen atom, a
• Cyano group an optionally substituted (Ci-Cio) alkyl group, or a (C- ⁇ -Cio) alkoxy
• R 3 is an optionally substituted by 1 to 3 hydroxy groups, 1 to 3
• Halogen atoms and / or 1 to 3 (CrC 5 ) alkoxy substituted
• C 1 -C 10 -alkyl group an optionally substituted (C 3 -C 7 ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, or optionally one or more groups independently selected from one another (C 1 -C 5 ) -alkyl groups which themselves may optionally be substituted by 1 to 3 hydroxyl or 1 to 3 -COOR 13 groups,
• Halogen atoms hydroxy groups, -NR 9 R 9a groups, and
• Exomethylene groups substituted, optionally 1 to 4 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms and / or 1 to 2 keto groups containing mono- or bicyclic heteroaryl group, this group linked via any position with the group X. and is optionally hydrogenated at one or more sites, R 4 is a hydroxy group, an -OR 10 group or an -O (CO) R 10 group,
• R 5 is a (CrCio) alkyl group which is optionally partially or completely fluorinated, a (C 3 -C 7) cycloalkyl, (C- ⁇ -C 8) alkyl (C 3 - C 7) cycloalkyl group, a (C 2 -C- 8) alkenyl (C 3 -C 7 cycloalkyl group), a heterocyclyl group, a (C- ⁇ -C 8) Alkylheterocyclyl distr, a (C 2 -C 8) - Alkenylheterocyclyl distr, an aryl group, a (CrC 8) Alkylaryl group, a (C 2 -C 8 ) alkenylaryl group, a (C 2 -C 8 ) alkynylaryl group, an optionally by 1 to 2 keto groups, 1 to 2 (C 1 -C 5 ) -alkyl groups, 1 to 2 (C 1 -C 5 ) Al
• R 6 is a hydrogen atom, a halogen atom, or an optionally substituted (C 1 -C 10) -alkyl group
• R 7 and R 8 are each independently a hydrogen atom, a halogen atom, an optionally substituted (Ci-Ci O ) alkyl group, a cyano group, together a (d-Cio) -alkylidenoli or together with the carbon atom of the tetrahydronaphthalene an optionally substituted (C 3 -C 6 ) cycloalkyl ring; or
• R 6 and R 7 together form a fused five- to eight-membered saturated or unsaturated carbo or heterocycle, optionally substituted by 1 to 2 keto groups, 1 to 2 (C r C 5 ) -alkyl groups, 1 to 2 (Ci-C 5 ) - alkoxy groups, and / or 1 to 4 halogen atoms substituted form; or
• R 1 and R 8 together form an annelated five- to eight-membered saturated or unsaturated carbocycle or heterocycle optionally substituted by 1 to 2 keto groups, 1 to 2 (-C 5) -alkyl groups, 1 to 2 (-C 5) - alkyl, and / or 1 to 4 halogen atoms is substituted;
• R 9 and R 9a independently of one another denote a hydrogen atom, (C 1 -C 5) -alkyl or - (CO) - (C 1 -C 5 ) -alkyl,
• R 10 represents a (C 1 -C 10) -alkyl group or an arbitrary hydroxy-protecting group
• R 13 represents a hydrogen atom or a (Ci-C 5 ) alkyl group
• the present invention further relates to processes for the preparation of compounds of general formula (I) as described herein. Furthermore, the present invention relates to pharmaceutical compositions comprising one or more compounds of general formula (I) in combination with one or more pharmaceutical excipients and / or excipients.
• the present invention also relates to the use of the compounds of general formula (I) for the preparation of pharmaceutical compositions having anti-inflammatory activity.
• the present invention furthermore relates to compounds of the general formula (IV)
• halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom.
• alkyl groups mentioned in the definitions of the general formula (I) may be straight-chain or branched and may be, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, and the hexyl, heptyl, nonyl, decyl group and their random branched derivatives.
• Preferred are Alkyl groups containing 1 to 10, 1 to 8, or 1 to 5 carbon atoms. A methyl or ethyl group is particularly preferred.
• the above-mentioned alkyl groups may be optionally substituted by 1 to 5, preferably 1 to 3, groups independently selected from hydroxy, cyano, nitro, -COOR 13 , CrC 5 alkoxy groups, halogen, -NR 9 R 9a , a partially or completely fluorinated Ci-C ß alkyl group.
• the alkyl groups may preferably be substituted by 1 to 3 halogen atoms and / or 1 to 3 hydroxy and / or 1 to 3 cyano and / or 1 to 3 -COOR 13 groups.
• a particularly preferred subgroup of substituents are fluorine atom, hydroxy-methoxy and / or cyano groups.
• substituents for the alkyl groups are 1 to 3 hydroxy and / or 1 to 3 -COOR 13 groups. Particularly preferred are the hydroxy groups.
• a partially or fully fluorinated alkyl group includes the following partially or fully fluorinated groups: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl , Pentafluoroethyl. Of these, preferred are the trifluoromethyl or the pentafluoroethyl group.
• the fully fluorinated group is also called perfluoroalkyl group.
• the reagents which may be used during the synthesis are commercially available, or the published syntheses of the corresponding reagents belong to the prior art, or published syntheses can be applied analogously.
• the alkynyl groups have at least one C ⁇ C triple bond and may be straight-chain or branched. Preferred are alkynyl groups having 2 to 8 carbon atoms.
• the alkoxy groups mentioned in the definitions of general formula (I) can be straight-chain or branched and are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy.
• CrC 5 - and C 1 -Ca, C 1 -Ce-, and CrClio alkoxy groups are preferred.
• a methoxy or ethoxy group is particularly preferred.
• alkylthio groups mentioned in the definitions of general formula (I) may be straight-chain or branched and may be, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group.
• CrCs-alkylthio groups are preferred.
• a methylthio or ethylthio group is particularly preferred.
• alkoxy and alkylthio groups described above may bear on their alkyl groups the same substituents as described above for the alkyl groups in general.
• Preferred substituents for alkoxy and alkylthio groups are independently selected from halogen atoms (especially fluorine and / or chlorine), hydroxy and cyano groups.
• the substituent -NR 9 R 9a is , for example, -NH 2 , -NH (CH 3 ), -N (CH 3 ) 2 , -NH (C 2 H 5 ), -N (C 2 Hs) 2 , -NH (C 3 H 7 ), -N (C 3 H 7 J 2 , -NH (C 4 H 9 ), -N (C 4 Hg) 2 , -NH (C 5 H 11 ), -N (C 5 Hn) 2 , -NH (CO) CH 3 , -NH (CO) C 2 H 5 , -NH (CO) C 3 H 7 , -NH (CO) C 4 H 9 , -NH (CO) C 5 H 11 .
• the cycloalkyl group optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (C r C 5) alkyl, (C r C 5) alkoxy, -NR 9 R 9a groups, -COOR 13 groups, - CHO, and cyano, substituted saturated cyclic group having 3 to 7 ring carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.
• a (C 1 -C 8 ) alkyl- (C 3 -C 7 ) cycloalkyl group R 5 is to be understood as meaning a cycloalkyl group (as defined above) which has a straight-chain or branched (C 1 -C 6 ) -alkyl unit (as defined above) linked to the ring system.
• Examples of such groups are - (CH 2 ) -cycloalkyl, - (C 2 H 4 ) -cycloalkyl, - (C 3 H 6 ) -cycloalkyl, - (C 4 H 8 ) -cycloalkyl, - (C 5 H 10 ) -Cycloalkyl, wherein cycloalkyl is defined as described above.
• R 5 By a (C 2 -C 8 ) alkenyl- (C 3 -C 7 ) cycloalkyl group R 5 is meant a cycloalkyl group (as defined above) which has a straight-chain or branched (C 2 -C 6) -alkenyl unit with the Ring system is linked.
• alkylidene or Exoalkylidenoli is to be understood a group having 1 to 10 carbon atoms, which is bound via an exodo double bond to the system (ring or chain). Preference is given to (CrC 5 ) - and (C- ⁇ -C 3 ) alkylidene, with particular preference to exomethylene.
• the heterocyclyl group is a cyclic, non-aromatic group containing one or more heteroatoms and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine.
• Perhydroquinoline and perhydroisoquinoline also belong to the heterocyclyl groups according to the invention.
• Suitable substituents for heterocyclyl and heteroaryl groups for example substituents from the following group: optionally substituted d- C ⁇ -alkyl, hydroxy, C r C 5 alkoxy, -NR 9 R 9, halogen, cyano, -COOR 13, - CHO.
• the substituents may optionally also be bonded to the nitrogen atom of the heterocyclyl or heteroaryl group; N-oxides are also included in the definition.
• Aryl groups in the context of the invention are aromatic or partially aromatic carbocyclic groups having 6 to 14 carbon atoms which contain a ring, such as Phenyl or phenylene or more condensed rings such as naphthyl or anthranyl. Examples include phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl. The optionally substituted phenyl group and the naphthyl group are preferred.
• the aryl groups may be substituted at any suitable point which leads to a stable compound by one or more radicals selected from the group consisting of hydroxy, halogen, optionally substituted by 1 to 3 hydroxyl groups or -COOR 13 groups substituted CrC 5 alkyl, CrC 5 - Alkoxy, cyano, -CF 3 , and nitro.
• the aryl groups may be partially hydrogenated and then additionally or alternatively to the abovementioned substituents also keto or Exoalkyliden, as defined above, carry.
• partially hydrogenated phenyl e.g. To understand cyclohexadienyl, cyclohexenyl, cyclohexyl.
• a partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.
• a (Ci-C 8 ) alkylaryl group is an aryl group, as already described above, which is linked via a straight-chain or branched (C- ⁇ -C 8 ) -Alkyliata (as defined above) with the ring system.
• a (C 2 -C 8 ) alkenylaryl group is an aryl group as already described above which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkenyl unit (as defined above).
• a (C 2 -C 8 ) alkynylaryl group is an aryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkynyl unit (as defined above).
• the mono- or bicyclic heteroaryl group may optionally contain 1 to 9 groups selected from nitrogen atoms, oxygen atoms, sulfur atoms or keto groups, of which a maximum of 4 nitrogen atoms, a maximum of 2 oxygen atoms, a maximum of 2 sulfur atoms and a maximum of 2 keto groups may be included. Any subcombination of these groups is possible.
• the heteroaryl group may be hydrogenated at one or more sites.
• Examples of monocyclic heteroaryl groups include pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and 4H-pyrazole, 1H- and 2H-pyrrole, Oxazole, thiazole, furazane, 1H- and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.
• cyclic heteroaryl groups include phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, benzo [b] thienyl, benzo [c] thienyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazin
• heteroaryl groups are partially or completely hydrogenated, compounds of the general formula (I) in which R 3 is, for example, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H- Pyridin-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, Decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1,
• the mono- or bicyclic heteroaryl group may optionally be substituted by one or more substituents selected from optionally substituted by 1 to 3 hydroxy groups or 1 to 3 -COOR 13 groups Ci-Cs-alkyl groups, Ci-C 5 alkoxy groups, halogen atoms, and / or Exomethylene be substituted.
• the substituents may, if possible, optionally also be bonded directly to the heteroatom (eg on the nitrogen atom). N-oxides are also part of the present invention.
• a (C 1 -C 8 ) alkyl heteroaryl group is a heteroaryl group as already described above, which is linked to the ring system via a straight-chain or branched (C 1 -C 8 ) -alkyl unit (as defined above).
• a (C 2 -C 8 ) alkenyl heteroaryl group is a heteroaryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkenyl unit (as defined above).
• a (C 2 -C 8 ) alkynylheteroaryl group is a heteroaryl group as already described above which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkynyl unit (as defined above).
• a (C 1 -C 8 ) alkyl heterocyclyl group is a heterocyclyl group as already described above which is linked to the ring system via a straight-chain or branched (C 1 -C 8 ) -alkyl unit (as defined above).
• a (C 2 -C 8 ) alkenyl heterocyclyl group is a heterocyclyl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 2 -C 8 ) -alkenyl unit (as defined above).
• Suitable hydroxy protective groups are all customary hydroxy protecting groups known to the person skilled in the art, in particular silyl ethers or esters of organic C 1 -C 10 -acids, C 1 -C 4 ethers, benzyl ethers or benzyl esters.
• the usual Hydroxy protecting groups are described in detail in TW Greene, PGM Wut's Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, 1991).
• the protecting groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, for example the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or Triisopropylsilyl groups (TIPS) or other common hydroxy protecting groups (eg, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, tetrahydropyranyl groups).
• TMS trimethylsilyl
• TES triethylsilyl
• TDMS tert-butyldimethylsilyl
• TDPS tert-butyldiphenylsilyl
• TIPS Triisopropylsilyl groups
• other common hydroxy protecting groups eg, methoxymethyl, methoxyethoxy
• the compounds of the general formula (I) according to the invention can be present as stereoisomers due to the presence of asymmetric centers.
• the present invention relates to all possible diastereomers both as racemates, as well as in enantiomerically pure form.
• stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the stereoisomers of the present invention may be present which are also included in the invention.
• the compounds according to the invention can also be present in the form of salts with pharmacologically acceptable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
• derivatives or prodrugs of the compounds of general formula (I) are encompassed by the invention.
• derivatives or prodrugs are esters, ethers or amides of the compounds of the general formula (I) or other compounds which metabolize in the organism to compounds of the general formula (I). Suitable compounds are listed, for example, in Hans Bundgaard (Ed.), Design of Prodrugs, Elsevier, Amsterdam 1985.
• a subgroup of compounds of the general formula (I) according to the invention are those compounds in which R 7 and R 8 independently of one another represent a hydrogen atom, a halogen atom, an optionally substituted (C 1 -C 10 ) -alkyl group, a cyano group, together a (C 1 -C 10 ) ) Alkylidene group or together with the carbon atom of the tetrahydronaphthalene system is an optionally substituted (C 3 -C 6 ) -cycloalkyl ring.
• Another subgroup of compounds of the general formula (I) according to the invention are those compounds in which R 6 and R 7 together have a fused five- to eight-membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1 to 2 keto groups, 1 to 2 ( Ci-C 5 ) - alkyl groups, 1 to 2 (CrC 5 ) alkoxy groups, and / or 1 to 4 halogen atoms substituted form.
• a further subgroup of compounds of the general formula (I) are those compounds in which R 1 and R 8 together form an annelated five- to eight-membered saturated or unsaturated carbocycle or heterocycle optionally substituted by 1 to 2 keto groups, 1 to 2 ( CrC 5 ) - alkyl groups, 1 to 2 (CrC 5 ) alkoxy groups, and / or 1 to 4 halogen atoms substituted form.
• R 1 and R 2 independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 4) -alkyl group, a (C 1 -C 10) radical ) Alkoxy group, a (C 1 -C 10) -alkylthio group, a (C 1 -C 5 ) -perfluoroalkyl group, a cyano group, a nitro group, or a -NR 9 R 9a group.
• Another preferred group of compounds of the general formula (I) are those compounds in which R 4 is a hydroxy group or an -OR 10 group. Particularly preferred are those compounds in which R 4 is a hydroxy group.
• R 5 is a (C 1 to C 5) alkyl group or a partially or completely fluorinated (C 1 to C 6) alkyl group, an aryl group, a (C 1 to C 2 alkyl) aryl group (C 2 -C 8 ) alkenylaryl group, a (C 3 -C 7 ) cycloalkyl group, a (CrC 8 ) alkyl (C 3 -C 7 ) cycloalkyl group or a (C 2 -C 8 ) alkenyl (C 3 -C 7 More preferred are those compounds in which R 5 represents a (C 1 -C 5 ) -alkyl group or a partially or completely fluorinated (C 1 -C 5 ) -alkyl group, Particular preference is given to those compounds in which R 5 is a Trifluoromethyl or pentafluoroethyl group.
• Another preferred group of compounds of the general formula (I) are those compounds in which R 7 represents a halogen atom or an optionally substituted methyl or ethyl group.
• Another preferred group of compounds of the general formula (I) are those compounds in which R 7 and R 8 each represent a methyl group, or together with the carbon atom of the tetrahydronaphthalene system form a cyclopropyl group. Particularly preferred are those compounds in which R 7 and R 8 each represent a methyl group.
• Another preferred group of compounds of the general formula (I) are those compounds in which R 3 represents an optionally substituted aryl or heteroaryl group.
• aryl or heteroaryl group is selected from the group consisting of naphthyl, benzofuranyl, pyrazolo [1,5-a] pyridinyl, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, Benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, chromanyl, isochromanyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoin
• a subgroup of compounds of the general formula (I) are those compounds in which the substituents R 11 and R 12 each independently represent a hydrogen atom, a halogen atom, in particular fluorine, a cyano or a methoxy group.
• the substituents R 11 and R 12 each represent a hydrogen atom.
• a particularly preferred group of compounds of the general formula (I) as defined above are those compounds in which R 1 , R 2 , R 11 , and R 12 independently of one another represent a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted ( Cio) alkyl group, or a (CrC- ⁇ o) alkoxy group, R 3 represents an optionally substituted aryl or heteroaryl group, R 4 represents a hydroxy group, an -OR 10 group or a -0 (CO) R 10 group , R 5 represents a (-C 10) alkyl group which is optionally partially fully fluorinated, or R 6 is a hydrogen atom, a halogen atom or an optionally substituted (Ci-do) alkyl group, R 7 and R 8 independently represent an optionally substituted ( C 1 -C 10 ) - alkyl group, together a (Ci-Cio) alkylidene group or together with the carbon atom of the te
• the replacement of the hydroxy against the amino group in the above-mentioned step b) can be realized, for example, by converting the compound of the general formula (III) into the corresponding azide by methods known in the art (nucleophilic substitution) which can be converted under appropriate conditions Conditions to the primary amine of the general formula (IV) can be reduced.
• a further possibility for introducing the amino group consists in the reaction of the compound of the general formula (III) with Burgess reagent (Tetrahedron Lett. 2002, 43, 3887-3890) and subsequent cleavage of the resulting heterocycle, which method known in the art is accessible.
• step c) The optional replacement of a carbonyl oxygen atom with sulfur described in step c) is known in the art and can be achieved, for example, by reaction with Lawesson's reagent or phosphorus pentasulfide.
• nucleofugic groups Nu in the compound R 3 -X-Nu used in step c for example, halogen atoms or leaving groups such as, for example, the acetate, tosylate, mesylate or triflate group are suitable.
• the compounds R 3 -X-Nu thus belong, for example, to the classes of the carboxylic acid, sulfonic acid, or sulfinic acid halides or the mixed anhydrides of these acids, as well as to the esters of chloroformic acid, toluenesulfonic acid, methylsulfonic acid and trifluoromethylsulfonic acid.
• process B for the preparation of compounds of the general formula (I) comprises reacting a compound of the general formula (IV) as described above with a compound of the general formula R 3 -CHO and the resulting imine is reduced.
• process D for the preparation of a compound of general formula (I) is characterized in that
• R 7 and R 8 together have the meaning of a (C 1 -C 10) -alkylidene group
• step b) of method D Methods for the selective reduction of a carboxylic acid or a carboxylic acid ester to the aldehyde, as used in step b) of method D, are known in the art.
• reaction steps for the modification of R 7 and R 8 may be included.
• the (C 1 -C 10 ) -alkylidene group in the intermediate (IIa) can be hydrogenated, whereby compounds of general formula (I) are available in which one of R 7 and R 8 has the meaning of a hydrogen atom, whereas the other radical is a (C 1 -C 10 ) -alkyl group.
• the (C 1 -C 10 ) -alkylidene group in the intermediate (IIa) can also be used as a substrate for a hydrohalogenation.
• Compounds of the general formula (I) are obtained as end products of the synthesis in which one of the radicals R 7 and R 8 has the meaning of a halogen atom, whereas the other radical represents a (C 1 -C 10 ) -alkyl group.
• cycloaddition reactions can also be carried out on the (C 1 -C 10) -alkylidene group in the intermediate (IIa).
• Particularly preferred here are cyclopropanation reactions which, as end products of the synthesis, are compounds of the general formula (I) in which the radicals R 7 and R 8 together with the ring carbon atom have the meaning of an (optionally substituted) cyclopropane ring.
• the anti-inflammatory activity of the compounds of general formula (I) is tested in animal experiments by testing in croton oil-induced inflammation in rat and mouse (J. Exp. Med. (1995), 182, 99-108).
• the animals are topically applied croton oil in ethanolic solution to the ears.
• the test substances are also applied topically or systemically simultaneously or two hours before the croton oil.
• ear weights are measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration.
• the compounds of the general formula (I) inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration.
• glucocorticoid receptor and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is checked using recombinant receptors.
• Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays.
• the substances show a high affinity for GR.
• an IC 50 (GR) 36 nM
• IC 50 (PR)> 1 ⁇ M was measured for the compound from Example 3L.
• GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is brought about by an interaction of the GR with other transcription factors, eg AP-1 and NF-kappa-B (for review see Cato ACB and Wade E, BioEssays 18, 371-378 1996).
• the compounds of the general formula (I) according to the invention inhibit the lipopolysaccharide (LPS) -derived secretion of the cytokine IL-8 in the human monocyte cell THP-1.
• the concentration of cytokines was determined in the supernatant by means of commercially available ELISA kits.
• glucocorticoid therapy One of the most common adverse effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines,ticianliche Verlagsgesellschaft mbH, Stuttgart, 1998].
• the reason for this is the stimulation of gluconeogenesis in the liver by induction of the responsible enzymes and by free amino acids, which arise from the degradation of proteins (catabolic effect of glucocorticoids).
• a key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids.
• the animals are sacrificed 8 hours after administration of the test substances, the liver removed and the TAT activity in the Homogenate measured.
• the compounds of the general formula (I) do not or only to a limited extent induce the tyrosine aminotransferase in doses in which they have an antiinflammatory effect in this test.
• 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 patients, especially mammals, more preferably humans.
• DISEASE refers to the following indications: (i) lung diseases associated with inflammatory, allergic and / or proliferative processes:
• rheumatic diseases especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica
• - collagenoses of any genesis e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjögren syndrome, still syndrome, Felty syndrome
• allergies associated with inflammatory and / or proliferative processes - All forms of allergic reactions, eg Quincke edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis
• Erythematous diseases triggered by different noxae e.g. Blasting, chemicals, burns etc.
• kidney disease associated with inflammatory, allergic and / or proliferative processes (vi) kidney disease associated with inflammatory, allergic and / or proliferative processes:
• liver disease associated with inflammatory, allergic and / or proliferative processes (vii) liver disease associated with inflammatory, allergic and / or proliferative processes:
• Acute liver cell decay - Acute hepatitis of various causes, eg viral, toxic, drug-induced
• Severe shock states eg, anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• SIRS systemic inflammatory response syndrome
• congenital secondary adrenal insufficiency e.g. congenital hypopituitarism
• the appropriate dose is different and depends for example on the potency of the compound of general formula (I), the patient (eg size, weight, sex, etc.), the mode of administration and the type and the severity of the conditions to be treated, as well as the use as prophylactic or therapeutic.
• the invention also relates to the use of the claimed compounds for the preparation of a pharmaceutical composition.
• the invention further provides
• a method for the treatment or prevention of inflammatory processes in particular for the treatment of a DISEASE (as defined above), which method comprises administering a pharmaceutically effective amount of a compound of general formula (I) wherein the amount is the disease or symptoms facilitated or suppressed, and wherein the compound is administered to a patient, preferably a mammal, more preferably a human, in need of such treatment;
• composition for anti-inflammatory, in particular for the treatment of a DISEASE (as defined above), wherein the composition comprises one of the compounds of general formula (I) according to the invention or mixtures thereof and optionally at least one pharmaceutical excipient and / or carrier.
• a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg of body weight.
• a dose of 10 to 30,000 ⁇ g per kg body weight more preferably a dose of 10 to 10,000 ⁇ g per kg body weight.
• this dose is conveniently administered several times a day.
• an acute shock e.g., anaphylactic shock
• single doses well above the above doses may be given.
• the formulation of the pharmaceutical preparations based on the compounds according to the invention is carried out in a manner known per se by reacting the active substance with the carriers customarily used in galenicals, fillers, disintegrants, binders, humectants, lubricants, absorbents,
• crystal suspensions For intraarticular injection appropriately prepared crystal suspensions may be used.
• aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
• the new compounds may be used in the form of suppositories, capsules, solutions (eg in the form of enemas) and ointments for both systemic and local therapy.
• these can be used in the form of aerosols and inhalants.
• the new compounds may be used as drops, ointments, tinctures and gels in appropriate pharmaceutical preparations.
• formulations in gels, ointments, fatty ointments, creams, pastes, powders, suspensions, emulsions or solutions are possible.
• the dosage of the compounds of general formula (I) should be 0.01% - 20% in these preparations in order to achieve a sufficient pharmacological effect.
• the invention likewise encompasses the compounds of the general formula (I) according to the invention as therapeutic active ingredient. Furthermore, the invention compounds of the general formula (I) according to the invention as a therapeutic agent together with one or more pharmaceutically acceptable and acceptable excipients and / or carriers.
• the compounds of the general formula (I) according to the invention may also be formulated and / or administered in combination with further active compounds.
• the invention therefore also relates to combination therapies or combined compositions wherein a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, is administered either simultaneously (optionally in the same composition) or sequentially together with one or more Medicaments for the treatment of one of the above-mentioned conditions.
• a compound of general formula (I) of the present invention may be combined with one or more medicaments for the treatment of such a condition.
• the drug to be combined may be selected from the following list:
• a PDE4 inhibitor including an isoform PDE4D inhibitor
• Adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
• a muscarinic receptor antagonist for example an M1, M2 or M3 antagonist such as a selective M3 antagonist
• M1, M2 or M3 antagonist such as a selective M3 antagonist
• ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
• a modulator of chemokine receptor function such as a CCR1 receptor antagonist
• such a combination with a compound of the general formula (I) or a pharmaceutically acceptable salt thereof is employed for the treatment of COPD, asthma or allergic rhinitis and may be administered by inhalation or orally in combination with xanthine (e.g. for example, aminophylline or theophylline), which may also be administered by inhalation or orally.
• xanthine e.g. for example, aminophylline or theophylline
• the c / s / frans nomenclature used in the examples below refers to the position of the substituents in the 1- and 2-positions of the saturated ring of the tetrahydronaphthalene system.
• ice means that the highest-ranking substitute (according to the Cahn-Ingold-Prelog definition) is in the axial position at the carbon atom 1 and the highest-ranking substituent at the carbon atom 2 is in the equatorial position; or that the highest-ranking substitute (according to the Cahn-Ingold-Prelog definition) is in the axial position at the carbon atom 1 in the equatorial position and the highest-ranking substituent at the carbon atom 2.
• trans means that the two highest-ranking substituents on carbon atom 1 and carbon atom 2 are either both in axial position or both in equatorial position.
• Example 1 Synthesis of Compounds of the General Formula (III) ⁇ -Fluoro- ⁇ -methoxy- ⁇ -dimethyl-trifluoromethyl-1-phthalo-naphthalene-1-diol (cis and frans isomers)
• Example 2A c / s-1-amino-6-fluoro-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-2-ol
• the solution is concentrated in vacuo, the residue at 0 0 C with 4 N sodium hydroxide solution adjusted to pH 14 and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure: 41% of the desired product.
• Example 2B Acid-amino-6-fluoro-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-2-ol
• Example 3A Naphthalene-2-carboxylic acid (c / s-6-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1 yl) -amide
• Example 3B Naphthalene-2-carboxylic acid (c / s-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-yl) amide

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