CN108191823A - A kind of alkyl substitution adamantane SSAO inhibitor, preparation method and its usage - Google Patents
A kind of alkyl substitution adamantane SSAO inhibitor, preparation method and its usage Download PDFInfo
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- 102100027159 Membrane primary amine oxidase Human genes 0.000 title abstract description 43
- 101710132836 Membrane primary amine oxidase Proteins 0.000 title abstract description 41
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 title abstract description 10
- 239000003112 inhibitor Substances 0.000 title abstract description 10
- 125000000217 alkyl group Chemical group 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000006467 substitution reaction Methods 0.000 title abstract description 3
- 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
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 56
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 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 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 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
- 230000008961 swelling Effects 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 4
- 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 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 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 3
- 102000016893 Amine Oxidase (Copper-Containing) Human genes 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 3
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
- 238000004458 analytical method Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 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
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-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
- 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
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- IHGMLLBMNDWLBL-UHFFFAOYSA-N [4-(trifluoromethyl)pyridin-2-yl]methanamine Chemical compound NCC1=CC(C(F)(F)F)=CC=N1 IHGMLLBMNDWLBL-UHFFFAOYSA-N 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
- 238000005516 engineering process 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
- 239000000203 mixture Substances 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
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 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
- 235000011008 sodium phosphates Nutrition 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 class [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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (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 alkyl substitution adamantane SSAO inhibitor, preparation method and the applications in treatment diseases associated with inflammation, immunity disease and tumour etc. is prepared.Wherein, R1Selected from C1‑C10Alkyl, C3‑C8Cycloalkyl；R2Selected from C1‑C5Alkyl.
Description
Technical field
The present invention relates to the fields of SSAO inhibitor.In particular it relates to inhibiting SSAO that there is therapeutic effect
A kind of noval chemical compound, preparation method and purposes in pharmacy for replacing adamantane and pyridine structure containing alkyl.
Background technology
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 enzymes.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 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 sequences
Row analysis and structure determination show and the people SSAO that organizes to combine is homodimeric glycoprotein, by two 90-100kDa's
Subunit forms, 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 cycle of people and rodent
(Stolen,et al.Circ.Res.,2004,95(1),50-57)。
The precise physiological effect of this abundant enzyme 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 based on the contact, 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 disease and inflammation
Illness in, the raising of SSAO activity in blood plasma (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 it is generated by endogenous amine oxidases
Active aldehydes and hydrogen peroxide promote angiocardiopathy, diabetic complication and alzheimer 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 have 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.
Replace the noval chemical compound of adamantane and pyridine structure containing alkyl the invention discloses one kind, these compounds can be used for
Prepare the medicine of the diseases such as diseases associated with inflammation, immunity disease and tumour.
Invention content
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 prepare the method with 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 in conjunction with the purpose of the present invention.
Compound of the present invention with logical formula (I) is with following structural formula：
Wherein, R1Selected from C1-C10Alkyl, C3-C8Cycloalkyl；
R2Selected from C1-C5Alkyl.
It is preferred that below general formula (I) compound,
Wherein, R1Selected from C1-C5Alkyl, C3-C6Cycloalkyl；
R2Selected from C1-C3Alkyl.
Wherein, R is selected from C1-C5Alkyl, C3-C6Cycloalkyl.
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 is alkali, Pd (OAc) in t-BuOK2/ BINAP catalysis is lower to be coupled, and obtains compound
IV；IV and amantadine V is alkali, Pd (OAc) in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I；R1、R2's
It is defined as described above.
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 medicine 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 processed tests to verify.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be 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 domain required by the application claim.
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-ethanes (DME) dried to 50mL, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reaction mixture is carefully poured 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 drying.It filtering and removes drier, 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-1 (0.83g, 5mmol), Pd (OAc)2(0.11g,
0.5mmol), BINAP (0.31g, 0.5mmol) and t-BuOK (1.12g, 10mmol) is added to the 1,2- dimethoxies of 20mL dryings
Base ethane (DME), reaction mixture is stirred overnight in a nitrogen atmosphere, and TLC detections find that reaction is completed.
Reaction mixture is carefully poured 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 drying.It filtering and removes drier, 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=348 ([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-ethanes (DME) dried to 50mL, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reaction mixture is carefully poured 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 drying.It filtering and removes drier, 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-1 (0.83g, 5mmol), Pd (OAc)2(0.11g,
0.5mmol), BINAP (0.31g, 0.5mmol) and t-BuOK (1.12g, 10mmol) is added to the 1,2- dimethoxies of 20mL dryings
Base ethane (DME), reaction mixture is stirred overnight in a nitrogen atmosphere, and TLC detections find that reaction is completed.
Reaction mixture is carefully poured 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 drying.It filtering and removes drier, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound I-2.ESI-MS, m/z=362 ([M+H]+), white solid.
The synthesis of 3 compound I-3 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-ethanes (DME) dried to 50mL, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reaction mixture is carefully poured 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 drying.It filtering and removes drier, 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-3
Compound IV-2 (1.39g, 5mmol), compound V-3 (0.90g, 5mmol), Pd (OAc)2(0.11g,
0.5mmol), BINAP (0.31g, 0.5mmol) and t-BuOK (1.12g, 10mmol) is added to the 1,2- dimethoxies of 20mL dryings
Base ethane (DME), reaction mixture is stirred overnight in a nitrogen atmosphere, and TLC detections find that reaction is completed.
Reaction mixture is carefully poured 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 drying.It filtering and removes drier, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound I-3.ESI-MS, m/z=377 ([M+H]+), white solid.
Embodiment 4-10
With reference to the method for embodiment 1,2 and 3, following compounds are synthesized
11 Compound ira vitro of embodiment inhibits SSAO analyses
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, two level and selectively measuring is carried out using from SSAO made from Various Tissues or purified rat recombinant SSAO.Use benzyl
Amine generates to measure enzymatic activity by using the hydrogen peroxide in horseradish peroxidase (HRP) coupling reaction as substrate.Letter
For it, test compound is dissolved in dimethyl sulfoxide (DMSO) (DMSO) to a concentration of 10mM.By carrying out 1 in DMSO:10
Be serially diluted to generate 7 point curves or by carrying out 1 in DMSO:3 be serially diluted measures agent to generate 11 point curves
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 detects：In horseradish peroxidase (HRP) coupling reaction, by 10- acetyl group -3,7- dihydroxy fens
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).By adding HRP, benzyl
Before the mixture of amine and Amplex reagents starts reaction, by the enzyme in 50mM sodium phosphates (pH 7.4) and compound flat micro-
Measure preincubate about 15 minutes in titer plate.The concentration of benzylamine is set to correspond to the concentration of Michaelis constant, uses standard side
Method measures.Then it during 1-2 hour, in several point in time measurement fluorescence intensities, is excited and at 590nm at 544nm
Read transmitting.Final concentration is measured for the people SSAO for measuring reagent in hole：1 μ g/mL of SSAO enzymes, 100 μM of benzylamine, Amplex reagents
20 μM, HRP 0.1U/mL and the various concentration for testing compound.Inhibiting effect is measured as with not having inhibitor (only diluted
DMSO the signal) compared reduces percentage.The background signal from the sample without SSAO enzymes is subtracted from all data points.It will
Data are fitted to four parameter logistic models, and calculate IC using 4 programs of GraphPad Prism50Value.
As a result it see the table below.
| Compound | IC50(nM) | Compound | IC50(nM) |
| Compound 1-1 | 74.5 | Compound I-6 | 77.4 |
| Compound 1-2 | 12.1 | Compound I-7 | 31.8 |
| Compound 1-3 | 19.3 | Compound I-8 | 26.2 |
| Compound 1-4 | 14.8 | Compound I-9 | 46.0 |
| Compound 1-5 | 25.7 | Compound I-10 | 105.9 |
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 medicine of the diseases such as standby diseases associated with inflammation, immunity disease and tumour.
Claims (5)
1. the compound with logical formula (I) structure,
Wherein, R1Selected from C1-C10Alkyl, C3-C8Cycloalkyl；
R2Selected from C1-C5Alkyl.
2. there is the compound of logical formula (I) defined in claim 1,
Wherein, R1Selected from C1-C5Alkyl, C3-C6Cycloalkyl；
R2Selected from C1-C3Alkyl.
3. compound of Formula I defined in claim 2, selected from following compounds,
Belong to the method for the compound of logical formula (I) defined in 4. synthesis claim 1-3 is any：
Dibromide II and cyclic amine III is alkali, Pd (OAc) in t-BuOK2/ BINAP catalysis is lower to be coupled, and obtains compound IV；IV
With amantadine V alkali, Pd (OAc) are in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I；R1、R2Definition such as
Claim 1-3 is any described.
5. lead to formula (I) compound defined in one of claim 1-3 preparing treatment diseases associated with inflammation, immunity disease and swelling
Application in terms of tumor medicine.
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| 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 |
| CN1863763A (en) * | 2003-08-08 | 2006-11-15 | 拉卓拉药物公司 | Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and vap-1 mediated adhesion useful for treatment of diseases |
| WO2007120528A3 (en) * | 2006-03-31 | 2008-07-24 | Jolla Pharma | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
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| 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 |
| CN1863763A (en) * | 2003-08-08 | 2006-11-15 | 拉卓拉药物公司 | Inhibitors of semicarbazide-sensitive amine oxidase (SSAO) and vap-1 mediated adhesion useful for treatment of diseases |
| WO2007120528A3 (en) * | 2006-03-31 | 2008-07-24 | Jolla Pharma | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
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