WO2005102326A2 - Utilisation d'inhibiteurs de c-kit dans le traitement des maladies renales - Google Patents

Utilisation d'inhibiteurs de c-kit dans le traitement des maladies renales Download PDF

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WO2005102326A2
WO2005102326A2 PCT/IB2005/001370 IB2005001370W WO2005102326A2 WO 2005102326 A2 WO2005102326 A2 WO 2005102326A2 IB 2005001370 W IB2005001370 W IB 2005001370W WO 2005102326 A2 WO2005102326 A2 WO 2005102326A2
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halogen
alkyl
group
optionally substituted
aryl
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PCT/IB2005/001370
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WO2005102326A3 (fr
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Alain Moussy
Jean-Pierre Kinet
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Ab Science
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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
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to a method for preventing or treating renal diseases and dysfunction comprising administering a compound capable of depleting mast cells or a compound inhibiting mast cells degranulation, to a human in need of such treatment.
  • a compound capable of depleting mast cells or a compound inhibiting mast cells degranulation can be chosen from c-kit inhibitors and more particularly non-toxic, selective and potent c-kit inhibitors.
  • said inhibitor is unable to promote death of IL-3 dependent cells cultured in presence of IL-3.
  • Renal failure or dysfunction is the cause of several diseases generally associated with hyper or hypotension. Renal diseases include acute nephritic syndrome, the nephrotic syndrome, progressive glomerulonephritis, asymptomatic hemaruria and proteinuria, acute renal failure, urinary tract infection, and nephiOlitliasis.
  • Acute nephritic syndrome is the result of inflammation of the internal structures of the kidney, caused by an immune response triggered most of the time by infection iriflammation. Inflammation disrupts the functioning of the glomerulus, which controls filtering and excretion. Inefficient glomerular functioning results in the loss of blood and protein in the urine and the accumulation of excess fluid in the body. This disease is linked to hypertension, interstitial inflammation and may lead to acute renal failure. Corticosteroids or other anti-mflammatory medications may be used to reduce inflammation. Chronic glomerulonephritis is a progressive destruction of the glomeruli due to unexplained immune triggered mflammation. Corticosteroids and immunosuppressives are currently used for treating this renal disease.
  • cytokines IL-1, TNF-c.
  • cytokines IL-1, TNF-c.
  • IL-1 interstitial inflammation and fibrosis results from the production of cytokines (IL-1, TNF-c.7) in glomerulus.
  • Chemokines are also found in tissue and are likely to promote cellular infiltration.
  • Infiltrated monocyte and T lymphocyte secrete new cytokines that act on tubular epithelial cells and infiltrated cells, further participating in the inflammation process.
  • Mast cells MCs
  • the role of MC in the development of renal fibrosis has not been fully elucidated.
  • the relation between mast cells and inflammation in renal diseases, and in particular glomeraloneplt itis has been overlooked.
  • SCF Stem cell factor
  • Renal interstitial fibrosis is the final common pathway leading to end-stage renal disease in various nephropathies including renal amyloidosis.
  • Toth and al. compared the distribution of MCs in renal biopsies from 30 patients with AA type renal amyloidosis and 20 control cases. Results indicate that MCs constitute an integral part of the overall Mlarrimatory process and play a crucial role in interstitial fibrosis in renal amyloidosis.
  • Toth T Toth-Jakatics R, Jimi S, Takebayashi S. Increased density of interstitial mast cells in amyloid A renal amyloidosis. Mod Pathol. 2000 Sep;13(9):1020-8.
  • the role of mast cells (MCs) in the fibrotic process of renal amyloidosis is not fully understood.
  • MC The distribution of MC was also compared in renal biopsies from 50 patients with different stages of rapidly progressive GN (RPGN) and in 20 control samples.
  • RPGN rapidly progressive GN
  • samples showing crescentic GN contained numerous tryptase-positive MC (MC(T)) (43.7+ ⁇ 4.65 versus 7.14+/-1.3/mm2) and fewer tryptase- and chymase-positive MC (MC(TC)) (13.8+/-1.86 versus 1.89+/-0.86/mm2) in the renal interstitium but never in the glomerulus.
  • mast cells are central in the renal mflammation process leading to interstitial mflammation and fibrosis.
  • Mast cells are tissue elements derived from a particular subset of hematopoietic stem cells that express CD34, c-kit and CD 13 antigens (Kirshenbaum, 1999 and Ishizaka, 1993). Mast cells act as an infiltrating hematopoietic cell and its growth factor (SCF) is up-regulated in glomerulonephritis.
  • SCF growth factor
  • MC also produce a large variety of mediators categorized into three groups: preformed granule-associated mediators (histamine, proteoglycans, and neutral proteases), lipid- derived mediators (prostaglandins, thromboxanes and leucotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-o GM-CSF, MJ -IQ M ⁇ P-1/3 and IFN-7), most of them having strong pro-inflammatory activities. When activated, these factors are secreted and participate in the development of fibrotic conditions ofthe kidneys.
  • preformed granule-associated mediators histamine, proteoglycans, and neutral proteases
  • lipid- derived mediators prostaglandins, thromboxanes and leucotrienes
  • cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL
  • Renal fibrosis is closely linked with a chronic inflammatory cell infiltrate within the interstitium, but it is the first time that a potential role for mast cells in this process is proposed.
  • the numbers of mast cells in normal and fibrotic kidneys with various pathologies were investigated.
  • An increased number of mast cells is a consistent feature of renal fibrosis, whatever the underlying pathology, and the number of mast cells correlates with the extent of interstitial fibrosis. This shows that mast cells play a ⁇ pathogenetic role in the fibrotic process and are are central players involved in renal diseases.
  • c-kit inhibitors could be a new route for preventing or treating renal diseases which consist of destroying mast cells playing a role in renal deterioration. It has been found that selective and potent c-kit inhibitors are especially suited to reach this goal.
  • the present invention relates to a method for treating and/or preventing or delaying the onset of renal diseases and dysfunction comprising administering a compound capable of depleting mast cells or blocking mast cells degranulation to a human in need of such treatment.
  • Said method for preventing or treating renal diseases can comprise actoinistering a c-kit inhibitor to a human in need of such treatment.
  • Preferred compounds are c-kit inhibitor, more particularly a non-toxic, selective and potent c-kit inhibitor.
  • Such inhibitors can be selected from the group consisting of 2-(3- SubstiMedaryl)ainmo-4-aryl-thiazoles such as 2-(3-ammo)arylammo-4-aryl-thiazoles, 2- aminoaryloxazoles, pyrimidine derivatives, pyirolopyrimidine derivatives, quinazoline derivatives, quinoxaline derivatives, pyrazoles derivatives, bis monocyclic, bicyclic or heterocyclic aryl compounds, vinylene-azaindole derivatives and pyridyl-quinolones derivatives, styryl compounds, styryl-substituted pyridyl compounds, seleoindoles, selenides, tricycl
  • pyrimidine derivatives such as N-phenyl-2-pyrimidine-amine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives and pyrrol-substituted indolinones (US 5,792,783, EP 934 931, US 5,834,504), US 5,883,116, US 5,883,113, US 5, 886,020, WO 96/40116 and WO 00/38519), as well as bis monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222, US 5,656,643 and WO 92/20642), quinazoline derivatives (EP 602 851, EP 520 722, US 3,772,295 and US 4,343,940), 4-amino-substituted quinazolines (US 3,470,182), 4-thienyl-2-(lH)-quin-izolones, 6,7-dialkoxyquinazolines (US 3,800,03
  • the invention relates to a method for preventing or treating renal diseases comprising administering a non toxic, potent and selective c-kit inhibitor is a pyrimidine derivatives, more particularly N-phenyl-2-pyrimidine-amine derivatives of formula I :
  • Rl, R2, R3, R13 to R17 groups have the meanings depicted in EP 564 409 Bl, incorporated herein in the description.
  • the N-phenyl-2-pyrimidine-amine derivative is selected from the compounds corresponding to formula ⁇ :
  • Rl, R2 and R3 are independently chosen from H, F, CI, Br, I, a C1-C5 alkyl or a cyclic or heterocyclic group, especially a pyridyl group;
  • R4, R5 and R6 are independently chosen from H, F, CI, Br, I, a C1-C5 alkyl, especially a methyl group; and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function.
  • R7 is the following group :
  • Rl is a heterocyclic group, especially a pyridyl group, R2 and R3 are H,
  • R4 is a C1-C3 alkyl, especially a methyl group
  • R5 and R6 are H, and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function, for example the group :
  • the invention relates to a method for preventing or treating renal diseases comprising the administration of an effective amount of the compound known in the art as CGP57148B :
  • the invention contemplates the method mentioned above, wherein said c-kit inhibitor is selected from 2-(3-Substitutedaryl)amino-4-aryl- thiazoles such as those for which the applicant filed PCT/IB2005/000401, incorporated herein by reference, especially compounds of formula III :
  • R 6 and R 7 are independently from each other chosen from one ofthe following: i) hydrogen, a halogen (selected from F, CI, Br or 1), ii) an alkyl 1 group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms, or from 2 or 3 to 10 carbon atoms, (for example methyl, ethyl, propyl, butyl, pentyl, hexyl%) and optionally substituted with one or more hetereoatoms such as halogen (selected from F, CI, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; (iii) an aryl 1 group defined as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I,
  • a heteroaryl 1 group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl , triazolyl, tefrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as - halogen (selected from F, CI, Br or I); - an alkyl 1 group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality, - trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(al
  • R 8 is one ofthe following:
  • R2, R3, R4 and R5 each independently are selected from hydrogen, halogen (selected from F, CI, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, CI, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Ci- ⁇ alkyloxy, amino, - 6 alkylamino, carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R, CONH-R, S02-R, and S02NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, CI, Br or I), oxygen, and nifrogen, the latter optionally in the form of
  • A is : CH2, O, S, S02, CO, or COO,
  • B is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, S02, CO, or COO,
  • B' is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, S02, CO or COO;
  • R* being an alkyl 1 , aryl 1 or heteroaryl 1
  • W is a bond or a linker selected from NH, NHCO, NHCOO, NHCONH, NHS02, NHS02NH, CO, CONH, COO, COCH2, (CH2)n (n is 0, 1 or 2), CH2-CO, CH2COO,
  • RMs a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; b) an aryl or heteroaryl group optionally substituted by an alkyl or aryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality c) an alkyl 1 , aryl 1 or heteroaryl 1 .
  • a C1-C10 alkyl encompasses a methyl, ethyl, propyl, and a C2 to C4 alkyl or a C2 to CIO alkyl.
  • a subset of compounds may correspond to
  • Rl, R4 and R6 have the meaning as defined above.
  • A-B-B' includes but is not limited to : CH2, CH2-CO, CH2-CO-CH2, CH2COO, CH2-CH2-CO, CH2-CH2-COO, CH2-NH,
  • A-B-B' also includes but is not limited to :
  • NH in B or B' can also be NCH3
  • - R6 is (iv), R4 is H or CH3, A-B-B' is CO-NH and Rl is as defined above.
  • - R6 is (iv), R4 is H or CH3, A-B-B' is CH2-CO-NH and Rl is as defined above.
  • R6 is (iv)
  • R4 is H or CH3
  • A-B-B' is CH2-CO and Rl is as defined above.
  • R6 is (iv)
  • R4 is H or CH3
  • A-B-B' is CH2-NH-CO and Rl is as defined above.
  • - R6 is (iv), R4 is H or CH3, A-B-B' is CH2-NH and Rl is as defined above.
  • - R6 is (iv), R4 is H or CH3, A-B-B' is CH2 and Rl is as defined above.
  • R6 is W-(iv)
  • R4 is a C1-C2 alkyl
  • A-B-B' is CO-NH
  • Rl is as defined above.
  • R6 is (iv)
  • R4 is a C1-C2 alkyl
  • A-B-B' is CH2-CO-NH
  • Rl is as defined above.
  • R6 is (iv)
  • R4 is a C1-C2 alkyl
  • A-B-B' is CH2-CO
  • Rl is as defined above.
  • R6 is a pyridyl according to (iv)
  • R4 is a C1-C2 alkyl
  • A-B-B' is CO-NH, CH2-CO-NH, CH2-CO, CH2-NH, CH2-NH-CO and Rl is as defined above.
  • Rl can be an alkyl 1 .
  • Rl can be an aryl 1 .
  • Rl can be an heteroaryl 1 .
  • the invention contemplated the method mentioned above, wherein said c-kit inhibitor is selected from 2-(3-amino)arylamino-4-aryl- thiazoles such as those for which the applicant filed WO 2004/014903, incorporated herein in the description, especially compounds of formula IN :
  • R 1 is : a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; b) an aryl or heteroaryl group optionally substituted by an alkyl or aryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; c) a -CO-NH-R, -CO-R, -CO-OR or a -CO-NRR' group, wherein R and R' are independently chosen from H or an aryl, heteroaryl, alkyl and cycloalkyl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality;
  • R 2 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;
  • R 3 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;
  • R 4 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy
  • R 5 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy
  • R 6 is one ofthe following:
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
  • a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from
  • R 7 is one of the following:
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
  • a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
  • H a halogen selected from I, F, CI or Br
  • NH2, N02 or S02-R wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.
  • R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality.
  • the invention is directed to amide-aniline, amide-benzylamine, amide-phenol, urea compounds ofthe following formulas respectively :
  • R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; or a a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F and
  • the invention is directed to N-Aminoalkyl-N'-thiazol ⁇ -yl-benzene-l ⁇ -diamine compounds of the folio wing formula IVbis: ' .
  • Y is a linear or branched alkyl group containing from 1 to 10 carbon atoms; wherein Z represents an aryl or heteroaryl group, optionally substituted at one or more ring position with any permutation ofthe following groups: - a halogen such as F, CI, Br, I; - a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a hal
  • Ra and Rb are a hydrogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; an NHCOR, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a
  • R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality;
  • Ra and Rb are a hydrogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality;
  • R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - an NRaOS0 2 Rb, where Ra and Rb are a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted
  • R 2 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;
  • R 3 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;
  • R 4 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy
  • R 5 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy
  • R 6 is one ofthe following:
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
  • a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
  • H a halogen selected from I, F, CI or Br
  • NH2, N02 or S02-R wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic mtrogen functionality
  • R 7 is one ofthe following: (i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy; (ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
  • a C1-C10 alkyl encompasses a methyl, ethyl, propyl, and a C2 to C4 alkyl or a C2 to C 10 alkyl.
  • X is R or NRR' and wherein R and R' are independently chosen from H, an aryl, a heteroaryl, an alkyl , or a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, CI and Br and optionally bearing a pendant basic nitrogen functionality; or an aryl, a heteroaryl, an alkyl or a cycloalkyl group substituted with an aryl, a heteroaryl, an alkyl or a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, CI and Br and optionally bearing a pendant basic mtrogen functionality,
  • R 2 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;
  • R 3 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy
  • R 4 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy
  • R 5 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;
  • R 6 is one ofthe following:
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
  • a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
  • H a halogen selected from I, F, CI or Br
  • NH2, N02 or S02-R wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.
  • substituent R6 which in the formula ⁇ is connected to position 4 ofthe thiazole ring, may instead occupy position 5 ofthe thiazole ring.
  • Rl or X is a substituted alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen functionality represented for example by the structures a to f and g to m shown below, wherein the wavy line corresponds to the point of attachment to core structure of formula HI, IV or V: h k m
  • group a to f is preferentially group d.
  • the arrow may include a point of attachment to the core structure via a phenyl group.
  • the invention concerns the compounds in which R 2 and R 3 are hydrogen.
  • R 4 is a methyl group and R 5 is H.
  • R 6 is preferentially a 3-pyridyl group (cf. structure g below), or a 4-pyridyl group (cf. structure h below) or a benzonitrile group.
  • the wavy line in structure g and h correspond to the point of attachment to the core structure of formula III, IV or V.
  • the invention concerns the compounds in which R6 or R7 is preferentially a cyanophenyl group as shown below, wherein the wavy line in structure p and q correspond to the point of attachment to the core structure of formula III, IV or V:
  • Rl in formula III and IV, X in formula V and Z in formula IVbis can be :
  • Ri, Rj, Rk, Rl, Rm, Ro, and Rp are independently chosen from : - H, an halogen such as CI, F, Br, I ; a trifluoromethyl group, a CN group, S02, OH, or a group selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; - a N
  • one of Ri, Rj, Rk, Rl, Rm, Ro or Rp is selected from group a, b, c, g, h, i, j, k, 1, m as defined above such as Rk is one of a, b, c, g, h, i, j, k, 1, m and Ri, Rj, Rl, Rm is H.
  • the invention contemplates: 1- A compound of fonnula V as depicted above, wherein X is group d and R is a 3- pyridyl group.
  • 5- A compound of formula in or IV as depicted above, wherein R 2 and/or R 3 and or R 5 is H and R 4 is a methyl group.
  • 6- A compound of formula in or IN as depicted above wherein R 2 and or R 3 and/or R 5 is H, R 4 is a methyl group and R 6 is a 3-pyridyl group.
  • X is R or ⁇ RR' and wherein R and R' are independently chosen from H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nifrogen functionality; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, notably a
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
  • a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
  • H a halogen selected from I, F, CI or Br
  • NH2, N02 or S02-R wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.
  • substituent R6 which in the formula III is connected to position 4 of the thiazole ring, may instead occupy position 5 of the thiazole ring.
  • the invention is particularly embodied by the compounds wherein X is a urea group, a -CO- ⁇ RR' group, corresponding to the [3- (thiazol-2-ylamino)-phenyl]-urea family and the following formula:
  • Ra, Rb are independently chosen from Y-Z as defined above or H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic -mtrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a
  • an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
  • a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
  • a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
  • H a halogen selected from I, F, CI or Br
  • NH2, N02 or S02-R wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.
  • the invention is particularly embodied by the compounds wherein X is a -OR group, corresponding to the family [3-(Thiazol-2- ylamino)-phenyl]-carbamate and the following formula IN-6
  • R is independently chosen from an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; R4 and R6 are as defined above.
  • said c-kit inhibitor is selected from 2-aminoaryloxazoles of formula X :
  • Rl, R2, R3 and R4 each independently are selected from hydrogen, halogen (selected from F, CI, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, CI, Br or I), oxygen, and nifrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, -eaikyloxy, amino, .
  • R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, CI, Br or I), oxygen, and nifrogen, the latter optionally in the form of a pendant basic nitrogen functionality.
  • R5 is one ofthe following:
  • R6 and R7 each independently are selected from: i) hydrogen, a halogen (selected from F, CI, Br or I), or ii) an alkyl 1 group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, CI, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO-R, COO-R, CONH-R, S02-R, and S02NH-R wherein R is a linear or branched alkyl group containing 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, CI, Br or 1), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality
  • X is:
  • R9 and / or R10 are hydrogen or: i) an alkyl 1 group, CF3 or ii) an aryl 1 , heteroaryl 1 or cycloalkyl group optionally substituted by a a pendant basic mfrogen functionality, or iii) a CO-R, COO-R, CON-RR'or S02-R, where R and R' are a hydrogen, alkyl 1 , aryl 1 or heteroaryl 1 , optionally substituted by a a pendant basic nifrogen functionality; or:
  • R9 and / or RIO are hydrogen or: i) an alkyl 1 group, CF3 or ii) an aryl 1 , heteroaryl 1 or cycloalkyl group optionally substituted by a a pendant basic nitrogen functionality.
  • Such compound may be selected from N-Aminoalkyl-N'-oxazol-2-yl-benzene-l,3- diamines ofthe following formula:
  • R5 H
  • Y is a linear or branched alkyl group containing from 1 to 10 carbon atoms and Z represents an aryl or a heteroaryl group, optionally substituted by a pendant basic nitrogen functionality.
  • the above 2-aminoaryloxazoles compounds may have the formula XI:
  • R5 is H
  • Y is selected from O
  • S and Z corresponds to H, alkyl, or NRR'
  • R and R' are independently chosen from H or alkyl 1 or aryl 1 or heteroaryl 1 , optionally substituted by a pendant basic nitrogen functionality, for example :
  • Ra, Rb are independently chosen from H or alkyl 1 or aryl 1 or heteroaryl 1 , optionally substituted by a pendant basic nitrogen functionality, for example :
  • R5 H
  • Z is an aryl 1 group, aryl 1 being selected from : a phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I, F, CI or Br); - an alkyl 1 group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nifrogen functionality; - trifluoromethyl, O-alkyl 1 , carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl 1 , N(alkyl 1 )(alkyl 1 ), and amino, the latter nifrogen substituents optionally in the form of a basic nifrogen functionality;
  • R5 H and R is independently alkyl 1 , aryl 1 or heteroaryl 1 as defined above.
  • Substituent "L" in formula 10 is a nucleofugal leaving group in nucleophilic substitution reactions (for example, L can be selected from chloro, bromo, iodo, toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc., with L being preferentially a bromo group).
  • Group Rl in formula 11a corresponds to group Rl as described in formula III.
  • Group "PG" in formula 1 lc is a suitable protecting group of a type commonly utilized by the person skilled in the art.
  • Formula 12b describes a precursor to compounds of formula III which lack substituent Rl. Therefore, in a second phase ofthe synthesis, substituent Rl is connected to the free amine group in 12b, leading to the complete structure embodied by formula III: 12b + "Rl" - in The introduction of Rl, the nature of which is as described on page 3 for the general formula m, is achieved by the use of standard reactions that are well known to the person skilled in the art, such as alkylation, acylation, sulfonylation, formation of ureas, etc.
  • Formula 12c describes an N-protected variant of compound 12b.
  • Group "PG" in formula 12c represents a protecting group of the type commonly utilized by the person skilled in the art. Therefore, in a second phase of the synthesis, group PG is cleaved to transform compound 12c into compound 12b. Compound 12b is subsequently advanced to structures of formula I as detailed above.
  • Formula 12d describes a nifro analogue of compound 12b.
  • the nitro group of compound 12d is reduced by any of the several methods utilized by the person skilled in the art to produce the corresponding amino group, namely compound 12b.
  • Compound 12b thus obtained is subsequently advanced to structures of formula III as detailed above.
  • renal diseases as referred herein includes the following potential therapeutic applications : all forms of AA and AL renal amyloidosis, renal interstitial fibrosis after allografted kidney transplantation, renal fibrosis, glomerulonephritis, nephropathy, Balkan nephropathy, acute interstitial nephritis, lupus nephritis, iriflammatory renal diseases, lupus nephropathy, ANCA-associated nephropathy, IgA nephropathy, glomerulopathy.
  • c-kit inhibitors as mentioned above are inhibitors of wild type or mutant activated c-kit.
  • the invention contemplates a method for treating and/or preventing or delaying the onset of renal diseases and dysfunction comprising administering to a human in need of such treatment a compound that is a selective, potent and non toxic inhibitor of c-kit obtainable by a screening method which comprises : a) bringing into contact (i) activated c-kit and (ii) at least one compound to be tested; under conditions allowing the components (i) and (ii) to form a complex, b) selecting compounds that inhibit activated c-kit, c) testing and selecting a subset of compounds identified in step b), which are unable to promote death of IL-3 dependent cells cultured in presence of IL-3.
  • This screening method can further comprise the step consisting of testing and selecting a subset of compounds identified in step b) that are inhibitors of mutant activated c-kit (for example in the transphosphorylase domain), which are also capable of inhibiting SCF- activated c-kit wild.
  • activated c-kit is SCF-activated c-kit wild.
  • step c) IL-3 is preferably present in the culture media of IL-3 dependent cells at a concentration comprised between 0.5 and 10 ng/ml, preferably between 1 to 5 ng/ml. These screening may be perfonned following our previous applcation WO 03/003006, which is incorporated herein by reference.
  • the invention embraces the use of the compounds defined above to manufacture a medicament for preventing or treating renal diseases including all forms of AA and AL renal amyloidosis, renal interstitial fibrosis after allografted kidney transplantation, renal fibrosis, glomerulonephritis, nephropathy, Balkan nephropathy, acute interstitial nephritis, lupus nephritis, mflammatory renal diseases, lupus nephropathy, ANCA-associated nephropathy, IgA nephropathy, glomerulopathy.
  • renal diseases including all forms of AA and AL renal amyloidosis, renal interstitial fibrosis after allografted kidney transplantation, renal fibrosis, glomerulonephritis, nephropathy, Balkan nephropathy, acute interstitial nephritis, lupus nephritis, mflammatory renal diseases, lupus n
  • compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra- arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, sublingual, or rectal means.
  • these pharmaceutical compositions may contain suitable pharmaceutically-acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
  • compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration.
  • Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
  • compositions suitable for use in the invention include compositions wherein compounds for depleting mast cells, such as c-kit inhibitors, or compounds inhibiting mast cells degranulation are contained in an effective amount to achieve the intended purpose.
  • a therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition.
  • Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% ofthe population).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred.
  • Example 1 AB compounds of formula III, IN, V and X are selective and potent c- Kit and mast cell inhibitors.
  • the specific compounds as listed above are non limitative illustrative examples of AB compounds. They display IC50 below 5 ⁇ M, 1 ⁇ M or even 0.1 ⁇ M. on different forms of c-KIT ( Figure 1). Also, these AB compounds are selective for c-KIT versus other tyrosine kinases (Table 1). Table 1 : Inhibition of various protein tyrosine kinases by the AB compound in vitro
  • the AB compounds potently and dose-dependently inhibited the growth of the mast cells (MC) when they were cultured in the presence of SCF (with an IC50 of ⁇ 0.1 ⁇ M). Again these in vitro data confirmed the potent and selective inhibitory activity of c-Kit tyrosine kinase activity as well as the ability of the AB compound to inhibit almost completely the survival of MC population at concentration lower than 0.1 ⁇ M. AB compounds have also been shown to deplete mast cells in vivo. The AB compound has successfully completed preclinical development in September 2003. Safety pharmacology studies revealed no significant effects ofthe AB compound on the central nervous, cardiovascular and respiratory systems.

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Abstract

La présente invention porte sur une méthode de prévention ou de traitement de maladies rénales et des dysfonctionnements, cette méthode consistant à administrer un composé capable d'épuiser les mastocytes ou un composé inhibant la dégranulation des mastocytes. Ces composés peuvent être choisis à partir des inhibiteurs de c-kit et plus particulièrement d'inhibiteurs de c-kit non toxiques, sélectifs et puissants. De préférence, cet inhibiteur est capable de favoriser la mort des cellules dépendant d'IL-3 et mises en culture en présence d'IL-3.
PCT/IB2005/001370 2004-04-23 2005-04-19 Utilisation d'inhibiteurs de c-kit dans le traitement des maladies renales WO2005102326A2 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8088806B2 (en) 2005-05-09 2012-01-03 Achillion Pharmaceuticals, Inc. Thiazole compounds and methods of use
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8106209B2 (en) 2008-06-06 2012-01-31 Achillion Pharmaceuticals, Inc. Substituted aminothiazole prodrugs of compounds with anti-HCV activity
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8183263B2 (en) 2007-05-22 2012-05-22 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US10172876B2 (en) * 2014-11-03 2019-01-08 Sheau-Long Lee Use of ginsenoside M1 for treating IgA nephropathy
US10357507B2 (en) * 2014-05-16 2019-07-23 Sheau-Long Lee Use of ginsenoside M1 for inhibiting renal fibrosis
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2021214019A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1205478A1 (fr) * 1999-08-06 2002-05-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
WO2003003006A2 (fr) * 2001-06-29 2003-01-09 Ab Science Nouveaux inhibiteurs selectifs puissants et non toxiques de c-kit
WO2003002109A2 (fr) * 2001-06-29 2003-01-09 Ab Science Utilisation d'inhibiteurs de tyrosine kinase destines a traiter des maladies auto-immunes
WO2003004467A2 (fr) * 2001-07-06 2003-01-16 Agouron Pharmaceuticals, Inc. Derives de benzamide de thiazole et compositions pharmaceutiques inhibant la proliferation cellulaire, et methodes d'utilisation
WO2004014903A1 (fr) * 2002-08-02 2004-02-19 Ab Science 2-(3-aminoaryl)amino-4-aryl-thiazoles et leur utilisation en tant que inhibiteurs de c-kit
WO2004096225A2 (fr) * 2003-04-28 2004-11-11 Ab Science Utilisation d'inhibiteurs de tyrosine kinase pour le traitement de l'ischemie cerebrale

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2602735B2 (ja) * 1989-09-27 1997-04-23 株式会社大塚製薬工場 抗活性酸素剤

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1205478A1 (fr) * 1999-08-06 2002-05-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
WO2003003006A2 (fr) * 2001-06-29 2003-01-09 Ab Science Nouveaux inhibiteurs selectifs puissants et non toxiques de c-kit
WO2003002109A2 (fr) * 2001-06-29 2003-01-09 Ab Science Utilisation d'inhibiteurs de tyrosine kinase destines a traiter des maladies auto-immunes
WO2003004467A2 (fr) * 2001-07-06 2003-01-16 Agouron Pharmaceuticals, Inc. Derives de benzamide de thiazole et compositions pharmaceutiques inhibant la proliferation cellulaire, et methodes d'utilisation
WO2004014903A1 (fr) * 2002-08-02 2004-02-19 Ab Science 2-(3-aminoaryl)amino-4-aryl-thiazoles et leur utilisation en tant que inhibiteurs de c-kit
WO2004096225A2 (fr) * 2003-04-28 2004-11-11 Ab Science Utilisation d'inhibiteurs de tyrosine kinase pour le traitement de l'ischemie cerebrale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 199138 Derwent Publications Ltd., London, GB; Class B03, AN 1991-278282 XP002336319 & JP 03 184914 A (OTSUKA SEIYAKU KOGYO KK) 12 August 1991 (1991-08-12) & JP 03 184914 A (OTSUKA PHARMACEUT FACTORY INC) 12 August 1991 (1991-08-12) *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8088806B2 (en) 2005-05-09 2012-01-03 Achillion Pharmaceuticals, Inc. Thiazole compounds and methods of use
US8183263B2 (en) 2007-05-22 2012-05-22 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles
US8106209B2 (en) 2008-06-06 2012-01-31 Achillion Pharmaceuticals, Inc. Substituted aminothiazole prodrugs of compounds with anti-HCV activity
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10357507B2 (en) * 2014-05-16 2019-07-23 Sheau-Long Lee Use of ginsenoside M1 for inhibiting renal fibrosis
US10172876B2 (en) * 2014-11-03 2019-01-08 Sheau-Long Lee Use of ginsenoside M1 for treating IgA nephropathy
WO2021214019A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
WO2021214020A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
US11964953B2 (en) 2020-04-24 2024-04-23 Bayer Aktiengesellschaft Substituted aminothiazoles as DGKzeta inhibitors for immune activation

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