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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- CN109988147A CN109988147A CN201711466603.0A CN201711466603A CN109988147A CN 109988147 A CN109988147 A CN 109988147A CN 201711466603 A CN201711466603 A CN 201711466603A CN 109988147 A CN109988147 A CN 109988147A
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- 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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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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| CN201711466603.0A CN109988147A (en) | 2017-12-29 | 2017-12-29 | SSAO inhibitor, preparation method and its usage containing adamantane structure |
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| CN201711466603.0A CN109988147A (en) | 2017-12-29 | 2017-12-29 | SSAO inhibitor, preparation method and its usage containing adamantane structure |
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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 |
-
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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