WO2005105097A2 - Derives de pyridopyrimidine - Google Patents

Derives de pyridopyrimidine Download PDF

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Publication number
WO2005105097A2
WO2005105097A2 PCT/EP2005/051892 EP2005051892W WO2005105097A2 WO 2005105097 A2 WO2005105097 A2 WO 2005105097A2 EP 2005051892 W EP2005051892 W EP 2005051892W WO 2005105097 A2 WO2005105097 A2 WO 2005105097A2
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Prior art keywords
pyrimidin
pyrido
dichlorophenyl
methyl
diseases
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WO2005105097A3 (fr
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Henrik Daub
Josef Wissing
Andrea Missio
Bert Klebl
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Agennix AG
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GPC Biotech AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to novel uses of known pyridopyrimidine derivatives, especially for prophylaxis and/or treatment of inflammations and inflammatory diseases, neurodegenerative disorders, immunological diseases, neuroimmunological diseases, autoimmune diseases, diabetes, transplant rejection, infective diseases, prio ⁇ diseases, cardiovascular diseases and disorders.
  • WO 96/34867 relates to the compounds of the present invention and their use as inhibitors of protein tyrosin kinases.
  • WO 96/34867 discloses the use of the compounds of the present invention as pharmaceutically active agents in treating cancer, atherosclerosis, restenosis, and psoriasis.
  • Object of the present invention is to provide compounds useful for prophylaxis and/or treatment of inflammatory diseases.
  • the present invention relates to the use of the compounds having the general formula (I)
  • R 1 represents -NR 3 R 4 , -SR 3 , -SO-R 3 , -SO 2 -R 3 , -OR 3 ;
  • R 2 , R 3 , and R 4 represent independently of each other hydrogen, - C ⁇ - ⁇ 2 ) n Ph * , heteroaryl, C 3 -C 7 -cycloalkyl, Ci-C ⁇ -alkyl, C ⁇ -C 6 -alkanoyI, C 2 -C B -alkenyl, C 2 -C 6 -alkynyl; wherein the cycloalkyl, alkyl, alkanoyl, alkenyl, alkynyl residues can optionally be substituted by one or more of the following groups: -NR s R ⁇ , phenyl, substituted phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, C 3 -C 7 -cycloalkyl; R 5 and R 5 represent independently of each other hydrogen, -(CH 2 )nPh*, heteroaryl, C 3 -C 7 -cycloalkyl, CrC 6 -alky
  • R 3 and R 4 can be taken together with the nitrogen to which they are attached to complete a ring having 3 to 7 carbon atoms, optionally containing 1 , 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
  • Ar represents phenyl, substituted phenyl, or heteroaryl; and pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of inflammatory diseases.
  • C 3 -C 7 -cycloalkyl refers to ⁇ ]
  • C C 6 -alkyr' refers to -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-C 2 H 5 . -C(CH 3 ) 3 , -C5H 11 .
  • -CH CH-C 2 H S
  • -CH 2 -C(CH 3 ) CH 2
  • -CH(CH 3 )-CH CH
  • -CH C(CH 3 ) 2
  • -C(CH 3 ) CH-CH 3
  • -C 2 H 4 -CH CH-CH 3
  • -CH(C ⁇ CH)-CH 2 -C CH, -C(C ⁇ CH) 2 -CH 3 , -CH 2 -CH(C ⁇ CH) 2 ,
  • halogen refers to -F, -Cl, -Br, and -I.
  • substituted phenyl refers to phenyl substituted by 1 , 2, or 3 groups independently selected from halogen, C ⁇ -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C ⁇ -C 6 -thioalkyl, C ⁇ -C 6 -alkenyl, C ⁇ -C 6 -alkynyl, C ⁇ -C 6 -alkoxy, -SH, -OH, -CN, -N0 2 , -NH 2 , -CFs, -OCF 3 , -COOH, -COOR 8 , -O-CO-R 8 , -NR S R 6 .
  • alkyl and alkoxy groups can be substituted as defined above.
  • Typical groups are, for instance, C-,-C 6 -alkyl d-Ce-alkyl carboxyalkyl: alkoxycarbonylalkyl: COOH COO— C C ⁇ -alkyl C-i-Ce-alkyi C ⁇ -C 6 -alkyl hydroxyalkyl: alkoxyalkyl: OH O— C ⁇ -C 6 -alkyl
  • Disubstituted phenyl is most preferred, and 2,6-disubstituted phenyl is especially preferred.
  • — (CH 2 ) n Ph* refers to phenyl or substituted phenyl.
  • heteroaryl refers to heteroaromatic groups which have from 4 to 9 ring atoms, from 1 to 4 of which are selected from O, N and/or S. Preferred groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic ring systems are included.
  • Typical heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzolhie ⁇ yl, 3,4-diethyIfura ⁇ yl, naphthyl, 4,7- dichloronaphthyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazyl, pyradizyl, tetrahydroquinolyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl, benzooxazolyl, benzo[1 ,3]dioxolyl, indolyl,
  • Preferred heteroaryl groups are phenyl and substituted phenyl.
  • Ar refers to phenyl, substituted phenyl, or heteroaryl.
  • thioalkyl refers to the residue -S-C-rC ⁇ -alkyl, wherein Ci-Ce-alkyl has the meanings as defined above.
  • the following groups are concerned -S-CH 3 , -S-C 2 H5, -S-C 3 H 7 , -S-CH(CH 3 ) 2 , -S-C 4 H 9 , -S-CH 2 -CH(CH 3 ) 2 , -S-CH(CH 3 )-C 2 H 5 , -S-C(CH 3 ) 3 , and -S-C 5 H1 1 .
  • Most preferred are -S-CH 3 , -S-C 2 H 5 , -S-C 3 H 7 , -S-CH(CH 3 ) 2 , and -S-C(CH 3 ) 3 .
  • alkyloxy refers to the residue -O-Ci-C ⁇ - alkyl, wherein C ⁇ -C 6 -alkyl has the meanings as defined above.
  • the following groups are concerned -O-CH 3 , -O-C2H 5 , -0-C 3 H 7 , -0-CH(CH 3 ) 2 , -0-C 4 Hg, -0-CH 2 -CH(CH 3 ) 2 , -0-CH(CH 3 )-C 2 H 5 , -0-C(CH 3 ) 3 , and -O-C 5 H 11 .
  • Most preferred are -0-CH 3 , -O-C 2 H 5 , -0-C 3 H 7 , -0-CH(CH 3 ) 2 , and -0-C(CH 3 ) 3 .
  • Ci-C ⁇ -alkyl has the meanings as defined above.
  • acyl means an aryl or Ci-C ⁇ -alkyl group bonded through a carbonyl group (-CO-).
  • acyl refers to -CO-Ar and -CO-C1- C ⁇ -alkyl, wherein Ci-Ce-alkyl has the meaning as defined above and Ar refers to phenyl, substituted phenyl and heteroaryl, wherein substituted phenyl and heteroaryl have the meanings as defined above.
  • C-i-Ce-alkyl, C ⁇ -C 6 -alkenyl, C ⁇ -C 6 -alkynyl, and Ci-C ⁇ -alkoxy groups as described above can optionally be substituted with one, two or more substituents.
  • Said substituents may be part of the Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, C-i-C ⁇ -thioalkyl, C-i-Ceralke ⁇ yl, Ci-Ce-alkynyl, and C ⁇ -C 6 -alkoxy groups listed above and/or may be selected from the group comprising phenyl, hydroxy, ami ⁇ o, substituted amino, halogen, carboxy, and 5- or 6-membered heterocyclic rings having 1 or 2 heteroatoms selected from nitrogen, oxygen, and/or sulfur.
  • “Substituted amino” means an amino group bearing one or two or three groups selected from Ci-Ce-alkyl and/or -(CH 2 ) n Ph*.
  • “Substituted amino” can be represented by the preferred general formulas -NH-C ⁇ -C6-alkyl, -N(C ⁇ -C ⁇ -
  • R in formula (I) is a -NR 3 R 4 group, wherein R 3 and R 4 independently of each other are hydrogen, C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkyl substituted with the group -NR 5 R 6 . If R 3 is hydrogen, it is preferred that R 4 represents C 1 -C 5 - alkanoyl or d-Ce-alka ⁇ oyl substituted with -COOH.
  • R 3 R 4 groups examples include amino, methylamino, diisopropylamino, acetyl-amino, propionyl-amino, 3-aminopropyl-amino, 3-ethylaminobutyl-amino, 3- di-n-propylamino-propylamino, 4-diethylamino-butylamino, 3-carboxypropionyl- amino.
  • R 3 and R 4 can be taken together with the nitrogen to which they are attached to complete a ring, which may contain 2 or more heteroatoms, preferably nitrogen.
  • cyclic -NR 3 R 4 groups examples include pyrrolidinyl, piperazinyl, 4-methylpiperaziny], 4-benzylpiperazinyI, pyridinyl, piperidinyl, pyrazi ⁇ yl, morpholinyl, and the like.
  • R 3 and R 4 can additionally complete a cyclic ring which is substituted with 1 or 2 oxo groups.
  • R 3 is hydrogen and R 4 is alkanoyl in which the alkyl residue bears a substituent such as carboxy or halogen
  • such group can be cyclized to form cyclic ketones.
  • Typical groups include 2-ketopyrrolidinyl and 1-pyrrolidinyl- 2,5-dione.
  • a preferred group of compounds are those wherein R 3 is hydrogen and R 4 is aryl, especially phenyl and phenyl substituted with groups such as aminoalkyl and ami ⁇ oalkoxy, e.g. dimethylaminoethyl or dimethylaminoethoxy.
  • Preferred compounds for the inventive uses are those wherein Ar is phenyl or phenyl substituted with 1 or 2 groups selected from C ⁇ -C 6 -alkyl and/or halogen, especially — Cl and — Br.
  • R 2 is C ⁇ -C 6 -alkyl, C 2 -C 6 -alke ⁇ yl, -(CH 2 ) n Ph * such as phenyl or benzyl, or C 3 -C 7 -cycloalkyl such as cyclopropyl.
  • An especially preferred group of compounds are those wherein X is O.
  • Another preferred group of compounds are those wherein X is NH. These are imines and are especially useful as intermediates leading to compounds wherein X is O.
  • R 1 is NH 2 or NHR 3 , wherein R 3 is C ⁇ -C 6 -alkyl optionally substituted with NR 5 R 6 .
  • R 1 , R 2 , and X have the meanings as defined above;
  • R 7 and R 8 independently of each other represent CrCg-alkyl and/or halogen.
  • Preferred alkyl groups are substituted with -NR 5 R 6 , wherein R s and R ⁇ are independently of each other hydrogen or alkyl, or together with the nitrogen to which they are attached complete a cyclic ring having 2 heteroatoms, for example
  • R 9 is hydrogen, C ⁇ -C 6 -alkyl, or -(CH 2 ) n Ph*
  • R , R 2 , R 7 , and R 8 have the meanings as defined above.
  • R 2 represents Ci-Ce-alkyl
  • R 3 represents hydrogen or C ⁇ -C 6 -alkyl
  • R 4 represents Ci-C ⁇ -alkyl or substituted C ⁇ -C 6 -alkyl
  • R 7 and R 8 independently of each other represent Ci-C ⁇ -alkyl and/or halogen.
  • R 2 , R 3 , R 4 , R r , and R 8 have the meanings as defined above.
  • R z represents C ⁇ -C 6 -alkyl or substituted C ⁇ -C 6 -alkyl
  • Ar represents phenyl, substituted phenyl, pyridyl, or substituted pyridyl.
  • R 2 is alkyl such as methyl or ethyl
  • R 7 and R ⁇ are halogen such as -Cl or -Br.
  • the most preferred Ar group is phenyl, ideally phenyl substituted with one, two, or three groups selected from halogen, C ⁇ -C 6 -alkyl, hydroxy, Ci-Crj-alkoxy, carboxy, Ci-C ⁇ -alkoxycarbonyl, and Ci-C ⁇ -alkyl substituted with hydroxy, carboxy, alkoxycarbonyl, amino, C -C ⁇ - alkyiamino, and di-C ⁇ -C 6 -alkylamino.
  • Ar represents phenyl or substituted phenyl.
  • R 10 is phenyl, chloro, bromo, methyl, methoxy, hydroxy, hydroxymethyl, 2- diethylaminoethoxy, methoxycarbonylmethyl, carboxy, carboxymethyl, ethoxycarbonyl, 2-carboxyethyl, or 2-ethoxycarbo ⁇ ylethyl.
  • the compounds of the general formulas (I) - (V) are able to form pharmaceutically acceptable salts with organic and inorganic acids.
  • acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, malelc acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaieic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfan
  • the compounds of the general formulas (I) — (V) are also able to form pharmaceutically acceptable salts with organic and inorganic bases.
  • Suitable organic and inorganic bases are bases derived from metal ions, e.g., aluminum, alkali metal ions, such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion or alkali- or alkaline-earth hydroxides, -carbonates or -bicarbonates.
  • metal ions e.g., aluminum, alkali metal ions, such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion or alkali- or alkaline-earth hydroxides, -carbonates or -bicarbonates.
  • Examples include aqueous sodium hydroxide, lithium hydroxyde, potassium carbonate, ammonia and sodium bicarbonate, ammonium salts, primary, secondary and terliary amines, such as, e.g., lower alkylamines such as methylamine, t-butylamine, procaine, ethanolamine, arylalkylamines such as dibenzylamine and N,N- dibenzylethyle ⁇ ediamine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, morpholine, giucamine, N-methyl- and N,N-dimethylglucamine, 1-adamantylamine, benzathine, or salts derived from amino acids like arginine, lysine, omithine or amides of originally neutral or acidic amino acids or the like.
  • lower alkylamines such as
  • the compounds of the present invention can be synthesized according to the procedures as outlined in PCT/US96/05819 (WO 96/34867), especially as described on pages 15 - 27 and schemes I - VI! (cf. pages 28 — 35).
  • the compounds according to formula (I) or any other formula (II) — (V) are pharmaceutically active agents for prophylaxis and/or treatment of inflammatory diseases.
  • these compounds are used for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of inflammations and inflammatory diseases in mammals, including humans.
  • Inflammatory diseases can emanate from infectious and non-infectious inflammatory conditions which may result from infection by an invading organism or from irritative, traumatic, metabolic, allergic, autoimmune, or idiopathic causes as shown in the following list.
  • the compounds disclosed herein can be used for prophylaxis and/or treatment of inflammations caused by invading organisms such as viruses, bacteria, prions, and parasites as well as for prophylaxis and/or treatment of inflammations caused by irritative, traumatic, metabolic, allergic, autoimmune, or idiopathic reasons.
  • the disclosed compounds are useful for prophylaxis and/or treatment of inflammatory diseases which are initiated or caused by viruses, parasites, and bacteria which are connected to or involved in inflammations.
  • mycoplasma pulmonis e.g. chronic lung diseases (CLD), murine chronic respiratory disease
  • ureaplasma urealyticum causes pneumonia in newborns
  • mycoplasma pneumoniae and chlamydia pneumoniae cause chronic asthma
  • C. pneumoniae causes atherosclerosis, pharyngitis to pneumonia with empyema, human coronary heart disease
  • Helicobacter pylori human coronary heart disease, stomach ulcers.
  • viruses are known to cause inflammatory diseases: herpesviruses especially cytomegalovirus (causes human coronary heart disease).
  • the compounds disclosed herein are useful for prophylaxis and/or treatment of inflammatory diseases caused and/or induced and/or initiated and/or enhanced by the afore-mentioned bacteria or viruses.
  • the compounds of formula (I) are useful for prophylaxis and/or treatment of inflammatory diseases of the central nervous system (CNS),
  • inflammatory rheumatic diseases inflammatory diseases of blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory disease uveitis, inflammatory diseases of the larynx.
  • inflammatory diseases of the central nervous system are algal disorders, protothecosis, bacterial disorders, abscessation, bacterial meningitis, idiopathic inflammatory disorders, eosinophiiic meningoencephalitis, feline polioencephalomyelitis, granulomatous meningoencephalomyelitis, meningitis, steroid responsive meningitis-arteritis, miscellaneous meningitis / meningoencephalitis, meningoencephalitis in greyhounds, necrotizing encephalitis, pug dog encephalitis, pyogranulomatous meningoencephalomyelitis, shaker dog disease, mycotic diseases of the CNS, parasitic encephalomyelitis, prion protein induced diseases, feline spongiform encephalopathy, protozoal encephalitis-encephalomyelitis, toxoplasmosis, neosporosis, sarcoc
  • inflammatory rheumatic diseases are rheumatoid arthritis, scleroderma, lupus, polymyositis, dermatomyosit ⁇ s, psoriatic arthritis, ankylosing spondylitis, Reiters's syndrome, juvenile rheumatoid arthritis, bursitis, tendinitis (tendonitis), and fibromyositis.
  • vasculitis examples for inflammatory diseases of blood vessels are vasculitis, autoantibodies in vasculitis, microscopic polyangiitis, giant cell artentis, Takayasu's arteritis, vasculitis of the central nervous system, thromboangiitis obliterans (Buerger's Disease), vasculitis secondary to bacterial, fungal, and parasitic infection, vasculitis and rheumatoid arthritis, vasculitis in systemic lupus erythematosus, vasculitis in the idiopathic inflammatory myopathies, relapsing
  • inflammatory diseases of the middle ear are acute suppurative otitis media, bullous myringitis, granular myringitis, and chronic suppurative otitis media, which can manifest as mucosal disease, cholesteatoma, or both.
  • Examples for inflammatory bowel diseases are ulcerative colitis, Crohn's disease.
  • Examples for inflammatory diseases of the skin are acute inflammatory dermatoses, urticaria (hives), spongiotic dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, erythemal multiforme (EM minor), Stevens-Johnson syndrome (SJS, EM major), toxic epidermal necrolysis (TEN), chronic inflammatory dermatoses, psoriasis, lichen planus, discoid lupus erythematosus, and acne vulgaris
  • Uveitis are inflammations located in and/or on the eye and may be associated with inflammation elsewhere in the body. In most circumstances, patients who have uveitis as part of a disease elsewhere in the body are aware of that illness- The majority of patients with uveitis do not have an apparent associated systemic illness.
  • causes of uveitis can be infectious causes, masquerade syndromes, suspected immune-mediated diseases, and/or syndromes confined primarily to the eye.
  • the following viruses are associated with inflammations: human immunodeficiency virus-l, herpes simplex virus, herpes zoster virus, and cytomegalovirus.
  • Bacterial or spirochetal caused, induced, initiated and/or enhanced inflammations are tuberculosis, leprosy, proprionobacterium, syphilis, Whipple's disease, leptospirosis, brucellosis, and lyme disease.
  • Parasitic (protozoan or helminthic) caused, induced, initiated and/or enhanced inflammations are toxoplasmosis, acanthameba, toxocariasis, cysticercosis, onchocerciasis.
  • inflammatory diseases caused, induced, initiated and/or enhanced by fungi are histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, sporotrichosis, blastomycos ⁇ s, and cryptococcosis.
  • Masquerade syndromes are, for instance, leukemia, lymphoma, retinitis pigmentosa, and retinoblastoma.
  • Suspected immune-mediated diseases can be selected from the group comprising ankylosing spondylitis, Behcet's disease, Crohn's disease, drug or hypersensitivity reaction, interstitial nephritis, juvenile rheumatoid arthritis, Kawasaki's disease, multiple sclerosis, psoriatic arthritis, Reiter's syndrome, relapsing polychondritis, sarcoidosis, Sjogren's syndrome, systemic lupus erythematosus, ulcerative colitis, vasculitis, vitiligo, Vogt Koyanagi Harada syndrome.
  • ankylosing spondylitis Behcet's disease, Crohn's disease, drug or hypersensitivity reaction
  • interstitial nephritis juvenile rheumatoid arthritis
  • Kawasaki's disease multiple sclerosis
  • psoriatic arthritis psoriatic arthritis
  • Reiter's syndrome relapsing polychondritis
  • Syndromes confined primarily to the eye are, for instance, acute multifocal placoid pigmentary epitheliopathy, acute retinal necrosis, birdshot choroidopathy, Fuch's heterochromic cyclitis, glaucomatocyclitic crisis, lens-induced uveitis, multifocal choroiditis, pars planitis, serpiginous choroiditis, sympathetic ophthalmia, and trauma.
  • Examples for inflammatory diseases of the larynx are gastroesophageal (laryngopharyngeal) reflux disease, pediatric laryngitis, acute laryngeal infections of adults, chronic (granulomatous) diseases, allergic, immune, and idiopathic disorders and miscellaneous inflammatory conditions.
  • Pediatric laryngitis is known as acute (viral or bacterial) infection such as laryngotracheitis (croup), supraglottitis (epiglottitis), diphtheria, and noninfectious causes are for example spasmodic croup and traumatic laryngitis.
  • Acute laryngeal infections of adults are, for instance, viral laryngitis, common upper respiratory infection, laryngotracheitis, herpes simplex, bacterial laryngitis, supraglottitis, laryngeal abscess, and gonorrhea.
  • Chronic (granulomatous) diseases can be selected from the group comprising bacterial diseases, tuberculosis, leprosy, scleroma, actinomycosis, tularemia, glanders, spirochetal (syphilis) diseases, mycotic (fungal) diseases, candidiasis, blastomycosis, histoplasmosis, coccidiomycosis, aspergillosis, idiopathic diseases, sarcoidosis, and Wegener's granulomatosis.
  • bacterial diseases tuberculosis, leprosy, scleroma, actinomycosis, tularemia, glanders, spirochetal (syphilis) diseases, mycotic (fungal) diseases, candidiasis, blastomycosis, histoplasmosis, coccidiomycosis, aspergillosis, idiopathic diseases, sarcoidosis, and Wegener's
  • Allergic, immune, and idiopathic disorders are, for example, hypersensitivity reactions, angioedema, Stevens-Johnson syndrome, immune and idiopathic disorders, infections of the immunocompromised host, rheumatoid arthritis, systeic lupus erythematosus, cicatricial pemphigoid, relapsing polychondritis, Sjogren's syndrome, and amyloidosis.
  • Miscellaneous inflammatory conditions are, for instance, parasitic infections, trichinosis, leishmaniasis, schistosomiasis, syngamus laryngeus, inhalation laryngitis, acute (thermal) injury, pollution and inhalant allergy, carcinogens, radiation injury, radiation laryngitis, radionecrosis, vocal abuse, vocal-cord hemorrhage, muscle tension dysphonias, and contact ulcer and granuloma.
  • the compounds of the general formula (I) or any other general formula (II) - (V) are also useful for prophylaxis and/or treatment of several other diseases such as neurodegenerative disorders, immunological diseases, neuroimmunological diseases, autoimmune diseases, diabetes, transplant rejection, infective diseases, prion diseases, cardiovascular diseases and disorders especially thombosis, cardiac hypertrophy, and myocardial ischemia.
  • diseases such as neurodegenerative disorders, immunological diseases, neuroimmunological diseases, autoimmune diseases, diabetes, transplant rejection, infective diseases, prion diseases, cardiovascular diseases and disorders especially thombosis, cardiac hypertrophy, and myocardial ischemia.
  • Another aspect of the present invention is directed to the use of at least one compound of any one of the general formulas (I), (la) — (It) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of cardiovascular diseases and cardiovascular disorders.
  • cardiovascular diseases and disorders are: aneurysm, stable angina, unstable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart diseases, congestive heart failure, heart valve diseases, heart attack, epidural hematoma, hematoma, subdural, Hippel- Lindau disease, hyperemia, hypertension, hypertension
  • Klippel-Trenaunay-Weber syndrome lateral medullary syndrome, long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud disease, Sneddon syndrome, superior vena cava syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary hemorrhagic telangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, vasospasm,
  • Another aspect of the present invention is directed to the use of at least one compound of any one of the general formulas (I), (la) - (It) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of neuro-degeneration and neurodegenerative disorders.
  • Neurodegenerative disorders of the central nervous system can be grouped into diseases of the cerebral cortex (Alzheimer disease), the basal ganglia (Parkinson disease), the brain-stem and cerebellum, or the spinal cord (amyotrophic lateral sclerosis).
  • neurodegeneration and neurodegenerative disorders are Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, AIDS-related dementia, retinitis pigmentosa, spinal muscular atrophy and cerebrellar degeneration, fragile X-associated tremor/ataxia syndrome (FXTAS), progressive supranuclear palsy (PSP), and striatonigral degeneration (SND), which is included with olivopontocerebellear degeneration (OPCD), and Shy Drager syndrome (SDS) in a syndrome known as multiple system atrophy (MSA).
  • FXTAS fragile X-associated tremor/ataxia syndrome
  • PSP progressive supranuclear palsy
  • SND striatonigral degeneration
  • OPCD olivopontocerebellear degeneration
  • SDS Shy Drager syndrome
  • Another aspect of the present invention is directed to the use of at least one compound of any one of the general formulas (I), (la) - (It) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of immunological diseases, neuroimmunological diseases, autoimmune diseases.
  • Immunological diseases are, for instance, asthma and diabetes, rheumatic and autoimmune diseases, AIDS, rejection of transplanted organs and tissues (cf. below), rhinitis, chronic obstructive pulmonary diseases, osteoporisis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, and other manifestations of allergic disease, as well as uncommon problems such as primary immunodeficiencies, including antibody deficiency states, cell mediated immunodeficiencies (e.g., severe combined immunodeficiency, DiGeorge syndrome, Hyper-lgE syndrome, Wiskott- Aldrich syndrome, ataxia- telangiectasia), immune mediated cancers, and white cell defects.
  • primary immunodeficiencies including antibody deficiency states, cell mediated immunodeficiencies (e.g., severe
  • autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or type 1 diabetes mellitus, immune mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel diseases, Crohn's disease, psoriasis, autoimmune thyroid diseases, and Hashimoto's disease, dermatomyositis, goodpastture syndrome, myasthenia gravis pseudoparalytica, ophtalmia sympatica, phakogene uveitis, chronical agressivce hepatitis, primary billiary cirrhosis, autoimunehemolytic anemy, Werlof disease, specific cells uncontrollably attack the body's own tissues and organs (autoimmunity), producing inflammatory reactions and other serious symptoms and
  • Hashimoto's thyroiditis is one of the most common autoimmune diseases. "Autoimmune disease” refers to a category of more than 80 chronic illnesses, each very different in nature, that can affect everything from the endocrine glands (like the thyroid) to organs like the kidneys, as well as to the digestive system.
  • autoimmune diseases There are many different autoimmune diseases, and they can each affect the body in different ways.
  • the autoimmune reaction is directed against the
  • autoimmune diseases such as systemic lupus erythematosus (lupus)
  • affected tissues and organs may vary among individuals with the same disease.
  • One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs.
  • damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus.
  • Transplant rejection Another aspect of the present invention is directed to the use of at least one compound of any one of the general formulas (I), (la) - (It) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of transplant rejection.
  • Transplant rejection is when a transplant recipient's immune system attacks a transplanted organ or tissue. No two people (except identical twins) have identical tissue antigens. Therefore, in the absence of immunosuppressive drugs, organ and tissue transplantation would almost always cause an immune response against the foreign tissue (rejection), which would result in destruction of the transplant. Though tissue typing ensures that the organ or tissue is as similar as possible to the tissues of the recipient, unless the donor is an identical twin, no match is perfect and the possibility of organ/tissue rejection remains.
  • inventive compounds of any one of the general formulas (I), (la) - (It) are used as immunosuppressive drugs and/or anti- rejection drugs in order to prevent transplant rejection.
  • transplant rejection is the graft-versus-host-disease (GVHD) that can occur following bone marrow transplant.
  • GVHD graft-versus-host-disease
  • the donor's immune cells in the transplanted marrow make antibodies against the host's (transplant patient's) tissues and attack the patient's vital organs.
  • Transplant rejections also known as graft rejection or tissue/organ rejection
  • Said organs comprise especially inner organs such as heart, heart-lungs, lungs, liver, kidney, pancreas, spleen, skin, tissue, bone marrow, spinal marrow, hormone producing glands, gonads and gonadal glands.
  • Another aspect of the present invention is directed to the use of at least one compound of any one of the general formulas (I), (la) - (It) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of infective diseases including opportunistic infections.
  • infective diseases are AIDS, Alveolar Hydatid Disease (AHD, Echinococcosis), Amebiasis (Entamoeba histolytica Infection), Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), Balantidium Infection (Balantidiasis), Baylisascaris Infection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystis hominis Infection (Blastomycosis), Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy), Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue Syndrome), Chagas Disease (American Trypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydia pneumoniae Infection, Cho
  • Coccidioidomycosis Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth Disease), Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (Cyclospora infection), Cysticercosis (Neurocysticercosis), Cytomegalovirus Infection, Dengue / Dengue Fever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (Alveolar Hydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection, Entomoeba hartmanni Infection, Entomoeba histolytica Infection (Amebiasis), Entomoe
  • Another aspect of the present invention is directed to the use of at least one compound of any one of the general formulas (I), (la) - (It) and/or pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of prion diseases.
  • Prions are infectious agents which do not have a nucleic acid genome. It seems that a protein alone is the infectious agent. A prion has been defined as "small proteinaceous infectious particle which resists inactivation by procedures that modify nucleic acids". The discovery that proteins alone can transmit an infectious disease has come as a considerable surprise to the scientific community. Prion diseases are often called “transmissible spongiform encephalopathies", because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum. Probably most mammalian species develop these diseases. Prion diseases are a group of neurodegenerative disorders of humans and animals and the prion diseases can manifest as sporadic, genetic or infectious disorders.
  • Examples for prion diseases acquired by exogenous infection are the Bovine spongiform encephalitis (BSE) of cattle and the new variant of Creutzfeld-Jakob disease (vCJD) caused by BSE as well as scrapie of animals.
  • BSE Bovine spongiform encephalitis
  • vCJD Creutzfeld-Jakob disease
  • human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatroge ⁇ ic CJD (iCJD), Gerstmann-Straussler-Scheinker (GSS) disease, fatal familial insomnia (FFI), and especially the new variant CJD (nvCJD or vCJD).
  • prion is used to describe the causative agents which underlie the transmissible spongiform encephalopathies.
  • a prion is proposed to be a novel
  • infectious particle that differs from viruses and viroids. It is composed solely of one unique protein that resists most inactivation procedures such as heat, radiation, and proteases. The latter characteristic has led to the term protease- resistant isoform of the prion protein.
  • protease-resistant isoform has been proposed to slowly catalyze the conversion of the normal prion protein into the abnormal form.
  • isoform in the context of prions means two proteins with exactly the same amino acid sequence that are folded into molecules with dramatically different tertiary structures.
  • the normal cellular isoform of the prion protein (PrP c ) has a high ⁇ -helix content, a low ⁇ -sheet content, and is sensitive to protease digestion.
  • the abnormal, disease-causing isoform (PrP Sc ) has a lower ⁇ -helix content, a much higher ⁇ -sheet content, and is much more resistant to protease digestion.
  • prion diseases refers to transmissible spongiform encephalopathies.
  • Examples for prion diseases comprise Scrapie (sheep, goat), TME (transmissible mink encephalopathy; mink), CWD (chronic wasting disease; muiedeer, deer, elk), BSE (bovine spongiform encephalopathy; cows, catties), CJD (Creutzfeld-Jac ⁇ b Disease), vCJD, GSS (Gerstmann-Straussler-Scheinker syndrome), FFI (Fatal familial Insomnia), Kuru, and Alpers Syndrome.
  • BSE vCJD
  • CJD transmissible spongiform encephalopathies.
  • CJD chronic wasting disease
  • CWD chronic wasting disease
  • muiedeer, deer, elk chronic wasting disease
  • BSE bovine spongiform encephalopathy
  • cows, catties
  • Figure 1 shows the chemical structure of compound A
  • Figure 2 shows the effect of Compound A on cellular p38 kinase activity.
  • Serum-starved HeLa cells were treated with the indicated Compound A concentrations for 15 min and then either stimulated for 30 min with 10 ⁇ g/ml anisomycin or for 5 min with 50 ng/ l EGF prior to cell lysis.
  • Total cell extracts were resolved by gel electrophoresis and then immunoblotted with specific antisera specifically recognizing phosphorylated Thr-344 in MAPKAP-K2 (upper left panel), Rsk1 dually phosphorylated on Thr-359 and Ser-363 (upper right panel), MAPKAP-K2 (lower left panel) or Rsk1 (lower right panel).
  • FIG. 3 shows the cellular inhibition of RICK kinase by Compound A.
  • COS-7 cells were transiently transfected with pPM7-RICK-KRdCst expression plasmid (1.35 ⁇ g/well) plus either control vector or pPM7- RICK plasmid encoding the full length kinase (0.15 ⁇ g/well).
  • pPM7-RICK-KRdCst expression plasmid (1.35 ⁇ g/well) plus either control vector or pPM7- RICK plasmid encoding the full length kinase (0.15 ⁇ g/well).
  • [ 32 P]orthophosphate labelling and affinity purification using StrepTactin beads cellular RICK-KRdC phosphorylation was visualized by autoradiography prior to protein detection with StrepTactin-HRP.
  • Figure 4 shows the inhibition of LPS-stimulated cytokine production in human PBMCs by Compound A.
  • human PBMCs were stimulated with 1 ⁇ g/ml LPS.
  • culture supernatants were harvested and the levels of the released cytokines TNF ⁇ , MIP-1 ⁇ and IL-8 were quantified by ELISA.
  • Cytokine levels in the absence of inhibitor were set to 100 % and their concentrations in the culture medium the presence of increasing Compound A doses are expressed relative to this value,
  • LPS stimulated the release of TNF ⁇ , MIP1 ⁇ and IL-8 by about 75-, 25- and 5-fold, respectively.
  • supernatant from LPS-treated cells were 12 ng/ml (TNF ⁇ ), 70 ng/ml (MIP-1 ⁇ ) and 247 ng/ml (IL-8).
  • Figure 5 HFF cells were pretreated with DMSO or the indicated Compound A concentrations for 15 min and then stimulated with either 50 ⁇ g/ml poly(l-C) or 1 ⁇ g/ml LPS. After 16 h, IL-8 levels in the cell culture supernatants were measured by ELISA.
  • FIG. 6 Following preincubation with the indicated Compound A concentrations for 15 min, U373 astrocytoma cells were stimulated for 2 h with 50 ⁇ g/ml poIy(l-C) prior to lysis and RNA isolation. After reverse transcription, quantitative PCR was performed to measure interferon- ⁇ (IFN ⁇ ) gene induction in control incubated and poly(l-C)- treated cells. Transcript levels from IFN ⁇ -treated cells were set to 100% and the levels upon inhibitor treatment are shown relative to this value.
  • IFN ⁇ interferon- ⁇
  • the compounds according to general formula (I) are inhibitors of several protein- tyrosine kinases such as FGFR1 (fibroblast growth factor receptor), Src, Abl and c- kit as well as inhibitors of Wee1 kinase. It is known that Compound A was developed as tyrosine kinase inhibitor for cancer treatment.
  • Compound A was tested in in vitro assays of Src kinase activity using myelin basic protein as a substrate (Wang, Q., Smith, J. B., Harrison, M. L., and Geahlen, R. L., Biochem. Biophys. Res. Commun. 1991 , 178, 1393-1399). Notably, Compound A inhibited Src with a subnanomolar IC50 value in said assays.
  • RICK Rip-like interacting caspase-like apoptosis-regulatory protein
  • Lipopolysaccharide (LPS)-regulated biosynthesis of MIP-1 ⁇ was also efficiently suppressed by Compound A with an IC50 of about 15 nM in human PBMCs.
  • Compound A also interfered with IL-8 biosynthesis upon exposure of human foreskin fibroblast (HFF) cells to the synthetic double- stranded RNA analogue poly(l:C), which acts on toll-like receptor 3 and triggers cellular signaling in a way similar to viral infection (Akira, S., Curr. Opin. Immunol. 2003, 15, 5-11 ).
  • IFN interferons
  • Frozen PBMCs were purchased from Cambrex Bio Science. Thawed and washed cells were re-suspended in RPMI medium containing 1% FBS and then seeded into 24 well dishes (1 x 10 6 cells per well). After 1 h, the medium was aspirated, the cell culture plates were washed with medium to remove non- adherent cells and fresh medium was added. The medium was exchanged again after a further 3.5 h prior to addition of either DMSO or different amounts of

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Abstract

La présente invention concerne l'utilisation de dérivés de pyridopyrimidine ayant la formule générale (I) où X représente =NH, =N-acyle, =O, or =S; R1 représente -NR3R4, -SR3, -SO-R3, -SO2-R3, -OR3; R2, R3 et R4 représentent indépendamment les uns des autres un hydrogène, -(CH2)nPh*, hétéroaryle, C3-C7-cycloalkyle, C1-C6-alkyle, C1-C6-alkanoyle, C2-C6-alcényle, C2-C6-alkynyle; les résidus cycloalkyle, alkyle, alkanoyle, alcényle, alkynyle pouvant éventuellement être substitués par au moins un des groupes suivants: -NR5R6, phényle, phényle substitué, thioalkyle, alkyloxy, hydroxy, carboxy, halogène, cycloalkyle; R5 et R6 représentent indépendamment un hydrogène, (CH2)nPh*, hétéroaryle, C3-C7-cycloalkyle, C1-C6-alkyle, C1-C6-alkanoyle, C2-C6-alcényle, C2-C6-alkynyle; R5 et R6 peuvent être pris ensemble avec l'azote auquel ils sont attachés pour compléter un cycle ayant 3 à 7 atomes de carbone, contenant éventuellement 1, 2 ou 3 hétéroatomes sélectionnés parmi azote, oxygène et soufre; Ph* représente un phényle ou un phényle substitué; n vaut 0, 1, 2 ou 3; R4 peut éventuellement représenter -CO-R3, -CO-OR3, -SO2-R3, -SO2-NR5R6, -CO-NR5R6, -CS-NR5R6, -C(=NH)-R3, -C(=NH)-NR5R6; R3 et R4 peuvent être pris ensemble avec l'azote auquel ils sont attachés pour compléter un cycle ayant 3 à 7 atomes de carbone, éventuellement contenant 1, 2 ou 3 hétéroatomes sélectionnés parmi l'azote, oxygène et soufre; Ar représente phényle, phényle substitué ou hétéroaryle; et leurs sels pharmaceutiquement acceptables pour la prévention et/ou le traitement de maladies inflammatoires, maladies neurodégénératives, maladies immunologiques, maladies neuroimmunologiques, maladies autoimmunes, diabètes, rejets d'implants, maladies infectieuses, maladies à prions, maladies et troubles cardiovasculaires.
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