CN105001180A - Novel calcium-ion selective chelating agent and preparation method and application thereof - Google Patents
Novel calcium-ion selective chelating agent and preparation method and application thereof Download PDFInfo
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- CN105001180A CN105001180A CN201510320576.0A CN201510320576A CN105001180A CN 105001180 A CN105001180 A CN 105001180A CN 201510320576 A CN201510320576 A CN 201510320576A CN 105001180 A CN105001180 A CN 105001180A
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- 229940003871 calcium ion Drugs 0.000 title abstract 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0279—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the cationic portion being acyclic or nitrogen being a substituent on a ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0292—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature immobilised on a substrate
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/49—Esterification or transesterification
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Abstract
The invention provides a novel calcium-ion selective chelating agent as shown in the formula (I) and a preparation method and application thereof. The compound has excellent capacity of ischemia and oxygen deprivation resistance, meanwhile has excellent transcellular capacity serving as a transport substrate of OATP1B1 transport proteins and has very important meaning and potential value in research of BAPTA derivates.
Description
Technical field
The present invention relates to a kind of medical compounds and its production and use, relate more particularly to a kind of novel calcium ion selective sequestrant and its production and use, belong to medicinal chemistry art.
Background technology
In multiple reasons of necrocytosis, ischemic, anoxic are the major causes of human body acute cell Large Scale Death, which results in the generation of multiple serious disease, as ishemic stroke, myocardial infarction cause brain cell, cardiomyocyte cell death etc.
In recent years, due to further investigation and a large amount of effort of scientist, there has also been certain progress for the research of ischemic, cell death mechanism that anoxic is relevant, this is development, exploitation can avoid the medicine of necrocytosis to guide direction, also provide theoretical basis and realistic basis.
In process of cell death, intracellular Ca2+ is excessive is causing necrocytosis major reason.Therefore, reduce the concentration of intracellular free calcium, to alleviate and/or to eliminate calcium excessive, can alleviate cell injury in theory, thus reduce the downright bad degree of infraction, this is the important channel of reducing mortality ratio and the degree that disables.
BAPTA (1, two (2-amino-benzene oxygen) ethane-N of 2-, N, N ', N '-tetraacethyl) be a kind of nontoxic calcium ion selective sequestrant and indicator, its chelating unit and EDTA (ethylenediamine tetraacetic acid (EDTA)) are similar, BAPTA is not easy to be protonated at physiological ph simultaneously, also just because it is not subject to the interference of proton a little, thus it is made to want far away excellent in EGTA (ethylene glycol bis-(2-amino-ethyl) tetraacethyl) to the chelation percent of calcium ion.
Described BAPTA is by (Tsien R Y etc. such as Tsien in 1980 at first, Biochemistry, 1980,19 (11): 2396) on the basis to calcium ion best selective structure, in EDTA, introduce fragrant chromophoric group to obtain, the highly selective to calcium ion is maintained by the introducing of phenyl ring, in physiological conditions can ionization completely, thus with calcium ion complexing by the impact that pH value changes, the speed in conjunction with calcium ion is also greatly improved.
But then, although BAPTA is a kind of calcium ion complexing agent of excellent property, also just because it has high dissociation properties, thus make it permeate through cell membranes can not enter cell interior performance drug effect.In order to overcome this defect, once used microinjection to introduce cell, but this is fundamental research, experimental technique is very difficult, uses also very inconvenience, cannot be able to practical application, more have it to be cannot be applied in medical treatment field.
In addition, although the multidigit scholars such as Tsien, Yang Liping have carried out certain research for BAPTA derivative attempt to improve that it is fat-soluble, its easier permeate through cell membranes has been made.
In addition, CN103288664A discloses a kind of BAPTA derivative, and this compound has good various pharmaceutical activity restraining effect, the rising etc. of the serum creatine kinase activity that isoproterenol such as can be suppressed to cause, thus can be used to treat various diseases.
As mentioned above, although be present in multiple BAPTA derivative in prior art, but novel B APTA derivative is still existed to necessity and demand of continuing research and development, this has very important pharmacology and pharmacokinetics meaning and economic worth at pharmaceutical field, and just the basic place that is accomplished of the present invention and power lean on.
Summary of the invention
As mentioned above, for providing a kind of novel calcium ion selective sequestrant and its production and use, the present inventor, to this has been deep research, after paying a large amount of creative work, thus completes the present invention.
Specifically, first aspect, the present invention relates to new Calcium Ion Selective sequestrant shown in a kind of following formula (I), its structural formula is as follows:
Wherein, R
1, R
2be selected from H, halogen, C independently of one another
1-5alkyl, C
1-5alkoxyl group or hydroxyl.
In described formula (I) compound of the present invention, unless otherwise prescribed, from start to finish, C
1-5the implication of alkyl refers to have the side chain of 1 to 5 carbon atom or the alkyl of straight chain, that includes C
1alkyl, C
2alkyl, C
3alkyl, C
4alkyl or C
5alkyl can be such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl etc. in non-limiting manner.
In described formula (I) compound of the present invention, unless otherwise prescribed, from start to finish, C
1-5the implication of alkoxyl group refers to above-mentioned C
1-5the group obtained after alkyl is connected with Sauerstoffatom.
In described formula (I) compound of the present invention, unless otherwise prescribed, from start to finish, halogen refers to haloid element, can be such as fluorine, chlorine, bromine or iodine in non-limiting manner.
In described formula (I) compound of the present invention, described formula (I) compound most preferably is following formula (II) compound:
Second aspect, the present invention relates to the preparation method of the new Calcium Ion Selective sequestrant of described formula (I), described preparation method is as follows:
In organic solvent, under catalyzer and aromatic acid promotor exist, following formula (III) compound and following formula (IV) compound react, thus obtain described formula (I) compound,
Wherein, R
1, R
2as defined above.
Wherein, R is worked as
1, R
2during for H, the compound obtained is above formula (II) compound.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), formula (III) compound as raw material belongs to known compound, its preparation method is visible CN103288664A such as, and this is no longer going to repeat them for concrete synthetic method.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), described catalyzer obtains according to following preparation method:
(1) SBA-15 mesopore molecular sieve is calcined 20-40 minute at 500-550 DEG C, then naturally cool to room temperature, obtain primary treatment molecular sieve;
(2) primary treatment molecular sieve is positioned in the steam atmosphere of 500 DEG C and places 60-80 minute, obtain secondary treatment molecular sieve;
(3) join in solvent by secondary treatment molecular sieve and ionic liquid, be fully uniformly mixed 4-8 hour, then filter at 40-50 DEG C, by gained solids deionized water wash 2-3 time, then vacuum-drying, obtains described catalyzer.
Wherein, in step (1), described SBA-15 mesopore molecular sieve is known material, and this is no longer going to repeat them; It is calcined 20-40 minute at 500-550 DEG C, such as, can calcine 20 minutes, 30 minutes or 40 minutes at 500 DEG C, 520 DEG C, 540 DEG C or 550 DEG C.
Wherein, in step (2), by being placed in high-temperature vapor atmosphere by primary treatment molecular sieve, thus the internal gutter of high-temperature vapor to molecular sieve can be used to be further processed.
Wherein, in step (3); described ionic liquid is selected from 1-(4-diacetyl iodophenyl)-3-methyl imidazolium tetrafluoroborate, 1-methyl-3-propyl sulfonic acid imidazole bisulfate, 1-normal-butyl-3-Methylimidazole dihydrogen phosphate, N; N; N '; N '-tetramethyl--N; any one in N '-disulfonic acid isopropylpropylenediamine hydrosulfate, 1-normal-butyl-3-Methylimidazole hexafluorophosphate; most preferably be N; N; N ', N '-tetramethyl--N, N '-disulfonic acid isopropylpropylenediamine hydrosulfate.
Wherein, in step (3), described solvent is any one in ethyl acetate, chloroform, acetone, benzene, toluene etc., and the consumption of this solvent is not particularly limited, as long as convenient operation and aftertreatment, those of skill in the art can carry out suitable selection.
Wherein, in step (3), the mass ratio of described secondary treatment molecular sieve and ionic liquid is 1:0.4-0.6, such as, be 1:0.4,1:0.5 or 1:0.6.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), described organic solvent is the binary solvent mixtures that the first component and second component are formed, wherein the volume ratio of the first component and second component is 1:2-3, such as, can be 1:2,1:2.5 or 1:3.
Wherein, the first component is any one in DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO), N-Methyl pyrrolidone (NMP), toluene, benzene, most preferably is DMSO;
Wherein, second component be polyvinyl alcohol 200 (PEG-200), 15-hat-6 or tributylamine in any one, most preferably be PEG-200.
Wherein, the consumption of this organic solvent is not particularly limited, as long as be convenient to follow-up operation and aftertreatment, those skilled in the art can carry out suitable selection, and this is no longer going to repeat them.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), described aromatic acid promotor is phenylformic acid, toluylic acid, to any one in Thiosalicylic acid or 3-nitrobenzoic acid, most preferably be 3-nitrobenzoic acid.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), the mol ratio of described formula (III) compound and formula (IV) compound is 1:6-8, such as, can be 1:6,1:7 or 1:8.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), in described formula (III) compound of mole (mol) with in the ratio of the described catalyzer of gram (g) for 1:1-2mol/g, namely formula (III) compound described in every 1mol uses catalyzer described in 1-2g, such as, can be 1:1mol/g, 1:1.5mol/g or 1:2mol/g.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), the mol ratio of described formula (III) compound and aromatic acid promotor is 1:0.2-0.6, such as, can be 1:0.2,1:0.4 or 1:0.6.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), temperature of reaction is 50-70 DEG C, such as, can be 50 DEG C, 60 DEG C or 70 DEG C.
In the preparation method of the new Calcium Ion Selective sequestrant of formula of the present invention (I), the reaction times is 4-8 hour, such as, can be 4 hours, 6 hours or 8 hours.
The third aspect, the present invention relates to above-mentioned formula (I) compound (especially formula (II) compound) or its pharmacy acceptable salt is preparing the purposes for the treatment of in the medicine of big area necrocytosis disease clinically.
Wherein, the described necrocytosis of big area clinically disease indefiniteness can be such as cerebral infarction, myocardial infarction, hepatic necrosis, renal ischaemia necrosis or necrotizing pancreatitis etc.
Fourth aspect, the present invention relates to above formula (I) compound (especially formula (II) compound) or the purposes of its pharmacy acceptable salt in preparation with OATP1B1 translocator relative disease medicine.
Wherein, describedly such as can be the red sanguinin disease of high courage, hepatobiliary calculus or liver cancer etc. with OATP1B1 translocator relative disease.
5th aspect, the present invention relates to the pharmaceutical composition comprising above formula (I) compound (especially formula (II) compound) or its pharmacy acceptable salt.
Wherein, described pharmaceutical composition is except comprising above formula (I) compound or its pharmacy acceptable salt, also can comprise pharmaceutically known various vehicle and pharmaceutical carrier etc., these vehicle and/or pharmaceutical carrier are all the known materials in this area, and this is no longer going to repeat them.
" pharmacy acceptable salt " in above-mentioned " formula (I) compound (especially formula (II) compound) or its pharmacy acceptable salt " refers to any salt that can be formed, such as can be inorganic acid salt, example hydrochloric acid salt, vitriol, hydrobromate, nitrate, carbonate, supercarbonate, phosphoric acid salt, hydrophosphate, phosphite, hydriodate etc., can be organic acid salt as acetate, propionic salt, isobutyrate, maleate, lactic acid salt, benzoate, succinate, mandelate, Citrate trianion, tartrate etc.These all belong to and well known to a person skilled in the art salifie form, and this is no longer going to repeat them.
As mentioned above, the invention provides a kind of novel calcium ion selective sequestrant and its production and use, described calcium ion selective sequestrant has excellent biological activity, can be used to treat various diseases, thus has a good application prospect and industrialization potential at field of medicaments; In addition, by the selection of catalyzer, aromatic acid promotor and organic solvent etc. and combination, described preparation method of the present invention can obtain object product with good productive rate, have good industrial production potential equally at field of medicaments.
Accompanying drawing explanation
Accompanying drawing 1 is the affinity curve of Conjugol and OATP1B1.
Accompanying drawing 2 is that formula (II) compound is to the inhibition concentration figure of OATP1B1 translocator.
Embodiment
Below by concrete example, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Preparation example 1: the preparation of catalyzer C1
(1) SBA-15 mesopore molecular sieve is calcined 40 minutes at 500 DEG C, then naturally cool to room temperature, obtain primary treatment molecular sieve;
(2) primary treatment molecular sieve is positioned in the steam atmosphere of 500 DEG C and places 60 minutes, obtain secondary treatment molecular sieve;
(3) by secondary treatment molecular sieve and ionic liquid N, N, N ', N '-tetramethyl--N, N '-disulfonic acid isopropylpropylenediamine hydrosulfate joins (wherein, described secondary treatment molecular sieve and N in appropriate ethyl acetate, N, N ', N '-tetramethyl--N, the quality of N '-disulfonic acid isopropylpropylenediamine hydrosulfate is 1:0.4), at 40 DEG C, be fully uniformly mixed 8 hours, then filter, by gained solids deionized water wash 2-3 time, then vacuum-drying, obtains catalyzer C1.
Preparation example 2: the preparation of catalyzer C2
(1) SBA-15 mesopore molecular sieve is calcined 30 minutes at 520 DEG C, then naturally cool to room temperature, obtain primary treatment molecular sieve;
(2) primary treatment molecular sieve is positioned in the steam atmosphere of 500 DEG C and processes 70 minutes, obtain secondary treatment molecular sieve;
(3) by secondary treatment molecular sieve and ionic liquid N, N, N ', N '-tetramethyl--N, N '-disulfonic acid isopropylpropylenediamine hydrosulfate joins (wherein, described secondary treatment molecular sieve and N in appropriate chloroform, N, N ', N '-tetramethyl--N, the mass ratio of N '-disulfonic acid isopropylpropylenediamine hydrosulfate is 1:0.5), at 45 DEG C, be fully uniformly mixed 6 hours, then filter, by gained solids deionized water wash 2-3 time, then vacuum-drying, obtains catalyzer C2.
Preparation example 3: the preparation of catalyzer C3
(1) SBA-15 mesopore molecular sieve is calcined 20 minutes at 550 DEG C, then naturally cool to room temperature, obtain primary treatment molecular sieve;
(2) primary treatment molecular sieve is positioned in the steam atmosphere of 500 DEG C and processes 80 minutes, obtain secondary treatment molecular sieve;
(3) by secondary treatment molecular sieve and ionic liquid N, N, N ', N '-tetramethyl--N, N '-disulfonic acid isopropylpropylenediamine hydrosulfate joins (wherein, described secondary treatment molecular sieve and N in appropriate benzene, N, N ', N '-tetramethyl--N, the mass ratio of N '-disulfonic acid isopropylpropylenediamine hydrosulfate is 1:0.6), at 50 DEG C, be fully uniformly mixed 4 hours, then filter, by gained solids deionized water wash 2-3 time, then vacuum-drying, obtains catalyzer C3.
Preparation example 4-7: the preparation of catalyzer C4-C7
Except respectively the ionic liquid in step (3) being replaced with as except the ionic liquid in following table, other operation is all constant, thus carried out preparation example 4-7 according to the same way with preparation example 1-3, use ionic liquid, corresponding relation and gained catalyzer name see the following form.
Preparation example 8-13: the preparation of catalyzer C8-C13
Preparation example 8-10: except not carrying out step (1), other operation all identically with preparation example 1-3 (does not carry out calcination processing by SBA-15 mesopore molecular sieve, but directly carry out steam atmosphere process and the step (3) of step (2)), thus respectively according to the same procedure of preparation example 1-3, carry out preparation example 8-10, by gained catalyzer called after C8, C9 and C10 in turn.
Preparation example 11-13: except not carrying out step (2), other operation all identically with preparation example 1-3 (does not carry out steam atmosphere process by SBA-15 mesopore molecular sieve, but after the calcination processing of carrying out step (1), directly carry out step (3)), thus respectively according to the same procedure of preparation example 1-3, carry out preparation example 11-13, by gained catalyzer called after C11, C12 and C13 in turn.
Embodiment 1: the preparation of formula (II) compound
Under room temperature, in the appropriate two-pack organic solvent that DMSO and the PEG-200 by volume ratio being 1:2 forms, add following formula (III) compound, catalyzer C1 and aromatic acid promotor 3-nitrobenzoic acid, fully be uniformly mixed, then following formula (IV) compound is added, after dropwising, be warming up to 50 DEG C, and stirring reaction 8 hours at such a temperature; Wherein, the mol ratio of formula (III) compound and formula (IV) compound be 1:6, in described formula (III) compound of mole (mol) and the mol ratio 1:0.2 taking the ratio of the described catalyzer C1 of gram (g) as 1:1mol/g, formula (III) compound and aromatic acid promotor M-NITROBENZOIC ACID;
After having reacted, reaction system is cooled to room temperature, adds enough methylene dichloride, abundant stirring, stratification, isolate dichloromethane layer, fully washed 2-3 time by this dichloromethane layer deionized water, discard water layer, organic over anhydrous dried over sodium sulfate, filters, and filter vacuum concentrates, gained residue is crossed 300-400 order silica gel column chromatography, take volume ratio as the acetone-propyl carbinol of 1:0.2 be elutriant, thus obtain described formula (II) compound, productive rate is 95.7%.
1H-NMR(500MHz,CDCl
3)δ(ppm)：1.28-1.34(m,8H),1.43-1.48(m,16H),2.75-2.84(t,16H),3.38-3.47(t,8H),4.29-4.35(t,8H),4.45(s,8H),4.62-4.67(t,4H),6.96-7.06(m,4H),7.35-7.44(m,4H)。
Embodiment 2: the preparation of formula (II) compound
Under room temperature, in the appropriate two-pack organic solvent that DMSO and the PEG-200 by volume ratio being 1:2.5 forms, add described formula (III) compound in embodiment 1, catalyzer C2 and aromatic acid promotor 3-nitrobenzoic acid, fully be uniformly mixed, then described formula (IV) compound in embodiment 1 is added, after dropwising, be warming up to 60 DEG C, and stirring reaction 6 hours at such a temperature; Wherein, the mol ratio of formula (III) compound and formula (IV) compound be 1:7, in described formula (III) compound of mole (mol) and the mol ratio 1:0.4 taking the ratio of the described catalyzer C2 of gram (g) as 1:1.5mol/g, formula (III) compound and aromatic acid promotor M-NITROBENZOIC ACID;
After having reacted, reaction system is cooled to room temperature, adds enough methylene dichloride, abundant stirring, stratification, isolate dichloromethane layer, fully washed 2-3 time by this dichloromethane layer deionized water, discard water layer, organic over anhydrous dried over sodium sulfate, filters, and filter vacuum concentrates, gained residue is crossed 300-400 order silica gel column chromatography, take volume ratio as the acetone-propyl carbinol of 1:0.2 be elutriant, thus obtain described formula (II) compound, productive rate is 96.1%.
Nuclear magnetic data is with embodiment 1.
Embodiment 3: the preparation of formula (II) compound
Under room temperature, in the appropriate two-pack organic solvent that DMSO and the PEG-200 by volume ratio being 1:3 forms, add described formula (III) compound in embodiment 1, catalyzer C3 and aromatic acid promotor 3-nitrobenzoic acid, fully be uniformly mixed, then described formula (IV) compound in embodiment 1 is added, after dropwising, be warming up to 70 DEG C, and stirring reaction 4 hours at such a temperature; Wherein, the mol ratio of formula (III) compound and formula (IV) compound be 1:8, in described formula (III) compound of mole (mol) and the mol ratio 1:0.6 taking the ratio of the described catalyzer C3 of gram (g) as 1:2mol/g, formula (III) compound and aromatic acid promotor M-NITROBENZOIC ACID;
After having reacted, reaction system is cooled to room temperature, adds enough methylene dichloride, abundant stirring, stratification, isolate dichloromethane layer, fully washed 2-3 time by this dichloromethane layer deionized water, discard water layer, organic over anhydrous dried over sodium sulfate, filters, and filter vacuum concentrates, gained residue is crossed 300-400 order silica gel column chromatography, take volume ratio as the acetone-propyl carbinol of 1:0.2 be elutriant, thus obtain described formula (II) compound, productive rate is 95.8%.
Nuclear magnetic data is with embodiment 1.
From embodiment 1-3, when adopting reaction system of the present invention, high yield can obtain object product, thus provide a kind of brand-new method for the preparation of this novel cpd, industrially especially medicine intermediate synthesis field has a good application prospect and the raw tea potentiality of industrialization.
Embodiment 4-7: the preparation of formula (II) compound
Except using following catalyzer, other operation is all constant, thus according to the same way of embodiment 1-3, has carried out embodiment 4-7, use catalyzer, corresponding embodiment and products collection efficiency to see the following form.
As can be seen here, in the preparation process of catalyzer, the ionic liquid kind of SBA-15 mesopore molecular sieve institute load has significant impact for final products collection efficiency.Wherein, N, N, N ', N '-tetramethyl--N, N '-disulfonic acid isopropylpropylenediamine hydrosulfate has best effect, and this is non-obvious.
Embodiment 8-13: the preparation of formula (II) compound
Except using following catalyzer, other operation is all constant, thus according to the same way of embodiment 1-3, has carried out embodiment 8-13, use catalyzer, corresponding embodiment and products collection efficiency to see the following form.
As can be seen here, the pre-treatment of SBA-15 mesopore molecular sieve has significant impact to products collection efficiency equally, when not carrying out calcination processing and not carrying out steam atmosphere process, productive rate all will be caused to have remarkable reduction, but when not carrying out steam atmosphere process, products collection efficiency declines more obvious.
Embodiment 14-19: the investigation of organic solvent
Except the first component in two-pack organic solvent wherein and second component are changed, other operation is all constant, thus implementing embodiment 14-19 according to the same procedure of embodiment 1-3, the organic solvent used, corresponding embodiment and products collection efficiency see the following form.
As can be seen here, in solvent system, only have the binary solvent mixtures system adopting DMSO and PEG-200, just can obtain excellent effect of the present invention.And when change first component and second component, productive rate all will be caused to have obvious reduction.
Embodiment 20-28: the investigation of aromatic acid promotor
Embodiment 20-22: except replacing with except phenylformic acid by the 3-nitrobenzoic acid in embodiment 1-3 respectively, other operation is all constant, thus obtains embodiment 20-22 respectively.
Embodiment 23-25: except replacing with except toluylic acid by the 3-nitrobenzoic acid in embodiment 1-3 respectively, other operation is all constant, thus obtains embodiment 23-25 respectively.
Embodiment 26-28: except replacing with except Thiosalicylic acid by the 3-nitrobenzoic acid in embodiment 1-3 respectively, other operation is all constant, thus obtains embodiment 26-28 respectively.
The results are shown in following table.
As can be seen here, the kind of aromatic acid promotor has significant impact to products collection efficiency equally, and 3-nitrobenzoic acid has best effect, even if with its very similar phenylformic acid, to Thiosalicylic acid, its productive rate also has obvious reduction, even wants significantly lower than toluylic acid the productive rate of Thiosalicylic acid.
From above-mentioned all embodiments, in preparation method of the present invention, by the kind selection etc. of the specific preparation technology of catalyzer, organic solvent, aromatic acid promotor, thus create synergy each other, thus achieve good products collection efficiency.And when changing any one key element wherein, products collection efficiency all will be caused to have significant reduction.
Biologic activity is tested
1, anoxia in mice experiment
It is one group by every 12 kunming mice parts, carry out three groups of parallel laboratory tests, test embodiment compound 1 in above-mentioned formula (II) compound of the present invention, BAPTA and patent documentation CN103288664A respectively, two (2-amino-benzene oxygen) ethane-N of 2-, N, the activity of N', N'-tetraacethyl four (diethylaminoethanol ester).
Specific experiment method is: with the dosage intravenous injection of 5mg/kg after 1 hour, the survival time of test mouse in closed environment gradually under oxygen consumption to anoxic condition, simultaneously other using 12 of non-injectable drug kunming mices one group as blank, being converted by the mean survival time of blank group is 100%, thus anoxic test has been carried out to three groups of mouse, experimental result is as follows:
2, Acute cerebral ischemia in mice experiment
Every 6 kunming mice parts are divided into one group, carry out three groups of parallel laboratory tests, test respectively above-mentioned formula (II) compound of the present invention, embodiment compound 1 in BAPTA and patent documentation CN103288664A, two (2-amino-benzene oxygen) ethane-N of 2-, N, the activity of N', N'-tetraacethyl four (diethylaminoethanol ester).
Specific experiment method is: with the dosage intravenous injection of 10mg/kg after 1 hour, rapid broken end modeling, and recording respiration number of times and breathing are held time, simultaneously other using 6 of non-injectable drug kunming mices one group as blank, conversion of the frequency of respiration of blank and breathing being held time is 100%, thus acute cerebral ischemia test has been carried out to three groups of mouse, experimental result is as follows:
Can be found out by above-mentioned ischemia and hypoxia experiment, formula (II) compound has excellent ischemia resisting and the ability of anti-hypoxia, not only be better than classical calcium ion selective sequestrant BAPTA, also other BAPTA derivative of the prior art is better than significantly, such as, embodiment compound in CN103288664A.
Contriver in depth have studied the pharmacological action of the compounds of this invention further, tested by the external model of drug transporter, characterize the excellent cross-cell membrane performance of the compounds of this invention further, thus disclose the principle that the compounds of this invention has excellent activity, also for the research of BAPTA derivative provides a kind of design completely newly.
3, liver absorption type translocator OATP1B1 absorption experiment
The function of A, OATP1B1 translocator confirms
OATP1B1-HEK293 cell is added in 24 porose discs, is positioned over 37 DEG C, 5%CO
2after cultivating 48h under condition, start administration experiment confirmation cell function.
The standard transhipment substrate of OATP1B1 translocator is Conjugol, be that the concentration that the 3H-Conjugol of 1.687TBq/mmol is configured to 50nmol/L is dissolved in DPBS damping fluid by specific radioactivity, add 100nM, 300nM, the nonisotopically labelled Conjugol of 1 μM, 3 μMs, 10 μMs, 30 μMs in addition respectively as inhibitor, by the blank HEK293 cell (MOCK cell) of expressing without OATP1B1 translocator as negative control, test-results is shown in accompanying drawing 1.
By the linear regression of Eadie-Hofstee method, calculate OATP1B1 standard transhipment substrate Conjugol Michaelis-Menten equation, K
mvalue is 0.5392 μM, V
maxbe worth is 20.569pmol/mg protein/minute.K
mvalue is less than 1 μM, and illustrate that Conjugol and OATP1B1 affinity are very good, the function simultaneously also demonstrating OATP1B1-HEK293 clone is good.
B, the compounds of this invention and OATP1B1 translocator affinity are tested
Using 50nM 3H-Conjugol (administration OATP1B1) as positive control 100%, add the compounds of this invention (II) of 1 μM, 3 μMs, 10 μMs, 30 μMs, 100 μMs, 300 μMs, 600 μMs respectively, measure the Change of absorption of positive substrate, experimental result is shown in accompanying drawing 2.
Calculated formula (II) compound is for the IC of OATP1B1
50value is about 4.62 μMs, proves to have ideal restraining effect for OATP1B1.Carry out conventional K further
m, V
maxchange experiment, by Eadie-Hofstee method linear regression determination formula (II) compound, OATP1B1 is taken in the impact of 3H-Conjugol, find that formula (II) compound causes OATP1B1 to take in the K of 3H-Conjugol
mvalue creates significant change: increase to 2.5714 μMs from 0.5392 μM, and V
maxvalue does not produce significant change, and this can prove that formula (II) compound is the competitive inhibitor of OATP1B1 translocator, and namely it is the transhipment substrate of OATP1B1.
C, prior art compound and OATP1B1 translocator affinity are tested
Adopt the identical experimental technique in above-mentioned B, demonstrate embodiment compound 1 in BAPTA and patent documentation CN103288664A, two (2-amino-benzene oxygen) ethane-N of 2-, N, N', N'-tetraacethyl four (diethylaminoethanol ester) and OATP1B1 translocator affinity, found that: BAPTA is for the IC of OATP1B1
50value, for being about 50 μMs, can think do not have significant restraining effect; And in CN103288664A embodiment compound for the IC of OATP1B1
50value is for being about 15 μMs, and restraining effect is also well below formula (II) compound.
Tested by the competitive inhibition of above-mentioned further OATP1B1 translocator, demonstrate the transhipment substrate that two kinds of compounds of the prior art are not all OATP1B1.
By the affinity experimental result with OATP1B1 translocator, can with find out the transhipment substrate of formula (II) compound as OATP1B1 translocator apparently, relative to the embodiment compound in BAPTA and CN103288664A of the prior art, can easier leap cytolemma, this result confirms that formula (II) compound has the ability of excellent leap cytolemma, solve technical problem in the urgent need to address in prior art, also explains the compounds of this invention simultaneously and why can have excellent ischemia resisting hypoxia activity, this is the effect of beyond thought excellence.
In sum, can clearly be found out by above-mentioned all embodiments, the invention provides a kind of new calcium ion selective sequestrant and its production and use, compound of the present invention has the ability of excellent ischemia resisting anoxic, simultaneously, it has also possessed excellent cross-cell membrane ability as the transhipment substrate of OATP1B1 translocator, and the research for BAPTA derivative has very important significance and potential value.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. a new Calcium Ion Selective sequestrant shown in following formula (I), its structural formula is as follows:
Wherein, R
1, R
2be selected from H, halogen, C independently of one another
1-5alkyl, C
1-5alkoxyl group or hydroxyl.
2. calcium ion selective sequestrant as claimed in claim, is characterized in that: it is following formula (II) compound:
3. the preparation method of new Calcium Ion Selective sequestrant described in claim 1 or 2, described preparation method is as follows:
In organic solvent, under catalyzer and aromatic acid promotor exist, following formula (III) compound and following formula (IV) compound react, thus obtain described formula (I) or formula (II) compound,
Wherein, R
1, R
2respectively as in claim 1 or 2 define.
4. preparation method as claimed in claim 3, is characterized in that: described catalyzer obtains according to following preparation method:
(1) SBA-15 mesopore molecular sieve is calcined 20-40 minute at 500-550 DEG C, then naturally cool to room temperature, obtain primary treatment molecular sieve;
(2) primary treatment molecular sieve is positioned in the steam atmosphere of 500 DEG C and places 60-80 minute, obtain secondary treatment molecular sieve;
(3) join in solvent by secondary treatment molecular sieve and ionic liquid, be fully uniformly mixed 4-8 hour, then filter at 40-50 DEG C, by gained solids deionized water wash 2-3 time, then vacuum-drying, obtains described catalyzer.
5. preparation method as claimed in claim 4; it is characterized in that: described ionic liquid is selected from 1-(4-diacetyl iodophenyl)-3-methyl imidazolium tetrafluoroborate, 1-methyl-3-propyl sulfonic acid imidazole bisulfate, 1-normal-butyl-3-Methylimidazole dihydrogen phosphate, N; N; N '; N '-tetramethyl--N; any one in N '-disulfonic acid isopropylpropylenediamine hydrosulfate, 1-normal-butyl-3-Methylimidazole hexafluorophosphate; most preferably be N; N; N '; N '-tetramethyl--N, N '-disulfonic acid isopropylpropylenediamine hydrosulfate.
6. the preparation method as described in any one of claim 3-5, is characterized in that: described organic solvent is the binary solvent mixtures that the first component and second component are formed, and wherein the volume ratio of the first component and second component is 1:2-3;
Wherein, the first component is any one in DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO), N-Methyl pyrrolidone (NMP), toluene, benzene, most preferably is DMSO;
Wherein, second component be polyvinyl alcohol 200 (PEG-200), 15-hat-6 or tributylamine in any one, most preferably be PEG-200.
7. the preparation method as described in any one of claim 3-6, is characterized in that: described aromatic acid promotor is phenylformic acid, toluylic acid, to any one in Thiosalicylic acid or 3-nitrobenzoic acid, most preferably be 3-nitrobenzoic acid.
8. (I) compound of formula described in claim 1 or its pharmacy acceptable salt are preparing the purposes for the treatment of in the medicine of big area necrocytosis disease clinically.
9. (I) compound of formula described in claim 1 or the purposes of its pharmacy acceptable salt in preparation with OATP1B1 translocator relative disease medicine.
10. comprise the pharmaceutical composition of (I) compound of formula described in claim 1 or its pharmacy acceptable salt.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5516911A (en) * | 1993-12-30 | 1996-05-14 | The United States Of America As Represented By The Department Of Health And Human Services | Fluorescent intracellular calcium indicators |
| CN102093885A (en) * | 2011-03-04 | 2011-06-15 | 西北大学 | Indole calcium ion fluorescent probes and preparation method and use thereof |
| CN102617376A (en) * | 2012-03-13 | 2012-08-01 | 沈阳化工大学 | Synthesis method of calcium ion selective chelating agents |
| CN103288664A (en) * | 2013-04-23 | 2013-09-11 | 合肥恒星药物研究所 | Novel BAPTA derivative, preparation method thereof and medicinal use thereof |
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2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5516911A (en) * | 1993-12-30 | 1996-05-14 | The United States Of America As Represented By The Department Of Health And Human Services | Fluorescent intracellular calcium indicators |
| CN102093885A (en) * | 2011-03-04 | 2011-06-15 | 西北大学 | Indole calcium ion fluorescent probes and preparation method and use thereof |
| CN102617376A (en) * | 2012-03-13 | 2012-08-01 | 沈阳化工大学 | Synthesis method of calcium ion selective chelating agents |
| CN103288664A (en) * | 2013-04-23 | 2013-09-11 | 合肥恒星药物研究所 | Novel BAPTA derivative, preparation method thereof and medicinal use thereof |
Non-Patent Citations (1)
| Title |
|---|
| ROBERT E. LONDON，等: "NMR-sensitive fluorinated and fluorescent intracellular calcium ion indicators with high dissociation constants", 《AMERICAN JOURNAL OF PHYSIOLOGY》 * |
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