CN108047213A - A kind of two ring nitrile compounds of the fluorine thiophene of sulfur-bearing ring and application thereof - Google Patents
A kind of two ring nitrile compounds of the fluorine thiophene of sulfur-bearing ring and application thereof Download PDFInfo
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- CN108047213A CN108047213A CN201711400561.0A CN201711400561A CN108047213A CN 108047213 A CN108047213 A CN 108047213A CN 201711400561 A CN201711400561 A CN 201711400561A CN 108047213 A CN108047213 A CN 108047213A
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- compound
- ssao
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to SSAO inhibitor fields.Specifically, the present invention relates to a kind of two ring nitrile compounds of the fluorine thiophene of new sulfur-bearing ring, the application as SSAO inhibitor and in treatment diseases associated with inflammation, immunity disease and tumour etc. is prepared.
Description
Technical field
The present invention relates to the fields of SSAO inhibitor.In particular it relates to there is therapeutic effect to inhibiting SSAO
The SSAO inhibitor of two ring nitrile compounds objects of fluorine thiophene of new sulfur-bearing ring a kind of, its preparation method and in pharmacy
On purposes.
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)。
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 cycling 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, having found recently (Noda, et are contacted 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 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 it is generated 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 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 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 inhibits 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 have been recorded in 062011 and PCT/EP2009/062018.
It is scorching available for preparing the invention discloses a kind of two ring nitrile SSAO inhibitor of fluorine thiophene of new sulfur-bearing ring
The medicine of the diseases such as disease property disease, 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 Formulas I.
It is a further object to provide the methods for preparing the compound with Formulas I.
It is also another object of the present invention to provide the compound containing Formulas I treatment diseases associated with inflammation, immunity disease and
Application in terms of tumour.
Present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the invention with formula (I) is with following structural formula：
Formula (I) compound of the present invention can be synthesized by following route：
Initial compounds III can be according to document (Magnin, D.R., et al.J.Med.Chem., 2004,47,2587-
2598) method synthesizes.Dibromide II and compound III is alkali, Pd (OAc) in t-BuOK2The lower coupling of/BINAP catalysis, obtains
Compound IV；IV and compound 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 such as inflammatory disease
The medicine of the diseases such as disease, immunity disease and tumour.The activity of compound of formula I of the present invention by inhibiting SSAO in vitro
It 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 lead compound I-1 of embodiment
The synthesis of step 1. compound IV
Compound II-1 (2.42g, 10mmol), compound III (1.08g, 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) 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-1,1.88g (yield 70%).ESI-MS, m/z=269 ([M+H
]+)。
The synthesis of step 2. compound I-1
Compound IV-1 (1.35g, 5mmol), compound V (0.57g, 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 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-1,1.02g (yield 74%).ESI-MS, m/z=292 ([M+H
]+), white solid.
The synthesis of 2 compound I-2 of embodiment
The synthesis of step 1. compound IV-2
Compound II-2 (2.59g, 10mmol), compound III (1.08g, 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) 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=288 ([M+H]+)。
The synthesis of step 2. compound I-2
Compound IV-2 (1.44g, 5mmol), compound V (0.57g, 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 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=310 ([M+H]+), pale solid.
3 Compound ira vitro of embodiment inhibits 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 generates to measure enzymatic activity by using the hydrogen peroxide in horseradish peroxidase (HRP) coupling reaction as substrate.Letter
For it, will test compound be dissolved in dimethyl sulfoxide (DMSO) (DMSO) to concentration be 10mM.By carrying out 1 in DMSO:10
Be serially diluted generate 7 point curves or by carrying out 1 in DMSO:3 are serially diluted to generate 11 point curves to 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 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, InvitrogenA22188).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 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 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.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.It will
Data are fitted to four parameter logistic models, and calculate IC using 4 programs of GraphPadPrism50Value.
As a result see the table below.
| Compound | IC50(nM) |
| Compound I-1 | 65.8 |
| Compound I-2 | 13.3 |
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 compound III is alkali, Pd (OAc) in t-BuOK2The lower coupling of/BINAP catalysis, obtains compound IV；IV
With compound 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.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11472769B2 (en) | 2019-10-29 | 2022-10-18 | Eccogene (Shanghai) Co., Ltd. | SSAO inhibitors and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106164071A (en) * | 2014-02-14 | 2016-11-23 | 不列颠哥伦比亚大学 | Human androgenic receptor DNA binding structural domain (DBD) compound and using method thereof as therapeutic agent |
-
2017
- 2017-12-22 CN CN201711400561.0A patent/CN108047213A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106164071A (en) * | 2014-02-14 | 2016-11-23 | 不列颠哥伦比亚大学 | Human androgenic receptor DNA binding structural domain (DBD) compound and using method thereof as therapeutic agent |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11472769B2 (en) | 2019-10-29 | 2022-10-18 | Eccogene (Shanghai) Co., Ltd. | SSAO inhibitors and use thereof |
| US11964942B2 (en) | 2019-10-29 | 2024-04-23 | Eccogene (Shanghai) Co., Ltd. | SSAO inhibitors and use thereof |
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Application publication date: 20180518 |