CN101602680B - Naphthyl ethylamine derivative and preparation method thereof and application of naphthyl ethylamine derivative in preparing weight-reducing medicament - Google Patents
Naphthyl ethylamine derivative and preparation method thereof and application of naphthyl ethylamine derivative in preparing weight-reducing medicament Download PDFInfo
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- CN101602680B CN101602680B CN 200910115507 CN200910115507A CN101602680B CN 101602680 B CN101602680 B CN 101602680B CN 200910115507 CN200910115507 CN 200910115507 CN 200910115507 A CN200910115507 A CN 200910115507A CN 101602680 B CN101602680 B CN 101602680B
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- ethylamine derivative
- naphthyl
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims abstract description 20
- RUJHATQMIMUYKD-UHFFFAOYSA-N 2-naphthalen-1-ylethanamine Chemical class C1=CC=C2C(CCN)=CC=CC2=C1 RUJHATQMIMUYKD-UHFFFAOYSA-N 0.000 title abstract 5
- 208000008589 Obesity Diseases 0.000 claims abstract description 17
- 235000020824 obesity Nutrition 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical group 0.000 claims description 38
- WJVGMHDMWXHVFE-UHFFFAOYSA-N ethanamine;naphthalene Chemical class CCN.C1=CC=CC2=CC=CC=C21 WJVGMHDMWXHVFE-UHFFFAOYSA-N 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 8
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 6
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 6
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052799 carbon Inorganic materials 0.000 claims description 3
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- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
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- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 7
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract 3
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 abstract 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 21
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
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- 229940045997 vitamin a Drugs 0.000 description 1
Abstract
The invention discloses a naphthyl ethylamine derivative and a preparation method thereof and application of the naphthyl ethylamine derivative in preparing medicaments for treating obesity. The naphthyl ethylamine derivative is characterized in that the composition exists in a form of alkali or pharmaceutical salt, and has the general structural formula shown in the formula (I), wherein R is halogen, halogenated methyl radical, nitryl or optionally-substituted C1 to C3 alkoxy; R1 and R2 are H, optionally-substituted C1 to C6 alkyl or a substituent group of which the structure is shown in general formula (II); in the formula (II), R4 is the H, aryl, or optional C1 to C6 alkyl or C1 to C3 alkoxy; and the R3 is the optionally-substituted C1 to C6 alkyl. Pharmacological tests prove that the composition has good function of treating the obesity.
Description
Technical field
The invention belongs to the medicine pharmaceutical technology field of obesity, relate to a kind of derivative with naphthalene ethylamine of antiobesity action, this invention has also related to preparation method and the application aspect the medicine of preparation treatment of obesity of this derivative.
Background technology
Obesity has become ubiquitous problem in countries in the world, various crowd.Studies show that obesity is closely related with diseases such as hypertension, coronary heart disease, apoplexy, type ii diabetes, can increase the M ﹠ M of these diseases.Therefore obesity more and more causes people's attention, and the medicine of developing treatment of obesity safe, effective, easy to use seems more and more important.
The medicine of at present treatment obesity comprises following a few class according to its mechanism of action.A kind of is appetite-inhibiting agent, and Main Function is in central nervous system with depress appetite or increase satietion.These medicines comprise phentermine, Diethylpropion etc., because there is potential cardiovascular adverse effects in it, use now less.Metabolism Reinforcing agent by strengthening the metabolic function of Digestive tract, reduces the deposit of energy and fat, if this class drug main thyroid hormone formulations, because its cardiovascular side effects is used gradually less.
Other two kinds of more medicines of application are thrombotonin and NRI and lipase inhibitor.Typical lipase inhibitor such as orlistat structure are similar with triglyceride level, by competitive inhibition, make the absorption of triglyceride level reduce 30% and discharge from ight soil with original shape, minimizing energy intake and reach the purpose of fat-reducing.Yet, this medicine owing in the ight soil fat be steatorrhea, mashed just.What thrombotonin and NRI application were more is sibutramine, the maincenter that acts on strengthens full sense, make the minimizing of ingesting, and pass through adrenergic receptor and promote thermogenesis, make and lose weight, although also have some such as untoward reactions such as nauseating, dry, constipation, yet because determined curative effect becomes comparatively widely used slimming medicine.
Sibutramine slimming medicine commonly used is Sibutramine hydrochloride, be N-{1-[1-(4 mono chloro benzene base) cyclobutyl]-the 3-methyl butyl }-N, N-dimethyl amine hydrochloride, it mainly is to suppress norepinephrine and 5-HT re-uptake, improves these mediators concentration in maincenter, produces the excitation of maincenter sympathetic nervous system, suppress feeding center, reduce feed; Can increase simultaneously glucose utilization and the calorigenic action of fatty tissue, increase energy expenditure, reduce body weight, thereby reach the fat purpose for the treatment of.Yet because the kind of application antiobesity agents is fewer, and the effect of fat-reducing can not satisfy increasing obese patient's needs far away, the present invention comes therefrom in the actual life.
Summary of the invention
The object of the invention is to provide a kind of brand-new structural compounds---naphthalene ethylamine derivative, as the medicine of new treatment of obesity, solved in the prior art obesity treating medicine select limited, the unconspicuous defective of curative effect.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
A kind of naphthalene ethylamine derivative is characterized in that described compound exists with alkali or pharmacologically acceptable salt formation, and has the general structure of formula (I):
Wherein, R is selected from halogen, halogenated methyl, nitro or the optional C that replaces
1~C
3Alkoxyl group; R
1, R
2Be selected from H, the optional C that replaces
1~C
6Alkyl or the substituted radical of structure with general formula (II):
Wherein, R
4Be selected from H, aryl, optional C
1~C
6Alkyl or C
1~C
3Alkoxyl group;
R
3Be selected from the optional C that replaces
1~C
6Alkyl.
Preferably, R in the described naphthalene ethylamine derivative general formula (I)
1, R
2Be selected from H, the optional C that replaces
1~C
6Alkyl, and R
1, R
2Identical.
Preferably, R in the general formula of described naphthalene ethylamine derivative (I)
1Be selected from the substituted radical that structure has general formula (II):
Wherein, R
4Be selected from H, aryl, optional C
1~C
6Alkyl or C
1~C
3Alkoxyl group; R
2Be selected from H.
Preferably, the pharmaceutical acceptable salt of compound is selected from hydrochloride, vitriol, phosphoric acid salt or mesylate.
Another object of the present invention provides a kind of preparation method of naphthalene ethylamine derivative, it is characterized in that said method comprising the steps of:
(1) the following structural formula (III) of an amount of mole proportioning
Compound and cyanoacetic acid under the condition that benzyl ammonia and enanthic acid exist, add the thermal condensation decarboxylation and obtain formula (IV)
(2) compound and the dichlorodicyanobenzoquinone dehydrogenation reaction that obtain of step (1) obtains formula (V)
(3) compound and 1, the 3 dihalopropane cyclization that obtain of step (2) obtains formula (VI)
Wherein R is selected from halogen, halogenated methyl, nitro or the optional C that replaces
1~C
3Alkoxyl group;
(4) the compound generation cyanogen solution reaction that step (3) is obtained obtains the compound of formula (I).
Preferably, the cyanogen solution reactions steps of described step (4) comprising:
A, compound and halogenated alkane that step (3) is obtained react the compound that obtains formula (VII);
B, compound and sodium borohydride that steps A is obtained react the compound that obtains formula (VIII) under the condition that acetic acid exists;
C, compound and suitable acid-respons that step B is obtained obtain the compound of formula (VI);
Wherein R is selected from halogen, halogenated methyl, nitro or the optional C that replaces
1~C
3Alkoxyl group; R
3Be selected from the optional C that replaces
1~C
6Alkyl.
The present invention, replaces its phenyl ring with naphthalene nucleus, and structural modification is carried out at some other position as Research foundation with the structure of Sibutramine hydrochloride, wonderfully obtains a series of naphthalene ethylamine derivatives that can carry out effective antiobesity action.
The synthetic method route of naphthalene ethylamine derivative of the present invention is as follows:
Another purpose of the present invention has been to provide the application of a kind of naphthalene ethylamine derivative in the preparation obesity treating medicine.
If naphthalene ethylamine derivative of the present invention contains the optical activity carbon atom, the present invention also provides enantiomorph or its mixture of these compounds.
Naphthalene ethylamine derivative of the present invention is when existing with pharmaceutical acceptable salt, and described salt is preferably the salt of following acid: Hydrogen bromide, sulfuric acid, methylsulfonic acid, formic acid, acetic acid, oxalic acid, succsinic acid, tartrate, amygdalic acid, fumaric acid, lactic acid, hydrochloric acid, citric acid, phosphoric acid, L-glutamic acid and/or aspartic acid.
And, wonderful discovery, derivative of the present invention has the biological activity for the treatment of of obesity; Particularly preferred pharmaceutical composition comprises that the salt of naphthalene ethylamine derivative or these compounds is as active substance, these active substances are selected from [1-(7-methoxy-1-naphthyl) cyclobutyl] methylamine, 1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-N, N-dimethyl methylamine, N-{[1-(7-methoxy-1-naphthyl) cyclobutyl] methyl } ethanamide, N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-2-methyl propylamine, N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-2-methyl-propyl-N, N dimethylamine, N-{[1-(7-methoxy-1-naphthyl) cyclobutyl]-the 2-methyl-propyl } ethanamide, N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-the 3-methylbutylamine, N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-3-methyl butyl-N, N dimethylamine, N-{[1-(7-methoxy-1-naphthyl) cyclobutyl]-the 3-methyl butyl } ethanamide.
For preparing corresponding pharmaceutical composition, except at least a active substance of the present invention, also use solid support material, filler, solvent, thinner, tinting material or binding agent.The selection of auxiliary agent and consumption thereof depend on the route of administration of this medicine, use such as in oral, intravenous injection, abdominal injection, intracutaneous, muscle, the nose or part.The preparation of the forms such as tablet, coating tablet, capsule, granule, drops, liquid dosage form and syrup is suitable for oral, and solution, suspension agent, sprays etc. are applicable to non-enteron aisle, part and inhalation.Give patient or laboratory animal dosage body weight, method of application according to patient or animal, refer to disease and the administration of illness situation.
The present invention is with respect to medicine scheme of the prior art, and advantage of the present invention is:
Confirm that through experimentation on animals the pharmaceutical composition of naphthalene ethylamine derivative provided by the invention has good fat-reducing and antihyperglycemic.
Embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are not limited to limit the scope of the invention for explanation the present invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in the normal experiment.
The preparation of embodiment 1 pharmaceutical intermediate of the present invention
Synthesizing of (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile:
7-methoxyl group naphthane-1-ketone (17.6g, 0.1mol), cyanoacetic acid (12.8g, 0.15mol), benzylamine (2.7g, 25mmol), enanthic acid (3.3g, 25mmol) drop in the toluene (160ml), reflux water-dividing 24 hours, be cooled to room temperature, reaction solution is used 2mol/L sodium hydroxide solution (60ml), water (60ml) and saturated aqueous common salt (60ml) washing successively, use anhydrous sodium sulfate drying, filter, filtrate is steamed except toluene, get oily matter (18.9g, 95%).
Synthesizing of (7-methoxy-1-naphthyl) acetonitrile:
DDQ (25g, 0.11mol) drop in the dry methylene dichloride (200ml), 20 ℃ of lower above-mentioned oily matter (20g that drip, 0.1mol) dichloromethane solution (100ml), dripped complete insulated and stirred 1 hour, reacting liquid filtering, filtrate is used saturated sodium bicarbonate solution (100ml * 3), water (100ml), saturated aqueous common salt (100ml) washing successively, use anhydrous sodium sulfate drying, filter filtrate steaming removal solvent, residuum alcohol-water (5: 3) recrystallization, oven dry gets pale powder (18.6g, 94%).
Synthesizing of 1-(7-methoxyl group naphthyl) cyclobutyronitrile:
With (7-methoxy-1-naphthyl) acetonitrile (16.6g, 0.083mol) and 1,3 dibromopropane (18.2g, 0.091mol) be dissolved in the 60ml methyl-sulphoxide, descend in the aaerosol solution of the 120ml methyl-sulphoxide that this solution is slowly splashed into 18.6 potassium hydroxide (fine powder) in 20~25 ℃ of abundant stirrings.Drip and finish, continue to stir 1h, reactant is cooled under 15 ℃, drip frozen water 150ml, keep simultaneously temperature to be no more than 20 ℃.With this solution of ethyl acetate extraction (80ml * 3), combined ethyl acetate, respectively water (100ml), saturated aqueous common salt (100ml) washing, anhydrous sodium sulfate drying, filter, filtrate steaming removal solvent gets orange red oily matter, with ethyl acetate-sherwood oil (1: 1) recrystallization, dry to get faint yellow solid (14g, 70%).
1H-NMR(δ,ppm,d-DMSO):2.16(m,2H);2.72(t,2H);2.93(t,2H);3.99(s,3H);7.12~7.89(m,6H)
The preparation of embodiment 2 the present invention [1-(7-methoxy-1-naphthyl) cyclobutyl] methylamine
Under the ice bath with 1-(7-methoxyl group naphthyl) cyclobutyronitrile (9.5g, 0.04mol), Nickel dichloride hexahydrate (9.5g, 0.04mol), the 30ml dehydrated alcohol joins in the 100ml eggplant-shape bottle, add sodium borohydride (4.6g under the vigorous stirring in batches, 0.12mol), the solution colour blackening finishes and continues to stir 30 minutes.Then slowly add the hydrochloric acid of 30ml concentration 4mol/L in the reaction solution, solution colour gradually becomes light green.Solution is concentrated to be steamed except ethanol, then removes by filter unreacted 1-(7-methoxyl group naphthyl) cyclobutyronitrile.Filtrate is regulated PH9~10 with sodium hydroxide, with this solution of ethyl acetate extraction (20ml * 3), combined ethyl acetate, respectively water (30ml), saturated aqueous common salt (30ml) washing, anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent gets orange red oily matter (7.2g, 76%), salify.
1H-NMR(δ,ppm,d-DMSO):2.10(m,2H)2.36~2.75(m,4H);2.92(s,2H);3.83(s,3H);5.24(s,2H)7.02~7.89(m,6H)
Embodiment 3 1-[1-of the present invention (7-methoxy-1-naphthyl) cyclobutyl]-N, the preparation of N-dimethyl methylamine
Get [1-(7-methoxy-1-naphthyl) cyclobutyl] methylamine (2.4g, 0.01mol) in the 50ml eggplant-shape bottle, slowly 88% formic acid (15ml), 37% formaldehyde solution (5ml) are added wherein, refluxed one hour, drip again 37% formaldehyde (5ml), continue backflow 24h, be cooled to room temperature, pour in the 40ml frozen water, regulate about PH to 9~10 with 50% sodium hydroxide, with ethyl acetate extraction three times (20ml * 3), combined ethyl acetate, respectively water (30ml), saturated aqueous common salt (30ml) washing.Anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent gets orange red oily matter (2.15g, 79.6%), salify.
1H-NMR(δ,ppm,d-DMSO):2.01(m,2H)2.26(s,6H);2.52~2.79(m,4H)2.63(s,2H);3.76(s,3H);7.10~7.75(m,6H)
Embodiment 4N-{[1-(7-methoxy-1-naphthyl) cyclobutyl] methyl } preparation of ethanamide
Get [1-(7-methoxy-1-naphthyl) cyclobutyl] methylamine (2.4g, 0.01mol) in the 50ml eggplant-shape bottle, add the 15ml diacetyl oxide in 40 ℃ of lower 1h of stirring.Cooling has solid to separate out to wherein adding 20ml water gradually, filters to get pale solid (2.6g, 92%).
1H-NMR(δ,ppm,d-DMSO):1.79(s,3H);2.11(m,2H);2.75~3.02(m,4H);3.47(s,2H);3.93(s,3H);7.12~7.97(m,6H)
Embodiment 5N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-preparation of 2-methyl propylamine
With 1-(7-methoxyl group naphthyl) cyclobutyronitrile (7.1g, 0.03mol) be dissolved in the 35ml dry toluene, this solution is splashed into { isopropyl bromide 11g (0.09mol), magnesium chips 3.24g (0.135mol), anhydrous diethyl ether 35ml} in the isopropyl magnesium bromide solution.During dropping, ether is removed by distillation.Rate of addition and distillation speed are about equally.Drip to finish, when treating interior temperature rise to 90 ℃, stop distillation, mixture continues to stir 12 hours.After the question response liquid cooling but, slowly dripping the 50ml saturated aqueous common salt under the ice bath is hydrolyzed, dropwise and continue to stir half an hour, filter, filtrate is told toluene layer, respectively water (40ml), saturated aqueous common salt (40ml) washing, anhydrous sodium sulfate drying, filter, filtrate steaming removal solvent gets orange red oily matter.
Above-mentioned oily matter is dissolved in the 40ml acetic acid, adds sodium borohydride (3.4g, 0.09mol) under the room temperature in batches, then continue stirring reaction half an hour.Slowly adding sodium hydrate solid under the ice bath regulates about PH to 9~10.Dichloromethane extraction (40ml * 3), combined dichloromethane be water (50ml), saturated aqueous common salt (50ml) washing respectively.Anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent gets orange red oily matter (6.9g, 81%).The hydrochloric acid salify gets yellow solid, and ethyl alcohol recrystallization gets white powder.
1H-NMR(δ,ppm,d-DMSO):0.88(d,6H);1.82~2.04(m,1H);1.98(m,2H);2.63~2.90(m,4H);2.97(d,1H);3.90(s,3H);5.60(s,2H);7.08~7.94(m,6H)
Embodiment 6N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-2-methyl-propyl-N, the preparation of N dimethylamine
Get N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-2-methyl propylamine (2.8g, 0.01mol) in the 50ml eggplant-shape bottle, slowly with 88% formic acid (15ml), 37% formaldehyde solution (5ml) adds wherein, refluxed one hour, drip again 37% formaldehyde (5ml), continue backflow 24h, be cooled to room temperature, pour in the 40ml frozen water, regulate about PH to 9~10 with 50% sodium hydroxide, with ethyl acetate extraction three times (20ml * 3), combined ethyl acetate, difference water (30ml), saturated aqueous common salt (30ml) washing.Anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent gets orange red oily matter (2.54g, 82%), salify.
1H-NMR(δ,ppm,d-DMSO):0.92(d,6H);1.76~1.89(m,1H);2.06(m,2H);2.30(s,6H);2.68~2.94(m,4H);2.85(d,1H);3.83(s,3H);7.12~7.97(m,6H)
Embodiment 7N-{[1-(7-methoxy-1-naphthyl) cyclobutyl]-the 2-methyl-propyl } preparation of ethanamide
Get N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-2-methyl propylamine (2.8g, 0.01mol) is in the 50ml eggplant-shape bottle, and adding 15ml diacetyl oxide is in 40 ℃ of lower 1h that stir.Cooling has solid to separate out to wherein adding 20ml water gradually, filters to get pale solid (2.83g, 88%).
1H-NMR(δ,ppm,d-DMSO):1.00(d,6H);1.84(s,3H);2.11(m,2H);2.45(m,1H);2.36~2.78(m,4H);3.94(d,1H);3.98(s,3H);7.22~7.88(m,6H)
Embodiment 8N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-preparation of 3-methylbutylamine
With 1-(7-methoxyl group naphthyl) cyclobutyronitrile (7.1g, 0.03mol) be dissolved in the 35ml dry toluene, this solution is splashed into { isobutyl bromide 12.15g (0.09mol), magnesium chips 3.24g (0.135mol), anhydrous diethyl ether 35ml} in the selenium alkynide solution.During dropping, ether is removed by distillation.Rate of addition and distillation speed are about equally. and drip to finish, when treating interior temperature rise to 90 ℃, stop distillation, mixture continues to stir 12 hours.After the question response liquid cooling but, slowly dripping the 50ml saturated aqueous common salt under the ice bath is hydrolyzed, dropwise and continue to stir half an hour, filter, filtrate is told toluene layer, respectively water (40ml), saturated aqueous common salt (40ml) washing, anhydrous sodium sulfate drying, filter, filtrate steaming removal solvent gets orange red oily matter.
Above-mentioned oily matter is dissolved in the 40ml acetic acid, adds sodium borohydride (3.4g, 0.09mol) under the room temperature in batches, then continue stirring reaction half an hour.Slowly adding sodium hydrate solid under the ice bath regulates about PH to 9~10.Dichloromethane extraction (40ml * 3), combined dichloromethane be water (50ml), saturated aqueous common salt (50ml) washing respectively.Anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent gets orange red oily matter (6.76g, 76%).The hydrochloric acid salify gets yellow solid, and ethyl alcohol recrystallization gets white powder.
1H-NMR(δ,ppm,d-DMSO):0.91~1.62(m,9H);2.06(m,2H);2.26~2.58(m,4H);2.98(t,1H);3.88(s,3H);5.60(s,2H);7.02~7.89(m,6H)
Embodiment 9N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-3-methyl butyl-N, the preparation of N dimethylamine
Get N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-3-methylbutylamine (2.97g, 0.01mol) in the 50ml eggplant-shape bottle, slowly with 88% formic acid (15ml), 37% formaldehyde solution (5ml) adds wherein, refluxed one hour, drip again 37% formaldehyde (5ml), continue backflow 24h, be cooled to room temperature, pour in the 40ml frozen water, regulate about PH to 9~10 with 50% sodium hydroxide, with ethyl acetate extraction three times (20ml * 3), combined ethyl acetate, difference water (30ml), saturated aqueous common salt (30ml) washing.Anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent gets orange red oily matter (2.6g, 80%), salify.
1H-NMR(δ,ppm,d-DMSO):0.98~1.54(m,9H);2.06(m,2H);2.32~2.66(m,4H);2.18(s,6H);3.02(t,1H);3.78(s,3H);7.18~8.02(m,6H)
Embodiment 10N-{[1-(7-methoxy-1-naphthyl) cyclobutyl]-the 3-methyl butyl } preparation of ethanamide
Get N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-3-methylbutylamine (2.97g, 0.01mol) is in the 50ml eggplant-shape bottle, and adding 15ml diacetyl oxide is in 40 ℃ of lower 1h that stir.Cooling has solid to separate out to wherein adding 20ml water gradually, filters to get pale solid (2.86g, 84%).
1H-NMR(δ,ppm,d-DMSO):0.92~1.60(m,9H);1.85(s,3H);2.12~2.59(m,6H);3.82(s,3H);4.02(t,1H);7.17~7.94(m,6H);8.30(s,1H)
The experiment of embodiment 11 pharmacological activities
Choose N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl that embodiment 9 obtains]-3-methyl butyl-N, N dimethylamine is as target compound, by confirm the pharmacologically active of this compounds for treating obesity with following experiment.
Copying and medication of rat alimentary obesity model:
72 of the SD rats of just ablactation are divided into 6 groups (n=12) at random, the Normal group normal diet of feeding, all the other rats nutritional feed of feeding.The composition of nutritional feed: every 1000g basal feed is with milk powder 100g, lard 100g, and 10 in egg, 100 of cleum jecoris piscis concentratums (contain vitamin A 1.7 * 105U, vitamins D 1.7 * 104U), an amount of fresh soybean sprout of feeding every day.The administration of dividing into groups behind the 7kw, Normal group (5g/L CMC-Na solution), model control group (5g/L CMC-Na solution), Sibutramine hydrochloride group (8mg/kg), target compound high dose group (30mg/kg), middle dosage group (10mg/kg), low dose group (3.0mg/kg).Gastric infusion, capacity are the 5ml/kg body weight, and every day 1 time, 6wk obtains following pharmacology result, such as table 1, table 2 continuously.
Table 1 is on the impact of rat body weight: (mean body weight/g, n=12)
Table 2 is on the impact of rat height, Lee ' s index, fat weight: (x ± s, n=12)
Compare with model control group:
aP<0.05,
bThere is the statistics difference p<0.01,
cP>0.05 is without the statistics difference
Above-mentioned experiment shows: target compound N-1-[1-(7-methoxy-1-naphthyl) cyclobutyl]-3-methyl butyl-N, N dimethylamine has certain fat-reducing and antihyperglycemic to nutritive obesity in rats when dosage is higher.
Above-mentioned example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with technique can understand content of the present invention and according to this enforcement, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (6)
1. naphthalene ethylamine derivative is characterized in that described compound forms with alkali or pharmacologically acceptable salt to exist, and has the general structure of formula (I):
Wherein, R is selected from C
1~C
3Alkoxyl group; R
1, R
2Be selected from respectively H, C
1~C
6Alkyl;
R
3Be selected from C
1~C
6Alkyl.
2. naphthalene ethylamine derivative according to claim 1 is characterized in that R in the described naphthalene ethylamine derivative general formula (I)
1, R
2Be selected from respectively H, C
1~C
6Alkyl, and R
1, R
2Identical.
3. naphthalene ethylamine derivative according to claim 1 is characterized in that the pharmaceutical acceptable salt of compound is selected from hydrochloride, vitriol, phosphoric acid salt or mesylate.
4. the preparation method of a naphthalene ethylamine derivative claimed in claim 1 is characterized in that said method comprising the steps of:
(1) the following structural formula (III) of an amount of mole proportioning
Compound and cyanoacetic acid under the condition that benzyl ammonia and enanthic acid exist, add the thermal condensation decarboxylation and obtain formula (IV)
(2) compound and the dichlorodicyanobenzoquinone dehydrogenation reaction that obtain of step (1) obtains formula (V)
Compound;
(3) compound and 1, the 3 dihalopropane cyclization that obtain of step (2) obtains formula (VI)
Compound;
Wherein R is selected from C
1~C
3Alkoxyl group;
(4) the compound generation cyanogen solution reaction that step (3) is obtained obtains the compound of formula (I).
5. method according to claim 4 is characterized in that the cyanogen solution reactions steps of described step (4) comprising:
A, compound and halogenated alkane that step (3) is obtained react the compound that obtains formula (VII);
B, compound and sodium borohydride that steps A is obtained react the compound that obtains formula (VIII) under the condition that acetic acid exists;
C, compound and suitable acid-respons that step B is obtained obtain the compound of formula (VI);
Wherein R is selected from C
1~C
3Alkoxyl group R
3Be selected from C
1~C
6Alkyl.
6. the application of naphthalene ethylamine derivative claimed in claim 1 in the preparation obesity treating medicine.
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CN106543034A (en) * | 2016-10-31 | 2017-03-29 | 苏州弘森药业股份有限公司 | A kind of method of 7 methoxynaphthalene acetonitriles of synthesis |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1557802A (en) * | 2004-01-13 | 2004-12-29 | 苏州市玮琪生物科技有限公司 | Sibutramine aromatic salt of organic acid and its preparation process |
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CN1557802A (en) * | 2004-01-13 | 2004-12-29 | 苏州市玮琪生物科技有限公司 | Sibutramine aromatic salt of organic acid and its preparation process |
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