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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- CN108191823A CN108191823A CN201711466750.8A CN201711466750A CN108191823A CN 108191823 A CN108191823 A CN 108191823A CN 201711466750 A CN201711466750 A CN 201711466750A CN 108191823 A CN108191823 A CN 108191823A
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- ssao
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- 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
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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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| Application Number | Priority Date | Filing Date | Title |
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| CN201711466750.8A CN108191823A (en) | 2017-12-29 | 2017-12-29 | A kind of alkyl substitution adamantane SSAO inhibitor, preparation method and its usage |
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| CN201711466750.8A CN108191823A (en) | 2017-12-29 | 2017-12-29 | A kind of alkyl substitution adamantane SSAO inhibitor, preparation method and its usage |
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Citations (5)
| 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 |
| 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 |
-
2017
- 2017-12-29 CN CN201711466750.8A patent/CN108191823A/en active Pending
Patent Citations (5)
| 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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