CN103554021A - Indanone tetrahydroisoquinoline derivative as well as preparation method and medical application thereof - Google Patents
Indanone tetrahydroisoquinoline derivative as well as preparation method and medical application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, in particular to an indanone tetrahydroisoquinoline derivative as well as a preparation method and a medical application thereof, and in particular to an application as a k-opioid receptor agonist on analgesia. The R1, R2, R3 and R4 in the general formula (I) are defined in the instructions.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a class indone tetrahydro isoquinoline derivative, their preparation method and their medicinal use, the particularly purposes in analgesia as κ-opioid receptor agonist.
Background technology
The market potential that pain therapy field is huge and urgency, the research and development of the new drug that makes to ease pain are one of study hotspots always.The clinical the most widely used opium kind analgesics that μ-opioid receptor agonist is representative of take, though as morphine has powerful analgesic effect, the side effects such as its dependency (habituation), respiration inhibition, calmness, anxiety have seriously limited their clinical application.
Research shows, κ-opioid receptor agonist can produce potent analgesic activity after being combined with κ-opiate receptor, and can exempt the side effect of part morphine sample.(6-chloro-2 for 1-(Pyrrolidine-1-methyl)-2-, 3-dihydro-indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline is Chinese patent (ZL200610088349.0,2009-06-24) and the κ-opioid receptor agonist of the structure novel of PCT patent (WO/2008/009215,2007-07-10) report, have analgesic activities strong, without good characteristics such as habituation.But in its structure, there are 2 chiral carbon, can produce 4 optical isomers, experimental result demonstration, its different optical isomer has different κ-opiate receptor selectivity, and also there were significant differences for analgesic activity, and the complex steps of synthetic its optical isomer, cost is high.Chinese Patent Application No. (201210078427.4, 2012-03-23), the preparation method of 1H-1-Indanone-3-formic acid compounds is the synthetic compounds of inventor's early-stage Study, it is characterized in that at 1 of 3-oxo-indane-1-carboxylic acid, 2-position is introduced two keys and is obtained 3-oxo-3H-indenes-1-carboxylic acid, eliminated the chiral centre in molecule, by its alternative 3-oxo-2, the preparation of 3-dihydro-indenes-1-carboxylic acid, indone tetrahydro isoquinoline derivative can reduce the chiral carbon atom of target molecule, thereby it is good likely to find κ-opiate receptor agonist activity, preparation method is simple, avoid or alleviate the analgesia new drug candidate molecules of side effect.
Summary of the invention
The invention discloses a series of new indone tetrahydro isoquinoline derivatives.Through Lance cAMP assay test, show, the compounds of this invention has higher exciting effect to κ-opiate receptor.In the middle of the research of mouse Glacial acetic acid writhing test, demonstrated stronger analgesic activity.Therefore, compound of Formula I of the present invention, can be used for prevention and treats the various diseases relevant to κ-opioid receptor agonist, as antalgic and inflammation relieving, diuresis, neuroprotective, or as pruritus.
Compound general formula I of the present invention is as follows: wherein
R
1representative:
R
2representative: hydrogen, fluorine, methoxyl group or 6,7-methylene-dioxy;
R
3, R
4representative: hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or 5,6-methylene-dioxy.
Compound of Formula I is even more preferably:
R
1representative:
R
2representative: hydrogen, fluorine, 6,7-methylene-dioxy;
R
3, R
4representative: hydrogen, fluorine, bromine, methyl or methoxy.
Preferred compound is:
R
1representative
r
2represent 6,7-methylene-dioxy; R
3represent hydrogen, R
4representation methoxy.
According to the present invention, pharmacy acceptable salt comprises the acid salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, methylsulfonic acid, Phenylsulfonic acid or tosic acid.
The preparation method of general formula target compound of the present invention (I) is as follows:
Wherein a represents reaction conditions: condensing agent is oxalyl chloride or 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI);
Catalyzer is DIPEA (DIPEA) or I-hydroxybenzotriazole (HOBT);
Solvent is methylene dichloride, 1,2-ethylene dichloride, acetonitrile or DMF.
Compound 1-(Pyrrolidine-1-methyl)-1 wherein, 2,3, the preparation of 4-tetrahydroisoquinoline series intermediate (II) can be with reference to Chinese patent (ZL200610088349.0,2009-06-24) with PCT patent (WO/2008/009215,2007-07-10), (replacement) β-phenylethylamine of take is raw material, and synthetic method is as follows:
The preparation of compound 1H-1-Indanone-3-formic acid series intermediate (III) with reference to Chinese Patent Application No. (201210078427.4, (replacement) diphenyl succinic acid of 2012-03-23), take is raw material, and synthetic method is as follows:
Below pharmacologically active testing method and the result of part of compounds of the present invention:
Screening has the compound of excitement or antagonistic action to κ-opiate receptor
Principle: Lance cAMP assay is a kind of homogeneous phase time discrimination fluorescence resonance energy transfer immunity analytical procedure, to detect the cAMP producing after AC activity change under GPCRs regulation and control.The cAMP tracer agent mixture of the method based on Eu mark and sample cAMP competition bonding mark the binding site of cAMP specific antibody of dyestuff AlexaFuor647.The cAMP tracer agent complex body of Eu mark consists of combining closely between the Eu of biotin-cAMP and streptavidin mark.
When antibodies Eu-SA/b-cAMP tracer agent, the laser at 340nm place can excite Eu-chelate molecule, its energy sending is transferred on the Alexa molecule of antibody, and send the fluorescence of 665nm, fluorescence intensity at 665nm place weakens along with the increasing of cAMP content in testing sample, so in strength of signal and sample, cAMP concentration is inversely proportional to.
Method:
Step1: culturing cell, with Lance, measure ratio, with graphpad mapping software, camp concentration is X, ratio value is Y, makes the typical curve of camp, as optimum cell number and standard control.
Step2: produce camp with forskolin stimulation 300,600,1200cells/ul cell, with Lance, measure the ratio under each cell concn, with graphpad mapping software, forskolin concentration is X, ratio value is Y, make under each cell count and produce camp curve, determine that 1200cells/ul is optimum cell number.
Step3: the agonism of checking agonist standard substance U50488 to cell, with Lance, measure the ratio under each cell concn, with graphpad mapping software, agonist U50488 concentration is X, ratio value is Y, makes typical curve, and measures its EC
50, the agonist activity of institute's SCREENED COMPOUND in contrast.
Step4: whether check institute SCREENED COMPOUND has agonist activity and agonist activity size, and method is as shown in step3.
Step5: the antagonistic action of checking antagonist standard substance compound N orbin to cell, method is as shown in step3.
Step6: whether check institute SCREENED COMPOUND has antagonistic activity and antagonistic activity size, and method is as shown in step3.
Part of compounds pharmacology test result is as follows:
Table 1 part of compounds of the present invention is checked the exciting effect of itself and κ-opiate receptor:
| Compound | EC 50(nmol／l) |
| Agonist U50488 | 1.77 |
| I-1 | 0.48 |
| I-2 | 1.11 |
| I-3 | 1.35 |
| I-4 | 1.06 |
| I-5 | 1.15 |
| I-6 | 1.21 |
| I-7 | 0.76 |
Table 2 part of compounds of the present invention is checked the antagonistic effect of itself and κ-opiate receptor:
| Compound | IC 50(nmol／l) |
| Antagonist Norbin (mol/l) | 0.40 |
| I-1 | Invalid |
| I-2 | Invalid |
| I-3 | Invalid |
| I-4 | Invalid |
| I-5 | Invalid |
| I-6 | Invalid |
| I-7 | Invalid |
Experimental result shows, compound is all without the effect of antagonism κ-opiate receptor.But Compound I-1～I-7 all has good agonism to κ-opiate receptor, and be better than positive drug U50488.The EC of I-1 wherein
50value (0.48nmol/l) is best, the EC of I-7
50value (0.76nmol/l) is better.
The experiment of mouse Glacial acetic acid writhing:
Body weight is the Kunming mouse male and female half and half of 20-30g, divides at random 8 groups, 10 every group.Comprising sample sets, κ-receptor stimulant U50488 positive controls and physiological saline negative control group.Sample adopts subcutaneous injection administration, and after administration 0.5h, every mouse peritoneal is injected 0.7% glacial acetic acid solution 10ml/kg, observe and record writhing number of times and latent period of 20min mouse after injection Glacial acetic acid, calculate analgesia percentage, carry out statistical procedures, with its significance of t test and judge.Be to start timing to occurring that for the first time writhing response obtains the time after Glacial acetic acid injection latent period.
Analgesia percentage (%)=(the average writhing number of times of the average writhing number of times-administration of negative control group group) average writhing number of times of/negative control group
Table 3 part of compounds of the present invention is compared with negative control group on the impact of mouse Glacial acetic acid writhing test
Conclusion: the analgesic effect of sample I-1 and I-7 is all better than positive control drug U50488, and there is dependency in analgesic effect and dosage.
Embodiment
Part active compound to prepare example as follows:
RY-1 type melting point tube; FTIR-8400 Fourier transform infrared spectrometer, KBr compressing tablet;
1bRUKER AM-500 type nuclear magnetic resonance analyser for H-NMR, interior mark TMS; Waters Micromass Q-TOF high-resolution mass spectrometer.
Embodiment 1
6,7-dimethoxy-1-(Pyrrolidine-1-methyl)-2-(6-methoxyl group-1-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-1)
In 50ml three-necked bottle, add compound 5-methoxyl group-1H-1-Indanone-3-formic acid III-1 (0.4g, 2.0mmol), anhydrous CH
2cl
215ml, oxalyl chloride (0.28ml, 2.9mmol), DMF1 drips, 0～5 ℃ of ice bath temperature control, N
2protective reaction to reaction solution is clarified, stand-by.Separately get 100ml three-necked bottle, add 1-(Pyrrolidine-1-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline II-1 (1.08g, 4.0mmol), anhydrous CH
2cl
220ml, DIPEA (0.69ml, 4.0mmol), slowly splashes into the acyl chloride reaction liquid making at 0～5 ℃ of ice bath temperature control wherein, drips Bi Shengzhi room temperature reaction 1h, saturated NaCl solution washing.Sherwood oil: ethyl acetate: triethylamine=3:1:0.05 column chromatography, obtain tawny oily matter, with 5ml ethyl acetate solution, dissolve, add saturated ethyl acetate/hydrogen chloride solution to acid, yellow solid is separated out, suction filtration, oven dry weighs to obtain I-10.21g, yield 21%.m.p.208～212℃。
1H-NMR(500MHz,CDCl
3)，δ(ppm)：1.83～2.16(4H,m,2×CH
2)，2.22～2.74(3H，m，1／2CH
2，CH
2)，2.79～3.14(4H,m,2×CH
2)，3.80(3H,s,OCH
3)，3.84(3H,s,OCH
3)，3.87(3H,s,OCH
3)，4.02～4.10(1H，m，1／2CH
2)，4.18～4.27(2H,m,CH
2)，6.10～6.11(1H,d,J=9.5Hz,CH)，6.57～6.58(2H,m,ArH)，6.63～6.65(1H,m,ArH)，6.68(1H,s,CH=CO)，6.80～6.81(1H,m,ArH)，7.40～7.42(1H,d,J=8Hz,ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
27H
30N
2O
5：463.2228，found463.2227；IR(cm
-1)：3414,2962,1708，1692,1617,1515,1260,1094,802,616
Embodiment 2
6,7-dimethoxy-1-(Pyrrolidine-1-methyl)-2-(6-fluoro-1-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-2)
Compound 5-fluoro-1H-1-Indanone-3-formic acid III-2 and compound 1-(Pyrrolidine-1-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline II-1, through with I-1 operation, obtains yellow solid I-2, yield 23%, m.p.194～196 ℃.
1H-NMR(500MHz,CDCl
3)，δ(ppm)：2.03～2.31(4H，m，2×CH
2)，2.75～2.87(3H，m，1／2CH
2，CH
2)，3.06～3.15(2H，m，CH
2)，3.78～3.83(1H，m，1／2CH
2)，3.85(3H，s，OCH
3)，3.92(3H，s，OCH
3)，4.10～4.12(2H，m，CH
2)，4.22～4.30(2H，m，CH
2)，6.09～6.11(1H，d，J=10.5Hz，CH)，6.61～6.62(2H,m,ArH)，6.70(1H，s，CH=CO)，6.88～6.91(1H,m,ArH)，6.99～7.01(1H，m,ArH)，7.44～7.47(1H,m,ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
26H
27FN
2O
4：451.2035，found451.2028；IR(cm
-1)：2959，1714，1630，1520，1446，1358，1253，1217，1113，915，799
Embodiment 3
1-(Pyrrolidine-1-methyl)-2-(5-methyl isophthalic acid-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-3)
Compound 6-methyl isophthalic acid H-1-Indanone-3-formic acid III-3 and compound 1-(Pyrrolidine-1-methyl)-1,2,3,4-tetrahydroisoquinoline II-2, through biconditional operation, obtains yellow solid I-3, yield 28%, m.p.216～218 ℃.
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：1.90～2.10(4H，m，2×CH
2)，2.32(3H，s，CH
3)，2.78～3.10(3H，m，1／2CH
2，CH
2)3.41～3.79(5H，m，1／2CH
2，2×CH
2)，3.88～3.93(1H，m，1／2CH
2)，4.03～4.07(1H，m，1／2CH
2)，6.04～6.06(1H，d，J=9.0Hz，CH)，6.44(1H，s，CH=CO)，7.01～7.03(1H,m,ArH)，7.18～7.28(4H，m,ArH)，7.29～7.49(2H,m,ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
25H
26N
2O
2：387.2076，found387.2067；IR(cm
-1)：2958，1711，1631，1436，1421，1327，1219，1151，834，544
Embodiment 4
The fluoro-1-of 7-(Pyrrolidine-1-methyl)-2-(5-methyl isophthalic acid-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-4)
Compound 6-methyl isophthalic acid H-1-Indanone-3-formic acid III-3 and compound 1-(Pyrrolidine-1-methyl)-7-is fluoro-1,2,3, and 4-tetrahydroisoquinoline II-3, through with I-1 operation, obtains dark green solid I-4, yield 26%, m.p.218～220 ℃.
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：1.95～2.13(4H，m，2×CH
2)，2.32(3H，s，CH
3)，2.80～3.09(3H，m，1／2CH
2，CH
2)3.45～3.76(5H，m，1／2CH
2，2×CH
2)，3.87～3.92(1H，m，1／2CH
2)，4.00～4.07(1H，m，1／2CH
2)，6.07～6.08(1H，d，J=9.0Hz，CH)，6.45(1H，s，CH=CO)，7.12～7.16(2H,m,ArH)，7.22～7.27(2H，m,ArH)，7.31～7.46(2H，m，ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
25H
25FN
2O
2：405.1980，found405.1973；IR(cm
-1)：2968，1699，1630，1590，1429，1289，1230，1080，1036，826，561
Embodiment 5
1-(Pyrrolidine-1-methyl)-2-(1-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-5)
Compound 1H-1-Indanone-3-formic acid III-4 and compound 1-(Pyrrolidine-1-methyl)-1,2,3,4-tetrahydroisoquinoline II-2, through with I-1 operation, obtains yellow solid I-5, yield 30%, m.p.213～215 ℃.
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：1.90～2.10(4H，m，2×CH
2)，2.79～3.10(3H，m，1／2CH
2，CH
2)，3.44～3.79(5H，m，1／2CH
2，2×CH
2)，3.89～3.94(1H，m，1／2CH
2)，4.05～4.09(1H，m，1／2CH
2)6.06～6.08(1H,d，J=9.0Hz，CH)，6.55(1H，s,CH=CO)，7.15～7.20(2H，m,ArH)，7.25～7.29(2H，m,ArH)，7.36～7.50(4H，m,ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
24H
24N
2O
2：373.1918，found373.1911：
IR(cm
-1)：3414，1711，1627，1492，1449，1278，1221，1043，766，595
Embodiment 6
7-fluorine 1-(Pyrrolidine-1-methyl)-2-(1-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-6)
Compound 1H-1-Indanone-3-formic acid III-4 and compound 1-(Pyrrolidine-1-methyl)-7-is fluoro-1,2,3, and 4-tetrahydroisoquinoline II-3, through with I-1 operation, obtains yellow solid I-6, yield 20%, m.p.216～218 ℃.
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：1.90～2.14(4H，m，2×CH
2)，2.78～3.15(3H，m，1／2CH
2，CH
2)，3.45～3.79(5H，m，1／2CH
2，2×CH
2)，3.88～3.94(1H，m，1／2CH
2)，4.06～4.10(1H，m，1／2CH
2)6.08～6.09(1H,d，J=9.0Hz，CH)，6.48(1H，s，CH=CO)，7.12～7.16(1H，m,ArH)，7.17～7.27(2H，m,ArH)，7.36～7.50(4H，m,ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
24H
23FN
2O
2：391.1822，found391.1816；IR(cm
-1)：2976，1711，1630，1602，1500，1451，1239，1187，760，561
Embodiment 7
7-fluorine 1-(Pyrrolidine-1-methyl)-2-(6-fluorine 1-hydrogen-indenes-3-ketone-1-carbonyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline (I-7)
Compound 5-fluoro-1H-1-Indanone-3-formic acid III-2 and compound 1-(Pyrrolidine-1-methyl)-7-is fluoro-1,2,3, and 4-tetrahydroisoquinoline II-3, through with I-1 operation, obtains dark green solid I-7, yield 36%, m.p.198～200 ℃.
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：1.95～2.12(4H，m，2×CH
2)，2.29～3.05(3H，m，1／2CH
2，CH
2)，3.45～3.75(5H，m，1／2CH
2，2×CH
2)，3.86～3.91(1H，m，1／2CH
2)，4.02～4.06(1H，m，1／2CH
2)6.07～6.09(1H,d，J=9.0Hz，CH)，6.49(1H，s，CH=CO)，7.01～7.03(1H，m,ArH)，7.11～7.26(3H，m,ArH)，7.31～7.47(2H，m,ArH)；HR-MS(ESI，M-H)m／z：calculated?for?C
24H
22F
2N
2O
2：409.1725，found?409.1722；IR(cm
-1)：2971，1714，1631，1595，1499，1239，1187，1054，817。
Claims (6)
1. the compound of general formula (I) or its pharmacy acceptable salt:
R wherein
1representative:
R
2representative: hydrogen, fluorine, methoxyl group or 6,7-methylene-dioxy;
R
3, R
4representative: hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or 5,6-methylene-dioxy.
2. the compound of claim 1, wherein:
R
1representative:
R
2representative: hydrogen, fluorine, 6,7-methylene-dioxy;
R
3, R
4representative: hydrogen, fluorine, bromine, methyl or methoxy.
3. the compound of claim 2, wherein:
R
1representative
r
2represent 6,7-methylene-dioxy; R
3represent hydrogen; R
4representation methoxy.
4. the preparation method of the general formula of claim 1 (I) compound, comprises the following steps:
Wherein a represents reaction conditions: condensing agent is oxalyl chloride or 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride;
Catalyzer is DIPEA or I-hydroxybenzotriazole;
Solvent is methylene dichloride, 1,2-ethylene dichloride, acetonitrile or DMF.
R
1, R
2, R
3, R
4definition with right 1.
In claims 1 to 3 the compound of any one in the purposes of the medicine for the preparation of prevention or the treatment disease relevant with κ-opioid receptor agonist.
6. the purposes of claim 5, wherein for preventing or the medicine of the disease that treatment is relevant with κ-opioid receptor agonist can be used as analgesic.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330469A2 (en) * | 1988-02-23 | 1989-08-30 | Glaxo Group Limited | Tetrahydroisoquinoline derivatives |
| US6048860A (en) * | 1997-07-14 | 2000-04-11 | Adolor Corporation | Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith |
| WO2008009215A1 (en) * | 2006-07-12 | 2008-01-24 | China Pharmaceutical University | Tetrahydro isoquinoline derivatives, preparation methods and medicinal uses thereof |
| CN102190650A (en) * | 2011-03-30 | 2011-09-21 | 中国药科大学 | Method for preparing indoquinoline tartrate |
| CN102603520A (en) * | 2012-03-23 | 2012-07-25 | 中国药科大学 | Method for preparing 1H-indene-1-ketone-3-methanoic acid compound |
-
2013
- 2013-11-25 CN CN201310596228.7A patent/CN103554021A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330469A2 (en) * | 1988-02-23 | 1989-08-30 | Glaxo Group Limited | Tetrahydroisoquinoline derivatives |
| US6048860A (en) * | 1997-07-14 | 2000-04-11 | Adolor Corporation | Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith |
| WO2008009215A1 (en) * | 2006-07-12 | 2008-01-24 | China Pharmaceutical University | Tetrahydro isoquinoline derivatives, preparation methods and medicinal uses thereof |
| CN102190650A (en) * | 2011-03-30 | 2011-09-21 | 中国药科大学 | Method for preparing indoquinoline tartrate |
| CN102603520A (en) * | 2012-03-23 | 2012-07-25 | 中国药科大学 | Method for preparing 1H-indene-1-ketone-3-methanoic acid compound |
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Inventor after: Wang Dechuan Inventor after: Feng Tao Inventor after: Cao Yan Inventor after: Xu Yungen Inventor after: He Ling Inventor after: Gan Zongjie Inventor after: Liang Yunan Inventor after: Wang Yun Inventor before: Wang Dechuan Inventor before: Feng Tao Inventor before: Cao Yan Inventor before: Xu Yungen Inventor before: He Ling Inventor before: Gan Zongjie Inventor before: Liang Yunan Inventor before: Wang Yun |
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Application publication date: 20140205 |