CN109988147A - SSAO inhibitor, preparation method and its usage containing adamantane structure - Google Patents
SSAO inhibitor, preparation method and its usage containing adamantane structure Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 102100027159 Membrane primary amine oxidase Human genes 0.000 title abstract description 45
- 101710132836 Membrane primary amine oxidase Proteins 0.000 title abstract description 43
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical group C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 title abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 230000036039 immunity Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 49
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- -1 cyclic amine Chemical class 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 230000008961 swelling Effects 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- 238000006243 chemical reaction Methods 0.000 description 5
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- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
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- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
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- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 206010012655 Diabetic complications Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- BCDGQXUMWHRQCB-UHFFFAOYSA-N aminoacetone Chemical compound CC(=O)CN BCDGQXUMWHRQCB-UHFFFAOYSA-N 0.000 description 2
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- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
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- XYEGZBUKNWVIMO-LURJTMIESA-N (2S)-3-(3,4-dihydroxyphenyl)-2-(hydroxyamino)propanoic acid Chemical compound ON[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1 XYEGZBUKNWVIMO-LURJTMIESA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- IBWBAMOFSRCNAD-UHFFFAOYSA-N C(C)(=O)N1C2=CC=C(C=C2OC=2C=C(C=CC12)O)O.N1CCNCC1 Chemical compound C(C)(=O)N1C2=CC=C(C=C2OC=2C=C(C=CC12)O)O.N1CCNCC1 IBWBAMOFSRCNAD-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101000694615 Homo sapiens Membrane primary amine oxidase Proteins 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- 238000007833 oxidative deamination reaction Methods 0.000 description 1
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- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 150000003349 semicarbazides Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to SSAO inhibitor fields.Specifically, the present invention relates to a kind of adamantane SSAO inhibitor, preparation method and the applications in preparation treatment diseases associated with inflammation, immunity disease and tumour etc..Wherein, R is selected from C1‑C10Alkyl, C3‑C8Naphthenic base.
Description
Technical field
The present invention relates to the fields of SSAO inhibitor.In particular it relates to which there is therapeutic effect to inhibition SSAO
A kind of novel SSAO inhibitor, preparation method containing adamantane structure, and the purposes in pharmacy.
Background technique
Semicarbazide-sensitive amine oxidizing ferment (semicarbazide-sensitive amine oxidase, SSAO) activity
It is by Vascular AdhesionProtein -1 (Vascular Adhesinon Protein-1, VAP-1) or copper-containing amine oxidases (Amone
Oxidase, Copper Containing 3, AOC3) enzymatic activity that is showed, the enzyme belongs to copper-containing amine oxidases family
(EC.1.4.3.6).Therefore, the biological function of VAP-1 albumen is also adjusted in the inhibitor of SSAO enzyme.The member of the enzyme family
It is sensitive to the inhibition of semicarbazides, and by bivalent cupric ion and from protein hydroxydopa quinone (topa quinine,
TPQ) co-factor is used for from primary amine to aldehyde, the oxidative deamination of hydrogen peroxide and ammonia.
The known substrate of people SSAO includes endogenous methylamine and aminoacetone and some exogenous amine such as benzylamines
(Lyles, Int.J.Biochem.Cell Biol., 1996,28,259-274).It is similar with other copper-containing amine oxidases, DNA sequence
Column analysis and structure determination show and organize the people SSAO that is combined for homodimeric glycoprotein, by two 90-100kDa's
Subunit composition, by single N-terminal transmembrane domain be anchored to plasma membrane (Morris, et al.J.Biol.Chem., 1997,272,
9388-9392)。
It has been found that SSAO activity in Various Tissues (including blood vessel and non-vascular smooth muscle tissue, endothelium and adipose tissue)
(Lewinsohn,Braz.J.Med.Biol.Res.,1984,17,223-256).In addition, SSAO albumen also found in blood plasma
And this soluble form seem with tissue combining form have similar performance (Kurkijarvi, et al.J.Immunol.,
1998,161,1549-1557).Recently it has been shown that SSAO derives from tissue combining form in the circulation of people and rodent
(Stolen,et al.Circ.Res.,2004,95(1),50-57)。
The precise physiological effect of this enzyme abundant is not yet fully defined, but seems SSAO and its reaction product thin
There may be several functionalities in born of the same parents' signal transduction and adjusting.For example, nearest discovery shows the glucose that SSAO is mediated in GLUT4
Absorb (Morin, et al.J.Pharmacol.Exp.Ther., 2001,297,563-572) and Adipocyte Differentiation
It all plays a role in (Fontana, Biochem.J., 2001,356,769-777).In addition, SSAO also shows to participate in inflammation mistake
Journey, wherein SSAO serve as leucocyte adhesion protein (Salmi&Jalkanen, Trends Immunol., 2001,22,211-
216) and be also possible to connective tissue matrix generate and maintain in play a role (Goktiirk, et al.Am.J.Pathol.,
2003,163(5),1921-1928).Moreover, recently it has been found that contacting (Noda, et between SSAO and angiogenesis
Al.FASEB J., 2008,22 (8), 2928-2935), and it is based on the connection, it is contemplated that SSAO inhibitor has anti-angiogenic generation
Effect.
Many researchs to the mankind are it has proven convenient that in such as congestive heart failure, diabetes, Alzheimer's disease and inflammation
Illness in, SSAO activity in blood plasma increase (del MarHernandez, et al.Neurosci.Lett., 2005,384
(1-2),183-187).The mechanism of these enzyme activity change behinds is not known.It has been proposed that being generated by endogenous amine oxidases
Active aldehydes and hydrogen peroxide promote cardiovascular disease, diabetic complication and Alzheimer's disease development (Jiang, et
al.Neuropathol.Appl.Neurobiol.,2008,34(2),194-204).In addition, the enzymatic activity of SSAO is related to inflammation
The Leukocyte extravasation process at position, wherein SSAO has shown high expression on skin in the blood vessels.Therefore, it has been suggested that the inhibition of SSAO
Agent has therapeutic value (Salter-Cid, et in prevention diabetic complication and inflammatory disease
al.J.Pharmacol.Exp.Ther.,2005,315(2),553-562)。
SSAO is raised in gastric cancer and in the tumor vascular system of human melanoma, hepatoma and H/N tumors
In be accredited (Forster-Horvath C, et al.Melanoma Res., 2004,14,135-140).One report
(Marttila-Ichihara F, et al.J.Immunol., 2010,184,3164-3173) has shown inactivating with enzyme
Melanoma growth is more slow in the mouse of SSAO, and its tumor vessel number and diameter are reduced.The growth of these tumours subtracts
It is also manifested in the reduction that marrow sample inhibits cellular infiltration less.It is encouraging that SSAO defect normal tissue medium vessels or lymph
Formation do not influence.
WO02/38153、WO 03/006003、WO 2005/014530、WO2007/120528、PCT/EP2009/
Some SSAO inhibitor are disclosed in 062011 and PCT/EP2009/062018.
Novel SSAO inhibitor the invention discloses one kind containing adamantane structure, these compounds can be used for preparing inflammation
The therapeutic agent of the diseases such as property disease, immunity disease and tumour.
Summary of the invention
It is an object of the present invention to provide a kind of SSAO inhibitor with general formula I.
It is a further object to provide the methods that preparation has compounds of formula I.
It is also another object of the present invention to provide treating diseases associated with inflammation, immunity disease containing compounds of formula I
With the application in terms of tumour.
The content of present invention is specifically described now in conjunction with the purpose of the present invention.
The present invention has following structural formula with the compound of logical formula (I):
Wherein, R is selected from C1-C10Alkyl, C3-C8Naphthenic base.
It is preferred that following general formula (I) compound,
Wherein, R is selected from C1-C5Alkyl, C3-C6Naphthenic base.
The more preferred compound with logical formula (I) is as follows,
Logical formula (I) compound of the present invention can be synthesized by following route:
Compound III can according to document (Hulin, B., et al.Bioorg.Med.Chem.Lett., 2005,15,
4770-4773) method synthesizes.
Dibromide II and cyclic amine III does alkali, Pd (OAc) in t-BuOK2The lower coupling of/BINAP catalysis, obtains compound
IV；IV and amantadine V does alkali, Pd (OAc) in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I；The definition of R
As previously described.
Compound of Formula I of the present invention has SSAO inhibiting effect, can be used as an active ingredient in the preparation of as inflammatory
The therapeutic agent of the diseases such as disease, immunity disease and tumour.The activity of compound of Formula I of the present invention is by pressing down in vitro
SSAO experiment processed is to verify.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and is not intended to limit the present invention.General technical staff's training centre according to the present invention in the art is made various
Variation should all be within the protection scope required by the claim of this application.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step 1. compound IV-1
Compound II-1 (2.37g, 10mmol), compound III (1.07g, 10mmol), Pd (OAc)2(0.22g,
1mmol), BINAP (2,2'- bis- diphenylphosphino -1,1'- dinaphthalenes, 0.62g, 1mmol) and t-BuOK (2.24g, 20mmol) adds
Enter 1, the 2- dimethoxy-ethane (DME) dry to 50mL, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hair
Now reaction is completed.
Reaction mixture carefully pours into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate are dry.It filtering and removes desiccant, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound IV-I, 1.76g (yield 67%).ESI-MS, m/z=264 ([M+H
]+)。
The synthesis of step 2. compound I-1
Compound IV-1 (1.32g, 5mmol), compound V (0.76g, 5mmol), Pd (OAc)2(0.11g,0.5mmol)、
BINAP (0.31g, 0.5mmol) and t-BuOK (1.12g, 10mmol) is added to the dry 1,2- dimethoxy-ethane of 20mL
(DME), reaction mixture is stirred overnight in a nitrogen atmosphere, and TLC detection discovery reaction is completed.
Reaction mixture carefully pours into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate are dry.It filtering and removes desiccant, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound I-I, 1.17g (yield 70%).ESI-MS, m/z=334 ([M+H
]+), white powder.
The synthesis of 2 compound I-2 of embodiment
The synthesis of step 1. compound IV-2
Compound II-2 (2.51g, 10mmol), compound III (1.07g, 10mmol), Pd (OAc)2(0.22g,
1mmol), BINAP (2,2'- bis- diphenylphosphino -1,1'- dinaphthalenes, 0.62g, 1mmol) and t-BuOK (2.24g, 20mmol) adds
Enter 1, the 2- dimethoxy-ethane (DME) dry to 50mL, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hair
Now reaction is completed.
Reaction mixture carefully pours into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate are dry.It filtering and removes desiccant, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound IV-2.ESI-MS, m/z=278 ([M+H]+)。
The synthesis of step 2. compound I-2
Compound IV-2 (1.39g, 5mmol), compound V (0.76g, 5mmol), Pd (OAc)2(0.11g,0.5mmol)、
BINAP (0.31g, 0.5mmol) and t-BuOK (1.12g, 10mmol) is added to the dry 1,2- dimethoxy-ethane of 20mL
(DME), reaction mixture is stirred overnight in a nitrogen atmosphere, and TLC detection discovery reaction is completed.
Reaction mixture carefully pours into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate are dry.It filtering and removes desiccant, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound I-2.ESI-MS, m/z=348 ([M+H]+), white solid.
Embodiment 3-7
Referring to the method for embodiment 1,2, following compounds have been synthesized.
8 Compound ira vitro of embodiment inhibits SSAO analysis
All Preliminary Determinations are all to be carried out at room temperature using purified recombinant expression people SSAO.Substantially such as
Enzyme is prepared described in Ohman etc. (Protein Expression and Purification, 2006,46,321-331).This
Outside, second level and selectively measuring using the SSAO or purified rat recombinant SSAO made from the Various Tissues carries out.Use benzyl
Amine is generated by using the hydrogen peroxide in horseradish peroxidase (HRP) coupling reaction as substrate to measure enzymatic activity.Letter
For it, will test compound be dissolved in dimethyl sulfoxide (DMSO) to concentration be 10mM.By carrying out 1:10 in DMSO
Be serially diluted to generate 7 point curves or generate 11 point curves by carrying out being serially diluted for 1:3 in DMSO and measure agent
Amount-response measurement value.Maximum concentration is adjusted according to the potency of compound, is then diluted, obtains in reaction buffer
DMSO final concentration≤2%.
Hydrogen peroxide detection: in horseradish peroxidase (HRP) coupling reaction, by 10- acetyl group -3,7- dihydroxy pheno
Piperazine (10-acetyl-3,7-dihydroxyphenoxazine) produces resorufin (resorufin) with hydrogen peroxide oxidation,
Resorufin be a kind of high-efficiency fluorescence compound (Zhout and Panchuk-Voloshina, Anal.Biochem., 1997,253,
169-174；Red hydrogen peroxide/peroxidase determination kit, Invitrogen A22188).Passing through addition HRP, benzyl
The mixture of amine and Amplex reagent starting reaction before, by 50mM sodium phosphate (pH 7.4) enzyme and compound flat micro-
It measures in titer plate preincubate about 15 minutes.The concentration of benzylamine is set to correspond to the concentration of Michaelis constant, uses standard side
Method measurement.Then it during 1-2 hour, in several point in time measurement fluorescence intensities, is excited at 544nm and at 590nm
Read transmitting.Final concentration: 1 μ g/mL of SSAO enzyme, 100 μM of benzylamine, Amplex reagent is measured for the people SSAO of reagent in measurement hole
20 μM, HRP 0.1U/mL and the various concentration for testing compound.Inhibiting effect is measured as and does not have inhibitor (only diluted
DMSO the signal) compared reduces percentage.The background signal from the sample without SSAO enzyme is subtracted from all data points.It will
Data are fitted to four parameter logistic models, and calculate IC using 4 program of GraphPad Prism50Value.
As a result it see the table below.
| Compound | IC50(nM) | Compound | IC50(nM) |
| Compound I-1 | 136.2 | Compound I-5 | 159.7 |
| Compound I-2 | 18.5 | Compound I-6 | 105.1 |
| Compound I-3 | 33.8 | Compound I-7 | 183.9 |
| Compound I-4 | 78.3 | _ | _ |
Can be seen that the compound of the present invention from upper table result has very strong inhibiting effect to SSAO, can be used as system
The therapeutic agent of the diseases such as standby diseases associated with inflammation, immunity disease and tumour.
Claims (5)
1. there is the compound of logical formula (I) structure,
Wherein, R is selected from C1-C10Alkyl, C3-C8Naphthenic base.
2. there is the compound of logical formula (I) defined in claim 1,
Wherein, R is selected from C1-C5Alkyl, C3-C6Naphthenic base.
3. compound of Formula I defined in claim 2 is selected from following compounds,
4. belonging to the method for the compound of logical formula (I) defined in synthesis claim 1-3 is any:
Dibromide II and cyclic amine III does alkali, Pd (OAc) in t-BuOK2The lower coupling of/BINAP catalysis, obtains compound IV；IV
Alkali, Pd (OAc) are done in t-BuOK with amantadine V2It is coupled again under/BINAP catalysis, obtains compound I；The definition of R is as weighed
Benefit requires 1-3 any described.
5. leading to formula (I) compound defined in one of claim 1-3 in preparation treatment diseases associated with inflammation, immunity disease and swelling
Application in terms of tumor medicine.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002038153A1 (en) * | 2000-11-09 | 2002-05-16 | Biovitrum Ab | New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives |
| WO2004024711A1 (en) * | 2002-09-10 | 2004-03-25 | Pharmacia Italia S.P.A. | Substituted pyridine derivatives as antitumor agent |
| CN1520290A (en) * | 2001-07-12 | 2004-08-11 | �Ƹ��� | Carbocyclic hydrorazino inhibitors of copper-containing amine oxidases |
| WO2007120528A2 (en) * | 2006-03-31 | 2007-10-25 | La Jolla Pharmaceutical Company | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
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2017
- 2017-12-29 CN CN201711466603.0A patent/CN109988147A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002038153A1 (en) * | 2000-11-09 | 2002-05-16 | Biovitrum Ab | New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives |
| CN1520290A (en) * | 2001-07-12 | 2004-08-11 | �Ƹ��� | Carbocyclic hydrorazino inhibitors of copper-containing amine oxidases |
| WO2004024711A1 (en) * | 2002-09-10 | 2004-03-25 | Pharmacia Italia S.P.A. | Substituted pyridine derivatives as antitumor agent |
| WO2007120528A2 (en) * | 2006-03-31 | 2007-10-25 | La Jolla Pharmaceutical Company | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
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