CN104292167A - Nitric oxide donor derivatives of bendamustine hydrochloride and preparation method of nitric oxide donor derivatives - Google Patents
Nitric oxide donor derivatives of bendamustine hydrochloride and preparation method of nitric oxide donor derivatives Download PDFInfo
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- CN104292167A CN104292167A CN201410478910.0A CN201410478910A CN104292167A CN 104292167 A CN104292167 A CN 104292167A CN 201410478910 A CN201410478910 A CN 201410478910A CN 104292167 A CN104292167 A CN 104292167A
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- 0 C[n](c(CCCC(***)=O)nc1c2)c1ccc2N(CCCl)CCCl Chemical compound C[n](c(CCCC(***)=O)nc1c2)c1ccc2N(CCCl)CCCl 0.000 description 7
- OSMBEXPJBGQZDF-UHFFFAOYSA-N OCc1[n+](O)[o]nc1-c1ccccc1 Chemical compound OCc1[n+](O)[o]nc1-c1ccccc1 OSMBEXPJBGQZDF-UHFFFAOYSA-N 0.000 description 1
- STZVUDCDDOZVOB-UHFFFAOYSA-N O[n+]1c(CCl)c(-c2ccccc2)n[o]1 Chemical compound O[n+]1c(CCl)c(-c2ccccc2)n[o]1 STZVUDCDDOZVOB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to nitrogen mustard antitumor drugs, namely nitric oxide donor derivatives of bendamustine and a preparation method of the nitric oxide donor derivatives. The general formula of a nitro-oxo derivative of bendamustine is as shown in the formula (I); the general formulas of furazan nitrogen oxide derivatives of bendamustine are as shown in formulas (II) and (III); and the general formula of a benzofurazan nitrogen oxide derivative of bendamustine is as shown in the formula (IV).
Description
Technical field
The present invention relates to nitric oxide donors analog derivative of a kind of novel nitrogen mustards antitumor drug bendamustine and preparation method thereof.This compounds is by obtaining as the NItroxyderivatives of nitric oxide donors, furazan nitroxides derivates or benzofuraxan nitrogen oxygen radical derivative and bendamustine coupling, can be used as the prodrug of antitumor drug bendamustine hydrochloride, discharge nitric oxide donors and bendamustine parent nucleus under lytic enzyme effect in vivo, reach synergistic object.
Background technology
Chronic lymphocytic leukemia (chronic myelogenous leukemia, CML) is a kind of comparatively common, originates from the malignant clone disease of hemopoietic stem cell.The bendamustine hydrochloride that Cephalon company develops is a kind of bifunctional alkylating agents, and this medicine is used for the treatment of chronic lymphocytic leukemia in March, 2008 by U.S. FDA approval, and commodity are called Rreanda.
Nitrogen protoxide (NO) is important messenger substances and effector molecule, and it take part in multiple physiology and pathologic process in body.Under pathology and physiological condition, NO is produced by different cell induction, and the apoptosis of various kinds of cell can be affected, play a role in multiple pathophysiological process: NO directly can bring out macrophage apoptosis, induce other cells as the apoptosis of myocardial cell, chondrocyte, endotheliocyte, islet cells, vascular smooth muscle cell; NO can suppress human B lymphocyte, splenocyte, eosinophil leucocyte, hepatocellular apoptosis.
Nitric oxide donors class medicine can discharge NO through enzyme or non-enzymatic effect in vivo, types of transportation in the body that namely it can be used as a kind of NO, can be used as again the transformation period that a kind of storage form extends NO.Nitroxide base class nitric oxide donors and furoxan-based NO donors class nitric oxide donors are the more nitric oxide donors of Recent study, classify according to discharging from NO the different of atom that position is connected, the nitric oxide donors of current discovery also comprises C-NO donor (such as oxime compounds except this two class, guanidine compound), N-NO donor (such as N-nitrosamine class, azo enediol salt), S-NO donor (such as Thionitrate, S-nitrosothiol) and transition metal-NO donor (such as iron-NO mixture).
Summary of the invention
Nitric oxide donors derivative that the object of this invention is to provide a kind of bendamustine hydrochloride and preparation method thereof.
For achieving the above object, the technical solution used in the present invention is: the compound of logical formula I, (II), (III) and (IV) and pharmacologically acceptable salt thereof:
Wherein: in logical formula I, X is O or S; Y is the group containing following meanings:
a)-(CH
2)n-，n＝2～8；
B)-CH
2cH (CH
3) (CH
2) n-, wherein n=1 ~ 6;
c)-CH
2CH＝CHCH
2-,-CH
2C≡CCH
2-；
D)-(CH
2) n-O-(CH
2) n-, wherein n=1 ~ 4;
E)-CH
2-phenyl-(CH
2) n-(adjacent, to), wherein n=1 ~ 4;
In logical formula II, (III) and (IV), Z is O or S; R
1the group containing following meanings:
a)-(CH
2)nOm-，n＝0～4，m＝0,1；
B)-CH
2cH (CH
3) (CH
2) nO-, wherein n=1 ~ 4;
c)-CH
2CH＝CHCH
2O-,-CH
2C≡CCH
2O-；
D)-(CH
2) nCOO-, wherein n=1 ~ 4;
e)
Further, wherein, in logical formula I, X is O or S; Y is the group containing following meanings:
a)-(CH
2)n-，n＝4；
B)-CH
2cH (CH
3) (CH
2) n-, wherein n=2;
c)-CH
2CH＝CHCH
2-,-CH
2C≡CCH
2-；
D)-(CH
2) n-O-(CH
2) n-, wherein n=2;
E)-CH
2-phenyl-(CH
2) n-(adjacent, to), wherein n=1, the structure of para-orientation;
In logical formula II, (III) and (IV), Z is O or S; R
1the group containing following meanings:
a)-(CH
2)nOm-，n＝0～4，m＝0,1；
B)-CH
2cH (CH
3) (CH
2) nO-, wherein n=2;
c)-CH
2CH＝CHCH
2O-,-CH
2C≡CCH
2O-；
D)-(CH
2) nCOO-, wherein n=3;
e)
Further, wherein, in logical formula II, (III) and (IV), Z is O or S; R
1-(CH
2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
(1), the nitrooxy novel derivative of the nitrogen mustards antitumor drug bendamustine hydrochloride of formula of of the present invention (I) or its pharmacologically acceptable salts or steric isomer;
According to compound of the present invention, containing can the nitrogen-atoms of salify in molecule, change into corresponding salt by reacting in organic solvent with corresponding organic acid or mineral acid;
Organic acid can be: oxalic acid, tartrate, toxilic acid, succsinic acid, citric acid; Mineral acid can be nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid;
Compound of the present invention has one or more unsymmetrical carbon, and existence form can be optically pure enantiomorph, pure diastereomer, mixture of enantiomers, non-enantiomer mixture, the racemic mixture of enantiomorph, racemoid or racemic mixture; The all possible isomer of formula I compound, steric isomer and their mixture are also objects of the present invention;
The following is the preferred compound of logical formula I
1. bendamustine-4-(nitrooxy) butyl ester, corresponding construction formula is:
2. bendamustine-4-(nitrooxy) isopentyl ester, corresponding construction formula is:
3. bendamustine-4-(nitrooxy)-2-butylene ester, corresponding construction formula is:
4. bendamustine-4-(nitrooxymethyl) benzyl ester.
The preparation method of formula I compound is led in the present invention:
The compound of logical formula I, wherein X=O, by formula III and formula IV compound being reacted obtained:
Wherein A is chlorine, bromine, iodine; B is nitrooxy or identical with A group; The definition of Y structure and the Compound Phase of logical formula I are together; Formula (V) compound is bendamustine, and can obtain or laboratory synthesis by market is bought, formula VI compound commercially can be bought and obtain.
When B is nitrooxy, formula (V) compound and formula VI compound at inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), benzene, toluene, many halogenated aliphatic, in the scope of 10 DEG C ~ 80 DEG C, react the compound that 0.5h to 3h can obtain formula I, molar ratio is 1:1 ~ 5;
When B and A group is identical, when being namely chlorine, bromine, iodine, first formula (V) compound and formula VI compound at inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), benzene, toluene, many halogenated aliphatic, in the scope of 10 DEG C ~ 50 DEG C, react 0.5h to 3h can obtain intermediate, molar ratio is 1:1 ~ 5, then the intermediate of gained again with Silver Nitrate at acetonitrile, tetrahydrofuran (THF), methylethylketone or N, in N`-dimethyl formamide, lucifuge reaction 1h to 3h obtains target compound, and route is as follows:
(2), the furazan nitroxides novel derivative of the nitrogen mustards antitumor drug bendamustine of formula of of the present invention (II) or its pharmacologically acceptable salts or steric isomer;
According to compound of the present invention, containing can the nitrogen-atoms of salify in molecule, change into corresponding salt by reacting in organic solvent with corresponding organic acid or mineral acid;
Organic acid can be: oxalic acid, tartrate, toxilic acid, succsinic acid, citric acid; Mineral acid can be nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid;
Compound of the present invention has one or more unsymmetrical carbon, and existence form can be optically pure enantiomorph, pure diastereomer, mixture of enantiomers, non-enantiomer mixture, the racemic mixture of enantiomorph, racemoid or racemic mixture; The all possible isomer of formula II compound, steric isomer and their mixture are also objects of the present invention;
The following is the preferred compound of logical formula II:
1. bendamustine-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) methyl esters, its concrete structure formula is as follows:
2. bendamustine-3-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) oxygen propyl ester, its concrete structure formula is as follows:
3. bendamustine-2-methyl-4-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) oxygen butyl ester, its concrete structure formula is as follows:
4. bendamustine-4-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) oxygen base-2-butylene ester, its concrete structure formula is as follows:
5. bendamustine-4-oxo-4-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) oxygen butyl ester, its concrete structure formula is as follows:
6. bendamustine-4-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) methoxyl group Bian ester, its concrete structure formula is as follows:
The preparation method of formula II compound is led in the present invention:
The compound of logical formula II, wherein during Z=O, by by formula (V) compound dissolution in inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), benzene, toluene, many halogenated aliphatic, formula (VII) compound is added under ice-water bath, under the catalysis of EDCI and DMAP, in the scope of 10 DEG C ~ 50 DEG C, react 0.5 ~ 24h obtain:
Wherein D is chlorine, bromine, iodine, hydroxyl; R
1the definition of structure and the Compound Phase of logical formula II are together.Formula (V) compound is bendamustine, can obtain or laboratory synthesis by market is bought; The preparation of formula (VII) compound, first needs the obtained furoxan-based NO donors containing hydroxyl:
Take styryl carbinol as starting raw material, react to obtain 3-methylol-4-phenyl-1,2,5-oxadiazole-2-oxide compound with Sodium Nitrite, this oxide compound can directly and compound (III) to react the compound generating and meet logical formula II; Or the compound generating and meet logical formula II that reacts with compound (III) after being reacted into ester with the acyl group of halo side chain again; Or react with sulfur oxychloride again after 3-chloromethyl-4-phenyl-1,2,5-oxadiazole-2-oxide compound, be obtained by reacting the furoxan-based NO donors containing hydroxyl with dihydroxy compound, synthetic route is as follows:
Wherein R
1-(CH
2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
(3) the furazan nitroxides novel derivative of the nitrogen mustards antitumor drug bendamustine of formula of of the present invention (III) or its pharmacologically acceptable salts or steric isomer;
According to compound of the present invention, containing can the nitrogen-atoms of salify in molecule, change into corresponding salt by reacting in organic solvent with corresponding organic acid or mineral acid;
Organic acid can be: oxalic acid, tartrate, toxilic acid, succsinic acid, citric acid; Mineral acid can be nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid;
Compound of the present invention has one or more unsymmetrical carbon, and existence form can be optically pure enantiomorph, pure diastereomer, mixture of enantiomers, non-enantiomer mixture, the racemic mixture of enantiomorph, racemoid or racemic mixture; The all possible isomer of formula III compound, steric isomer and their mixture are also objects of the present invention;
The preparation method of formula III compound is led in the present invention:
1. bendamustine-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide compound-4-) oxygen propyl ester], its concrete structure formula is as follows:
2. bendamustine-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide compound-4-) oxygen butyl ester], its concrete structure formula is as follows:
3. bendamustine-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide compound-4-) oxygen-2-butylene-1-ester], its concrete structure formula is as follows:
4. bendamustine-[1-methyl-2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide compound-4-) oxygen-3-butyl ester], its concrete structure formula is as follows:
Prepare universal process:
The compound of logical formula III, wherein during Z=O, by by formula (V) compound dissolution in inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), benzene, toluene, many halogenated aliphatic, formula (VIII) compound is added under ice-water bath, under the catalysis of EDCI and DMAP, in the scope of 10 DEG C ~ 50 DEG C, react 0.5 ~ 24h obtain:
Wherein D is chlorine, bromine, iodine, hydroxyl; R
1the definition of structure and the Compound Phase of logical formula III are together.Formula (V) compound is bendamustine, can obtain or laboratory synthesis by market is bought; The preparation of formula (VIII) compound, first needs the obtained furoxan-based NO donors containing hydroxyl:
Thiophenyl acetic acid is in glacial acetic acid; 30% aqueous hydrogen peroxide solution is dripped under condition of ice bath; to reacting completely; react with nitrosonitric acid under ice bath 3; 4-disulfonyl base-1; 2,5-oxadiazole-2-oxide compound, this oxide compound and dihydroxy compound are obtained by reacting the furoxan-based NO donors containing hydroxyl.Synthetic route is as follows:
Wherein R
1be-(CH2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
(4) the furazan nitroxides novel derivative of the nitrogen mustards antitumor drug bendamustine of formula of of the present invention (IV) or its pharmacologically acceptable salts or steric isomer;
According to compound of the present invention, containing can the nitrogen-atoms of salify in molecule, change into corresponding salt by reacting in organic solvent with corresponding organic acid or mineral acid;
Organic acid can be: oxalic acid, tartrate, toxilic acid, succsinic acid, citric acid; Mineral acid can be nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid;
Compound of the present invention has one or more unsymmetrical carbon, and existence form can be optically pure enantiomorph, pure diastereomer, mixture of enantiomers, non-enantiomer mixture, the racemic mixture of enantiomorph, racemoid or racemic mixture; The all possible isomer of formula IV compound, steric isomer and their mixture are also objects of the present invention.
The preparation method of formula IV compound is led in the present invention:
Bendamustine-[4-benzo (1,2,5-oxadiazole)-1-] oxygen-5-methyl esters, its concrete structure formula is as follows:
Prepare universal process:
The compound of logical formula IV, wherein during Z=O, by by formula (V) compound dissolution in inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), benzene, toluene, many halogenated aliphatic, formula (Ⅸ) compound is added under ice-water bath, under the catalysis of EDCI and DMAP, in the scope of 10 DEG C ~ 50 DEG C, react 0.5 ~ 24h obtain:
Wherein D is chlorine, bromine, iodine, hydroxyl; R
1the definition of structure and the Compound Phase of logical formula IV are together.Formula (V) compound is bendamustine, can obtain or laboratory synthesis by market is bought; The preparation of formula (Ⅸ) compound, first needs the obtained furoxan-based NO donors containing hydroxyl:
With 2-nitro-4-phenylaniline for raw material, react with under sodium ethylate, clorox ice bath, gained solid reacts with N-bromo-succinimide under benzoyl peroxide causes, obtain 5-brooethyl-benzo (1,2,5-oxadiazole)-1-] oxygen, this oxide compound can directly and compound (V) react the compound generating and meet logical formula IV, or be obtained by reacting the benzofuraxan oxynitride containing hydroxyl with dihydroxy compound, synthetic route is as follows:
Wherein R
1be-(CH2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
Embodiment
Below in conjunction with the embodiment of the present invention, be clearly and completely described the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1:
The synthesis of 4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-4-(nitrooxy) butyl ester (bendamustine-4-(nitrooxy) butyl ester):
1a), 4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-4-bromine butyl ester 1,4-dibromobutane (0.5g, 2.34mmol) be dissolved in N, in dinethylformamide (10ml), add K2CO3 (0.2g in batches, 1.45mmol), stirring at room temperature 10min, by compound 1 (0.2g, 0.56mmol) be dissolved in N, dinethylformamide (5ml) is slowly added dropwise in reaction system afterwards, room temperature reaction 3h.Plate inspection reacts completely (developping agent: sherwood oil: ethyl acetate=2:1).Methylene dichloride (20ml) and water (20ml) extraction, organic phase is spin-dried for saturated.Ice bath can separate out white crystal.
1b), 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) vinyl] phenylformic acid-4-(nitrooxy) butyl ester:
To 1a) gained compound (0.20g, 0.41mmol) is dissolved in acetonitrile (10ml), after adding Silver Nitrate (0.11g, 0.62mmol), 80 DEG C of lucifuges reaction 2h.After reacting liquid filtering, in filtrate, add saturated nacl aqueous solution stir precipitation, again filter, be spin-dried for after going the drying of filtrate EA layer.Residue crosses silica column purification, with n-hexane/ethyl acetate 10.0/1.0 wash-out.Obtain 0.12g oily target compound.
MS:474.1
+
Embodiment 2
The synthesis of 4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-4-nitrooxy-2-butylene ester (bendamustine-4-(nitrooxy)-2-butylene ester), corresponding construction formula is:
1), 4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] the bromo-2-butylene ester of butyric acid-4-
This step reaction ratio and the same 1a of method), but the reaction times shorten to 1h, same to 1a) after aftertreatment, ice bath crystallization must loosen light yellow crystal, not treated direct input next step react.
2), 4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-4-nitrooxy-2-butylene ester
By 2) the gained faint yellow compound that loosens is dissolved in acetonitrile (5ml), the same 1b of reaction method), temperature of reaction is reduced to 60 DEG C, and residue crosses silica column purification, with n-hexane/ethyl acetate 12.0.0/1.0 wash-out.Obtain 0.10g oily target compound.
MS:472(M+1)
+
Embodiment 3
4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) methyl esters (bendamustine-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) methyl esters) synthesis:
After bendamustine (0.10g, 0.28mol) is dissolved in 10ml methylene dichloride, under ice-water bath, add furoxan-based NO donors class nitric oxide donors (0.05g, 0.27mmol), afterwards EDCI (0.06g, 0 is added rapidly, 29mmol), DMAP number.Room temperature is proceeded to, reaction 3h after stirring 10min.Pickling reaction solution after washing, extraction into ethyl acetate, adopts ethyl acetate-hexane system crystallization, can obtain white crystal 0.06 after concentrated
g.
MS:532.1(M+1)
+
Embodiment 4
4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-(4-phenyl-1; 2; 5-oxadiazole-2-oxide compound-3-) methyl esters (bendamustine-[2-(3-benzenesulfonyl-1; 2,5-oxadiazole-2-oxide compound-4-) oxygen butyl ester]) synthesis:
After bendamustine (0.10g, 0.28mol) is dissolved in 10ml methylene dichloride, under ice-water bath, add furoxan-based NO donors class nitric oxide donors (0.05g, 0.16mmol), afterwards EDCI (0.06g, 0 is added rapidly, 29mmol), DMAP number.Room temperature is proceeded to, reaction 3h after stirring 10min.Pickling reaction solution after washing, extraction into ethyl acetate, adopts ethyl acetate-hexane system crystallization, can obtain white crystal 0.06g after concentrated.
MS:654.2(M+1)
+
Embodiment 5
4-[5-[two (2-chloroethyl) is amino]-1-tolimidazole-2-base] butyric acid-(4-phenyl-1,2,5-oxadiazole-2-oxide compound-3-) methyl esters (bendamustine-[4-benzo (1,2,5-oxadiazole)-1-] oxygen-5-methyl esters]) synthesis:
Bendamustine (0.10g, 0.28mol) and 0.4g salt of wormwood are dissolved in 10mlDMF, will drop in reaction system under benzofuraxan (0.04g, 0.16mmol) solution ice bath, reaction 1h.Pickling after washing, then be extracted with ethyl acetate, be spin-dried for after drying, with acetate-methanol system crystallization, white crystal 0.06g can be obtained.
MS:506.1(M+1)
+
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (8)
1. the compound of logical formula I, (II), (III) and (IV) and pharmacologically acceptable salt thereof:
Wherein: in logical formula I, X is O or S; Y is the group containing following meanings:
a)-(CH
2)n-，n＝2～8；
B)-CH
2cH (CH
3) (CH
2) n-, wherein n=1 ~ 6;
c)-CH
2CH＝CHCH
2-,-CH
2C≡CCH
2-；
D)-(CH
2) n-O-(CH
2) n-, wherein n=1 ~ 4;
E)-CH
2-phenyl-(CH
2) n-(adjacent, to), wherein n=1 ~ 4;
In logical formula II, (III) and (IV), Z is O or S; R
1the group containing following meanings:
a)-(CH
2)nOm-，n＝0～4，m＝0,1；
B)-CH
2cH (CH
3) (CH
2) nO-, wherein n=1 ~ 4;
c)-CH
2CH＝CHCH
2O-,-CH
2C≡CCH
2O-；
D)-(CH
2) nCOO-, wherein n=1 ~ 4;
2. compound according to claim 1, wherein, in logical formula I, X is O or S; Y is the group containing following meanings:
a)-(CH
2)n-，n＝4；
B)-CH
2cH (CH
3) (CH
2) n-, wherein n=2;
c)-CH
2CH＝CHCH
2-,-CH
2C≡CCH
2-；
D)-(CH
2) n-O-(CH
2) n-, wherein n=2;
E)-CH
2-phenyl-(CH
2) n-(adjacent, to), wherein n=1, the structure of para-orientation;
In logical formula II, (III) and (IV), Z is O or S; R
1the group containing following meanings:
a)-(CH
2)nOm-，n＝0～4，m＝0,1；
B)-CH
2cH (CH
3) (CH
2) nO-, wherein n=2;
c)-CH
2CH＝CHCH
2O-,-CH
2C≡CCH
2O-；
D)-(CH
2) nCOO-, wherein n=3;
3. the compound described in any one of claim 2, wherein, in logical formula II, (III) and (IV), Z is O or S; R
1-(CH
2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
4. the compound described in any one of claims 1 to 3, described compound is used for antitumor drug.
5. the preparation method of the logical formula I compound of any one of claims 1 to 3, is characterized in that:
The compound of logical formula I, wherein X=O, by formula (V) and formula VI compound are reacted obtained:
Wherein A is chlorine, bromine, iodine; B is nitrooxy or identical with A group; The definition of Y structure and the Compound Phase of logical formula I are together;
When B is nitrooxy, formula (V) compound and formula IV compound at inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), stupid, toluene, many halogenated aliphatic, in the scope of 10 DEG C ~ 50 DEG C, react the compound that 0.5 ~ 3h can obtain formula I, molar ratio is 1:1 ~ 5;
When B and A group is identical, when being namely chlorine, bromine, iodine, first formula (V) compound and formula VI compound at inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), stupid, toluene, many halogenated aliphatic, in the scope of 10 DEG C ~ 80 DEG C, react 0.5 ~ 3h can obtain intermediate, molar ratio is 1:1 ~ 5, then the intermediate of gained again with Silver Nitrate at acetonitrile, tetrahydrofuran (THF), methylethylketone or N, in N`-dimethyl formamide, lucifuge reaction 1 ~ 3h obtains target compound, and route is as follows:
6. the synthetic method of any one of claims 1 to 3 formula of (II) compound, is characterized in that:
The compound of logical formula II, wherein during Z=O, by by formula (V) compound dissolution in inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), stupid, toluene, many halogenated aliphatic, formula (VII) compound is added under ice-water bath, under the catalysis of EDCI and DMAP, in the scope of 10 DEG C ~ 50 DEG C, react 0.5 ~ 24h obtain:
Wherein D is chlorine, bromine, iodine, hydroxyl; R
1together, the preparation of formula (VII) compound, first needs the obtained furoxan-based NO donors containing hydroxyl for the definition of structure and the Compound Phase of logical formula II:
Take styryl carbinol as starting raw material, react to obtain 3-methylol-4-phenyl-1,2,5-oxadiazole-2-oxide compound with Sodium Nitrite, this oxide compound can directly and compound (V) to react the compound generating and meet logical formula II; Or react with sulfur oxychloride again after 3-chloromethyl-4-phenyl-1,2,5-oxadiazole-2-oxide compound, be obtained by reacting the furoxan-based NO donors containing hydroxyl with dihydroxy compound, synthetic route is as follows:
Wherein R
1-(CH
2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
7. the synthetic method of any one of claims 1 to 3 formula of (III) compound, is characterized in that:
The compound of logical formula III, wherein during Z=O, by by formula (V) compound dissolution in inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), stupid, toluene, many halogenated aliphatic, formula (VIII) compound is added under ice-water bath, under the catalysis of EDCI and DMAP, in the scope of 10 DEG C ~ 50 DEG C, react 0.5 ~ 24h obtain:
Wherein D is chlorine, bromine, iodine, hydroxyl; R
1the definition of structure and the Compound Phase of logical formula III are together; The preparation of formula III compound, first needs the obtained furoxan-based NO donors containing hydroxyl:
Thiophenyl acetic acid is in glacial acetic acid; 30% aqueous hydrogen peroxide solution is dripped under condition of ice bath; to reacting completely; react with nitrosonitric acid under ice bath 3; 4-disulfonyl base-1,2,5-oxadiazole-2-oxide compound; this oxide compound and dihydroxy compound are obtained by reacting the furoxan-based NO donors containing hydroxyl, and synthetic route is as follows:
Wherein R
1-(CH
2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
8. the synthetic method of any one of claims 1 to 3 formula of (IV) compound, is characterized in that:
The compound of logical formula IV, wherein during Z=O, by by formula (V) compound dissolution in inert organic solvents as N, in the hydrocarbon polymer of N`-dimethyl formamide, tetrahydrofuran (THF), stupid, toluene, many halogenated aliphatic, formula (Ⅸ) compound is added under ice-water bath, under the catalysis of EDCI and DMAP, in the scope of 10 DEG C ~ 50 DEG C, react 0.5 ~ 24h obtain:
Wherein D is chlorine, bromine, iodine, hydroxyl; R
1the Compound Phase of organization definition and logical formula IV is same; The preparation of formula IV compound, first needs the obtained furoxan-based NO donors containing hydroxyl:
With 2-nitro-4-phenylaniline for raw material, react with under sodium ethylate, clorox ice bath, gained solid reacts with N-bromo-succinimide under benzoyl peroxide causes, obtain 5-brooethyl-benzo (1,2,5-oxadiazole)-1-] after oxygen, be obtained by reacting the benzofuraxan oxynitride containing hydroxyl with dihydroxy compound, synthetic route is as follows:
Wherein R
1-(CH
2) nOm-, m=0 time, n=0; During m=1, n=1 ~ 4.
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|---|---|---|---|---|
| CN110305036A (en) * | 2019-01-15 | 2019-10-08 | 江南大学 | A kind of nitrogen mustards anti-tumor predrug and preparation method thereof of hydrogen peroxide response |
| CN112300004A (en) * | 2020-11-16 | 2021-02-02 | 成都大学 | Retinoid derivative based on NO donor, and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812059A (en) * | 2010-04-14 | 2010-08-25 | 中国药科大学 | Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof |
| CN103508896A (en) * | 2013-08-26 | 2014-01-15 | 中国医药集团总公司四川抗菌素工业研究所 | Nitric monoxide donor derivatives of Bexarotene, and preparation method thereof |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812059A (en) * | 2010-04-14 | 2010-08-25 | 中国药科大学 | Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof |
| CN103508896A (en) * | 2013-08-26 | 2014-01-15 | 中国医药集团总公司四川抗菌素工业研究所 | Nitric monoxide donor derivatives of Bexarotene, and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 任健等: "盐酸苯达莫司汀(bendamustine hydrochloride)", 《中国药物化学杂志》, vol. 18, no. 5, 31 October 2008 (2008-10-31), pages 399 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305036A (en) * | 2019-01-15 | 2019-10-08 | 江南大学 | A kind of nitrogen mustards anti-tumor predrug and preparation method thereof of hydrogen peroxide response |
| CN112300004A (en) * | 2020-11-16 | 2021-02-02 | 成都大学 | Retinoid derivative based on NO donor, and preparation method and application thereof |
| CN112300004B (en) * | 2020-11-16 | 2022-06-07 | 成都大学 | Retinoid derivative based on NO donor, and preparation method and application thereof |
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