CN103864759A - Tacrine- nicotinic acid conjugate, preparation method and medical application thereof - Google Patents
Tacrine- nicotinic acid conjugate, preparation method and medical application thereof Download PDFInfo
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- IYPJWKLHPNECFJ-UHFFFAOYSA-N Clc1c(CCCC2)c2nc2c1cccc2 Chemical compound Clc1c(CCCC2)c2nc2c1cccc2 IYPJWKLHPNECFJ-UHFFFAOYSA-N 0.000 description 1
- MTPGMAOIWNBPSP-UHFFFAOYSA-N NCCNc1c(CCCC2)c2nc2c1cccc2 Chemical compound NCCNc1c(CCCC2)c2nc2c1cccc2 MTPGMAOIWNBPSP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the medical field and in particular relates to tacrine- nicotinic acid conjugates. The invention further discloses a preparation method of the tacrine- nicotinic acid conjugates as well as medical salts, pharmaceutical compositions or pharmaceutical agents containing the compounds and application of the compounds in medicines, especially treating Alzheimer disease.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to class tacrine-nicotinic acid conjugate.The invention also discloses the preparation method of these tacrine-nicotinic acid conjugates and pharmaceutical salts, pharmaceutical composition or the pharmaceutical preparation that contains described compound, and described compound is in the pharmaceutically particularly application in treatment Alzheimer's disease.
Background technology
Alzheimer's disease (Alzheimer ' s disease, AD) is commonly called as senile dementia, is a kind of lethality nerve degenerative diseases that carries out sexual development, damages as feature taking cognitive disorder and memory.Along with aging population is day by day serious, the morbidity of AD also obviously improves, and China AD patient has more than 600 ten thousand, occupies first place in the world, and is the fourth-largest killer who causes old man's death.Mechanism of causing a disease about AD is still not exclusively distinct, and its mechanism of action hypothesis has upper ten kinds.AD patient's cerebral tissue has three large significant pathological changes: the neurofibrillary tangle that the Protein tau of Hyperphosphorylationof causes, the interior basal nuclei of senile plaque, brain that beta amyloid peptide (A β) forms and forebrain cholinergic neuron are impaired is that main neurone is lost in a large number.
Current, clinically using the acetylcholinesterase depressant (Acetylcholerestrase inhibitors, AChEIs) based on the research and development of cholinergic theory as most widely used anti-AD medicine.Such medicine, by acetylcholine esterase inhibition, maintains the normal level of vagusstoff in synaptic cleft, thereby is conducive to increase the transmission of cholinergic nerve signal and the recovery of cognitive function of patients.So far, AChEIs is as the choice drug of current treatment or alleviation alzheimer's disease, successively had two generations totally 5 kinds of AChEIs successfully go on the market, comprise tacrine (tacrine), E2020 (donepezil, have another name called aricept, aricept, E2020), profit is cut down this bright (exelon, have another name called rivastigmine, rivastigmine), selagine ((-)-huprine A) and lycoremine (galantamine).Tacrine is the reversibility anticholinesterase of the first FDA of obtaining approval listing, has potent cholinesterase inhibition, can see through hemato encephalic barrier after oral, clinically for the gently treatment of moderate AD.But tacrine exists two subject matters: (1) liver toxicity is larger, patient takes medicine needs to carry out strict transaminase monitoring simultaneously; (2) compared with other AD medicines such as E2020, taking dose is larger, and the treatment later stage needs 80mg/d.
The research of AChE crystalline structure is found, the active cavity of AChE is the passage (gorge) of a mountain valley shape, opening part is periphery anionic sites (peripheral anionic site, PAS), the lowest point is catalytic site (catalytic active site, CAS).Pang etc., according to the result of molecular simulation, have designed tacrine dimer (bis7tacrine, 2) (JBiol Chem, 1996,271:23646-23649), can act on CAS and PAS site simultaneously.After this, researchist passes through tacrine to be connected with other active fragmentss, or two active fragmentss are connected, and has synthesized dibit point inhibitor (BioorgMedChem, 2005, the 13:6588-6597 of a series of AChE; EurJMedChem, 2011,46:2609-2616).2008, Cavalli etc. further clearly propose the hypothesis of " middle action site ", introduce different groups in the bridging region of dibit point inhibitor to strengthen the interaction between bridging part and middle site, and then biological activity (the JMed Chem of raising inhibitor, 2008,51:347-372).
Nicotinic acid (nicotinic acid, niacin), trade(brand)name
being one of 13 kinds of VITAMIN necessary in human body, is also a kind of water-soluble vitamins, belongs to vitamin B complex.Nicotinic acid is converted into rapidly niacinamide in vivo, and niacinamide is nadide and coenzyme II integral part, participates in HypercholesterolemicRats, the process that the oxidising process of tissue respiration and carbohydrate anaerobic are decomposed.
Research shows, the famine of nicotinic acid is one of paathogenic factor of AD (JNeurol Neurosurg Psychiatry, 2004,75:1093-1099).Nicotinic acid raises the expression of LXR-α and peroxisome proliferation-activated receptors γ (PPAR γ) mRNA, and promotes the high density lipoprotein cholesterol of induction to flow out.Therefore, nicotinic acid reduces serum and cell inner cholesterol level, and this may be to protection Alzheimer play a role (Open Drug Discovery J, 2010,2:181-186).In addition, niacinamide is the competitive inhibitor of sirtuins.Green etc. have evaluated the result for the treatment of of niacinamide in transgenosis AD mouse, find that niacinamide can reverse the Cognitive deficiency of AD transgenic mice.Research is found, uses niacinamide 4 months to 4 months large transgenic mices, can prevent cognition dysfunction and the spatial memory that improves short-term.The Protein tau level of the niacinamide elective reduction Thr231 site phosphorylation relevant with the depolymerization of microtubule, and sharply increase acetylizad α-microtubule, thus increase the stability of microtubule.Niacinamide also can raise the expression of the p25 albumen that can improve learning and m emaory.(JNeurosci，2008，28(45)：11500-11510)。Therefore, oral nicotinic acid is of value to the control of AD and other old relevant cognitive disorders.At present, Schreiber etc. carries out II phase clinical study to the security of nicotinic acid treatment AD.(http：／／clinicaltrials.gov／ct2／show／NCT00580931)
Summary of the invention
The present invention discloses tacrine-nicotinic acid conjugate, preparation method and the medicinal use thereof with pharmaceutical use shown in general formula (I) first, particularly the application in treatment Alzheimer's disease.In addition, the present invention also provides pharmaceutical salts, pharmaceutical composition or the pharmaceutical preparation that one contains general formula (I) compound.
The technical problem to be solved in the present invention is the basic medicinal design principle of application, finds and has than less, the stronger nootropic effect of tacrine liver toxicity, can act on the PAS of AChE and " the many targets of a medicine " the anti-AD medicine of type in CAS site simultaneously.The present invention also for provide a kind of anti-AD medicine can suitability for industrialized production preparation method.
For solving the problems of the technologies described above, the invention provides following technical scheme:
1. compound and pharmaceutical salts thereof shown in general formula (I):
Wherein, L representative
or
time, m represents the arbitrary integer in 1～4; N represents the arbitrary integer in 2～12; P represents the arbitrary integer in 1～3.
2. compound and pharmaceutical salts thereof shown in general formula (I), is characterized in that:
M represent 1,2 or 3, n represent 6 or 7, p represent 1.
3. more preferred compound has:
N-(6-((2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) amino) hexyl) nicotinamide;
N-(6-((1,2,3,4-tetrahydro acridine-9-yl) amino) hexyl) nicotinamide;
N-(7-(1,2,3,4-tetrahydro acridine-9-base amino) heptyl) nicotinamide;
N-(7-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-base amino) heptyl) nicotinamide;
N-(6-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-base amino in heptan) hexyl) nicotinamide;
N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-12,3,4-tetrahydro acridine-9-amino;
N-(2-(2-(2-(1,2,3,4-tetrahydro acridine-9-base amino) oxyethyl group) oxyethyl group) ethyl) nicotinamide;
4. compound of the present invention can prepare by following method:
(1) when L is
or
step preparation by reaction formula () Suo Shu:
A. reference Bioorg.Med.Chem.1999,7,351-357, anthranilic acid reacts and obtains compound 1 from different cycloalkanones in phosphorus oxychloride;
C. nicotinic acid and compound 2 obtain the compound of general formula (I) in organic solution through condensation.
Reaction formula (one)
Wherein L is
or
m is 1,2 or 3; N is 1,2 or 3; P is 1.
(2) when L is
step preparation by reaction formula (two) Suo Shu:
A. nicotinic acid and N-Boc-quadrol obtain compound 3 through catalyzed reaction in organic solution;
C. anthranilic acid reacts and obtains compound 1 from different cycloalkanones in phosphorus oxychloride;
Reaction formula (two)
Wherein L is
time, m is 1,2 or 3;
Concrete preparation method of the present invention, comprising:
(1) when L is
or
right: the preferred 100-110 DEG C of temperature of reaction in step a, preferred 2-3h of reaction times; The preferred Pentyl alcohol of organic solution in step b, answers the preferred 140-150 DEG C of temperature, preferred 24-48h of reaction times.The preferred DMF of organic solution in step c, the preferred HOBt/EDCI of condensing agent and DMAP/DCC, preferred 2-4h of reaction times, the preferred room temperature of temperature of reaction.
(2) when L is
time: the preferred methylene dichloride of organic solvent in step a, ethyl acetate, ethanol, methyl alcohol, acetone.Triethylamine and EDCI catalysis obtain compound 3, the preferred room temperature of temperature of reaction, preferred 3-4h of reaction times.The preferred room temperature of temperature of reaction of step b, the reaction times is 0.5-1h; The preferred 100-110 DEG C of temperature of reaction in step c, preferred 2-3h of reaction times; The preferred Pentyl alcohol of organic solution in steps d, the preferred 140-150 DEG C of temperature of reaction, preferred 5-6h of reaction times; The preferred room temperature of temperature of reaction in step e, preferred 3-4h of reaction times, the preferred DCM/MeOH mixed solvent of solvent solvent, proportion optimization 1: 1.
The present invention includes the pharmaceutical salts, prodrug or the solvate that contain general formula (I) compound.Described pharmaceutical salts comprises inorganic salt example hydrochloric acid salt, hydrobromate, hydriodate, vitriol, nitrate, and organic acid salt is as acetate, maleate, fumarate, Citrate trianion, oxalate, succinate, tartrate, malate, mandelate and tosylate.Any compound that contains general formula (I) prodrug is also within the scope of the present invention.Term " prodrug " is with its broadest sense use and comprise those derivatives that are converted in vivo the compounds of this invention.These derivatives are apparent for those skilled in the art, and comprise according to the functional group existing in molecule the following derivative that is not limited to the compounds of this invention: ester, amino acid ester, phosphoric acid, carbamate and acid amides.The method of solvation is well known in the art, and suitable solvate is medicinal solvent compound.
The present invention includes a kind of pharmaceutical composition, wherein contain formula (I) compound and pharmaceutical salts or the pharmaceutically acceptable carrier for the treatment of significant quantity.
The present invention also comprises a kind of pharmaceutical preparation, contain formula (I) compound or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additive is or/and carrier.Described pharmaceutical preparation, comprises solid oral agent, oral liquid or injection; Described solid oral agent can be tablet, pill, dispersible tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine can be oral solution; Described injection can be injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
The present invention includes formula (I) compound and pharmaceutical salts, prodrug or solvate, pharmaceutical composition and pharmaceutical preparation, for the preparation of the purposes in the disease treatment by acetylcholinesterase (AChE) and butyrylcholine esterase (BuChE) mediation.
The present invention also comprises formula (I) compound and pharmaceutical salts, prodrug or solvate, pharmaceutical composition and pharmaceutical preparation, for the preparation of the purposes in the nervous system disease medicine that fails relevant to cognitive function being mediated by AChE/BuChE.Described that mediated by AChE/BuChE and the cognitive function relevant nervous system disorders that fails comprises Alzheimer's disease and other dementias.
Brief description of the drawings
Reaction formula (one) represents that L is
or
time embodiment preparation method.
Reaction formula (two) as L is
time embodiment preparation method.
Fig. 1 represents the hepatic tissue pathology section (amplifying 200 times) of tacrine, duplex tacrine, embodiment 2 and embodiment 5.
Fig. 2 represents that (A is embodiment 2 for the binding pattern figure of embodiment 2, duplex tacrine (Bis7Tacrine), tacrine and TcAChE, B is duplex tacrine, and C is tacrine, PDB id:2CKM, key amino acid is light blue, and hydrogen bond is yellow breakpoint line).
embodiment
The universal method of preparing the compounds of this invention has below been described.Provide the following example in order further to illustrate the present invention instead of limiting the scope of the invention.
The preparation of N-(6-((2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) amino) hexyl) nicotinamide
(1) 9-is chloro-2,3-dihydro-1H-cyclopentano [b] quinoline
Anthranilic acid (5.55g, 40.5mmol) and cyclopentanone (4.02ml, 45mmol) are put in the three-necked bottle of 100ml, under ice bath, slowly drip the POCl of 33.6ml
3, reflux 3h at 105 DEG C, lets cool to room temperature, and reduced vacuum is spin-dried for, mixed solvent C H
2cl
2.CH
3oH (100ml, v: v=2: 1) dissolve, saturated potassium carbonate neutralization, saturated common salt washing (200ml*5), organic layer anhydrous sodium sulfate drying, column chromatography for separation (PE:EtOAc, v: v=20: 4), 9-is chloro-2,3-dihydro-1H-cyclopentano [b] quinoline 5.76g, productive rate 70%.m.p.58-61℃.
1H?NMR(CDCl
3，500MHz)：8.17-8.15(1H，d，J=8.35Hz)，8.05-8.03(1H，d，J=8.35Hz)，7.69-7.66(1H，t，J=8.2Hz)，7.58-7.55(1H，t，J=8.05Hz)，3.26-3.23(2H，t，J=7.75Hz)，3.19-3.16(2H，t，J=7.4Hz)，2.28-2.22(2H，m)；MS(m/z)：204.1([M+H]
+).
(2) N
1-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) hexane-1,6-diamines
By chloro-9-2,3-dihydro-1H-cyclopentano [b] quinoline (2.17g, 10mmol) and 1,6-hexanediamine (8.12g, 70mmol) in 250ml flask, add Pentyl alcohol 80ml, 145 DEG C of reaction 30h, reaction solution lets cool to room temperature, add ethyl acetate 100ml, saturated common salt washing (100ml*6), organic layer anhydrous sodium sulfate drying, decompression is spin-dried for, column chromatography for separation (CH
2cl
2: MeOH:TEA, v: v: v=20: 1.5: 0.5) obtain tawny oily matter N
1-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) hexane-1,6-diamines 2.12g, productive rate: 75%.
1H?NMR(DMSO-d6，300MHz)：8.64-8.61(1H，d，J=8.58Hz)，7.93-7.91(1H，d，J=8.28Hz)，7.87-7.82(1H，t，J=6.90Hz)，7.64-7.58(1H，t，J=7.71Hz)，3.72-3.70(2H，m)，3.09-3.02(2H，m)，2.75(2H，s)，2.19-2.14(2H，m)，1.67-1.59(6H，m，，，
)，1.38(4H，m)；MS(m／z)：284.2([M+H]
+).
(3) N-(6-((2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) amino) hexyl) nicotinamide
Nicotinic acid (0.15g, 1.2mmol) is dissolved in the DMF of 20ml, adds the HOBt of equimolar amount, stirring at room temperature 2h, then adds the N of 2 times of molar equivalents
1-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) hexane-1,6-diamines and EDCI, room temperature reaction 4h.TLC detection reaction is complete, frozen water (30ml) adds water, ethyl acetate (100ml) is extracted, saturated sodium bicarbonate washing, organic layer anhydrous sodium sulfate drying, decompression is spin-dried for, column chromatography for separation (developping agent: methylene dichloride: ethyl acetate: methyl alcohol, v: v: v=10: 2: 1) separate and obtain compound N-(6-((2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) amino) hexyl) nicotinamide 0.41g, productive rate 70%.m.p.118-120℃.
1H?NMR(CDCl
3，500MHz)：8.97(s，1H)，8.71-8.70(d，1H，J=4.4Hz)，8.12-8.10(d，1H，J=7.9Hz)，7.90-7.89(d，1H，J=8.4Hz)，7.77-7.76(d，1H，J=8.3Hz)，7.55-7.52(t，1H，J=7.4Hz)，7.37-7.34(m，2H，)，6.45(s，1H)，4.80(s，1H)，3.59(s，2H)，3.49-3.46(q，2H，J=6.7)，3.19-3.16(t，2H，J=7.2Hz)，3.05-3.02(t，2H，J=7.7Hz)，2.16-2.09(m，2H)，1.68-1.62(m，4H)，1.48-1.44(m，4H).
13C?NMR(DMSO-d
6，125MHz)：165.3，164.6，151.6，148.3，144.3，134.8，130.0，129.2，129.2，125.2，123.9，123.3，122.1，118.1，111.7，43.9，33.1，30.7，30.6，28.9，28.9，26.1，25.7，22.5.IR(KBr)：v
max3376.7，2925.5，2853.4，1655.8，1571.7cm
-1；MS(m／z)：389.0[M+H]
+
The preparation of N-(6-((1,2,3,4-tetrahydro acridine-9-yl) amino) hexyl) nicotinamide
(1) 9-is chloro-1,2,3,4-tetrahydro acridine
Anthranilic acid (5.55g, 40.5mmol) and pimelinketone (4.02mL, 45.0mmol) are joined in 100ml three-necked bottle, under ice bath, slowly drip 33.6ml POCl
3, 105 DEG C of backflow 3h, reaction solution lets cool to room temperature.Decompression is spin-dried for, mixed solvent C H
2cl
2: CH
3oH (100ml, v: v=2: 1) dissolve saturated potassium carbonate neutralization, saturated common salt washing (200ml*5), organic layer anhydrous sodium sulfate drying, column chromatography for separation (PE:EtOAc, v: v=20: 4), obtain solid 9-chloro-1,2,3,4-tetrahydro acridine 4.8g.M.p.67-69 DEG C, hydrogen spectrum data are consistent with bibliographical information.
(2) N
1-(1,2,3,4-tetrahydro acridine-9-yl) hexane-1,6-diamines
9-is chloro-1,2,3,4-tetrahydro acridine (2.17g, 1mmol) and 1, and 6-hexanediamine (8.12g, 7mmol) adds Pentyl alcohol 80ml in 250ml flask, 145 DEG C of reaction 30h.Reaction solution is chilled to room temperature, adds ethyl acetate 100ml, saturated common salt water washing (100ml*6).Get organic layer, anhydrous sodium sulfate drying, is spin-dried for, and crosses post (methylene dichloride: methyl alcohol: triethylamine, v: v: v=20: 1.5: 0.5) and obtains tawny liquid N
1-(1,2,3,4-tetrahydro acridine-9-yl) hexane-1,6-diamines 0.8g.
1H?NMR(CDCl
3,300MHz)：7.96-7.90(2H，m)，7.65-7.53(1H，m)，7.63-7.32(1H，m)，3.96(br，1H)，3.48(2H，t，J=7.2Hz)，3.06(2H，br)，2.72-2.66(4H，m)，1.93-1.90(4H，m)，1.78(2H，br)，1.70-1.64(2H，m)，1.47-1.32(6H，m).
(3) N-(6-((1,2,3,4-tetrahydro acridine-9-yl) amino) hexyl) nicotinamide
The synthesis step of reference example 1, with N
1-(1,2,3,4-tetrahydro acridine-9-yl) hexane-1,6-diamines and nicotinic acid are synthetic oily matter N-(6-((1,2,3, the 4-tetrahydro acridine-9-yl) amino) hexyl) nicotinamide of raw material, productive rate 80%.
1H?NMR(CDCl
3，500MHz)：9.01(s，1H)，8.66-8.65(d，1H，J=4.7Hz)，8.14-8.12(d，1H，J=7.9Hz)，7.96-7.94(d，1H，J=8.5Hz)，7.89-7.88(d，1H，J=8.5Hz)，7.53-7.50(t，1H，J＝7.2Hz)，7.34-7.29(m，2H)，7.11(s，1H)，4.26(s，1H)，3.49-3.45(q，2H，J=7.2Hz)，3.45-3.41(q，2H，J=6.9)，3.02(s，2H)，2.68(s，2H)，1.88(s，4H)，1.66-1.59(m，4H)，1.40(m，4H)；
13C-NMR(CDCl
3，75MHz)：165.6，157.8，151.9，151.0，148.0，146.7，135.0，130.3，128.5，127.8，123.6，123.3，122.9，119.8，115.5，49.1，39.8，33.4，31.5，29.4，26.5，26.4，24.6，22.9，22.5；IR(KBr)：v
max3290.9，2931.3，2857.0，1648.2，1581.0cm
-1；MS(m／z)：403.1[M+H]
+
The preparation of N-(7-(1,2,3,4-tetrahydro acridine-9-base amino) heptyl) nicotinamide
(1) N
1-(1,2,3,4-tetrahydro acridine-9-yl) heptane-1,7-diamines
Reference example 2, chloro-1,2,3 with 9-, 4-tetrahydro acridine and 1,7-heptamethylene diamine are the synthetic thick compound N of raw material
1-(1,2,3,4-tetrahydro acridine-9-yl) heptane-1,7-diamines, productive rate: 75%.
1H?NMR(DMSO-d6，300MHz)：8.20-8.17(1H，d，J=8.76Hz)，7.69-7.66(1H，d，J=8.16HZ)，7.54-7.49(1H，t，J=6.90Hz)，7.35-7.30(1H，t，J=7.92Hz)，3.51-3.50(2H，m)，3.24-3.23(2H，m)，3.03-3.01(2H，m)，2.89-2.84(2H，m)，2.76-2.73(4H，m)，2.09-2.00(4H，m)，1.52(6H，br)；MS(m／z)：312.2[M+H]
+.
(2) N-(7-(1,2,3,4-tetrahydro acridine-9-base amino) heptyl) nicotinamide
Reference example 2, with N
1-(1,2,3,4-tetrahydro acridine-9-yl) heptane-1,7-diamines and nicotinic acid are synthetic N-(7-(1,2,3, the 4-tetrahydro acridine-9-base amino) heptyl) nicotinamide of raw material, productive rate 85%.
1H?NMR(CDCl
3，500MHz)：9.06-9.05(d，1H，J=1.65Hz)，8.68-8.66(dd，1H，J
1＝4.8Hz，J
2=1.45Hz)，8.22-8.20(d，1H，J=7.95Hz)，8.15-8.13(d，1H，J=8.20Hz)，8.09-8.07(d，1H，J=8.40Hz)，7.60-7.57(t，1H，J=7.35Hz)，7.39-7.34(m，2H)，6.99(s，1H)，3.62-3.57(q，2H，J=7.25)，3.46-3.42(q，2H，J=6.75Hz，)，.15-3.12(t，2H，J=6.00)，2.68-2.66(t，2H，J=5.35)，1.89-1.88(m，4H)，1.75-1.72(m，2H)，1.61-1.60(m，2H)，1.26-1.22(m，6H)；
13C?NMR(CDCl
3，75MHz)：165.6，153.9，151.8，148.2，148.2，142.0，135.3，130.8，124.5，123.8，123.7，123.4，123.4，117.5，112.7，52.9，39.9，31.0，30.4，29.7，29.3，28.6，26.5，26.4，22.3，21.4；IR(KBr)：v
max3443.4，2926.7，2853.8，1642.2，1384.6cm
-1；MS(m／z)：417.3[M+H]
+
The preparation of N-(7-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-base amino) heptyl) nicotinamide
(1) N
1-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) heptane-1,7-diamines
Reference example 1, chloro-2 with 9-, 3-dihydro-1H-cyclopentano [b] quinoline and 1,7-heptamethylene diamine are that raw material makes tawny oily matter N
1-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) heptane-1,7-diamines, productive rate 65%.
1h NMR (DMSO-d6,300MHz): 8.49-8.46 (1H, d, J=8.37Hz), 7.85-7.83 (1H, d, J=8.31Hz), 7.76-7.71 (1H, t, J=7.89Hz), 7.54-7.49 (1H, t, J=7.53Hz), 3.64-3.62 (2H, m), 3.41-3.34 (2H, m), 3.26-3.21 (2H, m), 2.76-2.71 (2H, m), 2.14-2.09 (2H, m), 1.64-1.55 (4H, m), 1.41-1.24 (6H, m); MS (m/z): 298.2[M+H]
+.
(2) N-(7-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-base amino) heptyl) nicotinamide
Reference example 1, with N
1-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) heptane-1,7-diamines and nicotinic acid are synthetic N-(7-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-base amino) heptyl) nicotinamide of raw material, productive rate 84%.
1H?NMR(CDCl
3，300MHz)：9.00(s，1H)，8.70-8.69(d，1H，J=4.32Hz)，8.16-8.14(d，1H，J=7.98Hz)，7.92-7.90(d，1H，J=8.31Hz)，7.84-7.81(d，1H，J=8.40Hz)，7.56-7.51(t，1H，J=7.38Hz)，7.38-7.33(m，2H)，6.62(s，1H)，5.11(s，1H)，3.64-3.58(q，2H，J=6.42Hz)，3.49-3.42(q，2H，J=6.72)，3.21-3.16(t，2H，J=7.14Hz)，3.08-3.03(t，2H，J=7.77Hz)，2.17-2.08(m，2H)，1.66-1.62(m，4H)，1.39(s，6H)；
13C?NMR(CDCl
3，75MHz)：167.1，165.6，152.0，147.9，147.6，147.6，135.2，130.5，128.8，127.4，124.3，123.5，120.3，118.6，113.6，52.9，40.0，34.3，31.2，31.1，30.9，28.8，28.6，26.7，26.5；IR(KBr)：v
max3374.7，2926.8，2849.3，1656.9，1571.5cm
-1；MS(m／z)：403.3[M+H]
+.
The preparation of N-(6-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-base amino in heptan) hexyl) nicotinamide
(1) 11-is chloro-7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline in heptan
Reference example 1, makes 11-chloro-7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline in heptan, productive rate 80% taking anthranilic acid and suberone as raw material.m.p.89-91℃.
1HNMR(CDCl
3,300MHz)：8.20-8.17(1H，d，J＝8.13Hz)，8.03-8.01(1H，d，J=7.98Hz)，7.70-7.65(1H，t，J=7.65Hz)，7.59-7.54(1H，t，J=7.95Hz)，3.28-3.21(4H，m)，1.91-1.74(6H，m)；MS(m／z)：232.1([M+H]
+).
(2) N
1-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-yl in heptan) hexane-1,6-diamines
Reference example 1, chloro-7,8,9 with 11-, 10-tetrahydrochysene-6H-ring [b] quinoline in heptan and 1,6-hexanediamine are that raw material makes tawny oily matter N
1-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-yl in heptan) hexane-1,6-diamines, productive rate 75%.
1H?NMR(CDCl
3，300MHz)：7.97-7.89(2H，m)，7.58-7.53(1H，t，J=7.2Hz)，7.44-7.39(1H，t，J=7.56Hz)，5.93(2H，s)，3.31-3.26(t，H，J=6.78Hz)，3.19-3.16(2H，t，J＝5.01Hz)，2.92-2.90(2H，m)，2.85-2.80?(2H，t，J=7.23Hz)，1.87-1.64(10H，m)，1.44-1.38(4H，m)；MS(m／z)：312.2([M+H]
+).
(3) N-(6-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-base amino in heptan) hexyl) nicotinamide
Reference example 1, with N
1-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-yl in heptan) hexane-1,6-diamines and nicotinic acid are the synthetic N-(6-(7,8 of raw material, 9,10-tetrahydrochysene-6H-ring [b] quinoline-11-base amino in heptan) hexyl) nicotinamide, productive rate 87%.
1H?NMR(CDCl
3，500MHz)：9.01-9.00(d，1H，J=1.6Hz)，8.65-8.64(dd，1H，J
1=4.8Hz，J
2＝1.6Hz)，8.13-8.10(m，1H)，7.92-7.88(m，2H)，7.55-7.52(m，1H)，7.40-7.37(m，1H)，7.31-7.29(m，1H),7.22(s，1H)，3.95(br.s，1H)，3.44-3.40(q，2H，J=6.80Hz)，3.26-3.23(t，2H，J=7.15Hz)，3.15-3.13(t，2H，J=5.60Hz)，2.90-2.88(t，2H，J=5.30Hz)，1.85-1.83(m，2H)，1.76-1.70(m，4H)，1.65-1.57(m，2H)，1.39-1.37(m，4H)；
13C?NMR(CDCl
3，75MHz)：165.6，165.3，152.1，149.8，147.7，146.6，135.1，130.4，128.9，128.3，124.7，124.0，123.5，122.1，121.8，50.5，40.0，39.9，31.9，31.4，31.3，29.6，29.5，27.6，26.9，26.7；IR(KBr)：v
max3337.2，2924.3，2853.4，1559.4，1502.9cm
-1；MS(m/z)：417.4[M+H]
+.
Embodiment 6
The preparation of N-(2-(2-(2-(1,2,3,4-tetrahydro acridine-9-base amino) oxyethyl group) oxyethyl group) ethyl) nicotinamide
(1) N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-12,3,4-tetrahydro acridine-9-amino
In 100ml eggplant-shape bottle by chloro-9-1,2,3, two (2-amino ethoxy) ethane (1.01ml of 4-tetrahydro acridine (0.50g, 2.30mmol) and 1,2-, 6.90mmol) be dissolved in 20ml Pentyl alcohol, 145 DEG C of backflow 48h to TLC detection reaction are complete.75 DEG C are steamed except Pentyl alcohol with water azeotropic, gained dark-brown oily matter are dissolved in to CH
2cl
2, saturated common salt water washing (50ml*3), pressure reducing and steaming solvent, through rapid column chromatography (developping agent CH
2cl
2: CH
3oH:TEA, v: v: v=50: 1: 1) obtain yellow oil N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-12,3, the amino 0.62g of 4-tetrahydro acridine-9-, yield is 81.88%.
1HNMR(CDCl
3，500MHz)：8.17-8.15(d，1H，J=8.SHz)，8.06-8.04(d，1H，J=8.4Hz)，7.30-7.28(t，1H，J=7.5Hz)，5.33(s，1H)，3.84-3.56(m，10H)，3.17(s，2H)，2.93-2.91(m，2H)，2.72(s，2H)，1.92-1.90(s，4H)；MS(m／z)：330.2([M+H]
+).
(2) N-(2-(2-(2-(1,2,3,4-tetrahydro acridine-9-base amino) oxyethyl group) oxyethyl group) ethyl) nicotinamide
In 10ml eggplant-shape bottle, add nicotinic acid (0.08g, 0.61mmol), HOBt (0.08g, 0.61mmol) and 2ml DMF, stirring at room temperature 1h, add N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-12 to this clear liquor, 3,4-tetrahydro acridine-9-amino (0.20g, 0.46mmol) and EDCI (0.14g, 0.73mmol), continuation stirring at room temperature 1h to TLC detection reaction is complete.In this reaction solution, add the saturated NaHCO of 5ml
3, CH after stirring at room temperature 10min
2cl
2extract organic layer, saturated common salt water washing 3 times, pressure reducing and steaming solvent, through rapid column chromatography (developping agent CH
2cl
2: CH
3oH=20: 1) obtain brown oil N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-12,3, the amino 0.13g of 4-tetrahydro acridine-9-, yield is 49.08%.IR(KBr)：v
max3386.6，2939.6，1647.5，1586.7，1100.2，708.4cm
-1.
1H?NMR(CDCl
3，300MHz)：8.99(s，1H)，8.61(s，1H)，8.07-8.05(d，1H，J=7.8Hz)，7.98-7.95(d，2H，J=8.5Hz)，7.57-7.52(t，1H，J=7.5Hz)，7.37-7.32(t，1H，J=7.6Hz)，7.25-7.21(m，1H)，7.12(s，1H)，4.85(s，1H)，3.69-3.64(m，12H)，3.06(s，2H)，2.70(s，2H)，1.87(s，4H)；
13C?NMR(CDCl
3，75MHz)：165.6，157.5，152.0，151.1，148.0，145.9，134.9，130.0，128.9，127.4，124.1，123.3，122.7，120.0，116.5，70.3，70.2，70.1，69.6，48.2，39.7，33.1，24.5，22.8，22.4；MS(m／z)：435.1([M+H]
+).
Embodiment 7
N
1-(2-(nicotinoyl amido) ethyl)-N
2-(the preparation of 2-((1,2,3,4-tetrahydro acridine-9-yl) amido) ethyl oxalic acid diamide
(1) (2-(nicotinoyl amido) ethyl) t-butyl carbamate
In the 50ml eggplant-shape bottle that is added with 5ml DCM, add successively TEA (0.7ml, 4.9mmol), nicotinic acid (0.5g, 4.1mmol), N-Boc-quadrol (0.74g, 4.5mmol), EDCI (2.35g, 12.2mmol), add rear stirring at room temperature 4h to TLC detection reaction complete.Saturated common salt water washing, CH
2cl
2extraction, organic layer anhydrous Na
2sO
4dry.Mixed solvent (PE:CHCl
3, v: v=10: 3.5) recrystallization, obtains white powder solid (2-(nicotinoyl amido) ethyl) t-butyl carbamate 0.62g, yield 57.4%.
1H?NMR(CDCl
3，300MHz)：9.14(s，1H)，8.74-8.72(m，1H)，8.25-8.22(d，1H，J=7.53Hz)，7.65-7.61(m，IH)，7.46-7.44(m，1H)，5.03(m，1H)，3.61-3.56(m，2H)，3.46-3.43(m，2H)，1.43(s，9H)；MS(m／z)：288.1[M+Na]
+.
(2) 2-((2-(nicotinoyl amido) ethyl) amino)-2-oxo ethyl acetate
In the eggplant-shape bottle of 50ml, (2-(nicotinoyl amido) ethyl) t-butyl carbamate (0.238g, 0.9mmol) is dissolved in to 8mlCH
2cl
2, slowly drip trifluoroacetic acid (0.7ml, 9.0mmol), and room temperature reaction 1h to TLC detection reaction is complete.Remove solvent under reduced pressure, in reaction flask, add 8ml EtOH and 1.2ml TEA.And slowly drip EtOH (1ml) solution of oxalic acid diethyl ester (0.4ml, 2.7mmol), drip off rear room temperature reaction 1h, steam desolventize after through rapid column chromatography (CH
2cl
2: MeOH, v: v=20: 1) obtain white powder solid 2-((2-(nicotinoyl amido) ethyl) amino)-2-oxo ethyl acetate 0.23g, productive rate 95%.
1H?NMR(CDCl
3，300MHz)：9.15(s，1H)，8.76-8.75(m，1H)，8.27-8.24(d，1H，J=7.53Hz)，7.79(m，1H)，7.51-7.46(m，1H)，7.43(m，1H)，4.39-4.34(q，2H，J=7.17Hz)，3.76-3.62(m，4H)，1.39(m，3H)；MS(m／z)：288.1[M+Na]
+.
(3) N
1-(1,2,3,4-tetrahydro acridine-9-yl)-1，2-diaminoethane
Reference example 2, chloro-1,2,3 with 9-, 4-tetrahydro acridine and anhydrous ethylenediamine are raw material synthesizing yellow pulverulent solids N
1-(1,2,3,4-tetrahydro acridine-9-yl)-1，2-diaminoethane, productive rate: 78%.
1H?NMR(DMSO-d6，500MHz)：8.12-8.10(d，1H，J=8.4Hz)，7.77-7.15(d，1H，J=8.05Hz)，7.61-7.58(m，1H)，7.43-7.40(m，1H)，7.19(m，2H)，3.58-3.55(m，2H)，3.07-3.05(m，2H)，2.96-2.93(m，2H)，2.77-2.75(m，2H)，1.86-1.82(m，4H)；MS(m／z)：242.2[M+H]
+.
(4) N
1-(2-(nicotinoyl amido) ethyl)-N
2-(2-((1,2,3,4-tetrahydro acridine-9-yl) amido) ethyl oxalic acid diamide
In 50ml eggplant-shape bottle, add 2-((2-(nicotinoyl amido) ethyl) amino)-2-oxo ethyl acetate (240mg, 0.9mmol) and 2 (241mg, 0.2mmol), add 10ml CH
2cl
2/ MeOH (v: v=1: 1) dissolve, room temperature reaction 4h to TLC detection reaction is complete.Through rapid column chromatography (CH
2cl
2: MeOH, v: v=15: 1), obtain pale yellow powder shape solid 0.43g, productive rate 90%.m.D.199～202℃；
1H?NMR(DMSO-d6,300MHz)：9.08-9.04(m，1H)，8.98-8.97(m，1H)，8.91-8.87(m，1H)，8.70-8.68(m，1H)，8.70-8.68(m，1H)，8.40-8.37(d，1H，J=8.5Hz)，8.16-8.13(m，1H)，7.82-7.81(m，1H)，7.82-7.81(m，1H)，7.56-7.47(m，1H)，7.56-7.47(m，2H)，3.95-3.93(m，2H)，3.49(m，2H)，3.40-3.38(m，2H)，3.17(m，2H)，2.97(m，2H)，2.66(m，2H)，1.81(m，4H)；
13CNMR(DMSO-d6，75MHz)：164.98，160.33，160.10，157.96，151.69，149.85，148.38，146.87，134.90，129.90，128.29，127.76，123.31，123.25，122.89，120.19，116.16，46.95，39.82，38.73，38.64，33.50，24.96，22.67，22.37；IR(KBr)：v
max3120.9，1646.4，1505.0，1400.3cm
-1；MS(m／z)：461.2[M+H]
+.
Embodiment 8
Embodiment 9
Biological assessment: external Pseudocholinesterase (AChE/BuChE) inhibition test adopts Ellman method (Ellman, the G.L. of improvement; Courtney, K.D.; Andres, B.; Featherstone, R.M.Biochem.Pharmacol.1961,7,88)
1. medicine and reagent
AChE(500unit，E.C.3.1.1.7，Type?VI-S，from?Electric?Eel，Sigma-Aldrich)
BChE(500unit，E.C.3.1.1.8，from?equine?serum，Sigma-Aldrich)
Two (2-nitrobenzoic acid) (5,5 '-Dithiobis (2-nitrobenzoic acid), DTNB, from J & K Chemical) of 5,5 '-bis-sulphur
Acetyl thio choline iodide (Acetylthiocholine iodide) and Butyryl thiocholine iodide (Butyrylthiocholine Iodide, from J & K Chemical), dimethyl sulfoxide (DMSO) (DMSO, from Sigma-Aldrich)
2. experimental implementation
(1) preparation buffered soln.13.6g potassium primary phosphate is dissolved in 1L water, regulates pH=8 ± 0.1 with potassium hydroxide.Be stored in 4 DEG C for subsequent use.
(2) take DTNB10.8mg for subsequent use in 50mL centrifuge tube, take substrate A TC/BTC3.5mg for subsequent use in 5ml centrifuge tube.
(3) preparation enzyme solution.The AChE/BChE of 500U/ml is dissolved in the gelating soln of 1mL1%, is then diluted with water to 100mL and makes the AChE/BChE solution that concentration is 5U/mL, be stored in-30C is for subsequent use.
(4) preparation tested material solution.Tested material is dissolved in in DMSO, to make concentration be 10
-2the mother liquor solution of M, then makes respectively the tested material solution of different concns with buffered soln dilution, be stored in-20 DEG C for subsequent use.
When experiment, by 20 times of (AChE:0.25U/ml of corresponding enzyme dilution, BuChE:0.25U/ml) be stored in ice chest, with 18ml damping fluid dissolving previously prepd DTNB (10.8mg), after dissolving, join immediately in 96 orifice plates, every hole 160 μ l add successively enzyme (every hole 50 μ 1) after adding, add again the test compounds 10 μ l of respective concentration, incubate at 37 DEG C and bathe 5min.Incubate bathe finish after, previously prepd substrate A CT/BTC (3.5mg) is dissolved in 3.5ml damping fluid, join fast successively (30 μ 1) in reacting hole.Under 405nm, test the ultraviolet absorptivity in 0～10min.Blank replaces tested material solution and enzyme solution with isometric water, and negative control replaces tested material solution to record with isometric water.The equal parallel running of all tests three times.Measured result GraphPad Prism
tM(GraphPad Software, San Diego, CA, USA) software calculates corresponding IC with non-linear decline analytical model (non-linear regression analysis model)
50value.The results are shown in Table 1.
The inhibition activity of the external AChE of table 1. and BuChE and selectivity (IC
50values)
a?Data?is?the?mean?of?three?determinations.
bAChE：E.C.3.1.1.7，Type?VI-S，from?Electric?Eel，Sigma-Aldrich.
cBuChE：E.C.3.1.1.8，from?equine?serum，Sigma-Aldrich.
dSelectivity?ratio=(IC
50of?AChE)／(IC
50of?BuChE)
Result demonstration, above-mentioned 7 embodiment all have significant restraining effect to AChE and BuChE, wherein embodiment 2 and the embodiment 5 inhibition (IC to AChE and BuChE
50) be all less than 10nM.
Embodiment 10
Biological assessment: cell growth inhibition assay (AlarmaBlue method)
1, cell strain and method
[cell strain]
1, HepG2 cell lines
2, neuroblastoma cell SH-SY5Y
3, Human normal hepatocyte is LO2
[method]
1. get in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion makes attached cell de-
Fall, counting 8 × 10
3individual/ml, makes cell suspension.
2. obtained cell suspension is inoculated on 384 orifice plates, and 45 μ l/ holes, put constant temperature CO
2in incubator, cultivate 24 hours.
3. change liquid, add tested medicine, 5 μ l/ holes, cultivate 72 hours.
4. AlarmaBlue reagent is added in 384 orifice plates, 5 μ l/ holes, detect after 10min.
5. be 540nm with enzyme-linked immunosorbent assay instrument in excitation wavelength, emission wavelength is the fluorescent value that 590nm place measures every hole, and calculates cell inhibitory rate.
Cell inhibitory rate %=(negative control-blank group) OD value-(compound-blank group) OD value/(negative control-blank group) OD value × 100%
Result (detecting after 2h) is in table 2
Table 27 embodiment suppresses experiment to the in-vitro multiplication of HepG2, SH-SY5Y and LO2 cell strain
Shown by the above results: (1) 7 embodiment compound is less to the toxicity of neurocyte SH-SY5Y cell; (2) embodiment 1 and embodiment 3 have weak effect restraining effect to the propagation of human liver cancer cell HepG2 in vitro, and embodiment 4 has middle effect restraining effect to the propagation of human liver cancer cell HepG2, and all the other compounds are less to HepG2 cytotoxicity; (3) 7 embodiment compounds are less to the toxicity of LO2 cell.
Embodiment 11
Biological assessment: study of behaviour experiment (Morris water maze method)
1, source, kind, strain, conformity certification: ICR mouse, clean level, is provided animal quality conformity certification number: SCXK (Soviet Union) 2007-0001 by Yangzhou University's comparative medicine center.
2, body weight: 20-25g
3, sex: male and female half and half
4, each treated animal number: 9-10/group
5, Morris water maze instrument (Jiliang Software Sci-Tech Co., Ltd., Shanghai);
Animal grouping
Mouse is divided into totally 5 groups of normal blank groups, modeling group, tacrine group (20 μ mol/kg), embodiment 2 (20 μ mol/kg), embodiment 5 (20 μ mol/kg) at random by body weight.
Medication
Abdominal injection Scopolamine modeling continuously, simultaneously gastric infusion 2 weeks.Normal blank group intraperitoneal injection of saline (0.4ml/20g), gavage gives the 0.5%CMC-Na solution (0.4ml/20g) of equivalent simultaneously; The metering such as modeling group, tacrine group and the other abdominal injection of drug component Scopolamine, the gavage of modeling group subsequently gives 0.5%CMC-Na solution (0.4ml/20g), and the other gavage of tacrine group and drug component gives tacrine and medicine to be measured (20 μ mol/kg).
Morris water maze test
Water maze test 6 days by a definite date, first 2 days is visible platform test, and 3-5 days is hiding platform test, within the 6th day, is space search test.During water maze test, continue gastric infusion every day, 10-15min abdominal injection Scopolamine before on-test.
1. visible platform training: the water maze platform (flag is higher than platform 5cm) that is inserted with flag is placed in to water maze the 4th quadrant, puts into 25 DEG C of left and right water to not having platform 5mm.Respectively by mouse towards pool wall put into water from 1,2,3,4 four quadrant (4 place of entry) every day, make its free swimming 90s, mouse is found platform and appears on the stage after stopping 10s it is taken off to rest from platform in 90s, and computer monitoring also records mouse and starts to climbing up the required time of platform (latent period) from entering water.If animal is not found platform in 90s, mouse is guided to platform, and stop 30s, be designated as 90s latent period.
2. hide platform training: the water maze platform that is not inserted with flag is placed in to water maze the 4th quadrant, puts into 25 DEG C of left and right water to not having platform 5mm.Training method is trained with visible platform.
3. space search test: test and remove platform on the 6th day, an optional quadrant is put into water from this quadrant towards pool wall successively by each group of mouse, make its free swimming 90s, recording the time that mouse stops at the 4th quadrant accounts for the per-cent of total time and (in study of behaviour test process, should keep light soft, room peace and quiet, each object of reference invariant position).Data acquisition and processing (DAP) is by having image automatic monitoring and treatment system to complete.
In visible platform training, respectively organize training latent period close (P>0.05) of mouse, illustrate that recognition capability and the colour vision of each group of mouse to target is all normal.In hiding platform test, compared with model group, significantly shorten (P<0.05) latent period of embodiment 2 and 5 mouse, the results are shown in Table 3.
Table 3 embodiment 2 and embodiment 5 cause the impact of Model of Dementia memory dysfunction on abdominal injection Scopolamine
(
n=9-10)
(* P<0.05, * * P<0.01, compared with model group)
In space exploration test, compared with model group, all there is extremely significantly increase (P<0.01) in the 4th quadrant residence time and distance percentage in the mouse that embodiment is 2 groups, embodiment 5 exists significantly increases (P<0.05), the results are shown in Table 4; Embodiment 2 and 5 exists significantly increases (P<0.05), the results are shown in Table 5.
Table 4 embodiment 4 and embodiment 5 on abdominal injection Scopolamine cause Model of Dementia memory dysfunction impact (
n=9-10)
(* P<0.05, * * P<0.01, compared with model group)
Table 5 embodiment 2 and embodiment 5 on abdominal injection Scopolamine cause Model of Dementia mouse platform traversing times impact (
n=9-10)
(* P<0.05, * * P<0.01, compared with model group)
The above results explanation, compared with tacrine, embodiment 2 and embodiment 5 have the ability of improving more by force memory deficits in mice.
Embodiment 12
Biological assessment: liver toxicity experiment
With reference to J Med Chem, 2012,55 (9): method described in 4309-4321, is divided into normal group, tacrine group and tested medicine group by the ICR mouse of body weight 20g left and right (Yangzhou University's comparative medicine center, clean level).Tacrine group gavage is to tacrine CMC-Na solution, and medicine group gavage is given the medicine CMC-Na solution with the volumetric molar concentration dosage such as tacrine.Each group mouse respectively at administration after 8h, 22h and 36h posterior orbit are got blood.The centrifugal 15min of 1000rpm, draw upper serum with microsyringe, be used for surveying the content of blood biochemistry index aspartate aminotransferase (aspartate aminotransferase, ASAT) and alanine aminotransferase (alanine aminotransferase, ALT).Get for the last time sacrificed by exsanguination mouse after blood, get 2 livers for every group, be dipped into 48h in 10% formalin solution, sample presentation carries out hepatic pathology sections observation.The results are shown in Table 6.
ALT after table 6 tacrine, duplex tacrine, embodiment 2 and embodiment 5 administrations and ASAT activity (mean value ± SEM; N=8-9, t inspection, p*≤0.05, p**≤0.01, p***≤0.001)
Result demonstration, compared with blank group, tacrine group mouse is respectively organized data and all shows significant difference, and ASAT and ALT level significantly rise, and show that tacrine brings out serious liver toxicity; And embodiment 2 and embodiment 5 numerical value there is no noticeable change, this shows, compared with tacrine, embodiment 2 and embodiment 5 have obvious liver provide protection.
The hematoxylin-eosin for Histological research (hematoxylin and eosin, HE) of liver, by having injected the hepatic pathology section statining of tested material, is observed under electron microscope.Result as shown in Figure 1.
Fig. 1
Result shows, has injected the liver of tacrine, liver cell oedema, and have spotty necrosis and steatosis; And injected the liver of duplex tacrine, embodiment 2 and embodiment 5, it is relatively less that techtology changes, and illustrates that the liver toxicity of embodiment 2 and embodiment 5 will be lower than tacrine.
Embodiment 13
The molecular docking of embodiment 2 and TcAChE
The active pocket of TcAChE is taken from the compound crystal structure (PDB is numbered 2CKM, and data are from Protein Data Bank) of duplex tacrine and TcAChE.Remove water molecules, add hydrogen atom, use Schrodinger software to process crystalline complex.Acceptor using crystalline complex conformation after treatment as molecular docking, active pocket is defined as the arbitrary atom of the original part of distance
all amino-acid residues in scope, adopt molecular docking method (Glide XP).
Application Chem Bio3D2010 draws the structural formula of series compound, adopts field of force of molecule optimized algorithm MMFF94 to be optimized molecule 3 D stereo conformation, obtains the lower conformation of ligand molecular energy, preserves with .mol2 form.
Application Glide XP (Schrodinger2013) flexible docking module, all the other parameters are default value, embodiment 2, duplex tacrine (Bis7Tacrine), tacrine are carried out to molecular docking, as shown in Figure 2.Result demonstration, the XP Gscore of embodiment 2, duplex tacrine (Bis7Tacrine) and tacrine is respectively-14.356 ,-16.198 and-8.809, more consistent with actual test result.The indole ring generation pi-pi accumulation of Trp84 in tacrine and enzymic activity pocket
there is π-π effect with the aromatic nucleus of Phe330
the amino of one end tacrine group of duplex tacrine (Bis7Tacrine) and His400 form hydrogen bond, the other end and Trp279, Tyr70 generation π-π effect (
with
); In embodiment 2, the amino of tacrine group and His400 form hydrogen bond
in PAS site, pyridine ring and Trp279, Tyr70, Ile287 have hydrophobic interaction, and the nitrogen-atoms on pyridine ring and Phe288 form hydrogen bond action
illustrate that embodiment 2 can act on PAS and the CAS site of AChE simultaneously.
Fig. 2
Claims (11)
1. compound and pharmaceutical salts, prodrug or solvate shown in general formula (I):
Wherein, L representative
or
time, m represents the arbitrary integer in 1～4, and n represents the arbitrary integer in 2～12, and p represents the arbitrary integer in 1～3.
2. the compound of claim 1 and pharmaceutical salts thereof, prodrug or solvate, is characterized in that:
M represent 1,2 or 3, n represent 6 or 7, p represent 1.
3. the compound of claim 1 and pharmaceutical salts thereof, prodrug or solvate, wherein compound can be following arbitrary compound and pharmaceutical salts, prodrug or solvate:
N-(6-((2,3-dihydro-1H-cyclopentano [b] quinoline-9-yl) amino) hexyl) nicotinamide
N-(6-((1,2,3,4-tetrahydro acridine-9-yl) amino) hexyl) nicotinamide
N-(7-(1,2,3,4-tetrahydro acridine-9-base amino) heptyl) nicotinamide
N-(7-(2,3-dihydro-1H-cyclopentano [b] quinoline-9-base amino) heptyl) nicotinamide
N-(6-(7,8,9,10-tetrahydrochysene-6H-ring [b] quinoline-11-base amino in heptan) hexyl) nicotinamide
N-(2-(2-(2-amino ethoxy) oxyethyl group) ethyl)-12,3,4-tetrahydro acridine-9-amino
N-(2-(2-(2-(1,2,3,4-tetrahydro acridine-9-base amino) oxyethyl group) oxyethyl group) ethyl) nicotinamide.
4. the preparation method of formula (I) compound described in claim 1,2,3, comprising:
(1) when L is
or
step preparation by reaction formula () Suo Shu:
A. anthranilic acid reacts and obtains compound 1 from different cycloalkanones in phosphorus oxychloride;
B. compound 1 obtains compound 2 from different alkyl diamine reacting by heating in organic solution;
C. nicotinic acid and compound 2 obtain the compound of general formula (I) in organic solution through condensation.
Wherein L is
or
m is 1,2 or 3; N is 1,2 or 3; P is 1.
(2) when L is
step preparation by reaction formula (two) Suo Shu:
A. nicotinic acid and N-Boc-quadrol nearly catalyzed reaction in organic solution obtains compound 3;
B. compound 3 reacts with trifluoroacetic acid and obtains compound 4;
C. anthranilic acid reacts and obtains compound 1 from different cycloalkanones in phosphorus oxychloride;
D. compound 1 reacts in organic solution with quadrol and obtains compound 5;
E. compound 4 and compound 5 reactions obtain general formula (I) compound.
Wherein L is
time, m is 1,2 or 3.
5. preparation method claimed in claim 4, is characterized in that:
(1) when L is
or
time: the preferred 100-110 DEG C of temperature of reaction in step a, preferred 2-3h of reaction times; The preferred Pentyl alcohol of organic solution in step b, answers the preferred 140-150 DEG C of temperature, preferred 24-48h of reaction times.The preferred DMF of organic solution in step c, the preferred HOBt/EDCI of condensing agent, DMAP/DCC, preferred 2-4h of reaction times, the preferred room temperature of temperature of reaction.
(2) when L is
time: the preferred methylene dichloride of organic solvent in step a, ethyl acetate, ethanol, methyl alcohol, acetone.Triethylamine and EDCI catalysis obtain compound 3, the preferred room temperature of temperature of reaction, preferred 3-4h of reaction times.The preferred room temperature of temperature of reaction of step b, the reaction times is 0.5-1h; The preferred 100-110 DEG C of temperature of reaction in step c, preferred 2-3h of reaction times; The preferred Pentyl alcohol of organic solution in steps d, the preferred 140-150 DEG C of temperature of reaction, preferred 5-6h of reaction times; The preferred room temperature of temperature of reaction in step e, preferred 3-4h of reaction times, the preferred DCM/MeOH mixed solvent of solvent solvent, proportion optimization 1: 1.
6. a pharmaceutical composition, is characterized in that, contains formula (I) compound and the pharmaceutical salts thereof for the treatment of significant quantity.
7. a pharmaceutical preparation, is characterized in that, contain to have formula (I) compound or pharmaceutically acceptable salt thereof described in claims 1 to 3, and pharmaceutically acceptable additive is or/and carrier.
8. pharmaceutical preparation claimed in claim 7, is characterized in that, its formulation is solid oral agent, oral liquid or injection, and described solid oral agent can be tablet, pill, dispersible tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine can be oral solution; Described injection can be injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
9. (I) compound of the formula described in claims 1 to 3 and pharmaceutical salts, prodrug or solvate, pharmaceutical composition and pharmaceutical preparation, for the preparation of the application in the disease by acetylcholinesterase (AChE) and butyrylcholine esterase (BuChE) mediation.
10. disease claimed in claim 9, it is characterized in that AChE and BuChE mediation to the cognitive function relevant nervous system disorders that fails.
11. diseases claimed in claim 10, what it is characterized in that described AChE and BuChE mediation is Alzheimer's disease or other dementias to the cognitive function relevant nervous system disorders that fails.
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| CN105503840A (en) * | 2015-12-04 | 2016-04-20 | 广东工业大学 | Tacrine-coumarin derivative containing triazole and application of derivative |
| CN106187891A (en) * | 2016-07-18 | 2016-12-07 | 南京中医药大学 | There is compound of anti-Alzheimer disease effect and preparation method and application |
| CZ306545B6 (en) * | 2016-01-14 | 2017-03-01 | Fakultní nemocnice Hradec Králové | Conjugates on the basis of tacrine and tryptophan, a method of their preparation and their use |
| CN107721925A (en) * | 2017-09-12 | 2018-02-23 | 上海交通大学 | A kind of new acetylcholinesteraseinhibitors inhibitors and its preparation method and application |
| CN108047202A (en) * | 2017-12-20 | 2018-05-18 | 东南大学 | A kind of aluminium ion response type compound and preparation method and application |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503840A (en) * | 2015-12-04 | 2016-04-20 | 广东工业大学 | Tacrine-coumarin derivative containing triazole and application of derivative |
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| CZ306545B6 (en) * | 2016-01-14 | 2017-03-01 | Fakultní nemocnice Hradec Králové | Conjugates on the basis of tacrine and tryptophan, a method of their preparation and their use |
| CN106187891A (en) * | 2016-07-18 | 2016-12-07 | 南京中医药大学 | There is compound of anti-Alzheimer disease effect and preparation method and application |
| CN106187891B (en) * | 2016-07-18 | 2019-04-23 | 南京中医药大学 | Compound and the preparation method and application thereof with anti-Alzheimer disease effect |
| CN107721925A (en) * | 2017-09-12 | 2018-02-23 | 上海交通大学 | A kind of new acetylcholinesteraseinhibitors inhibitors and its preparation method and application |
| CN107721925B (en) * | 2017-09-12 | 2020-02-14 | 上海交通大学 | Novel acetylcholinesterase inhibitor and preparation method and application thereof |
| CN108047202A (en) * | 2017-12-20 | 2018-05-18 | 东南大学 | A kind of aluminium ion response type compound and preparation method and application |
| CN108047202B (en) * | 2017-12-20 | 2021-06-11 | 东南大学 | Aluminum ion response type compound and preparation method and application thereof |
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