CN107880032A - Two ring nitrile SSAO inhibitor, preparation method and its usage containing thiophene - Google Patents
Two ring nitrile SSAO inhibitor, preparation method and its usage containing thiophene Download PDFInfo
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- CN107880032A CN107880032A CN201711400526.9A CN201711400526A CN107880032A CN 107880032 A CN107880032 A CN 107880032A CN 201711400526 A CN201711400526 A CN 201711400526A CN 107880032 A CN107880032 A CN 107880032A
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- compound
- ssao
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- ssao inhibitor
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- UVNMOMIVZZLLKJ-LOACHALJSA-N CCCC(C[C@H]1C#N)N1c1cc(C(C)(C)C)c(N2CCOCC2)[s]1 Chemical compound CCCC(C[C@H]1C#N)N1c1cc(C(C)(C)C)c(N2CCOCC2)[s]1 UVNMOMIVZZLLKJ-LOACHALJSA-N 0.000 description 1
- 0 CCCOCCNc1c(C(C)C)cc(N2[C@](*)C[C@@]3(C)[C@]2C3)[s]1 Chemical compound CCCOCCNc1c(C(C)C)cc(N2[C@](*)C[C@@]3(C)[C@]2C3)[s]1 0.000 description 1
- XEEKFMLEEDPZAI-KVULBXGLSA-N CCc1c(N2CCOCC2)[s]c(N(C(C2)[C@@]2(C)C2)C2C#N)c1 Chemical compound CCc1c(N2CCOCC2)[s]c(N(C(C2)[C@@]2(C)C2)C2C#N)c1 XEEKFMLEEDPZAI-KVULBXGLSA-N 0.000 description 1
- MVRMCJMFXOYDLH-JVCSGSNQSA-N C[C@@H]([C@@H]1C[C@H]2C#N)C1N2c1cc(C2CC2)c(N2CCOCC2)[s]1 Chemical compound C[C@@H]([C@@H]1C[C@H]2C#N)C1N2c1cc(C2CC2)c(N2CCOCC2)[s]1 MVRMCJMFXOYDLH-JVCSGSNQSA-N 0.000 description 1
Classifications
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to SSAO inhibitor field.Specifically, the present invention relates to two ring nitrile SSAO inhibitor of the one kind containing thiophene, its preparation method and the application in treatment diseases associated with inflammation, immunity disease and tumour etc. is prepared.Wherein, R is selected from C1‑C10Alkyl, C3‑C8Cycloalkyl.
Description
Technical field
The present invention relates to the field of SSAO inhibitor.In particular it relates to there is therapeutic action to suppressing SSAO
A kind of two ring nitrile derivatives containing thiophene SSAO inhibitor, 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 can adjust 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 OHDA quinone (topa quinine,
TPQ) co-factor be used for from primary amine to aldehyde, the oxidative deamination of hydrogen peroxide and ammonia.
People SSAO known substrate 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, and it is by two 90-100kDa's
Subunit forms, by single N-terminal membrane spaning 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 regulation.For example, nearest discovery shows, the glucose that SSAO mediates in GLUT4
Absorb (Morin, et al.J.Pharmacol.Exp.Ther., 2001,297,563-572) and Adipocyte Differentiation
All played 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, SSAO enzymatic activity 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 SSAO suppression
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 SSAO mouse, 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 have been recorded in 062011 and PCT/EP2009/062018.
The invention discloses a kind of new two ring nitrile SSAO inhibitor containing thiophene, these compounds can be used for preparing
The medicine of 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 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.
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, R is selected from C1-C10Alkyl, C3-C8Cycloalkyl.
It is preferred that below general formula (I) compound,
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：
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-BuOK2/ BINAP catalysis is lower to be coupled, and is obtained
Compound IV；IV and compound V is alkali, Pd (OAc) in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I；R's
It is defined as described above.
Compound of Formula I of the present invention has SSAO inhibitory action, and active ingredient can be used as to be used to prepare 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.
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.In general technical staff in the art is made various according to the teachings of the present invention
Change all should be within the protection domain required by the application claim.
The compound I-1 of embodiment 1 synthesis
Step 1. compound IV-1 synthesis
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, reactant mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merge extraction phase, according to
Secondary 1% watery 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, 1.88g (yield 70%).ESI-MS, m/z=269 ([M+H
]+)。
Step 2. compound I-1 synthesis
Compound IV-1 (1.35g, 5mmol), compound V (0.44g, 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), reactant mixture is stirred overnight in a nitrogen atmosphere, and TLC detections find that reaction is completed.
Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merge extraction phase, according to
Secondary 1% watery 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, 1.02g (yield 74%).ESI-MS, m/z=276 ([M+H
]+), white solid.
The compound I-2 of embodiment 2 synthesis
Step 1. compound IV-1 synthesis
Compound II-2 (2.70g, 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, reactant mixture is stirred overnight in a nitrogen atmosphere, TLC detection hairs
Now reaction is completed.
Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merge extraction phase, according to
Secondary 1% watery 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=298 ([M+H]+)。
Step 2. compound I-2 synthesis
Compound IV-2 (1.49g, 5mmol), compound V (0.44g, 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), reactant mixture is stirred overnight in a nitrogen atmosphere, and TLC detections find that reaction is completed.
Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merge extraction phase, according to
Secondary 1% watery 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=304 ([M+H]+), white solid.
Embodiment 3-6
With reference to the method for embodiment 1,2, compound listed in Table has been synthesized.
The Compound ira vitro of embodiment 7 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 determine enzymatic activity as substrate by using the hydrogen peroxide in horseradish peroxidase (HRP) coupling reaction.Letter
For it, it is 10mM that test compound, which is dissolved in dimethyl sulfoxide (DMSO) (DMSO) to concentration,.By carrying out 1 in DMSO:10
Be serially diluted to produce 7 point curves or by carrying out 1 in DMSO:3 are serially diluted to produce 11 point curves to determine 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, 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 determines.Then during 1-2 hour, in several point in time measurement fluorescence intensities, excited at 544nm and at 590nm
Read transmitting.Final concentration is determined for the people SSAO of reagent in measure hole：The μ g/mL of SSAO enzymes 1,100 μM of benzylamine, Amplex reagents
20 μM, the various concentrations of HRP 0.1U/mL and test 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 the programs of GraphPadPrism 450Value.
As a result see the table below.
| Compound | IC50(nM) | Compound | IC50(nM) |
| The compound of embodiment 1 | 46.4 | The compound of embodiment 4 | 41.9 |
| The compound of embodiment 2 | 9.7 | The compound of embodiment 5 | 83.1 |
| The compound of embodiment 3 | 11.6 | The compound of embodiment 6 | 53.5 |
The compound that can be seen that the present invention from upper table result has very strong inhibitory action 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, R is selected from C1-C10Alkyl, C3-C8Cycloalkyl.
2. there is the compound of logical formula (I) defined in claim 1,
Wherein, R is selected from C1-C5Alkyl, C3-C6Cycloalkyl.
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 compound III is alkali, Pd (OAc) in t-BuOK2/ BINAP catalysis is lower to be coupled, and obtains compound IV；IV
With compound V alkali, Pd (OAc) are in t-BuOK2It is coupled again under/BINAP catalysis, obtains compound I；R definition such as right
It is required that 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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| Application Number | Priority Date | Filing Date | Title |
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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 |
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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 |
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