JPH0920792A - Nucleotide dimer - Google Patents
Nucleotide dimerInfo
- Publication number
- JPH0920792A JPH0920792A JP7197113A JP19711395A JPH0920792A JP H0920792 A JPH0920792 A JP H0920792A JP 7197113 A JP7197113 A JP 7197113A JP 19711395 A JP19711395 A JP 19711395A JP H0920792 A JPH0920792 A JP H0920792A
- Authority
- JP
- Japan
- Prior art keywords
- azt
- formula
- compound
- hiv
- nucleotide dimer
- 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
- 125000003729 nucleotide group Chemical group 0.000 title claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims description 2
- 229940124411 anti-hiv antiviral agent Drugs 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 20
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 230000036436 anti-hiv Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 8
- 208000030507 AIDS Diseases 0.000 abstract description 7
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 abstract description 4
- -1 triethylamine salt Chemical class 0.000 abstract description 4
- HRBGUGQWTMBDTR-UHFFFAOYSA-N 2,3,4-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC=C(S(Cl)(=O)=O)C(C(C)C)=C1C(C)C HRBGUGQWTMBDTR-UHFFFAOYSA-N 0.000 abstract description 3
- 102100034343 Integrase Human genes 0.000 abstract description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 3
- 241000894007 species Species 0.000 abstract 6
- 230000002401 inhibitory effect Effects 0.000 abstract 2
- 230000001225 therapeutic effect Effects 0.000 abstract 2
- IWDFHWZHHOSSGR-UHFFFAOYSA-N 1-ethylimidazole Chemical compound CCN1C=CN=C1 IWDFHWZHHOSSGR-UHFFFAOYSA-N 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HHUZWDREJDTDKG-UHFFFAOYSA-N 5-ethyl-1-(2-phenylmethoxyethoxymethyl)-6-phenylsulfanylpyrimidine-2,4-dione Chemical compound C=1C=CC=CC=1COCCOCN1C(=O)NC(=O)C(CC)=C1SC1=CC=CC=C1 HHUZWDREJDTDKG-UHFFFAOYSA-N 0.000 description 4
- BIJQIBCCCCBNON-UHFFFAOYSA-N 6-(3,5-dimethylphenyl)sulfanyl-5-ethyl-1-(2-hydroxyethoxymethyl)pyrimidine-2,4-dione Chemical compound OCCOCN1C(=O)NC(=O)C(CC)=C1SC1=CC(C)=CC(C)=C1 BIJQIBCCCCBNON-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000007788 liquid Substances 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
- 238000000034 method Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- PVJZBZSCGJAWNG-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1 PVJZBZSCGJAWNG-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940124522 antiretrovirals Drugs 0.000 description 1
- 239000003903 antiretrovirus agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 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
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明は、抗HIV活性を有する
新規なヌクレオチドダイマー及びその用途に関するもの
である。FIELD OF THE INVENTION The present invention relates to a novel nucleotide dimer having anti-HIV activity and its use.
【0002】[0002]
【従来の技術】3’−アジド−3’−デオキシチミジン
(AZT)は優れた抗HIV活性を有し、エイズ治療剤
として広く使用されている。しかし、AZTは、治療有
効量と毒性発生量との差が少なく、重篤な副作用を有す
るという欠点があった。かかる観点から、AZTに代わ
りうる抗レトロウイルス剤の開発が活発に行なわれた結
果、AZT−P−DDIが優れた抗HIV作用を有し、
かつ安全性も高いことからエイズ治療剤として有用であ
ることが報告されている(特公平5−46358号公
報、米国特許第5187163号、AIDS RESEARCH AND
HUMAN RETROVIRUSES,4(6),449-455(1988)、ANTIMICROBIA
L AGENTS AND CHEMOTHERAPY,34(6),1061-1067(199
0))。2. Description of the Related Art 3'-Azido-3'-deoxythymidine (AZT) has excellent anti-HIV activity and is widely used as a therapeutic agent for AIDS. However, AZT has a drawback in that there is a small difference between the therapeutically effective dose and the toxicity-causing dose, and that it has serious side effects. From this point of view, as a result of active development of antiretroviral agents that can replace AZT, AZT-P-DDI has an excellent anti-HIV action,
It is also reported to be useful as a therapeutic agent for AIDS due to its high safety (Japanese Patent Publication No. 5-46358, US Pat. No. 5,187,163, AIDS RESEARCH AND
HUMAN RETROVIRUSES, 4 (6), 449-455 (1988), ANTIMICROBIA
L AGENTS AND CHEMOTHERAPY, 34 (6), 1061-1067 (199
0)).
【0003】[0003]
【発明が解決しようとする課題】しかしながら、後述の
試験例でも明らかなようにAZT−P−DDIはAZT
耐性株に対して必ずしも満足できる抗HIV活性を示さ
ないということが本発明者らの試験により明らかにされ
た。したがって、本発明は、この新しい知見に基づき、
AZT野生株はもとよりAZT耐性株さらには非核酸系
逆転写酵素阻害剤耐性株に対しても優れた抗HIV活性
を有する物質を得るという新規な課題を解決することを
主たる目的とするものである。However, as will be apparent from the test examples described later, AZT-P-DDI is not suitable for AZT.
Our tests revealed that they do not always show satisfactory anti-HIV activity against resistant strains. Therefore, the present invention is based on this new finding,
The main object is to solve the novel problem of obtaining a substance having an excellent anti-HIV activity not only for AZT wild-type strains but also for AZT-resistant strains as well as non-nucleic acid reverse transcriptase inhibitor-resistant strains. .
【0004】[0004]
【発明の開示】本発明者らは、上記目的を達成するため
鋭意検討を重ねた結果、下記式(I)で表される新規な
ヌクレオチドダイマーが、野生株はもとよりAZT耐性
株さらには非核酸系逆転写酵素阻害剤耐性株に対しても
優れた抗HIV活性を有することを見いだし、本発明を
完成させた。すなわち、本発明は、下記式(I)で表さ
れるヌクレオチドダイマーに関するものである。また、
本発明は、該ヌクレオチドダイマー(以下、本発明化合
物と称する。)を有効成分として含有する医薬組成物に
関するものである。DISCLOSURE OF THE INVENTION As a result of intensive studies to achieve the above object, the present inventors have found that a novel nucleotide dimer represented by the following formula (I) is found to be a wild strain, an AZT resistant strain, and a non-nucleic acid. The present invention was completed by discovering that it also has excellent anti-HIV activity against strains resistant to reverse transcriptase inhibitors. That is, the present invention relates to a nucleotide dimer represented by the following formula (I). Also,
The present invention relates to a pharmaceutical composition containing the nucleotide dimer (hereinafter referred to as the compound of the present invention) as an active ingredient.
【0005】[0005]
【化2】 (式中、R1〜R3は水素または低級アルキルを示す。)Embedded image (In the formula, R 1 to R 3 represent hydrogen or lower alkyl.)
【0006】以下、本発明を詳細に説明する。 (1)化合物 本発明化合物は上記式(I)で表されるものである。式
中、R1〜R3で表される低級アルキルとしては炭素数1
〜5程度のものを意味し、具体的にはメチル、エチル、
プロピルなどが例示される。また、R2およびR3の置換
位置は特に制限されるものではないが、活性の点からは
メタの位置が好ましい。このような本発明化合物の中で
好ましい化合物としては、例えば後述の実施例で合成さ
れた化合物などを例示することができる。また、本発明
化合物は塩の形態であってもよく、たとえば、ナトリウ
ム、カリウムなどアルカリ金属塩、カルシウム、マグネ
シウムなどのアルカリ土類金属塩などの各種金属塩を例
示することができる。Hereinafter, the present invention will be described in detail. (1) Compound The compound of the present invention is represented by the above formula (I). In the formula, the lower alkyl represented by R 1 to R 3 has 1 carbon atom.
~ 5, specifically, methyl, ethyl,
Examples include propyl and the like. The substitution position of R 2 and R 3 is not particularly limited, but the meta position is preferable from the viewpoint of activity. Examples of preferable compounds among the compounds of the present invention include compounds synthesized in Examples described later. Further, the compound of the present invention may be in the form of a salt, and examples thereof include various metal salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium.
【0007】(2)製造法 本発明化合物の反応経路をフローチャートで示せば、次
のとおりである。(2) Production Method The reaction route of the compound of the present invention is shown by a flow chart as follows.
【0008】[0008]
【化3】 Embedded image
【0009】最初の工程は、AZT−CEP・TEAと
下記式(II)で表されるHEPT誘導体(HEPT)
とを縮合剤を用いて反応させてAZT−CEP−HEP
Tを調製する工程である。なお、反応に使用するAZT
−CEP・TEAおよびHEPTは公知化合物であり、
常法により調製することができる(AIDS Research and
Human Retroviruses, 1988, 4, 449-455、 J.Med.Chem.,
1981,24,1177-1181、J.Med.Chem., 1981,24,1078-1083、
J.Med.Chem., 1991,34,349-357、J.Med.Chem.,1992,35,3
37-345、特公平7−51567号公報)。The first step is AZT-CEP.TEA and a HEPT derivative (HEPT) represented by the following formula (II).
Are reacted with a condensing agent to produce AZT-CEP-HEP
This is a step of preparing T. The AZT used in the reaction
-CEP-TEA and HEPT are known compounds,
It can be prepared by a conventional method (AIDS Research and
Human Retroviruses, 1988, 4, 449-455, J.Med.Chem.,
1981,24,1177-1181, J.Med.Chem., 1981,24,1078-1083,
J.Med.Chem., 1991,34,349-357, J.Med.Chem., 1992,35,3
37-345, Japanese Patent Publication No. 7-51567).
【0010】[0010]
【化4】 (式中、R1〜R3は水素または低級アルキルを示す。)Embedded image (In the formula, R 1 to R 3 represent hydrogen or lower alkyl.)
【0011】反応に使用する縮合剤としては、メシチル
スルホニルクロライド、トリイソプロピルベンゼンスル
ホニルクロライドなどの酸性触媒を例示することができ
る。縮合反応は、ピリジン、トリエチルアミンなどの塩
基性溶媒中、AZT−CEP・TEA 1モルに対し1
〜3倍モルのHEPT及び0.5〜2倍モルの縮合剤を
用い、10〜30℃で10〜50時間程度撹拌混合させ
ることにより実施することができる。また、反応液中に
1−メチルイミダゾールなどの酸受容体を添加すること
により、縮合反応を効率的に進行させることができる。
得られた反応液の溶媒を留去し、さらに必要により上記
と同様の吸着樹脂を用いたカラムクロマトグラフィ−処
理に付してAZT−CEP−HEPTを精製し、次の工
程に供する。Examples of the condensing agent used in the reaction include acidic catalysts such as mesityl sulfonyl chloride and triisopropylbenzene sulfonyl chloride. The condensation reaction is carried out in a basic solvent such as pyridine or triethylamine with 1 mol per 1 mol of AZT-CEP.TEA.
It can be carried out by using 3 to 3 times mol of HEPT and 0.5 to 2 times mol of the condensing agent and stirring and mixing at 10 to 30 ° C. for about 10 to 50 hours. Moreover, the condensation reaction can be efficiently progressed by adding an acid acceptor such as 1-methylimidazole to the reaction solution.
The solvent of the obtained reaction solution is distilled off, and if necessary, the same AZT-CEP-HEPT is purified by subjecting it to column chromatography using the same adsorption resin as described above, and then used in the next step.
【0012】次の工程は、AZT−CEP−HEPTと
アルカリとを反応させてシアノエチル基を除去し、本発
明化合物のAZT−P−HEPTを調製する工程であ
る。反応に使用するアルカリとしては、アンモニア、水
酸化ナトリウム、水酸化カリウム、水酸化カルシウムな
ど通常の塩基性触媒を使用することができる。反応は、
たとえばアルカリとして水酸化ナトリウムを使用する場
合には、水酸化ナトリウム水溶液に上記AZT−CEP
−HEPTを加え、20〜50℃で1〜20時間程度反
応させることによりAZT−P−HEPTのナトリウム
塩を得ることができる。The next step is a step of reacting AZT-CEP-HEPT with an alkali to remove the cyanoethyl group to prepare AZT-P-HEPT of the compound of the present invention. As the alkali used in the reaction, a usual basic catalyst such as ammonia, sodium hydroxide, potassium hydroxide or calcium hydroxide can be used. The reaction is
For example, when sodium hydroxide is used as the alkali, the above AZT-CEP is added to the sodium hydroxide aqueous solution.
The sodium salt of AZT-P-HEPT can be obtained by adding -HEPT and reacting at 20 to 50 ° C for about 1 to 20 hours.
【0013】かくして得られた本発明化合物は、後述の
試験例でも示されているように、野生株はもとよりAZ
T耐性株および非核酸系逆転写酵素阻害剤耐性株に対し
ても抗HIV活性を有し、医薬品として優れた特性を有
するものである。従って、本発明化合物を有効成分とし
て含有する医薬組成物は、RNAウイルス、特にHIV
などのレトロウイルスの感染の予防または治療に有用で
あり、ヒトのウイルスの感染の予防または治療のために
(特にエイズの治療のために)使用されうる。本発明化
合物の投与方法は経口、経腸、非経口、局所投与などの
いずれの投与経路であってもよく、投与量は、患者の年
齢、病態、体重などに応じ適宜決定されるが、通常は1
日当たり0.01〜1000mg/kg体重、好ましく
は1〜100mg/kg体重の範囲内から選ばれ、一回
または複数回に分けて投与される。The compound of the present invention thus obtained can be used not only in the wild strain but also in AZ, as shown in the test examples described below.
It also has anti-HIV activity against T-resistant strains and non-nucleic acid reverse transcriptase inhibitor-resistant strains, and has excellent properties as a drug. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient is an RNA virus, particularly HIV.
It is useful for the prevention or treatment of retroviral infections such as and may be used for the prevention or treatment of human viral infections, especially for the treatment of AIDS. The administration method of the compound of the present invention may be any of the administration routes such as oral, enteral, parenteral, and topical administration, and the dose is appropriately determined according to the age, pathological condition, body weight, etc. of the patient. Is 1
It is selected from the range of 0.01 to 1000 mg / kg body weight, preferably 1 to 100 mg / kg body weight per day, and is administered in one or multiple doses.
【0014】本発明の医薬組成物は、通常医薬に使用さ
れる賦形剤、その他の添加剤を含む組成物として使用す
るのが普通である。これらの例として、固体状のものと
しては、乳糖、カオリン、ショ糖、結晶セルロース、コ
ーンスターチ、タルク、寒天、ペクチン、ステアリン
酸、ステアリン酸マグネシウム、レシチン、塩化ナトリ
ウムなどが挙げられ、液体状のものとしてはグリセリ
ン、落花生油、ポリビニルピロリドン、オリーブ油、エ
タノール、ベンジルアルコール、プロピレングリコー
ル、水などが挙げられる。組成物の剤形としては任意の
形態を採ることができ、例えば錠剤、散剤、顆粒剤、カ
プセル化剤、坐剤、トローチ剤などの固形製剤、シロッ
プ、乳液、軟ゼラチンカプセル、クリーム、ゲル、ペー
スト、スプレー、注射などの液状製剤が挙げられる。The pharmaceutical composition of the present invention is usually used as a composition containing excipients and other additives usually used in medicine. As examples of these, solid ones include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride, etc., and liquid ones. Examples thereof include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water and the like. The composition may take any form, for example, tablets, powders, granules, capsules, suppositories, solid preparations such as troches, syrups, emulsions, soft gelatin capsules, creams, gels, Liquid preparations such as pastes, sprays and injections can be mentioned.
【0015】[0015]
【発明の効果】本発明化合物は、野生株はもとよりAZ
T耐性株および非核酸系逆転写酵素阻害耐性株に対して
優れた抗HIV活性を有し、抗HIV剤等の医薬品とし
て有用である。なお、本発明化合物は、耐性株の出現率
が現在の医薬品より低いと考えられる。INDUSTRIAL APPLICABILITY The compound of the present invention is used in AZ
It has excellent anti-HIV activity against T-resistant strains and non-nucleic acid reverse transcriptase inhibition resistant strains, and is useful as a drug such as an anti-HIV agent. The compound of the present invention is considered to have a lower incidence of resistant strains than the current pharmaceutical products.
【0016】[0016]
【実施例】次に実施例を挙げて本発明を詳細に説明する
が、本発明にはこれに何ら限定されるものではない。 合成例:AZT−P−(E−HEPU−dM)ナトリウ
ム塩〔式(I);R1=エチル、R2(3位)=メチル、
R3(5位)=メチル〕の調製EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto. Synthesis example: AZT-P- (E-HEPU-dM) sodium salt [Formula (I); R 1 = ethyl, R 2 (3-position) = methyl,
Preparation of R 3 (5-position) = methyl]
【0017】AZT−CEP・TEA0.5gのピリジ
ン溶液(10ml)にトリイソプロピルベンゼンスルホ
ニルクロライド605mgを加え、室温で30分間撹拌
し、1−メチルイミダゾール0.35mlを加え、室温
で30分間撹拌した後、E−HEPU−dM〔式(I
I);R1=エチル、R2(3位)=メチル、R3(5
位)=メチル〕350mgを加え、室温で1時間撹拌し
てAZT−CEP−(E−HEPU−dM)を合成し
た。反応液を水(50ml)及び酢酸エチル(50m
l)を用いて分配し、有機層を飽和食塩水(50mlx
2)で洗浄後、有機層を無水硫酸ナトリウムを用いて脱
水し、溶媒を乾固した。得られた残渣をシリカゲルカラ
ムクロマトグラフィー(溶出溶媒:クロロホルム)で精
製後、1N水酸化ナトリウム溶液(1.3ml)を加
え、40℃で2時間加熱反応させた。反応後、イソプロ
パノールを用いて結晶化した後、エタノールにより再結
晶化してAZT−P−(E−HEPU−dM)ナトリウ
ム塩(362mg,53.3%)を得た。After adding 605 mg of triisopropylbenzenesulfonyl chloride to a pyridine solution (10 ml) of 0.5 g of AZT-CEP.TEA and stirring at room temperature for 30 minutes, 0.35 ml of 1-methylimidazole was added and after stirring at room temperature for 30 minutes. , E-HEPU-dM [Formula (I
I); R 1 = ethyl, R 2 (3-position) = methyl, R 3 (5
Position) = methyl] 350 mg, and the mixture was stirred at room temperature for 1 hour to synthesize AZT-CEP- (E-HEPU-dM). The reaction solution was mixed with water (50 ml) and ethyl acetate (50 m).
l), and the organic layer was saturated brine (50 ml x
After washing in 2), the organic layer was dehydrated with anhydrous sodium sulfate and the solvent was evaporated to dryness. The obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform), 1N sodium hydroxide solution (1.3 ml) was added, and the mixture was heated at 40 ° C. for 2 hr. After the reaction, the product was crystallized with isopropanol and then recrystallized with ethanol to obtain AZT-P- (E-HEPU-dM) sodium salt (362 mg, 53.3%).
【0018】NMR(DMSO−d6):8.30
(s,1H,NH),7.76(s,1H,6H),
6.81(s,1H,フェニル−4),6.76(s,
2H,フェニル−2,6),6.14(t,1H,1’
−H),5.27(s,2H,NCH2O4),4.4
7(m,1H,3’−H),3.91(m,1H,4’
−H),3.80(m,2H,5’−H),3.78〜
3.52(m,4H,OCH2CH20),2.43
(m,3H,2’−H及び−CH2−),2.35
(m,1H,2’−H),2.20(s,6H,−CH
3×2),1.80(s,3H,−CH3),0.85
(t,3H,−CH3)NMR (DMSO-d 6 ): 8.30
(S, 1H, NH), 7.76 (s, 1H, 6H),
6.81 (s, 1H, phenyl-4), 6.76 (s,
2H, phenyl-2,6), 6.14 (t, 1H, 1 '
-H), 5.27 (s, 2H , NCH 2 O4), 4.4
7 (m, 1H, 3'-H), 3.91 (m, 1H, 4 '
-H), 3.80 (m, 2H, 5'-H), 3.78-.
3.52 (m, 4H, OCH 2 CH 2 0), 2.43
(M, 3H, 2'-H and -CH 2 -), 2.35
(M, 1H, 2'-H), 2.20 (s, 6H, -CH
3 × 2), 1.80 (s , 3H, -CH 3), 0.85
(T, 3H, -CH 3)
【0019】試験例:HIV感染の防止効果 10%牛胎児血清、100UのペニシリンGおよび10
0μg/mlのストレプトマイシンを含むRPMI 1
640培地中でMT−4細胞(HIVの感染を受けると
死滅する)1×104個に、細胞1個当り0.02個の
HIVを感染させ、直ちに本発明化合物を含む検体を所
定量添加し、37℃で培養した。培養後5日後に生存細
胞数をMTT法により測定し、MT−4細胞の細胞死を
50%防ぐのに要する化合物濃度(EC50)を求めた。
また、HIVを感染させずに上記と同様に培養し、MT
−4細胞の50%が死滅する化合物濃度(CC50)を求
めた。Test Example: Preventive effect against HIV infection 10% fetal bovine serum, 100 U penicillin G and 10
RPMI 1 containing 0 μg / ml streptomycin
1 × 10 4 MT-4 cells (which die when infected with HIV) in 640 medium are infected with 0.02 HIV per cell, and a predetermined amount of a sample containing the compound of the present invention is immediately added. And cultured at 37 ° C. After 5 days of culture, the number of surviving cells was measured by the MTT method to determine the compound concentration (EC 50 ) required to prevent 50% cell death of MT-4 cells.
In addition, the same culture as above was carried out without infection with HIV, and MT
The compound concentration at which 50% of -4 cells were killed (CC 50 ) was determined.
【0020】[0020]
【表1】表1 HTLV−IIIBは、野性型HIV−1を、HTLV
−IIIB/AZT及びHTLV−IIIB-Rは夫々AZT耐
性突然変異体及び非核酸系逆転写酵素阻害剤耐性突然変
異体を表わす。[Table 1] Table 1 HTLV-III B converts wild type HIV-1 into HTLV
-III B / AZT and HTLV-III BR represent AZT resistant mutants and non-nucleic acid reverse transcriptase inhibitor resistant mutants, respectively.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 馬 場 昌 範 鹿児島県鹿児島市西陵7−10−16 (72)発明者 藤 原 将 寿 福島県福島市蓬莱町3−4−16 (72)発明者 横 田 智 之 福島県福島市飯坂町平野字北下里20−1 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masanori Baba 7-10-16 Nishiryo, Kagoshima City, Kagoshima Prefecture (72) Inventor Masatoshi Fujiwara 3-4-16 Horai Town, Fukushima City, Fukushima Prefecture (72) Invention Tomoyuki Yokota 20-1 Kitashitasato, Hirano, Iizaka-cho, Fukushima-shi, Fukushima Prefecture
Claims (6)
マー。 【化1】 (式中、R1〜R3は水素または低級アルキルを示す。)1. A nucleotide dimer represented by the formula (I). Embedded image (In the formula, R 1 to R 3 represent hydrogen or lower alkyl.)
ある、請求項1記載のヌクレオチドダイマー。2. The nucleotide dimer according to claim 1, wherein R 1 is ethyl and R 2 and R 3 are methyl.
オチドダイマー。3. The nucleotide dimer according to claim 1, which is in the form of a salt.
を有効成分として含有する医薬組成物。4. A pharmaceutical composition containing the nucleotide dimer according to claim 1 as an active ingredient.
組成物。5. The pharmaceutical composition according to claim 4, which is an anti-HIV agent.
薬組成物。6. The pharmaceutical composition according to claim 4, which is an oral dosage form.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7197113A JPH0920792A (en) | 1995-07-11 | 1995-07-11 | Nucleotide dimer |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7197113A JPH0920792A (en) | 1995-07-11 | 1995-07-11 | Nucleotide dimer |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0920792A true JPH0920792A (en) | 1997-01-21 |
Family
ID=16368953
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7197113A Pending JPH0920792A (en) | 1995-07-11 | 1995-07-11 | Nucleotide dimer |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0920792A (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004112838A3 (en) * | 2003-05-21 | 2005-04-07 | Control Delivery Sys Inc | Codrugs of diclofenac |
WO2006013203A3 (en) * | 2004-08-03 | 2006-07-27 | Protera S R L | Prodrugs activated by rna-dependent dna-polymerases |
US8119800B2 (en) | 2007-12-21 | 2012-02-21 | Korea Research Institute Of Chemical Technology | Processes for preparing HIV reverse transcriptase inhibitors |
US8334295B2 (en) | 2007-06-29 | 2012-12-18 | Korea Research Institute Of Chemical Technology | Pyrimidine derivatives as HIV reverse transcriptase inhibitors |
US8354421B2 (en) | 2007-06-29 | 2013-01-15 | Korea Research Insitute Of Chemical Technology | HIV reverse transcriptase inhibitors |
-
1995
- 1995-07-11 JP JP7197113A patent/JPH0920792A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004112838A3 (en) * | 2003-05-21 | 2005-04-07 | Control Delivery Sys Inc | Codrugs of diclofenac |
WO2006013203A3 (en) * | 2004-08-03 | 2006-07-27 | Protera S R L | Prodrugs activated by rna-dependent dna-polymerases |
JP2008509110A (en) * | 2004-08-03 | 2008-03-27 | プロテラ ソシエタ ア レスポンサビリタ リミタータ | Prodrug activated by RNA-dependent DNA polymerase |
US8334295B2 (en) | 2007-06-29 | 2012-12-18 | Korea Research Institute Of Chemical Technology | Pyrimidine derivatives as HIV reverse transcriptase inhibitors |
US8354421B2 (en) | 2007-06-29 | 2013-01-15 | Korea Research Insitute Of Chemical Technology | HIV reverse transcriptase inhibitors |
US8119800B2 (en) | 2007-12-21 | 2012-02-21 | Korea Research Institute Of Chemical Technology | Processes for preparing HIV reverse transcriptase inhibitors |
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