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CN104016919A - Lorcaserin hydrochloride analogue, as well as preparation method and application thereof - Google Patents

Lorcaserin hydrochloride analogue, as well as preparation method and application thereof Download PDF

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Publication number
CN104016919A
CN104016919A CN201410271436.4A CN201410271436A CN104016919A CN 104016919 A CN104016919 A CN 104016919A CN 201410271436 A CN201410271436 A CN 201410271436A CN 104016919 A CN104016919 A CN 104016919A
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Prior art keywords
analogue
acceptable salt
pharmacy acceptable
green card
preparation
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Inventor
徐奎
刘经星
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Anhui Province Yi Xinming Pharmaceutical Technology Co Ltd
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Anhui Province Yi Xinming Pharmaceutical Technology Co Ltd
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Priority to CN201410271436.4A priority Critical patent/CN104016919A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the field of medical chemicals, and particularly relates to a lorcaserin hydrochloride analogue with a general formula (I) and a preparation method thereof, and a medicinal preparation containing the lorcaserin hydrochloride analogue and a medical application thereof. In the lorcaserin hydrochloride analogue, R1 is halogen, trifluoromethyl, methoxyl or trifluoromethoxy.

Description

A kind of green card look woods analogue and its production and use
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of green card look woods analogue and preparation method thereof and comprise its pharmaceutical preparation and medicinal use thereof.
Background technology
Body-mass index is to weigh in the world the fat or thin degree of human body and a healthy common counter whether, its method of calculation be body weight (kilogram) divided by height (rice) square, exceed 25 for overweight, more than 30 genus obesity.
CDC of the U.S. issues prediction address and claim last month, and by development trend, to the year two thousand thirty, the ratio of U.S.'s population of being obese will rise to 42% by current approximately 1/3rd.
The diet pill listing of food and drug administration's approval on June 27th, 2012 commodity Belviq by name, green card look forest tract is produced by A Leina drugmaker of Switzerland.The assessment of pencil office medicine and director janet Wood Cork, research centre said the same day, and obesity is an important public health concern, and this medicine gets the Green Light provides a kind of new treatment selection for U.S. obese person and super severe one.
This is that this office has ratified new diet pill listing first since 1999.This medicine is applicable to body-mass index (BMI) and exceedes 27 adult overweight or obese person, and they at least suffer from the one in hypertension, type II diabetes and hypercholesterolemia etc. and overweight relative disease.Pill taker must go on a diet simultaneously and take exercise and just be expected to obtain comparatively ideal fat-reducing effect.Green card look woods has antiobesity action, and on heart valve and pulmonary artery without any impact.Different from other diet pill, green card look woods in fat-reducing simultaneously, can also be improved heart rate and press and low-density lipoprotein-Bai cholesterol (LDL-C) level.The more important thing is, take green card look woods and can control better the blood sugar of type II diabetes.Its common untoward reaction is that respiratory tract infection, headache, string are dizzy and feel sick, and compared with other diet pill, side effect is little, does not affect slimmer's the healthy and mental status.The advantage of green card look woods fat-reducing is in curative effect, but is that its security is obviously good than existing medicine, and in addition for diabetes B and there is cardiovascular risk factors crowd also to have clear and definite benefit, therefore green card look woods has good market outlook.
The essential information of green card look woods is as follows:
English name: Lorcaserin
Noon chemical name: the chloro-1-of (R)-8-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine
English chemical name: (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Structural formula:
Fluorine is the atom that electronegativity is the strongest, when introducing in organism after fluorine atom or fluoro-containing group, the strong electronegativity of fluorine atom has strengthened the affinity interaction of fluorine and carbon, has affected the acid-basicity of compound internal structure thereby changed significantly the electrical effect of fluorinated organic compound and mimic effect.When fluorine atom has replaced the hydrogen atom in compound, the solvability of esterified thing of its class on microbial film is enhanced, and promotes its absorption and transmission speed in vivo, and physiological action is changed.
On a certain key position of the physiologically active substances such as pharmaceuticals, import fluorine atom or trifluoromethyl, its successful improves, and side effect is suppressed.The number of the fluorine-containing physiologically active substance of having developed is so far very many, Drugs Containing Fluorine reaches hundreds of both at home and abroad at present, there are many medicines to become the principal item of some disease for the treatment of, some product annual sales amounts have exceeded 1,000,000,000 dollars, there is very important position at medicine circle, as fluoroquinolone antibiotics, due to the introducing of fluorine, make its has a broad antifungal spectrum, activity not only far wins existing same veriety, and be better than the anti-infectives of other at present conventional type, be one of Antibiotics drug research focus over nearly 20 years.In addition, also have 5 FU 5 fluorouracil series antineoplastic medicament, fluorine-containing nonsteroidal anti-inflammatory agent etc.
The inventor, in the time of suitability for industrialized production green card look woods bulk drug, according to the knowwhy that enriches of pharmaceutical chemistry accumulation, has synthesized a large amount of green card look woods derivative, analogue, and wherein typical compound has: R 1for fluorine, chlorine, bromine, iodine, methoxyl group, trifluoromethoxy, trifluoro ethoxy, sulfydryl, hydroxyl, methylol, chloromethyl, trifluoromethyl, 1 is the compound of (R)-trifluoromethyl simultaneously, wherein, compound of the present invention has beyond thought medicinal effect, has completed the present invention for this reason.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art part, and provide green card look woods compounds or its pharmacy acceptable salt that a class is new, technical problem to be solved is to use traditional principle of isotone and pharmaceutical chemistry reversal of poles principle, filters out a series of new compounds of the new green card look woods compounds of high-efficiency low-toxicity.
Compound general formula of the present invention is as follows:
Wherein R 1for halogen, trifluoromethyl, chloromethyl, methylol, hydroxyl, sulfydryl, methoxyl group and trifluoromethoxy.
Wherein said a kind of green card look woods analogue or further R of its pharmacy acceptable salt 1for chlorine, bromine, trifluoromethyl, chloromethyl and methoxyl group.
Another object of the present invention is to provide implements optimised form compound of the present invention:
I 1 I 2 I 3
The present invention also comprises a kind of green card look woods analogue or its pharmacy acceptable salt shown in general formula (I), described pharmacy acceptable salt is hydrochloride, hydrobromate, hydriodate, hydrofluoride, vitriol, nitrate, phosphoric acid salt, formate, acetate, propionic salt, oxalate, malonate, butyrates, lactic acid salt, mesylate, esilate, tosilate, maleate, benzoate, succinate, picrate, tartrate, Citrate trianion, fumarate.
The invention also discloses a kind of green card look woods analogue shown in general formula (I) or the preparation method of its pharmacy acceptable salt.
A kind of green card look woods analogue shown in general formula (I) or the preparation method of its pharmacy acceptable salt, comprising:
Wherein R 1definition with claim 1.
A further object of the present invention is that described a kind of green card look woods analogue or its pharmacy acceptable salt and pharmaceutically acceptable carrier are made common pharmaceutical preparation, as solid preparations such as tablet, capsule, orally disintegrating tablet, oral liquid, dispersible tablet, buccal tablets, can add the common medicinal supplementary material such as weighting agent, disintegrating agent, tackiness agent, glidant.
The clinical dosage used of compound of the present invention is 0.1mg～50mg/ days, also can depart from this scope according to the difference of the weight of the state of an illness or dosage.
Another object of the present invention is to provide described a kind of green card look woods analogue or its pharmacy acceptable salt exceed adult overweight or obese person's medicine of 27 purposes for the preparation for the treatment of body-mass index (BMI).
Main points of the present invention are:
The present invention obtains the green card look woods analogue shown in general formula (I), experimental mouse by the molecular structure transformation of many green cards look woods.
Embodiment
The following examples can conduct further description the present invention, but these embodiment should not served as limitation of the scope of the invention.
embodiment 1compound i 1 preparation
(1) preparation of 1-(2-bromotrifluoromethane)-4-chlorobenzene
In 10L reactor, add chlorophenethylol (1000mL, 7.7mol), be cooled to the slow phosphorus tribromide (560mL, 3.8mol) that drips at 0～5 DEG C.After dropwising, under room temperature, stir 2 hours, gradient increased temperature to 75～80 DEG C insulation 3 hours, TLC follows the tracks of, after question response.Stirring is cooled to room temperature, slowly drips 2000mL water.Stratification, upper strata methylene dichloride (1500mL) extraction 2 times for water, merging organic phase neutralizes with saturated sodium bicarbonate aqueous solution, making its pH value is 7～8, washing organic phase to pH value is 7 left and right, organic phase anhydrous sodium sulfate drying, concentrates to obtain colourless liquid 1-(2-bromotrifluoromethane)-4-chlorobenzene (1638g, yield 97.7%).GC content: 98.6%.Be directly used in next step reaction.
(2) 3-amino-1, the preparation of 1,1-trifluoro propane-2-alcohol
In 10L reactor, add 2-trifluoromethyl-oxyethane (200g, 1.79mol), stir, add ammoniacal liquor (28%, 4000ml), stirring at room temperature 25h, is concentrated into and does and obtain white solid powder, is directly used in next step reaction.
1H—NMR（500MHz,CDCl 3+D 2O/TMS，ppm）：3.94（1H，pd），2.77（1H，dd），2.62（1H，dd）。
19F—NMR（300MHz,CDCl 3，ppm）：δ-78.00（d）。
(3) 1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation of-2-hydroxyl trifluoromethyl ethane
In 10L reactor, add 3-amino-1,1,1-trifluoro propane-2-alcohol (1100mL, 13.7mol), is warming up to 85～90 DEG C, slowly drips 1-(2-bromotrifluoromethane)-4-chlorobenzene (1000g, 4.6mol).After dropwising, be warming up to 95 DEG C, be incubated 4 hours, TLC follows the tracks of, after question response.Be cooled to 80 DEG C of left and right, add water (2000mL) and toluene (4000mL), stir 0.5 hour.Stratification, toluene for water (8500mL) extraction 2 times, merge organic phase water (1000mL) washing 2 times, concentrate to obtain micro-yellow solid, move in other reactor, add toluene (400mL) and sherwood oil (4000mL), stirring and refluxing 0.5 hour, slow cooling to 5 DEG C left and right, stirs 1 hour, filters, sherwood oil for filter cake (1000mL) washing 2 times, be dried to obtain white solid 1-[[2-(4-chloro-phenyl-) ethyl] amino]-2-hydroxyl trifluoromethyl ethane (783g, yield 61.5%), HPLC content 86.7%.
(4) 1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation of the chloro-trifluoromethyl ethane of-2-
In 10L reactor, add 1-[[2-(4-chloro-phenyl-) ethyl] amino] (the 750g of-2-hydroxyl trifluoromethyl ethane, 3.0mol), toluene (5800mL) and DMF (100g), be warming up to 55 DEG C, after solid dissolves completely, slowly drip sulfur oxychloride (410mL, 5.7mol).Dropwise rear insulation 3 hours, TLC follows the tracks of, after completion of the reaction.Be cooled to 25 DEG C, filter, toluene for filter cake (1000ml) washing 2 times, obtains yellow solid.Move in other reactor, add Virahol (5000mL) and water (300ml), reflux 1 hour.Be down to stirring at room temperature 0.5 hour, slowly being down to about 5 DEG C stirs 2 hours, filter, Virahol for filter cake (600mL) washing 2 times, be dried to obtain white solid 1-[[2-(4-chloro-phenyl-) ethyl] amino] the chloro-trifluoromethyl ethane of-2-(503g, yield 51.8%).HPLC content 90.3%.
(5) the chloro-1-of 8-trifluoromethyl-2, the preparation of 3,4,5-tetrahydrochysene-1H, 3 benzazepines
In 10L reactor; add 1-[[2-(4-chloro-phenyl-) ethyl] amino] the chloro-trifluoromethyl ethane of-2-(1670g, 5.6mol) and aluminum trichloride (anhydrous) (1120g, 8.4mol); under nitrogen protection, be warming up to 120 DEG C of reactions 3 hours, TLC follows the tracks of.After completion of the reaction, stir and be cooled to 50 DEG C of left and right, slowly drip water (3000mL), stir and make dissolution of solid.With saturated sodium hydroxide solution adjusting pH value to 14 left and right, add diatomite (100g), stir and be cooled to room temperature.Add ethyl acetate (5000mL), stir, stratification, gets upper organic phase, washing pH value to 7 left and right, with anhydrous sodium sulfate drying, filter, concentrate to obtain the chloro-1-of brown color oily matter 8-trifluoromethyl-2,3,4,5-tetrahydrochysene-1H, 3 benzazepines (1120g. yield 91.6%).HPLC content 89.6%.
(6) the chloro-1-of (R)-8-trifluoromethyl-2,3,4, the 5. preparation of tetrahydrochysene-1H-3-benzazepine half tartrate
In 10L reactor, add the chloro-1-of 8-trifluoromethyl-2,3,4,5-tetrahydrochysene-1H, 3 benzazepines (914g, 4.3mol) and acetone (3100ml), be warming up to 50 DEG C of left and right.Slowly splash into the solution that L-type tartrate (160g, 1.1mol) and water (280mL) are made into, be incubated 3 hours, add acetone (800mL).Be down to stirring at room temperature l hour, be slowly down to 3 DEG C and stir 2 hours, acetone for filter cake (1000mL) washing 2 times, suction filtration is dried to obtain the chloro-1-of white solid crude product 8-trifluoromethyl-2,3,4,5. tetrahydrochysene-1H-3-benzazepine half tartrate.
In 10L reactor, add above-mentioned crude product, acetone (1300mL) and water (1300mL).Be warming up to 70 DEG C of left and right, after dissolution of solid, add 20g pin activated carbon to reflux 0.5 hour.Suction filtration moving in clean there-necked flask while hot, add acetone (2200ml), slowly be down to stirring at room temperature 1 hour, slowly be down to 3 DEG C and stir 2 hours, suction filtration, by acetone (400mL) washed twice, be dried to obtain the chloro-1-of white brilliant solid (R)-8-trifluoromethyl-2,3,4,5. tetrahydrochysene-1H-3-benzazepine half tartrate.
(7) compound i 1 'spreparation [the chloro-1-of (R)-8-trifluoromethyl-2,3,4,5. tetrahydrochysene-1H-3-benzazepine]
In 10L reactor, add the chloro-1-of (R)-8-trifluoromethyl-2,3,4,5. tetrahydrochysene-1H-3-benzazepine half tartrate (93g, 0.15mol), salt of wormwood (44g, 0.42mol), methylene dichloride (600ml) and water (400mL), mixture at room temperature stirs 0.5 hour, and solid dissolves completely, stratification.Washing organic phase 2 times, with anhydrous sodium sulfate drying, filters, and organic solvent is removed in decompression, obtains the chloro-1-of faint yellow oily matter (R)-8-trifluoromethyl-2, and 3,4,5. tetrahydrochysene-1H-3-benzazepine (35g, yield 84.5%).
HPLC 98.7%(acetonitrile: water=3:1, flow velocity is lmL/min, retention time is 11.3min).
1H—NMR（500MHz,CDCl 3/TMS，ppm）:
δ：7.15～6.98(m，3H)，3.09～2.65(m，6H)，1.93(s，1H)。
MS：m/z （M +）249（100%），180，166。
embodiment 2compound i 1 the preparation of hydrochloride
Compound i 1 (30g) be dissolved in 260ml methyl alcohol, stirring at room temperature, splashes into the methanol solution of hydrogenchloride, regulates pH value to 2.5～3.0, stirs 1h, filtration, and appropriate methanol wash for solid, 60 DEG C of vacuum-drying 5h, obtain 29g compound i 1 hydrochloride, HPLC 99.6%(acetonitrile: water=3:1, flow velocity is lmL/min, retention time is 11.3min).
embodiment 3compound i 2 preparation
With reference to the preparation method of embodiment 1, so that chlorophenethylol is done to starting raw material, make target compound i 2 , yellow oil.
HPLC 98.0%(acetonitrile: water=3:1, flow velocity is lmL/min, retention time is 17.5min).
1H—NMR（500MHz,CDCl 3/TMS，ppm）:
δ：7.21～7.08(m，3H)，3.03～2.59(m，6H)，1.97(s，1H)。
MS：m/z （M +）293（100%），180，166。
embodiment 4compound i 2 the preparation of hydrochloride
With reference to the preparation method of embodiment 2, obtain white crystalline powder, HPLC 99.8%(acetonitrile: water=3:1, flow velocity is lmL/min, retention time is 17.5min).
embodiment 5compound i 3 preparation
With reference to the preparation method of embodiment 1, so that trifluoromethyl phenylethyl alcohol is done to beginning raw material, make target compound i 3 , light yellow oil.
HPLC 98.0%(acetonitrile: water=3:1, flow velocity is lmL/min, retention time is 26.9min).
1H—NMR（500MHz,CDCl 3/TMS，ppm）:
δ：7.34～7.12(m，3H)，3.05～2.56(m，6H)，2.01(s，1H)。
MS：m/z （M +）283（100%），180，166。
embodiment 6compound i 3 the preparation of hydrochloride
With reference to the preparation method of embodiment 2, obtain white crystalline powder, HPLC 99.9%(acetonitrile: water=3:1, flow velocity is lmL/min, retention time is 26.9min).
embodiment 7compound i 1 the preparation of hydrochloride sheet
Element tablet recipe:
Embodiment compound i 1 hydrochloride 13g
Microcrystalline Cellulose 120g
Cross-linked carboxymethyl cellulose is received 183g
Colloid silica 3.0g
Magnesium Stearate 2.6g
Make 1000
Make after tablet, by medicinal film-coating premixing auxiliary material film coating for tablet, its main component: hypromellose, red iron oxide, synthetic Huang, talcum powder, titanium dioxide etc.
Preparation technology:
(1) by embodiment compound i 1 hydrochloride, Magnesium Stearate are crossed respectively 120 mesh sieves, and croscarmellose sodium, Microcrystalline Cellulose are crossed respectively 100 mesh sieves, for subsequent use;
(2) take prescription proportional quantity embodiment compound i 1 hydrochloride, Microcrystalline Cellulose mixed grinding, cross 80 mesh sieves with recipe quantity croscarmellose sodium and mix;
(3) get above powder mix, by purified water, as wetting agent softwood processed, 24 mesh sieves are granulated, 50 DEG C of forced air dryings 3～4 hours, the whole grain of 16 mesh sieves;
(4) get above particle, add Magnesium Stearate and the colloid silica of recipe quantity, mix, survey intermediate content, qualified rear be that 14.2 mm, short diameter are the stamping of 7.5mm plano-concave with long diameter, radial pressure is controlled at 4～10kg/mm 2.
(5) the qualified rear dressing of the full review of sampling.
embodiment 8pharmacological testing
Test method:
By 75 4 week age mouse C57BL/6J be divided at random control group, model group and medicine group, average 15 every group.Embodiment 2 compound 10 mgkg are fed in filling every day of medicine group -1d -1, embodiment 4 compound 10 mgkg -1d -1, embodiment 6 compound 10 mgkg -1d -1, control group and model group are all filled with and are fed isodose placebo (0.1% tween 80).Within every 4 weeks, mouse is weighed.After 20 weeks, detect the level of blood sugar, Regular Insulin and the leptin of different treatment group mouse.
Test-results:
Group Blood sugar/mgdL －1 Regular Insulin/ngmL －1 Leptin/ngmL －1
Control group 68.3±4.3 0.60±0.01 0.52±0.01
Embodiment 2 compounds 71.2±5.3 0.67±0.01 0.55±0.01
Embodiment 4 compounds 72.1±5.4 0.68±0.01 0.51±0.01
Embodiment 6 compounds 74.6±5.8 0.63±0.01 0.52±0.01
Model group 123.2±8.9 1.34±0.05 1.69±0.04
Result surface, medicine group is compared with model group, and Mouse Weight significantly increases, and also there is significant difference in serum leptin, blood sugar, insulin level.Model group and control group mice body weight there was no significant difference, also there was no significant difference of serum leptin, blood sugar and insulin level.Conclusion: the body weight that the compounds of this invention all can obviously suppress high fat diet mouse increases, and reduces serum leptin, blood sugar and insulin level.

Claims (7)

1. a kind of green card look woods analogue or its pharmacy acceptable salt shown in general formula (I):
Wherein R 1for halogen, trifluoromethyl, chloromethyl, methylol, hydroxyl, sulfydryl, methoxyl group and trifluoromethoxy.
2. a kind of green card look woods analogue claimed in claim 1 or its pharmacy acceptable salt, is characterized in that: wherein R 1for chlorine, bromine, trifluoromethyl, chloromethyl and methoxyl group.
3. according to a kind of green card look woods analogue or its pharmacy acceptable salt described in claim 1～2, it is characterized in that: the preferred following structure of described compound:
I 1 I 2 I 3
。
4. a kind of green card look woods analogue or its pharmacy acceptable salt described in claim 1～3, it is characterized in that: described pharmacy acceptable salt is hydrochloride, hydrobromate, hydriodate, hydrofluoride, vitriol, nitrate, phosphoric acid salt, formate, acetate, propionic salt, oxalate, malonate, butyrates, lactic acid salt, mesylate, esilate, tosilate, maleate, benzoate, succinate, picrate, tartrate, Citrate trianion, fumarate.
5. a kind of green card look woods analogue of the logical formula I of claim 1 or the preparation method of its pharmacy acceptable salt, comprising:
Wherein R 1definition with claim 1.
6. a pharmaceutical composition, wherein contains a kind of green card look woods analogue or its pharmacy acceptable salt and pharmaceutically acceptable carrier described in claim 1～4.
7. a kind of green card look woods analogue claimed in claim 1 or its pharmacy acceptable salt exceed the purposes of adult overweight or obese person's medicine of 27 for the preparation for the treatment of body-mass index (BMI).
CN201410271436.4A 2014-06-18 2014-06-18 Lorcaserin hydrochloride analogue, as well as preparation method and application thereof Pending CN104016919A (en)

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Publication number Priority date Publication date Assignee Title
WO2006018260A1 (en) * 2004-08-16 2006-02-23 Glaxo Group Limited Tetrahydrobenzazepines as antagonists and/or reverse agonists of the histamine h 3 receptor
CN1805938A (en) * 2003-06-17 2006-07-19 艾尼纳制药公司 Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases
CN101466684A (en) * 2006-04-03 2009-06-24 艾尼纳制药公司 Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto
WO2011153206A1 (en) * 2010-06-02 2011-12-08 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-ht2c receptor agonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1805938A (en) * 2003-06-17 2006-07-19 艾尼纳制药公司 Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases
WO2006018260A1 (en) * 2004-08-16 2006-02-23 Glaxo Group Limited Tetrahydrobenzazepines as antagonists and/or reverse agonists of the histamine h 3 receptor
CN101466684A (en) * 2006-04-03 2009-06-24 艾尼纳制药公司 Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto
WO2011153206A1 (en) * 2010-06-02 2011-12-08 Arena Pharmaceuticals, Inc. Processes for the preparation of 5-ht2c receptor agonists

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Application publication date: 20140903