CN101239053A - New purpose of 1,7,7-trimethyl bicycle [2.2.1] heptane (bornane, thujane, menthane) analogue and its derivative in treating oxidative damage neurological disease - Google Patents

New purpose of 1,7,7-trimethyl bicycle [2.2.1] heptane (bornane, thujane, menthane) analogue and its derivative in treating oxidative damage neurological disease Download PDF

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CN101239053A
CN101239053A CNA2007100033594A CN200710003359A CN101239053A CN 101239053 A CN101239053 A CN 101239053A CN A2007100033594 A CNA2007100033594 A CN A2007100033594A CN 200710003359 A CN200710003359 A CN 200710003359A CN 101239053 A CN101239053 A CN 101239053A
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isoborneol
camphane
heptane
oxidative damage
trimethyl
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王升启
田琳琳
周喆
王学军
贾高龙
程畅河
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Institute of Radiation Medicine of CAMMS
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Institute of Radiation Medicine of CAMMS
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Abstract

The invention relates to a new usage of the analog and the ramification of 1,7,7-trimethyl-bicyclo[2.2.1]heptan(bornane,camphane,camphane) used for curing oxidative damage neuropathic diseases. The usages of the analog and the ramification of 1,7,7-trimethyl-Bicyclo[2.2.1]heptan(bornane,camphane,camphane) and the ramification of the 1,7,7-trimethyl-Bicyclo[2.2.1]heptan-2-hydroxide radical(2-hydroxycamphane, borneol) and the medicine are combined materials of the officinal character body or carrier, and medicine combination or each unit being jointly used with current other medicine curing oxidative damage neuropathic diseases in curing oxidative damage neuropathic disease(such as parkinsonism).

Description

1,7,7-trimethyl bicyclo-[2.2.1] heptane (camphane, bornane, camphane) analog and derivant thereof the new purposes in treatment oxidative damage neurological disease
[technical field]
The present invention relates to 1,7,7-trimethyl bicyclo-[2.2.1] heptane (camphane, bornane, camphane) derivant and analog thereof the new purposes in oxidative damage neurological diseases such as treatment senile dementia, parkinson disease.
[background technology]
More and more evidences shows in recent years, multiple nerve retrograde affection and oxidative stress are closely related, as ischemic brain injury, Alzheimer (Alzheimer ' s disease, AD), parkinson disease (Parkinson diease, PD), spinal cord injury (spinal cordinjury, SCI), multiple sclerosis (multiple sclerosis, MS) etc.
PD is a kind of senile carrying out property nervous system disease, its main pathological change is substantia nigra of midbrain dopamine (dopamine, DA) serotonergic neuron degeneration necrosis causes striatum DA level to descend, symptoms such as trembling appears in the result, muscular rigidity, bradykinesia and position shakiness.The cause of disease and the mechanism of substantia nigra dopaminergic neuron forfeiture are paid close attention to always, discover that more and more oxidative stress, radical damage are the co-channels of the dopaminergic neuron death due to the multiple factor, also are considered to the principal element of PD patient's black substance neuronal death.
Cerebral ischemia claims apoplexy again, is commonly encountered diseases clinically.Its pathogenesis is very complicated, relates to many aspects such as acidosis, calcium overload, free radical, toxicity of excitatory amino acid, inflammatory cytokine infringement, and wherein free radical mechanism is to study more one side at present.Oxygen is for reducing during cerebral ischemia, and ATP decomposes, and the cerebral tissue blood supply insufficiency causes that glutamic acid discharges and the Ca2+ channel opener, and Ca2+ increases in the cell, and its consequence is to produce free radical.The free radical that produces acts on polyvalent unsaturated fatty acid generation oxidation reaction, and inducing DNA, RNA, proteinic interlinkage and oxidation reaction make the polysaccharide molecule depolymerization, mitochondrion degeneration, apoptosis or necrosis.
AD is modal nervous system degenerated disease, and it is a kind of many because of different substantiality disease, and its pathogenic factor comprises multiple factor.Relate to pathological processes such as cytoskeletal protein is modified unusually, A β deposition (β-myloid depo sition), the formation of neuritis's blanket in its morbidity, final encephalopathy Li Tezheng is a large amount of neurofibrillary tangleses (neurofibrillary tangle, NF T), a large amount of senile plaque and the atrophy of brain cortex.AD is with neuron loss, oxidative stress received much attention in the AD neuron loss in recent years, and there are many free radicals that studies show that to participate in the morbidity of AD, and the free radical that causes neuron loss is considered to be produced by A β, free radical destroys cell by the lipid peroxidation of cell membrane, neuron is lost in a large number, caused AD.
MS is a kind of autoimmune disease, a kind of central nervous system's demyelination, and radical damage and MS morbidity are closely related.It is too much that MS exists free-radical generating, and the oxidative stress degree strengthens, the lipid peroxidation of myelin membrane phospholipid and the myelin sheath degeneration and the destruction that cause thus.The free radical scavenger uric acid can be kept the integrity of blood brain barrier, stops inflammatory cell to immerse the central nervous system, thereby effectively treats MS.Antioxidant also can obviously alleviate the order of severity of MS.
Oxidative stress has important function in the generation of above-mentioned nervous system disease, development, so antioxidant has prevention and treats the effect of this class disease.
Document " West China pharmaceutical journal; 1989,4 (1): 23-25. " has reported that isoborneol can prolong the time of mice anoxia enduring, the mouse sleep time that can also the significant prolongation pentobarbital causes, produce synergism with pentobarbital, this effect of isoborneol is particularly remarkable; Document " West China pharmaceutical journal, 1990,5 (3): 190-191. " isoborneol has antibacterial action, and isoborneol can also significantly suppress the mice auricle swelling due to the Oleum Tiglii.It may have antagonism PGE and suppress the effect that inflammatory mediator discharges by machine-processed isoborneol.
As seen, isoborneol has very strong antioxidation, antiinflammatory action, and neuroprotective is arranged.
Up to now, also do not find any about 1,7,7-trimethyl bicyclo-[2.2.1] heptane (camphane, bornane, camphane) and the derivant report that is isoborneol in the treatment parkinson disease, the treatment for other oxidative damage nervous system disease also lacks system evaluation.This laboratory passes through the checking repeatedly of cellular level, animal level, thereby has finished the present invention.
[summary of the invention]
The object of the invention just provides the Parkinsonian novel drugs of a kind of treatment.Checking by experiment, 1,7,7-trimethyl bicyclo-[2.2.1] heptane-2-hydroxyl is that isoborneol can suppress the SH-SY5Y cell viability forfeiture that never poison 6-hydroxy dopamine causes, and can suppress the reduction of PD rat model model striatum DOPAMINE CONTENT IN RABBIT.Purpose of the present invention relates to 1,7,7-trimethyl bicyclo-[2.2.1] heptane (camphane, bornane, camphane) analog and derivant thereof the new purposes in the treatment parkinson disease.
Figure A20071000335900051
According to the present invention, medicine of the present invention can be made into by means known in the art, tablet, capsule, granule, injection etc.
According to the present invention, the present invention can make various dosage form, or closes other chemical compound combinations and make various dosage form, is used for oxidative damage nervous system disease (as parkinson disease) by different route of administration.
Term used herein " treatment " refers to treat, cure, relax, alleviate, change, correct, improve or prevent oxidative damage nervous system disease (as parkinson disease).
Enforcement of the present invention has important social benefit and economic benefit to the treatment of the oxidative damage nervous system disease (as parkinson disease) of serious harm human health.
[description of drawings]
In conjunction with chart, description of drawings specific implementation method of the present invention:
Fig. 1 chemical compound isoborneol is to the value-added influence of SH-SY5Y cell
Fig. 2 chemical compound isoborneol please add ROS the influence of the SH-SY5Y cell viability forfeiture that 6-hydroxy dopamine (6-OHDA) causes, and membrane potential influences data.
Table 1 chemical compound isoborneol is to the detection of Parkinson disease model rat striatum DOPAMINE CONTENT IN RABBIT influence
[specific embodiment]
Set forth in the external and body of medicine isoborneol of the present invention neuroprotective by following examples and estimate, but be not limited to following approach.Mainly comprise in these biotic experimenies: 1. chemical compound isoborneol pair cell toxicity detects; 2. the influence of chemical compound isoborneol SH-SY5Y cell viability forfeiture that 6-hydroxy dopamine (6-OHDA) is caused; 3. the chemical compound isoborneol is to the detection of PD rat model model striatum DOPAMINE CONTENT IN RABBIT influence.
[embodiment one] chemical compound isoborneol cytotoxicity detects
Materials and methods
1.SH-SY5Y cell culture
The SH-SY5Y cell is in the DMEM culture medium that contains 10% hyclone (Gibco) and 100IU/ml penicillin, 100 μ g/ml streptomycins, in 37 ℃, 5%CO 2Cultivate in the incubator.The observation of cell growth conditions is good, is cultured to the logarithmic growth after date, with SH-SY5Y cell inoculation 96 orifice plates, 2 * 10 5Cells/well, 37 ℃, 5%CO 2Hatched 24 hours, and after waiting to grow to 80～90% cells and converging, carried out the administration experiment.
2. the chemical compound isoborneol is to the value-added influence of SH-SY5Y cell
The SH-SY5Y cell is in the DMEM culture medium that contains 10% hyclone (Gibco) and 100IU/ml penicillin, 100 μ g/ml, in 37 ℃, 5%CO 2Cultivate in the incubator.The observation of cell growth conditions is good, is cultured to the logarithmic growth after date, with SH-SY5Y cell inoculation 96 orifice plates, 2 * 10 5Cells/well, 37 ℃, 5%CO 2Hatched 24 hours, after waiting to grow to 80～90% cells and converging, with the chemical compound isoborneol with final concentration 2.5 μ M/L, 5 μ M/L, 10 μ M/L, 20 μ M/L, 40 μ M/L, 80 μ M/L administration respectively, every concentration 3 holes, establish no drug cell contrast and blank simultaneously, 37 ℃, 5%CO 2Cultivate observed result after 24 hours.It is the MTT of 500 μ g/ml that every hole adds final concentration, 37 ℃ of lucifuges, 5%CO 2Cultivated 3 hours, at multiple labeling inspection enzyme-linked immunosorbent assay instrument (VICTOR TMWallac 1420 Multilabel Counter, TurKu Finland) goes up the mensuration 570nm light absorption value A of place.Simultaneously in inverted microscope following every day of observation of cell form.
3. the processing of chemical compound isoborneol exercising result and statistics
Isoborneol is represented with the percentage ratio that different group absorbances do not have the drug cell matched group relatively the influence of SH-SY5Y cell proliferation:
=(A570 Administration-A570 Blank)/(A570 Contrast--A570 Blank) * 100
The result carries out statistical analysis with Origin Pro 7.5.
The result
The chemical compound isoborneol is that every day is the observation of cell form under inverted microscope in 6 concentration treatment S H-SY5Y cell processes of Concentraton gradient with 2 times of dilutions, and dosing group cellular morphology and cellular control unit form do not have obvious variation.Test independent triplicate, the MTT testing result is seen Fig. 1.Isoborneol does not all have toxicity at 2.5～40 μ mol pair cells.
The SH-SY5Y cell viability forfeiture that [embodiment two] chemical compound isoborneol causes 6-hydroxy dopamine (6-OHDA) influence materials and methods
1.SH-SY5Y cell culture
Method is seen embodiment one
2. the chemical compound isoborneol causes the detection of SH-SY5Y cell viability forfeiture influence to 6-hydroxy dopamine (6-OHDA)
The SH-SY5Y cell is in the DMEM culture medium that contains 10% hyclone (Gibco) and 100IU/ml penicillin, 100 μ g/ml, in 37 ℃, 5%CO 2Cultivate in the incubator.The observation of cell growth conditions is good, is cultured to the logarithmic growth after date, with SH-SY5Y cell inoculation 96 orifice plates, 2 * 10 5Cells/well, 37 ℃, 5%CO 2Hatched 24 hours, after waiting to grow to 80～90% cells and converging, wherein one group with the chemical compound isoborneol with final concentration 2.5 μ M/L, 5 μ M/L, 10 μ M/L administration respectively, every concentration 3 holes give 6-hydroxy dopamine (final concentration is 100 μ mol/L) then; Other one group with the chemical compound isoborneol with final concentration 2.5 μ M/L, 5 μ M/L, 10 μ M/L administration respectively, every concentration 3 holes, cultivate after 3 hours, it is inferior to give a baby a bath on the third day after its birth with serum-free DMEM culture medium, give 6-hydroxy dopamine (final concentration is 100 μ mol/L) then, establish no drug cell contrast and blank simultaneously, 37 ℃, 5%CO 2Cultivate observed result after 24 hours.It is the MTT of 500 μ g/ml that every hole adds final concentration, 37 ℃ of lucifuges, 5%CO 2Cultivated 3 hours, at multiple labeling inspection enzyme-linked immunosorbent assay instrument (VICTOR TMWallac 1420 Multilabel Counter, TurKu Finland) goes up the mensuration 570nm light absorption value A of place.Simultaneously in inverted microscope following every day of observation of cell form.
3. the processing of chemical compound isoborneol exercising result and statistics
Isoborneol causes the influence of SH-SY5Y cell viability forfeiture to be represented with the percentage ratio that different group absorbances do not have the drug cell matched group relatively to the 6-hydroxy dopamine:
=(A570 Administration-A570 Blank)/(A570 Contrast--A570 Blank) * 100
The result carries out statistical analysis with Origin Pro 7.5.
The result
Test independent triplicate, the MTT testing result is seen Fig. 2.Isoborneol causes the forfeiture of SH-SY5Y cell viability to be dose-dependent inhibitory action to the 6-hydroxy dopamine.The protective effect of isoborneol mainly occurs in the born of the same parents.
[embodiment three] chemical compound isoborneol is to the detection of Parkinson disease model rat striatum DOPAMINE CONTENT IN RABBIT influence
Materials and methods
1.SD rat is cultivated
Select 40 of healthy adult SD male rats for use, between body weight 200～300g, provide by Military Medical Science Institute zoopery center.25 ℃ of rat feeding ambient temperatures.
2. the chemical compound isoborneol is to the detection of Parkinson disease model rat striatum DOPAMINE CONTENT IN RABBIT influence
The parkinson rat model is made: the micro-6-OHDA method of directed injection: with pentobarbital sodium (30mg/kg) the intraperitoneal injection of anesthesia rat of 3% (ω), rat head is fixed on the brain solid positioner, the front and back fontanel is equal, exposes skull, the cleaning surface of bone.Determine that with reference to Paxinos and Watson Mus brain stereotaxic atlas the substantia nigra zona compacta coordinate is 5.3mm behind the bregma, sagittal suture is other to the right opens 2.0mm., and the degree of depth is 7.6mm under meninges.The dental burr punching is injected 6-OHDA and the 0.2mg/ml vitamin C injection that 4 μ L mass concentrations are 2 μ g/ μ L with 10 μ L microsyringes, injects speed 1 μ L/min, injection Bi Liuzhen 5min, gelfoam hemostasis, skin suture are inserted in the slowly withdraw of the needle, drill hole.Continuous lumbar injection penicillin 1,000,000 U/ of postoperative (kgd-1) 3d infects with control.Sham-operated control group is then injected Isodose (4 μ L) 0.2mg/ml vitamin C injection in substantia nigra zona compacta.Animal grouping and processing: therapeutic medication experiment: in 40 rats, select for use 8 to be matched group (irritating stomach equal-volume normal saline).Cause Parkinson disease model, all modeling successes with all the other 32.Be divided into 4 groups at random, every group 8: isoborneol high-dose therapy group (press 100mg/kg dosage and irritate stomach isoborneol solution), dosage treatment group in the isoborneol (press 30mg/kg dosage and irritate stomach isoborneol solution), isoborneol low dose therapy group (press 10mg/kg dosage and irritate stomach isoborneol solution), model group (irritating stomach equal-volume normal saline).Administration 1 time/day, continuous 14 days.
The circling behavior observation index: circling behavior detects, and lumbar injection apomorphine 0.5mg/kg (0.5g/L Sigma) brings out rat and produces to anticlockwise, after the record apomorphine injects, and the rotating cycle in the 30min.Constant turning left, revolution 〉=210r/30min is decided to be the parkinson model of success.
The striatum DOPAMINE CONTENT IN RABBIT detects: therapeutic administration group breaks end each group rat after 14 days in administration, take out brain rapidly, on ice pan, separate the bilateral striatum,-70 ℃ of preservations, analytical balance claims weight in wet base, the sucrose solution that adds 0.32mol/L by 100 μ l/10mg, make homogenate, add equivalent 0.4mol/L perchloric acid solution, behind the vibration mixing,, get supernatant and place-50 ℃ of refrigerators to take out vacuum after 24 hours and drain with the centrifugal 4min of 12000r/min, add distilled water to the debita spissitudo multiple, adopt the high pressure liquid chromatograph UV-detector to measure dopamine concentration.
3. the processing of chemical compound isoborneol exercising result and statistics
Influence to rat bilateral striatum DOPAMINE CONTENT IN RABBIT after the administration of PD rat model therapeutic.The result carries out statistical analysis with Origin Pro 7.5.
The result
The high pressure liquid chromatograph UV-detector is measured dopamine concentration and be the results are shown in Table 1.The administration of isoborneol therapeutic can dose-dependent inhibition parkinson rat model striatum DOPAMINE CONTENT IN RABBIT reduction.
Figure A20071000335900081
Figure A20071000335900091
The administration of table 1 isoborneol therapeutic is to the influence (x ± s, n=8, μ g/g) of PD rat model striatum DOPAMINE CONTENT IN RABBIT

Claims (5)

1. 1,7 of following formula, 7-trimethyl bicyclo-[2.2.1] heptane (camphane, bornane, camphane) analog and derivant thereof the new purposes in treatment oxidative damage neurological disease.
Figure A2007100033590002C1
Wherein R1 and R2 can be identical or different, are respectively hydrogen, oxygen (carbonyl), nitrogen (as oxime, semicarbazones structure), hydroxyl, amino, C 1-6Alkyl, C 1-6The carboxylic acid group.
2. according to the purposes of claim 1,1,7,7-trimethyl bicyclo-[2.2.1] heptane analog and derivant thereof can be 1,7 of following formula, 7-trimethyl bicyclo-[2.2.1] heptane-2-hydroxyl (2-hydroxyl camphane, Borneolum Syntheticum).
Figure A2007100033590002C2
Wherein parent nucleus 1,7, and 7-trimethyl bicyclo-[2.2.1] heptane-2-hydroxyl can be any one or two of following stereoisomer or optical isomer, and is wherein preferential with (+)-Isoborneol or (-)-Isoborneol;
Figure A2007100033590002C4
(1R，2S)-form (1S，2R)-form
(+)-borneol (-)-borneol
Figure A2007100033590002C5
Figure A2007100033590002C6
(1S，2S)-form (1R，2R)-form
(+)-Isoborneol (-)-Isoborneol
R can be hydrogen, (pentose is or/and hexose for glycosyl; Glycosyl number≤3), C 1-6Alkyl, C 1-6Acyl group, 3 (4)-hydroxy benzoyls, 3,4-dihydroxy benzenes formoxyl, cinnamoyl, coffee acyl, green former acyl group, quinine acyl group.
3. pharmaceutical composition that is used for the treatment of the oxidative damage neurological disease, it comprises as 1 of the claim 1 of active ingredient, 7,7-trimethyl bicyclo-[2.2.1] heptane (camphane, bornane, camphane) analog and derivant thereof and claim 2 desired 1,7, the derivant of 7-trimethyl bicyclo-[2.2.1] heptane-2-hydroxyl (2-hydroxyl camphane, Borneolum Syntheticum), and medicinal inborn nature body or carrier.
4. the pharmaceutical composition of claim 3 or each monomer and other treatment oxidative damage neurological disease medicament coupling, the purposes in treatment oxidative damage neurological disease.
5. the pharmaceutical composition of claim 3, wherein said pharmaceutical composition or each monomer can be formulated into tablet, capsule, injection or other dosage form.
CNA2007100033594A 2007-02-06 2007-02-06 New purpose of 1,7,7-trimethyl bicycle [2.2.1] heptane (bornane, thujane, menthane) analogue and its derivative in treating oxidative damage neurological disease Pending CN101239053A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8658684B2 (en) 2008-03-04 2014-02-25 Jiangsu Simcere Pharmaceutical R & D Co., Ltd. Pharmaceutical composition and its use in the preparation of a medicament for the treatment of cerebrovascular diseases
WO2019127746A1 (en) * 2017-12-30 2019-07-04 苏州沪云肿瘤研究中心股份有限公司 Phenylpropionate compound, preparation method for same, and applications thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8658684B2 (en) 2008-03-04 2014-02-25 Jiangsu Simcere Pharmaceutical R & D Co., Ltd. Pharmaceutical composition and its use in the preparation of a medicament for the treatment of cerebrovascular diseases
WO2019127746A1 (en) * 2017-12-30 2019-07-04 苏州沪云肿瘤研究中心股份有限公司 Phenylpropionate compound, preparation method for same, and applications thereof
US11767286B2 (en) 2017-12-30 2023-09-26 Suzhou Pharmavan Co., Ltd Phenylpropionate compound, preparation method for same, and applications thereof

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