CN104161758A - Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases - Google Patents
Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases Download PDFInfo
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Abstract
Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases are disclosed. The derivatives can be separated and obtained from the seed of stizolobium cochinchinensis, and can also be obtained by chemical synthesis by subjecting amino acid precursors phenylalanine and tyrosine, or levodopa with corresponding aldehydes or ketones to Pictet-Spengler condensation. Rat experiments show that: when the derivatives are administrated in combination with a levodopa component, the concentration of the levodopa in blood and brain tissues can be significantly increased, thus improving the bioavailability of the levodopa. In addition, the derivatives significantly inhibit highly-spontaneous rat movement induced by morphine, and penetrate the blood brain barrier, so that the derivatives can adjust the dopaminergic nerve functions. The derivatives can be used for treating the Parkinson's disease, psychosis, and other dopaminergic nerve diseases.
Description
Technical field
The present invention relates to a kind of application of 3-carboxylic acid tetrahydro isoquinoline derivative, in particular, relate to the application of 3-carboxylic acid tetrahydro isoquinoline derivative in preparation treatment dopaminergic nerve disease medicament, belong to biomedicine field.
Background technology
Parkinson disease are one of modal neurodegenerative diseases in old people, and in over-65s old people, sickness rate is about 1.7%, and 80 years old above sickness rate is 2%.The whole world approximately has 1,800 ten thousand people to suffer from this disease at present, and approximately there are 1,700,000 patients in China.The main pathology change list of parkinson disease is now the degeneration of carrying out property of substantia nigra of midbrain dopaminergic neuron, death, thereby cause this position nervous system to lose its motor adjustment function, the clinical symptoms such as appearance static tremor, muscle rigidity, bradykinesia and postural reflex are impaired, part patient is also with mental symptoms such as depression, cognitive impairments.Its cause of disease is completely unclear, does not also have so far effective means can diagnose early parkinson disease, and its treatment is just more difficult, does not even also have method can delay the process of this disease.If at present clinical treatment drug main levodopa (LD) and compound preparation thereof, as peaceful in madopar, breath, its curative effect is comparatively sure.But during due to the independent oral administration of LD, arrive effective dose in human brain only approximately 1%, after long-term taking LD4-5, can cause side effect, as vomiting, the unusual fluctuation diseases such as involuntary movement, and untoward reaction at a specified future date is as motor fluctuation, agent end phenomenon, on-off phenomenon, freeze phenomenon.It is relevant that the tolerance of carrying out sexually transmitted disease (STD) change, LD of this main and dopaminergic nerve and in-vivo content fluctuate etc., makes the state of an illness be difficult to control, finally even can use without medicine.Therefore effectively improving LD bioavailability, reducing its side effect is one of important channel for the treatment of parkinson disease drug development.
The disease relevant to dopaminergic nerve also comprises that dopaminergic nerve disease is cognitive impairment, generalized-anxiety disorder, acute catatonia, social phobia, simple phobias, month premenstrual irritated disease, social anxiety disorder, adult's depression, eating disorder, obesity, nervous anorexia, bulimia nervosa, disease of eating too much at one meal, substance abuse disease, chemicals dependence syndrome, nicotine addiction, cocaine addiction, drinking habit, amphetamine addiction, LaCie-Ni Heng syndrome, neurodegenerative disease, late luteal phase syndrome, sleeping sickness, spirit condition of illness is angry, repel responsive, the dyskinesia, the outer syndrome of cone, cramp disease, restless leg syndrome, tardive dyskinesia, the relevant eating disorder of sleeping, the syndrome of taking food night, diabetic neuropathy, fibrosarcoma syndrome, chronic fatigue syndrome, sexual dysfunction, premature ejaculation and male sexual impotence etc., the ages that these diseases relate to are larger, and the persistent period, from several thoughtful several years varying lengths, is having a strong impact on patient's physiology and mental health.Therefore the medicine of this type of dopaminergic nerve disease of research treatment is significant.
Pulse family Stizolobium Cochinchinesis belongs to (Mucuna) plant and is distributed widely in global tropical, subtropical zone, and Stizolobium Cochinchinesis platymiscium is the primary raw material that extracts levodopa.In the traditional medicine application such as China, India, it is found that directly taking Stizolobium Cochinchinesis extract can lower unusual fluctuation disease incidence rate.Bala V.Manyama (Parkinsonism and Related Disorders, 2010,458-465) with Micaela Morelli (Neurotox.Res., 2009,111 – 122) seminar studies have shown that, when rat long term administration Stizolobium Cochinchinesis extract, the side effect of unusual fluctuation disease significantly reduces.Laxminarain Misra (Phytochemistry, 2004,2565-2567) report, from Stizolobium Cochinchinesis isolation identification four kinds of 3-carboxylic acid tetrahydroisoquinolicompounds compositions.Peng Shiqi (replacement-tetrahydroisoquinoline-3-carboxylic acid compound, its preparation method and application, number of patent application 200710100029.7,201110118456.4, CN101200493 etc.) pass through in (3S)-1,2, the upper amino acid residue of introducing of 2 N of 3,4-tetrahydroisoquinoline-3-carboxylic acid, prepares a class and has the compound of antithrombotic acitivity.3-carboxylic acid tetrahydroisoquinolicompounds composition is a kind of simple amino acids, but the research of the active aspect of pharmacologically active, especially neuro pharmacology to such composition report is rare at present.Inventor is in to Stizolobium Cochinchinesis platymiscium research work, find that first 3-carboxylic acid tetrahydroisoquinoline composition wherein can strengthen levodopa bioavailability, significantly suppress the high autonomic movement of rat of morphine induction, and can see through blood brain barrier, point out such composition can regulate dopaminergic nerve function, thereby can be used for treating the dopaminergic nerve such as parkinson disease, psychosis disease.
Summary of the invention
The object of the invention has been to provide the new purposes of 3-carboxylic acid tetrahydro isoquinoline derivative, i.e. application in preparation treatment dopaminergic nerve disease medicament.
Technical scheme of the present invention is: the application of 3-carboxylic acid tetrahydro isoquinoline derivative in preparation treatment dopaminergic nerve disease medicament.Preferably, described 3-carboxylic acid tetrahydro isoquinoline derivative has following chemical constitution:
Wherein, R
1be selected from 1-4 hydrogen or hydroxyl, comprise and be selected from hydrogen, 6-hydroxyl, 7-hydroxyl, 6,7-dihydroxy, or 7,8-dihydroxy; R
2, R
3, R
4and R
5be selected from independently of one another heteroaryl, the heteroaryl alkyl of aryl alkyl, heteroaryl, the replacement of aryl, aryl alkyl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, the heteroaryl alkyl of replacement.
Further, preferably, described 3-carboxylic acid tetrahydro isoquinoline derivative is (3S)-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-1-methyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-1, 1-dimethyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-1, 1-dimethyl-3-carboxyl-7, 8-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, 1-benzyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, 1-methyl isophthalic acid-phenyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-3-carboxyl-6-hydroxyl-1, 2, 3, 4-tetrahydroisoquinoline, or (3S)-3-carboxyl-1, 2, 3, 4-tetrahydroisoquinoline.
Further, preferred, described 3-carboxylic acid tetrahydro isoquinoline derivative comprises its stereoisomer, or enantiomer, or pharmaceutically acceptable salt, or hydrate, or prodrug, or any solvate wherein.
Further, preferred, described medicine is the pharmaceutical composition of the upper acceptable carrier composition of one or more 3-carboxylic acid tetrahydro isoquinoline derivatives and physiology.
Further, preferred, described dopaminergic nerve disease is parkinson disease.
Further, preferred, treating Parkinsonian medicine is 3-carboxylic acid tetrahydro isoquinoline derivative and the compositions of clinging to amine energy medicine, or take with interior for 2 hours at medicine and the Dopaminergic Drugs interval of 3-carboxylic acid tetrahydro isoquinoline derivative composition.
Further, preferred, above-mentioned Dopaminergic Drugs is levodopa, or the compound preparation that contains levodopa.
Advantage of the present invention is to reduce LD degradation rate when 3-carboxylic acid tetrahydro isoquinoline derivative coordinates administration with the levodopa for the treatment of Parkinson's disease in the present invention, significantly strengthens LD blood plasma and brain bioavailability.
Brief description of the drawings
Below in conjunction with drawings and Examples, the invention will be further described:
Fig. 1 is curve when MD01+LD group and MDE organize the blood plasma medicine of LD in embodiment 9;
Fig. 2 is curve when MD01+LD group and MDE organize the blood plasma medicine of MD01 in embodiment 9.
Detailed description of the invention
3-carboxylic acid tetrahydroisoquinolicompounds composition described in the present invention is a kind of simple amino acids, in Stizolobium Cochinchinesis genus and other various plants, all has distribution.Its preparation method comprises directly separation and chemosynthesis from plant.From plant, separate one or more technical points that mainly adopt in ion-exchange chromatography, silica gel column chromatography, reversed-phase silica gel column chromatography from obtaining, chemosynthesis is mainly to adopt corresponding amino acid precursor phenylalanine, tyrosine, or levodopa and corresponding aldehydes or ketones class are prepared by Pictet-Spengler condensation.Below in conjunction with specific embodiment explanation its preparation method and the present invention's application.
Embodiment 1:
The preparation of 3-carboxylic acid tetrahydro isoquinoline derivative in cat bean
Cat bean (MD20091101) medical material is adopted in Baise of Guangxi, through being accredited as the seed of pulse family Mucuna plant dragon's paw Stizolobium Cochinchinesis (Mucuna pruriens var.utilis A.Cheval.).Get dry cat bean 3.0kg, be ground into coarse powder, extract 24h except degrease through acetone room temperature, medicinal residues continue to extract 2 times with methanol eddy, and each 2h reclaims methanol and obtains cat bean extract (MDE) 214g.Get MDE104g, through silica gel medium pressure column chromatography repeatedly, with chloroform-methanol-0.5% acetic acid 7:3:0.5 (volume ratio) eluting, obtain MD02 (30mg); Continue with 6.5:3.5:0.5 eluting, obtain successively MD01 (200mg), MD03 (12mg); Continue with 5:5:0.5 eluting, obtain successively MD04 (15mg), LD (35mg); .The chemical constitution warp of MD01-MD04
1h-NMR, IR, the Spectrum Analysis such as MS, and document (Laxminarain Misra, Phytochemistry, 2004, 2565-2567) contrast, be accredited as successively (3S)-1, 1-dimethyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (MD01), (3S)-1 Alpha-Methyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (MD02), (3S)-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (MD03) and (3S)-1, 1-dimethyl-3-carboxyl-7, 8-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (MD04).
Embodiment 2:
(3S)-3-carboxyl-6,7-dihydroxy-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline (MD03)
Get 100mg levodopa, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralizes, and adds the formalin of 0.35ml40%, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains target product 20mg.
Embodiment 3:
1-methyl-3-carboxyl-6,7-dihydroxy-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline
Get 100mg levodopa, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralizes, and adds the acetaldehyde solution of 0.35ml, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains product 50mg.This product is through further HPLC separation, and its chromatographic condition is: ODS chromatographic column, 20 × 250mm, 10% methanol-0.1% acetic acid is mobile phase, obtains respectively 1 Alpha-Methyl-3-carboxyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 15mg, 1 Beta-methyl-3-carboxyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 8mg.
Embodiment 4:
1,1-dimethyl-3-carboxyl-6,7-dihydroxy-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline
Get 100mg levodopa, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralization, adds 1ml acetone soln, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains target product 60mg.
Embodiment 5:
1-benzyl-3-carboxyl-6,7-dihydroxy-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline
Get 100mg levodopa, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralization, adds 2ml hyacinthin solution, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains target product 24mg.
Embodiment 6:
1-methyl isophthalic acid-phenyl-3-carboxyl-6,7-dihydroxy-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline
Get 100mg levodopa, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralization, adds 3ml 1-Phenylethanone. solution, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains product 35mg.This product is through further HPLC separation (ODS chromatographic column, 20 × 250mm, 10% methanol-0.1% acetic acid), obtain respectively 1 beta-phenyl-3-carboxyl-6, Alpha-Methyl-1,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 12mg, 1 Beta-methyl-1 α-phenyl-3-carboxyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 6mg.
Embodiment 7:
1-methyl-(3S)-3-carboxyl-6-hydroxyl-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline
Get 100mg tyrosine, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralizes, and adds the acetaldehyde solution of 0.35ml, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains target product 18mg.
Embodiment 8:
1-methyl-(3S)-3-carboxyl-1, the chemosynthesis of 2,3,4-tetrahydroisoquinoline
Get 100mg phenylalanine, add appropriate 0.1N dissolving with hydrochloric acid, sodium hydroxide solution neutralizes, and adds the acetaldehyde solution of 0.35ml, and jolting mixes, stirring reaction 72h at 30 DEG C.Reactant liquor is carried out to centrifugal (4000r/min, 10min), taking precipitate, drying under reduced pressure, obtains target product 25mg.
Embodiment 9:
The test of blood plasma pharmacokinetics
Adopt normal male rat model, get 24 (body weight 200～230g of normal male rat, purchased from Joinn (Suzhou) Laboratories Co., Ltd., the animal quality certification number: SLXK (Soviet Union) 2013-0003), be divided into test compounds group (MD01 group), levodopa group (LD group), test compounds and add levodopa group (MD01+LD group) and four experimental grouies of cat bean extract reference group (MDE group), 6 every group.Wherein test compounds group gives MD01, dosage 10mg/kg; Levodopa group gives levodopa LD to every rat, dosage 20mg/kg; Test compounds adds levodopa group and gives MD01 and LD to every rat, and dosage is respectively 10mg/kg and 20mg/kg; Cat bean extract group gives cat bean extract MDE to rat, dosage 100mg/kg (wherein levodopa content is counted 20mg/kg).Administering mode is intraperitoneal injection.Respectively at after administration 0,5,10,20,40,60,90,120,150,180min gets blood 0.3ml through eye socket, in 10000rmin
-1centrifugal 15min, the accurate blood plasma 100 μ l that draw, add 0.2mol/L perchloric acid-0.5% ascorbic acid solution 20 μ l, and vortex mixes 1min, then 10000rmin
-1centrifugal 15min, gets supernatant 10 μ l to be measured.Adopt HPLC-FD to detect MD01 and LD medicament contg in this supernatant.Testing conditions is: fluorescence exciting wavelength 280nm, detect wavelength 310nm, and 5C18AR-II chromatographic column (4.6 × 250mm), methanol-0.1mol/L acetic acid (5:95, v/v) is mobile phase, flow velocity 1ml/min.Curve when the blood plasma Chinese medicine concentration recording according to each time obtains LD and MD01 blood plasma medicine, as illustrated in fig. 1 and 2.
In the present embodiment, blood plasma pharmacokinetics test result Fig. 1 and 2 can find out: MD01 and LD medicine plasma half-life T
1/2be about respectively 25min and 40min; When MD01 compatibility LD administration, blood plasma pharmacokinetic parameter is unaffected, but can make LD blood drug level significantly increase; Also there is a small amount of existence MD01～04 in MDE, and when administration MDE, LD blood drug level does not substantially reduce in 180min.Result shows that MDE and MD01～04 wherein have the effect of rising LD blood drug level, enhancing LD bioavailability.
Embodiment 10:
Cerebral tissue drug level is analyzed
Adopt normal male rat model, get 18 of rats, be divided into test compounds group (MD01 group), levodopa group (LD group), test compounds and add three experimental grouies of levodopa group (MD01+LD group), every group of 6 rats.Wherein test compounds group rat gives MD01, dosage 10mg/kg; Levodopa group gives rat levodopa LD, dosage 20mg/kg; Test compounds adds levodopa group and gives MD01 and LD, and dosage is respectively 10mg/kg and 20mg/kg; Administering mode is intraperitoneal injection.Respectively at after administration 30,60,90,120min gets blood 0.3ml, takes out rat cerebral tissue simultaneously, claims frozen standby survey after weight in wet base.Get blood and cerebral tissue is weighed, add respectively 1mL normal saline, homogenate, centrifugal (10000rmin-1,15min), gets supernatant 100 μ L, measures each Chinese medicine concentration of organizing with blood sample determination of drug concentration method in embodiment 9.Table 1 is depicted as after MD01+LD group rat injection MD01 and LD MD01, LD content results in different time blood plasma and cerebral tissue.
Experimental result shows: MD01 can pass through blood brain barrier, and when individually dosed, in brain, concentration is about 10% in blood plasma; When MD01 and LD administering drug combinations, make all obviously risings (referring to table 1) of drug level in blood plasma and brain, in administration 60min, all can significantly increase levodopa plasma concentration more than 50%, and substantially do not reduce in 120min, result shows that MD01 has brain permeability, and can significantly strengthen LD bioavailability in brain.
LD and MD01 assay result in the blood/cerebral tissue of table 1MD01+LD group different time
Change respectively above-mentioned MD01 into compound MD02, MD03, MD04, (3S)-3-carboxyl-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline, (3S)-3-carboxyl-1,2,3,4-tetrahydroisoquinoline, repeats above-mentioned experimental procedure, and result can be measured to its prototype molecule in brain.Show that these materials all can blood brain barrier, improve LD bioavailability in brain.
Embodiment 11:
The high autonomic movement Behavior Test of rat
Rat is divided into three groups of blank group, solvent control group and test compounds at random, 6 every group, after grouping, before every rat experiment, all in spontaneous activity case, adapts to 5-10 minute.The rat skin lower injection 10mg/kg morphine of testing drug group and dosage matched group excites excessive autonomic movement, blank group rat injection same volume normal saline.After 30min, test compounds group rats by intraperitoneal injection test compounds MD01, dosage 10mg/kg.Then, blank group, test compounds group, solvent control group are put into multi-functional spontaneous activity case simultaneously, the motion of infrared monitoring three treated animals in 1.5hr process, the video file recording with corresponding software (Shanghai lucky amount provide) analysis, obtains movable total distance and the motion distance of each period in rat 1.5 hours.
Test result shows: test compounds MD01-04 (10mg/kg) all significantly suppresses the high autonomic movement of rat of morphine induction, can regulate Ba Anneng function of nervous system.
Can draw by above-described embodiment, 3-carboxylic acid tetrahydro isoquinoline derivative composition, in the time being combined administration with levodopa, can obviously improve levodopa blood plasma and cerebral tissue Chinese medicine concentration, has therefore improved levodopa bioavailability.In addition, significantly suppressed the high autonomic movement of rat at morphine induction.Its ingredient can see through blood brain barrier, shows that this derivant composition can regulate dopaminergic nerve function, thereby can coordinate the dopaminergic nerve diseases such as levodopa treatment parkinson disease or psychosis.
Claims (9)
- The application of 1.3-carboxylic acid tetrahydro isoquinoline derivative in preparation treatment dopaminergic nerve disease medicament.
- 2. application according to claim 1, is characterized in that, described 3-carboxylic acid tetrahydro isoquinoline derivative structure is suc as formula shown in (I):Wherein, R 1be selected from 1-4 hydrogen or hydroxyl, comprise and be selected from hydrogen, 6-hydroxyl, 7-hydroxyl, 6,7-dihydroxy, or 7,8-dihydroxy; R 2, R 3, R 4and R 5be selected from independently of one another heteroaryl, the heteroaryl alkyl of aryl alkyl, heteroaryl, the replacement of aryl, aryl alkyl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement, the heteroaryl alkyl of replacement.
- 3. application according to claim 2, it is characterized in that, described 3-carboxylic acid tetrahydro isoquinoline derivative is (3S)-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-1-methyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-1, 1-dimethyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-1, 1-dimethyl-3-carboxyl-7, 8-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, 1-benzyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, 1-methyl isophthalic acid-phenyl-3-carboxyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, (3S)-3-carboxyl-6-hydroxyl-1, 2, 3, 4-tetrahydroisoquinoline, or (3S)-3-carboxyl-1, 2, 3, 4-tetrahydroisoquinoline.
- 4. according to the application described in claim 2 or 3, it is characterized in that, described 3-carboxylic acid tetrahydro isoquinoline derivative is its stereoisomer, or enantiomer, or pharmaceutically acceptable salt, or hydrate, or prodrug, or any solvate wherein.
- 5. application according to claim 1, is characterized in that, described medicine is the pharmaceutical composition of the upper acceptable carrier composition of one or more 3-carboxylic acid tetrahydro isoquinoline derivatives and physiology.
- 6. application according to claim 1, is characterized in that, described dopaminergic nerve disease is parkinson disease.
- 7. application according to claim 6, is characterized in that, treats the compositions that Parkinsonian medicine is 3-carboxylic acid tetrahydro isoquinoline derivative and Dopaminergic Drugs.
- 8. application according to claim 6, is characterized in that, treating Parkinsonian medicine is that take with interior for 2 hours at medicine and the Dopaminergic Drugs interval that 3-carboxylic acid tetrahydro isoquinoline derivative forms.
- 9. according to the application described in claim 7 or 8, it is characterized in that, described Dopaminergic Drugs is levodopa, or the compound preparation that contains levodopa.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105372367A (en) * | 2015-11-10 | 2016-03-02 | 苏州大学 | Detection method of extract of seed of Mucuna macrocarpa Wall |
| FR3067711A1 (en) * | 2017-06-19 | 2018-12-21 | Institut Du Cerveau Et De La Moelle Epiniere | INHIBITORS OF CATECHOL-O-METHYL-TRANSFERASE (COMT) |
-
2014
- 2014-07-02 CN CN201410312868.5A patent/CN104161758B/en active Active
Non-Patent Citations (3)
| Title |
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| LAXMINARAIN MISRA等: "Alkaloidal constituents of Mucuna pruriens seeds", 《PHYTOCHEMISTRY》 * |
| 刘志婷: "4-取代的1，2，3，4-四氢异喹啉化合物的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
| 陈吉生: "《新编临床药物学》", 31 August 2013, 中国中医药出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105372367A (en) * | 2015-11-10 | 2016-03-02 | 苏州大学 | Detection method of extract of seed of Mucuna macrocarpa Wall |
| CN105372367B (en) * | 2015-11-10 | 2017-06-06 | 苏州大学 | A kind of detection method of lamb's-quarters beans extract |
| FR3067711A1 (en) * | 2017-06-19 | 2018-12-21 | Institut Du Cerveau Et De La Moelle Epiniere | INHIBITORS OF CATECHOL-O-METHYL-TRANSFERASE (COMT) |
| WO2018234333A1 (en) * | 2017-06-19 | 2018-12-27 | Institut Du Cerveau Et De La Moëlle Epiniere | Catechol-o-methyl transferase (comt) inhibitors |
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