CN108033945A - A kind of adamantane and nitropyridine structural compounds and purposes - Google Patents
A kind of adamantane and nitropyridine structural compounds and purposes Download PDFInfo
- Publication number
- CN108033945A CN108033945A CN201711466573.3A CN201711466573A CN108033945A CN 108033945 A CN108033945 A CN 108033945A CN 201711466573 A CN201711466573 A CN 201711466573A CN 108033945 A CN108033945 A CN 108033945A
- Authority
- CN
- China
- Prior art keywords
- compound
- ssao
- nitropyridine
- adamantane
- buok
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 NC1(CC(C2)C3)C*3CCC2C1 Chemical compound NC1(CC(C2)C3)C*3CCC2C1 0.000 description 2
- REAQJHZLMPLHQQ-OBNKKRCSSA-N CC(CC(C1)C2)(CC2C23)C12N3c1nc(N(C2)CC3(CC3)[C@H]2F)cc([N+]([O-])=O)c1 Chemical compound CC(CC(C1)C2)(CC2C23)C12N3c1nc(N(C2)CC3(CC3)[C@H]2F)cc([N+]([O-])=O)c1 REAQJHZLMPLHQQ-OBNKKRCSSA-N 0.000 description 1
- IDOLUFXSILTEPR-UHFFFAOYSA-N CC1C(Br)=NC(Br)=CC1 Chemical compound CC1C(Br)=NC(Br)=CC1 IDOLUFXSILTEPR-UHFFFAOYSA-N 0.000 description 1
- BQWQIGWFVSNAHY-UHNVWZDZSA-N F[C@H](CCNC1)[C@H]1F Chemical compound F[C@H](CCNC1)[C@H]1F BQWQIGWFVSNAHY-UHNVWZDZSA-N 0.000 description 1
- DPQBUPZBIFARIC-FFHVKTBCSA-N F[C@H](CN(C1)C2NC(NC3(CC(C4)C5)CCC5CC4C3)=CC=C2)[C@H]1F Chemical compound F[C@H](CN(C1)C2NC(NC3(CC(C4)C5)CCC5CC4C3)=CC=C2)[C@H]1F DPQBUPZBIFARIC-FFHVKTBCSA-N 0.000 description 1
- PHFTVEADDMICLE-ZXZARUISSA-N F[C@H](CNC1)[C@H]1F Chemical compound F[C@H](CNC1)[C@H]1F PHFTVEADDMICLE-ZXZARUISSA-N 0.000 description 1
- ZGGFZXDREYITIC-UHFFFAOYSA-N NC(CC1C2)(C3)C11C2CC3C1 Chemical compound NC(CC1C2)(C3)C11C2CC3C1 ZGGFZXDREYITIC-UHFFFAOYSA-N 0.000 description 1
- XIPATZUHJFQGQC-UHFFFAOYSA-N [O-][N+](c1cc(Br)nc(Br)c1)=O Chemical compound [O-][N+](c1cc(Br)nc(Br)c1)=O XIPATZUHJFQGQC-UHFFFAOYSA-N 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
Abstract
The present invention relates to SSAO inhibitor field.Specifically, the present invention relates to a kind of compound containing adamantane and nitropyridine structure, its preparation method and the application in treatment diseases associated with inflammation, immunity disease and tumour etc. is prepared.
Description
Technical field
The present invention relates to the field of SSAO inhibitor.In particular it relates to there is therapeutic effect to suppressing SSAO
A kind of compound containing adamantane and nitropyridine structure, its preparation method, and the purposes in pharmacy.
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 inhibitor of SSAO enzymes also adjusts the biological function of VAP-1 albumen.The member of the enzyme family
Suppression to semicarbazides is sensitive, and by bivalent cupric ion and from protein hydroxydopa quinone (topa quinine,
TPQ) co-factor be 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 sequences
Row analysis and structure determination show that the people SSAO combined with tissue is homodimeric glycoprotein, it is 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)。
SSAO activity is had found 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 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
All play 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 produce and maintain in play a role (Goktiirk, et al.Am.J.Pathol.,
2003,163(5),1921-1928).Moreover, having found recently (Noda, et are contacted between SSAO and angiogenesis
Al.FASEB J., 2008,22 (8), 2928-2935), and it is 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 rise of SSAO in blood plasma activity (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 produced by endogenous amine oxidases
Active aldehydes and hydrogen peroxide promote angiocardiopathy, development (Jiang, the et of diabetic complication and alzheimer disease
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 suppression 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 stomach 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
The reduction that marrow sample suppresses cellular infiltration is also manifested in less.It is encouraging that SSAO defect normal tissue medium vesselses 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.
The invention discloses a kind of new SSAO inhibitor containing adamantane and nitropyridine structure, these compounds can use
In the medicine for preparing the diseases such as diseases associated with inflammation, immunity disease and tumour.
The content 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 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 containing compounds of formula I
Application in terms of disease and tumour.
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：
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-BuOK2The lower coupling of/BINAP catalysis, obtains compound
IV；IV and amantadine V is alkali, Pd (OAc) in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I.
Compound of Formula I of the present invention has SSAO inhibitory action, can be used to prepare as active ingredient 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 is tested to verify.
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
Change 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'- double diphenylphosphino -1,1'- dinaphthalenes, 0.62g, 1mmol) and t-BuOK (2.24g, 20mmol) add
Enter 1, the 2- dimethoxy-ethanes (DME) to 50mL dryings, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reaction mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Filtering and remove 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 (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 1,2- dimethoxy-ethanes of 20mL dryings
(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 frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Filtering and remove 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=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 (2.82g, 10mmol), compound III (1.07g, 10mmol), Pd (OAc)2(0.22g,
1mmol), BINAP (2,2'- double diphenylphosphino -1,1'- dinaphthalenes, 0.62g, 1mmol) and t-BuOK (2.24g, 20mmol) add
Enter 1, the 2- dimethoxy-ethanes (DME) to 50mL dryings, reaction mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reaction mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Filtering and remove drier, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound IV-2.ESI-MS, m/z=309 ([M+H]+)。
The synthesis of step 2. compound I-2
Compound IV-2 (1.54g, 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 1,2- dimethoxy-ethanes of 20mL dryings
(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 frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, according to
Secondary 1% dilute hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Filtering and remove drier, filtrate is evaporated on a rotary evaporator,
Residue is purified using silica gel column chromatography, obtains compound I-2.ESI-MS, m/z=379 ([M+H]+), white solid.
3 Compound ira vitro of embodiment suppresses SSAO analyses
All Preliminary Determinations are all to be carried out at room temperature using purified recombination 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 is produced to measure enzymatic activity as substrate by using the hydrogen peroxide in horseradish peroxidase (HRP) coupling reaction.Letter
For it, will test compound to be dissolved in dimethyl sulfoxide (DMSO) (DMSO) to concentration be 10mM.By carrying out 1 in DMSO:10
Be serially diluted to produce 7 point curves or by carrying out 1 in DMSO:3 be serially diluted measures agent to produce 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) generates 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, it uses standard side
Method measures.Then during 1-2 hour, in several point in time measurement fluorescence intensities, excited and at 590nm at 544nm
Read transmitting.Final concentration is measured for the people SSAO of reagent in measure hole：1 μ g/mL of SSAO enzymes, 100 μM of benzylamine, Amplex reagents
20 μM, HRP 0.1U/mL and the various concentrations for testing compound.Inhibitory action 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.Will
Data are fitted to four parameter logistic models, and calculate IC using 4 programs of GraphPad Prism50Value.
As a result see the table below.
| Compound | IC50(nM) |
| Compound I-1 | 136.2 |
| Compound I-2 | 14.4 |
Can be seen that the compounds of this invention from upper table result has very strong inhibitory action to SSAO, can be used as and prepare
The medicine of the diseases such as diseases associated with inflammation, immunity disease and tumour.
Claims (3)
1. the compound with logical formula (I) structure,
2. synthesize the method for compound described in claim 1：
Dibromide II and cyclic amine III is alkali, Pd (OAc) in t-BuOK2The lower coupling of/BINAP catalysis, obtains compound IV；IV
With amantadine V alkali, Pd (OAc) are in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I.
3. application of the compound described in claim 1 in terms for the treatment of diseases associated with inflammation, immunity disease and tumour medicine is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711466573.3A CN108033945A (en) | 2017-12-29 | 2017-12-29 | A kind of adamantane and nitropyridine structural compounds and purposes |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711466573.3A CN108033945A (en) | 2017-12-29 | 2017-12-29 | A kind of adamantane and nitropyridine structural compounds and purposes |
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| Publication Number | Publication Date |
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| CN108033945A true CN108033945A (en) | 2018-05-15 |
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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 |
| 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 |
-
2017
- 2017-12-29 CN CN201711466573.3A patent/CN108033945A/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 |
| 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 |
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Application publication date: 20180515 |