CN107311988B - A kind of drug for treating Alzheimer disease - Google Patents

A kind of drug for treating Alzheimer disease Download PDF

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CN107311988B
CN107311988B CN201710578019.8A CN201710578019A CN107311988B CN 107311988 B CN107311988 B CN 107311988B CN 201710578019 A CN201710578019 A CN 201710578019A CN 107311988 B CN107311988 B CN 107311988B
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formula
alzheimer disease
drug
treating alzheimer
bis
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CN107311988A (en
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巨德峰
魏佳
付艳丽
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SHANGHAI PUKANG PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

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Abstract

The invention discloses a kind of drug for treating Alzheimer disease, chemical constitution is formula（Ⅰ）, after 15 μM of amyloid betas handle the SH SY5Y cells 48h of differentiation, cell survival rate falls to the 21% of blank control group.Positive controls and Formula（Ⅰ）Processed cell can significantly improve the survival rate of cell, and Formula（Ⅰ）All reach 99% better than positive controls, especially I a and I d cell survival rates, it is close with blank control group.Illustrate Formula（Ⅰ）Protective effect to the SH SY5Y cellular damages of amyloid beta induction can be developed as the drug for the treatment of alzheimer's disease.

Description

A kind of drug for treating Alzheimer disease
Technical field
The present invention relates to a kind of drugs for treating Alzheimer disease.
Background technology
Alzheimer disease (AD) is a kind of with progressive, irreversible cognitive ability decline, memory capability decline It is the nervous system degenerative disease of clinical manifestation extremely with mental act.Currently, AD does not have the medical means of early detection, face When bed symptom occurs, pathological change has occurred that several years or even decades, so made a definite diagnosis after clinical symptoms generation, patient's Life cycle is only 6~10 years remaining.With the increasingly aging of world population, solve the problems, such as that the treatment of Alzheimer disease is compeled in eyebrow Eyelash.The drug for treating the disease at present has the drug for acting on neurotransmitter and receptor, neuroprotective agent, inhibits beta-amyloid protein The drug of generation or aggregation, the drug etc. for reducing Protein tau Hyperphosphorylationof.
According to existing research, one of major pathologic features of AD are that intracerebral accumulates a large amount of beta-amyloid protein (Amyliod- β, A β), and then a series of neurotoxicities are induced, eventually lead to cognition dysfunction.Therefore Amyliod- β It is the main research target spot of quite a few AD treatments at this stage.Numerous studies show that brain tissue declines the Scavenging activity of A β, It is the main reason for causing early stage A β to accumulate.
Chinese patent 201710444718.3 has been described above one group of compound, and specifies in Alzheimer disease Application.With going deep into for research, the compound of new construction is designed, and has been carried out Alzheimer disease drugs and tentatively sieved Choosing.
Invention content
The purpose of the present invention is to provide a kind of drug for treating Alzheimer disease, chemical constitution is formula (I)
Wherein, R isIn one kind.
Wherein, * C atom adjacents are bonding atom.
Further, the salt or solvated compounds for the compound that formula (I) indicates.
Another object of the present invention is to provide the synthetic routes that chemical constitution is formula (I)：
Wherein, R isIn one kind.
Wherein, * C atom adjacents are bonding atom.
Another object of the present invention is to provide a kind of pharmaceutical composition, described pharmaceutical composition includes a effective amount of formula (I) and pharmaceutically acceptable carrier,
Wherein, R isIn one kind.
Described pharmaceutical composition is capsule, tablet, injection, granule, pill or powder；It is preferred that：Tablet, capsule Or injection.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable other drugs administering drug combinations.
Specific implementation mode
Embodiment 1：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- of the chloro- 7- of -4- are secondary The synthesis of amine (intermediate 1)
Step 1：The synthesis of 3,6- bis- (furans -2)-pyrazine -2- formaldehyde
3,6 two bromo-pyrazine -2- formaldehyde (10mmol) are dissolved in 40ml tetrahydrofurans, then leads to argon gas and drives the sky in system out of Catalyst tetra-triphenylphosphine palladium (2mmol) is added in gas thereto, flows back one hour.By 2- furan boronic acids in another bottle (12mmol) is dissolved in 10ml tetrahydrofurans, and the aqueous solution (mass fraction 10%) of 5ml sodium carbonate is added thereto stirring half an hour. Two bottles of solution are mixed, is reacted under counterflow condition four hours, adds 50ml water thereto, extracted with 50ml dichloromethane, organic phase It is dried with anhydrous sodium sulfate, solvent evaporated after filtering, is beaten half an hour, filtering with petroleum ether, 40 DEG C of vacuum drying can obtain 2.1g Faint yellow 3,6- bis- (furans -2)-pyrazine -2- formaldehyde solids, yield 88%.1H-NMR(400MHz,CDCl3)δ:6.98(t, 2H),7.59(d,2H),8.07(d,2H),8.79(s,1H),9.75(s,1H).
Step 2：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methylene } fluoro- quinazolyl -6- amine of the chloro- 7- of -4- Synthesis
3,6- bis- (furans -2)-pyrazine -2- formaldehyde (10mmol) is dissolved in 40ml methanol, by the fluoro- quinazolines of the chloro- 7- of 4- The methanol solution of base -6- amine (15mmol) is slowly added dropwise into above-mentioned system, continues stirring one hour after being added dropwise, then to it Middle addition 30ml water stirs half an hour, has a large amount of tea green powder and is precipitated, and filtering is washed with water, and 40 DEG C of vacuum drying 4 are small When, obtain 3.9g yellow N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methylene } fluoro- quinazolyl -6- of the chloro- 7- of -4- Amine, yield 93%.1H-NMR(400MHz,CDCl3)δ:6.98(t,2H),7.59(dd,2H),7.74(d,2H),8.07(dd, 2H),8.29(d,1H),8.37(s,1H),8.79(s,1H),9.56(s,1H).
Step 3：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- secondary amine of the chloro- 7- of -4- Synthesis
By N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methylene } fluoro- quinazolyl -6- amine of the chloro- 7- of -4- (10mmol) is added in 40ml tetrahydrofurans, stirs half an hour, has a small amount of insoluble matter, system to be cooled to 0 DEG C or so, three second are added Triacetoxyborohydride (20mmol), stirring are warmed to room temperature after one hour, continue stirring 4 hours, water is added thereto, has yellowish Color Precipitation, filtering, 50 DEG C of vacuum drying can obtain 3.7g yellow N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- first Base } the fluoro- quinazolyl -6- secondary amine of the chloro- 7- of -4- solid powder, yield 88%.1H-NMR(400MHz,CDCl3)δ:4.39(s, 2H),4.86(s,1H),6.98(t,2H),7.52-7.59(m,4H),8.07(d,2H),8.54(s,1H),9.54(s,1H).
Embodiment 2：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- of -4- phenyl -7- The synthesis of secondary amine (I a)
By N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- amine of the chloro- 7- of -4- (10mmol) is dissolved in 30 milliliters of N,N-Dimethylformamides, and system rouses argon gas 20 minutes, the air in emptying system, then Tetra-triphenylphosphine palladium (3mmol) is added, is warming up to 60 DEG C, continues stirring 1 hour, phenyl boric acid (12mmol) is added thereto, then 10 milliliters of sodium carbonate (1g) aqueous solutions are added, are warming up to 90 DEG C, stir 5 hours, whole process holding is passed through argon gas, then drops Temperature, removes solvent under reduced pressure, and solid obtains 4.3g off-white powders, as N- { [3,6- bis- (2- furans quickly through chromatographic column Base)]-pyrazinyl -2- methyl } the fluoro- quinazolyl -6- secondary amine of -4- phenyl -7-, yield 93%.1H-NMR(400MHz,CDCl3) δ:4.39(s,1H),4.55(s,1H),6.96(t,2H),7.38(d,1H),7.49-7.65(m,6H),7.79(m,2H),8.07 (dd,2H),8.53(s,1H),9.33(s,1H).13C-NMR(75MHz,CDCl3)δ:45.93,107.95,109.44, 110.08,110.99,114.5,124.54,128.34,128.99,130.56,133.03,136.58,139.73,142.9, 143.63,146.66,146.98,147.71,149.34,149.79,150.08,155.81,162.97.LC-MS(ESI,pos, ion)m/z:464[M+1].
Embodiment 2：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- of -4- phenyl -7- The synthesis of secondary amine fumarate
By N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- secondary amine of -4- phenyl -7- (10mmol), which is dissolved in 40 milliliters of acetonitriles, forms clear solution, and fumaric acid (10mmol) is added under room temperature into this solution, has big The white insoluble matter of amount, is then heated to reflux, until all solids all dissolve, beginning Temperature fall, until being down to 40 DEG C of left sides The right side has a large amount of white powders to be precipitated, until temperature is down to 10 DEG C or so, growing the grain 2 hours, filtering is washed, 40 DEG C of vacuum with acetonitrile It is 5 hours dry, 4.2gN- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyls-of -4- phenyl -7- can be obtained 6- secondary amine fumarates, yield 72%.The dissolubility of I a fumarates is better than I a, it is contemplated that richness in the preparation of pharmaceutical preparation The form of horse hydrochlorate,.1H-NMR(400MHz,CDCl3)δ:4.37(s,2H),5.34(s,1H),6.28(s,2H),6.95(t, 2H),7.39-7.62(m,7H),7.76(d,2H),8.04(d,2H),8.51(s,1H),9.30(s,1H),14.84(s,2H) .13C-NMR(75MHz,CDCl3)δ:45.93,107.95,109.44,110.08,110.99,114.5,124.54,128.34, 128.99,130.56,133.03,133.23,136.58,139.73,142.9,143.63,146.66,146.98,147.71, 149.34,149.79,150.08,155.81,162.97,169.68.
Embodiment 3：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } -4- is to the fluoro- quinazolines of cyano-phenyl -7- The synthesis of base -6- secondary amine (I b)
By N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- secondary amine of the chloro- 7- of -4- (10mmol) is dissolved in 30 milliliters of N,N-Dimethylformamides, and system rouses argon gas 20 minutes, the air in emptying system, then Tetra-triphenylphosphine palladium (3mmol) is added, is warming up to 60 DEG C, continues stirring 1 hour, is added thereto to cyanophenylboronic acid (12mmol) adds 10 milliliters of sodium carbonate (1g) aqueous solutions, is warming up to 90 DEG C, stirs 5 hours, and whole process holding is passed through argon Then gas cools down, remove solvent under reduced pressure, and solid obtains 4.3g off-white powders, as N- { [3,6- bis- quickly through chromatographic column (2- furyls)]-pyrazinyl -2- methyl } -4- quinazolyl -6- secondary amine fluoro- to cyano-phenyl -7-, yield 88%.1H-NMR (400MHz,CDCl3)δ:4.38(s,2H),4.70(s,1H),6.96(t,2H),7.15(d,1H),7.57-7.66(m,3H), 7.89-7.93(m,4H),8.05(dd,2H),8.52(s,1H),9.31(s,1H).13C-NMR(75MHz,CDCl3)δ:45.93, 107.95,109.44,110.08,110.99,114.5,117.15,118.94,124.54,131.1,133.02,133.03, 139.73,141.53,142.9,143.63,146.66,146.98,147.71,149.34,149.79,150.08,155.81, 162.97.LC-MS(ESI,pos,ion)m/z:489[M+1].
Embodiment 4：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinoline azoles of -4- p-isopropyl phenyl -7- The synthesis of quinoline base -6- secondary amine (I c)
By N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- secondary amine of the chloro- 7- of -4- (10mmol) is dissolved in 30 milliliters of N,N-Dimethylformamides, and system rouses argon gas 20 minutes, the air in emptying system, then Tetra-triphenylphosphine palladium (3mmol) is added, is warming up to 60 DEG C, continues stirring 1 hour, p-isopropyl phenyl boric acid is added thereto (12mmol) adds 10 milliliters of sodium carbonate (1g) aqueous solutions, is warming up to 90 DEG C, stirs 5 hours, and whole process holding is passed through argon Then gas cools down, remove solvent under reduced pressure, and solid obtains 4.8g off-white powders, as N- { [3,6- bis- quickly through chromatographic column (2- furyls)]-pyrazinyl -2- methyl } the fluoro- quinazolyl -6- secondary amine of -4- p-isopropyl phenyl -7-, yield 95%.1H- NMR(400MHz,CDCl3)δ:1.20(d,6H),2.86(m,1H),4.37-4.38(m,2H),6.97(t,2H),7.38(d, 1H),7.56-7.63(m,7H),8.06(dd,2H),8.52(s,1H),9.31(s,1H).13C-NMR(75MHz,CDCl3)δ: 23.38,33.96,45.93,107.95,109.44,110.08,110.99,114.5,124.4,124.54,131.31, 131.65,133.03,139.73,142.9,143.63,146.66,146.98,147.71,149.34,149.79,150.08, 151.02,155.81,162.97.LC-MS(ESI,pos,ion)m/z:506[M+1].
Embodiment 5：N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinolines of -4- (3,5 difluorophenyl) -7- The synthesis of oxazoline base -6- secondary amine (I d)
By N- { [3,6- bis- (2- furyls)]-pyrazinyl -2- methyl } fluoro- quinazolyl -6- secondary amine of the chloro- 7- of -4- (10mmol) is dissolved in 30 milliliters of N,N-Dimethylformamides, and system rouses argon gas 20 minutes, the air in emptying system, then Tetra-triphenylphosphine palladium (3mmol) is added, is warming up to 60 DEG C, continues stirring 1 hour, 3,5 difluoro phenyl boric acids is added thereto (12mmol) adds 10 milliliters of sodium carbonate (1g) aqueous solutions, is warming up to 90 DEG C, stirs 5 hours, and whole process holding is passed through argon Then gas cools down, remove solvent under reduced pressure, and solid obtains 4.2g off-white powders, as N- { [3,6- bis- quickly through chromatographic column (2- furyls)]-pyrazinyl -2- methyl } the fluoro- quinazolyl -6- secondary amine of -4- (3,5 difluorophenyl) -7-, yield 84%.1H- NMR(400MHz,CDCl3)δ:4.39(s,2H),4.82(s,1H),6.98-7.03(m,3H),7.21-7.29(m,3H),7.59 (dd,2H),7.68(d,1H),8.07(dd,2H),8.54(s,1H),9.35(s,1H).13C-NMR(75MHz,CDCl3)δ: 45.93,105.25,107.95,109.44,110.08,110.99,111.47,114.5,124.49,133.03,133.12, 139.73,142.9,143.63,146.66,146.98,147.71,149.43,149.96,150.08,155.81,162.29, 166.36.LC-MS(ESI,pos,ion)m/z:500[M+1].
Test example 1：Protective effect to the SH-SY5Y cellular damages of beta-amyloid protein induction
One, experimental method and grouping
SH-SY5Y cells are with 1 × 104A/mL is inoculated in porous plate, cultivates rear replace adherent for 24 hours and contains 10 μM of retinoic acids (RA) DMEM culture mediums.It replaces a subculture within every two days, handles 7 days, Cell differentiation inducing activity.The cell of differentiation is induced, is used D-Hank ' s liquid gently washs 2 times, and experiment is divided into blank control group, model group, positive controls, medicine group to be measured.
Blank control group is replaced containing 10% activated carbon/glucan processing fetal calf serum without phenol red 1640 culture medium；Model Final concentration of 15 μM of beta-amyloid protein is added in group；Beta amyloid egg is added in positive controls after 10 μM of bisdemethoxycurcumin h are added In vain；15 μM of beta-amyloid proteins are added after 10 μM of drugs to be measured are added and incubate 3h in advance in medicine group to be measured.
With mtt assay detection cell survival rate, (blank control group cell survival rate is after each processing group cell culture 48h 100%).Two, experimental result
The protective effect for the SH-SY5Y cellular damages that formula (I) induces beta-amyloid protein, cell survival rate are shown in Table 1.
The protective effect for the SH-SY5Y cellular damages that 1 formula of table (I) induces beta-amyloid protein
Group Cell survival rate
Blank control group 100
Model group 21
Positive controls 74
Ⅰa 99
Ⅰb 76
Ⅰc 88
Ⅰd 99
As can be seen from Table 1, after the SH-SY5Y cells 48h of 15 μM of beta-amyloid protein processing differentiation, under cell survival rate It is reduced to the 21% of blank control group.Positive controls and Formula (I) processed cell can significantly improve depositing for cell Motility rate, and Formula (I) is better than positive controls, especially I a and I d cell survival rates have all reached 99%, with blank Control group is close.
Conclusion：The protective effect for the SH-SY5Y cellular damages that Formula (I) induces beta-amyloid protein, Ke Yizuo Drug to treat alzheimer's disease is developed.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.

Claims (5)

1. a kind of compound for treating Alzheimer disease, chemical constitution is formula（Ⅰ）
Wherein, R isIn one kind.
2. a kind of salt of compound that treating Alzheimer disease, characterized in that the chemical constitution of the compound is formula（Ⅰ）
Wherein, R isIn one kind.
3. a kind of synthetic method of compound that treating Alzheimer disease as described in claim 1, characterized in that synthesis road Line is as follows：
Wherein, R isIn one kind.
4. a kind of pharmaceutical composition for treating Alzheimer disease, characterized in that described pharmaceutical composition includes a effective amount of formula （Ⅰ）Compound and pharmaceutically acceptable carrier,
Wherein, R isIn one kind.
5. a kind of pharmaceutical composition for treating Alzheimer disease as claimed in claim 4, characterized in that the pharmaceutical composition Object is capsule, tablet, injection, granule, pill or powder.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101218206A (en) * 2005-07-04 2008-07-09 诺沃-诺迪斯克有限公司 Histamine H3 receptor antagonists
WO2008099210A2 (en) * 2007-02-12 2008-08-21 Merck & Co., Inc. Piperazine derivatives for treatment of ad and related conditions
WO2009037247A1 (en) * 2007-09-17 2009-03-26 Neurosearch A/S Pyrazine derivatives and their use as potassium channel modulators
CN103328468A (en) * 2010-10-27 2013-09-25 普罗克斯马根有限公司 Alpha-7 nicotinic receptor modulators for the treatment of pain, a psychotic disorder, cognitive impairment or alzheimer's disease
WO2014165263A1 (en) * 2013-03-12 2014-10-09 The Regents Of The University Of California, A California Corporation Gamma-secretase modulators
CN105189494A (en) * 2013-03-13 2015-12-23 普罗克西梅根有限公司 Imidazo[4,5-c]pyridine and pyrrolo[2,3-c]pyridine derivatives as SSAO inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101218206A (en) * 2005-07-04 2008-07-09 诺沃-诺迪斯克有限公司 Histamine H3 receptor antagonists
WO2008099210A2 (en) * 2007-02-12 2008-08-21 Merck & Co., Inc. Piperazine derivatives for treatment of ad and related conditions
WO2009037247A1 (en) * 2007-09-17 2009-03-26 Neurosearch A/S Pyrazine derivatives and their use as potassium channel modulators
CN103328468A (en) * 2010-10-27 2013-09-25 普罗克斯马根有限公司 Alpha-7 nicotinic receptor modulators for the treatment of pain, a psychotic disorder, cognitive impairment or alzheimer's disease
WO2014165263A1 (en) * 2013-03-12 2014-10-09 The Regents Of The University Of California, A California Corporation Gamma-secretase modulators
CN105189494A (en) * 2013-03-13 2015-12-23 普罗克西梅根有限公司 Imidazo[4,5-c]pyridine and pyrrolo[2,3-c]pyridine derivatives as SSAO inhibitors

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