CN101072554A - Therapeutic treatment of accelerated bone resorption - Google Patents
Therapeutic treatment of accelerated bone resorption Download PDFInfo
- Publication number
- CN101072554A CN101072554A CNA2005800380014A CN200580038001A CN101072554A CN 101072554 A CN101072554 A CN 101072554A CN A2005800380014 A CNA2005800380014 A CN A2005800380014A CN 200580038001 A CN200580038001 A CN 200580038001A CN 101072554 A CN101072554 A CN 101072554A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- amino
- agonist
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 65
- 208000006386 Bone Resorption Diseases 0.000 title claims abstract description 40
- 230000024279 bone resorption Effects 0.000 title claims abstract description 40
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 239000000556 agonist Substances 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 30
- 230000004054 inflammatory process Effects 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 206010061218 Inflammation Diseases 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000003379 purinergic P1 receptor agonist Substances 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 230000001133 acceleration Effects 0.000 claims description 23
- -1 trifluoro Chemical group 0.000 claims description 23
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 206010003246 arthritis Diseases 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- IPSYPUKKXMNCNQ-PFHKOEEOSA-N (2s,3s,4r,5r)-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC(Cl)=NC(NCC=3C=C(I)C=CC=3)=C2N=C1 IPSYPUKKXMNCNQ-PFHKOEEOSA-N 0.000 claims description 5
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 5
- XTPOZVLRZZIEBW-SCFUHWHPSA-N (2r,3r,4s,5r)-2-[6-[2-(4-aminophenyl)ethylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical group C1=CC(N)=CC=C1CCNC1=NC=NC2=C1N=CN2[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XTPOZVLRZZIEBW-SCFUHWHPSA-N 0.000 claims description 4
- LDYMCRRFCMRFKB-MOROJQBDSA-N (2s,3s,4r,5r)-5-[6-[(4-aminophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=CC(N)=CC=3)=C2N=C1 LDYMCRRFCMRFKB-MOROJQBDSA-N 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 150000005215 alkyl ethers Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 208000008784 apnea Diseases 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- MWEQTWJABOLLOS-UHFFFAOYSA-L disodium;[[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-oxidophosphoryl] hydrogen phosphate;trihydrate Chemical compound O.O.O.[Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP([O-])(=O)OP(O)([O-])=O)C(O)C1O MWEQTWJABOLLOS-UHFFFAOYSA-L 0.000 claims description 4
- 229940032465 fenethylline Drugs 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000002777 nucleoside Substances 0.000 claims description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 150000007970 thio esters Chemical class 0.000 claims description 4
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 4
- 150000003568 thioethers Chemical class 0.000 claims description 4
- 230000003203 everyday effect Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims 15
- 125000002521 alkyl halide group Chemical group 0.000 claims 9
- HUJXGQILHAUCCV-MOROJQBDSA-N 3-iodobenzyl-5'-N-methylcarboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=C(I)C=CC=3)=C2N=C1 HUJXGQILHAUCCV-MOROJQBDSA-N 0.000 claims 6
- 230000001939 inductive effect Effects 0.000 claims 3
- 125000004407 fluoroaryl group Chemical group 0.000 claims 2
- 101150046889 ADORA3 gene Proteins 0.000 abstract 1
- 229940122614 Adenosine receptor agonist Drugs 0.000 abstract 1
- JTZRECOPNKCRTE-MOROJQBDSA-N (2s,3s,4r,5r)-3,4-dihydroxy-5-[6-[(4-iodophenyl)methylamino]purin-9-yl]-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=CC(I)=CC=3)=C2N=C1 JTZRECOPNKCRTE-MOROJQBDSA-N 0.000 description 42
- 241000700159 Rattus Species 0.000 description 32
- 210000000988 bone and bone Anatomy 0.000 description 28
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 239000012190 activator Substances 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 206010065687 Bone loss Diseases 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 210000002997 osteoclast Anatomy 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 230000004913 activation Effects 0.000 description 10
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 108010025832 RANK Ligand Proteins 0.000 description 8
- 102000014128 RANK Ligand Human genes 0.000 description 8
- 229960005305 adenosine Drugs 0.000 description 8
- 230000002596 correlated effect Effects 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 210000002683 foot Anatomy 0.000 description 8
- 102000003945 NF-kappa B Human genes 0.000 description 7
- 108010057466 NF-kappa B Proteins 0.000 description 7
- 102100040247 Tumor necrosis factor Human genes 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241001111421 Pannus Species 0.000 description 6
- 239000005864 Sulphur Substances 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 230000037058 blood plasma level Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000000370 acceptor Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 210000000845 cartilage Anatomy 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 230000008595 infiltration Effects 0.000 description 5
- 238000001764 infiltration Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 210000002356 skeleton Anatomy 0.000 description 5
- 230000008961 swelling Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000003076 Osteolysis Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 4
- 210000000963 osteoblast Anatomy 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000037147 Hypercalcaemia Diseases 0.000 description 3
- 206010020880 Hypertrophy Diseases 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000000148 hypercalcaemia Effects 0.000 description 3
- 208000030915 hypercalcemia disease Diseases 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 210000003127 knee Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 210000001258 synovial membrane Anatomy 0.000 description 3
- 102100036006 Adenosine receptor A3 Human genes 0.000 description 2
- 101710128949 Adenosine receptor A3 Proteins 0.000 description 2
- 102000009346 Adenosine receptors Human genes 0.000 description 2
- 108050000203 Adenosine receptors Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 206010007710 Cartilage injury Diseases 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 206010031264 Osteonecrosis Diseases 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 208000032183 Scleromalacia Diseases 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 210000000544 articulatio talocruralis Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Chemical class 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 210000001145 finger joint Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000005067 joint tissue Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 108020004084 membrane receptors Proteins 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000004409 osteocyte Anatomy 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 210000002536 stromal cell Anatomy 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000001179 synovial fluid Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001226 toe joint Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- TZMYBSXAAPQZIA-CENLXECGSA-N (2R,3R,4S,5R)-2-(6-amino-9-oxidopurin-9-ium-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound NC1=NC=NC2=C1N=C[N+]2([O-])[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O TZMYBSXAAPQZIA-CENLXECGSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 1
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 201000002980 Hyperparathyroidism Diseases 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 241001484259 Lacuna Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical class [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241001049988 Mycobacterium tuberculosis H37Ra Species 0.000 description 1
- 229910003813 NRa Inorganic materials 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101150101537 Olah gene Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- FRYDSOYOHWGSMD-UHFFFAOYSA-N [C].O Chemical class [C].O FRYDSOYOHWGSMD-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- CQCUZORMKRFLAX-UHFFFAOYSA-N azane;barium(2+) Chemical class N.[Ba+2] CQCUZORMKRFLAX-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 208000018339 bone inflammation disease Diseases 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000002805 bone matrix Anatomy 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 231100000749 chronicity Toxicity 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003280 clastogen Substances 0.000 description 1
- 231100000506 clastogen Toxicity 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 210000004268 dentin Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011981 development test Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000001624 hip Anatomy 0.000 description 1
- 238000010231 histologic analysis Methods 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108010000947 protamine zinc Chemical class 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The present invention concerns the use of an A3 adenosine receptor agonist (A3AR agonist) for treatment of accelerated bone resorption, particularly, inflammation induced bone resorption. Specifically, there is provided by the present invention a method and pharmaceutical composition for treatment of said condition, the A3AR agonist being formulated as a pharmaceutical composition which is administered to a subject having accelerated bone resorption. The invention also provides the use of A3AR agonist in the preparation of said pharmaceutical composition.
Description
Invention field
The present invention relates to treat or prevent the Therapeutic Method of acceleration bone loss.
Prior art
Following is the prior art inventory, and they are suitable for describing the prior art state in field of the present invention.
(1)Olah?M.E.and?Stiles?G.L.The?role?of?receptor?structurein?determining?adenosine?receptor?activity，Pharmacol.There.，85：55-75(2000)；
(2)Poulsen?S.A.and?Quinn?R.J.，Adenosine?receptors：newopportunities?for?future?drugs.Bioorg.Med.Chem.，6：619-641(1998)；
(3)Fang?X.et?al.Phosphorylation?and?inactivation?ofglycogen?synthase?kinase?3?by?protein?kinase?A.，Proc.Natl.Acad.Sci.USA，97：11960-11965(2000)；
(4)Fishman，P.，et?al.，Involvement?of?Wnt?SignalingPathway?in?IB-MECA?Mediated?Suppression?of?Melanoma?Cells，Oncogene?21：4060-4064(2002)；
(5)Ferkey，D.M.，and?Kimelman，D.GSK-3：New?Thoughts?onan?Old?Enzyme，Dev.Biol，225：471-479(2000)；
(6)Bonvini，R，et?al.Nuclear?beta-catenin?displaysGSK-3beta-and?APC-independent?proteasome?sensitivity?inmelanoma?cells，Biochim.Biophys.Acta.，1495：308-318(2000)；
(7)Olah，M.E.and?Stiles，G.L，The?role?of?receptorstructure?in?determining?adenosine?receptor?activity，Pharmacol.Ther，85：55-75(2000)；
(8)Szabo?C，et?al.Suppression?of?macrophage?inflammatoryprotein(MQP)-1αproducing?and?collagen?induced?arthritis?byadenosine?receptor?agonists.，British?Journal?of?Pharmacology，125：379-387(1998)；
(9)U.S.5,773,423；
(10)Nicole?C.Walsh?and?Ellen?M.Gravallese.Bone?loss?ininflammatory?arthritis：Mechanism?and?trea?tment?strategies.Current?Opinion?in?Rheumatology，16：419-427(2004)；
(11)Zang?Hee?Lee?and?Hong-Hee?Kim.Signal?transduction?byreceptor?activator?of?nuclear?factor?kappa?B?in?osteoclasts.，Biochemical?and?Biophysical?Research?Communication?305：211-214(2003)；
Background of invention
Human and other mammiferous multiple disease comprises or is relevant with the acceleration bone resorption.These diseases include but not limited to osteoporosis, scleromalacia, the loss of reparation bone or osteolysis and malignant hypercalcemia.Modal disease is an osteoporosis, and it is the most normal to betide the postmenopausal women.Because the disease relevant with the bone loss is chronic sympton, therefore believe normally chronic treatment of suitable treatment.
Rheumatoid arthritis (RA) is the relevant chronic inflammatory disease autoimmune disease of a kind of and bone loss.1% adult suffers from RA, it is characterized in that the hyperplasia of stromal cell and hematopoietic cell in IA a large amount of infiltrations, cause the infringement of chronic synovitis and cartilage, skeleton, tendon and ligament.RA patient's bone volume reduces and has reduced the bone turnover to some extent, and it has further aggravated osteoporosis [Perez-Edo L, et al.J.Scand J Rheumatol., 31:285-290 (2002)].Cumulative joint injury causes function decline and disabled [Harris ED.N.Eng.1 J.Med., 322:1277-1289 (1990)].About 80% patient has become people with disability [Paulos CM, et al.Adv.Drug.Deliv.Rev., 56:1205-1217 (2004)] in 20 years of beginning to fall ill.
Proved that the bone destruction in RA and other disease relevant with the acceleration bone resorption is mainly mediated by osteoclast, also proved because osteoclast is broken up from its precursor, the skeleton clastogen activates in the inflammation site and has promoted osteoclast to activate and survival, therefore need TNF family material--receptor stimulating agent [the Hsu H of NF-κ B part (RANKL), et al.Proc.Natl.Acad.ScL U.S.A., 96:3540-3545 (1999)].RANKL has highly expression [Kwan Tat S, et al.Cytokine Growth.FactorRev., 5:49-60 (2004) on the epicyte of osteoblast, stromal cell, synovial fluid fibroblast and the T cell in arthritis joint; Kotake S, et al.Arthritis.Rheum., 44:1003-1012 (2001)].RANKL combines with its receptor RANK, and RANK is present on the osteoclast germinal cell, causes catchment PI3 K-PKB signalling channel, causes activation [Udagawa N, et al.Arthritis.Res., the 4:281-289. (2002) of transcription factor NF-KB; Gingery A, et al.J.Cell.Biochem., 89:165-179 (2003)].
Existing evidence points out that adenosine has important function at the restriction aspect of inflammation, mainly is that prevention proinflammatory cytokine produces for example TNF-α, IL-1 and IL-6[Cronstein, B.N.J.Appl.Physiol.76:5-13 (1994); Eigler, A., et al.Scand.J.Immunol, 45:132-139 (1997); Mabley, J., et al.Eur.J.Pharmacol.466:323-329 (2003)].The adenosine membrane receptor relevant with selectivity G-albumen that is released into from activatory or metabolic excitatory cells in the extracellular environment combines membrane receptor called after A
1, A
2A, A
2BAnd A
3[Stiles, G.L., Clin.Re be (1990) s.38:10-18].The antiinflammatory action of having found adenosine is by A
3[Szabo, C, the et al.Br.J.Pharmacol.125:379-387 (1998)] of AR mediation.Particularly, high selectivity A
3AR agonist IB-MECA can effectively prevent arthritic clinical and pathology sign in different test models, comprise adjuvant inductivity arthritis (AJA), collagen-induced property arthritis (CIA) and thropomyosine inductivity arthritis.The mechanism of action is that the decrement of NF-kB, TNF-α and MIP-1 α is regulated [Baharav E., et al.J.Rhematol.Accepted (2004)].
Brief summary of the invention
The present invention has found high selectivity A surprisingly
3AR agonist IB-MECA can prevent the bone loss of adjuvant inductivity arthritis (AIA) mouse model.As hereinafter illustrating, the main signal protein of selective agonist decrement modulability for example NF-kB and RANKL has caused that the decrement of TNF-α regulates, with the loss of prevention bone.
Therefore,, the invention provides a kind of method for the treatment of mammalian subject acceleration bone resorption, comprise having the patient of treatment needs to use a certain amount of A described according to an aspect
3Adenosine receptor agonist (A
3The AR agonist), described dosage can suppress bone resorption effectively.
Term used herein " treatment " expression treatment and preventive therapy.Especially, treatment comprises the inhibition of acceleration bone resorption and osteolytic lesion development.Without limitation, the treatment of bone resorption comprises improve (for example pain, fracture, bone marrow pressurized and the hypercalcemia) of not expecting symptom relevant with bone resorption, before taking place, these symptoms prevent them to show, slowing down or prevention are by losing the diseases related irreversible damage that chronic phase caused (for example preventing the development of osteolytic lesion and each several part) with bone, alleviate the diseases related order of severity of bone resorption, improve bone restoration, the development of prevention bone resorption, prevention bone necrosis, and for any improvement of patient health situation.For example, can be by following one or multinomially prove this improvement: the bone amount increases, the minimizing of the alleviating of the pain relevant with bone resorption, skeleton flow point or the like.According to the present invention, treatment can also comprise above-mentioned two or more combination.
Term in the description of the present invention " acceleration bone resorption " or the term " acceleration bone loss " suitable with it, " acceleration bone destruction " and " broken bone " refer to any disease, disease or the pathological state that comprise that skeleton destroys, can be result or any other pathological states of the metabolic osteopathy that caused by inflammation mediated acceleration metabolic process.The diseases related non-limitative example of bone resorption comprises osteoporosis, scleromalacia, the loss of reparation bone, osteonecrosis (by wound, lose blood or the dead or infringement of osseous tissue that disease causes), myeloma, osteolysis and malignant hypercalcemia.
Term " A in the description of the present invention
3Adenosine receptor agonist " (A
3The AR agonist) refer to can with A
3Adenosine receptor (" A
3AR ") the bonded any chemical compound of specificity, it can completely or partially activate described receptor.A
3The AR agonist be by with A
3AR in conjunction with and its activation is brought into play the chemical compound of main effect.A
3The preferred example of AR agonist is as mentioned below.
A in the description of the present invention
3" dosage " of AR agonist (being also referred to as " effective dose " in this article) refers to and can make mammal avoid bone resorption and the diseases related dosage of bone resorption effectively.According to the present invention, most of experimenters are used the A of various dose
3The AR agonist writes down its physiological responses then as dose function (integration " SS index " of for example having gathered several treatment beneficial effects), can measure the dosage that can reach predictive role effectively at an easy rate.Select a ground, effective dose also can be carried out test operation sometimes in appropriate animal model, is measured thereby use a kind of method of converting to infer to human then; Perhaps by measuring plasma concentration or measuring the following area of plasma concentration time graph (AUC) and calculate effective dose to obtain comparable plasma concentration or AUC.As everyone knows, effective dose depends on for example mode of administration (for example oral administration needs higher dosage than intravenous injection, to reach required blood plasma level or AUC) of multiple factor; Age, body weight, body surface area, sex, health status and individual inherited genetic factors; Other drug that uses or the like.
Hereinafter, unless stated otherwise, the expression mode of dosage is weight/Kg, is meant to be treated the employed A of the every kg body weight of patient when each administration
3The weight of AR agonist.For example, mg/Kg and microgram/Kg are meant respectively and are treated milligram number and the micrograms that the every kg body weight of patient is accepted medicine.
For mice, effective dose is usually less than about 1000 micrograms/Kg, preferably less than about 500 micrograms/Kg.Representational dosage is extremely about 200 micrograms/Kg of about 1 microgram/Kg, and preferred dose is that about 5 micrograms/Kg is to about 150 micrograms/Kg.Human corresponding effective dose is people's equivalent of mice dosage, and it can adopt method hereinafter described to measure.
Term " people's equivalent " refers to the A that can produce on mankind with to mice or rat use 0.001-1mg/Kg
3The AR agonist has the dosage of same effect.As known, this dosage depends on and can be according to multiple parametric measurement, for example the absorbance of body weight, body surface area, active agent, medicine clearance rate and metabolic rate or the like.
People's equivalent can calculate according to multiple transformation standard hereinafter described; Perhaps people's equivalent is the dosage that can have similar blood plasma level to the mice of accepting above-mentioned given dose; Or can produce the dosage of similar total exposure value to the mice of accepting the given dose scope (be called area under curve, ' AUC ' is the function of the blood plasma level of described medicine for the time).
As everyone knows, utilize a kind of known feasibility conversion formula in this area just the X mg/Kg dosage to rat can be converted into equivalent for other species (particularly human).The example of conversion formula is as mentioned below:
Conversion formula I:
| Species | Body weight (Kg) | Body surface area (m 2) | The Km factor |
| Mice | 0.2 | ?0.0066 | ?3.0 |
| Rat | 0.15 | ?0.025 | ?5.9 |
| The child | 20.0 | ?0.80 | ?25 |
| The adult | 70.0 | ?1.60 | ?37 |
The conversion of body surface area dependency dosage: rat (150g) and people's (70Kg) ratio is 1/7 rat dosage.In other words, for example, the 0.001-1mg/Kg of rat is equivalent to about 0.14-140 microgram/Kg of people.The average weight of supposing the people is 70Kg, and conversion is exactly about 0.01-10mg for people's absolute dosages value so.
Conversion formula II:
Following conversion factor: mice=3, rat=67.The weight of animals multiply by conversion factor will become mg/m by mg/kg
2Human dosage equivalent.
| Species | Body weight (Kg) | BSA(m 2) |
| The people | 70.00 | ?1.710 |
| Mice | 0.02 | ?0.007 |
| Rat | 0.15 | ?0.025 |
| Canis familiaris L. | 8.00 | ?0.448 |
According to this formula, the human dosage suitable with rat 0.001-1mg/Kg is 0.16-64 μ g/Kg; That is to say that body weight is about 0.011 to about 11mg for the mankind's of about 70Kg absolute dosages, and is similar to the scope shown in the conversion formula I.
Conversion formula III:
Another kind of optional conversion is can produce and animal-use drug is had identical blood plasma level or the dosage of AUC.For example, mice is orally used measurement result behind the IB-MECA, carry out identical measurement after in clinical research, the healthy male volunteer being used IB-MECA, on the basis of two measurement structure, can calculate mice 1 microgram/Kg-1, the dosage of 000 microgram/KG is equivalent to the dosage of human about 0.14-140 microgram/Kg, that is to say that body weight is that the people's of 70Kg accumulated dose is 0.01-10mg.
According to above-mentioned conversion method, for two kinds of specific A
3The AR agonist is IB-MECA and C1-IB-MECA for example, and its preferred dose is less than 4mg, be generally about 0.01 to about 2mg (be respectively about 0.14-28 microgram/Kg), and preferably about 0.1-1.5mg (about respectively 1.4-21 microgram/Kg).This dosage can be administered once in one day, twice or administration sometimes, administration for several times.Human research (herein not enumerated data) shows that the half-life of IB-MECA in human plasma is about 8-10 hour, and its half-life in mice only is 1.5 hours.If multiple dosing in a day is considered accumulative effect, need to proofread and correct dosage (carry out the administration second time before the first administration decay, it can produce cumulative blood plasma level compared to single-dose) sometimes.On the basis of above-mentioned human trial, be administered once every day or be for twice preferred mode of administration, yet this does not get rid of other mode of administration.
It should be noted that except described Therapeutic Method, the present invention also comprises the pharmaceutical composition that is used for the treatment of the acceleration bone resorption, said composition comprises a certain amount of active components A
3AR agonist and drug acceptable carrier, described dosage need can suppress patient's bone resorption of this treatment effectively.
In the description of the present invention, term " medicine acceptable carrier " is meant any inertia, nontoxic material, its not with A
3AR agonist reaction can be added in the preparation as diluent, carrier, and preparation is formed or firm preparation.
Carrier also comprises the material (for example antimicrobial preservative, antioxidant, chelating agen and buffer) that makes preparation have stability, aseptic and isotonicity, with prophylaxis of microbial activity (for example antimicrobial and antifungal, as metagin, chlorobutanol, phenol, sorbic acid or the like), and make preparation have edibility taste or color or the like.
Sometimes carrier can also improve A
3The AR agonist is used to improve A for the transportation or the penetrance of target tissue
3The stability of AR agonist, reduce clearance rate, have slow-releasing, reduce side effect of not expecting or the like.
In addition, the present invention includes A
3The AR agonist is used for the treatment of purposes in the pharmaceutical composition of acceleration bone resorption in preparation.
Brief description
In order to understand the present invention better and to understand how it works in practice on earth, will the preferred specific embodiment be described by nonrestrictive example and accompanying drawing as a reference now, wherein:
Figure 1A-1C comprises clinical scores curve (Figure 1A), uses the AIA rat foot thickness (Figure 1B) after IB-MECA treats, and the figure (left figure) of serious rubescent and swelling appears in Fig. 1 C for the whole foot of proof matched group, corresponding is representative foot in the IB-MECA treatment group, and it shows as fully normal (right figure).
Fig. 2 A-2C comprises the fractional bar diagram of inflammation (Fig. 2 A), and shows IB-MECA treatment rat and the correlated histology of control rats intraarticular inflammatory activity cross section (x20 and x40) (Fig. 2 B).
Fig. 3 A-3B comprises fibrosis mark bar diagram (Fig. 3 A), and shows that IB-MECA treatment rat and control rats synovial membrane change correlated histology cross section (Fig. 3 B).
Fig. 4 A-4B comprises pannus mark bar diagram (Fig. 4 A), and shows that IB-MECA treatment rat and control rats joint space pannus tissue change correlated histology cross section (Fig. 4 B).
Fig. 5 A-5B comprises that cartilage damages mark bar diagram (Fig. 5 A), and shows that IB-MECA treatment rat and control rats cartilage change correlated histology cross section (Fig. 5 B).
Fig. 6 A-6B comprises osteoclast mark bar diagram (Fig. 6 A), and shows that IB-MECA treatment rat and control rats osteoclast change correlated histology cross section (Fig. 6 B).
Fig. 7 A-7B comprises bone destruction's mark bar diagram (Fig. 7 A), and shows IB-MECA treatment rat and the correlated histology of control rats bone quantitative changeization cross section (Fig. 7 B).
Fig. 8 A-8B comprises osteoblast mark bar diagram (Fig. 8 A), and shows that IB-MECA treatment rat and control rats osteoblast group change correlated histology cross section (Fig. 8 B).
Fig. 9 A-9B comprises new osteogenesis mark bar diagram (Fig. 9 A), and shows the IB-MECA treatment rat and the correlated histology of the new osteogenesis of the rat cross section (Fig. 9 B) of being untreated.
Figure 10 A-10D has shown the IB-MECA treatment for A3AR expression (Figure 10 A), and the crucial albumen of regulating of other in the sufficient extract comprise RANKL (Figure 10 B), PI3K; PKB/Akt; IKK α, β; The effect of NF-κ B and TNF-α (Figure 10 C), and the leukocyte (WB) of apoptosis enzyme caspase-3 is analyzed (Figure 10 D).
Detailed Description Of The Invention
The process that bone forms (ostosis) comprises three key steps: produce extracellular organic substrate product (osteoid), mineralized dentin matrix to be forming bone, and by absorb again and again the formation effect finish building again of bone. The cytoactive of Gegenbaur's cell, osteocyte and osteoclast is necessary for this process. Gegenbaur's cell has synthesized the precursor of collagen of bone matrix, also regulates its mineralization. Form in the process of development at bone, Gegenbaur's cell is arranged in very little space (lacuna), surrounds the matrix of mineralising on every side, then is called as osteocyte. In order to reach the needs of bone growth and mechanical performance, bone has experienced dynamic remodeling process, and the bone that the bone resorption that causes for osteoclast and Gegenbaur's cell cause forms again.
The feature of some metabolic bone diseases (for example hyperparathyroidism, sex change osteitis etc.) is that mouldability and osteoclasia activity increase to some extent. In addition, osteoclast and class osteoclast are considered to be in the bone loss that transmitting inflammation induces has important function, for example inflammation arthritis (rheumatoid arthritis and psoriatic arthritis).
Target of the present invention provides a kind of method that suppresses the acceleration bone resorption, treats or prevent the consequence of abnormality bone loss with this. Therefore, according to first aspect, the invention provides a kind of resorbent method of mammalian subject acceleration bone for the treatment of, the method comprises the A that the patient that these treatment needs are arranged is used doses3Adenosine receptor agonist (A3The AR activator), described dosage can effectively suppress bone and absorbs.
As described herein, A3The AR activator preferably by with A3The AR combination also activates A3AR and bring into play the compound of its Main Function. In a specific embodiment, A3The AR activator in less than the scope of 100nM for human adenosine A3Acceptor has binding affinity (Ki), normally less than 50nM, preferably less than 20nM, preferably less than 10nM, and it is desirable to less than 5nM. According to this specific embodiment, preferred A3RAgs is for human A3The K of RiLess than 2nM, expectation is less than 1nM.
It should be noted that some A3The AR activator can (that is to say higher K with lower affinityi) and other acceptors occur to interact and make its activation. In present specification, if a compound is for A3The affinity of AR is it to other adenosine receptors (A for example1、A
2aAnd A2b) (for example it is for A at least 3 times of affinity3The K of ARiAt least low 3 times) time, think that so this compound is A3The AR activator (that is to say that a kind of compound passes through and A3The AR combination also makes its activation performance Main Function), preferred 10 times, be contemplated to be 20 times, most preferably be at least 50 times.
A
3The AR activator is for human A3The affinity of AR with and for other human adenosine receptor (A1、A
2aAnd A2b) relative affinity can measure by various analysis, for example in conjunction with measuring. Comprise in conjunction with the example of measuring and the film that comprises acceptor to be provided and to measure A3Ability aspect the radioactivity activator that the AR activator combines in displacement is utilized can show the cell of various human adenosine acceptors and measure A in functional assays3The ability of AR activator activation or deactivation (decide such as condition), for example send the catchment signal as increase by cAMP or the minimizing measurement for the effect of adenyl cyclase, etc. Very clearly, if give with A3AR activator level rises to some extent, works as so its blood plasma level near A1、A
2aAnd A2bThe K of adenosine receptoriDuring value, may after administration, occur except A3The activation of these acceptors beyond AR activates. Therefore, preferred A3The AR activator uses with a such dosage, namely only has A under this dosage3AR can be activated.
Some A3The character of AR activator and their preparation method be to some extent record in following document, especially, and US5,688,774, US5,773,423, US5,573,772, US 5,443,836, US6,048,865, WO95/02604, WO99/20284, WO99/06053, WO97/27173 and the applicant's homologous series application 09/700,751 (WO01/19360), above-mentioned all documents are incorporated by reference in this text to be examined.
According to a specific embodiment of the present invention, A3The AR activator be a kind of by with A3AR in conjunction with and its activation is brought into play the compound of Main Function, be purine derivative and the acceptable salt of physiology thereof with general formula (I) structure:
Wherein
-R1 is alkyl, hydroxy alkyl, carboxyalkyl or cyano group alkyl or following general formula (II) group:
Wherein:
-Y represents oxygen, sulphur or CH2；
-X
1Represent H, alkyl, RaR
bNC (=O)-or HORc-, wherein
-R
aAnd RbCan be identical or different, be selected from hydrogen, alkyl, amino, halogen alkyl, aminoalkyl, BOC-aminoalkyl and cycloalkyl, perhaps in conjunction with forming the heterocycle that comprises 2-5 carbon atom; With
-R
cBe selected from alkyl, amino, halogen alkyl, aminoalkyl, BOC-aminoalkyl and cycloalkyl;
-X
2H, hydroxyl, alkyl amino, alkyl amido or hydroxy alkyl;
-X
3And X4Represent respectively hydrogen, hydroxyl, amino, acyl amino, azido, halogen, alkyl, alkoxyl, carboxyl, inferior amino, nitro, three fluorine ethers, aryl, alkane aryl, sulphur, thioesters, thioether ,-OCOPh ,-OC (=S) OPh or X3And X4All be to form 5 yuan of rings, perhaps X with＞oxygen that C=S is connected2And X3Form formula (III) ring:
Wherein R ' and R " represent respectively the alkyl group;
-R
2Be selected from hydrogen, halogen, alkyl ether, amino, hydrazide group (hydrazido), alkyl amino, alkoxyl, thioalkoxy group, pyridine radicals sulphur, alkene base; Alkynes base, sulphur and alkyl sulphur; With
-R
3Formula-NR4R
5Group, wherein
-R
4Be hydrogen atom or be selected from alkyl, substituted alkyl or aryl-NH-C (Z)-, wherein Z is O, S or NRa, R whereinaImplication is the same; Wherein work as R4When being hydrogen
-R
5Be selected from R-and S-1-phenethyl, benzyl, phenethyl or aniline group, one or more positions are replaced or do not replace by following substituting group therein, and described substituting group is selected from alkyl, amino, halogen, halogen alkyl, nitro, hydroxyl, acetyl amino, alkoxyl and sulfonic acid or its salt; Benzo two alkane methyl, fururyl, L-propyl group alanyl-aminobenzyl, β-alanyl amino-benzyl, T-BOC-β-alanyl aminobenzyl, phenyl amino, carbamyl, phenoxy group or cycloalkyl; Perhaps R5The following formula group:
Perhaps work as R4Be alkyl or aryl-NH-C (Z)-time, R so5Then be selected from assorted aryl-NRa-C (Z)-, assorted aryl-C (Z)-, alkane aryl-NRa-C (Z)-, alkane aryl-C (Z)-, aryl-NR-C (Z)-and aryl-C (Z)-; Z represents oxygen, sulphur or amine; Or the physiologically acceptable salt of above-claimed cpd.
According to a kind of preferred specific embodiment, A
3RAg is the nucleoside derivates shown in the general formula (IV):
X wherein
1, R
2And R
4As indicated above, and the physiologically acceptable salt of described chemical compound.
The acyclic carbohydrate (for example alkyl, thiazolinyl, alkynyl, alkoxyl, aralkyl, alkaryl, alkylamine or the like) that forms The compounds of this invention substituent group part is side chain or non-branched structure, preferably comprises one or two to 12 carbon atoms.
Herein, term " alkyl " refers to any saturated carbohydrate, no matter is straight or branched.Herein, term " low alkyl group " refers to the saturated carbon hydrate (straight or branched) that main chain comprises 1-10 carbon atom.
Herein, term " thiazolinyl " and " alkynyl " refer to the straight or branched carbohydrate, and wherein at least two adjacent carbon atoms are connected by one two key or triple bond respectively.Correspondingly, term " low-grade alkenyl " and " low-grade alkynyl " refer to the straight or branched carbohydrate that main chain comprises 2-10 carbon atom.
Mention A when in the present invention
3During AR agonist " physiologically acceptable salt ", it refers to common any non-toxic alkali, alkaline-earth metal and the ammonium salt of using in medical industry, comprises sodium, potassium, lithium, calcium, magnesium, barium ammonium and protamine zinc salt, can prepare according to means known in the art.This term also comprises the non-toxic acid addition salts, and it is prepared from by The compounds of this invention and suitable organic or inorganic acid reaction usually.The acid-addition salts that makes has kept the character of biological effectiveness and free alkali, and does not have toxicity or other character of not expecting.Particularly, example comprises the acid derivative that is obtained by mineral acid, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, Metaphosphoric acid or the like.Organic acid comprises, particularly, tartaric acid, acetic acid, propanoic acid, citric acid, malic acid, malonic acid, lactic acid, fumaric acid, benzoic acid, cinnamic acid, mandelic acid, glycolic, Fructus Vitis viniferae acid, acetone acid, succinic acid, salicylic acid and aryl sulfonic acid, for example p-toluenesulfonic acid.
The A of general formula of the present invention (IV)
3The specific examples of AR agonist includes but not limited to, N
6-2-(4-aminophenyl) ethyl adenosine (APNEA), N
6-(4-amino-3-benzyl iodide) adenosine-5 '-(N-methyl uronic amide) (AB-MECA), N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (IB-MECA) and 2-chloro-N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (Cl-IB-MECA).
The preferred A of the present invention
3The AR agonist is IB-MECA.
Yet, according to the another kind of specific embodiment, A
3The AR agonist can be adenosine oxide, for example N
6-benzyl adenosine-5 '-N-alkyl uronic amide-N
1Oxide or N
6-benzyl adenosine-5 '-N-dialkyl group uronic amide-N
1-oxide, wherein 2-purine position alkoxy, amino, thiazolinyl, alkynyl or halogen replace.
Acceleration bone loss may be that the acceleration metabolic process by the osteopathia result causes, or produce by inflammation-induced.It will be appreciated by persons skilled in the art that the chronicity inflammation can remove calcareous in the skeleton, slackens it and atrophy.Inflammation mediated bone loss results from the various diseases, for example some form of periodontal disease, bone and rheumatoid arthritis and osteoporosis.
Therefore, according to a kind of specific embodiment, the present invention relates to treat the acceleration bone resorption that brings out by inflammation.According to a kind of preferred specific embodiment, method of the present invention is used for the treatment of the acceleration bone resorption that is caused by inflammatory arthritis.
The invention still further relates to the pharmaceutical composition that is used for the treatment of described acceleration bone resorption herein, said composition comprises a certain amount of A
3The AR agonist is as active component, and drug acceptable carrier, and described dosage can suppress to have this to treat the patient's of needs bone resorption effectively.
Can determine the administration and the dosage of the present composition according to good medical experience, according to known other factors of clinical condition, administration position and method, administration schedule, patient age, sex, body weight and medical practitioner of individual patient.The selection of carrier is somewhat dependent upon specific active ingredient, and the ad hoc approach that uses compositions.Correspondingly, the suitable pharmaceutical composition of the present invention has a variety of.
According to the preferred specific embodiment, pharmaceutical composition is the appropriate format of oral administration.The representative example that is suitable for the carrier of oral administration comprises (a) solution, wherein with the A of effective dose
3The AR agonist is dissolved in diluent for example in water, saline, natural juice, ethanol, the syrup etc.; (b) capsule (, for example comprising surfactant, lubricant and inert filler), tablet, lozenge (A wherein as common hard or Perle
3AR agonist and sweeting agent for example sucrose mix, perhaps A
3AR agonist and inert base be gelatin and glycerol mixing for example) and lozenge, each dosage form all comprises the scheduled volume A of solid or graininess
3The AR agonist; (c) powder; (d) suspensoid in the suitable liquid; (e) suitable Emulsion; (f) Liposomal formulation; Or the like.
In addition, the invention still further relates to A
3The AR agonist is used for the treatment of application in the pharmaceutical composition of acceleration bone resorption in preparation.
Below, the present invention will be illustrated by concrete example.Be understandable that these fact Examples are unrestricted the present invention for explanation.Obviously, under instruction above, might much modify and be out of shape these fact Examples.Therefore be understandable that the present invention can implement according to other possible modes of countless versions within the scope of the following claims, and is not limited to ad hoc fashion described below.
Specific embodiment describes in detail
Material and method
Medicine
A
3The AR agonist is GMP level chemical compound, called after 1-deoxidation usually-1-[6-[[(3-iodine substituted phenyl) methyl] amino]-9H-purine-9-yl]-N-methyl D-nuclear furan uronic amide or N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (IB-MECA), can be synthetic according to Can-Fite bio-pharmaceuticals method, Albany Molecular Research Inc, Albany, NY, USA.The mother solution of preparation 10mM in DMSO dilutes to reach ideal concentration with culture medium or PBS then.
Buy incomplete Freund's adjuvant from Sigma, (Detroit USA) buys no heating power Mycobacterium tuberculosis H37Ra from Difco.
Antagonism rat A
3The rabbit polyclonal antibody of AR and signal protein IKK, TNF-α, GSK-3 β, apoptosis enzyme caspase-3 and phosphoric acid specificity PKB/Akt, RANKL be all from Santa Cruz Biotechnology Inc., Ca, and USA buys.The NF-kappa B antibody is buied from cell signaling.
Animal model
According to Can-Fite BioPharma, Kiryat-Matalon, Petach Tikva, the established guide of Israel animal protection and use committee is carried out test.Animal is at random accepted standard diet and tap water.
Female Louis rat, in age in 8-10 week, from Harlan laboratory (Jerusalem, Israel), at the suspensoid of tail root subcutaneous injection (SC) 100 μ l incomplete Freund's adjuvants, the concentration of wherein not having the heating power Mycobacterium tuberculosis is 10mg/ml.Every group has 10 animals, and each test is carried out three times at least.
Handle record
With gavage twice pair of animal oral administration every day.Positive controls is only accepted carrier (corresponding with the medicine group, that DMSO is only arranged), and the treatment winding is subjected to the IB-MECA of 10 μ g/kg.The inoculation back began to handle on the 14th day.
The clinical disease mark
Every other day check the clinical arthritis of animal.The marking system scope of extremity is that 0-4:0-does not have arthritis; Rubescent or swelling of toe/finger-joint of 1-; Rubescent or swelling of above toe/finger-joint of 2-; 3-comprises ankle joint and shank-metatarsal joints; The all rubescent or swelling of all foots of 4-.Simultaneously inflammation intensity is measured, method is to use side footpath device (Mitotoyo, Tokyo, Japan) increase of measurement rat hindleg diameter.
Histology score
Collect vehicle group and CF101 treatment treated animal foot, knee and hip zone, and be fixed in 10% formalin buffer, in hydrochloric acid (decalcification fast) (USA) decalcification is 24 hours for PationalDiagnostics, Gr.Then sample is embedded in the paraffin, is prepared into 4-μ m histology and cuts, use h and E dyeing.Estimate section by the pathologist who does not know therapeutic scheme, for each joint record respectively all.Evaluation of tissue is learnt record by the following method: be used to represent that the mark 0-4 implication of inflammatory cell infiltration scope is as follows: 0-is normal; 1-minimum degree inflammatory infiltration; 2-slightly soaks into: the 3-moderate is soaked into; 4-significantly soaks into.Pannus structure joint tissue, the SLC hyperplasia.Mark is divided into the 0-4 level: 0-is normal; The compact bone minimum degree loss at 1-minority position; 2-crust spongy bone petty loss; The moderate bone loss of a lot of position of 3-; The remarkable bone loss in a lot of positions of 4-; The remarkable bone loss of a lot of positions of 5-, and run through inflammatory processes or broken and completeness thickens at the pannus generation bone of cortical bone.The fractional implication of above-mentioned all Histological parameters is refered in particular to " histology score ".
The protein extract of pawl
Cut the ankle joint top of metapedes.Osseous tissue beaten fragmentate, in liquid nitrogen freezing and in-80 ℃ of storages until use.The foot tissue is added in (4ml/g tissue) RIPA extract buffer, and described buffer comprises 150mM NaCl, 50mM Tris, 1%NP40,0.5% dexycholate and 0.1%SDS.Be organized in and use polytron to handle on ice, centrifugal, supernatant is carried out western blot analysis.
Western blot analysis
Carry out the western blot analysis (WB) of sufficient extract according to following method.Make ice-cold PBS clean sample, transfer to then in the dissolving buffer of ice pre-cooling (the TNN buffer, 50mM tromethamine pH=7.5,150mM NaCl, NP40).7500xg removed cell debris in centrifugal 10 minutes.Utilize Bio-Rad protein analysis stain to measure protein concentration.Utilize 12% polyacrylamide gel to separate the sample (50 μ g) of a great deal of by SDS-PAGE.Then with the protein electrotransfection of resolving to NC Nitroncellulose film (Schleicher﹠amp; Schuell, Keene, NH, USA) on.Use 1%BSA that film is blocked, utilize ideal main antibody (diluting 1: 1000) then 4 ℃ of hatchings 24 hours.Wash stains away then, utilize second antibody at room temperature to hatch 1 hour.Use BCIP/NBT color development test kit (Promega, Madison, W1, USA) record combination.Data in the different graphic are representatives of at least four different tests.
Conclusion
IB-MECA is to the effect of arthritis mark development in the AIA model
The arthritic clinical appearance in the 14th day that is characterized in.In the matched group, the highest record of clinical arthritis has reached 8.7 ± 0.76, and the clinical arthritis highest record of IB-MECA treatment group is 4.8 ± 0.95 lower (Figure 1A).IB-MECA treatment group has reduced podedema significantly.Equally, IB-MECA treatment group is producing 35% ± 1.2 inhibition (Figure 1B) aspect the sufficient thickness.What Fig. 1 C represented is the serious rubescent and swelling of the whole foot of matched group, and corresponding with it is representative pawl in the IB-MECA treatment group, and it shows as fully normal (right side).
IB-MECA is for the effect of AIA histologic characteristics
Animal skin is scratched in after disease is induced the 23rd day, takes out the joint of two metapedes of each animal, and carries out the histological structure inspection.On the basis that inflammatory cell infiltration, synovial fluid hyperplasia, cartilage and osseous tissue damage, carry out histologic analysis.Between the phalanx of foot area discover most histology change.Also found similar variation at knee area in the matched group, the knee portions of leg regions of IB-MECA treatment group then is kept perfectly, and this has just proved the order of severity of disease in the not treatment group.In sum, pathological severity of joint tissue and clinical severity correlation of indices connection.
Compare with large-scale inflammation area in the control rats, in the joint of treatment rat, observing significant inflammation minimizing (refer to gross score and be respectively 0.4 ± 0.034 and 3.2 ± 0.14) (Fig. 2 A-2B) on the statistics.Other synovial cell proliferation have caused that synovial membrane thickens, fibrosis, hypertrophy and hypertrophy, have observed the granulocytic infiltration of monokaryon (Fig. 3 A-3B) in matched group.On the contrary, in IB-MECA treatment group, almost do not observe the slight hypertrophy of fibrosis and synovial membrane.
There is a large amount of pannus tissues in the failure area of replacement normal structure in the matched group joint space, and only has slight pannus tissue to produce (Fig. 4 A-4B) in the IB-MECA treatment group.Occurred the seriousness cartilage injury in the matched group, next it can cause the cartilage loss, and the cartilage structure in the IB-MECA treatment treated animal is normal (Fig. 5 A-5B).
Compare with matched group, the osteoclast in the IB-MECA treatment group has reduced by 73% (Fig. 6 A-6B).High-caliber osteoclasia (destraction) (Fig. 7 A-7B) appears in matched group subsequently.Consequently, in the animal of IB-MECA treatment, a spot of osteoblast (Fig. 8 A-8B) and a spot of new osteogenesis (Fig. 9 A-9B) have been observed.
IB-MECA expresses the effect of downstream A3AR activation levels to main signal protein the pawl extract that obtains from the AIA Mus
The metapedes of animal in excision matched group and the IB-MECA treatment group is used for WB with sample behind the extraction protein and analyzes.Observed A in the IB-MECA treatment group
3The adjustment of AR self, this has proved the activation of receptor and degraded (Figure 10 A) had taken place afterwards.A
3The activation of AR causes that the RANKL protein expression level reduces by 40%, and described protein is the pawl extract that the AIA rat from the IB-MECA treatment obtains.As described in Figure 10 C, another signalling channel is PI3K-PKB/AKT, and it can regulate the IB-MECA treatment downwards.Compare with matched group, the protein expression level of PI3K and PKB/AKT reduces to some extent in the IB-MECA treatment group, next is the level of regulating the dirty kinases IKK of PKB/AKT downwards.As the result of IKK and the reduction of RANKL level, in IB-MECA treatment animal, observed the NF-κ B that level reduces.In the IB-MECA treatment, these incidents make the expression of TNF-α reduce by 50%.
Claims (26)
1. method for the treatment of mammalian subject acceleration bone resorption, this method comprise has patient of these treatment needs to use a certain amount of A to described
3Adenosine receptor agonist (A
3The AR agonist), described dosage can suppress bone resorption effectively.
2. the method for claim 1, wherein said mammal are human.
3. the method for claim 1 is used for the treatment of the inflammation-induced bone resorption.
4. method as claimed in claim 3 is used for the treatment of the inductive bone resorption of inflammatory arthritis.
5. the method for claim 1, wherein said treatment comprises has the patient of these needs to orally use A to described
3The AR agonist.
6. method as claimed in claim 5, wherein said treatment comprise uses A to described patient every day
3The AR agonist once or twice.
7. the method for claim 1, wherein said A
3The AR agonist is general formula (I) chemical compound:
Wherein
-R1 is alkyl, hydroxy alkyl, carboxyalkyl or cyano group alkyl or following general formula (II) group:
Wherein:
-Y represents oxygen, sulfur or CH
2
-X
1Represent H, alkyl, R
aR
bNC (=O)-or HOR
c-, wherein
-R
aAnd R
bCan be identical or different, be selected from hydrogen, alkyl, amino, alkylhalide group, aminoalkyl, BOC-aminoalkyl and cycloalkyl, perhaps in conjunction with forming the heterocycle that comprises 2-5 carbon atom; With
-R
cBe selected from alkyl, amino, alkylhalide group, aminoalkyl, BOC-aminoalkyl and cycloalkyl;
-X
2Be H, hydroxyl, alkyl amino, alkyl amido or hydroxy alkyl;
-X
3And X
4Represent respectively hydrogen, hydroxyl, amino, acylamino-, azido, halogen, alkyl, alkoxyl, carboxyl, inferior amino, nitro, trifluoro, aryl, alkaryl, sulfur, thioesters, thioether ,-OCOPh ,-OC (=S) OPh or X
3And X
4All be with＞oxygen that C=S is connected to form 5 yuan of rings, perhaps X
2And X
3Form formula (III) ring:
Wherein R ' and R " represent alkyl group respectively;
-R
2Be selected from hydrogen, halogen, alkyl ether, amino, hydrazide group, alkyl amino, alkoxyl, thioalkoxy group, pyridine radicals sulfur, thiazolinyl; Alkynyl, sulfur and alkyl sulfide; With
-R
3Be formula-NR
4R
5Group, wherein
-R
4Be hydrogen atom or be selected from alkyl, substituted alkyl or aryl-NH-C (Z)-, wherein Z is O, S or NR
a, R wherein
aImplication is the same; Wherein work as R
4When being hydrogen
-R
5Be selected from R-and S-1-phenethyl, benzyl, phenethyl or aniline group, one or more therein positions are replaced or do not replace by following substituent group, and described substituent group is selected from alkyl, amino, halogen, alkylhalide group, nitro, hydroxyl, acetylamino, alkoxyl and sulfonic acid or its salt; Benzo two alkane methyl, fururyl, L-propyl group alanyl-aminobenzyl, β-alanyl amino-benzyl, T-BOC-β-alanyl aminobenzyl, phenyl amino, carbamyl, phenoxy group or cycloalkyl; Perhaps R
5Be the following formula group:
Perhaps work as R
4Be alkyl or aryl-NH-C (Z)-time, R so
5Then be selected from heteroaryl-NR
a-C (Z)-, heteroaryl-C (Z)-, alkaryl-NR
a-C (Z)-, alkaryl-C (Z)-, aryl-NR-C (Z)-and aryl-C (Z)-; Z represents oxygen, sulfur or amine; Or the physiologically acceptable salt of above-claimed cpd.
8. the method for claim 1, wherein said A
3The AR agonist is the nucleoside derivates shown in the general formula (IV):
X wherein
1, R
2And R
4As described in claim 3, and the physiologically acceptable salt of described chemical compound.
9. the method for claim 1, wherein said A
3The AR agonist is selected from N
6-2-(4-aminophenyl) ethyl adenosine (APNEA), N
6-(4-amino-3-benzyl iodide) adenosine-5 '-(N-methyl uronic amide) (AB-MECA), N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (IB-MECA) and 2-chloro-N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (C1-IB-MECA).
10. method as claimed in claim 9, wherein said A
3The AR agonist is IB-MECA.
11. a pharmaceutical composition that is used for the treatment of the acceleration bone resorption, said composition comprises a certain amount of A
3The AR agonist, described dosage can suppress the mammalian subject bone resorption effectively.
12. pharmaceutical composition as claimed in claim 11, its dosage form is suitable for oral administration.
13. pharmaceutical composition as claimed in claim 11 is used for the treatment of the inflammation-induced bone resorption.
14. pharmaceutical composition as claimed in claim 13 is used for the treatment of the inductive bone resorption of inflammatory arthritis.
15. pharmaceutical composition as claimed in claim 11, wherein said A
3The AR agonist is general formula (I) chemical compound:
Wherein
-R1 is alkyl, hydroxy alkyl, carboxyalkyl or cyano group alkyl or following general formula (II) group:
Wherein:
-Y represents oxygen, sulfur or CH
2
-X
1Represent H, alkyl, R
aR
bNC (=O)-or HOR
c-, wherein
-R
aAnd R
bCan be identical or different, be selected from hydrogen, alkyl, amino, alkylhalide group, aminoalkyl, BOC-aminoalkyl and cycloalkyl, perhaps in conjunction with forming the heterocycle that comprises 2-5 carbon atom; With
-R
cBe selected from alkyl, amino, alkylhalide group, aminoalkyl, BOC-aminoalkyl and cycloalkyl;
-X
2Be H, hydroxyl, alkyl amino, alkyl amido or hydroxy alkyl;
-X
3And X
4Represent respectively hydrogen, hydroxyl, amino, acylamino-, azido, halogen, alkyl, alkoxyl, carboxyl, inferior amino, nitro, trifluoro, aryl, alkaryl, sulfur, thioesters, thioether ,-OCOPh ,-OC (=S) OPh or X
3And X
4All be with＞oxygen that C=S is connected to form 5 yuan of rings, perhaps X
2And X
3Form formula (III) ring:
Wherein R ' and R " represent alkyl group respectively;
-R
2Be selected from hydrogen, halogen, alkyl ether, amino, hydrazide group, alkyl amino, alkoxyl, thioalkoxy group, pyridine radicals sulfur, thiazolinyl; Alkynyl, sulfur and alkyl sulfide; With
-R
3Be formula-NR
4R
5Group, wherein
-R
4Be hydrogen atom or be selected from alkyl, substituted alkyl or aryl-NH-C (Z)-, wherein Z is O, S or NR
a, R wherein
aImplication is the same; Wherein work as R
4When being hydrogen
-R
5Be selected from R-and S-1-phenethyl, benzyl, phenethyl or aniline group, one or more therein positions are replaced or do not replace by following substituent group, and described substituent group is selected from alkyl, amino, halogen, alkylhalide group, nitro, hydroxyl, acetylamino, alkoxyl and sulfonic acid or its salt; Benzo two alkane methyl, fluoro aryl, L-propyl group alanyl-aminobenzyl, β-alanyl amino-benzyl, T-BOC-β-alanyl aminobenzyl, phenyl amino, carbamyl, phenoxy group or cycloalkyl; Perhaps R
5Be the following formula group:
Perhaps work as R
4Be alkyl or aryl-NH-C (Z)-time, R so
5Then be selected from heteroaryl-NR
a-C (Z)-, heteroaryl-C (Z)-, alkaryl-NR
a-C (Z)-, alkaryl-C (Z)-, aryl-NR-C (Z)-and aryl-C (Z)-; Z represents oxygen, sulfur or amine; Or the physiologically acceptable salt of above-claimed cpd.
16. pharmaceutical composition as claimed in claim 11, wherein said A
3The AR agonist is the nucleoside derivates shown in the general formula (IV):
X wherein
1, R
2And R
4As described in claim 3, and the physiologically acceptable salt of described chemical compound.
17. pharmaceutical composition as claimed in claim 11, wherein said A
3The AR agonist is selected from N
6-2-(4-aminophenyl) ethyl adenosine (APNEA), N
6-(4-amino-3-benzyl iodide) adenosine-5 '-(N-methyl uronic amide) (AB-MECA), N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (IB-MECA) and 2-chloro-N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (Cl-IB-MECA).
18. pharmaceutical composition as claimed in claim 11, wherein said A
3The AR agonist is IB-MECA.
19.A
3The purposes of AR agonist in the pharmaceutical composition of preparation treatment acceleration bone resorption.
20. purposes as claimed in claim 19 is used for preparation and is suitable for liquid preparations for oral administration.
21. purposes as claimed in claim 20 is used to prepare the compositions for the treatment of the inflammation-induced bone resorption.
22. purposes as claimed in claim 21 is used to prepare the compositions for the treatment of the inductive bone resorption of inflammatory arthritis.
23. purposes as claimed in claim 19, wherein said A
3The AR agonist is general formula (I) chemical compound:
Wherein
-R1 is alkyl, hydroxy alkyl, carboxyalkyl or cyano group alkyl or following general formula (II) group:
Wherein:
-Y represents oxygen, sulfur or CH
2
-X
1Represent H, alkyl, R
aR
bNC (=O)-or HOR
c-, wherein
-R
aAnd R
bCan be identical or different, be selected from hydrogen, alkyl, amino, alkylhalide group, aminoalkyl, BOC-aminoalkyl and cycloalkyl, perhaps in conjunction with forming the heterocycle that comprises 2-5 carbon atom; With
-R
cBe selected from alkyl, amino, alkylhalide group, aminoalkyl, BOC-aminoalkyl and cycloalkyl;
-X
2Be H, hydroxyl, alkyl amino, alkyl amido or hydroxy alkyl;
-X
3And X
4Represent respectively hydrogen, hydroxyl, amino, acylamino-, azido, halogen, alkyl, alkoxyl, carboxyl, inferior amino, nitro, trifluoro, aryl, alkaryl, sulfur, thioesters, thioether ,-OCOPh ,-OC (=S) OPh or X
3And X
4All be with＞oxygen that C=S is connected to form 5 yuan of rings, perhaps X
2And X
3Form formula (III) ring:
Wherein R ' and R " represent alkyl group respectively;
-R
2Be selected from hydrogen, halogen, alkyl ether, amino, hydrazide group, alkyl amino, alkoxyl, thioalkoxy group, pyridine radicals sulfur, thiazolinyl; Alkynyl, sulfur and alkyl sulfide; With
-R
3Be formula-NR
4R
5Group, wherein
-R
4Be hydrogen atom or be selected from alkyl, substituted alkyl or aryl-NH-C (Z)-, wherein Z is O, S or NR
a, R wherein
aImplication is the same; Wherein work as R
4When being hydrogen
-R
5Be selected from R-and S-1-phenethyl, benzyl, phenethyl or aniline group, one or more therein positions are replaced or do not replace by following substituent group, and described substituent group is selected from alkyl, amino, halogen, alkylhalide group, nitro, hydroxyl, acetylamino, alkoxyl and sulfonic acid or its salt; Benzo two alkane methyl, fluoro aryl, L-propyl group alanyl-aminobenzyl, β-alanyl amino-benzyl, T-BOC-β-alanyl aminobenzyl, phenyl amino, carbamyl, phenoxy group or cycloalkyl; Perhaps R
5Be the following formula group:
Perhaps work as R
4Be alkyl or aryl-NH-C (Z)-time, R so
5Then be selected from heteroaryl-NR
a-C (Z)-, heteroaryl-C (Z)-, alkaryl-NR
a-C (Z)-, alkaryl-C (Z)-, aryl-NR-C (Z)-and aryl-C (Z)-; Z represents oxygen, sulfur or amine; Or the physiologically acceptable salt of above-claimed cpd.
24. purposes as claimed in claim 19, wherein said A
3The AR agonist is the nucleoside derivates shown in the general formula (IV):
X wherein
1, R
2And R
4As described in claim 3, and the physiologically acceptable salt of described chemical compound.
25. purposes as claimed in claim 19, wherein said A
3The AR agonist is selected from N
6-2-(4-aminophenyl) ethyl adenosine (APNEA), N
6-(4-amino-3-benzyl iodide) adenosine-5 '-(N-methyl uronic amide) (AB-MECA), N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (IB-MECA) and 2-chloro-N
6-(3-benzyl iodide)-adenosine-5 '-N-methyl uronic amide (Cl-IB-MECA).
26. purposes as claimed in claim 19, wherein said A
3The AR agonist is IB-MECA.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62556404P | 2004-11-08 | 2004-11-08 | |
| US60/625,564 | 2004-11-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101072554A true CN101072554A (en) | 2007-11-14 |
Family
ID=36001028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800380014A Pending CN101072554A (en) | 2004-11-08 | 2005-11-08 | Therapeutic treatment of accelerated bone resorption |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1811982A1 (en) |
| JP (1) | JP2008519029A (en) |
| KR (1) | KR20070085839A (en) |
| CN (1) | CN101072554A (en) |
| AU (1) | AU2005302090A1 (en) |
| BR (1) | BRPI0517639A (en) |
| CA (1) | CA2586845A1 (en) |
| MX (1) | MX2007005525A (en) |
| WO (1) | WO2006048884A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102427819A (en) * | 2009-05-17 | 2012-04-25 | 坎-菲特生物药物有限公司 | A3 adenosine receptor agonists for the reduction of intraocular pressure |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080300213A1 (en) * | 2005-11-30 | 2008-12-04 | Pnina Fishman | Use of A3 Adenosine Receptor Agonist in Osteoarthritis Treatment |
| DK2137202T3 (en) | 2007-03-14 | 2017-10-02 | Can-Fite Biopharma Ltd | PROCEDURE FOR SYNTHESIS OF IB-MECA |
| WO2009061516A1 (en) * | 2007-11-08 | 2009-05-14 | New York University School Of Medicine | Medical implants containing adenosine receptor agonists and methods for inhibiting medical implant loosening |
| MX356509B (en) | 2011-12-22 | 2018-05-30 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof. |
| US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5294100A (en) * | 1999-05-27 | 2000-12-18 | University Of Virginia Patent Foundation | Method and compositions for treating the inflammatory response |
| IL133680A0 (en) * | 1999-09-10 | 2001-04-30 | Can Fite Technologies Ltd | Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist |
| WO2004045627A1 (en) * | 2002-11-19 | 2004-06-03 | Can-Fite Biopharma Ltd. | A3ar agonists for the treatment of inflammatory arthritis |
| GB0305150D0 (en) * | 2003-03-07 | 2003-04-09 | Cambridge Biotechnology Ltd | Use of therapeutic compounds |
| KR20070004792A (en) * | 2004-03-05 | 2007-01-09 | 캠브리지 바이오테크놀로지 리미티드 | Adenosine receptor agonists |
-
2005
- 2005-11-08 AU AU2005302090A patent/AU2005302090A1/en not_active Abandoned
- 2005-11-08 WO PCT/IL2005/001166 patent/WO2006048884A1/en active Application Filing
- 2005-11-08 BR BRPI0517639-5A patent/BRPI0517639A/en not_active IP Right Cessation
- 2005-11-08 EP EP05799989A patent/EP1811982A1/en not_active Withdrawn
- 2005-11-08 CN CNA2005800380014A patent/CN101072554A/en active Pending
- 2005-11-08 CA CA002586845A patent/CA2586845A1/en not_active Abandoned
- 2005-11-08 MX MX2007005525A patent/MX2007005525A/en not_active Application Discontinuation
- 2005-11-08 KR KR1020077012806A patent/KR20070085839A/en not_active Application Discontinuation
- 2005-11-08 JP JP2007539712A patent/JP2008519029A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102427819A (en) * | 2009-05-17 | 2012-04-25 | 坎-菲特生物药物有限公司 | A3 adenosine receptor agonists for the reduction of intraocular pressure |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2005302090A1 (en) | 2006-05-11 |
| KR20070085839A (en) | 2007-08-27 |
| EP1811982A1 (en) | 2007-08-01 |
| MX2007005525A (en) | 2007-07-05 |
| BRPI0517639A (en) | 2008-10-14 |
| CA2586845A1 (en) | 2006-05-11 |
| WO2006048884A1 (en) | 2006-05-11 |
| JP2008519029A (en) | 2008-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101072554A (en) | Therapeutic treatment of accelerated bone resorption | |
| CN111201039B (en) | Cannabidiol and 5-HT 2B Use of a combination of receptor agonists amphetamine for the treatment of epilepsy | |
| JP5339916B2 (en) | Use of A3 adenosine receptor agonists in the treatment of osteoarthritis | |
| US20080051364A1 (en) | Therapeutic Treatment of Accelerated Bone Resorption | |
| CN100423723C (en) | Method for treatment of multiple sclerosis | |
| JP2020090532A (en) | A3 adenosine receptor ligands for treating ectopic fat accumulation | |
| KR20140062143A (en) | Compositions and methods for treating cancer using pi3k beta inhibitor and mapk pathway inhibitor, including mek and raf inhibitors | |
| IE912237A1 (en) | Pharmaceutical preparations | |
| AU2017245292B2 (en) | Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor | |
| HU229309B1 (en) | Novel use of (r)-(-)-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and its salts | |
| KR102436875B1 (en) | Composition comprising a PI3 kinase inhibitor and a BCL-2 inhibitor | |
| WO2017077445A1 (en) | Dosage regimen for a phosphatidylinositol 3-kinase inhibitor | |
| Polosa et al. | Adenosine as a pro-inflammatory mediator in asthma | |
| JP2005526086A (en) | Combination of CDK inhibitor and 5-FU for the treatment of cancer | |
| TW201934123A (en) | Pharmaceutical composition for preventing or treating cancer comprising PI3 kinase inhibitor and cytotoxicity anticancer agents | |
| KR102525941B1 (en) | Composition for preventing or treating bone disease of 2,4,6-tripehenyl-1-hexene | |
| WO2010025266A1 (en) | Inhibitors of phosphodiesterase type 5a for treating or preventing muscle disease or the symptoms thereof in a patient | |
| Iwamoto et al. | Antihypertensive effects of 2-octynyladenosine (YT-146), a selective adenosine A2 receptor agonist, in Dahl salt-sensitive rats | |
| JP2023100928A (en) | A3 adenosine receptor ligand for use for achieving fat loss effect | |
| Antiallergic | C15H19Cl2N3O4 Glaxo Wellcome |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20071114 |