TWI535444B - 熱休克蛋白抑制劑用於製備治療b型肝炎或肝癌之醫藥組合物的用途 - Google Patents
熱休克蛋白抑制劑用於製備治療b型肝炎或肝癌之醫藥組合物的用途 Download PDFInfo
- Publication number
- TWI535444B TWI535444B TW103121657A TW103121657A TWI535444B TW I535444 B TWI535444 B TW I535444B TW 103121657 A TW103121657 A TW 103121657A TW 103121657 A TW103121657 A TW 103121657A TW I535444 B TWI535444 B TW I535444B
- Authority
- TW
- Taiwan
- Prior art keywords
- heat shock
- shock protein
- protein inhibitor
- pharmaceutical composition
- hepatitis
- Prior art date
Links
- 108010004889 Heat-Shock Proteins Proteins 0.000 title claims description 39
- 102000002812 Heat-Shock Proteins Human genes 0.000 title claims description 39
- 229940121649 protein inhibitor Drugs 0.000 title claims description 38
- 239000012268 protein inhibitor Substances 0.000 title claims description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 18
- 208000006454 hepatitis Diseases 0.000 title description 7
- 231100000283 hepatitis Toxicity 0.000 title description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 title description 2
- ZXGGCBQORXDVTE-UMCMBGNQSA-N 4-[[(2R,3S,4R,5R)-5-[6-amino-8-[(3,4-dichlorophenyl)methylamino]-9-purinyl]-3,4-dihydroxy-2-oxolanyl]methoxymethyl]benzonitrile Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1NCC=1C=C(Cl)C(Cl)=CC=1)N)OCC1=CC=C(C#N)C=C1 ZXGGCBQORXDVTE-UMCMBGNQSA-N 0.000 claims description 37
- ZZUZYEMRHCMVTB-UHFFFAOYSA-N 2-phenylethynesulfonamide Chemical compound NS(=O)(=O)C#CC1=CC=CC=C1 ZZUZYEMRHCMVTB-UHFFFAOYSA-N 0.000 claims description 36
- 208000002672 hepatitis B Diseases 0.000 claims description 25
- 241000700721 Hepatitis B virus Species 0.000 claims description 19
- 201000007270 liver cancer Diseases 0.000 claims description 18
- 208000014018 liver neoplasm Diseases 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 3
- 229960005305 adenosine Drugs 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 19
- 239000003814 drug Substances 0.000 description 13
- 210000003494 hepatocyte Anatomy 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 9
- 239000000427 antigen Substances 0.000 description 8
- 102000036639 antigens Human genes 0.000 description 8
- 108091007433 antigens Proteins 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 101710084021 Large envelope protein Proteins 0.000 description 7
- 241000700605 Viruses Species 0.000 description 6
- 210000005229 liver cell Anatomy 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 3
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 3
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001768 cations 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
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 description 2
- 101150112743 HSPA5 gene Proteins 0.000 description 2
- 101710113864 Heat shock protein 90 Proteins 0.000 description 2
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 230000004900 autophagic degradation Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 229960005311 telbivudine Drugs 0.000 description 2
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010036652 HSC70 Heat-Shock Proteins Proteins 0.000 description 1
- 108010027814 HSP72 Heat-Shock Proteins Proteins 0.000 description 1
- -1 He-psera Chemical compound 0.000 description 1
- 102100040352 Heat shock 70 kDa protein 1A Human genes 0.000 description 1
- 102100027421 Heat shock cognate 71 kDa protein Human genes 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101100111629 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR2 gene Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007961 artificial flavoring substance Substances 0.000 description 1
- 229940002637 baraclude Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- QDGZDCVAUDNJFG-FXQIFTODSA-N entecavir (anhydrous) Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)C1=C QDGZDCVAUDNJFG-FXQIFTODSA-N 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 101150028578 grp78 gene Proteins 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940118537 p53 inhibitor Drugs 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 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
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 239000010455 vermiculite Substances 0.000 description 1
- 229910052902 vermiculite Inorganic materials 0.000 description 1
- 235000019354 vermiculite Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Biotechnology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本發明係關於製備治療B型肝炎或肝癌之醫藥組合物，特別關於熱休克蛋白抑制劑用於製備治療B型肝炎或肝癌之醫藥組合物的用途。
肝炎是台灣的「國病」，迄今B型肝炎盛行率16%仍高居世界第一，長久以來，肝病一直是亞洲盛行的「本土病」，肝癌更是台灣、中國大陸、泰國、韓國最常見的腫瘤。原發性肝癌(Hepatocellular carcinoma)是亞非地區常見的癌症，一般發現後，即使經過外科手術、化學或放射治療，平均存活率亦不高。而根據流行病學的統計，世界各地肝炎病毒(hepatitis virus)的高感染區都有較高的肝癌病例。進一步以台灣為例，肝癌病例中百分之九十以上都是B型肝炎的帶原者。
B型肝炎病毒的患者在病毒感染之後，病毒在肝臟中大量複製。目前已有的B型肝炎藥物主要分為皮下注射的干擾素型藥物以及口服型的類核苷酸藥物，例如干安能（Lamivudine, Zeffix）、干適能（Adefovir Dipivoxil, He-psera）、貝樂克（Entecavir, Baraclude）、喜必福（Telbivudine, Sebivo）、惠立妥（Tenofovir, Viread）等藥物。上述藥物之主要機制為抗病毒作用，其可抑制B型肝炎病毒在肝臟複製。因此臨床上感染慢性B型肝炎病毒的患者，只能透過抗病毒藥物抑制病毒複製，然而這些抗病毒藥物並不能清除被病毒感染的細胞，使得目前B型肝炎僅能被控制而難以根治。因此目前仍需尋找可清除被B型肝炎病毒感染的細胞之藥物。
本發明之一目的是提供可治療及/或控制B型肝炎之藥物，其係清除被B型肝炎病毒所感染的細胞。
依據本發明之一實施例，一種熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中熱休克蛋白抑制劑包含VER-155008、皮斐松-µ(Pifithrin-µ)或其醫藥上可接受之鹽類。
本發明之另一目的是提供可治療肝癌之藥物，其可清除被B型肝炎病毒感染的細胞。
依據本發明之另一實施例，一種熱休克蛋白抑制劑用於製備治療肝癌之醫藥組合物的用途，其中熱休克蛋白抑制劑包含VER-155008、皮斐松-µ(Pifithrin-µ)或其醫藥上可接受之鹽類。
本發明上述及其他態樣、特性及優勢可由附圖及實施例之說明而可更加了解。
本發明是關於一種熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中熱休克蛋白抑制劑包含VER-155008、皮斐松-µ(Pifithrin-µ)或其醫藥上可接受之鹽類。
本發明所述的VER-155008之代表式為下列所示 ，化學名稱為5'-O-[(4-氰基苯基)甲基]-8-[[(3,4-二氯苯基)甲基]氨基]-腺苷 (5’-O-[(4-Cyanophenyl)methyl]-8-[[(3,4-dichlorophenyl)methyl]amino]-adenosine)。VER-155008已知是一種有效的HSP70家族抑制劑，作用於HSP70和Grp78時，IC50分別為0.5 μM和2.6 μM，比作用於HSP90選擇性高100倍以上。VER-155008
本發明所述的皮斐松-µ(Pifithrin-µ)，化學名稱為2-苯基乙炔磺酰胺(2-Phenylethynesulfonamide)，其代表式為下列所示。Pifithrin-µ已知是一種特異性的p53抑制劑，通過降低其與Bcl-xL和Bcl-2的親和力而發揮作用，也抑制HSP70功能和細胞自噬。VER-155008及Pifithrin-µ皆為市售可得(分別為Sigma SML0271及Sigma P0122)，但應註明的是本案熱休克蛋白抑制劑並不限於市售VER-155008及Pifithrin-µ商品，其亦包括由化學合成而得到之化合物。Pifithrin-µ
US20110189125揭示以Pifithrin-µ治療腫瘤細胞導致胞漿空泡化，蛋白質聚集，從基材剝離並誘導自噬。此外，腫瘤細胞較正常細胞對Pifithrin-µ的細胞毒殺作用更敏感，但目前並無相關前案揭示Pifithrin-µ應用於治療B型肝炎及肝癌。
請參照圖1，本發明提供一個新穎清除慢性B型肝炎病毒(HBV)的方法，其中顯示正常肝細胞1及HBV感染之肝細胞2。本發明之熱休克蛋白抑制劑可針對特定的熱休克蛋白進行調控，可以達到特異性毒殺被B型肝炎病毒感染之肝細胞。其中在熱休克蛋白抑制劑中發現VER-155008 (抑制HSC70、 GRP78、HSP90)及 Pifithrin-µ(抑制HSP72)具有專一性殺死病毒感染的肝細胞並可降低小鼠體內的病毒量，因此可應用做為臨床治療B型肝炎的藥物。如前所述，B肝病毒本身所帶有的基因本身及其表現的蛋白質已被認為扮演重要的致癌因子，亦即肝炎病毒感染能導致肝癌，台灣肝癌病例中B型肝炎的帶原者非常地高。因此本發明可用以清除慢性B型肝炎病毒，而可治療肝癌。在一具體實施例中，本發明可用以治療肝癌，其係由肝炎所引起；在一具體實施例中，其中肝炎是由B型肝炎病毒所造成。再者Pifithrin-µ具有選擇性抑制癌症之作用，因此本發明之熱休克蛋白抑制劑可應用為治療癌症之用途。
本發明所述之「控制」是指使病毒量限制在受控範圍，特別是限制在未檢出之範圍。
本發明所公開的熱休克蛋白抑制劑可以其相應的鹽、酯或前藥存在。如本文所述，「醫藥上可接受的鹽」指的是本發明化合物之鹽或兩性離子形式。這些化合物的鹽類之製備例如可在化合物反應的最終分離和純化或是獨立通過使化合物與具有合適陽離子的酸類反應而製得。合適的藥學上可接受的陽離子包括鹼金族（如鈉或鉀）和鹼土族（如鈣或鎂）陽離子。此外，對於包含鹼性中心的本發明化合物，其藥學上可接受的鹽是藉由與藥學上可接受的酸形成的酸加成鹽。可用於形成藥學上可接受的鹽的酸類實例包括無機酸(例如鹽酸、氫溴酸、硫酸和磷酸)，以及有機酸(例如草酸、馬來酸、琥珀酸、丙二酸、乳酸和檸檬酸)。有鑑於此，本文中出現的化合物意在包括本文所揭示的化合物以及其藥學上可接受的鹽、溶劑合物(solvate)(例如，水合物）、酯類或前藥。其中，舉例而言，VER-155008及Pifithrin-µ皆具有胺基，因此可與酸類形成藥學上可接受的鹽。
本文所述的「醫藥上可接受之載劑」指的是為了藥物製造過程之需要、便於藥物劑量調配，或不同投藥劑型等需求，根據習知醫藥組合技術將醫藥組合物與醫藥可接受載劑混合，合適之醫藥可接受載劑為此項技術領域中所熟知，其中載劑可有廣泛之形式。舉例而言，錠劑、膠囊、凝膠、溶液或懸浮液亦可包含下述成分：醫藥可接受賦形劑或載劑，其為無毒性、惰性固體或半固體、稀釋劑、封裝物質凝膠基劑或任何形式之配方佐劑，例如：微晶纖維素、葡萄糖、脫脂奶粉、澱粉、矽石、無水磷酸氫鈣、磷酸鎂、硬脂酸、硬脂酸鎂，或人工香料等物質。
以下通過具體實施例配合附圖詳加說明，可更容易瞭解本發明的目的、技術內容、特點及所達成的功效，並據以實施，但不能以此限定本發明的保護範圍。 本案熱休克蛋白抑制劑對肝細胞之毒性
請參照圖2a及2b，其為數據顯示Pifithrin-µ對於親代肝細胞株 SNAP、WT及Pre-S2的IC50分別為17.5、12.2及11.8 µM。 VER-155008對於親代肝細胞株 SNAP、WT及Pre-S2的IC50分別為36.2、18.0及18.8 µM。亦即Pifithrin-µ與VER-155008的IC50皆為µM等級，因此對肝細胞的毒性相當低。 體外選擇性殺死病毒感染的肝細胞
藉由時間推移活細胞顯微檢測VER-155008對於HBV-LHBs(hepatitis B virus Large S protein)表現細胞的選擇性細胞毒殺作用。LHBs陽性細胞標記有綠色螢光(使用SNAP細胞505)並且與未標記的親代NeHepLxHT細胞共培養。混合細胞群以40 µM VER-155008處理，並隨後進行長時間隔記錄48小時。細胞數量顯示監測的未標示(親代)和綠色標示(LHBs陽性細胞)所進行的典型的細胞凋亡。圖3a 顯示，親代(白色箭頭)及LHBs陽性(綠色)細胞在VER-155008處理之前皆為存活。圖3b 顯示在VER-155008處理24小時後，檢測到LHBs陽性細胞的顯著細胞死亡，親代細胞仍然存活，如白色箭頭(下圖像)所示。圖3c顯示親代及LHBs陽性細胞反應VER-155008而進行細胞死亡顯示為時間對應關係，其中VER-155008處理後48小時，可達成LHBs陽性細胞近全部死亡。 VER-155008和Pifithrin-µ降低小鼠體內血清B型肝炎表面抗原水平
靜脈注射VER-155008和Pifithrin-µ成功地降低以腺病毒基因組轉移HBV (AdHBV)持續性感染的小鼠中B型肝炎病毒表面抗原(HBsAg)的血清水平。各組以三隻小鼠進行測試。小鼠藥物處理的實驗設計如下。以AdHBV持續28天注射小鼠，隨後以空白(mock)、20毫克/毫升VER-155008，或20毫克/毫升Pifithrin-µ靜脈注射。收集小鼠血清和肝臟標本以進行血清學和病理分析。圖4a顯示空白、VER-155008及 Pifithrin-µ處理的小鼠血清均表現B型肝炎表面抗原。VER-155008及Pifithrin-µ處理後的小鼠血清B型肝炎表面抗原水平顯著降低。 VER-155008和Pifithrin-µ與小鼠肝功能試驗
小鼠的肝功能依血清谷丙轉氨酶(GPT)的水平進行監測。圖4b顯示在這些處理之後，血清GTP水平並沒有顯著改變，表示VER-155008和Pifithrin-µ並未影響小鼠正常肝功能的作用。
小鼠肝臟的肝細胞中表達HBV表面抗原(HBcAg)族群在VER-155008治療一個月後顯著降低。圖5a顯示以HBcAg染色的肝切片的代表圖像。圖5b顯示在低劑量(20毫克/千克)及高劑量(40毫克/千克)VER-155008(VE)或Pifithrin-µ(PI)治療後的肝臟的HBcAg陽性肝細胞百分比。其中低劑量及高劑量的VER-155008對於減少肝臟中B型肝炎病毒抗原陽性的肝細胞均有顯示差異；高劑量Pifithrin-µ(40毫克/千克)也殺死部分肝臟中B型肝炎病毒抗原陽性的肝細胞。*表示P,0.05; **表示P＜0.01。
以上所述之實施例僅是為說明本發明之技術思想及特點，其目的在使熟習此項技藝之人士能夠瞭解本發明之內容並據以實施，當不能以之限定本發明之專利範圍，即大凡依本發明所揭示之精神所作之均等變化或修飾，仍應涵蓋在本發明之專利範圍內。
1‧‧‧正常肝細胞
2‧‧‧HBV感染之肝細胞
2‧‧‧HBV感染之肝細胞
圖1為示意圖說明依據本發明一實施例使用熱休克蛋白抑制劑清除慢性B型肝炎病毒感染細胞的方法。 圖2a至圖2b為實驗數據說明本案熱休克蛋白抑制劑對親代肝細胞之毒性。 圖3a至圖3c為實驗數據說明本案熱休克蛋白抑制劑對HBV-LHBs表現細胞的選擇性細胞毒殺作用。 圖4a為實驗數據說明本案熱休克蛋白抑制劑對小鼠之B型肝炎表面抗原表現量之作用。 圖4b為實驗數據說明本案熱休克蛋白抑制劑對小鼠肝功能之作用。 圖5a至圖5b為實驗數據說明本案熱休克蛋白抑制劑對治療後的肝臟的HBcAg陽性肝細胞之作用。
1‧‧‧正常肝細胞
2‧‧‧HBV感染之肝細胞
Claims (10)
- 一種熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中該熱休克蛋白抑制劑包含5'-O-[(4-氰基苯基)甲基]-8-[[(3,4-二氯苯基)甲基]氨基]-腺苷 (5’-O-[(4-Cyanophenyl)methyl]-8-[[(3,4-dichlorophenyl)methyl]amino]-adenosine, VER-155008)、2-苯基乙炔磺酰胺(2-Phenylethynesulfonamide, 皮斐松-µ(Pifithrin-µ))或其醫藥上可接受之鹽類。
- 如申請專利範圍第1項所述之熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中該熱休克蛋白抑制劑係選自由VER-155008 及 Pifithrin-µ所組成的群組。
- 如申請專利範圍第1項所述之熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中該熱休克蛋白抑制劑為VER-155008。
- 如申請專利範圍第1項所述之熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中該熱休克蛋白抑制劑為Pifithrin-µ。
- 如申請專利範圍第1項所述之熱休克蛋白抑制劑用於製備治療或控制B型肝炎之醫藥組合物的用途，其中該醫藥組合物進一步包括一醫藥上可接受之載劑。
- 一種熱休克蛋白抑制劑用於製備治療肝癌之醫藥組合物的用途，其中該熱休克蛋白抑制劑包含5'-O-[(4-氰基苯基)甲基]-8-[[(3,4-二氯苯基)甲基]氨基]-腺苷 (5’-O-[(4-Cyanophenyl)methyl]-8-[[(3,4-dichlorophenyl)methyl]amino]-adenosine, VER-155008)、2-苯基乙炔磺酰胺(2-Phenylethynesulfonamide, 皮斐松-µ(Pifithrin-µ))或其醫藥上可接受之鹽類。
- 如申請專利範圍第6項所述之熱休克蛋白抑制劑用於製備治療肝癌之醫藥組合物的用途，其中該熱休克蛋白抑制劑係選自由VER-155008 及 Pifithrin-µ所組成的群組。
- 如申請專利範圍第6項所述之熱休克蛋白抑制劑用於製備治療肝癌之醫藥組合物的用途，其中該熱休克蛋白抑制劑為VER-155008。
- 如申請專利範圍第6項所述之熱休克蛋白抑制劑用於製備治療肝癌之醫藥組合物的用途，其中該熱休克蛋白抑制劑為Pifithrin-µ。
- 如申請專利範圍第6項所述之熱休克蛋白抑制劑用於製備治療肝癌之醫藥組合物的用途，其中該肝癌是由B型肝炎病毒所引起。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW103121657A TWI535444B (zh) | 2014-06-24 | 2014-06-24 | 熱休克蛋白抑制劑用於製備治療b型肝炎或肝癌之醫藥組合物的用途 |
| US14/749,091 US9687499B2 (en) | 2014-06-24 | 2015-06-24 | Method using heat shock protein inhibitor for treating hepatitis and hepatoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW103121657A TWI535444B (zh) | 2014-06-24 | 2014-06-24 | 熱休克蛋白抑制劑用於製備治療b型肝炎或肝癌之醫藥組合物的用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201600091A TW201600091A (zh) | 2016-01-01 |
| TWI535444B true TWI535444B (zh) | 2016-06-01 |
Family
ID=54868669
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW103121657A TWI535444B (zh) | 2014-06-24 | 2014-06-24 | 熱休克蛋白抑制劑用於製備治療b型肝炎或肝癌之醫藥組合物的用途 |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US9687499B2 (zh) |
| TW (1) | TWI535444B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106633048B (zh) * | 2016-11-30 | 2019-04-09 | 华南理工大学 | 一种聚炔胺类化合物及其制备方法 |
| US11266675B2 (en) * | 2018-04-30 | 2022-03-08 | City University Of Hong Kong | Methods of treatment of viral infection and uses of anti-HSC70 inhibitors |
| CN113995829B (zh) * | 2021-10-25 | 2023-05-05 | 重庆医科大学 | Grp78调控抗乙型肝炎病毒颗粒分泌的抑制剂 |
-
2014
- 2014-06-24 TW TW103121657A patent/TWI535444B/zh not_active IP Right Cessation
-
2015
- 2015-06-24 US US14/749,091 patent/US9687499B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| US20150366892A1 (en) | 2015-12-24 |
| US9687499B2 (en) | 2017-06-27 |
| TW201600091A (zh) | 2016-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102224081B1 (ko) | 치환된 피롤리진 화합물 및 그의 용도 | |
| WO2020247665A1 (en) | Peptidomimetics for the treatment of coronavirus and picornavirus infections | |
| CA2856529C (en) | Compositions and methods for treating hepatitis c virus | |
| JP2020500862A5 (zh) | ||
| WO2014032481A1 (zh) | 一种替诺福韦前药及其在医药上的应用 | |
| CN109641868A (zh) | 流感病毒复制抑制剂及其使用方法和用途 | |
| TWI535444B (zh) | 熱休克蛋白抑制劑用於製備治療b型肝炎或肝癌之醫藥組合物的用途 | |
| JP5923167B2 (ja) | 抗ｂ型肝炎薬の調製のためのアンドログラホリドｃ１５位置換シリーズ誘導体の使用 | |
| JP2021028338A (ja) | テノホビルアラフェナミドの結晶形態 | |
| CN112675174A (zh) | 多聚adp核糖聚合酶抑制剂治疗乙肝病毒相关疾病的新用途 | |
| JP6843616B2 (ja) | アモルファステコビリマット調製 | |
| JP2016537432A5 (zh) | ||
| JP2008543735A (ja) | 抗腫瘍化合物及びその医薬組成物 | |
| JP2015526504A5 (zh) | ||
| WO2009154248A1 (ja) | Hbv感染症を治療または予防するための医薬組成物 | |
| JP2023550638A (ja) | ウイルス感染症の処置に使用するための、ｖｓｐ３４阻害剤としてのモルホリノ誘導体 | |
| JP7446587B2 (ja) | 抗ヒトノロウイルス剤 | |
| US6441009B1 (en) | Agent and method of preventing and treating heavy metal exposure and toxicity | |
| RU2662161C1 (ru) | Ингибитор входа вируса гепатита и фармацевтическая композиция для лечения гепатита | |
| CA3152450A1 (en) | Mek inhibitors for the treatment of hantavirus infections | |
| JP2011207764A (ja) | Ｃｄｋ阻害剤によるｃ型肝炎ウイルスの複製抑制 | |
| JPH06506929A (ja) | Ｂ型肝炎ウイルス感染の治療のための、１，３−オキサチオラン誘導体の使用 | |
| WO2019120071A1 (zh) | 用于抗病毒的新型核苷类逆转录酶抑制剂 | |
| JP2020509046A (ja) | シクロブチル（ｓ）−２−［［［（ｒ）−２−（６−アミノプリン−９−イル）−１−メチル−エトキシ］メチル−フェノキシ−ホスホリル］アミノ］−プロパノエート、ならびにそれを生産および使用する方法 | |
| US20130059812A1 (en) | Composition for treating chronic hepatitis b, containing clevudine and adefovir dipivoxil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |