CN105017037B - 6 substituted aryl amino methyl tetrahydro naphthaline derivatives or its esters, and its production and use - Google Patents
6 substituted aryl amino methyl tetrahydro naphthaline derivatives or its esters, and its production and use Download PDFInfo
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- 0 **(cc1)c(C2CC2)cc1-c(cc1CCC2)ccc1C2=O Chemical compound **(cc1)c(C2CC2)cc1-c(cc1CCC2)ccc1C2=O 0.000 description 4
- OSDHOOBPMBLALZ-UHFFFAOYSA-N O=C(CCCc1c2)c1ccc2Br Chemical compound O=C(CCCc1c2)c1ccc2Br OSDHOOBPMBLALZ-UHFFFAOYSA-N 0.000 description 3
- DNOVEZFEGKYJKE-UHFFFAOYSA-N CN(C)CC(CCc1cc(-c(cc2)ccc2OC)ccc11)C1(c1cccc(OC)c1)O Chemical compound CN(C)CC(CCc1cc(-c(cc2)ccc2OC)ccc11)C1(c1cccc(OC)c1)O DNOVEZFEGKYJKE-UHFFFAOYSA-N 0.000 description 1
- LBWBFOKTEDHYHO-UHFFFAOYSA-N CN(C)CC(CCc1cc(-c(cc2)ccc2OC)ccc11)C1=O Chemical compound CN(C)CC(CCc1cc(-c(cc2)ccc2OC)ccc11)C1=O LBWBFOKTEDHYHO-UHFFFAOYSA-N 0.000 description 1
- AEZZBALZRVGGDH-UHFFFAOYSA-N CN(C)CC(CCc1cc(-c2ccccc2)ccc11)C1(c1cccc(OC)c1)O Chemical compound CN(C)CC(CCc1cc(-c2ccccc2)ccc11)C1(c1cccc(OC)c1)O AEZZBALZRVGGDH-UHFFFAOYSA-N 0.000 description 1
- WMDOAKIRUXFABB-UHFFFAOYSA-N Nc(cc1CCC2)ccc1C2=N Chemical compound Nc(cc1CCC2)ccc1C2=N WMDOAKIRUXFABB-UHFFFAOYSA-N 0.000 description 1
- FNSQPQKPPGALFA-UHFFFAOYSA-N Oc(cc1CCC2)ccc1C2=O Chemical compound Oc(cc1CCC2)ccc1C2=O FNSQPQKPPGALFA-UHFFFAOYSA-N 0.000 description 1
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Abstract
6 substituted aryl amino methyl tetrahydro naphthaline derivatives or its esters, and its production and use.The invention belongs to pharmaceutical field, it is related to the logical substituted aryl amino methyl tetrahydro naphthaline derivatives of formula (I) 6 and pharmaceutically acceptable salt class, preparation method, and its as lead compound synthesizing new μ, κ and the purposes of delta opiate receptor activator or antagonist activities, μ involved in the present invention, κ and delta opiate receptor activator or antagonist can be used for preparing analgesic.In formula：R1For H or CH3Or OH, R2For H, OCH3、OC2H5、CF3、OCF3, 13 substitutions F, Cl, Br and I, R3For H, F, Cl, Br, I and C1‑C6The alkoxy of straight or branched.
Description
Technical field
The invention belongs to pharmaceutical field, be related to 6- substituted aryl amino methyl tetrahydro naphthaline derivatives with logical formula (I) or
Its esters and preparation method, and purposes of the compound in the disease for the treatment of opioid receptors.
Background technology
It is the common sympton appeared in a variety of disease process prior art discloses pain.Studies have shown that opiates town
Pain medicine plays the role of irreplaceable in pain therapy.Opium kind analgesicses may act on internal tri- kinds of opium Asias of μ, δ and κ
Receptor, practice display, potent type antalgesic, such as morphine, fentanyl are mostly μ receptor stimulating agents, serious breathing suppression be present
System and additive side effect, cause its clinical practice to be restricted.However, selective κ and delta agonists can play certain analgesia
Do not cause while active similar to respiration inhibition caused by the μ receptor stimulating agents such as morphine and the side effect such as additive, it is recognized
For with the potentiality for developing into less toxic side effect analgesic.
High selectivity kappa agonist research to not typical opium sample effect once caused the great interest of researcher, and
And wherein derive from selective kappa agonist Enadoline (enadoline) and the Spiradoline of fragrant ethanamide structure
(spirodoline) once entering the clinical II phases studies, but due to its limited bioavailability and anxiety and cause it is unreal in
Pivot side effect, clinical test be not finally successful.Based in addition to maincenter, kappa receptor is also distributed in periphery, exciting periphery
Kappa receptor can play the effect of anti-inflammatory pain, in the recent period studies have found that periphery kappa agonist has good effect for alleviating visceral pain,
Also there are obvious antiphlogistic effects to rheumatic inflammation.Therefore kappa agonist of the research selectively acting in periphery shows clinical answer
Prospect.
Research also shows that selective delta agonists play certain analgesia to pain caused by inflammation and neuropathic pain
Effect, and it will not cause μ receptor stimulating agents caused by respiration inhibition and the side effect such as additive, and do not cause kappa receptor
Activator causes anxiety and causes unreal maincenter side effect；Delta opiate receptor can also mediate the disease of a variety of maincenter regulation and control, such as depression
With Parkinson's etc..Therefore, the research of the compound with delta opiate receptor activity also causes the concern of researcher.
The content of the invention
It is an object of the invention to provide the novel 6- substituted aryl amino methyl tetralin quasi-compounds of structure, describedization
Compound can be used as μ, κ and delta opiate receptor activator or antagonist.
It is a further object of the present invention to provide the preparation method of the 6- substituted aryl amino methyl Tetrahydronaphthalencompounds compounds.
The present invention also aims to purposes of the open above-claimed cpd in terms of pain is treated.
The invention provides the 6- substituted aryl amino methyl Tetrahydronaphthalencompounds compounds shown in below formula (I) and its pharmacologically
Acceptable inorganic or organic salt：
In formula：
R1For H or CH3Or OH,；
R2For H, OCH3、OC2H5、CF3、OCF3, 1-3 substitution F, Cl, Br and I；
R3For H, F, Cl, Br, I and C1-C6The alkoxy of straight or branched.
Its pharmaceutically acceptable salt class of the compound of the present invention, can be the salt with inorganic acid or organic acid formation, such as
Hydrochloride, hydrobromate, hydriodate, sulfate or disulfate, phosphate or hydrophosphate, acetate, benzoate, wine
Stone hydrochlorate, succinate, maleate, fumarate, lactate, citrate, gluconate, mesylate, benzene sulfonate
Or tosilate, preferred hydrochloride.
Unless otherwise indicated, there is with the following term used in claims following specified contain in this manual
Justice：
The carbon number content of various hydrocarbonaceous parts represents by prefix, indicates in the part minimum number of carbon atom and most
Big number, i.e. prefix Ci-jRepresent integer " i " to the part of integer " j " individual carbon atom, including end points.Thus, for example, C1-6Alkyl refers to
The carbonyl of 1 to 6 carbon atom, including 1 and 6 carbon atoms.
It can be different substituents that the substituent of " independence " selection, which refers to wherein described substituent,.It is therefore intended that number
Carbon atom (such as C1-7) should independently refer to the carbon number in alkyl or cycloalkyl part or refer to wherein alkyl as its prefix word
The moieties for the relatively large-substituent that root occurs.
Term " alkyl ", represent that there is 1-8 carbon atom or the within this range group of any number of straight chain and side chain,
But straight chain group is then only included to independent group such as " propyl group ", branched chain isomer such as " isopropyl " will explicitly indicate that.Alkane
The substituent that base arbitrarily can be selected from the group by one, two or three substitutes：Halogen, aryl, heteroaryl.Representational example
Son includes but is not limited to：Difluoromethyl, 2- fluoro ethyls, 3- fluoropropyls, 4- fluorine butyl, 3- cyanobutyls ,-CH=CH- aryl etc..
Term " halogen " is fluorine, chlorine, bromine and iodine.The substituent substituted with multiple halogens is to provide the side of stable compound
Formula is substituted.
The invention provides the preparation method of described 6- substituted aryl amino methyl Tetrahydronaphthalencompounds compounds, it includes：Through
Suzuki reactions, Mannich reactions, Grignard react three steps and pass through sequence reaction preparation；
Pass through following formulas：
General synthetic routes I
Reagent and conditions:(a)NaOH DMA(b)HBr CuBr H2O(c)Pd(PPh3)4,K2CO3,
toluene90℃(d)N-methyl-N-methylenemethanaminium,MeCN rt；(e)n-BuLi,3-
Bromoanisole-78℃THF；
Or,
General synthetic routes II
Reagent and conditions:(a)NaOH DMA(b)HBr CuBr H2O(c)Pd(PPh3)4,K2CO3,
toluene90℃(d)N-methyl-N-methylenemethanaminium,MeCN rt；(e)
n-BuLi,(3-bromophenoxy)(tert-butyl)dimethylsilane-78℃THF；(f)CsCO3,
DMF:H2O10:1rt.
In embodiments of the invention, the following crucial universal synthesis method in said synthesis route formula is respectively adopted, makes
Standby 6- substituted aryl amino methyl tetrahydro naphthaline derivatives or its esters：
Universal synthesis method 1：
10.0g (61.7mmol) is added in the 500mL three-necked flasks equipped with reflux condensing tube, thermometer and charging hopper
6- hydroxyls-ALPHA-tetralone, 90mL DMAC N,N' dimethyl acetamides and 7.4g (185mmol) sodium hydroxide.Reaction solution 20~
Stirred 1 hour at 30 DEG C.The bromo- 2- methyl propanamides of 20.7g (185mmol) 2- are added in reaction solution and at 25~35 DEG C after
5 hours of continuous stirring.After 5 hours to be mixed, 22.2g (555mmol) sodium hydroxide, heating are now added into reaction solution again
Reaction solution is to 50~60 DEG C and stirs 1 hour at this temperature.To be mixed 1 as a child, 90mL water is added into system and by instead
It should be heated to flowing back, flow back 1 hour.Then as adding 180mL water in system, system is allowed to naturally cool to 20~30 DEG C.Pass through
Filter the crystal powder that is settled out, and rinsed for 3 times with 90mL moisture, finally give brown crystal powder 7.15g, yield
71.9%.
Universal synthesis method 2：
5.04g (31mmol) 6- amino -1- four is added in the 500mL three-necked flasks equipped with 100mL constant pressure funnels
Hydrogen naphthalenone, 50mL hydrobromic acids and 50mL water.Reaction system is sufficiently stirred under ice salt bath and is cooled to less than 0 DEG C.Dripped to constant pressure
2.50g natrium nitrosums and 20mL water are added in liquid funnel.Make natrium nitrosum be completely dissolved in water in backward reaction solution dropwise to delay
The slow sodium nitrite in aqueous solution that is added dropwise makes the interior temperature of reaction be no more than 5 DEG C.Continue stirring 15 minutes after charging.To constant pressure addition
5.14g cuprous bromides and 25mL hydrobromic acids are added in funnel.The hydrobromic acid solution of cuprous bromide is added dropwise in reaction solution dropwise,
Continue stirring 15 minutes after being added dropwise.60mL ethyl acetate extractive reaction liquid in three times is used in reaction after terminating, merge acetic acid second
Ester layer, washed with 20mL saturated common salts, anhydrous sodium sulfate drying, be finally spin-dried for obtaining brown oil 2.50g, yield under low pressure
35.51%
Universal synthesis method 3：
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder, is obtained.
Universal synthesis method 4：
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease.
Universal synthesis method 5：
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise hydrochloride is made
Universal synthesis method 6：
Compound A (0.73mmol) is added in 50mL eggplant type bottles, is dissolved in the mixed solution of 10mLDMF and 1mL water composition,
0.12g cesium carbonates (0.36mmol) are added, are stirred overnight at room temperature, reaction terminates, and 30mL water is added, then with 15mL acetic acid second
Ester extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：Methanol=
20:1) yellow oil, is obtained, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise hydrochloride is made.
The 6- substituted aryl amino methyl tetrahydro naphthaline derivatives or its esters of the present invention can be used as lead compound to close
Into new μ, κ and delta opiate receptor activator or antagonist, involved μ, κ and delta opiate receptor activator or antagonist can be used for
Prepare analgesic.
Invention further provides above-claimed cpd to prepare the purposes in treating idicatio related to opiate receptor, especially
It is the purposes in medicine in terms of pain is treated in preparation, and more particularly it is by adjusting opiate receptor improvement or treatment about pain
The application in medicine in the disease of pain.Wherein described disease may be selected from but be not limited to pain, IBS, itch, into
Addiction, depression；For example, pain may be selected from but be not limited to pain, the pain and structure or soft tissue of periphery mediation that maincenter mediates
Damage relevant pain, with the pain of inflammation-related, the pain relevant with progressive disease, neuropathic pain, Acute Pain and
Chronic ache, especially adapt to treatment or alleviate perioperative pain, chronic ache, neuropathic pain, cancer pain.
Embodiment
The present invention is illustrated by following examples, it should be understood that these embodiments are merely to illustrate, and do not limit the present invention
Scope.Compound of formula I can be prepared such as following general synthetic routes and embodiment description.
The prepare compound A-1 of embodiment 1 (2- ((dimethylamino) methyl) -1- (3- methoxyphenyls) -6- phenyl -1,
2,3,4- naphthane -1- alcohol)
Based on above-mentioned formula, synthetic method as the following formula, using compound 2 and phenyl boric acid as raw material, compound 3a (6- are obtained
Phenyl -3,4- dihydronaphthalene -1 (2H) -one),
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder (compound 3a), is made；
Using compound 3a as raw material, synthetic method as the following formula,
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, 2- ((dimethylamino) methyl) -6- phenyl -3,4- dihydronaphthalene -1 (2H) -one (compound 4a) is made；
Using compound 4a as raw material, synthetic method as the following formula,
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, compound A-1 (2- ((dimethylamino) methyl) -1- (3- methoxyphenyls) -6- benzene is made
Base -1,2,3,4- naphthane -1- alcohol), this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise hydrochloride is made；
1H NMR (400MHz, DMSO-d6)1H NMR (400MHz, DMSO) δ 7.63 (d, J=7.3Hz, 2H), 7.43 (t, J
=7.6Hz, 3H), 7.39-7.28 (m, 2H), 7.23 (d, J=8.2Hz, 1H), 7.15 (t, J=7.9Hz, 1H), 6.83-6.70
(m, 3H), 6.60 (d, J=7.8Hz, 1H), 3.68 (s, 3H), 3.00 (d, J=5.2Hz, 2H), 2.30-2.11 (m, 8H),
1.78–1.63(m,2H),1.53–1.37(m,1H).13C NMR(101MHz,DMSO)δ159.29,158.90,149.83,
143.54,141.89,139.10,137.25,136.67,131.00,129.35,128.96,128.72,127.85,127.05,
126.84,126.53,124.95,124.71,120.86,119.63,114.57,113.49,111.88,111.70,75.50,
59.32,55.48,42.77,28.82,23.36.ESI-MSm/z388.1[M+H]+。
The prepare compound A-2 of embodiment 2 (2- ((dimethylamino) methyl) -1- (3- methoxyphenyls) -6- (2- methoxies
Base phenyl) -1,2,3,4- naphthane -1- alcohol)
Based on above-mentioned formula, synthetic method as the following formula, using compound 2 and phenyl boric acid as raw material, compound 3b is made
(6- phenyl -3,4- dihydronaphthalene -1 (2H) -one),
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1), obtain white powder and compound 3b (6- phenyl -3,4- dihydronaphthalene -1 (2H) -one) is made；
Using compound 3b as raw material, synthetic method as the following formula, be made compound 4b (2- ((dimethylamino) methyl)-
6- phenyl -3,4- dihydronaphthalene -1 (2H) -one),
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease (compound 4b)；
Using compound 4b as raw material, synthetic method as the following formula, be made compound A-2 (2- ((dimethylamino) methyl)-
1- (3- methoxyphenyls) -6- (2- methoxyphenyls) -1,2,3,4- naphthane -1- alcohol),
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, compound A-2 (2- ((dimethylamino) methyl) -1- (3- methoxyphenyls) -6- (2- are made
Methoxyphenyl) -1,2,3,4- naphthane -1- alcohol), this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise salt is made
Hydrochlorate；
1H NMR (400MHz, DMSO-d6)δ9.65(s,1H),7.36–7.30(m,1H),7.29–7.22(m,3H),7.16
(dd, J=8.2,1.6Hz, 1H), 7.12-7.06 (m, 2H), 7.00 (t, J=7.4Hz, 1H), 6.89 (d, J=7.8Hz, 1H),
6.85 (dd, J=8.1,2.3Hz, 1H), 6.76 (d, J=8.2Hz, 1H), 5.97 (s, 1H), 3.76 (s, 3H), 3.74 (s,
3H), 3.10-2.98 (m, 2H), 2.90 (d, J=16.6Hz, 1H), 2.77 (d, J=8.8Hz, 1H), 2.70 (d, J=4.2Hz,
3H), 2.45 (d, J=4.3Hz, 3H), 2.17 (d, J=11.8Hz, 1H), 2.03-1.91 (m, 1H)13C NMR(101MHz,
DMSO)δ159.35,156.62,149.49,141.00,137.27,136.19,130.76,129.98,129.91,129.40,
129.36,129.29,127.41,121.18,119.62,113.50,112.13,111.97,75.26,65.39,59.10,
55.89,55.50,44.97,42.45,41.47,28.82,23.41,15.64.ESI-MSm/z418.2[M+H]+。
The prepare compound A-3 of embodiment 3 (2- ((dimethylamino) methyl) -1- (3- methoxyphenyls) -6- phenyl -1,
2,3,4- naphthane -1- alcohol)
Based on above-mentioned formula, synthetic method as the following formula, using compound 2 and phenyl boric acid as raw material, compound 3c (6- are made
Phenyl -3,4- dihydronaphthalene -1 (2H) -one (3c)),
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder, is obtained, compound 3c is made；
Using compound 3c as raw material, synthetic method as the following formula, according to universal synthesis method 4, compound 4c (2- are made
((dimethylamino) methyl) -6- phenyl -3,4- dihydronaphthalene -1 (2H) -one),
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, compound 4c is made.
Using compound 4c as raw material, synthetic method, is made compound A-3 (2- ((dimethylamino) methyl) -1- as the following formula
(3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, compound A-3 is made, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise salt is made
Hydrochlorate；
1H NMR (400MHz, DMSO-d6) δ 10.27 (s, 1H), 7.47 (d, J=1.4Hz, 1H), 7.36 (ddd, J=
7.9,4.7,3.0Hz, 2H), 7.26 (t, J=8.0Hz, 1H), 7.20 (d, J=7.9Hz, 1H), 7.17-7.13 (m, 1H),
7.08 (s, 1H), 6.93 (dd, J=8.2,2.2Hz, 1H), 6.90-6.81 (m, 3H), 5.97 (s, 1H), 3.81 (s, 3H),
3.76 (s, 3H), 3.02 (qd, J=16.7,4.4Hz, 3H), 2.78 (d, J=13.0Hz, 4H), 2.44 (s, 2H), 2.28 (s,
1H),2.03–1.90(m,1H).13C NMR(101MHz,DMSO-d6)δ160.18,159.34,149.54,141.85,
141.79,139.04,137.16,130.96,130.41,129.39,126.94,124.84,119.61,119.40,113.47,
113.37,112.64,112.00,75.31,59.02,55.59,55.50,42.50,28.73,23.40.ESI-MSm/z418.2
[M+H]+。
Embodiment 4
Based on above-mentioned formula, using compound 2 and phenyl boric acid as raw material, synthetic method, is made compound 3d (6- benzene as the following formula
Base -3,4- dihydronaphthalene -1 (2H) -one (3d))
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder (6- phenyl -3,4- dihydronaphthalene -1 (2H) -one (3d)), is obtained；
Using compound 3d as raw material, synthetic method, is made compound 4d (2- ((dimethylamino) methyl) -6- as the following formula
Phenyl -3,4- dihydronaphthalene -1 (2H) -one)
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, compound 4d is made；
Using compound 4d as raw material, synthetic method, is made compound A-4 (2- ((dimethylamino) methyl) -1- as the following formula
(3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol),
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, compound A-4 is made, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise salt is made
Hydrochlorate；
1H NMR (400MHz, DMSO-d6) δ 9.67 (s, 1H), 7.57 (d, J=8.7Hz, 2H), 7.40 (s, 1H), 7.31
(d, J=8.2Hz, 1H), 7.25 (t, J=8.0Hz, 1H), 7.06 (s, 1H), 7.00 (d, J=8.7Hz, 2H), 6.89-6.79
(m,3H),5.96(s,1H),3.79(s,3H),3.76(s,3H),3.11–2.90(m,3H),2.84–2.75(m,1H),2.70
(d, J=3.6Hz, 3H), 2.45 (d, J=3.7Hz, 3H), 2.15 (d, J=11.1Hz, 1H), 2.02-1.88 (m, 1H)13C
NMR(101MHz,DMSO)δ159.34,149.55,140.89,138.82,137.08,132.62,130.96,129.38,
128.13,126.23,124.28,119.62,114.79,113.47,111.99,75.29,59.02,55.64,55.49,
44.92,42.47,41.51,28.75,23.39.ESI-MSm/z418.2[M+H]+。
Embodiment 5
Based on above-mentioned formula, using compound 2 and phenyl boric acid as raw material, synthetic method, is made compound 3e (6- benzene as the following formula
Base -3,4- dihydronaphthalene -1 (2H) -one (3e))
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder, is obtained, compound 3e is made；
Using compound 3e as raw material, synthetic method, is made compound 4e (2- ((dimethylamino) methyl) -6- as the following formula
Phenyl -3,4- dihydronaphthalene -1 (2H) -one)
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, compound 4e is made；
Using compound 4e as raw material, synthetic method, is made compound A-5 (2- ((dimethylamino) methyl) -1- as the following formula
(3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, compound A-5 is made, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise salt is made
Hydrochlorate；
1H NMR (400MHz, DMSO) δ 7.88 (d, J=8.2Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.53 (d, J
=1.6Hz, 1H), 7.44 (dd, J=8.2,1.9Hz, 1H), 7.22 (t, J=8.0Hz, 1H), 7.01 (s, 1H), 6.95 (d, J
=8.2Hz, 1H), 6.81 (dd, J=8.1,2.8Hz, 2H), 3.75 (s, 3H), 3.48-3.22 (m, 1H), 3.06-2.89 (m,
2H), 2.56 (s, 1H), 2.35-1.99 (m, 8H), 1.93-1.79 (m, J=16.0Hz, 1H)13C NMR(101MHz,DMSO)δ
163.93,155.18,149.17,148.29,142.43,142.02,135.87,133.84,133.02,132.80,132.54,
131.94,130.94,130.51,129.68,128.71,124.37,118.25,116.33,80.71,64.69,60.18,
49.99,48.12,33.66,28.00ESI-MSm/z456.2[M+H]+。
Embodiment 6
Based on above-mentioned formula, using compound 2 and phenyl boric acid as raw material, synthetic method, is made compound 3f (6- benzene as the following formula
Base -3,4- dihydronaphthalene -1 (2H) -one (3f)
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder, is obtained, compound 3f is made；
Using compound 3f as raw material, synthetic method, obtains compound 4f (2- ((dimethylamino) methyl) -6- as the following formula
Phenyl -3,4- dihydronaphthalene -1 (2H) -one)
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, obtain compound 4f；
Using compound 4f as raw material, synthetic method, obtains compound A-6 (2- ((dimethylamino) methyl) -1- as the following formula
(3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, obtains compound A-6, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise salt is made
Hydrochlorate；
1H NMR (400MHz, DMSO) δ 7.67 (d, J=8.6Hz, 2H), 7.50 (d, J=8.6Hz, 2H), 7.45 (d, J
=1.6Hz, 1H), 7.36 (dd, J=8.2,1.9Hz, 1H), 7.22 (t, J=7.9Hz, 1H), 7.01 (s, 1H), 6.90 (d, J
=8.2Hz, 1H), 6.81 (dd, J=8.1,2.6Hz, 2H), 3.74 (s, 3H), 3.37 (s, 1H), 3.04-2.87 (m, 2H),
2.59 (s, 1H), 2.26 (d, J=32.1Hz, 7H), 2.07 (d, J=12.2Hz, 1H), 1.86 (s, 1H) .ESI-MSm/
z422.2[M+H]+。
Embodiment 7
Based on above-mentioned formula, using compound 2 and phenyl boric acid as raw material, synthetic method, is made compound 3g (6- benzene as the following formula
Base -3,4- dihydronaphthalene -1 (2H) -one (3g))
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder, is obtained, compound 3g is made；
Using compound 3g as raw material, synthetic method, obtains compound 4g (2- ((dimethylamino) methyl) -6- as the following formula
Phenyl -3,4- dihydronaphthalene -1 (2H) -one),
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, obtain compound 4g；
Using compound 4g as raw material, synthetic method, obtains compound A-7 (2- ((dimethylamino) methyl) -1- as the following formula
(3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthanes -1-)
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, obtains compound A-7, this compound is dissolved in absolute ether, HCl diethyl ether solutions is added dropwise salt is made
Hydrochlorate；
1H NMR (400MHz, DMSO) δ 7.92 (d, J=2.0Hz, 1H), 7.73-7.63 (m, 2H), 7.52 (d, J=
1.6Hz, 1H), 7.41 (dd, J=8.2,1.9Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 6.99 (s, 1H), 6.92 (d, J=
8.2Hz, 1H), 6.80 (dd, J=8.2,2.4Hz, 2H), 3.74 (s, 3H), 3.37 (s, 2H), 2.96 (d, J=4.6Hz, 2H),
2.39-2.11 (m, 7H), 2.05 (d, J=11.2Hz, 1H), 1.84 (s, 1H)13C NMR(151MHz,CDCl3)δ163.92,
155.36,148.20,145.78,142.42,140.90,136.90,136.18,135.82,135.24,133.83,133.49,
131.97,131.75,129.42,124.37,118.25,116.31,80.74,64.71,60.18,60.13,50.04,
48.11,34.20,33.57,27.98.ESI-MSm/z456.2[M+H]+。
Embodiment 8
Based on above-mentioned formula, using compound 2 and phenyl boric acid as raw material, synthetic method, is made compound 3h (6- benzene as the following formula
Base -3,4- dihydronaphthalene -1 (2H) -one (3h))
1g compounds 7 (4.4mmol) are added in there-necked flasks of the 100mL with reflux condensing tube, substitute phenyl boric acid
(6.6mmol) and 1.21g potassium carbonate (8.8mmol), 20mL toluene is dissolved in, argon gas is replaced three times, adds tetra-triphenylphosphine palladium
20mg, back flow reaction is overnight, after reaction terminates, adds filtered off through Celite insoluble matter, concentrates toluene solution, column chromatography (petroleum ether：Second
Acetoacetic ester=20:1) white powder, is obtained, (2H) -one (3h) of compound 6- phenyl -3,4- dihydronaphthalene -1 is made；
Using compound 3h as raw material, synthetic method, obtains compound 4h (2- ((dimethylamino) methyl) -6- as the following formula
Phenyl -3,4- dihydronaphthalene -1 (2H) -one),
6- phenyl-tetrahydro naphthalenone 6.8mmol, N, N- dimethyl alkene inferior amine salt hydrochlorates 1.28g is added in 100mL eggplant type bottles
(14mmol), 20mL acetonitriles are dissolved in, are stirred overnight at room temperature, there are a large amount of white solids to separate out, after reaction terminates, removed under reduced pressure molten
Agent, in addition 20mL water, extracted three times with 15mL ethyl acetate, merging organic phase, after anhydrous sodium sulfate drying, concentrate dry Huang
Color grease, obtain compound 4h；
Using compound 4h as raw material, synthetic method, obtains compound A-8 (2- ((dimethylamino) methyl) -1- as the following formula
(3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)
After argon gas displacement in dry 100mL there-necked flasks, the anhydrous THF of 10mL, bromo-derivative are added with syringe
(12.3mmol), reaction is cooled to -78 DEG C with dry ice-ethyl acetate system, added into reaction 2.5N n-BuLis just oneself
Alkane solution 4.92mL, after reacting one hour, compound 500mg is dissolved in the anhydrous THF of 10mL, is slowly added in reaction solution, -78
Continue reaction 2 hours under the conditions of DEG C, reaction terminates, and reaction is quenched with saturated aqueous ammonium chloride, adds 30mL water, uses 15mL
Ethyl acetate extracts three times, merges organic phase, anhydrous sodium sulfate drying, column chromatography (dichloromethane are used after saturated common salt washing：First
Alcohol=20:1) grease, is obtained, obtains Compound Compound A-8, this compound is dissolved in absolute ether, HCl diethyl ether solutions are added dropwise
Hydrochloride is made；
1H NMR(400MHz,DMSO)δ10.10(s,1H),7.31–7.22(m,4H),7.20–7.15(m,1H),7.14
(s, 1H), 7.10 (s, 1H), 7.05 (dd, J=8.1,1.6Hz, 1H), 6.90 (d, J=7.8Hz, 1H), 6.85 (dd, J=
8.2,2.3Hz, 1H), 6.81 (d, J=8.1Hz, 1H), 5.98 (s, 1H), 3.77 (s, 3H), 3.12-2.89 (m, 2H), 2.77
(s, 2H), 2.68 (s, 3H), 2.56 (d, J=10.6Hz, 1H), 2.43 (s, 3H), 2.24 (d, J=6.5Hz, 4H), 2.05-
1.93(m,1H).13C NMR(101MHz,DMSO)δ159.35,149.47,141.38,141.03,140.33,136.49,
135.11,130.81,130.21,129.92,129.43,129.11,127.73,127.08,126.38,119.59,113.51,
112.01,75.30,59.09,55.49,44.97,42.37,41.51,28.68,23.33,20.69.ESI-MSm/z402.0[M
+H]+。
Embodiment 9
By universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3a (6- phenyl -3,4- dihydros are obtained
Naphthalene -1 (2H) -one (3a))；
According to universal synthesis method 4, using compound 3a as raw material, obtain compound 4a (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4a as raw material, compound AOH-1 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6) δ 9.31 (s, 1H), 7.64 (d, J=7.1Hz, 2H), 7.50-7.40 (m, 4H),
7.33 (dd, J=16.2,7.7Hz, 2H), 7.07 (t, J=7.9Hz, 1H), 6.67 (d, J=8.0Hz, 1H), 6.60 (d, J=
7.7Hz, 1H), 6.51 (s, 1H), 6.01 (s, 1H), 3.18 (dd, J=17.8,9.2Hz, 1H), 3.04 (s, 2H), 2.09-
1.98((m,6H),2.46–2.32(m,2H),2.09–1.98(m,1H),1.72–1.58(m,1H).ESI-MSm/z374.1[M+
H]+。
Embodiment 10
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3b (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3b))；
According to universal synthesis method 4, using compound 3b as raw material, obtain compound 4b (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4b as raw material, compound AOH-2 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6) δ 9.36 (s, 2H), 7.37-7.29 (m, 1H), 7.24 (dd, J=6.8,
2.3Hz, 2H), 7.18 (d, J=8.2Hz, 1H), 7.16-7.07 (m, 2H), 7.01 (t, J=7.4Hz, 1H), 6.87 (s, 1H),
6.80 (t, J=8.4Hz, 2H), 6.66 (dd, J=7.9,2.0Hz, 1H), 5.91 (s, 1H), 3.74 (s, 3H), 3.11-2.76
(m,4H),2.72(s,3H),2.14–2.04(m,4H),2.14–2.04(m,1H),2.02–1.88(m,1H).ESI-MSm/
z404.3[M+H]+。
Embodiment 11
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3c (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3c))；
According to universal synthesis method 4, using compound 3c as raw material, obtain compound 4c (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4c as raw material, compound AOH-3 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6)δ9.73(s,1H),9.38(s,1H),7.46(s,1H),7.40–7.32(m,
2H), 7.20 (d, J=8.0Hz, 1H), 7.13 (dd, J=13.1,5.1Hz, 2H), 6.95-6.87 (m, 2H), 6.85 (s, 1H),
6.76 (d, J=7.8Hz, 1H), 6.66 (dd, J=7.9,1.9Hz, 1H), 5.92 (s, 1H), 3.81 (s, 3H), 3.01 (dt, J
=13.2,9.8Hz, 3H), 2.87-2.77 (m, 1H), 2.70 (s, 3H), 2.44 (s, 4H), 2.21-2.08 (d, J=10.7Hz,
1H),2.02–1.87(m,1H).ESI-MSm/z404.3[M+H]+。
Embodiment 12
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3d (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3d))；
According to universal synthesis method 4, using compound 3a as raw material, obtain compound 4d (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4d as raw material, compound AOH-4 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6) δ 9.36 (s, 1H), 7.57 (d, J=8.8Hz, 2H), 7.39 (s, 1H), 7.33
(d, J=8.2Hz, 1H), 7.12 (t, J=7.9Hz, 1H), 7.01 (d, J=8.8Hz, 2H), 6.90-6.82 (m, 2H), 6.76
(d, J=7.7Hz, 1H), 6.65 (dd, J=7.9,2.0Hz, 1H), 5.91 (s, 1H), 3.79 (s, 3H), 2.98 (dt, J=
21.6,14.0Hz,3H),2.88–2.77(m,1H),2.71(s,3H),2.48–2.34(m,4H),2.17–2.04(m,1H),
2.01–1.88(m,1H).ESI-MSm/z404.3[M+H]+。
Embodiment 13
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3e (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3e))；
According to universal synthesis method 4, using compound 3e as raw material, obtain compound 4e (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4e as raw material, compound AOH-5 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6) δ 9.85 (s, 1H), 9.40 (s, 1H), 7.88 (d, J=8.3Hz, 2H), 7.81
(d, J=8.5Hz, 2H), 7.56 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.2,1.8Hz, 1H), 7.14 (t, J=7.9Hz,
1H), 6.95 (d, J=8.2Hz, 1H), 6.86 (s, 1H), 6.77 (d, J=7.7Hz, 1H), 6.67 (dd, J=7.9,1.9Hz,
1H), 5.97 (s, 1H), 3.11-2.96 (m, 3H), 2.83 (d, J=12.3Hz, 1H), 2.70 (s, 3H), 2.44 (s, 4H),
2.24–2.14(m,1H),2.03–1.89(m,1H).ESI-MSm/z442.2[M+H]+。
Embodiment 14
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3f (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3f))；
According to universal synthesis method 4, using compound 3f as raw material, obtain compound 4f (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4f as raw material, compound AOH-6 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6) δ 10.05 (s, 1H), 9.40 (s, 1H), 7.68 (d, J=8.6Hz, 2H),
7.55-7.45 (m, 3H), 7.39 (dd, J=8.2,1.9Hz, 1H), 7.13 (t, J=7.9Hz, 1H), 6.91 (d, J=8.2Hz,
1H), 6.86 (s, 1H), 6.77 (d, J=7.8Hz, 1H), 6.67 (dd, J=7.7,2.1Hz, 1H), 5.92 (s, 1H), 2.99
(ddd, J=17.3,16.8,8.2Hz, 3H), 2.89-2.78 (m, 1H), 2.69 (s, 3H), 2.43 (s, 4H), 2.27-2.15
(m,1H),2.03–1.88(m,1H).ESI-MSm/z408.2[M+H]+。
Embodiment 15
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3g (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3g))
According to universal synthesis method 4, using compound 3g as raw material, obtain compound 4g (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4g as raw material, compound AOH-7 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6) δ 9.97 (s, 1H), 9.40 (s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.74-
7.64 (m, 2H), 7.55 (d, J=1.6Hz, 1H), 7.49-7.41 (m, 1H), 7.13 (t, J=7.9Hz, 1H), 6.92 (d, J=
8.3Hz, 1H), 6.85 (s, 1H), 6.76 (d, J=7.7Hz, 1H), 6.67 (dd, J=7.9,2.1Hz, 1H), 5.96 (s, 1H),
3.12-2.92 (m, 3H), 2.82 (dd, J=21.6,10.1Hz, 2H), 2.70 (s, 3H), 2.44 (s, 4H), 2.19 (s, 1H),
2.02–1.87(m,1H).ESI-MSm/z442.2[M+H]+。
Embodiment 16
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3h (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3h))；
According to universal synthesis method 4, using compound 3h as raw material, obtain compound 4h (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4h as raw material, compound AOH-8 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO-d6)δ9.30(s,1H),7.31–7.20(m,3H),7.20–7.14(m,1H),
7.14-7.07 (m, 2H), 7.04 (dd, J=8.1,1.6Hz, 1H), 6.87 (d, J=8.1Hz, 2H), 6.75 (d, J=7.7Hz,
1H), 6.63 (dd, J=8.0,1.9Hz, 1H), 3.37 (d, J=8.7Hz, 1H), 2.99-2.88 (m, 2H), 2.63 (d, J=
10.7Hz, 1H), 2.24 (s, 10H), 2.07 (d, J=11.8Hz, 1H), 1.97-1.82 (m, 1H) .ESI-MSm/z388.0 [M+
H]+。
Embodiment 17
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3i (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3i))；
According to universal synthesis method 4, using compound 3i as raw material, obtain compound 4i (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4i as raw material, compound AOH-9 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO) δ 9.33 (s, 1H), 7.83 (dd, J=7.7,3.2Hz, 1H), 7.71 (dd, J=
11.7,7.2Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.39 (dd, J=12.1,7.6Hz, 1H), 7.26 (d, J=8.1Hz,
1H), 7.06 (ddd, J=27.7,12.1,8.0Hz, 3H), 6.93-6.50 (m, 4H), 3.39 (dd, J=55.5,34.6Hz,
1H), 3.06-2.77 (m, 2H), 2.61 (s, 1H), 2.46-2.12 (m, 7H), 2.07 (d, J=10.9Hz, 1H), 1.98-1.75
(m,2H).13CNMR(101MHz,DMSO)δ157.19,144.00,142.80,141.07,138.10,136.27,132.70,
129.96,128.93,128.77,128.37,126.64,126.55,119.00,117.89,115.54,114.38,113.74,
75.82,59.84,43.45,42.46,28.90,23.24.ESI-MSm/z442.2[M+H]+。
Embodiment 18
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3j (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3j))
According to universal synthesis method 4, using compound 3j as raw material, obtain compound 4j (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4j as raw material, compound AOH-10 (2- ((dimethylaminos are obtained
Base) methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO) δ 9.39 (s, 1H), 7.63-7.40 (m, 4H), 7.26 (s, 1H), 7.18 (d, J=
8.2Hz, 1H), 7.11 (t, J=7.9Hz, 1H), 6.96-6.81 (m, 2H), 6.73 (d, J=7.7Hz, 1H), 6.65 (dd, J=
7.9,1.8Hz, 1H), 2.98 (ddd, J=29.8,27.1,16.6Hz, 3H), 2.76 (d, J=22.4Hz, 1H), 2.37 (s,
7H), 2.15 (d, J=11.1Hz, 1H), 2.04-1.81 (m, 2H)13CNMR(101MHz,DMSO)δ157.29,149.65,
145.80,142.62,136.81,134.97,134.57,132.13,130.53,129.77,129.06,128.32,126.87,
121.64,117.86,114.39,113.94,75.52,59.49,44.11,43.08,28.86,23.30.ESI-MSm/
z458.2[M+H]+。
Embodiment 19
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3k (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3k))；
According to universal synthesis method 4, using compound 3k as raw material, obtain compound 4k (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4k as raw material, compound A-11 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR(400MHz,DMSO)δ9.32(s,1H),7.58–7.47(m,1H),7.46–7.21(m,5H),7.09
(dt, J=12.7,7.8Hz, 1H), 6.92 (d, J=8.2Hz, 1H), 6.84 (s, 1H), 6.74 (d, J=7.8Hz, 1H), 6.63
(dd, J=13.7,5.9Hz, 2H), 3.33 (d, J=10.4Hz, 1H), 2.96 (ddd, J=20.7,12.2,4.1Hz, 2H),
2.66 (s, 1H), 2.35 (d, J=55.1Hz, 7H), 2.10 (d, J=10.4Hz, 1H), 2.03-1.76 (m, 1H)13CNMR
(101MHz,DMSO)δ160.82(s),158.38(s),157.20(s),150.03(s),142.88(s),137.00(s),
133.89(s),131.15(s),130.70(s),129.85(s),128.98(s),128.44(s),126.75(s),125.35
(s),117.91(s),116.65(s),115.59(s),114.40(s),113.81(s),75.71(s),59.72(s),49.06
(s),43.42(s),28.95(s),23.28(s).ESI-MSm/z392.2[M+H]+。
Embodiment 20
According to universal synthesis method 3, using compound 2 and phenyl boric acid as raw material, compound 3l (6- phenyl -3,4- bis- is obtained
Hydrogen naphthalene -1 (2H) -one (3l))；
According to universal synthesis method 4, using compound 3l as raw material, obtain compound 4l (2- ((dimethylamino) methyl)-
(2H) -one of 6- phenyl -3,4- dihydronaphthalene -1)；
According to universal synthesis method 5 and 6, using compound 4l as raw material, compound A-12 (2- ((dimethylamino) are obtained
Methyl) -1- (3- methoxyphenyls) -6- phenyl -1,2,3,4- naphthane -1- alcohol)；
1H NMR (400MHz, DMSO) δ 9.30 (s, 1H), 7.55 (ddd, J=7.7,3.6,1.8Hz, 1H), 7.46-
7.34 (m, 3H), 7.15 (dddd, J=20.1,18.8,16.0,8.2Hz, 3H), 6.94-6.70 (m, 2H), 6.66-6.55 (m,
2H), 3.35 (s, 1H), 3.07-2.82 (m, 2H), 2.55 (s, 1H), 2.41-2.12 (m, 7H), 2.06 (d, J=12.0Hz,
1H),1.96–1.72(m,2H).13CNMR(101MHz,DMSO)δ157.14,150.21,144.08,142.95,140.03,
137.41,136.70,131.97,130.34,129.51,129.30,128.91,127.96,127.16,117.90,115.57,
114.36,113.68,75.81,59.93,49.06,45.48,43.72,42.55,29.13,23.25.ESI-MSm/z408.2
[M+H]+。
The Competition binding assay of embodiment 21
Prepare membrane receptor：Cell kind is in 10cm2(NBCS of F-12 culture mediums+10%) a couple of days is cultivated in culture dish,
Cell sucks nutrient solution after covering with ware bottom；Add PBS/EDTA solution (0.1MNaCl, 0.01MNaH2PO4, 0.04%EDTA) and 3ml
3-5min is digested, is blown and beaten with suction pipe, completely falls off cell, cell is collected in 40ml centrifuge tubes, 5000rpm centrifugation 5min, goes
Supernatant；Ice-cold homogenate (50mMHEPESPH7.4,3mMMgCl, 1mMEGTA) is added in centrifuge tube, by solution and precipitation
It is transferred in homogenizer and is homogenized；Then homogenate is transferred in centrifuge tube, 18000rpm centrifugation 15min, centrifuged 2 times altogether；
The precipitation arrived adds appropriate 50mMTris-HCl, and PH7.4 buffer solution is homogenized and is sub-packed in centrifuge tube, and -70 DEG C of refrigerators preserve
It is stand-by；
Total binding pipe add the expression equivalent to 20-30 μ g membrane receptor protein and [3H] mark part (1-2nM), relatively
The non-specific binding pipe answered separately adds 1 μM of respective ligand, and sample cell adds the opioid ligand class medicine of the various screenings of various concentrations
Thing, final volume are 100 μ l, 30 DEG C of incubation 30min, terminating reaction in frozen water are put, through GF/C on Millipore sample dividers
(whatman) glass fiber filter paper negative pressure leaching, flushed three times with 4ml50mMTris-HCl (PH7.4), after filter paper drying, put
Managed in 0.5mlEppendorf, add 0.5ml lipophilic scintillation solutions, PERKINELMERPRI-CARB2910 liquid scintillation counters are surveyed
Determine radioactive intensity, calculate inhibiting rate, test more than in triplicate, every group three is managed again,
Supression rate=(total binding rate dpm- sample cell dpm)/(total binding pipe dpm- non-specific bindings pipe dpm) ×
100%
IC is calculated with Prism5.0 softwares50.K is calculated as followsiValue, Ki=IC50/ (1+ [L]/Kd), [L] is is labelled
The concentration of part, KdFor the balance dissociation parameters of tagged ligand.
Table 1 shows affinity costant K of the representative compound to opiate receptoriValue, wherein, use independent measurement three times
Average value ± standard deviation represents.
Table 1
Embodiment 22
Preparing expression according to embodiment 21 has the cell membrane of opiate receptor；[35S] GTP γ S experiment set base set (basal),
Non-specific group (nonspecific) and testing sample group (sample).Membrane receptor (15 μ g/ samples), 0.1nM are added in base set
[35S] GTP γ S (1,030Ci/mmol, AmershamPharmacia), 40 μM of GDP, with buffer solution (50mMTris-HCl, 5mM
MgCl2, 100mM NaCl, 1mM EDTA, 1mM DTT, pH=7.5) and volume is adjusted to 100 μ L.Testing sample group is in identical
Under the conditions of add various concentrations testing compound or morphine；Non-specific group of addition on-radiation GTP γ S (10 μM)；Each group is 30
DEG C water-bath 1h, then puts ice bath terminating reaction, is filtered on Millipore sample dividers through GF/C (Whatman) glass fibre
Paper negative pressure leaching, filter paper is rinsed three times with ice-cold 50mM Tris-HCl (pH=7.4), each 4ml, be placed in after filter paper drying
0.5ml Eppendorf are managed, and add 0.5ml lipophilic scintillation solutions, and Beckman LS6500 full-service fluids scintillation counter measure is put
Penetrating property intensity；[35S] GTP γ S Percentage bounds are calculated by equation below：100% × (cpmsample- cpmnonspecific)/
(cpmbasal- cpmnonspecific).Each concentration is three multiple pipes, and each independent experiment repeats 3-4 times, determines EC50Value.
Table 2 shows that representative compound (uses EC to each opiate receptor excitement ability50Value represent) with efficiency (with benchmark
Exciting percentage represents under state).
Table 2
Claims (7)
1. the 6- substituted aryl amino methyl tetrahydro naphthaline derivatives or its pharmaceutically acceptable salt of logical formula (I),
In formula：
R1For H,
R2For 2- methoxyl groups, 2- methyl or hydrogen,
R3For OH.
2. 6- substituted aryl amino methyl tetrahydro naphthaline derivatives or its pharmaceutically acceptable salt as described in claim 1, its
It is characterised by, described pharmaceutically acceptable salt includes the salt that inorganic acid or organic acid are formed.
3. 6- substituted aryl amino methyl tetrahydro naphthaline derivatives or its pharmaceutically acceptable salt as described in claim 1 or 2,
Characterized in that, described salt is hydrochloride, hydrobromate, hydriodate, sulfate or disulfate, phosphate or phosphoric acid hydrogen
Salt, acetate, benzoate, tartrate, succinate, maleate, fumarate, lactate, citrate, gluconic acid
Salt, mesylate, benzene sulfonate or tosilate.
4. the preparation method of the 6- substituted aryl amino methyl tetrahydro naphthaline derivatives described in any one of claim 1-3, it is special
Sign is that it includes：Reacted through Suzuki, Mannich reaction, Grignard react three steps pass through sequence reaction prepare, it is under
State synthetic route：
5. 6- substituted aryl amino methyl tetrahydro naphthaline derivatives described in any one of claim 1-3 or its is pharmaceutically acceptable
Salt preparing the purposes in treating related to opiate receptor idicatio medicine.
6. purposes as claimed in claim 5, it is characterised in that the idicatio related to opiate receptor is that pain, intestines are easy
Bowel syndrome, itch, habituation or depression.
7. purposes as claimed in claim 6, it is characterised in that described pain is perioperative pain, chronic ache, god
Through property pain or cancer pain.
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