CN1634859A - Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent - Google Patents
Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent Download PDFInfo
- Publication number
- CN1634859A CN1634859A CN 200410086807 CN200410086807A CN1634859A CN 1634859 A CN1634859 A CN 1634859A CN 200410086807 CN200410086807 CN 200410086807 CN 200410086807 A CN200410086807 A CN 200410086807A CN 1634859 A CN1634859 A CN 1634859A
- Authority
- CN
- China
- Prior art keywords
- derivative
- glutamic acid
- group
- preparation
- amantadine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to symmetrel derivatives and their synthesis process and use as neuron damage protector. Said symmetrel derivatives are N-alkyl monosubstituted, N-alkyl disubstituted and N-acidylated derivative of symmetrel compounds. In vitro experiment shows that the tested compounds can make the growth of damaged neuron SY5Y normal under condition of some concentration.
Description
Technical field:
The present invention relates to the two replacements of the replacement of N-alkyl list, N-alkyl of amantadine compounds and structure, synthetic method and the application aspect the nerve injury provide protection of N-acylated derivatives, it is laid a good foundation at the preventive and therapeutic effect aspect the neurodegenerative disorders to researching and developing said compound from now on.
Background technology:
Studies have shown that 70% brain cell is that neurotransmitter is carried out the fast signal conduction with L-glutamic acid.Being subjected to L-glutamic acid activated nerve synapse acceptor is N-methyl-D-aspartate type (NMDA) glutamate receptor.Being overexcited of nmda receptor causes Ca in the nerve synapse
2+Excessive concentration, signal conduction background noise increases, and the information change when consequently study or memory take place is not obvious or be difficult to identification, shows as dementia (McBrain CJ et al, Physiol.Rev 74:723-760,1994).All to make nmda receptor be overexcited for a long time relevant with the long-time excessive concentration of the secretion of brain cell L-glutamic acid for chronic brain nervous system diseases such as senile dementia, HUNTINGTON disease, atrophic myelitis and AIDS dementia.In addition, when cerebral ischemia, anoxic, the secretion of L-glutamic acid also sharply increases, and sharply being overexcited of nmda receptor is brain operation hindbrain cell loss and the major cause that causes multiple disease of brain.
The amantadine compounds is small molecules, the reversibility antagonist of nmda receptor; can effectively suppress being overexcited of nmda receptor; have protection cortex nerve and make its injury-free effect (Rogawski MAet al, Amino Acids.19:133-149,2000).Wherein, hydrochloric acid 3,5-dimethyladamantane amine (M
1)
Be used to treat multiple diseases (Li Yanping etc., The Chinese Journal of Clinical Pharmacology 19:461-463,2003) such as Parkinson's disease, senile dementia, AIDS dementia, the recovery of postoperative brain clinically.Meanwhile, also has the detoxification of peripheral nerve poison, as retinal neurons protection and lower oxygen concentration resistance effect etc.
Document shows the experimentation on animals result of the nmda receptor antagonistic action that the dozens of series compound that contains adamantyl carries out: single-amino compound such as amantadine (Ad), 3, though 5-dimethyladamantane amine has shown the effect that can block nmda receptor, but acute toxicity just obviously strengthens when dosage is increased to 2-8 times of subliminal dose, and the bisamination compound then all is being better than single-amino compound aspect validity and the security.Thus, the present invention is with amantadine and 3, and 5-dimethyladamantane amine is guide's thing, carries out the synthetic of N-substitutive derivative, with the stronger compound of screening neuroprotective activity.On the other hand,, require compound used therefor should be able to pass through hemato encephalic barrier, and in brain, keep certain concentration, promptly have certain fat-soluble based on the mechanism of neurocyte protection effect.The present invention has synthesized amantadine and 3, and the amide derivatives of 5-dimethyladamantane amine is in the hope of reaching the purpose that improves the brain target.
Promptly the objective of the invention is by to amantadine and 3; the amido of 5-dimethyladamantane amine partly carries out structural modification and transformation, in the hope of providing active higher or have better brain neuroblastoma tissue selectivity, reduce the novel neuronal injury protective material to the neural side effect of periphery.The present invention has synthesized amantadine and 3, and the amido of 5-dimethyladamantane amine has been studied institute's synthetic compound in the external neurovirulent restraining effect that L-glutamic acid is caused by the different alkyl or the derivative of acyl substituted.Relevant report is not seen in the research of compound involved in the present invention and nerve injury provide protection thereof so far as yet.
Summary of the invention:
The present invention is with amantadine and 3, and 5-dimethyladamantane amine is lead compound, has carried out the replacement of N-alkyl list, the two replacements of N-alkyl and the synthetic research that reaches the nerve injury provide protection of N-acylated derivatives.The external activity result of study shows that the nerve injury that The compounds of this invention causes L-glutamic acid all shows and suppresses active effect, for the said compound of research and development is from now on laid a good foundation at the preventive and therapeutic effect aspect the neurodegenerative disorders.
Primary aspect of the present invention has provided the compound of formula (I):
Wherein, R
1=CH
3Or H; R
2=CH
3, H or R
1
R
3=H or contain the company's shape or the ring-type hydroxyl substituted hydrocarbon radical of 3-8 carbon atom;
R
4=H, alkyl replace carbonyl oxygen acyl group, the company's shape that contains 3-8 carbon atom or ring-type hydroxyl substituted hydrocarbon radical or camphoroyl.
Preferred compound of the present invention, specifically with the following formula representative,
Ad
1：R
1＝R
2＝R
3＝H；R
4＝CO
2CH
3
Ad
2：R
1＝R
2＝R
3＝H；R
4＝CO
2CH(CH
3)
2
Ad
3：R
1＝R
2＝R
3＝H；R
4＝(-)-camphanyl
M
1-1：R
1＝R
2＝CH
3；R
3＝H；R
4＝CO
2CH
3
M
1-2：R
1＝R
2＝CH
3；R
3＝H；R
4＝CO
2CH(CH
3)
2
M
1-3：R
1＝R
2＝CH
3；R
3＝H；R
4＝(-)-camphanyl
M
1-4：R
1＝R
2＝CH
3；R
3＝H；R
4＝CH
2CHOHCH
3
M
1-5：R
1＝R
2＝CH
3；R
3＝R
4＝CH
2CH
2OH
The code name Ad of compound wherein
1Ad
2Ad
3M
1-1M
1-2M
1-3M
1-4M
1-5Expression, English camphanyl wherein represents camphyl.
The present invention also provides the preparation method of The compounds of this invention.The preparation of The compounds of this invention can be adopted following method: with formula (II) is starting raw material (amantadine: R
1=R
2=H; 3,5-dimethyladamantane amine: R
1=R
2=CH
3), in non-proton property solvent, exist down in alkaline reagents (as triethylamine, pyridine etc.), with condensation reactions such as alkyl substituted epoxy ethane or carbalkoxy chlorine or camphor acyl chlorides, obtain the N-substitutive derivative shown in the formula (I).The starting raw material amantadine is bought from ACROS company and is obtained, and 3,5-dimethyladamantane amine referenced patent US P 3,391,142 methods are synthetic to be obtained.Reagent alkyl substituted epoxy ethane and carbalkoxy chlorine are bought from Nanjing celestial worthy chemistry service centre and are obtained, and the camphor acyl chlorides is bought from ACROS company and obtained.Synthetic route is as follows:
The synthetic route of The compounds of this invention
The present invention also provides the application of The compounds of this invention at preparation neuroprotective unit damage medicine.
L-glutamic acid is excitatory neurotransmitter main in the central nervous system, plays regulating effect by receptor-mediated conduction to synaptic excitation under the normal physiological situation.Under pathological state or when irritable injure occurring, L-glutamic acid excessively release can cause neuronic damage, causes neurotransmission miopragia even forfeiture.Thereby; when the neuro-protective that detects said compound is active; the present invention has used the L-glutamic acid damage model; spill rate by mensuration MTT metabolic rate and LDH and reflect of the influence of institute's synthetic compound the human neuroblastoma strain SY5Y growth of L-glutamic acid damage; from of the provide protection of cell levels assessing compound to L-glutamic acid injured nerve cell, and by effect power and the usefulness of dose-effect curve ratio than compound.
The pharmaceutical composition that also provides of the present invention, pharmaceutical composition of the present invention can contain formula of the present invention (I) compound for the treatment of significant quantity, can add one or more pharmaceutically acceptable carriers in case of necessity.
Pharmaceutical composition of the present invention, it can be any formulation that is fit to take, the various formulations of pharmaceutical composition of the present invention can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, are made into required formulation then.
Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5%-95%.
Compound of the present invention and pharmaceutical composition can be used for preparing because of L-glutamic acid excessively discharges the neuronal damage that causes protects medicine.
The invention effect:
The cell in vitro model trial is the result show, all test compounds all can make injured nerve cells SY5Y under certain or some concentration conditions growth recovery is to normal level, and effect all is better than lead compound amantadine and 3,5-dimethyladamantane amine.Wherein, M
1-3And Ad
3Can make the MTT metabolic rate return to normal level under 5 μ M concentration, and can keep maintenance level in bigger concentration range, these effect characteristics meet the safety evaluation standard of drug screening.The present invention has selected contrast medicine M
1With sample M
1-3Carry out L-glutamic acid injured nerve cell LDH and spilt rate influence test.The result shows, M
1And M
1-3The neurocyte LDH that is caused by the L-glutamic acid damage has been spilt obvious restraining effect.Western-blotting measures the expression of results of neurocyte nutrient protein p-CREB, and L-glutamic acid can make that the p-CREB protein content obviously reduces in the neurocyte, and compound M
1-3And M
1Can obviously suppress the reduction of the p-CREB expression amount that causes by L-glutamic acid.Verified the protection activity of The compounds of this invention once more from the Proteometabolism angle to nerve injury.
Description of drawings:
Fig. 1 is 3, and 5-dimethyladamantane amine and N-substitutive derivative thereof are to the relation curve that influences of neurocyte MTT metabolic rate
Wherein, M
1Be 3,5-dimethyladamantane amine; M
1-1To M
1-4Be its N-substitutive derivative.
Fig. 2 is amantadine and N-substitutive derivative thereof the relation curve that influences to neurocyte MTT metabolic rate
Wherein, Ad is an amantadine; Ad
1To Ad
3Be its N-substitutive derivative.
Fig. 3 is M
1And M
1-3Neurocyte LDH is spilt rate influence test-results
Wherein, Glu is L-glutamic acid (500 a μ M) group; Glu+M
1-3Be L-glutamic acid (500 μ M)+M
1-3(30M μ) group; Glu+M
1Be L-glutamic acid (500 μ M)+M
1(20 μ M).
Fig. 4 expresses Western-blotting electrophoresis result figure for neurocyte p-CREB
Wherein, Glu is L-glutamic acid (500 a μ M) group; Control is the blank group; Glu+M
1-3Be L-glutamic acid (500 μ M)+M
1-3(30M μ) group; Glu+M
1Be L-glutamic acid (500 μ M)+M
1(20 μ M).
Embodiment:
Following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
(0.24ml 1.7mmol) adds M with triethylamine
1(300mg in THF solution 1.67mmol), stirs after 10 minutes ice-water bath and N
2Protection is added dropwise to methoxy acyl chlorides (1.67mmol), stirring at room 3 hours down in mixed solution.Filtering reacting liquid, THF washes insolubles, and merging filtrate adds silica gel 2 grams, stirs 40 minutes, transfers on the silicagel column after boiling off solvent, and (haxane: EA=25: 1) wash, obtain acid amides 0.37g behind the concentrate eluant, yield is 93% to eluent.The structure authentication data is as follows:
M
1-1：
1HNMR(ppm，CDCl
3)：0.82(s，6H，2CH
3)，1.07(s，2H，4-CH
2)，1.2-1.5(m，J＝12，4H，7，9-2CH
2)，1.5-1.6(s，4H，2，6-2CH
2)，1.75(d，J＝2.4，2H，10-CH
2)，2.08-2.10(m，1H，8-CH)，3.6(s，3H，-OCH
3)，4.58(s，-NH).
FAB-MS：[2M
++1]475.3，[M
++1]238.2，mp：38-40℃。
Embodiment 2.N-methoxy acyl group amantadine (Ad
1) synthetic
Use method similar to Example 1, the synthetic N-methoxy acyl group amantadine (Ad that obtains
1), yield is 89%.
The structure authentication data is as follows:
Ad
1：
1HNMR(ppm，CDCl
3)：1.66(m，6H，3CH
2)，1.9(m，6H，3CH2)，2.09(m，3H)，3.6(s，3H，OCH
3).
FAB-MS:[M
++ 1] 210.1, mp:90 ℃ (crystal formation change), 112 ℃ (fusing).
The different third oxygen acyl group-3 of embodiment 3.N-, 5-dimethyladamantane amine (M
1-2) synthetic
Use method similar to Example 1, the synthetic M that obtains
1-2, yield 79%.The structure authentication data is as follows:
M
1-2：
1HNMR(ppm，CDCl
3)：0.82(s，6H，2CH
3)，1.07(d，J＝1.8Hz，CH
2)，1.2(m，6H，2CH3)，1.1-1.4(m，6H，3CH
2)，1.6(m，4H，2CH2)，1.76(s，2H，CH
2)，2.08-2.10(m，1H，CH)，4.42(s，-NH)，4.83(m，1H，CH)。
FAB-MS：[M
++1]266.1。
The different third oxygen acyl group amantadine (Ad of embodiment 4.N-
2) synthetic
Method similar to Example 1, the synthetic N-methoxy acyl group amantadine (Ad that obtains
2), yield is 89%.The structure authentication data is as follows:
Ad
2：
1HNMR(ppm，CDCl
3)：1.2(m，6H，2CH3)，1.6-1.7(m，6H)，1.9(m，6H，3CH2)，2.09(s，3H)，4.83(m，1H)。
FAB-MS:[M
++ 1] 238.2, mp:95 ~ 115 ℃ (decomposition).
Embodiment 5.N-camphoroyl-3,5-dimethyladamantane amine (M
1-3) synthetic
Under the ice-water bath cooling conditions, to containing triethylamine (1.7mmol) and M
1The THF that adds camphor acyl chlorides (1.36mmol) in the 6ml THF solution (1.3mmol) finishes, and stirring at room is 3 hours under the nitrogen protection, filters, and filtrate decompression concentrates, and silicagel column separates. obtain M
1-30.4g.
M
1-3：
1HNMR(ppm，CDCl
3)：0.82(s，6H，3CH2)，0.9(s，3H，CH3)，1.1(d，6H，2CH3)，1.18(d，2H，CH2)，1.2-1.4(m，4H，2CH2)，1.63(m，6H)，1.8-2.0(m，4H)，2.5(m，1H)。
FAB-MS：[M
++1]360.3，mp：118-120℃。
Embodiment 6.N-camphoroyl amantadine (Ad
3)
Use method similar to Example 5, the synthetic N-camphoroyl amantadine (Ad that obtains
3), yield is 90%.
The structure authentication data is as follows:
Ad
3：
1HNMR(ppm，CDCl
3)：0.9(s，3H，CH3)，1.1(d，6H，2CH3)，1.64(m，8H)，1.85(m，2H)，2.0(s，6H)，2.1(s，3H)。
FAB-MS:[M
++ 1] 332.2, mp:145 ℃ (decomposition).
Embodiment 7.N-(2-hydroxyl-1-propyl group) amino-3,5-dimethyl-diamantane (M
1-4) synthetic
To M
1(350mg, add in THF solution 1.95mmol) 1,2 epoxy prapane (230mg, 4.0mmol) stir after, the airtight stirring of room temperature, TLC follows the tracks of reaction, added propylene oxide (0.11g 1.95mmol) disappeared to raw material every 4 hours.Evaporated under reduced pressure reaction solution, resistates add the chloroform dissolving, and with sodium hydroxide, water, aqueous sodium persulfate solution washing, organic layer silicagel column separation and purification after dried over mgso obtains colorless oil product 0.31g successively.Yield: 67%.The structure authentication data is as follows:
1H-NMR：(CDCL3，ppm)0.8(s，6H，2CH
3)，1-1.5(m，16H)，2.3(dd，1H)，2.7(dd，1H)，2.1(s，-NH)，2.4(s，-OH)3.6(m，1H)。
FAB-MS：238(M
++1)。
Embodiment 8.N-two (2-hydroxyethyl) amino-3,5-dimethyl-diamantane (M
1-5) synthetic
Method is with embodiment 7, and adding excessive response reagent is oxyethane, finally obtains two substitution products.The structure authentication data is as follows:
1H-NMR：(DMSO，ppm)0.8(s，6H，2CH3)，1.04(s，2H，CH2)，1.2(m，8H，4CH
2)，1.4(d，2H)，2.05(m，1H，CH)，2.58(m，4H，N(CH
2)
2)，3.26(m，4H，2CH
2OH)，4.38(s，OH)。
FAB-MS：268(M
++1)。
Embodiment 9. neurocyte L-glutamic acid injury protection activity tests
Material: human neuroblastoma strain SY5Y is provided by Sweden Caroline Si Ka institute.L-glutamic acid (L-glutamic acid): Sigma product, 20H0797; The MTT:Sigma product; Serum lactic dehydrogenase (LDH) is measured test kit: Beijing Chemical Plant's product, numbering 020623; NT-3 antibody, NF antibody, horseradish peroxidase-labeled two anti-: produce by Beijing Zhong Shan chemical reagents corporation; Acrylamide, DAB are the Sigma product; Tris is the Promager product; Protein determination reagent (1 * 1 Bio-Rad protein Assay, 1-800-424-6723): be the Bio-Rad product.
The adding volume fraction is 10% foetal calf serum (Hyclone, SH 30 070 03) 15mmolL in cell culture condition: MEM (Gibco BRL, the 41 500-067) substratum
-1HEPES (DNN company), penicillin 1 * 10
5IUL
-1, Streptomycin sulphate 1 * 10
5IUL
-1, 0.05CO
2, 37 ℃, change liquid weekly 2 times, go down to posterity 1 time.
Instrument: the DYY-of Liuyi Instruments Plant, Beijing type 28A voltage stabilization and current stabilization electrophoresis apparatus and DYY-type electrophoretic blotting instrument.
Method: it is every milliliter 1 * 10 with density that (1) MTT metabolic rate is measured the SY5Y cell
3Individual cell inoculation is divided into control group, L-glutamic acid group (500 μ molL in 96 orifice plates (Costar product) behind the 3d
-1) and compound be respectively 5 μ molL
-1, 10 μ molL
-1, 20 μ molL
-1, 30 μ molL
-1, 40 μ molL
-1, 50 μ molL
-1, 60 μ molL
-1Add L-glutamic acid 500 μ molL
-1Group, every group 8 hole.4 every holes, inoculation back add MTT (5gl
-1) 20 μ l, hatch 4H for 37 ℃, the sucking-off nutrient solution, every hole adds 200 μ l DMSO, and jolting 10min measures 550nm place's optical density value (OD) with microplate reader (Diagnostic Pasteur LP400).
Cell counting is every milliliter 1 * 10 with the SY5Y cell with density
3So individual cell inoculation 24 orifice plates are divided into control group 500 L-glutamic acid groups and different concns compound and add the L-glutamic acid group, every group 8 hole behind the 3d.Inoculation back d4, d5, d6 carry out cell counting to each group.
(2) to spill that rate measures the SY5Y cell be every milliliter 1 * 10 with density to serum lactic dehydrogenase (LDH)
3Individual cell inoculation is divided into control group, L-glutamic acid group and compound and adds the L-glutamic acid group in 24 orifice plates behind the 3d, every group 8 hole, and inoculation back 4d leaves and takes and respectively organizes cell culture fluid, and LDH measures method (colorimetry) shown in the test kit, measures 450nm place optical density value.
Sds page electrophoretic blotting (Western Blot) extracts and detects in the protein content ice bath and extract control group, L-glutamic acid group, application of sample L-glutamic acid group SY5Y cell protein.Use protein determination reagent and detect protein content, with the control charging capacity.It is NT-3 and NF that spacer gel 5%, separation gel 12%, resist, and two is anti-by horseradish peroxidase-labeled, and developer is DAB.Encapsulating is assembled, and adds electrophoresis liquid; Last sample; Run glue; Change film; Wash film; Sealing; Adding one resists; Wash film; Adding two resists; Wash film; Exposure; Develop; Photographic fixing; Each band position of record marker.Statistical procedures is used SPSS software and is done the T inspection statistics.
Measurement result: (1) MTT metabolic rate measurement result: MTT is a tetrazolium bromide, after the cultured cells picked-up, generate first by the plastosome metabolism and praise (formazan), so the plastosome vigor is vigorous more, it is many more that first is praised generation, optical density value is also high more, by measuring the MTT metabolic rate, can reflect the cells survival situation.In institute's test sample product, derivative is all strong than the provide protection of relative lead drug, and can both make cell MTT metabolic rate return to normal level even show under finite concentration that the calibration ordinary water is flat also will good effect.Each compound dose-effect relationship is compared to Fig. 1 and Fig. 2, and the OD peak value and the respective concentration quantity of each compound are compared to table 1.
Table 1, each compound OD peak value and respective concentration quantity are relatively
sample M
1 M
1-1 M
1-2 M
1-3 M
1-4 Ad Ad
1 Ad
2 Ad
3
control
OD
base
0.92 0.91 0.87 0.93 0.96 0.92 0.92 0.95 0.96
value
peak
0.97 0.99 1.03 1.12 1.03 1.03 1.229 1.279 1.086
value
peak
20 50 30 5 40 10 45 45 5
con.μM
By Fig. 1, Fig. 2 and table 1 as can be seen, all test compounds all can make neurocyte SY5Y under certain or some concentration conditions growth recovery is to normal level, and effect all is better than contrasting medicine Memantine hydrochloride and amantadine.Wherein, M
1-3And Ad
3Can make the MTT metabolic rate return to normal level under 5 μ M concentration, and can keep maintenance level in bigger concentration range, these effect characteristics meet the safety evaluation standard of drug screening.
(2) LDH spills the rate measurement result:
Test compound influences measurement result such as table 2 and shown in Figure 3 to what LDH spilt rate.
Table 2, M
1And M
1-3The influence that LDH is spilt rate is compared
Control group Glu Glu+M
1Glu+M
1-3
n 22 21 24 24
317.1818± 403.4762± 161.0000± 164.5417±
LDH
132.30219 206.55644
#↑ 65.62608
*↓ 52.28515
**↓
Compare #P＜0.027 with control group, * P＜0, * * P＜0
The result shows: it is 403.4762 ± 206.55644U that the LDH of L-glutamic acid damage group (Glu group) spills rate, apparently higher than control group (317.1818 ± 132.30219U), P＜0.027; Application of sample group Glu+M
1(161.0000 ± 65.62608U) and Glu+M
1-3(164.5417 ± 52.28515U) LDH spills the rate value and is starkly lower than L-glutamic acid group (P＜0) even control group.
(3) to the proteic influence of p-CREB:
P-CREB albumen is the nutrient protein of neurocyte, and Western-blotting result shows (Fig. 4), and the p-CREB protein content obviously reduces than the Control control group in the L-glutamic acid group cell, dosing group (M
1-3And M
1) significantly raise than the L-glutamic acid group, near normal value.Be compound M
1-3And M
1Can obviously suppress the minimizing of the p-CREB expression amount that causes by L-glutamic acid.Prove the protection activity of The compounds of this invention once more from the Proteometabolism angle to nerve injury.
L-glutamic acid injured nerve cells provide protection conclusion (of pressure testing) proves that The compounds of this invention all contrasts medicine amantadine and 3, and the effect of 5-dimethyladamantane amine obviously strengthens; but consider the needs of the reversibility effect of addressing previously; comprehensive validity and security two aspects it is considered herein that M
1-3And Ad
3May tool research and development be worth.
Claims (9)
1, one group of amantadine analog derivative, its chemical structure is suc as formula shown in (I):
Wherein, R
1=CH
3Or H;
R
2=CH
3, H or R
1
R
3=H or contain the chain or the ring-type hydroxyl substituted hydrocarbon radical of 3～8 carbon atoms;
R
4=H, alkyl replace carbonyl oxygen acyl group, the chain that contains 3～8 carbon atoms or ring-type hydroxyl substituted hydrocarbon radical or camphoroyl.
2, derivative as claimed in claim 1, it is meant following compound:
Ad
1：R
1＝R
2＝R
3＝H；R
4＝CO
2CH
3
Ad
2：R
1＝R
2＝R
3＝H；R
4＝CO
2CH(CH
3)
2
Ad
3：R
1＝R
2＝R
3＝H；R
4＝(-)-camphanyl
M
1-1：R
1＝R
2＝CH
3；R
3＝H；R
4＝CO
2CH
3
M
1-2：R
1＝R
2＝CH
3；R
3＝H；R
4＝CO
2CH(CH
3)
2
M
1-3：R
1＝R
2＝CH
3；R
3＝H；R
4＝(-)-camphanyl
M
1-4：R
1＝R
2＝CH
3；R
3＝H；R
4＝CH
2CHOHCH
3
M
1-5：R
1＝R
2＝CH
3；R
3＝R
4＝CH
2CH
2OH
3, a kind of preparation method of derivative according to claim 1 is characterized in that with formula (II) be starting raw material: R wherein
1=R
2=H; Or R
1=R
2=CH
3, in non-proton property solvent, exist down in alkaline reagents, with condensation reactions such as alkyl substituted epoxy ethane or carbalkoxy chlorine or camphor acyl chlorides, obtain the N-substitutive derivative shown in the formula (I).
4, preparation method as claimed in claim 3, wherein non-proton property solvent is meant tetrahydrofuran (THF).
5, preparation method as claimed in claim 3, wherein alkaline reagents is meant triethylamine or pyridine.
6, a kind of is the pharmaceutical composition of effective constituent with the described derivative of claim 1.
7, composition as claimed in claim 6 can add pharmaceutically acceptable one or more carriers in case of necessity.
8, the described composition of claim 6 is meant to be fit to medicinal any dosage form.
9, the application of the described amantadine analog derivative of claim 1 in preparation neuroprotective unit damage medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100868078A CN100351225C (en) | 2004-10-28 | 2004-10-28 | Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100868078A CN100351225C (en) | 2004-10-28 | 2004-10-28 | Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634859A true CN1634859A (en) | 2005-07-06 |
| CN100351225C CN100351225C (en) | 2007-11-28 |
Family
ID=34847447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100868078A Expired - Fee Related CN100351225C (en) | 2004-10-28 | 2004-10-28 | Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100351225C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017193870A1 (en) * | 2016-05-07 | 2017-11-16 | Sunshine Lake Pharma Co., Ltd. | Memantine compounds and their preparation and uses thereof |
| CN108125939A (en) * | 2018-01-19 | 2018-06-08 | 徐州医科大学 | Treat the drug for neuroinflamation mediate neuronal being caused to damage after HIV infection |
| CN109862887A (en) * | 2016-11-03 | 2019-06-07 | 广东东阳光药业有限公司 | A kind of crystal form of adamantane aminated compounds, composition and application thereof |
| CN111662216A (en) * | 2019-03-05 | 2020-09-15 | 广东东阳光药业有限公司 | Crystal form of amantadine compound and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334618A (en) * | 1991-04-04 | 1994-08-02 | The Children's Medical Center Corporation | Method of preventing NMDA receptor-mediated neuronal damage |
| DE58905637D1 (en) * | 1989-04-14 | 1993-10-21 | Merz & Co Gmbh & Co | Use of adamantane derivatives for the prevention and treatment of cerebral ischemia. |
| CN1193981C (en) * | 2003-08-12 | 2005-03-23 | 江苏省原子医学研究所 | Method for preparing memantine hydrochloride |
| CN1216035C (en) * | 2003-10-10 | 2005-08-24 | 常州市东吴医药化工技术开发有限公司 | Method for preparing amantadine sulfate |
-
2004
- 2004-10-28 CN CNB2004100868078A patent/CN100351225C/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017193870A1 (en) * | 2016-05-07 | 2017-11-16 | Sunshine Lake Pharma Co., Ltd. | Memantine compounds and their preparation and uses thereof |
| CN109152752A (en) * | 2016-05-07 | 2019-01-04 | 广东东阳光药业有限公司 | A kind of adamantane aminated compounds and its preparation method and application |
| US10800734B2 (en) | 2016-05-07 | 2020-10-13 | Sunshine Lake Pharma Co., Ltd. | Memantine compounds and their preparation and uses thereof |
| JP2021119163A (en) * | 2016-05-07 | 2021-08-12 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co., Ltd. | Memantine compounds and their preparation and uses thereof |
| CN113336673A (en) * | 2016-05-07 | 2021-09-03 | 广东东阳光药业有限公司 | Amantadine compound and preparation method and application thereof |
| CN109862887A (en) * | 2016-11-03 | 2019-06-07 | 广东东阳光药业有限公司 | A kind of crystal form of adamantane aminated compounds, composition and application thereof |
| CN109862887B (en) * | 2016-11-03 | 2021-09-10 | 广东东阳光药业有限公司 | Crystal form, composition and application of amantadine compound |
| CN108125939A (en) * | 2018-01-19 | 2018-06-08 | 徐州医科大学 | Treat the drug for neuroinflamation mediate neuronal being caused to damage after HIV infection |
| CN108125939B (en) * | 2018-01-19 | 2020-06-26 | 徐州医科大学 | Medicine for treating neuroinflammation mediated neuron injury caused by HIV infection |
| CN111662216A (en) * | 2019-03-05 | 2020-09-15 | 广东东阳光药业有限公司 | Crystal form of amantadine compound and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100351225C (en) | 2007-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DD283374A5 (en) | PROCESS FOR PREPARING 2-HYDROXY-3-PHENOXYPROPYLAMINO COMPOUNDS | |
| EP2786986B1 (en) | Novel benzamide derivative and use thereof | |
| JPH07509468A (en) | Drugs that increase synaptic responsiveness mediated by AMPA receptors | |
| AU8899698A (en) | Furansulfonic acid derivatives and pharmaceutical compositions containing the same | |
| DE69825062T2 (en) | MONOAMINOXIDASE INHIBITOR AND H5-HT 1 BETA ANTAGONIST OR PARTIAL AGONIST MIXTURE | |
| JPH05507062A (en) | Trisubstituted- and tetrasubstituted guanidines and their use as excitatory amino acid antagonists | |
| US20200000801A1 (en) | Methods for treating central nervous system disorders using vdac inhibitors | |
| JP2012523418A (en) | Cognitive decline inhibitors | |
| EP2643292A1 (en) | Calcium-sensing receptor-active compounds | |
| US11571432B2 (en) | Compositions that preferentially potentiate subtypes of GABAA receptors and methods of use thereof | |
| WO2012069402A1 (en) | Substituted cyclopentyl - azines as casr- active compounds | |
| RU2584163C2 (en) | Trans-2-decenoic acid derivative and pharmaceutical agent containing same | |
| CN100351225C (en) | Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent | |
| TWI670058B (en) | Co-crystals of substituted glycine compounds and uses thereof | |
| NO326939B1 (en) | Calcium channel blocking compounds and pharmaceutical composition | |
| DE69814883T2 (en) | HIGH-SPEED STRIP TRANSFER IN A STRIP PROCESSING APPLICATION | |
| WO2005067930A2 (en) | Serotonin receptor antagonists for the treatment of neurological disease | |
| CN1080918A (en) | New aminopropanol derivatives contains their pharmaceutical composition and preparation method thereof | |
| Waszkielewicz et al. | Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy) alkyl]-and N-{2-[2-(phenoxy) ethoxy] ethyl} aminoalkanols as anticonvulsant agents | |
| Du et al. | Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain | |
| EP4135710A1 (en) | Compositions that preferentially potentiate subtypes of gabaa receptors and methods of use thereof | |
| DE69030665T2 (en) | (1,2N) AND (3,2N) -BOXYCLICAL-2-AMINO-TETRALINE DERIVATIVES | |
| Pańczyk et al. | Synthesis and anticonvulsant activity of phenoxyacetyl derivatives of amines, including aminoalkanols and amino acids | |
| CN1104018A (en) | Substituted (arylalkylaminobenzyl) aminopropionamide derivatives, their preparation and use anti-eptic, neuroprotective and antidepressant agents | |
| EA002031B1 (en) | Benzamides for neurodegenerative disorder treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |