WO2003068225A1 - Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma - Google Patents

Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma Download PDF

Info

Publication number
WO2003068225A1
WO2003068225A1 PCT/EP2003/000467 EP0300467W WO03068225A1 WO 2003068225 A1 WO2003068225 A1 WO 2003068225A1 EP 0300467 W EP0300467 W EP 0300467W WO 03068225 A1 WO03068225 A1 WO 03068225A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
ring
alkanediyl
alkyl
radicals
Prior art date
Application number
PCT/EP2003/000467
Other languages
German (de)
English (en)
Inventor
Thorsten Blume
Wolf-Dietrich DÖCKE
Wolfgang Halfbrodt
Joachim Kuhnke
Ursula MÖNNING
Bernd Elger
Herbert Schneider
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to KR10-2004-7012557A priority Critical patent/KR20040084909A/ko
Priority to BR0307706-3A priority patent/BR0307706A/pt
Priority to MXPA04007943A priority patent/MXPA04007943A/es
Priority to UA20040907401A priority patent/UA81111C2/uk
Priority to JP2003567407A priority patent/JP2005522447A/ja
Priority to YU71304A priority patent/RS71304A/sr
Priority to CA002475770A priority patent/CA2475770A1/fr
Priority to EP03739380A priority patent/EP1474138A1/fr
Priority to AU2003245523A priority patent/AU2003245523A1/en
Publication of WO2003068225A1 publication Critical patent/WO2003068225A1/fr
Priority to NO20043840A priority patent/NO20043840L/no

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention relates to the use of a microglial inhibitor for the manufacture of a medicament which inhibits interleukin 12 (IL 12) and interferon- ⁇ mediated immune responses, and its use for the treatment of T cell mediated immunological disorders and non-T cell mediated inflammatory responses ,
  • IL 12 interleukin 12
  • IL 12 interleukin 12
  • the immune system includes a variety of cells and tissue complexes that communicate primarily via soluble factors. It is known that many immunological diseases are characterized by an imbalance of soluble immune factors, such as. Rev. Immunol., 7: 145-173 (1989, Street and Mosman, FASEB J. 5: 171-177 (1991); Lucey et al., Clin. Microbiol. Rev.
  • cytokine interleukin 12 is produced by phagocytic cells, such as macrophages / monocytes, dendrites, B cells, and other antigen presenting cells (APCs), and affects both function of natural killer cells (NK cells) as well as of T lymphocytes IL 12 can stimulate the production of interferon gamma (IFN ⁇ ) in both cell types.
  • T lymphocytes can be roughly classified into two categories characterized by the expression of certain surface antigens (CD4 and CD8): CD4-positive T cells (helper T cells) and CD8-positive T cells (cytotoxic T cells) T-cells).
  • CD4 and CD8-positive T cells helper T cells
  • cytotoxic T cells cytotoxic T cells
  • Th1-mediated immune responses are more numerous with the pathogenesis Immune disorders, especially autoimmune diseases, such as: type I insulin-dependent diabetes mellitus (IDDM), multiple sclerosis, allergic contact dermatitis, psoriasis, rheumatoid arthritis, chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis) ), Lupus diseases and other collagenoses as well as acute graft-versus-host disease (“host-versus-graft”) allografts.
  • IDDM type I insulin-dependent diabetes mellitus
  • multiple sclerosis sclerosis
  • allergic contact dermatitis psoriasis
  • rheumatoid arthritis chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis)
  • Lupus diseases and other collagenoses as well as acute graft-versus-host disease ("host-versus-graft”) allografts.
  • Interleukin 12 is known to play a critical role in regulation Interleukin 12 induces production of primarily IL-2, IFN ⁇ , TNF ⁇ and TNF ⁇ in these cells (Mosmann and Sad, Immunol., Today 17: 138-146 (1996); Gately et al., Annu. Rev Immunol., 16: 495-521 (1998)).
  • IFN ⁇ is a potent mediator of IL-12 activity.
  • Overproduction of interferon gamma may be exemplified by MHC II (Major Histocompatibility Comp lex) -associated autoimmune diseases (.
  • IL-12 and IL ' -12 / IL-18-induced IFN ⁇ from NK cells are essential in the pathomechanism of non-T cell-mediated inflammatory responses (eg, "Toxic shock syndrome", endotoxemia, sepsis and septic shock, ARDS, "first dose response "in antibody therapy eg OKT3 administration in allotransplantation)
  • Toxic shock syndrome endotoxemia, sepsis and septic shock, ARDS, "first dose response "in antibody therapy eg OKT3 administration in allotransplantation
  • IL-12 also plays a role in inflammation with currently unclear pathomechanisms (eg, eclampsia) (Hayakawa et al., J. Reprod Immunol 47: 121-138 (2000); Daniel et al., Am J. Reprod., Immunol 39: 376-380 (1998)).
  • pathomechanisms eg, eclampsia
  • TNF ⁇ inflammatory mediated inflammatory reaction
  • TNF ⁇ plays a significant pathological role in infectious diseases (such as sepsis, "toxic shock syndrome” (Tracey et al., Nature 330: 662-664 (1987);
  • Activation of the microglia is a central step in the inflammatory process of almost all degenerative diseases of the central nervous system.
  • the microglia may remain in the activated state for a prolonged period of time by causing various inflammatory factors, e.g. B. reactive oxygen / nitrogen intermediates,
  • microglia Proteases, cytokines, complement factors and neurotoxins, produce and secrete. These in turn cause neuronal dysfunction and degeneration.
  • the activation of microglia can be done by various stimuli, such as. 569: 141-145 (1992)), phonon protein, cytokines, or by cell fragments (Combs, CK et al., J. Neurosci 19: 928-939 (1999); Wood, P.L., Neuroinflammation: Mechanisms and Management, Humana Press (1998).
  • benzimidazoles which inhibit the activation of microglia are useful in the treatment of neuroinflammatory diseases such as AIDS dementia, amyotrophs Lateral Sclerosis, Creutzfeldt-Jakob Disease, Down's Syndrome, Diffuse Lewy Body Disease, Huntington's Disease, Leukencephalopathy, Multiple Sclerosis, Parkinson's Disease, Pick's Disease, Alzheimer's Disease, Stroke, Temporary Lobe Epilepsy, and Tumors.
  • neuroinflammatory diseases such as AIDS dementia, amyotrophs Lateral Sclerosis, Creutzfeldt-Jakob Disease, Down's Syndrome, Diffuse Lewy Body Disease, Huntington's Disease, Leukencephalopathy, Multiple Sclerosis, Parkinson's Disease, Pick's Disease, Alzheimer's Disease, Stroke, Temporary Lobe Epilepsy, and Tumors.
  • the invention is based on the problem of providing a means suitable for the treatment of immunological diseases wherein the immunological diseases are triggered by increased production of cytokines, e.g. IL 12, IFN and TNF ⁇ without other factors in the
  • Immune system act, whereby side effects are reduced or prevented.
  • microglial inhibitors inhibit the production of IL 12 and IFN ⁇ and induce interleukin-10 production (IL 10) and are therefore used for the preparation of a medicament for the treatment of a monocyte, macrophage or T cell - Mediated, specifically Th1-cell-mediated, immunological disease and non-T-cell-mediated pathophysiological inflammatory reactions.
  • T lymphocytes can be subdivided into CD4-positive T cells (helper T cells) and CD8-positive T cells (cytotoxic T cells) and the CD4 helper cells T-cells (Th cells) turn into T-helper cells 1 (Th1) and T-helper cells 2 (Th2), which are u. a. differ in their ability to prevent tolerance.
  • the cytokines IL 12 and IFN ⁇ play an important role in the induction and maintenance of THI cell differentiation. Differentiated Th1 cells secrete IFN ⁇ , interleukin 2 and TNF ⁇ / ⁇ . These cytokines in turn activate macrophages and cytotoxic CD8 positive T cells.
  • the invention relates to the use of microglial inhibitors for the preparation of a medicament for interrupting IL 12 or IFN ⁇ production in cells of monocytic origin or T cells and NK cells.
  • microglial inhibitors for the preparation of a medicament for interrupting IL 12 or IFN ⁇ production in cells of monocytic origin or T cells and NK cells.
  • cytokines such as TNF ⁇ . ⁇ , IFN ⁇ , IL-2 and IL12
  • inflammatory diseases which are not based on neuroinflammation, autoimmune diseases, allergic and infectious diseases, toxin-induced inflammation , pharmacologically triggered inflammatory reactions as well as pathophysiologically relevant inflammatory reactions of currently unclear origin.
  • inflammatory and autoimmune diseases are: chronic inflammatory bowel disease (inflammatory bowel disease, Crohn's disease, ulcerative colitis), arthritis, allergic contact dermatitis, psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, type I insulin-dependent diabetes mellitus, Rheumatoid arthritis, lupus and other collagenosis, Graves' disease, Hashimoto's disease, graft versus host disease and graft rejection.
  • allergic, infectious and toxin-induced and ischemia-induced diseases are: Sarcoidosis, Asthma, Hypersensitive Pneumonitis, Sepsis, Septic shock, Endotoxin shock, Toxic shock syndrome, Toxic liver failure, ARDS (Acute Respiratory Syndrome), Eclampsia, Cachexia, Acute Viral infections (eg mononucleosis, fulminant hepatitis), organ damage after reperfusion.
  • An example of a pharmacologically triggered inflammation with pathophysiological relevance is the "first dose response" after administration of anti-T cell antibodies such as OKT3.
  • Suitable microglial inhibitors according to the invention are compounds which, upon stimulation with the A ⁇ peptide, achieve an inhibition of the microglial activity of at least 20% and an inhibition of the cytokine activity of at least 30%.
  • the biological properties of the microglial inhibitors can be demonstrated by the methods known to the person skilled in the art, for example with the aid of the investigation methods described below and in WO 01/51473.
  • microglial inhibitors with the properties described above are benzimidazoles of the formula I, their tautomeric and isomeric forms and salts.
  • R 1 is an aryl group or a five- or six-membered one
  • Heteroaryl group having one or two heteroatoms selected from the group comprising N, S and O, wherein the aryl or
  • Heteroaryl group having up to three radicals independently of one another, selected from the group comprising:
  • R 4 wherein X is a bond, CH 2 , (CH 2 ) 2 or CH (CH 3 ) 2 , wherein furthermore the radicals R 4 and R 4 are selected independently of one another according to the meanings given below and wherein two substituents on R 1 if they are ortho on each other, can each be linked together so that they together form a Methandiylbisoxy-, ethane-1, 2-diylbisoxy, propane-1, 3-diyl or butane-1, 4-diyl group, or
  • -ZR 2 ' is an aryl group or a five- or six-membered one
  • Heteroaryl group having one or two heteroatoms selected from the group comprising N, S and O, a benzothienyl group or an indolyl group, wherein said aryl or heteroaryl group may be substituted with up to three independently selected from the group consisting of
  • R 4 wherein a bond, CH 2 , (CH 2 ) 2 , or CH (CH 3 ) 2 , further wherein the radicals R 4 and R 4 'are independently selected according to the meanings given below and where two radicals of R 1 , if they are ortho on each other, can be linked to each other so that they together form a methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1, 4 form diyl group,
  • Z is NH, NR 2 ", O, S, SO or SO 2 , where R has the meaning given below,
  • R 2 and R 2 are each independently a radical selected from the group comprising:
  • R 3 are independently one or two radicals selected from
  • NHCOR 4 NHCOOR 4 , NHCONHR 4 and R 4 , where the radicals R 4 , R 4 and R 6 are selected independently of one another according to the meanings given below,
  • A is a group selected from the group comprising Ci.-io
  • Alkyl (C 1-3 alkanoyl), may be substituted, B is a radical selected from the group comprising COOH, COOR 5 ,
  • Y is a group selected from the group comprising O, NH, where R 4 and R 6 have the meanings given below,
  • R 4 , R 4 , R 5 , R 5 and R 6 have the following meanings; in it are:
  • R 4 and R 4 are each independently a radical selected from among
  • R 5 and R 5 ' are each independently a radical selected from among
  • Group comprising C ⁇ -6 alkyl, C2-6 alkenyl, C 2- 6 -alkynyl, where one C atom to O, S, SO, S0 2, NH, N-alkyl or C ⁇ -3 NC 1- 3- alkanoyloxy, furthermore (co-3-alkanediyl-C 3-7 -cycloalkyl), wherein in a five-membered cycloalkyl ring, a ring member ring-N or ring-0 may be and in a six- or seven-membered Cycloalkyl ring may be one or two ring members each ring N and / or ring O atoms, wherein the ring N atoms may optionally be substituted by -CC 3-alkyl or C 3 alkanoyl, and also (C 0 - 3-alkanediyl-aryl) and (C 0-3 -alkanediyl-heteroaryl) wherein the heteroaryl group is five-
  • R 5 and R 5 together with the amide N atom of B form a five- to seven-membered, saturated or unsaturated heterocyclic ring which is another N- or O- or may contain S atom and which may be substituted by C 1-4 alkyl,
  • the present invention also includes physiologically acceptable salts and esters of the abovementioned compounds, in particular the acid salts of the nitrogen bases of the benzimidazole derivatives according to the invention, furthermore the salts of carboxylic acids of the derivatives according to the invention with bases and the esters of the carboxylic acids of the derivatives and of carboxylic acids derived from carboxylic acid derivatives are, for example of Carbsonäureamiden.
  • the benzimidazole derivatives may have one or more chiral centers such that the compounds may exist in several isomeric forms.
  • the compounds of the formula I can also be present as tautomers, stereoisomers or geometric isomers.
  • the invention also includes all possible isomers, such as E and Z isomers, S and R enantiomers, diastereomers, racemates and mixtures thereof, including the tautomeric compounds. All these isomeric compounds are - even if not expressly stated - part of the present invention.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods, for example crystallization, chromatography or salt formation.
  • heteroaryl groups contained in the benzimidazole compounds are composed of five or six skeleton atoms and may contain one or two heteroatoms. Heteroatoms are oxygen (O), nitrogen (N) and sulfur (S). Examples of heteroaryl groups are pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.
  • heteroaryl groups are part of R 1 or R 2 , the group is bonded via a C atom to the respective N atom of the benzimidazole skeleton or to the substituent Z.
  • Suitable aryl radicals are, in particular, the phenyl radical, but also the naphthyl radical.
  • the aryl and heteroaryl radicals can be attached in any manner to the benzimidazole skeleton or another group, for example as 1- or 2-naphthyl or as 2-, 3- or 4-pyridinyl.
  • Alkyl groups can be straight-chain or branched. Examples of alkyl groups are methyl, ethyl, ⁇ -propyl, / 'so-propyl, n-butyl, s /-butyl, tert-butyl, n-pentyl, s / -pentyl, erf-pentyl, neo-pentyl, ⁇ - Hexyl, sec-hexyl, heptyl, octyl, nonyl, decyl. Also, the higher homologues comprise both the linear and the branched alkyl groups, that is, for example, 2-ethylhexyl for octyl and 3-propyl-hexyl for nonyl.
  • Perfluorinated alkyls are preferably CF 3 and C 2 F 5 .
  • Alkenyl groups can be straight-chain or branched. Examples are vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl and 3-methyl-2-propenyl Akenylreste in the context of the invention.
  • Alkynyl groups can be straight-chain or branched. Examples of these are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • Cycloalkyl groups are in each case preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl (corresponds to C 3-7 -cycloalkyl).
  • saturated heterocyclic rings or cycloalkyls containing one or more heteroatoms are: piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepine and 2,6-dimethylmorpholine, N-phenylpiperazine, methoxymethylpyrrolidine, where the
  • Alkanediyl, alkenediyl, alkynediyl and cycloalkanediyl radicals mentioned in the description of the invention are synonymous with alkylene, alkenylene, alkynylene and cycloalkylene. Insofar as the number of C atoms contained in the general formulas of the alkanediyl radicals is given and the lower limit of this number is given as the value 0, this alkanediyl radical is not included in the respective case.
  • alkanes, alkenes and alkynes for A are: straight-chain or branched alkanediyl having one to eight carbon atoms, for example methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, furthermore 1-methylethanediyl, 1-ethylethanediyl, 1-methylpropanediyl, 2-methylpropanediyl, 1-methylbutanediyl, 2-methylbutanediyl, 1-ethylbutanediyl, 2-ethylbutanediyl, 1-methylpentanediyl, 2-methylpentanediyl, 3-methylpentanediyl and analogous compounds.
  • Straight-chain or branched alkenediyl and alkynediyl having two to eight carbon atoms are alkenediyl groups or alkynediyl groups having double and triple bonds in all possible positions and with all possible methyl or ethyl substitutions.
  • these radicals in each case one or two C-atoms by O, NH, N-alkyl or N-C ⁇ -3 -3 C ⁇ can alkanoyl be exchanged, wherein the replaced group is separated by at least two C-atoms of V.
  • two radicals are ortho-stationary, they can form a common ring with the adjacent aromatic.
  • O- or S-atoms are bonded directly to each other are excluded, unless these links are not explicitly defined, for example in the recited in the claim functional groups or in heteroaromatics.
  • the physiologically acceptable acid salts of the nitrogen bases of the benzimidazole derivatives according to the invention can be formed with inorganic and organic acids, for example with oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid and methanesulfonic acid.
  • the inorganic or organic bases are suitable, which are known for the formation of physiologically acceptable salts, such as, for example
  • Alkali hydroxides in particular sodium and potassium hydroxide, alkaline earth hydroxides, such as calcium hydroxide, also ammonia, and amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and tris (hydroxymethyl) - methylamine.
  • Ester Guess are all monohydric lower, divalent and trivalent alcohols suitable, in particular methanol, ethanol, / 'so-propanol and tert-butanol, and ethylene glycol and glycerol.
  • R 1 is a phenyl group which may be substituted with up to two independently selected radicals selected from the group comprising:
  • R 4 wherein the radicals R 4 and R 4 are selected independently of one another according to the meanings given below, and where two substituents on R 1 can be linked to one another such that they together form a methanediylbisoxy, ethane-1, 2-diylbisoxy, propane Form 1, 3-diyl or butane-1, 4-diyl group, if they are ortho on each other,
  • R 2 is a mono- or bicyclic C ⁇ -io-aryl group or a mono- or bicyclic 5-10-membered heteroaryl group having 1-2 heteroatoms selected from the group consisting of N, S or O, said aryl or heteroaryl group with up to three of the following substituents independently of one another: F, Cl, Br,
  • R 3 is a radical selected from the group comprising hydrogen, F,
  • C ⁇ - 3 alkanoyl may be substituted, wherein, in the above-mentioned aliphatic chains one carbon atom or two carbon atoms for O, NH, NC ⁇ -3 - alkyl, alkanoyl NC ⁇ - 3 may be replaced,
  • B is a radical selected from the group comprising COOH, COOR 5 ,
  • R 4 , R 4 , R 5 , R 5 and R 6 have the following meanings; in it mean:
  • R 4 and R 4 are the same as stated above,
  • R 5 and R 5 each independently represent a radical selected from the group consisting of C ⁇ -6 alkyl, C 2- 6 alkenyl, C 2- 6-alkynyl, where a
  • C-atom is replaced by O, S, SO, S0 2
  • NH, N-C ⁇ -3 alkyl or NC 1-3 alkanoyl may be exchanged, also (C 0- 3-alkanediyl-C 3- 7 cycloalkyl), wherein in a five-membered cycloalkyl ring, a ring member Ring-N or Ring-0 may be and in a six- or seven-membered cycloalkyl ring one or two ring members may each be ring N and / or ring O atoms, wherein the ring N-atoms optionally with C ⁇ - 3 alkyl or -C 3- alkanoyl, as well as (C 0-3 alkanediyl-phenyl) and
  • C ⁇ -4 alkyl (C 0-2 alkanediyl-C ⁇ - alkoxy), C ⁇ - alkoxycarbonyl, aminocarbonyl or phenyl,
  • a phenyl or heteroaryl group wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group comprising N, S and O, and wherein the phenyl and heteroaryl groups may be substituted with up to two radicals selected from the group comprising F, Cl, Br, CH 3 , C 2 H 5 , OH, OCH 3, OC 2 H 5 , NO 2) N (CH 3 ) 2 , CF 3 , C 2 F 5 and
  • R 3 is preferably hydrogen.
  • the group YA is represented in a preferred embodiment by a C 1-6 alkyleneoxy group which is bonded via the O atom to the benzimidazole skeleton.
  • the invention relates to pharmaceutical compositions containing one or more compounds of the general formula I and one or more excipients.
  • the pharmaceutical compositions or compositions of the invention are prepared with conventional solid or liquid carriers or diluents and customary pharmaceutical and technical excipients according to the desired mode of administration with a suitable dosage in a manner known per se.
  • Preferred preparations consist of a dosage form which is suitable for oral, enteral or parenteral, for example i.p. (intraperitoneal), i.v. (intravenous), i.m. (intramuscular), or percutaneous, application is appropriate.
  • Such dosage forms are, for example, tablets, film-coated tablets, dragees, pills, capsules, powders, creams, ointments, lotions, liquids, such as syrups, gels, injectable liquids, for example for ip, iV, im, or percutaneous injection, etc.
  • depot forms, as implantable preparations, and suppositories suitable are suitable. Depending on their nature, the individual preparations give the derivatives according to the invention gradually or the entire amount to the body in a short time.
  • capsules, pills, tablets, dragees and liquids or other known oral dosage forms may be used as pharmaceutical preparations.
  • the drugs may be formulated to either release the drugs in a short time and deliver them to the body or have a depot effect, so that a longer-lasting, slow supply of active ingredient to the body is achieved.
  • the dosage units may contain, in addition to the at least one benzimidazole derivative one or more pharmaceutically acceptable carriers, for example rheology of the drug, surfactants, solubilizers, microcapsules, microparticles, granules, thinners, binders such as starch, sugar, sorbitol and Gelatin, further fillers such as silica and talc, lubricants, dyes, fragrances and other substances.
  • pharmaceutically acceptable carriers for example rheology of the drug, surfactants, solubilizers, microcapsules, microparticles, granules, thinners, binders such as starch, sugar, sorbitol and Gelatin, further fillers such as silica and talc, lubricants, dyes, fragrances and other substances.
  • Corresponding tablets can be prepared, for example, by mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate , to be obtained.
  • excipients for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate , to be obtained.
  • the tablets can also consist of several
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Active ingredients containing capsules can be prepared, for example, by mixing the active ingredient with an inert carrier such as lactose or sorbitol and encapsulated in gelatin capsules.
  • an inert carrier such as lactose or sorbitol
  • the active compounds may also be formulated in the form of a solution intended for oral administration which, in addition to the active benzimidazole derivative, contains as ingredients a pharmaceutically acceptable oil and / or a pharmaceutically acceptable lipophilic surfactant and / or a pharmaceutically acceptable hydrophilic, surfactant and / or a pharmaceutically acceptable water-miscible solvent.
  • the compounds can also be formulated as Cyclodextrinchlatrate. To do this the compounds reacted with ⁇ -, ß- or ⁇ -cyclodextrin or derivatives thereof.
  • creams, ointments, lotions and externally applicable liquids are to be used, they must be such that the
  • adjuvants are included, such as drugs to adjust the rheology of the drugs, surfactants, preservatives, solubilizers, thinners, substances to increase the permeability of the active ingredients through the skin, dyes, fragrances and skin protection agents, such as conditioners and moisture regulators.
  • Other active ingredients may also be present in the drug together with the compounds [Ullmanns Enzyklopadie der ischen Chemie, Vol. 4 (1953), pages 1-39; J. Pharm. Sci., 52, 918 et seq. (1963); H. v. Czetsch-Lindenwald, adjuvants for pharmacy and adjacent areas; Pharm. Ind., 2, 72 ff. (1961); Dr. H. P. Fiedler, Lexicon of adjuvants for pharmacy, cosmetics and adjacent areas, Cantor AG, Aulendorf / Württ., 1971].
  • the substances can also in suitable solutions such as saline, as an infusion or injection solution for
  • the active ingredients may be dissolved or suspended in a physiologically acceptable diluent.
  • a physiologically acceptable diluent are oily solutions, for example solutions in sesame oil, castor oil and cottonseed oil.
  • solubilizers such as benzyl benzoate or benzyl alcohol, may be added.
  • any liquid carrier can be used in which the compounds according to the invention are dissolved or emulsified. These liquids often also contain substances for the regulation of viscosity, surfactants, preservatives, solubilizers, thinners and other additives with which the solution isotonic. Other active ingredients can also be administered together with the benzimidazole derivatives.
  • the substances are also possible to incorporate the substances into a transdermal system and thus transdermally apply them.
  • the benzimidazole derivatives are applied in the form of a depot injection or an implant preparation, for example subcutaneously. Such preparations may be formulated to allow sustained release of the active ingredient.
  • known techniques can be used, for example, dissolving or working with a membrane depots.
  • Implants may contain as inert materials, for example biodegradable polymers or synthetic silicones, for example silicone rubber.
  • the benzimidazole derivatives may also be incorporated into a patch for percutaneous administration, for example.
  • the dosage of the substances will be determined by the attending physician and depends inter alia on the substance administered, the route of administration, the disease to be treated and the severity of the disease.
  • the daily dose is not more than 1000 mg, preferably not more than 100 mg, which dose may be given as a single dose to be administered once or divided into two or more daily doses.
  • LPS-activated THP-1 cells were used. For this purpose, 2.5 ⁇ 10 6 cells / ml were seeded in RPMI medium (RPMI 1640 + 10% FCS). The compounds of the invention were added at a concentration of 5 ⁇ M and preincubated for 30 minutes. The cells were stimulated overnight at 37 ° C with 1 ⁇ g / ml LPS. Thereafter, the medium was harvested and the amount of TNF ⁇ was quantified. The treatment of the cells with the substances according to the invention resulted in a reduction of the TNF ⁇ amount of at least 30%.
  • the inhibition of cytokine production can be determined, for example, by measuring
  • TNF ⁇ and interleukin 12 in lipopolysaccharide (LPS) -stimulated THP-1 cells are examples of lipopolysaccharide (LPS) -stimulated THP-1 cells.
  • TNF ⁇ or Interleukin 12 quantified.
  • a commercially available TNF ⁇ kit from CIS bio international was used (product no. 62TNFPEB).
  • the interleukin 12 amount was determined using the ORIGEN technology (IGEN International, Inc., Gaithersburg, Maryland).
  • the calculated IC50 value corresponds to the concentration of test substance needed to achieve a 50% inhibition of maximal TNF ⁇ or interleukin 12 production.
  • the substances show an IC50 below 10 ⁇ M in this experiment. With the help of similar methods, the inhibition of IL 12 and TNF ⁇ with the substances can also be demonstrated with the use of peripheral blood leukocytes and comparable stimuli.
  • the measurement of IFN ⁇ secretion can be used.
  • Human whole blood was used to isolate peripheral mononuclear cells (blood collection via Na citrate S monovettes "Coagulation 9 NC / 10 ml" / Sarstedt.) Enrichment of the blood cells was carried out by density gradient centrifugation: 15 ml of Histopaque 1077 (Sigma, Cat No H8880) in LEUCOSEP tubes (Greiner, cat # 227290) and centrifuged for 30 seconds at 1000 g, then 15 ml of whole blood are added and centrifuged for 10 minutes at 1000 g.Finally, the upper plasma layer Pipette and transfer the underlying cell layer (peripheral blood mononuclear cells) into 15 ml sample tubes (Falcon) and then wash several times with 10 ml HBSS (HANKS balanced solution (without Mg2 + and Ca2 +), cat no 14175-53) Cell pellet in culture medium RP
  • Substance 1 6 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester
  • Induction of IL-10 Production of Peripheral Blood Mononuclear Cells is exemplified by measurement of IL-10 in phytohemagglutinin (PHA) or lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells.
  • PHA phytohemagglutinin
  • LPS lipopolysaccharide
  • For the isolation of peripheral blood mononuclear cells whole human blood was used (blood collection via Na citrate S monovettes "Coagulation 9 NC / 10 ml7 Sarstedt). Enrichment of the lymphocytes and monocytes was carried out by density gradient centrifugation. 15 ml of Histopaque-1077 (Sigma, cat. No. H8880) were introduced into 50 ml of LEUCOSEP tubes (Greiner, cat. No.
  • the substances according to the invention were added in different concentrations as a 3-fold concentrated substance solution (100 ⁇ l / well).
  • the stimulation of the cells was carried out at 37 ° C and 5% C0 2 over a period of 24 h. Thereafter, the cell culture supernatant was harvested and IL-10 quantified.
  • the IL-10 concentration was determined using a commercially available ELISA kit from BioSource International (Human IL-10, cat.No .: KHC0101C).
  • the calculated EC 50 value corresponds to the concentration of test substance needed to increase IL-10 secretion by 50% of the maximum increase.
  • the compounds of the invention increase the IL-10 production of peripheral blood mononuclear cells.
  • Example 5 The compounds of the invention increase the IL-10 production of peripheral blood mononuclear cells.
  • TNF ⁇ and IL-12 HD production of Peripheral Blood Mononuclear Cells The inhibition of TNF ⁇ and IL-12 HD p70 production is demonstrated, for example, by measuring TNF ⁇ and IL-12 HD p70 in with lipopolysaccharide (LPS) and interferon gamma (IFN ⁇ ). shown stimulated peripheral blood mononuclear cells.
  • LPS lipopolysaccharide
  • IFN ⁇ interferon gamma
  • H8880 H8880 were introduced into 50 ml of LEUCOSEP tubes (Greiner, cat. No. 227290) and centrifuged for 30 seconds at 250g pushed down through the frit in the tube. Subsequently, 20 ml of whole blood are added and centrifuged for 15 min. At 800 g and room temperature. After centrifugation, the supernatant (plasma and platelets) is pipetted off and discarded and the underlying cell layer (lymphocytes and monocytes) transferred to 50 ml centrifuge tubes (Falcon) and then washed 3 times in culture medium VLE RPMI 1640 (Seromed, No. FG1415) (centrifugation 10 min. each at 250g, room temperature).
  • VLE RPMI 1640 Seromed, No. FG1415
  • the cell pellet is incubated in culture medium VLE RPMI 1640 (Seromed, No. FG1415), 10% FCS (Life Technologies, cat. No. 16000-044, low endotoxin, heat-inactivated 1 h, 56 ° C), 50 ⁇ g / ml Penicillin-streptomycin solution (Life Technologies, cat. No. 15140-106) and after cell counting by trypan blue staining set to 3 x 10 6 cells / ml.
  • Each 100 ⁇ l of cell suspension solution was distributed to 96-well flat-bottomed cell culture plates (Costar, product no. 3599). To this was added in each case 100 ⁇ l of 3 ⁇ concentrated stimulation solution (3 ⁇ g / ml LPS of E.
  • the substances according to the invention were added in different concentrations as a 3-fold concentrated substance solution (100 ⁇ l / well).
  • the cells were stimulated at 37 ° C and 5% C0 2 over a period of 24 h. Thereafter, the cell culture supernatant was harvested and the concentrations of TNF ⁇ and IL-12 HD p70 using commercially available ELISA kits from BioSource International (TNF- ⁇ EASIA, cat.
  • the calculated IC 50 value corresponds to the concentration of test substance that is needed to prevent a 50% inhibition of the maximum TNF ⁇ or
  • Interleukin 12 HD p70 production.
  • the compounds according to the invention inhibit TNF ⁇ and IL-12 HD p70
  • Substance 1 6 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Virology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'inhibiteurs de la microglie dans la fabrication de médicaments, qui inhibent des réactions immunitaires induites par les monocytes, les macrophages et les lymphocytes T, et l'utilisation de ces inhibiteurs dans le traitement de maladies immunologiques induites par les lymphocytes T et de réactions d'inflammation non induites par les lymphocytes T.
PCT/EP2003/000467 2002-02-15 2003-01-17 Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma WO2003068225A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
KR10-2004-7012557A KR20040084909A (ko) 2002-02-15 2003-01-17 인터루킨 12 및 ＩＦＮγ에 의하여 유도되는 면역 반응을차단하기 위한 소교세포 억제제
BR0307706-3A BR0307706A (pt) 2002-02-15 2003-01-17 Inibidores de microglia para a interrupção da interleucina 12 e reações imunológicas induzidas por ifn-gama
MXPA04007943A MXPA04007943A (es) 2002-02-15 2003-01-17 Inhibidores de microglia para interrumpir reacciones inmunologicas inducidas por interleucina 12 e ifn-gamma.
UA20040907401A UA81111C2 (en) 2002-02-15 2003-01-17 Use of a microglia inhibitor for the production of a pharmaceutical agent that inhibits immune reactions mediated by interleukin 12 (il 12) and interferon-? (variants)
JP2003567407A JP2005522447A (ja) 2002-02-15 2003-01-17 インターロイキン１２及びＩＦＮγにより介在される免疫反応を中断するための微小グリア細胞インヒビター
YU71304A RS71304A (en) 2002-02-15 2003-01-17 Microlia inhibitors for iterrupting immune reactions inducted by interleukin 12 and ifn$(g)
CA002475770A CA2475770A1 (fr) 2002-02-15 2003-01-17 Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma
EP03739380A EP1474138A1 (fr) 2002-02-15 2003-01-17 Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma
AU2003245523A AU2003245523A1 (en) 2002-02-15 2003-01-17 Microglia inhibitors for interrupting immune reactions induced by interleukin 12 and ifn$g(g)
NO20043840A NO20043840L (no) 2002-02-15 2004-09-14 Mikrogliahemmere til stopping av immunreaksjoner som er indusert av indusert av interleukin-12 og IFN-gamma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10207843.2 2002-02-15
DE10207843A DE10207843A1 (de) 2002-02-15 2002-02-15 Mikrolia-Inhibitoren zur Unterbrechung von Interleukin 12 und IFN-gamma vermittelten Immunreaktionen

Publications (1)

Publication Number Publication Date
WO2003068225A1 true WO2003068225A1 (fr) 2003-08-21

Family

ID=27674912

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/000467 WO2003068225A1 (fr) 2002-02-15 2003-01-17 Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma

Country Status (21)

Country Link
EP (1) EP1474138A1 (fr)
JP (1) JP2005522447A (fr)
KR (1) KR20040084909A (fr)
CN (1) CN1756546A (fr)
AR (1) AR039556A1 (fr)
AU (1) AU2003245523A1 (fr)
BR (1) BR0307706A (fr)
CA (1) CA2475770A1 (fr)
DE (1) DE10207843A1 (fr)
EC (1) ECSP045297A (fr)
MX (1) MXPA04007943A (fr)
NO (1) NO20043840L (fr)
PE (1) PE20030906A1 (fr)
PL (1) PL371327A1 (fr)
RS (1) RS71304A (fr)
RU (1) RU2004127677A (fr)
TW (1) TW200306823A (fr)
UA (1) UA81111C2 (fr)
UY (1) UY27662A1 (fr)
WO (1) WO2003068225A1 (fr)
ZA (1) ZA200407382B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008533107A (ja) * 2005-03-17 2008-08-21 プロイェクト、デ、ビオメディシナ、シーマ、ソシエダッド、リミターダ 自己免疫疾患および／または移植拒絶反応の予防および／または治療における５’−メチルチオアデノシン（ｍｔａ）の使用
US9586949B2 (en) 2015-02-09 2017-03-07 Incyte Corporation Aza-heteroaryl compounds as PI3K-gamma inhibitors
US10065963B2 (en) 2015-11-06 2018-09-04 Incyte Corporation Heterocyclic compounds as PI3K-γ inhibitors
US10138248B2 (en) 2016-06-24 2018-11-27 Incyte Corporation Substituted imidazo[2,1-f][1,2,4]triazines, substituted imidazo[1,2-a]pyridines, substituted imidazo[1,2-b]pyridazines and substituted imidazo[1,2-a]pyrazines as PI3K-γ inhibitors
US10738057B2 (en) 2017-10-18 2020-08-11 Incyte Corporation Tertiary alcohols as PI3K-γ inhibitors
US11186580B2 (en) 2018-09-05 2021-11-30 Incyte Corporation Crystalline forms of a phosphoinositide 3-kinase (PI3K) inhibitor
US11352340B2 (en) 2016-01-05 2022-06-07 Incyte Corporation Pyridine and pyridimine compounds as PI3K-gamma inhibitors
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10207844A1 (de) * 2002-02-15 2003-09-04 Schering Ag 1-Phenyl-2-heteroaryl-substituierte Benzimidazolderivate, deren Verwendung zur Herstellung von Arzneimitteln sowie diese Derivate enthaltende pharmazeutische Präparate
CA2874303C (fr) * 2012-06-11 2020-10-13 Ucb Biopharma Sprl Benzimidazoles modulant l'activite tnf -alpha
KR20180094989A (ko) * 2015-12-15 2018-08-24 더 보드 오브 트러스티스 오브 더 리랜드 스탠포드 주니어 유니버시티 노화 관련 인지장애 및 신경염증의 예방 및/또는 치료 방법
CN112341451B (zh) * 2019-08-09 2022-06-17 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341450B (zh) * 2019-08-09 2022-05-17 成都先导药物开发股份有限公司 一种免疫调节剂

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4330959A1 (de) * 1993-09-09 1995-03-16 Schering Ag Neue Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
WO2001051473A1 (fr) * 2000-01-14 2001-07-19 Schering Aktiengesellschaft 1,2-diaralbenzimidazoles utilises pour traiter des affections associees a une activation de la microglie
WO2003004023A1 (fr) * 2001-07-06 2003-01-16 Schering Aktiengesellschaft Derives de 1-alkyl-2-aryl-benzimidazole, leur utilisation pour produire des medicaments, et preparations pharmaceutiques les contenant
WO2003006438A1 (fr) * 2001-07-09 2003-01-23 Schering Aktiengesellschaft Derives de benzimidazole pour le traitement d'affections associees a une activation de la microglie ainsi que d'affections inflammatoires, allergiques, infectieuses ou auto-immunes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4330959A1 (de) * 1993-09-09 1995-03-16 Schering Ag Neue Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
WO2001051473A1 (fr) * 2000-01-14 2001-07-19 Schering Aktiengesellschaft 1,2-diaralbenzimidazoles utilises pour traiter des affections associees a une activation de la microglie
WO2003004023A1 (fr) * 2001-07-06 2003-01-16 Schering Aktiengesellschaft Derives de 1-alkyl-2-aryl-benzimidazole, leur utilisation pour produire des medicaments, et preparations pharmaceutiques les contenant
WO2003006438A1 (fr) * 2001-07-09 2003-01-23 Schering Aktiengesellschaft Derives de benzimidazole pour le traitement d'affections associees a une activation de la microglie ainsi que d'affections inflammatoires, allergiques, infectieuses ou auto-immunes

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008533107A (ja) * 2005-03-17 2008-08-21 プロイェクト、デ、ビオメディシナ、シーマ、ソシエダッド、リミターダ 自己免疫疾患および／または移植拒絶反応の予防および／または治療における５’−メチルチオアデノシン（ｍｔａ）の使用
US10596184B2 (en) 2015-02-09 2020-03-24 Incyte Corporation Aza-heteroaryl compounds as PI3K-gamma inhibitors
US9586949B2 (en) 2015-02-09 2017-03-07 Incyte Corporation Aza-heteroaryl compounds as PI3K-gamma inhibitors
US10022387B2 (en) 2015-02-09 2018-07-17 Incyte Corporation Aza-heteroaryl compounds as PI3K-gamma inhibitors
US11091491B2 (en) 2015-11-06 2021-08-17 Incyte Corporation Heterocyclic compounds as PI3K-y inhibitors
US10065963B2 (en) 2015-11-06 2018-09-04 Incyte Corporation Heterocyclic compounds as PI3K-γ inhibitors
US10472368B2 (en) 2015-11-06 2019-11-12 Incyte Corporation Heterocyclic compounds as PI3K-γ inhibitors
US11773102B2 (en) 2015-11-06 2023-10-03 Incyte Corporation Heterocyclic compounds as PI3K-γ inhibitors
US11952367B2 (en) 2016-01-05 2024-04-09 Incyte Corporation Pyridine and pyridimine compounds as PI3K-gamma inhibitors
US11352340B2 (en) 2016-01-05 2022-06-07 Incyte Corporation Pyridine and pyridimine compounds as PI3K-gamma inhibitors
US10479795B2 (en) 2016-06-24 2019-11-19 Incyte Corporation Substituted imidazo[2,1-f][1,2,4]triazines, substituted imidazo[1,2-a]pyridines and substituted imidazo[1,2-b]pyridazines as PI3K-gamma inhibitors
US10138248B2 (en) 2016-06-24 2018-11-27 Incyte Corporation Substituted imidazo[2,1-f][1,2,4]triazines, substituted imidazo[1,2-a]pyridines, substituted imidazo[1,2-b]pyridazines and substituted imidazo[1,2-a]pyrazines as PI3K-γ inhibitors
US10975088B2 (en) 2016-06-24 2021-04-13 Incyte Corporation Imidazo[2,1-f][1,2,4]triazine compounds as pi3k-y inhibitors
US12030885B2 (en) 2016-06-24 2024-07-09 Incyte Corporation Substituted imidazo[2,1-f][1,2,4]triazines as PI3K-gamma inhibitors
US10738057B2 (en) 2017-10-18 2020-08-11 Incyte Corporation Tertiary alcohols as PI3K-γ inhibitors
US11225486B2 (en) 2017-10-18 2022-01-18 Incyte Corporation Tertiary alcohols as PI3K-γ inhibitors
US11926630B2 (en) 2017-10-18 2024-03-12 Incyte Corporation Tertiary alcohols as PI3K-γ inhibitors
US11186580B2 (en) 2018-09-05 2021-11-30 Incyte Corporation Crystalline forms of a phosphoinositide 3-kinase (PI3K) inhibitor
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

Also Published As

Publication number Publication date
ZA200407382B (en) 2005-09-14
MXPA04007943A (es) 2004-11-26
CN1756546A (zh) 2006-04-05
CA2475770A1 (fr) 2003-08-21
UA81111C2 (en) 2007-12-10
RU2004127677A (ru) 2005-06-10
TW200306823A (en) 2003-12-01
AR039556A1 (es) 2005-02-23
RS71304A (en) 2006-10-27
PE20030906A1 (es) 2004-01-17
NO20043840L (no) 2004-11-12
KR20040084909A (ko) 2004-10-06
BR0307706A (pt) 2005-01-11
UY27662A1 (es) 2003-09-30
DE10207843A1 (de) 2003-09-04
JP2005522447A (ja) 2005-07-28
AU2003245523A1 (en) 2003-09-04
ECSP045297A (es) 2004-10-26
PL371327A1 (en) 2005-06-13
EP1474138A1 (fr) 2004-11-10

Similar Documents

Publication Publication Date Title
EP1294682B1 (fr) Derives d'acylphenyluree, leurs procedes de preparation et leur utilisation comme medicaments
EP1474138A1 (fr) Inhibiteurs de la microglie servant a interrompre des reactions immunitaires induites par l'interleukine 12 et l'interferon gamma
DE69924607T2 (de) Benzimidazol-derivate als ige-modulatoren
EP1404650B1 (fr) Derives de phenyluree substitues par amide d'acide carboxylique, procede pour leur production en tant que medicaments
EP1218341B1 (fr) Derives de sulfonylcarboxamide, leur procede de production et leur utilisation comme medicaments
DE69725825T2 (de) 5-HT1F-Agonisten
WO1991017748A1 (fr) Amides d'acide carboxylique-4 d'isoxazol et cyanamides acetiques d'hydroxyalkylidene, medicaments contenant ces composes et leur application
DE602005004142T2 (de) 4-hydroxy-4-methylpiperidin-1-carbonsäure-(4-methoxy-7-morpholin-4-ylbenzothiazol-2-yl)-amid
WO1996002246A1 (fr) Utilisation de composes heterocycliques comme ligands de la dopamine-d¿3?
DE10035927A1 (de) Neue Heteroaryl-Derivate und deren Verwendung als Arzneimittel
DE10035908A1 (de) Neue Heteroaryl-Derivate und deren Verwendung als Arzneimittel
US20070249676A1 (en) Cyanoguanidine prodrugs
EP1465613A2 (fr) Combinaison d'inhibiteurs de mtp ou d'inhibiteurs de secretions apob avec des fibrates en vue d'une utilisation comme medicament
WO2003004023A1 (fr) Derives de 1-alkyl-2-aryl-benzimidazole, leur utilisation pour produire des medicaments, et preparations pharmaceutiques les contenant
US20060211690A1 (en) Microglia inhibitors for interrupting interleukin 12 and IFNgamma-mediated immune reactions
EP1507759A1 (fr) Promedicaments constitues de cyanoguanidine
DE60312342T2 (de) 1,4,5-substituierte 1,2-dihydro-pyrazol-3-one und 3-alkoxy-1h-pyrazole derivate als tnf-alpha und interleukin senkende wirkstoffe zur behandlung von entzündungen
DE60020556T2 (de) Ionenkanal modulierende mittel
EP1474415B1 (fr) Derives de benzimidazole 1-phenyl-2-heteroaryl substitues et leur utilisation pour produire des medicaments servant a traiter des maladies immunologiques
DE3750979T2 (de) 5-Aryl-3H-1,2,4-triazol-3-one und ihre Verwendung in der Behandlung neurodegenerativer Beschwerden.
DE3751362T2 (de) 5-Aryl-3H-1,2,4-triazol-3-one und ihre Verwendung als Antikonvulsiva.
EP1317430B1 (fr) Derives de (2-azabicyclo [2.2.1]hept-7-yl)methanol utilises comme angonistes du recepteur de l'acetylcholine nicotinique
DE60221104T2 (de) Substituierte diarylharnstoffe als stimulatoren der fas-vermittelten apoptose
DE3873210T2 (de) Verwendung von benzylpyridin-derivaten zur herstellung eines arzneimittels zur behandlung der demenz.
DE10116768A1 (de) Acylphenylharnstoffderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-713/04

Country of ref document: YU

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 163432

Country of ref document: IL

Ref document number: 2475770

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 534661

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/007943

Country of ref document: MX

Ref document number: 2353/DELNP/2004

Country of ref document: IN

Ref document number: 1020047012557

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2003567407

Country of ref document: JP

Ref document number: 20038039923

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2003739380

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1-2004-501428

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2004/07382

Country of ref document: ZA

Ref document number: 200407382

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2004127677

Country of ref document: RU

Ref document number: 2003245523

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2003739380

Country of ref document: EP