WO2010049073A1 - 1,1,1-trifluoro-3-amino-3-hétéroaryl-2-propanols, procédé pour leur production et leur utilisation comme agents anti-inflammatoires - Google Patents

1,1,1-trifluoro-3-amino-3-hétéroaryl-2-propanols, procédé pour leur production et leur utilisation comme agents anti-inflammatoires Download PDF

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Publication number
WO2010049073A1
WO2010049073A1 PCT/EP2009/007469 EP2009007469W WO2010049073A1 WO 2010049073 A1 WO2010049073 A1 WO 2010049073A1 EP 2009007469 W EP2009007469 W EP 2009007469W WO 2010049073 A1 WO2010049073 A1 WO 2010049073A1
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alkyl
group
compounds
amino
hydroxy
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PCT/EP2009/007469
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English (en)
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Markus Berger
Hartmut Rehwinkel
Heike Schäcke
Ekkehard May
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Bayer Schering Pharma Aktiengesellschaft
Astrazeneca Ab
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Publication of WO2010049073A1 publication Critical patent/WO2010049073A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to compounds of formula I, a process for their production and their use as anti-inflammatory agents.
  • glucocorticoids are small molecules having a steroidal structure that interact with the glucocorticoid receptor (GR), whether endogenous, like Cortisol, or synthetic, like dexamethasone and others.
  • GR glucocorticoid receptor
  • the GCs potently inhibit pro-inflammatory cytokines and chemokines at the site of administration, whereas they elicit only limited systemic effects
  • Desired physico chemical properties for example are a good solubility and/or a suitable partition coefficient log P.
  • anti-inflammatory agents of the following general formula
  • the present invention therefore relates to compounds of general formula I
  • R 1 is a group in which
  • # denotes the point of attachment of the R 1 group via a single bond
  • X 1 , X 2 , X 3 , X 4 , X 5 independently of one another are nitrogen, or a group C- R 4 and the R 1 group contains a minimum of 1 and a maximum of 3 nitrogen atoms in the ring
  • R 4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, (Ci-C 5 )-alkoxy, (Ci-C 5 )-alkyl, (CrC 5 )- halo-alkyl and COOR 5 ,
  • R 5 is selected from the group consisting of hydrogen and Ci-C 5 -alkyl group
  • R 2 means a monocyclic, or bicyclic, aromatic, partially aromatic, or non-aromatic ring system, which optionally contains 1-4 nitrogen atoms,
  • R 3 means a group selected from
  • R 6 means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (d-CsJ-alkyl, (Ci-C 5 )-alkoxy, cyano, CF 3 , nitro, COO(Ci-C 5 -alkyl) or C(O)OCH 2 -phenyl or a heteroaryl group whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, and in which R 7 and R 8 , independently of one another, can be hydrogen, (Ci-C 5 )-alkyl or (CO)-(Ci-C 5 )-alkyl.
  • R 1 is a group , in which
  • # denotes the point of attachment of the R 1 group via a single bond, and the R 1 group contains 1 or 2 nitrogen atoms in the ring,
  • X 1 , X 2 , X 3 , X 4 , X 5 independently of one another are nitrogen, or a group C-R 4
  • R 4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, (CrC 5 )-alkoxy, (Ci-C 5 )-alkyl, (d-CsJ-halo-alkyl and COOR 5 ,
  • R 5 is selected from the group consisting of hydrogen and Ci-C 5 - alkyl group
  • R 2 means a monocyclic or bicyclic, aromatic, partially aromatic, or non- aromatic ring system, which optionally contains 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (Ci-CsJ-alkyl, partially fluorinated (Ci-C 5 )-alkyl, (Ci-C 5 )- perfluoroalkyl, (d-CsJ-alkoxy, (Ci-C 5 )-alkylthio or, cyano,
  • R 3 means a group selected from -(Ci-CsJ-alkyl, which may be optionally partially or completely halogenated, -(C 2 -C 5 )-alkenyl R 6 -(Ci-C 5 )-alkyl, R 6 -(C 2 -C 5 )-alkenyl, -S-(CrC 5 )-alkyl,
  • R 6 means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (Ci-C 5 )-alkyl, (Ci-C 5 )-alkoxy, cyano, CF 3 , nitro, COOCd-Cs-alkyl) or C(O)OCH 2 -phenyl or a heteroaryl group whereby the heteroaryl group may contain 1-3 hetero atoms which may optionally be substituted by 1-3 alkyl groups, hydroxy, halogen and cyano, and in which R 7 and R 8 , independently of one another, can be hydrogen, (d-CsJ-alkyl or (CO)-(C r C 5 )-alkyl.
  • R is a group , in which # denotes the point of attachment of the R 1 group via a single bond, and the R 1 group contains 1 or 2 nitrogen atoms in the ring,
  • X 1 , X 2 , X 3 , X 4 , X 5 independently of one another are nitrogen, or a group C- R 4
  • R 4 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (Ci-C 5 )-alkoxy, and (C-i-CsJ-alkyl,
  • R 2 means a monocyclic, or bicyclic, aromatic, partially aromatic, or non- aromatic ring system, which optionally contains 1-3 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom and optionally is substituted in one or more places by a radical that is selected from the group of carbonyl, halogen, hydroxy, (Ci-C 5 )-alkyl, (Ci-C 5 )-perfluoroalkyl or (Ci-C 5 )-alkoxy,
  • R 3 means a group selected from
  • R 7 and R 8 independently of one another, can be hydrogen, (Ci-C 5 )-alkyl or (COHCrCsJ-alkyl, -OH, or -O-Cd-CsJ-alkyl.
  • the invention relates to compounds of general formula I according to the claims in which the R 1 group contains a minimum of 1 or 2 nitrogen atoms in the ring.
  • R 3 means a group selected from -(C r C 5 )-alkyl, which may be optionally partially or completely halogenated, -(C 2 -C 5 )-alkenyl -(C 2 -C 5 )-alkynyl,
  • R is a group , in which # denotes the point of attachment of the R 1 group via a single bond, and the R 1 group contains 1 or 2 nitrogen atoms in the ring, and
  • R 3 means a group selected from
  • R 6 means an aryl group which may optionally be substituted by 1-3 hydroxy, halogen, (Ci-C 5 )-alkyl, (d-C 5 )-alkoxy, cyano, CF 3 , nitro,
  • R 2 means an optionally substituted phthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydroquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1 ,7- or 1 ,8-naphthyridinyl, indolonyl, isoindolonyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole, coumarin
  • R 2 means phenyl, naphthyl, quinolin-5-yl, phthalazinyl, quinazolinyl which can be optionally substituted independently with 1-3 radicals selected from the group carbonyl, (Ci-C 5 )-alkyl, chlorine or fluorine. Preferably there is only one carbonyl group in R 2 .
  • R 2 means, quinolin-5-yl, phthalazinyl, quinazolinyl which can be optionally substituted independently with 1-3 radicals selected from the group carbonyl, (CrCsJ-alkyl, chlorine or fluorine.
  • R 2 means phenyl, naphthyl, quinolin-5-yl, phthalazinyl, quinazolinyl which can be optionally substituted independently one or two times by carbonyl, methyl or halogen.
  • R 2 means quinolin-5-yl, which can be substituted independently one or two times by carbonyl, methyl or fluorine.
  • R 2 is a heterocycle containing one or more nitrogen atoms , such as pyridine, pyrimidine, indolizine, indol or isoindol, pyrazole, imidazole, triazole, quinoline, isoquinoline, cinnoline, phthalazine, or quinazoline.
  • R 2 is an oxygen containing heterocycle, such as coumaron (benzofurane) or chromane.
  • R 2 is a heterocycle, containing two or more different heteroatoms, such as thiazole, isothiazole, oxazole or benzothiazole.
  • R 2 can be substituted in one or more positions with a radical selected from the group carbonyl, halogen, hydroxy, (Ci-C 5 )-alkyl, (d-C 5 )-alkoxy, (Ci-C 5 )- alkylthio, (Ci-C 5 )-perfluoroalkyl, cyano, nitro, COOR 5 , NR 7 R 8 ,(CO)NR 7 R 8 or a (Ci-C 5 -alkylene)-O-(CO)-(Ci.C 5 )alkyl group, preferably hydroxy, halogen, or carbonyl; preferably with methyl, chlorine or fluorine.
  • the substituents can be the same or different.
  • the substituent carbonyl for a group R 2 is to be defined such that the carbonyl carbon atom is a ring carbon atom, to which an oxygen atom is double-bound.
  • radical R 2 is substituted with none, one or several of the same or different radicals from the group (CrC 5 )-alkyl, (C-i-CsJ-alkoxy, hydroxy, halogen, or carbonyl, preferably with none or one or several of the same or different radicals from the group (Ci-CsJ-alkyl, hydroxy, carbonyl or halogen, in particular by one or more of the same or different radicals from the group methyl, chlorine or fluorine, especially by methyl, chlorine or fluorine, are an object of the invention.
  • nitrogen atom of radical R 2 of general claim 1 (such as in in the indazole, quinolone, isoquinolone and phthalazine) can also be alkylated with a (Ci-C 5 )-alkyl group.
  • R 2 means a monocyclic 5- or 6- membered heterocyclic ring system that is linked via any position, such as, e.g., furan or thiophene, are another object of the invention.
  • R 2 means an substituted phenyl ring or an substituted naphthyl ring are another object of the invention.
  • At least one of the substituents for rings contained in R 1 is selected from methoxy or fluoro,
  • R 2 is quinolin-5-yl which can be substituted independently one or two times by carbonyl, methyl or fluoro,
  • R 3 is selected from methylsulfanyl, ethylsulfanyl, dimethylamino, hydroxy, methoxy, ethoxy,
  • alkyl refers to a straight or branched, substituted or unsubstituted chain.
  • propyl comprises "- propyl and /so -propyl
  • butyl comprises "-butyl, /so -butyl and fert -butyl.
  • the alkyl groups can be straight-chain or branched and stand e.g. for a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or n-pentyl group, or a 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group.
  • One aspect are (C 1 - C 5 )alkyl groups.
  • a methyl or ethyl group is preferred.
  • a partially or completely fluorinated CrCs-alkyl group the following partially or completely fluorinated groups are considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1 ,1-difluoroethyl, 1 ,2-difluoroethyl, 1 ,1 ,1-trifluoroethyl, tetrafluoroethyl, and pentafluoroethyl. Of the latter, the trifluoromethyl group or the pentafluoroethyl group is preferred.
  • the CrC 5 -alkoxy groups can be straight-chain or branched and stand for a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group.
  • a methoxy or ethoxy group is preferred. They can optionally be substituted by CrC 5 -alkyl groups, cyano groups or halogen
  • the Ci-C 5 -alkylthio groups can be straight-chain or branched and stand for a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert- butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3- methylbutylthio group.
  • a methylthio or ethylthio group is preferred.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom. Preferred is a fluorine, chlorine or bromine atom.
  • haloalkyl is to be understood as preferably meaning branched and unbranched alkyl, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen.
  • said haloalkyl is, e.g. chloromethyl, fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof.
  • the NR 7 R 8 group includes, 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 .
  • C 2 -C 5 -alkenyl is a straight or branched, substituted or unsubstituted, chain including isomers having an E- or Z-configurated double bond such as e.g. vinyl, propen-1-yl, propen-2-yl (AIIyI), but-1-en-1-yl, but-1-en-2-yl, but-2- en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1- en-3-yl, but-3-en-1-yl.
  • alkenyl means alkenylene such as e.g.
  • heterocyclyl means e.g. piperidinyl-, morpholinyl-, thiomorpholinyl-, piperazinyl-, tetrahydrofuranyl-, tetrahydrothienyl-, imidazolidinyl- or pyrrolidinyl- whereby the heterocyclyl group may be bound via any possible ring atom.
  • the heterocyclyl group may be substituted by Ci-Cs-alkyl (optionally substituted), hydroxy-, C r C 5 -alkoxy-, NR 7 R 8 -, halogen, cyano-, COOR 5 -, CHO-. If possible these substitutens may also be bound to one of the free nitrogen atoms if any. N-oxides are also included in the definition.
  • aryl in the sense of the invention means aromatic or partially aromatic carbocyclic rings having 6 to 14 carbon atoms, e.g. phenyl and which may also may have a condensed a second or third ring such as e.g. napthyl or anthranyl. Further examples are phenyl, naphthyl, tetralinyl, anthranyl, benzoxazinone, dihydroindolone, indanyl, and indenyl.
  • the aryl groups may be substituted at any position leading to a stable molecule by one or several substitutents, e.g. 1-3 substitutents, such as e.g.
  • Ci-C 5 -alkyl hydroxy, halogen, Ci-C 5 -alkyl, Ci-C 5 -alkoxy, cyano, CF 3 , nitro, COO(C 1 -Cs- alkyl or benzyl) or a heteroaryl group, preferably by 1-3 Ci-C 5 -alkyl groups, hydroxyl, halogen, cyano or Ci-C 5 -alkoxy.
  • the optionally substituted phenyl group is one aspect of the invention. Yet another aspect are the compounds of formula I whereby R 8 is not phenyl.
  • heteroaryl means an aromatic ring system having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, for five membered rings the maximum number of heteroatoms is three whereby only two oxygen or sulfur atoms are allowed provided that these two are not directly bound to each other. Possible heteroaryl rings are e.g.
  • the term or "moncyclic or bicyclic, aromatic or partially aromatic or non- aromatic ring system which optionally contains 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms” includes the definitions of aryl, heteroaryl and heterocyclyl.
  • the preferred number of heteroatoms is 1-5, more preferred 1-3.
  • the heteroatoms are 1-2 nitrogen atoms.
  • the ring systems are to be understood as the ring systems as disclosed under the definitions for these three terms having a partially or completely hydrogenated ring and in case of bicyclic systems one or two rings being partially or completely hydrogenated. Should the substituents exemplified under the definition section differ from the group as defined in the claims both groups are one aspect of the invention, preferred the group as shown in the claims.
  • the substituent carbonyl for a group R 2 is to be defined such that the carbonyl carbon atom is a ring carbon atom, which is bound to an oxygen atom via a double bond.
  • R 2 Generally as substituents for R 2 are preferred halogen or carbonyl.
  • partially aromatic ring system refers to bicyclic systems that contain an aromatic ring and a non-aromatic ring, such as, e.g., benzoxazinones or dihydroindolone.
  • the compounds of the present invention can exist in stereoisomeric forms such as enantiomers of diastereoisomers depending on their structure and residues as defined in formula I. In one aspect of the invention therefore all these enantiomers, diastereoisomers or mixtures thereof are encompassed.
  • the isolation of enantiomerically or diastereomerically pure isomers can be done by methods of the state of the art, e.g. using column chromatography with a chiral solid phase.
  • Salts in the sense of the present invention are not only physiologically unobjectable salts but also salts which might be objectable for pharmaceutical use but which are useful e.g. during the process of isolation or purification.
  • physiologically unobjectable salts includes addition salts of mineral acids, carbonic acids, sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluolsulfonic acid, benzenesulfonic acid, naphthalinesulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, pivalic acid, maleic acid, succinic acid and benzoic acid.
  • mineral acids e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluolsulfonic acid, benzenesulfonic acid, naphthalinesulf
  • physiologically unobjectable salts includes salts of commonly suitable bases, e.g. salts of alkalimetall (e.g.. sodium- and potassium salts), alkaline earth salts (e.g. calcium- and magnesium salts) and ammonium salts, derivatized from NH 3 or organic amines with 1 to 16 carbon atoms, e.g.
  • alkalimetall e.g. sodium- and potassium salts
  • alkaline earth salts e.g. calcium- and magnesium salts
  • ammonium salts derivatized from NH 3 or organic amines with 1 to 16 carbon atoms, e.g.
  • ethylamine diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, prokaine, dibenzylamine, N-methylmorpholin, arginin, lysin, ethylendiamine and N-methylpiperidin.
  • Solvates in the sense of the invention are such forms of the compounds of the present combinations which build complexes by coordination of solvent molecules in a liquid or a solid phase. Hydrates are special forms of a solvate wherein water molecules are coordinated.
  • the compounds can be produced by the various processes that are described below (a-b).
  • the hydrazino ketones of formula (III) can be reacted with Grignard, organo-lithium reagents or organo-indium reagents of type R 3 -CH 2 -Met to yield hydrazino alcohols of type (IV).
  • Catalytic hydrogenation reduces the hydrazino carboxylates (IV) to amines of type (V) which can be substrates for aromatic amination with arylhalogens R 2 HaI under copper, nickel or palladium catalysis to yield compound (I).
  • Cbz has the meaning of a Carboxybenzyl group.
  • nucleophiles are alkylcuprates, vinylcuprates, thioles, allylsilanes, vinylsilanes, vinylstannanes, grignard compounds, in the presence of Lewis acids like BF 3 or AIMe 3 , AICI 3 , cyanides, amines, alcoholes and thioalcoholes.
  • a further object of the invention are compounds of general formulae V, VII and IX,
  • R 1 , R 2 and R 3 have the meanings described in the claims, especially the intermediates used in the examples, and their use for the manufacture of compounds
  • the various compounds according to the invention can be separated into pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art.
  • the racemic mixtures can be separated by chromatography on an even optically active carrier material (CHIRALPAK AD®) into the pure isomers.
  • esters it is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereoisomeric esters that are obtained by fractionated crystallization or by chromatography, and to saponify the separated esters in each case to the optically pure isomers.
  • an optically active acid for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
  • glucocorticoid receptor glucocorticoid receptor
  • MR mineral corticoid receptor
  • PR progesterone receptor
  • AR androgen receptor
  • the GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is considered. This inhibition is produced by an interaction of the GR with other transcription factors, e.g., AP-1 and NF-kappa-B (for a survey, see Cato, A. C. B., and Wade, E., BioEssays 18, 371-378, 1996).
  • AP-1 and NF-kappa-B for a survey, see Cato, A. C. B., and Wade, E., BioEssays 18, 371-378, 1996.
  • the compounds of general formula I according to the invention inhibit the secretion of cytokine IL-8 into the human monocyte cell line THP-1 that is triggered by lipopolysaccharide (LPS).
  • the concentration of the cytokines was determined in the supernatant by means of commercially available ELISA kits.
  • the anti-inflammatory action of the compounds of general formula I was tested in the animal experiment by tests in the croton oil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108).
  • croton oil in ethanolic solution was applied topically to the animals' ears.
  • the test substances were also applied topically or systemically at the same time or two hours before the croton oil.
  • the ear weight was measured as a yardstick for inflammatory edema, the peroxidase activity as a yardstick for the invasions of granulocytes, and the elastase activity as a yardstick for the invasion of neutrophilic granulocytes.
  • the compounds of general formula I inhibit the three above-mentioned inflammation parameters both after topical administration and after systemic administration.
  • the compounds of general formula I possess superior physico chemical properties.
  • the compounds described in Examples 4 and 8 for example showed a water solubility of 136 mg per liter.
  • glucocorticoid therapy One of the most frequent undesirable actions of a glucocorticoid therapy is the so-called "steroid diabetes" [cf., Hatz, H. J., Glucocorticoide: lmmunsammlunguben, Pharmakologie und Therapierichtlinien [Glucocorticoids: Immunological Bases, 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 enzymes responsible in this respect and by free amino acids, which are produced from the degradation of proteins (catabolic action of glucocorticoids).
  • a key enzyme of the catabolic metabolism in the liver is tyrosinamino transferase (TAT).
  • the activity of this enzyme can be determined from liver homogenates by photometry and represents a good measurement of the undesirable metabolic actions of glucocorticoids.
  • To measure the TAT induction the animals are sacrificed 8 hours after the test substances are administered, the livers are removed, and the TAT activity is measured in the homogenate. In this test, at doses in which they have an anti-inflammatory action, the compounds of general formula I induce little or no tyrosinamino transferase.
  • the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans:
  • DISEASE stands for the following indications: (i) Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes:
  • ARDS Adult respiratory distress syndrome
  • rheumatic diseases especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, Behget's disease
  • Vitiligo - Collagenoses of any origin, e.g., systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, Sjogren's syndrome, Still's syndrome, Felty's syndrome
  • eczema All forms of eczema, such as, e.g., atopic eczema (primarily in children)
  • - Bullous dermatoses such as, e.g., autoimmune pemphigus vulgaris, bullous pemphigoid - Diseases of the lichenoid group, - Pruritis (e.g., of allergic origin)
  • Kidney diseases which coincide with inflammatory, allergic and/or proliferative processes:
  • Gastrointestinal diseases which coincide with inflammatory, allergic and/or proliferative processes:
  • Tumor diseases which coincide with inflammatory, allergic and/or proliferative processes, such as, e.g.: carcinomas or sarcomas
  • Severe shock conditions e.g., anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Innate primary suprarenal insufficiency e.g., congenital adrenogenital syndrome - Acquired primary suprarenal insufficiency, e.g., Addison's disease, autoimmune adrenalitis, meta-infective tumors, metastases, etc.
  • diabetes type I insulin-dependent diabetes
  • osteoarthritis a progressive hypertension
  • Guillain-Barre syndrome a progressive hypertension
  • restenoses after percutaneous transluminal angioplasty Alzheimer's disease, acute and chronic pain
  • arteriosclerosis a progressive hypertension
  • reperfusion injury a progressive hypertension
  • myocardial infarction a progressive hypertension
  • thermal injury multiple organ injury secondary to trauma
  • acute purulent meningitis necrotizing enterocolitis and syndromes associated with hemodialysis
  • leukopheresis granulocyte transfusion.
  • the compounds of formula (I) can also be used to treat disorders such as: Conies Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's Syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, oesophageal varicies, muscle weakness, increased melanin pigmentation of the skin, weight loss, hypotension, hypoglycemia, Cushing's Syndrome, obesity, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation
  • disorders such as: Con
  • the compounds of general formula I according to the invention can be used for treatment and prophylaxis of additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this respect Hatz, H. J., Glucocorticoide: lmmunologische Grundlagen, Pharmakologie und Therapierichtlinien, Academicliche Verlagsgesellschaft mbH, Stuttgart, 1998).
  • the suitable dose varies and depends on, for example, the active strength of the compound of general formula I, the host, the type of administration, and the type and severity of the conditions that are to be treated, as well as the use as a prophylactic agent or therapeutic agent.
  • the invention provides:
  • a process for treating a DISEASE comprises an administration of an amount of the compound according to the invention, in which the amount suppresses the disease and in which the amount of compound is given to a patient who requires such a medication;
  • a pharmaceutical composition for treating a DISEASE comprises one of the compounds according to the invention or mixture thereof and at least one pharmaceutical adjuvant and/or vehicle.
  • the daily doses comprise a range of 1 ⁇ g to 100,000 ⁇ g of the compound according to the invention per kg of body weight.
  • a recommended daily dose lies 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 of body weight and more preferred is a dose of 10 to 10,000 ⁇ g per kg of body weight.
  • this dose is suitably administered several times daily.
  • individual doses can be given that are significantly above the above-mentioned doses.
  • the formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art by the active ingredient being processed with the vehicles that are commonly used in galenicals, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, coloring agents, etc., and converted into the desired form of administration.
  • the vehicles that are commonly used in galenicals, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, coloring agents, etc.
  • parenteral administration injection and infusion preparations are possible.
  • intra-articular injection correspondingly prepared crystal suspensions can be used.
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments both for systemic and for local treatment.
  • the latter 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.
  • formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible.
  • the dosage of the compounds of general formula I should be 0.01 %-20% in these preparations to achieve a sufficient pharmacological action.
  • the invention also comprises the compounds of general formula I according to the invention as therapeutic active ingredients.
  • the compounds of general formula I according to the invention are part of the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles.
  • the invention also comprises a pharmaceutical composition that contains one of the pharmaceutically active compounds according to the invention or mixtures thereof or a pharmaceutically compatible salt thereof and a pharmaceutically compatible salt or pharmaceutically compatible adjuvants and vehicles.
  • the compounds of general formula (I) according to the invention can optionally also be formulated and/or administered in combination with other active inqredients.
  • the invention further relates to combination therapies or compositions wherein a GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a GR agonist of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with one or more agents for the treatment of any of the above disease states.
  • a GR agonist of the invention can be combined with one or more agents for the treatment of such a condition.
  • the one or more agents is selected from the list comprising:
  • a PDE4 inhibitor including an inhibitor of the isoform PDE4D
  • adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
  • a muscarinic receptor antagonist for example a M1 , M2 or M3 antagonist, such as a selective M3 antagonist
  • a muscarinic receptor antagonist such as a M1 , M2 or M3 antagonist, such as a selective M3 antagonist
  • M1 , M2 or M3 antagonist such as a selective M3 antagonist
  • a modulator of chemokine receptor function such as a CCR1 receptor antagonist
  • an inhibitor of matrix metalloproteases most preferably targeting MMP- 2, MMP-9 or MMP-12, or
  • neutrophil serine proteases most preferably neutrophil elastase or proteinase 3.
  • the GR agonist of formula (I), or a pharmaceutically acceptable salt thereof can be administered by inhalation or by the oral route and this is in combination with a xanthine (such as aminophylline or theophylline) which can be administered by inhalation or by the oral route.
  • a xanthine such as aminophylline or theophylline
  • HPLC HPLC was performed on analytical columns packed with a commercially available solid phase containing long hydrocarbon chains (C 18 ) chemically bound onto silica. Compounds injected onto such a column move along it by partitioning between the mobile solvent phase and the hydrocarbon stationary phase. The compounds are retained in proportion to their hydrocarbon-water partition coefficient, with water-soluble compounds eluted first and oil-soluble compounds last. This enables the relationship between the retention time on a reverse-phase column and the n-octa no I/water partition coefficient to be established.
  • the partition coefficient P is deduced from the capacity factor K, given by the expression
  • the calibration graph plots logK versus logP.
  • the partition coefficients P of the test compound was obtained by interpolation of the calculated capacity factor K on the calibration graph.
  • Used Instrumentation were a Knick pH-Meter 766, a Waters Alliance HT 2790, DAD Waters 996, MS Micromass ZQ HPLC devices with a Spherisorb ODS 3 ⁇ m 4.6 x 60 mm HPLC column (Mobile phase: 1.54 g NH4OAc solved in 500 ml Water. Addition of 1500 ml MeOH, pH adjusted to pH 7.0 with cone. Acetic acid, Flow: 1 ml/min) and MassLynx V4.1 SCN562 software for HPLC (Waters GmbH, Helfmann-Park 10, DE-65760 Eschborn) and in house developed POW determination software for logP evaluation by interpolation of determined logK to logP. Stock solution of reference compounds were solved in methanol (s. table above). 100 ⁇ l of each stock solution and 450 ⁇ l methanol and 550 ⁇ l water are combined in a HPLC vial.
  • a stock solution of 7 mg formamide (dead time compound) solved in 10 ml methanol was prepared. 100 ⁇ l of this stock solution was mixed with 1250 ⁇ l methanol and 550 ⁇ l water.
  • Test compounds in 10 mM DMSO stock solutions were diluted 1 :10 with methanol/water 75:25.
  • the following injection scheme was used: formamide, reference mixture, test compound, test compound, formamide, reference mixture (injection volume: formamide 5 ⁇ l, references 5 ⁇ l, test compounds 15 ⁇ l).
  • Retention times of samples and references were analysed by HPLC with diode-array detection (200-400nm). MS was used as verification of compound identity.
  • the logP value was calculated automatically by the POW determination software by interpolation of determined logK to logP.
  • the title compound can be prepared by treating 5- ⁇ [(6-methoxypyridine-3-yl)(2-trifluoromethyloxiran-2-yl)methyl]amino ⁇ -1/-/- quinolin-2-one with caesium carbonate in ethanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne les composés de formule (I), des procédés pour leur production et leur utilisation comme agents anti-inflammatoires.
PCT/EP2009/007469 2008-10-30 2009-10-17 1,1,1-trifluoro-3-amino-3-hétéroaryl-2-propanols, procédé pour leur production et leur utilisation comme agents anti-inflammatoires WO2010049073A1 (fr)

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EP08167907.8 2008-10-30

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040023999A1 (en) * 2002-03-26 2004-02-05 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2005100335A1 (fr) * 2004-03-30 2005-10-27 Boehringer Ingelheim Pharmaceuticals, Inc. Synthese stereoselective de certains oxydes d'ethylene a substitution trifluoromethyle
WO2008006627A1 (fr) * 2006-07-14 2008-01-17 Bayer Schering Pharma Aktiengesellschaft Benzyl amines, procédé pour leur préparation et leur utilisation en tant qu'agents anti-inflammatoires
WO2009040288A1 (fr) * 2007-09-27 2009-04-02 F. Hoffmann-La Roche Ag Dérivés de 1,1,1-trifluoro-2-hydroxy-3-phénylpropane

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040023999A1 (en) * 2002-03-26 2004-02-05 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2005100335A1 (fr) * 2004-03-30 2005-10-27 Boehringer Ingelheim Pharmaceuticals, Inc. Synthese stereoselective de certains oxydes d'ethylene a substitution trifluoromethyle
WO2008006627A1 (fr) * 2006-07-14 2008-01-17 Bayer Schering Pharma Aktiengesellschaft Benzyl amines, procédé pour leur préparation et leur utilisation en tant qu'agents anti-inflammatoires
WO2009040288A1 (fr) * 2007-09-27 2009-04-02 F. Hoffmann-La Roche Ag Dérivés de 1,1,1-trifluoro-2-hydroxy-3-phénylpropane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. BETAGERI ET. AL: "Trifluoromethyl group as a pharmacophore: Effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand.", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 15, 19 August 2005 (2005-08-19), pages 4761 - 4769, XP025313923 *

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