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WO2006038112A1 - Utilisation d'inhibiteurs de kinases pour favoriser la neochondrogenese - Google Patents

Utilisation d'inhibiteurs de kinases pour favoriser la neochondrogenese Download PDF

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Publication number
WO2006038112A1
WO2006038112A1 PCT/IB2005/003058 IB2005003058W WO2006038112A1 WO 2006038112 A1 WO2006038112 A1 WO 2006038112A1 IB 2005003058 W IB2005003058 W IB 2005003058W WO 2006038112 A1 WO2006038112 A1 WO 2006038112A1
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Prior art keywords
phenyl
dihydro
pyrimido
pyrimidin
dimethoxy
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PCT/IB2005/003058
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English (en)
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Vijaykumar Mahalingappa Baragi
David Wayne Brammer
Cynthia Lee Courtney
Brian Craig Korniski
Charles Alfred Lesch
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Warner-Lambert Company Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • This invention relates to the use of kinase inhibiting compounds, including tyrosine kinase inhibiting compounds, in the promotion of neochondrogenesis and the enhancement, protection and repair of cartilage.
  • the methods particularly use substituted pyrimidopyrimidines, dihydropyrimidopyrimidines, pyridopyrimidines, naphthylf ⁇ pes and pyridopyrazines that inhibit cyclin-dependent kinase and tyrosine kinase enzymes.
  • Tyrosine kinases are an integral part of growth factor receptors and are essential for the propagation of growth factor signal transduction leading to cellular proliferation, differentiation, and migration.
  • Growth factor receptors are also known as receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • FGF Fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • Solid tumors are dependent upon the formation of new blood vessels from preexisting vessels (angiogenesis) to nourish their growth and to provide a conduit for metastases.
  • Neochondrogenesis is the process of forming new cartilage, including the proliferation and differentiation of mesenchymal stem cells and formation of cartilage matrix.
  • This invention comprises methods of inhibiting, ameliorating, repairing or preventing damage or degradation of, or of inducing growth and repair of, cartilage in a recipient, the methods comprising applying or administering directly to the recipient's cartilage a pharmaceutically effective amount of a tyrosine kinase inhibitor.
  • Direct application or administration of the tyrosine kinase inhibitor as used herein refers to a non-systemic administration of the inhibitor in a site-specific manner to or near the cartilage(s) in question.
  • the methods herein include parenteral application of the compound into or onto the cartilage or local or topical application of the inhibitor such that a pharmaceutically effective amount of the inhibitor will reach the cartilage and promote localized chondrocyte proliferation without significant systemic distribution of the inhibitor.
  • One in vivo measure of desired distribution of a pharmaceutically effective amount of the tyrosine kinase inhibitor in question is the delivery of an amount of inhibitor sufficient to enhance chondrocyte growth at or near the locus of administration, without measurably increasing chondrocyte proliferation at other sites in the body.
  • the methods herein include the application or administration directly or topically on cartilage tissue, including articular or hyaline cartilage, fibrocartilage and elastic cartilage, that is experiencing or subject to degradation, including the damage associated with trauma and degenerative disorders, such as cartilage damage associated with Osteoarthritis, rheumatoid arthritis and rheumatoid variants.
  • One method of this invention comprises administering a pharmaceutically effective amount of a tyrosine kinase inhibitor intra-articularly to a cartilaginous tissue experiencing or subject to degradation or damage.
  • the pharmaceutically effective amount of a tyrosine kinase inhibitor is administered in a formulation including one or more pharmaceutically acceptable carriers or excipients.
  • the methods of this invention may be used in the protection and repair of cartilage tissues and used to foster rehabilitation and quality of life in a recipient.
  • the methods herein may be utilized for repair or recovery of cartilaginous tissues resulting from osteoarthritis, trauma, including traumatic mechanical destruction or progressive mechanical degradation or destruction (wear and tear), or infections, including bacterial, viral and fungal infections, sometimes referred to as septic or infectious arthritis, supperative arthritis, reactive arthritis or Gonococcal arthritis.
  • chondritis may further assist in cartilage damage, degradation or atrophy resulting from maladies including chronic inflammatory synovitis, forms of chondritis, such as nasal, bilateral auricular or respiratory tract chondritis, initial or relapsing polychondritis, chronic atrophic polychondritis, or generalized or systemic chondromalacia, or cartilaginous neoplasias.
  • maladies including chronic inflammatory synovitis, forms of chondritis, such as nasal, bilateral auricular or respiratory tract chondritis, initial or relapsing polychondritis, chronic atrophic polychondritis, or generalized or systemic chondromalacia, or cartilaginous neoplasias.
  • the repair may also be utilized to treat cartilage damage associated with connective or bone tissue diseases including osteomyelitis, gout, chondromalacia, juvenile rheumatoid arthritis, psoriatic arthritis, hemophilic arthritis, Reiters Syndrome, Scleroderma, Systemic Lupus Erythematosus, Ankylosing Spondylitis, herniated vertebral discs, etc.
  • connective or bone tissue diseases including osteomyelitis, gout, chondromalacia, juvenile rheumatoid arthritis, psoriatic arthritis, hemophilic arthritis, Reiters Syndrome, Scleroderma, Systemic Lupus Erythematosus, Ankylosing Spondylitis, herniated vertebral discs, etc.
  • the methods, formulation and regimens herein may also be utilized to repair, strengthen or rebuild cartilage tissues following surgical procedures requiring reduction, building up or manipulation of cartilage tissues, including reconstructive or cosmetic reductions or manipulations of cartilage.
  • a method of increasing the strength, thickness or mass of an existing cartilage tissue may be useful in the prophylactic strengthening or supporting of cartilaginous tissue where the existing tissue may have potential for failure due to age, use or exceptional physical demands. lncreasing the thickness, mass or strength of cartilaginous tissues may also be desired at sites wherein the tissue will encounter prosthetic devices.
  • the methods of this invention are useful in treating or enhancing recovery of cartilage damage or degradation brought about due to the trauma associated with repetition or sports injuries, including the degradation, tearing, compression and dislocation of cartilaginous tissues.
  • Non-limiting examples of repetition- or sports-related cartilage injuries and maladies that may be improved with the methods of this invention include chondromalacia, or tearing or damage to articular, meniscal cartilage, wrist, ankle, acromioclavicular, or vertebral cartilage.
  • the methods of this invention may also be characterized as methods of initiating, enhancing or promoting neochondrogenesis in a cartilage tissue, the method comprising administering locally or directly to the cartilage tissue a neochondrogenesis enhancing amount of a tyrosine kinase inhibitor, as described herein.
  • Tyrosine kinase inhibitors may be administered within the scope of this invention in conjunction with medical procedures designed to clean, repair or evaluate cartilaginous tissues, such as arthroscopic lavage (arthroscopic washout) and debridement procedures.
  • the methods herein include veterinary methods of treatment, amelioration, inhibition or prevention of cartilage damage or diminishment associated with veterinary maladies, including osteochondritis, joint dysplasias or spondylosis, degenerative joint disease, Osteoarthritis, Rheumatoid Arthritis, and the maladies and methods described herein that are equally relevant to non-human mammals.
  • veterinary maladies including osteochondritis, joint dysplasias or spondylosis, degenerative joint disease, Osteoarthritis, Rheumatoid Arthritis, and the maladies and methods described herein that are equally relevant to non-human mammals.
  • Another use of the compounds of this invention comprises utilizing an effective amount of a tyrosine kinase inhibitor to promote and enhance the growth of chondrocytes in vitro.
  • Cartilage cells grown in vitro may then be utilized in physiologically acceptable solutions, formulations and matrices to enhance cartilage repair or growth in damaged, degraded or otherwise insufficiently developed cartilage in vivo.
  • These methods may be further understood as comprising the addition of a cartilage enhancing amount of a tyrosine kinase inhibitor to an in vitro culture of chondrocytes.
  • Such in vitro cultures include those known in the art for the growth of chondrocytes and may include cartilage enhancing growth media and components including bone morphogenetic protein (BMP)-
  • BMP bone morphogenetic protein
  • dexamethasone transforming growth factor (TGF)-beta3, etc.
  • Tyrosine kinase inhibitor compounds may also be used to foster cartilage growth following cartilage cells or tissues allografted or autografted into a recipient. Fostering greater chondrocyte growth using the modes of administration described herein may be used to hasten the integration of new cells or tissues and strengthen the resulting cartilaginous presence in the concerned area. DETAILED DESCRIPTION OF THE INVENTION
  • One embodiment of the methods of this invention comprises administering to an animal in need thereof, particularly to a mammal in need thereof, a pharmaceutically effective amount of a compound of formula:
  • A is O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , or -NHC(O)-NHR 12 ;
  • R 12 is C 1 -C 6 straight or branched chain alkyl, preferably C-1-C4 straight or branched chain alkyl, or -(CH 2 ) n -C3-C3 cycloalkyl ring, preferably -(CH 2 ) n -C3-C7 cycloalkyl, wherein n is an integer of from 1 to 3;
  • B and D and E are independently selected from CH or N;
  • E is from CH (when the dashed line indicates a double bond), CH 2 or N, with the proviso that E and D are not both N;
  • R 1 is selected from the group of C1-C5 straight or branched chain alkyl, preferably C 1 ⁇ straight or branched chain alkyl, optionally substituted by -COOH, or; a) a phenyl, benzyl or C3-C8 cycloalkyl group, preferably C3-C7 cycloalkyl, or - CH 2 -C3"C3 cycloalkyl group, preferably -CH 2 -C3-C7 cycloalkyl, with the rings of the phenyl, benzyl or cycloalkyl groups being optionally substituted by 1 or 2 COOH or -CH 2 -COOH groups; or b) a piperidinyl or piperazinyl moiety selected from group of:
  • X is C 1 -C 6 alkyl, or optionally substituted phenyl, benzyl, C 3 -C 7 cycloalkyl, -CH 2 - C 3 -C 7 cycloalkyl, or 6-membered or 7-membered heterocyclic or heteroaromatic moieties containing one or two heteroatoms selected from N, O or S; with each of the phenyl, benzyl, cycloalkyl, heterocyclic or heteroaromatic moieties being optionally substituted by from 1 to 4 substituents selected from C 1 -C 6 alkyl, preferably C-1-C3 alkyl, C 1 -C 6 alkoxy, preferably C1-C3 alkoxy, halogen, -NH 2 , NO 2 , OH, C 1 -C 6 haloalkyl, preferably C-1-C3 haloalkyl, C-] -C 6 haloalkoxy, preferably C1-C3 hal
  • Rg a is selected from H or C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl;
  • R ⁇ b is selected from the group of H, -(C 1 -C 5 alkyl)-NH2, -(C-) -C5 alkyl)-NH-(C-
  • each of the alkyl chains of any group in this R4 definition being optionally substituted by from 1 to 4 OH groups;
  • R7 in each instance is independently selected from H, -NH2, NH(C 1 -C 3 alkyl),
  • R3 is H, OH or C-1-C3 alkyl
  • R 9 is H, OH, -NH 2 , NH(C 1 -C 3 alkyl), or N(C 1 -C 3 alkyl) 2 ;
  • R 1 1 is H, CN, OH, NH 2 , F, Or CF 3 ; or a pharmaceutically acceptable salt thereof.
  • the compound of formula I is selected from the group of:
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of: 3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-(2,3-dihydroxy-butylamino)-1-ethyl-3,4- dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;
  • the methods of the present invention comprise treating a mammal suffering from osteoarthritis.
  • the methods of the present invention comprise treating a mammal suffering from cartilage degradation.
  • the methods of the present invention comprise administered intra-articularly a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the methods of the present invention comprise administered intra-articularly to a knee joint a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the methods of the present invention comprise administered intra-articularly to a knee joint a compound of formula I, or a pharmaceutically acceptable salt thereof, at a dose from 0.001 to 0.1 mg/kg.
  • the present invention relates to the use of a compound, or a pharmaceutically acceptable salt thereof, of formula I:
  • A is O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , Or -NHC(O)-NHR 12 ;
  • R 12 is C 1 -C 6 straight or branched chain alkyl, or -(CH 2 ) n -C3-Cs cycloalkyl ring; n is an integer of from 1 to 3;
  • B, D and E are independently selected from CH or N, with the proviso that E and D are not both N;
  • R 1 is selected from the group of C 1 -C 6 straight or branched chain alkyl, optionally substituted by -COOH, or; a) a phenyl, benzyl or C3-C8 cycloalkyl ring, or -CH2-C3-C3 cycloalkyl ring, with the phenyl, benzyl or cycloalkyl rings being optionally substituted by 1 or 2 COOH or -CH 2 -COOH groups; or b) a piperidinyl or piperazinyl moiety selected from group of:
  • R 2 is H, Cl or F
  • R3 is H, Cl or F, with the proviso that at least one of R2 or R3 is F;
  • R4 is H, OH, -OCH3, or -OCH2CH3, with the proviso that, if R4 is H, R2 and R3 are not H;
  • R5 is -OCH3, or -OCH2CH3;
  • R6 is selected from the group of H, -(C 1 -Cs alkylJ-Nht ⁇ , -(C 1 -C 5 alkyl)- NH-(C 1 -C 3 8IkVl)-R 11 , -(C 1 -C 5 SIkYl)-N-(C 1 -C 3 alkyl-R 11 ) 2 , -0-(C 1 -C 5 alkyl)- NH 2 , -0-(C 1 -C 5 alkyl)-NH-(Ci-C 3 8IkYl)-R 111 -O-(C 1 -C 5 8IkYl)-N-(C 1 -C 3 alkyl- R 11 J 2 , -CH(CH 2 OH) 2 , -(C 1 -C 3 alkyl)-(CH 2 OH) 2 , -(C 1 -C 3 SIkYl)-O-(C 1 -C 3 alkyl)- R
  • each of the alkyl chains of any group in this R4 definition being optionally substituted by from 1 to 4 OH groups;
  • R7 in each instance is independently selected from H, -NH2, NH(C-i-C3 alkyl), N(C 1 -Cs alkyl)2, or C1-C3 alkyl;
  • R 8 is H, OH or C1-C3 alkyl;
  • R-IO is H or C-J-C 3 alkyl
  • R 1 -I is H, CN, OH, NH 2 , F, or CF 3 - in the manufacture of a medicament for promoting neochondrogenesis in a mammal in need thereof.
  • the methods of this invention comprise administration to an animal in need thereof, particularly to a mammal in need thereof, compounds of formula
  • A is O, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , or -NHC(O)-NHR 12 ;
  • R 12 is C-
  • B and D and E are independently selected from CH or N;
  • E is from CH (when the dashed line indicates a double bond), CH 2 or N, with the proviso that E and D are not both N;
  • R 1 is selected from the group of C 1 -Ce straight or branched chain alkyl, preferably C 1 -C 4 straight or branched chain alkyl, optionally substituted by -COOH, or; a) a phenyl, benzyl or C3-C8 cycloalkyl group, preferably C3-C7 cycloalkyl, or - CH2-C3-C8 cycloalkyl group, preferably -CH2-C3-C7 cycloalkyl, with the rings of the phenyl, benzyl or cycloalkyl groups being optionally substituted by 1 or 2 COOH or -CH2-COOH groups; or b) a piperidinyl or piperazinyl moiety selected from group of:
  • R 2 is H, Cl or F
  • R3 is H, Cl or F, with the proviso that at least one of R2 or R 3 is F;
  • R4 is H, OH, -OCH3, or -OCH2CH3, with the proviso that, if R 4 is H, R2 and R3 are not H;
  • R 5 is -OCH 3 , or -OCH 2 CH 3 ;
  • Rga is selected from H or C 1 -Ce alkyl, preferably C1-C3 alkyl;
  • R ⁇ D is selected from the group of H, -(C-
  • each of the alkyl chains of any group in this R4 definition being optionally substituted by from 1 to 4 OH groups;
  • R7 in each instance is independently selected from H, -NH2, NH(C 1 -C 3 alkyl), N(C-J-C 3 alkyl)2, or C 1 -C 3 alkyl;
  • R3 is H, OH or C 1 -C 3 alkyl
  • R 9 is H, OH, -NH 2 , NH(C 1 -C 3 alkyl), or N(C 1 -C 3 alkyl) 2 ;
  • R 1 O is H or C1-C3 alkyl;
  • R 1 • is H, CN, OH, NH 2 , F 1 or CF 3 ; or a pharmaceutically acceptable salt thereof.
  • This invention also includes subgroups of the compounds described above in which the core structure designated:
  • variable A is O.
  • Another subgroup within each group or subgroup of compounds comprises those wherein A is selected from NH 2 , NH(C-J-Cs alkyl) or N(C-J-Cs a!M)2-
  • a further subgroup therein comprises those compounds wherein A is selected from NH2, NH(C- ] -C3 alkyl) or N(C-] -C3 alkyl)2-
  • R2 and R3 are H and the other is F, and R4 and R5 are as defined above.
  • R2 and R3 are both F and R4 and R5 are as defined above.
  • R-) is selected from C ⁇ -C ⁇ straight or branched chain alkyl, preferably C1-C4 straight or branched chain alkyl, optionally substituted by -COOH, or a benzyl or C3-C8 cycloalkyl ring, preferably C3-C7 cycloalkyl, with the benzyl or cycloalkyl rings being optionally substituted by 1 or 2 COOH groups.
  • Two groups of compounds of this invention comprises those of the formulae III and IV:
  • R ⁇ is C-
  • R 2 is H or F; and A, B, D, E, R3, R4, R5, R 6a (when present), RQ ⁇ , RJ, RQ, R 9 ,
  • R 10- R 11 and R 12 are as defined above; or a pharmaceutically acceptable salt thereof.
  • C3-C8 cycloalkyl ring includes fully saturated rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, partially saturated carbocyclic rings having from 3 to 8 ring carbon atoms, such as cyclohexene, and bridged cycloalkyl groups, such as bicyclo[2.2.1]heptane.
  • kinase inhibiting compounds known in the art may be used in the methods of treatment, combination therapies and drug regimens of this invention. These include, but are not limited to, the kinase inhibiting compounds disclosed in U.S. Patent No. 5,620,981, U.S. Patent No. 5,733,914, WO
  • the present invention relates to methods of promoting the growth of mammalian chondrocytes in vitro comprising administering to the chondrocytes in vitro a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the compounds of Formula I are capable of further forming both pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvates and N-oxides.
  • This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms are within the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge, et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977;66:1-19.
  • the acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediami ⁇ e, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge, supra, 1977.
  • the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • 3-Phenyl-pyrimido[4,5-d]pyrimidin-2-one compounds of this invention may be prepared by methods known in the art, including those described in WO 99/61444 (Dobrusin et al.), and WO 01/29042 (Dunn et al.).
  • An example of useful synthetic routes includes that seen in Scheme 1.
  • This treatment may be carried out in an art recognized solvent, such as tetrahydrofuran, or dichloromethane.
  • Reduction of the ester (2a-2h) to the corresponding alcohol (3a-3h) can be carried out in art recognized methods, such as using lithium aluminum hydride in tetrahydrofuran.
  • the 5-arylamino compound (8c) may then be reduced to the corresponding 5- aryl-amine (13c) using conventional reducing agents, such as sodium borohydride, lithium aluminum hydride or sodium triacetoxyborohydride under art recognized conditions.
  • conventional reducing agents such as sodium borohydride, lithium aluminum hydride or sodium triacetoxyborohydride under art recognized conditions.
  • -7-methylsulfany!-3-aryl-1 H- pyrimido[4,5-d]pyrimidin-2-one (18c) may be accomplished using sodium hydride and carbonyldiimidazole (CDI).
  • Oxaziridine-mediated oxidation of the 7-position sulfanyl compounds (18c) provides the corresponding sulfinyl compounds (23c), which may then be reacted with an Rg-substituted amine, wherein the Rg positional groups are as defined herein, to provide the desired 7-Rg-amino-3-Phenyl-pyrimidin-2-one compounds.
  • this application also comprises compounds useful in preparation of the pharmaceutically useful compounds described herein, the compounds having the formulae: wherein R- j , R2, R3, R4, and R5 may be as defined in each instance herein.
  • naphthyridone compounds useful in the methods of this invention can also be accomplished by methods known in the art, such as those described in
  • the 3-aryl-[1 ,6]napthyridine-2,7-diamine (2) may be converted to 3-aryl-7-fluoro-[1 ,6]napthyridine-2-one (3) by a diazotization reaction in 50% aqueous fluoroboric acid in a large excess (up to 8 equivalents) of solid sodium nitrite at low temperature (at or below -5°C) for several days, after the manner previously described by Rewcastle et al., J. Med. Chem., 1996;39,1823.
  • R ⁇ - substituted compounds (4) of this invention may be produced by treatment of the 3-aryl-7-fluoro-[1 ,6]napthyridine-2-one (3) with an appropriate R - j -iodide, such as an appropriate alkyl iodide, in the presence of a base in a suitable dry, unreactive solvent, such as dimethylformamide, at from about 0 0 C to about 20°C.
  • R - j -iodide such as an appropriate alkyl iodide
  • Pteridinone compounds of this invention may be prepared by methods known in the art, including those described in WO 01/19825 (Denny et al.).
  • An example of these methods is the reaction of 2,4-Dichloro-5-nitro-pyrimidine (1) with an appropriate R- ) - amine, preferably at reduced temperatures, to form 2-Chloro-5-nitro-pyrimidin-4-yl)-R-
  • Additional treatment with Rs-primary amine preferably at ambient temperatures, provides the corresponding 5-nitro-2,4-diamin ⁇ pyrimidine compound (3), wherein Rs is as defined for the corresponding positional groups herein.
  • the nitro compound (3) can then be reduced by conventional methods to the corresponding 2,4,5-triaminopyrimidine (4) through conventional means, such as catalytic hydrogenation.
  • R-] , R2, R ⁇ , R4, and R5 may be as defined in each instance herein.
  • Synthetic routes to prepare pteridinone ureas (5), as defined herein, include the techniques described in WO 01/19825 (Denny et al.). As seen in Scheme 4, 2,4-Dichloro- 5-nitro-pyrimidine (1 ) may be treated with ammonia to provide the corresponding 2- Chloro-5-nitro-pyrimidin-4yl-amine (2). Reduction of the nitro group, for instance by reaction with hydrogen in the presence of a catalyst such as palladium on carbon, and treatment with an Rg-substituted amine yields the N-Rg-pyrimidine-2,4,5-triamine (3).
  • a catalyst such as palladium on carbon
  • Cyclization to pteridine (4) is accomplished by reaction of the triamine (3) with an agent such as an aryl ketonitrile (ArCOCN). Subsequent treatment of the pteridine (4) with an appropriate isocyanate, wherein R7 is as defined herein, in the presence of NaH provides the desired urea (5).
  • an agent such as an aryl ketonitrile (ArCOCN).
  • R-] and R5 are as defined herein, which may be used in the synthesis of the pharmaceutically useful pteridinone compounds of this invention.
  • Pyridopyrimidine compounds useful in the methods of this invention can also be prepared by methods known in the art. Examples of references describing their synthesis include U.S. Pat. No. 5,733,913 (Blankley et al.), U.S. Pat. No. 5,733,914 (Blankley et al.), WO 02/12237 (Beylin et al.), and WO 9833798 (Boschelli et al.). Scheme 5, below, demonstrates a procedure for preparation of pyridopyrimidine compounds of this invention. As depicted, an appropriate 4-(substituted amino)-2-methylsulfanyl-pyrimidine- 5-carboxaldehyde (1) (J. Med.
  • a further synthesis of pyridopyrimidone compounds of this invention can be accomplished by the alternate condensation route demonstrated in Scheme 6,
  • the initial preparation of the 4-thioalkyl-7-keto compound (2) is accomplished by condensation of the 4-(substituted amino)-2-methylsulfa ⁇ yl-pyrimidine-5-carboxaldehyde (1) with a substituted aryl acetic acid ester, such as a phenyl acetic acid alkyl ester, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • the reaction can be accomplished neat or in a solvent such as dimethylformamide or dimethyl sulfoxide.
  • This invention also comprises methods of treatment, inhibition or prevention of cartilage damage or degradation utilizing compounds of the formulae:
  • variables R-j, R2, R3, R4, and R5 may be as defined in each instance herein.
  • R- ⁇ , R2, R3, R4, and R5 may be as defined in each instance herein.
  • 2,6-Difluoro-3,5-dimethoxyaniline can be prepared as follows:
  • Methyl pentafluorobenzoate (41.4 g, 183 mmol) was treated with N-methylpyrrolidinone (36.0 g) and the solution stirred and cooled to 5°C under a N 2 atmosphere.
  • Benzylamine (19.8 g, 185 mmol) was added dropwise over 27 min. at 5°C- 20 0 C.
  • the resulting thick yellow slurry was cooled to 2 0 C over 25 min. and N 1 N- diisopropyl ethylamine (27.0 g, 209 mmol) was added over 30 min. at 3°C-10°C. The mixture was allowed to warm to 18°C and stirred for 2 hrs.
  • Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoale (24.0 g, 76.6 mmol) was cooled to 5°C-10°C under a nitrogen atmosphere and a 25 weight % solution of sodium methoxide in methanol (53.5 mL, 234 mmol) was added dropwise over 5 minutes with continued cooling. The resulting mixture was stirred with ice bath cooling for another 10 minutes, the ice bath was removed and the mixture allowed to warm to 35°C-40°C. It was recooled to room temperature and held for 4.5 hours before heating to 65°C-70°C where it was held for 3.5 hours. The mixture was cooled to room temperature and held overnight.
  • Methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate (24.0 g) was dissolved in ethanol (75 mL) and the solution stirred and cooled to 10 0 C under a nitrogen atmosphere.
  • Sodium hydroxide, 50% aqueous solution (12.5 g, 156 mmol) was added dropwise over 10 minutes at 10°C-15°C followed by ethanol (10 mL). The solution was stirred at 15°C-25°C. A thick precipitate formed. Stirring was continued for a total of 2 hours at 15°C-25°C. The mixture was heated to 50°C-55°C where it was held for 1.5 hours. The mixture was allowed to cool to room temperature and held overnight.
  • N-Benzyl-2,6-difluoro-3,5-dimethoxyaniline (6.0 g, 21.5 mmol) was dissolved in THF (40 ml.) and the solution hydrogenated over 20% palladium hydroxide on carbon catalyst (0.6 g) at 20°C-25°C 48-50 psi hydrogen pressure for 16 hours. The mixture was filtered, the catalyst washed with THF (2 x 15 mL) and the combined filtrates concentrated to a solid. This was recrystallized from heptane (10 mL) and toluene (4.5 mL). The mixture was cooled to -10 0 C before filtering.
  • the ethyl acetate solution was added back into the reaction vessel containing the residue, followed by 40 mL of 0.5 M NaOH. The reaction was agitated and the aqueous layer removed. The ethyl acetate solution was washed twice with 0.5 M NaOH and once with a saturated solution of sodium chloride. The ethyl acetate layer was dried with magnesium sulfate and concentrated in vacuo. The residue was stirred with pentane and evaporated to give the desired product.
  • the cooled mixture was treated dropwise via syringe with 23.79 mL (23.79 mol) of 1 M solution of lithium aluminum hydride in tetrahydrofuran which resulted initially with vigorous bubbling.
  • the resulting mixture continued to stir at O 0 C for 1 hour under nitrogen atmosphere.
  • the ice bath was removed and the reaction mixture was allowed to warm up to room temperature and continued stirring at room temperature overnight.
  • the reaction mixture was cooled to 0 0 C using an ice/acetone bath and quenched by the slow addition of 23.79 mL of water,
  • the ice bath was removed and the reaction mixture was allowed to warm up to room temperature and continued stirring at room temperature overnight.
  • the reaction mixture was cooled to O 0 C using an ice/acetone bath and quenched by the slow addition of 78.50 ml. of water, 78.50 mL of 15% sodium hydroxide and 157 mL of water.
  • the salts were filtered over a bed of Celite and removed the tetrahydrofuran in vacuo. The residue was redissolved in dichloromethane and filtered again. The layers were separated and dried the organic layer over sodium sulfate, filtered and evaporated.
  • the reaction mixture was treated with 1.16 g (28.95 mmol) of sodium hydride and continued stirring at 0 0 C for 30 minutes. After 30 minutes, 5.63 g (34.74 mmol) of 1 ,1'-carbonyldiimidazole was added and continued to stir at 0 0 C for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture healed at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 250 mL dichloromethane.
  • This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefore.
  • Liquid form preparations include solutions, suspensions, and emulsions such as water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, lactated Ringer's solution and the like.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, and stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • the pharmaceutical preparations of the invention are preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation.
  • a pharmaceutically or therapeutically effective amount or dose of a compound of this invention for intraarticular administration to a joint will generally be from about 0.1 mg to about 10 mg per joint, such as a knee joint, shoulder joint, elbow joint, etc.
  • the dose administered intra-articularly is from 0.001 to 0.1 mg/kg, or from
  • a pharmaceutically or therapeutically effective amount or dose of a compound of this invention is an amount that will provide inhibition of cartilage damage or degradation or stimulate new growth of damaged or degraded cartilage tissues.
  • a pharmaceutically or therapeutically effective amount or dose of a compound of this invention will also be understood to be an amount sufficient to provide a preventative, inhibitory, ameliorating or diminishing effect on damage or degradation described herein, their symptoms or physiological origins.
  • the kinase inhibiting compounds described herein can be administered neat to cartilage tissues or applied in formulations known in the art for direct or intraarticular administration to cartilaginous tissues. The compounds may also be administered into spaces or tissues adjacent the cartilage in question such that the compound will encounter the cartilage in question without substantial relative systemic dispersal. Such administrations may include injection or other delivery of a pharmaceutically effective amount of a kinase inhibiting compound into the synovial fluid or bursa(e) associated with a joint.
  • the formulations may include pharmaceutically acceptable adjuvants, excipients and carriers, including biodegradable polymers and co-polymers, buffers, solvents, surfactants, diluents, emulsifiers, emollients, hydrogels, hydrophilic agents, lipoproteins and other fatty acid derivatives, liposomes and other micelles, microporous membranes, mucoadhesives and biodegradable microspheres.
  • the compounds may be suspended or maintained in a solution of physiologically acceptable aqueous media, such as buffered saline, Ringer's Injection, etc.
  • Useful formulations known in the art include the emulsion and micellular formulations described in U.S. Pat. Nos. 6,586,003 and 6,120,794 (both to Liu et al.), the polymeric systems described in U.S. Pat. Application 20020164374 (Jackson et al.), the porous drug matrices disclosed in U.S. Pat. Application 20020142050 and WO 0072827 (both to Straub et al.), and in soluble polymeric solutions, such as those described in U.S.
  • the compounds of this invention may also be integrated into or onto physiologically acceptable matrices, polymers, gels, etc., for application to cartilage in need of repair or additional cartilaginous growth.
  • physiologically acceptable carriers or materials known in the art include thermosensitive polysaccharide gels, such as chitosan-based polymer solutions, natural hydrogels, such as alginates, fibrin, collagen gels, etc., natural polymeric materials (such as devitalized cartilage matrix, collagen fibers, etc.), synthetic polymers (including permanent materials and those to be resorbed over time), biodegradable polymers, and polymers with adsorbed proteins or immobilized functional groups.
  • Useful biodegradable polymers include polymethylmethacrylate, glycolic acid, polyglycolic acid (PGA), polylactic acid (PLA), poly-DL-lactic-co-glycolic acid (PLGA), copolymers of glycolic, polyglycolic and polylactic acids, polyhydroxyaikonat.es, poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly ( ⁇ -caprolactone) homopolymers and copolymers, poly anhydrides and polyorthoesters.
  • Combinations of physiologically acceptable polymers and natural materials may also be used, such as a combination of poly-DL-lactic-co-glycolic acid (PLGA) and collagen gel.
  • physiologically acceptable materials described above may include extracellular matrix molecules of connective tissues, such as collagen, hyaluronan and glycosaminoglycans, or their physiologically acceptable synthetic equivalents.
  • Tyrosine kinase inhibiting agents may also be added to regiments and agents known in the art for promoting or assisting cartilage repair or replacement, including Carticel (autologous cultured chondrocytes), available from Genzyme Corporation, Cambridge, MA.
  • Carticel autologous cultured chondrocytes
  • Compounds of this invention may be administered to a specified site over time as a dosed, regimented or continuous infusion using infusion pump technologies.
  • useful infusion pumps known in the art include the 2000 PlusTM Ambulatory Infusion Pump, 4000 PlusTM Ambulatory Infusion Pump, and 4000 CMSTM (Clinical Management System) Multi-therapy Ambulatory Infusion System with Flexible Communication
  • the compounds described herein may be administered through infusion in any biocompatible formulation or material compatible with the infusion technology in question.
  • biocompatible materials include sterile physiologic saline, buffered Ringer's solution, etc.
  • the crude product was purified using medium-pressure chromatography eluting with a gradient of 9:0.5:0.25 to 9:1:0.5 ethyl acetate/methanol/triethylamine to give 8.14 g (86%) of the title compound as a pure partially crystalline solid.
  • a 50 mg portion of the solid was recrystallized with 25% ethanol in hexanes to give 35 mg of title compound as pure crystalline solid: mp 132°C-133°C.
  • Example 7 using 0.50 g (1.11 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy- phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-c/]pyrimidin-2-one and 0.33 mL (3.32 mmol) of 2-(2-aminoethoxy)ethanol.
  • the crude product was purified using medium- pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (92%) of the title compound: mp 160°C-163°C. MS (APCI) (m+1 )/z 494.3.
  • 3-(2,6-Difiuoro-3,5-dimethoxy-phenyl)-1-ethyl-7-(2-hydroxy-1-hydroxymethyl- ethylamino)-3,4-dihydro-1 H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.5 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7- methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-£/]pyrimidin-2-one and 0.33 g (3.64 mmol) of serinol.
  • the crude product was purified using medium-pressure chromatography eluting with a gradient of 9:1 ethyl acetate/methanol to 9:1 :0.25 to 9:1 :0.5 ethyl acetate/methanol/triethylamine to give 0.43 g
  • Compound A is 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-(pyridin-4-ylamino)-8H-pyrido[2,3- d]pyrimidine-7-one hydrocholoride.
  • Compound B is 1-cyclope ⁇ tyl-7-(4-diethylamino-butylami ⁇ o)-3-(2,6-difluoro-3,5- dimethoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one.
  • Compound C is 3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylamino-1-piperidin-4-yl-3,4- dihydro-1 H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate.
  • a medial parapatellar arthrotomy was performed, and the patella was luxated laterally.
  • a sterilized steel drill bit and a dual torque low speed drill was used to create a 5 mm diameter defect in the articular cartilage of the trochlear groove. This defect was used to contain the test compound and the various delivery vehicles described below.
  • the test compound-vehicle 'plug' was held in the defect by the patellar ligament.
  • peroiosteum removed from the medial aspect of tibia was used as graft patch. The patch was sutured on to the defect using 8-0 suture.
  • the graft was then sealed with a fibrin-based glue (Tiseel VH Fibrin Sealant, available from Baxter Healthcare Corp.) to minimize leakage from the defect.
  • a fibrin-based glue Tiseel VH Fibrin Sealant, available from Baxter Healthcare Corp.
  • the patella was repositioned to its original location within the trochlear groove.
  • a three layer closure was be used to close the surgery site on the knee and tibia.
  • animals were returned to their cages and given food and water ad libitum. Throughout the study, animals appeared normal, with no detectable effects on appetite or movement.
  • Drug Delivery The test compounds were administered to the experimental animals either orally or intra-articularly (IA).
  • Compound B was formulated into a 7.8% solution containing 47% PLGA (Poly-lactide-co- glycolide copolymer).
  • Compound A was formulated into a 5.8% solution containing 36% PLGA.
  • the vehicle controls for these various groups used identically formulated solutions without the compounds.
  • Tissue samples (stomach, heart, aorta and kidney) collected for assessing systemic toxicity of compounds were fixed in buffered neutral formalin and embedded in paraffin. Sections of tissue were cut and stained with H&E (hematoxylin & eosin) stain. Several soft tissue mineralization sections were also subjecting to von Kossa staining method that is used for visualizing tissue mineralization.
  • H&E hematoxylin & eosin
  • IA administration of Compound A reduced drug exposure and averted systemic toxicity that was observed in animals dosed orally. Moreover, IA delivery promoted chondrogensis specifically in the joint of interest. More importantly, IA delivery, especially using the controlled-release formulations, was effective in inducing chondrogeneis at significantly lower doses than those employed in the oral dosing paradigm (Table 2).
  • kinase inhibitors when given intraarticularly can induce neochondrogensis specifically in the cartilage tissues of a joint of interest without inducing systemic toxicity.
  • Kinase inhibiting compounds may be used in promoting cartilage repair and regeneration at doses of less than 10 mg per localized administration. While the lowest effective pharmaceutically effective concentration may vary with the compound, it is recommended that for the purpose of cartilage repair and regeneration doses ranging between 0.1 to 10 mg per localized administration be given preferably using the controlled-release formulations such as the ones discussed herein.
  • the frequency and length of administration will depend on the formulations used and the extent of repair/regeneration needed, the frequency of IA drug application may be limited in some recipients to a maximum of one application every 4 weeks.
  • Other delivery vehicles including use of osmotic pumps can also be employed. In order to avoid systemic toxicity, it is recommended that the use of these vehicles does not result in systemic kinase inhibitor blood levels of greater than 50 ng/ml.
  • the single plus (+) in the Toxicity column represents evidence of increased chondrocyte proliferation in the adjacent growth plate, but no evidence of soft tissue mineralization.
  • the double plus (++) indicates both evidence of growth plate chondrocyte proliferation and systemic soft tissue mineralization.
  • the (-) sign in toxicity column indicates no apparent evidence of either soft tissue mineralization or growth plate chondrocyte proliferation.
  • BLQ in Tables 1 and 2 indicates a concentration below a level of quantification, which was about 6.25 ng/ml. Table 2. Effect of intraarticular administration of FGFr inhibitors on Chondrogenesis
  • the single, double and triple plus indicators in the right column indicate relative amounts of chondrogenesis resulting from intraarticular administration of FGFr inhibitors.
  • a single plus (+) represents evidence of increased chondrocyte proliferation at the site of administration, while double plus (++) and triple plus (+++) signs indicate clear and increasing evidence of neochondrogenesis following intraarticular administration of FGFr inhibitor.
  • Biological Example 2 Protocol The experiment began on day 0 using New Zealand Male Rabbits (2.5 kg) at doses of 5, 1, and 0.1 mg/kg/day delivered via pump intra-articularly into the knee joint. Alzet osmotic pumps (2ML1) were implanted subcutaneously, under sterile surgical conditions in the rabbit's left hindquarter. Compound B was dissolved in 1-methyl-2- pyrolidinone (NMP) (25%) + propylene glycol (75%). The rabbits were sacrificed 7-days later. Plasma was collected in EDTA containing tubes (Vacutainer 7861, BD Biosciences) at Days 0, 3, 5 and 7 for drug level determination as well as determination of sodium and phosphorus levels.
  • NMP 1-methyl-2- pyrolidinone
  • the knee joints were lavaged with saline (1.0ml) + Protease Inhibitor Cocktail (Complete, Roche Diagnostics) (1 tablet dissolved in 1 ml H 2 O + 49 ml Saline).
  • saline 1.0ml
  • Protease Inhibitor Cocktail Complete, Roche Diagnostics
  • the rabbits' heart, stomach and kidneys were harvested for histology (H&E and von Kossa stained sections were examined by trained pathologist for signs of soft tissue mineralization).
  • Compound B was extracted from plasma and knee lavage matrix via protein precipitation in a 96-well format.
  • An eleven-point calibration curve was prepared using rabbit plasma or knee lavage in a range from 0.1 - 100 ng/mL
  • a 50 ⁇ l_ aliquot of each sample was precipitated with 100 ⁇ L of acetonitrile. Samples were vortexed for about 5 min, then centrifuged for 5 min at 4000 rpm. A 10O ⁇ L aliquot of supernatant was transferred to a 96 well deep-well plate. A 2 ⁇ L aliquot of each sample was injected onto the LC/MS/MS. Analysis was performed on a HTS PAL Leap auto sampler and Shimadzu LC-10 ADVP pump with an Applied Biosystems Sciex 4000 triple-quadrupole mass spectrometer using positive electrospray ionization in multiple reaction monitoring
  • Control animals exhibited a normal weight gain with no observable histological changes in any target tissue or knee joints.
  • mice experienced normal weight gain and no discernable clinical toxicity. Animals were devoid of tissue mineralization at the time of necropsy in the heart, stomach and liver. Calcium levels were in the normal range (5.0+1.0 mg/dL) as were Phosphorus levels (13.7+0.78 mg/dL).
  • Compound B was extracted from plasma and knee lavage matrix via protein precipitation in a 96-well format.
  • An eleven-point calibration curve was prepared using rabbit plasma or knee lavage in a range from 0.1 - 100 ng/mL.
  • a 50 ⁇ L aliquot of each sample was precipitated with 100 ⁇ L of acetonitrile. Samples were vortexed for about 5 min, then centrifuged for 5 min at 4000 rpm. A 10O ⁇ L aliquot of supernatant was transferred to a 96 well deep-well plate. A 2 ⁇ L aliquot of each sample was injected onto the LC/MS/MS.
  • Control animals exhibited a slight weight loss (3%) with no observable histological changes in any target tissue or knee joints. Calcium levels were 12.7 + 1.0 mg/dL and Phosphorus 5.7 + 0.15 mg/dL. 0.5 mg/kg/day: animals experienced a 5% weight loss. Moderate tissue mineralization was seen on histology sections of the heart, stomach and liver. Calcium levels were 12.5 + 0.06 mg/dL and Phosphorus 6.9 + 0.03 mg/dL.
  • mice experienced 3%l weight loss. Animals showed no signs of tissue mineralization on histology sections of the heart, stomach and liver. Calcium levels were in the normal range (5.9+ 1.5 mg/dL) as were Phosphorus levels (12.6+ 0.15 mg/dL).
  • the lavage levels of compound B in individual animals is reported in Table 4 for the animals' right knee (compound B) and left knee (control). The high levels of compound were detected in some of the samples from control samples (left knee samples). This was due to contamination of control samples with compound B that had adhered to the analytical column used for chromatographic separations of samples from drug treated animals.
  • ALQ refers to above a level of quantitation.
  • Plasma concentrations for Compound B for the 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg samples at every time-point were below quantitation levels (which was approximately below 0.1 ng/ml).
  • Biological Example 2 demonstrated that compound B induced tissue mineralization even at lower doses over a period of 7 days. In the 0.5 mg/kg/day dose- group, mineralization was mild in the heart and moderate in the kidney and lung tissues. On the other hand, the mineralization in the 0.3 mg/kg day dose-group was minimal in the heart and kidney and mild in the stomach.
  • Biological Example 4 was designed to determine the threshold at which mineralization is persists over a 4-week period of time. Biological Example 4 employed intra-articular administration of Compound B directly into the rabbit knee joint. In order to maintain the same rate of delivery as previous studies have employed, pumps were replaced after a period of two weeks. Protocol:
  • Biological Example 4 was begun on Day 0 using New Zealand Male Rabbits (2.5 -2.7 kg) at doses of 0.2, 0.1, 0.05 mg/kg/day, given intra-articularly via the use of Alzet (2ML1) pumps.
  • Compound B was dissolved in lactic acid (50 mM), pH 3.
  • a PE 60 polypropylene catheter was sewn into the left knee joint and run under the skin and attached to an Alzet (2ML1) osmotic pump implanted just above the rabbit's hindquarter. Rabbits were sacrificed on Day 28. Plasma was collected at Days 0, 7, 14, 21 and 28 for drug level determination as well as determination of sodium and phosphorus levels.
  • the knee joints were lavaged with saline (1.0ml) + Protease Inhibitor Cocktail (Complete, Roche Diagnostics) (1 Tablet dissolved in 1ml H 2 O + 49 ml Saline).
  • saline 1.0ml
  • Protease Inhibitor Cocktail Complete, Roche Diagnostics
  • 1 Tablet dissolved in 1ml H 2 O + 49 ml Saline The rabbits' heart, stomach and kidneys were harvested for histology (H&E and von Kossa stained sections were examined by trained pathologist for signs of soft tissue mineralization).
  • Compound B was extracted from plasma and knee lavage matrix via protein precipitation in a 96-well format.
  • An eleven-point calibration curve was prepared using rabbit plasma or knee lavage in a range from 0.1 - 100 ng/mL.
  • a 50 ⁇ l_ aliquot of each sample was precipitated with 100 ⁇ L of acetonitrile. Samples were vortexed for about 5 min, then centrifuged for 5 min at 4000 rpm.
  • a 100 ⁇ l_ aliquot of supernatant was transferred to a 96 well deep-well plate.
  • a 2 ⁇ L aliquot of each sample was injected onto the LC/MS/MS. Analysis was performed on a HTS PAL Leap auto sampler and Shimadzu LC-10 ADVP pump with an Applied Biosystems Sciex 4000 triple-quadrupole mass spectrometer using positive electrospray ionization in multiple reaction monitoring
  • MRM monoChrom 5um CN, 2.0 x 50 cm analytical column was used for chromatographic separations provided by MetaChem. Results: Co ⁇ trol (vehicle): animals experienced a normal weight gain over the course of the study with no observable histological changes in any target tissue or knee joints. Calcium levels were 13.07 + 0.37 mg/dL and phosphorus 6.20 + 0.25 mg/dL.
  • mice experienced a normal weight gain. Moderate tissue mineralization was seen on histology sections of the heart, stomach and liver. Calcium levels were 12.65 + 0.15 mg/dL and phosphorus 7.6 + 0.14 mg/dL. Histological changes observed in the joint treated with the compound included moderate necrosis of articular cartilage, mild cartilage hyperplasia and minimal changes in the growth plate.
  • mice experienced a normal weight gain. Minimal tissue mineralization was seen on histology section of the heart, stomach and liver. Calcium levels were in the normal range (6.9 + 0.10 mg/dL) and phosphorus levels were also in the normal range (12.75 + 0.45 mg/dL). Histological changes observed in the joint treated with the compound included moderate necrosis of articular cartilage, mild cartilage hyperplasia and minimal changes in the growth plate
  • mice experienced normal weight gain. Animals showed no signs of tissue mineralization on histology sections of the heart, stomach and liver. Calcium levels were in the normal range (5.63+ 0.34 mg/dL) as were phosphorus levels (13.03 + 0.12 mg/dL). Minimal hyperplasia of cartilage was the only histological change observed in the joint treated with the compound.
  • the lavage levels of compound B in individual animals are reported in Table 6 for the animals' right knee (compound B) and left knee (control). The high levels of compound were detected in some of the samples from control samples (left knee samples). This was due to contamination of control samples with compound B that had adhered to the analytical column used for chromatographic separations of samples from drug treated animals.
  • ALQ refers to above a level of quantitation.
  • Bone marrow was harvested from the femurs of 3-8 months old New Zealand White Rabbits. The bone marrow was diluted in sterile phosphate buffered saline and the mononuclear cells were obtained after centrifugation in Hitsopaque 1077 (Sigma H8889; St. Louis, MO), a 1.077 g/mL solution of polysucrose and sodium diatrizoate. The mononuclear cells were expanded by subculture in tissue culture plates with Dulbecco's Modified Eagle Media (DMEM) (Gibco 11885; Grand Island, NY), antibiotic/antimycotic (Gibco 15240), and 10% fetal bovine serum (Gibco 10082).
  • DMEM Dulbecco's Modified Eagle Media
  • the cells were differentiated in pellet culture. 250,000 cells in 1 mL media were centrifuged at 500 x g for 5 minutes in 15 mL polypropylene tubes.
  • the media for pellet culture included DMEM (Gibco 11995), antibiotic/antimycotic (Gibco 15240), 100 nM dexamethasone (Sigma D2915), 100 ⁇ M ascorbic acid - 2 phosphate (Sigma A8960), ITS+ Premix (BD Biosciences 354352; Bedford, MA) (6.25 ug/mL Insulin,
  • the pellet culture media was also supplemented with basic Fibroblast Growth Factor (FGF-2) (R&D Systems 233-FB-025/CF), Compound A, Compound B, or Compound C to determine the effect of stimulation or inhibition of FGF receptors.
  • FGF-2 basic Fibroblast Growth Factor
  • Cells were cultured for 14 days with media changed twice a week. Conditioned media was saved and frozen at -80 0 C.
  • GAG accumulation was measured by 1,9- dimethylmethylene blue assay.
  • Chondroitin sulfate (Sigma C4384) standards measured as ⁇ g/ml, pellet digest, and media samples were mixed at 1:20 in dye measured by absorbance at 525 nm.
  • the dye was composed of 16mg/L 1 ,9-dimethylmethylene blue powder (Polysciences 3610; Warrington, PA), 4 g/L sodium formate (Sigma 247596), 0.25% ethanol (Sigma E7023), and 0.4% formic acid (Mallinckrodt 2592; Paris, KY) (see Farndale et al. (1986) Biochim Biophys Acta. 883(2):173-7.
  • DNA content of the pellet digest was measured by the fluorochrome Hoechst 33258 (Rio Rad 1702480; Hercules, CA) and compared to a standard of calf thymus DNA measured as ⁇ g/ml (see Kim et al. (1988) Anal Biochem. 1988 Oct;174(1):168-76). Results:
  • Histology and immunohistochemistry of bone marrow cells cultured in a pellet culture system displayed a phenotype that included chondrocyte like morphology, positive staining for proteoglycan and collagen II, and minimal collagen I staining at the periphery.
  • Compound A, Compound B, and Compound C were able to increase GAG/DNA accumulation within this system.
  • Compound A, Compound B, or Compound C was added to the pellet culture system at 100 nM.
  • the GAG/DNA accumulation is compared to control in Table 8.
  • Vehicle control animals had deep defects with fibro-osseous proliferation and few foci of chondrocyte formation.
  • the cartilage defects were covered by proliferating chondrocytes. At the base of the defect, chondrocyte and fibro- myxomatous proliferation were noted. New bone formation within subchondral bone of epiphysis was observed.
  • the cartilage defects were filled with spindle cells and fibrin within myxomatous matrix. New bone formation was also observed in these animals.

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Abstract

La présente invention se rapporte à des procédés d'utilisation de composés qui inhibent les enzymes kinases et tyrosine kinases dépendantes des cyclines, pour favoriser la néochondrogenèse et pour la consolidation, la protection et la réparation du cartilage. Dans certains modes de réalisation, l'invention a trait à des procédés d'utilisation de composés représentés par la formule (I), et de sels pharmaceutiquement acceptables de ceux-ci, pour favoriser la néochondrogenèse ; dans ladite formule, R1, R2, R3, R4, R5, R6, A, B, D et E sont tels que définis dans le descriptif de l'invention.
PCT/IB2005/003058 2004-10-01 2005-09-21 Utilisation d'inhibiteurs de kinases pour favoriser la neochondrogenese WO2006038112A1 (fr)

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JP2008031169A (ja) * 2006-07-26 2008-02-14 Novartis Ag 線維芽細胞増殖因子受容体が仲介する障害の処置法
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US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
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JP2008031169A (ja) * 2006-07-26 2008-02-14 Novartis Ag 線維芽細胞増殖因子受容体が仲介する障害の処置法
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