CN1660833A - Compound containing structure of o-naphthaquinone and application - Google Patents
Compound containing structure of o-naphthaquinone and application Download PDFInfo
- Publication number
- CN1660833A CN1660833A CN 200410077778 CN200410077778A CN1660833A CN 1660833 A CN1660833 A CN 1660833A CN 200410077778 CN200410077778 CN 200410077778 CN 200410077778 A CN200410077778 A CN 200410077778A CN 1660833 A CN1660833 A CN 1660833A
- Authority
- CN
- China
- Prior art keywords
- pyrans
- dihydro
- diketone
- group
- methyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 46
- 206010020575 Hyperammonaemia Diseases 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 19
- -1 substituted-phenyl Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 208000014644 Brain disease Diseases 0.000 claims description 10
- 208000032274 Encephalopathy Diseases 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 7
- 208000007386 hepatic encephalopathy Diseases 0.000 abstract description 6
- 238000005457 optimization Methods 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 84
- 229910021529 ammonia Inorganic materials 0.000 description 42
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 19
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- 238000006243 chemical reaction Methods 0.000 description 18
- 241000700159 Rattus Species 0.000 description 16
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 14
- 239000002994 raw material Substances 0.000 description 14
- GVKKJJOMQCNPGB-JTQLQIEISA-N Cryptotanshinone Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1[C@@H](C)CO2 GVKKJJOMQCNPGB-JTQLQIEISA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
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- 239000008280 blood Substances 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
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- 230000000694 effects Effects 0.000 description 10
- 235000019257 ammonium acetate Nutrition 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
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- 239000000047 product Substances 0.000 description 8
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- 238000003756 stirring Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical class C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 7
- GVKKJJOMQCNPGB-UHFFFAOYSA-N Cryptotanshinone Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)CO2 GVKKJJOMQCNPGB-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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- 241001465754 Metazoa Species 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
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- 238000005406 washing Methods 0.000 description 6
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 5
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 5
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 5
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- 208000019425 cirrhosis of liver Diseases 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 208000019423 liver disease Diseases 0.000 description 4
- 150000002791 naphthoquinones Chemical class 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007787 solid Substances 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
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 2
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 2
- RJTJVVYSTUQWNI-UHFFFAOYSA-N 2-ethylnaphthalene Chemical compound C1=CC=CC2=CC(CC)=CC=C21 RJTJVVYSTUQWNI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000028399 Critical Illness Diseases 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 125000006278 bromobenzyl group Chemical group 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- SXTLQDJHRPXDSB-UHFFFAOYSA-N copper;dinitrate;trihydrate Chemical compound O.O.O.[Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O SXTLQDJHRPXDSB-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
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- 235000019439 ethyl acetate Nutrition 0.000 description 2
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- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
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- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 2
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- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- HARGZZNYNSYSGJ-UHFFFAOYSA-N 1,2 dihydrotanshinquinone Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)CO1 HARGZZNYNSYSGJ-UHFFFAOYSA-N 0.000 description 1
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- HARGZZNYNSYSGJ-JTQLQIEISA-N Dihydrotanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2[C@@H](C)CO1 HARGZZNYNSYSGJ-JTQLQIEISA-N 0.000 description 1
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- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
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- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000028547 Inborn Urea Cycle disease Diseases 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- JFLIEFSWGNOPJJ-JTQLQIEISA-N N(2)-phenylacetyl-L-glutamine Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CC1=CC=CC=C1 JFLIEFSWGNOPJJ-JTQLQIEISA-N 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 229930183118 Tanshinone Natural products 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
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- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
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- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
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- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- LCQLHJZYVOQKHU-VKHMYHEASA-N carglumic acid Chemical compound NC(=O)N[C@H](C(O)=O)CCC(O)=O LCQLHJZYVOQKHU-VKHMYHEASA-N 0.000 description 1
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
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- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
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- 229950006768 phenylethanolamine Drugs 0.000 description 1
- 150000007925 phenylethylamine derivatives Chemical class 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound containing o-naphthalene quinone structure for preparing medicines to prevent and treat hyperammonemia and hepatic encephalopathy is prepared from natural Masonate F through structure reformation and optimization.
Description
Technical field
The present invention relates to the medical compounds field, relate to a kind of medical compounds and its production and application specifically.
Background technology
Hepatogenic encephalopathy (Hepatic encephalopathy is called for short HE) is mainly by due to serious imbalance of liver function or the obstacle, with the metabolism disorder is central nervous system function imbalance syndromes (pathology, Li Yulin chief editor, the People's Health Publisher of principal character, 2000, p340-350).Slight HE also claims patients with subclinical hepatic encephalopathy, and patient's major part there is no the disturbance of consciousness, and work and life and ordinary person are as good as, and feel good substantially, owing to lack clinical symptom, ignored by the people easily, even the oneself also can not perceive.But in study, operation is understood, ability and sleeps such as strain, and all there is deficiency in the quality of life aspect.If be engaged in some meticulous work break such as driving, working aloft, building, diving, very likely bring inestimable consequence (Wang Mingyu, Chinese hepatopathy magazine, 2004,12 (5), 305-306).
Although its pathogenesis complexity of hepatogenic encephalopathy has the ammonia poisoning theory, ammonia, mercaptan, the collaborative toxicity theory of short chain fatty acid, false neurotrasmitter theory, amino acid metabolism is unbalance, neurobiology theory, (Yao Xixian etc. such as receptor theory, the anxious critical illness magazine of internal medicine, 1998,4 (1), 28), but the depletion of liver function, ammonia and multiple poisonous substance exist with collaborative, in the generation of hepatogenic encephalopathy, occupy critical role in the development.During liver failure, liver goes down the ability of ammonia synthesis urea, the existence of door body shunting, make enteron aisle ammonia directly enter the body circulation without the liver detoxifcation, blood ammonia is increased, ammonia sees through hemato encephalic barrier and enters cerebral tissue, in addition, liver is to the removing generation obstacle of die aromatischen Aminosaeuren during liver failure, aromatic amino acid as: phenylalanine forms Phenylethanolamine through decarboxylase and B-hydroxylase effect in brain, similar to the normal neurotransmitter norepinephrine on chemical structure, but the agonism of itself is very weak, replace normal neurotransmitter in the cynapse, make nerve conduction generation obstacle, thereby cause cerebral disorder.Therefore remove ammonia unnecessary in the body and phenylethylamine class to hepatogenic encephalopathy patient significant (Yao Xixian etc., the anxious critical illness magazine of internal medicine, 1998,4 (1), 28).
Hyperammonemia generally is because urea cycle disorder in the body, causes vivo acid decomposes and produce ammonia and by the ammonia of intestinal absorption, urea synthesis excretes smoothly, causes free ammonia to be accumulated in vivo, forms hyperammonemia.The overwhelming majority causes by hepatic disorder, also has part to be because the factor of genetic aspect, causes the defective of certain enzyme of ornithine cycle process.Excess of ammonia has neurotoxicity, shows as serious disordered brain function clinically.Hyperammonemia during the ornithine cycle defective often needs long-term treatment.As: give low protein diet, serious can do dialysis, can also set up metabolic bypass with medicine in addition, to discharge too much ammonia in the body.The available medicine has (1) Sodium Benzoate, can combine with glycine, forms urobenzoic acid, and is very fast by the urine discharge.(2) sodium phenylacetate can be combined into phenylacetylglutamine with glutamine, and is very fast by the urine discharge.(3) arginine is the substrate of ornithine cycle, the discharge that can urge nitrogen product (ammonia).(4) carbamylglutamic acid can provide N-acetylglutamat, with the required carbamyl phosphate synthetase (CPS) of the activation ornithine cycle the first step (Liu Houyu etc., gastroenterology, 2003,8 (1), 61-62).But these medicines or need the participation of body endoenzyme, or only act on intermediate product, be not to directly act on intravital ammonia, so curative effect is satisfied inadequately.
The hepatogenic encephalopathy that causes for hyperammonemia and by hyperammonemia and the methods of treatment of patients with subclinical hepatic encephalopathy are desirable not enough at present, and existing clinical medicine is a Sodium Glutamate; Using the enema therapy of medicines such as dilute acetic acid, lactulose, also only is to make by enteron aisle to produce and the ammonia that absorbs reduces, and the ammonia that generates for internal metabolism is then often powerless.Operation and dialysis meeting bring very big misery to patient.Pharmacological agent often only can be at a kind of enzyme or the substrate in the ornithine cycle process, so curative effect is limited.These therapeutic processes need the participation of body endoenzyme simultaneously, and exactly the hyperammonemia patient often merges serious liver dysfunction, therefore influence result of treatment.Ideal pharmacological agent should excrete the interior too much ammonia of body for setting up non-enzymatic metabolic bypass as early as possible.This research department once used Cryptotanshinone, and dihydrotanshinone I is used for anti-hyperammonemia and the hepatogenic encephalopathy that caused by hyperammonemia and the treatment of patients with subclinical hepatic encephalopathy, and has applied for patent (PCT/CN01/00861), but its action effect also is not very satisfactory.
Summary of the invention
The objective of the invention is to overcome the problem that exists in existing hyperammonemia and the hepatogenic encephalopathy treatment, a kind of compound that contains o-naphthaquinone is provided.
Another object of the present invention is to provide the above-mentioned application of compound in preparation treatment hyperammonemia and hepatogenic encephalopathy medicine that contains o-naphthaquinone.
The compound that contains o-naphthaquinone of the present invention, its structure is shown in (I) formula:
In the formula (I), R
1Be C
2-C
6Alkyl, C
1-C
6Alkoxyl group, n=1-2-(CH2) the nAr base ,-F ,-Cl ,-Br or-I,
R
2For H ,-OH or-OCOR, wherein R is C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) nAr base,
R
3Be H, C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) nAr base,
R
4Be H, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
Or:
R
1Be H or CH
3,
R
2For H ,-OH or-OCOR, wherein R is C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) n Ar base,
R
3Be C
6-C
10Aryl or n=1-2-(CH2) n Ar base,
R
4Be H, C
1-C
6Alkyl or C
1-C
6Alkoxyl group.
R in the above-mentioned compound that contains o-naphthaquinone, formula (I)
1For-F ,-Cl ,-Br or-I;
R
2For H ,-OH or-OCOR, wherein R is C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) n Ar base;
R
3Be H, C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) nAr base;
R
4Be H, C
1-C
6Alkyl or C
1-C
6Alkoxyl group.
The above-mentioned compound that contains o-naphthaquinone, wherein R
1For-Cl or-Br; R
2For H ,-OH or C
1-C
6Ester group; R
3Be H, C
1-C
3Alkyl, allyl group, phenyl or substituted-phenyl; R
4Be H or C
1-C
3Alkyl.
The above-mentioned compound that contains o-naphthaquinone, wherein R
1For-Cl or-Br; R
2For H ,-OH, ethyl ester or phenyl ester; R
3Be H, methyl, allyl group or phenyl; R
4Be H or methyl.
The above-mentioned compound that contains o-naphthaquinone, its preferred compound are 3-methyl-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone, 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone, 3-allyl group-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone, 3-allyl group-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone, 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone.
The present invention also provides the preparation method of the adjacent naphthoquinone compound shown in the formula (I), mainly is to be undertaken by following reaction formula 1-4:
Reaction formula 1:R
1The preparation of this compounds that replaces for halogen and H
Reaction formula 1 has been narrated R in the formula (I)
1The preparation of this compounds that replaces for halogen and H.R in the formula
3, R
4Definition cotype (I).Starting material compound [1] can reference Suh Young-Ger, et al.chem..commun., 2000,1203-1204 and Pearson, D.E., et al., J.Org.Chem., 1967,32 (7), 2358-2360 preparation.
Reaction formula 2:
The compound of formula [6] is easy to and acyl chlorides or anhydride reaction, high yield obtain compound [7].
Reaction formula 3:
With different 2, the two naphthoquinones that replace of 5-are that raw material is (with reference to ancient power etc., organic chemistry, 1991,11, the 481-487 of practicing; ), the method of reference (Ruth L.Nunes, Lothar W.Bieber, Richar L.Longo, J.Nat.Prod., 1999,62,1643-1645) make and have different 2, the disubstituted compound of 5-[8], obtain [9] by the Pd-C/H2 catalytic hydrogenation again, obtain compound [10], the R in the formula through the tin anhydride oxidation again
1, R
3, R
4Definition cotype (I).
Reaction formula 4:
Different with reaction formula 1 is, when compound [2] carries out nitration reaction, will extend to 1 hour the reaction times, and nitrated product is [11] rather than [3], also will cause the difference of final product simultaneously.
Beneficial effect of the present invention: o-naphthaquinone compound and the patent drug Cryptotanshinone of containing of the present invention is similar falling aspect the mechanism of action of blood ammonia, mainly is to remove intravital blood ammonia and phenylethylamine by setting up non-enzymatic metabolic bypass.But aspect action effect, the o-naphthaquinone compound that contains of the present invention is under same dosage, and its speed of action and action effect are better than the patent drug Cryptotanshinone.
Compare with existing clinical medicine Sodium Glutamate, the compound that contains o-naphthaquinone of the present invention is no matter be at the hyperammonemia animal model, still at acute rats with liver cirrhosis hyperammonemia model, its contrast experiment shows that all action effect is better than Sodium Glutamate, and using dosage is littler.The compound that contains o-naphthaquinone of the present invention does not in addition need the participation of body endoenzyme when removing blood ammonia and phenylethylamine, so whether irrelevant its effect and liver function of removing blood ammonia and phenylethylamine be normally.And Sodium Glutamate needs the participation of enzyme when reducing blood ammonia, and often with to a certain degree liver dysfunction, this just greatly reduces the result of use and the range of application of Sodium Glutamate to the hyperammonemia patient.The compound that contains o-naphthaquinone of the present invention just in time can remedy this shortcoming.
Simultaneously, a large amount of toxicological experiment shows that the compound that contains o-naphthaquinone of the present invention is safe as drug use under normal dose.
Embodiment
Embodiment 1
3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the preparation of 8-diketone:
Compound 9-chloronaphthalene also [1,8-b, c] pyrans-3 (2H)-ketone 7g is dissolved in the 200ml anhydrous diethyl ether, and the anhydrous ether solution 70ml of previously prepared Grignard reagent MeMgI (100-150mmol) is put in the dropping funnel, added in 1.5-2 hour under the water-bath, stirring at room 30 minutes, reaction solution is poured in the 250ml frozen water solution into chloroform extraction, washing, anhydrous sodium sulfate drying, concentrate red-brown thick liquid 6.4g.With this product 6.4g, be dissolved in aceticanhydride 80-100ml, add nitrate trihydrate copper 8.5g rapidly, stirring at room 15 minutes adds termination reaction in the frozen water, uses ether extraction, the aqueous sodium carbonate washing, washing again, anhydrous sodium sulfate drying, concentrate silica gel column layer separation and purification, chloroform wash-out, get 4.2g product 9-chloro-7-nitro-3-methyl-2, and the 3-dihydro-naphtho [1,8-b, c] pyrans-3-alcohol, be the orange thick liquid.
Compound 9-chloro-7-nitro-3-methyl-2, and the 3-dihydro-naphtho [1,8-b, c] pyrans-3-alcohol 0.5g, be dissolved in the 20ml ethanol, add ammonium formiate (1.1g, 17.8mmol), 10%Pd-C 0.1-0.2g, stirring at room reaction 15-20 minute is filtered, concentrated filtrate, add acetone 50ml, after stirring was molten entirely, (1.86g was dissolved in the NaH of 250ml0.06M to add Fremy ' the s solution for preparing in advance
2PO
4), behind the 30min, chloroform extraction, washing, anhydrous sodium sulfate drying concentrates the silica gel column layer separation and purification of gained crude product, sherwood oil: ethyl acetate=1: 1 wash-out gets orange solid 3-methyl-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone 0.30g.
In embodiment 1, replace methyl iodide with following different haloalkane and prepare Grignard reagent:
1, N-PROPYLE BROMIDE
2, bromohexane
3, bromobenzene
4, bromobenzyl
5, P-Bromofluorobenzene
6, to the methyl bromobenzene
Adopt identical with embodiment 1 method, can synthesize corresponding compound:
1,3-propyl group-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
2,3-hexyl-3-hydroxy-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
3,3-phenyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
4,3-benzyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
5,3-(the fluorine-based phenyl of 4-)-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
6,3-(4-aminomethyl phenyl)-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
With different 6-replacement-9-chloronaphthalenes also [1,8-b, c] pyrans-3 (2H)-ketone be raw material, adopt the method identical to obtain with embodiment 1:
1,3,6-dimethyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone
2,3-methyl-6-propyl group-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
3,3-methyl-6-hexyl-3-hydroxy-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
4,3-methyl-6-methoxyl group-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
5,3-methyl-6-propoxy--3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
6,3-methyl-6-hexyloxy-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
Replace methyl iodide with chlorallylene and prepare Grignard reagent, adopt Na in one step of reduction
2S
2O
4For adopting the method identical with embodiment 1, reductive agent makes:
3-allyl group-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
Embodiment 2
3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the preparation of 8-diketone:
Adopt the 9-bromonaphthalene also [1,8-b, c] pyrans-3 (2H)-ketone be raw material, adopt the method identical, just at reduction one step employing Na with embodiment 1
2S
2O
4Be reductive agent, can obtain also [1,8-b, c] pyrans-7 of 3-methyl-9-bromonaphthalene, the 8-diketone.
Employing 9-bromonaphthalene also [1,8-b, c] pyrans-3 (2H)-ketone is raw material and different Grignard reagent reactions, adopts the method identical with embodiment 1 and 2 to obtain:
1,3-propyl group-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
2,3-hexyl-3-hydroxy-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
3,3-allyl group-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
Embodiment 3
3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the preparation of 8-diketone:
With compound 9-chloronaphthalene also [1,8-b, c] pyrans-3 (2H)-ketone is raw material, adopt the method similar, 9-chloro-3-methyl-2 just, 3-dihydro-naphtho [1 with embodiment 1,8-b, c] pyrans-3-alcohol extends to 1 hour with aceticanhydride, the reaction times in a nitrated step of nitrate trihydrate copper, obtains 9-chloro-7-nitro-3-methyl-2,3-dihydro-naphtho [1,8-b, c] pyrans-3-alcohol acetic ester, other is operated with embodiment 1, obtain at last orange solid 3-methyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone.
Can also obtain with method:
3-propyl group-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
3-benzyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
Embodiment 4
3-methyl-9-chloro-3-acetoxyl group-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the preparation of 8-diketone
Compound 3-methyl-3-hydroxyl-9-chloro-2 by embodiment 1 gained; 3-dihydro-naphtho [1; 8-b; c] pyrans-7,8-diketone 0.5g is dissolved in THF20ml; add Acetyl Chloride 98Min. 0.3g and triethylamine 0.5ml; stirring at room 2-3 hour, concentrate, add big water gaging and stirred 15 minutes; chloroform extraction; the washing of 5% dilute hydrochloric acid, washing again, the separation and purification of post layer obtains yellow solid 3-methyl-9-chloro-3-acetoxyl group-2; 3 dihydro-naphthos [1; 8-b, c] pyrans-7,8-diketone 0.42g replaces Acetyl Chloride 98Min. with following acylating agent respectively:
1, butyryl chloride
2, hexamethylene acyl chlorides
3, Benzoyl chloride
4, phenyllacetyl chloride
5, acrylate chloride
6,3-methyl-2-butene acyl chlorides
Can obtain by embodiment 4 same preparation methods:
1,3-methyl-9-chloro-3-butyryl acyloxy-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone
2,3-methyl-9-chloro-3-cyclohexanecarbonyl oxygen base-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone
3,3-methyl-9-chloro-3-benzoyloxy-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone
4,3-methyl-9-chloro-3-phenylacetyl oxygen base-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone
5,3-methyl-9-chloro-3-acryloxy-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone
6,3-methyl-9-chloro-3-(3-methyl-2-butene acyloxy)-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone
Embodiment 5
3-phenyl-3-hydroxyl-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the preparation of 8-diketone:
The reaction times in one step of reduction among the embodiment 1 is extended to 1-2 hour, and other are operated with embodiment 1, can obtain 3-phenyl-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone.Adopting following different halides is raw material:
1, bromobenzyl
2, P-Bromofluorobenzene
3, to the methyl bromobenzene
Can obtain:
1,3-benzyl-3-hydroxyl-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone,
2,3-(the fluorine-based phenyl of 4-)-3-hydroxyl-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone,
3,3-(4-aminomethyl phenyl)-3-hydroxyl-2,3 dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone
Embodiment 6
3-methyl-9-ethyl-2,3-dihydro-naphtho [1,8-b, c] pyrans-7, the preparation of 8-diketone:
With the 2-ethylnaphthalene quinone is raw material, the method Ruth L.Nunes of reference, Lothar W.Bieber, Richar L.Longo, J.Nat.Prod., 1999,62,1643-1645 makes 9-ethyl-3-methyl benzo [de] pyrans-7-alcohol 4g and is dissolved among the ethanol 100ml, adds 10%Pd-C 1g, and 50 ℃ are descended logical hydrogen hydrogenation 24 hours, filter, filtrate concentrates, and gets product 9-ethyl-3-methyl-2, and 3-dihydrobenzo [de] is than muttering-7-alcohol 3.2g, this product is dissolved in chloroform 70ml, add tin anhydride 7.2g, stirring at room reaction 6 hours, suction filtration, concentrate, the gained crude product is with silica gel column chromatography separating purification, and the chloroform wash-out gets 0.8g atropurpureus solid 3-methyl-9-ethyl-2,3-dihydro-naphtho [1,8-b, c] pyrans-7, the 8-diketone.
Replacing naphthoquinones with following different 2-is raw material:
1,2-propyl group-1, the 4-naphthoquinones
2,2-cyclohexyl-1, the 4-naphthoquinones
3,2-benzyl-1, the 4-naphthoquinones
4, the 2-tertiary butyl-1, the 4-naphthoquinones
5,2-methoxyl group-1, the 4-naphthoquinones
6,2-propoxy--1, the 4-naphthoquinones
7,2-hexyloxy-1, the 4-naphthoquinones
Adopt identical with embodiment 6 method, can synthesize corresponding compound:
1,3-methyl-9-propyl group-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
2,3-methyl-9-cyclohexyl-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
3,3-methyl-9-benzyl-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
4,3-methyl-9-tertiary butyl-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
5,3-methyl-9-methoxyl group-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
6,3-methyl-9-propoxy--2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
7,3-methyl-9-hexyloxy-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone
Embodiment 7
Adjacent naphthoquinone compound is in external and reaction ammonia:
Get respectively by embodiment 1-embodiment 6 prepared each 0.5mmol of compound and put in the test tube, add 2ml ethanol, after jolting is molten entirely, add 1mmol ammoniacal liquor, room temperature jolting 30 minutes, silica gel thin-layer detects, and the raw material quinone all disappears.Show that above compound can react rapidly with ammonia external, reduces the concentration of ammonia fast.
Adjacent naphthoquinone compound is in external and reaction phenylethylamine:
Get respectively by embodiment 1-embodiment 6 prepared each 0.5mmol of compound and put in the test tube, add 2ml ethanol, after jolting is molten entirely, add the 1mmol phenylethylamine, room temperature jolting 30 minutes, silica gel thin-layer detects, and the raw material quinone all disappears.Show that above compound can react rapidly with phenylethylamine external, reduces the concentration of phenylethylamine fast.
Cryptotanshinone is in external and effect ammonia
Get each 0.5mmol of Cryptotanshinone and put in the test tube, add 2ml ethanol, after jolting is molten entirely, add 1mmol ammoniacal liquor, room temperature jolting 30 minutes, silica gel thin-layer detects, and raw material changes not obvious, has only low amounts of product to generate, stirring at room 12 hours, raw material disappears substantially.Show above compound at external energy and ammonia react, but speed is slow.
Cryptotanshinone is in external and effect phenylethylamine
Get Cryptotanshinone 0.5mmol and put in the test tube, add 2ml ethanol, after jolting is molten entirely, add the 1mmol phenylethylamine, room temperature jolting 30 minutes, silica gel thin-layer detects, and raw material changes not obvious, has only low amounts of product to generate, stirring at room 6 hours, raw material disappears substantially.Show above compound at external energy and ammonia react, but speed is slow.
Above-mentioned chemical reaction test confirms, the compound that contains o-naphthaquinone of the present invention at normal temperatures can be promptly and fat primary amine reactions such as ammonia, methylamine, ethamine and phenylethylamine, i.e. reaction finishes in the several minutes, its speed of response will be far away faster than tanshinone compound, point out this compounds that the hepatogenic encephalopathy and the patients with subclinical hepatic encephalopathy of preventing and treating the hyperammonemia that is caused by chronic hepatitis and liver cirrhosis, comprising to be caused by hyperammonemia had unique therapeutic action.
Embodiment 8
Adjacent naphthoquinone compound the active experimentation on animals (injection) of blood ammonia falls
Animal for research is that healthy male SD is 90 of rats, and body weight is 250-300g.Be divided into 9 groups at random, as shown in table 1.Except that the normal control group, by the physiological saline or the medicine (containing low quantity of surfactant) of dosage shown in the abdominal injection table, behind the administration 45min, except that the normal control group, all the other respectively organize the ammonium acetate of abdominal injection 5.5mmol/kg, continuous four days respectively.The 4th day 30min behind the injection Spirit of Mindererus, each is organized rat and plucks eye immediately and get blood, use the EDTA-Na anti-freezing, uses ordinary method mensuration ammonia concentration.The results are shown in Table 1.The dosage of the Sodium Glutamate among present embodiment and the following embodiment is with reference to the clinical practice dosage of this medicine and definite.Ammonia concentration measuring method among present embodiment and the following embodiment adopts enzyme-UV method, uses instrument to be the HITACHI-7071 automatic analyser, and the test kit that uses is AMMONIA.
Table 1
| Group | Dosage (mg/kg) | Ammonia concentration (μ mol/L) | Reduced rate (%) |
| The normal control group | ???- | ????125 | ????- |
| The physiological saline group | ????- | ????900 | ????- |
| The Sodium Glutamate group | ????410 | ????495 | ????53 |
| The Cryptotanshinone group | ????10 | ????440 | ????59 |
| 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????250 | ????84 |
| 3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????235 | ????86 |
| 3-allyl group-3-hydroxyl-9-bromo-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????260 | ????83 |
| 3-allyl group-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????235 | ????86 |
| 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????240 | ????85 |
By same experiment condition, the 4th day 90min behind the injection Spirit of Mindererus, each is organized rat and plucks eye immediately and get blood, measures ammonia concentration.Gained the results are shown in Table 2.
Table 2
| Group | Dosage (mg/kg) | Ammonia concentration (μ mol/L) | Reduced rate (%) |
| The normal control group | ????- | ????125 | ??- |
| The physiological saline group | ????- | ????315 | ??- |
| The Sodium Glutamate group | ????410 | ????135 | ??95 |
| The Cryptotanshinone group | ????10 | ????125 | ??100 |
| 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????125 | ??100 |
| 3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????120 | ??100 |
| 3-allyl group-3-hydroxyl-9-bromo-2, the 3-dihydro-naphtho | ????10 | ????120 | ??100 |
| [1,8-b, c] pyrans-7,8-diketone group | |||
| 3-allyl group-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????110 | ????100 |
| 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????120 | ????100 |
Embodiment 9
Adjacent naphthoquinone compound the active experimentation on animals (oral) of blood ammonia falls
Press embodiment 8 experiment conditions, different is that the Sodium Glutamate injection changes oral glutamic acid tablet into, and other various medicines all change oral administration into, and dosage is as shown in table 3.The 4th day 30min behind the injection Spirit of Mindererus, each is organized rat and plucks eye immediately and get blood, uses ordinary method and measures ammonia concentration.The results are shown in Table 3.
Table 3
| Group | Dosage (mg/kg) | Ammonia concentration (μ mol/L) | Reduced rate (%) |
| The normal control group | ????- | ????125 | ????- |
| The physiological saline group | ????- | ????900 | ????- |
| The Sodium Glutamate group | ????200 | ????530 | ????48 |
| The Cryptotanshinone group | ????100 | ????460 | ????57 |
| 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????310 | ????76 |
| 3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????275 | ????81 |
| 3-allyl group-3-hydroxyl-9-bromo-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????285 | ????79 |
| 3-allyl group-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????260 | ????83 |
| 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????270 | ????81 |
By same experiment condition, the 4th day 90min behind the injection Spirit of Mindererus, each is organized rat and plucks eye immediately and get blood, measures ammonia concentration.Gained the results are shown in Table 4.
Table 4
| Group | Dosage (mg/kg) | Ammonia concentration (μ mol/L) | Reduced rate (%) |
| The normal control group | ????- | ????125 | ????- |
| The physiological saline group | ????- | ????315 | ????- |
| The Sodium Glutamate group | ????200 | ????140 | ????92 |
| The Cryptotanshinone group | ????100 | ????130 | ????97 |
| 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????125 | ????100 |
| 3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????120 | ????100 |
| 3-allyl group-3-hydroxyl-9-bromo-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????125 | ????100 |
| 3-allyl group-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????115 | ????100 |
| 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????125 | ????100 |
Embodiment 10
Adjacent naphthoquinone compound causes stupor and dead influence (injection) to acute rats with liver cirrhosis hyperammonemia:
Animal for research is that healthy male SD is 90 of rats, and body weight is 250-300g.Be divided into 9 groups at random, as shown in table 5.Except that the normal control group, by the physiological saline or the medicine (containing low quantity of surfactant) of dosage shown in the abdominal injection table 5, behind the administration 45min, abdominal injection contains 0.1% tetracol phenixin peanut oil solution (dosage is 10mg/kg), continuous four days respectively.The 4th day behind drug administration by injection and injection tetracol phenixin peanut oil solution 45min, each organizes rat (comprising the normal control group) abdominal injection 8.5mmol/kg Spirit of Mindererus, record is respectively organized rat and is begun to enter to rat time (latent period) of comatose state, (stupor time) and mortality ratio from comatose state to the time of reviving from the injection ammonium acetate.It the results are shown in Table shown in 5:
Table 5
| Group | Dosage (mg/kg) | Latent period (min) | The stupor time (min) | Mortality ratio (%) |
| The normal control group | ????- | ????10 | ????120 | ????60 |
| The physiological saline group | ????- | ????5 | ????145 | ????70 |
| The Sodium Glutamate group | ????410 | ????10 | ????80 | ????50 |
| The Cryptotanshinone group | ????10 | ????12 | ????65 | ????20 |
| 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????14 | ????40 | ????10 |
| 3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????18 | ????30 | ????10 |
| 3-allyl group-3-hydroxyl-9-bromo-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????15 | ????38 | ????10 |
| 3-allyl group-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????20 | ????28 | ????10 |
| 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????10 | ????18 | ????31 | ????10 |
Embodiment 11
Adjacent naphthoquinone compound causes stupor and dead influence (oral) to acute rats with liver cirrhosis hyperammonemia:
Press embodiment 14 experiment conditions, different is that the Sodium Glutamate injection changes oral L-glutamic acid tablet (dosage 200mg/kg) into, and adjacent naphthoquinones class medicine is also changed into oral by injection, and dosage is as shown in table 6.The 4th day behind drug administration by injection and injection tetracol phenixin peanut oil solution 45min, each organizes rat (comprising the normal control group) abdominal injection 8.5mmol/kg Spirit of Mindererus, record is respectively organized rat and is begun to enter to rat time (latent period) of comatose state, (stupor time) and mortality ratio from comatose state to the time of reviving from the injection ammonium acetate.It the results are shown in Table shown in 6:
Table 6
| Group | Dosage (mg/kg) | Latent period (min) | The stupor time (min) | Mortality ratio (%) |
| The normal control group | ????- | ????10 | ????120 | ????60 |
| The physiological saline group | ????- | ????6 | ????145 | ????70 |
| The Sodium Glutamate group | ????200 | ????8 | ????95 | ????50 |
| The Cryptotanshinone group | ????100 | ????12 | ????75 | ????20 |
| 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????12 | ????46 | ????10 |
| 3-methyl-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????21 | ????32 | ????10 |
| 3-allyl group-3-hydroxyl-9-bromo-2,3- | ????100 | ????16 | ????40 | ????10 |
| Dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ||||
| 3-allyl group-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????20 | ????32 | ????10 |
| 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone group | ????100 | ????18 | ????35 | ????10 |
Embodiment 12
Adjacent naphthoquinone compound toxicological experiment:
Acute toxicity test in mice: animal for research is a healthy male mice.Adopt and irritate the stomach method test.Dosage does not find for the examination mouse toxicity symptom and death are arranged during to 1.0g/kg yet.Experiment shows, such adjacent naphthoquinones analogue LD50＞1g/kg.
30 days toxicity tests of mouse: animal for research is a healthy male mice.Adopt and irritate the stomach method test.Dosage is 200mg/kg day, continuous 30 days.Experiment shows, is tried rat and does not have death, grows, hemopoietic function, biochemical indicator etc., does not all have tangible ANOMALOUS VARIATIONS or toxic reaction; The dissection inspection of important organ and organize microscopy not find pathological change.
Claims (6)
1, a kind of compound that contains o-naphthaquinone, its structure is shown in (I) formula:
In the formula (I), R
1Be C
2-C
6Alkyl, C
1-C
6Alkoxyl group, n=1-2-(CH2) the nAr base ,-F ,-Cl ,-Br or-I,
R
2For H ,-OH or-OCOR, wherein R is C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) n Ar base,
R
3Be H, C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) nAr base,
R
4Be H, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
Or:
R
1Be H or CH
3,
R
2For H ,-OH or-OCOR, wherein R is C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) n Ar base,
R
3Be C
6-C
10Aryl or n=1-2-(CH2) n Ar base,
R
4Be H, C
1-C
6Alkyl or C
1-C
6Alkoxyl group.
2, the compound that contains o-naphthaquinone according to claim 1 is characterized in that R in the formula (I)
1For-F ,-Cl ,-Br or-I;
R
2For H ,-OH or-OCOR, wherein R is C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) n Ar base;
R
3Be H, C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
6-C
10Aryl or n=1-2-(CH2) nAr base;
R
4Be H, C
1-C
6Alkyl or C
1-C
6Alkoxyl group.
3, the compound that contains o-naphthaquinone according to claim 2 is characterized in that wherein R
1For-Cl or-Br; R
2For H ,-OH or C
1-C
6Ester group; R
3Be H, C
1-C
3Alkyl, allyl group, phenyl or substituted-phenyl; R
4Be H or C
1-C
3Alkyl.
4, the compound that contains o-naphthaquinone according to claim 3 is characterized in that wherein R
1For-Cl or-Br; R
2For H ,-OH, ethyl ester or phenyl ester; R
3Be H, methyl, allyl group or phenyl; R
4Be H or methyl.
5, the compound that contains o-naphthaquinone according to claim 4 is characterized in that described compound is 3-methyl-3-hydroxyl-9-chloro-2,3-dihydro-naphtho [1,8-b, c] pyrans-7,8-diketone, 3-methyl-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone, 3-allyl group-3-hydroxyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone, 3-allyl group-3-hydroxyl-9-bromo-2,3 dihydro-naphthos [1,8-b, c] pyrans-7,8-diketone, 3-methyl-9-chloro-2,3 dihydro-naphthos [1,8-b, c] pyrans-7, the 8-diketone.
6, claim 1 or 2 or 3 or the 4 or 5 described compounds that contain o-naphthaquinone are used for preventing and treat the application of the medicine of hyperammonemia and hepatogenic encephalopathy in preparation.
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| CNB2004100777789A CN1318414C (en) | 2004-12-30 | 2004-12-30 | Compound containing structure of o-naphthaquinone and application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100777789A CN1318414C (en) | 2004-12-30 | 2004-12-30 | Compound containing structure of o-naphthaquinone and application |
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| Publication Number | Publication Date |
|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125545A (en) * | 2010-12-07 | 2011-07-20 | 中山大学 | Application of o-quinone structure-contained compounds in preparing tumor resistant medicament |
| CN103183668A (en) * | 2013-02-19 | 2013-07-03 | 中山大学 | Derivative of natural product Mansonone E and preparation and application thereof |
| CN104744421A (en) * | 2015-01-08 | 2015-07-01 | 中山大学 | Mansonone F derivative as well as preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100406736B1 (en) * | 2000-01-10 | 2003-11-21 | 주식회사 코오롱 | Anti-cancer agent containing naphthoquinone compound |
-
2004
- 2004-12-30 CN CNB2004100777789A patent/CN1318414C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125545A (en) * | 2010-12-07 | 2011-07-20 | 中山大学 | Application of o-quinone structure-contained compounds in preparing tumor resistant medicament |
| CN102125545B (en) * | 2010-12-07 | 2013-11-06 | 中山大学 | Application of o-quinone structure-contained compounds in preparing tumor resistant medicament |
| CN103183668A (en) * | 2013-02-19 | 2013-07-03 | 中山大学 | Derivative of natural product Mansonone E and preparation and application thereof |
| CN104744421A (en) * | 2015-01-08 | 2015-07-01 | 中山大学 | Mansonone F derivative as well as preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1318414C (en) | 2007-05-30 |
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