CN101906069B - (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid as well as preparation method and application thereof - Google Patents
(S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid as well as a preparation method and application thereof. The preparation method thereof comprises the following steps of preparing N-acetoacetyl-L-amino acid methyl ester by condensing L-amino acid methyl ester and dicthenone; preparing N-[2-(5,5-dimethyl-1,3 dioxane-diyl-)vinyl]-N-acetoacetyl-L-amino acid methyl ester through reaction between N-acetoacetyl-L-amino acid methyl ester and 2-glyoxyl-5,5-dimethyl-1,3-dioxane; preparing (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) methyl acetate by the N-(2-(5,5-dimethyl-1,3 dioxane-diyl-)vinyl)-N-acetoacetyl-L-amino acid methyl ester; obtaining the (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) acetic acid by saponifying the (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl) methyl acetate. A high-iron animal model is adopted to evaluate the detoxification activity when iron poisoning occurs in a compound body. An experimental result shows that the compound has excellent iron expulsion action and can be clinically used as antidote in the process of iron poisoning.
Description
Technical field
The present invention relates to N-substituted pyridines ketone compounds, relate in particular to (S)-2-replace-(acetate and preparation method thereof of 3 '-ethanoyl-2 '-pyridone-1 '-yl) the invention still further relates to their application as the agent of heavy metal drive row, belongs to biomedicine field.
Background technology
Excessive iron or accumulate in the iron and can cause the human organ dysfunction in the middle of tissue, and cause serious illness such as hemochromatosis, β-thalassemia, nerve degenerative diseases, myelodysplastic syndrome, alcoholic liver disease and relevant kidney disease.In addition, body accumulation iron cause the tissue/organ damage of free radical mediated and finally cause death.At present, the iron chelation therapy is unique treat-ment, and N-substituted pyridines ketone compounds has many-sided physiologically active, like sterilization, analgesia, antitumor and treatment Parkinson's disease etc.Because this type pyridinone compounds has very strong coordination ability; Particularly 1; 2-dimethyl--3-hydroxyl-4 (1H)-pyridone and 1,2-diethylammonium-3-hydroxyl-4 (1H)-pyridine compounds can with metallic ion coordination such as iron, the treatment thalassemia has better curative effect.The contriver recognizes, (S)-2-replaces-and (3 '-ethanoyl-2 '-pyridone-1 '-yl) acetate uses as the agent of iron drive row, possibly promote the drainage of iron.According to this conception, the contriver proposes the present invention.
Summary of the invention
One of the object of the invention provides one type of (S)-2-and replaces-(the acetic acid compound of 3 '-ethanoyl-2 '-pyridone-1 '-yl);
Two of the object of the invention provides above-mentioned (the S)-2-of a kind of preparation and replaces-(the method for acetic acid compound of 3 '-ethanoyl-2 '-pyridone-1 '-yl);
Above-mentioned purpose of the present invention realizes through following technical scheme:
One type of (S)-2-replaces-(acetic acid compound of 3 '-ethanoyl-2 '-pyridone-1 '-yl), its structural formula is shown in formula I, formula II or the formula III:
Formula I formula II formula III
Wherein, R is selected from hydrogen, CH
3, CH (CH
3)
2, CHCH (CH
3)
2, CH (CH
3) C
2H
5, CH
2C
6H
5, CH
2C
6H
4-OH-p, CH
2OH, CH (CH
3) OH, CH
2CO
2CH
3, CH
2CH
2CO
2CH
3, 3-indoles acetyl, CH
2CH
2SCH
3, CH
2CH
2CH
2NHC-(NH) NH (NO
2), CH
2CONH
2Or CH
2CH
2CONH
2
A kind of method for preparing above-mentioned formula I compound may further comprise the steps:
(1) changes L-amino acid into the L-amino acid methyl ester; Wherein, described L-amino acid comprises: L-glycocoll, L-L-Ala, L-Xie Ansuan; The L-leucine, L-Isoleucine, L-phenylalanine(Phe), L-tyrosine; The L-Serine, L-Threonine, L-aspartic acid, L-L-glutamic acid; The L-tryptophane, L-methionine(Met), L-l-arginine, altheine or L-glutamine;
(2) with 1,1,3,3-tetramethyl-propane and 2 carry out the acetal shift reaction, generate 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane;
(3) with 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1, the hydrolysis of 3-dioxane generates 2-aldehyde-base-5,5-dimethyl--1,3-dioxane;
(4) L-amino acid methyl ester and dicthenone condensation prepared N-acetoacetyl-L-amino acid methyl ester that step (1) is prepared;
(5) with N-acetoacetyl-L-amino acid methyl ester and 2-aldehyde-base-5,5-dimethyl--1, the reaction of 3-dioxane, generation N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-amino acid methyl ester;
(6) at H
2SO
4Have down with dioxane that (1,3-two carbonyl butyls-L-amino acid methyl ester generates (S)-2-and replace-(the methyl acetate of 3 '-ethanoyl-2 '-pyridone-1 '-yl) with N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-;
(7) (S)-2-is replaced-(3 '-ethanoyl-2 '-pyridone-1 '-yl) methyl acetate saponification obtains the described compound of formula I.
A kind of method for preparing above-mentioned formula II compound may further comprise the steps:
(1) changes the L-halfcystine into the L-acthiol-J;
(2) with 1,1,3,3-tetramethyl-propane and 2 carry out the acetal shift reaction, generate 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane;
(3) with 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1, the hydrolysis of 3-dioxane generates 2-aldehyde-base-5,5-dimethyl--1,3-dioxane;
(4) with L-acthiol-J and dicthenone condensation prepared N-acetoacetyl-L-Gelucystine methyl esters;
(5) with N-acetoacetyl-L-Gelucystine methyl esters and 2-aldehyde-base-5,5-dimethyl--1, the reaction of 3-dioxane generates N ', N-two-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-cystine dimethyl;
(6) with N ', N-two-[2-(5,5-dimethyl--1; 3 dioxane-2 base-) vinyl]-intramolecular aldol reaction takes place, generates (2S, 2S ')-3 in N-acetoacetyl-L-cystine dimethyl; 3 '-two sulphur-2, and 2-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-propionic acid dimethyl ester;
(7) with (2S, 2S ')-3,3 '-two sulphur-2, and 2-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-saponification of 3-propionic acid dimethyl ester, obtain formula II compound.
A kind of method for preparing above-mentioned formula III compound may further comprise the steps:
(1) changes L-Methionin into the L-lysine methyl ester;
(2) with 1,1,3,3-tetramethyl-propane and 2 carry out the acetal shift reaction, generate 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane;
(3) with 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1, the hydrolysis of 3-dioxane generates 2-aldehyde-base-5,5-dimethyl--1,3-dioxane;
(4) with L-lysine methyl ester and dicthenone condensation prepared N, N ε-acetoacetyl-L-lysine methyl ester;
(5) with N, N ε-acetoacetyl-L-lysine methyl ester and 2-aldehyde-base-5,5-dimethyl--1, the reaction of 3-dioxane, generation N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-lysine methyl ester;
(6) intramolecular aldol reaction is taken place in N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-lysine methyl ester, generate (2S)-2, and 6-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-methyl caproate;
(7) with (2S)-2, and 6-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-the methyl caproate saponification, obtain the formula III compound.
Detoxicating activity during the iron poisoning in the The compounds of this invention body that adopted the high ferro animal model evaluation.Experimental result shows that compound of the present invention has excellent iron expulsion action, and the toxinicide when can be used as iron poisoning is clinically used.
Another purpose of the present invention provides a kind of pharmaceutical composition of drive row heavy metal, and this pharmaceutical composition is gone up effective dose by treatment The compounds of this invention is with pharmaceutically acceptable excipient or assist and add agent and form; That is: with the The compounds of this invention of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
Description of drawings
The synthetic route chart of Fig. 1 formula I compound of the present invention.
The synthetic route chart of Fig. 2 formula II compound of the present invention.
The synthetic route chart of Fig. 3 formula III compound of the present invention.
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment 12-(2,2-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane
With 4.92g (30mmol) 1,1,3,3-tetramethoxy propane; 0.78g (7.5mmol) 2 adds in the 25ml methylene dichloride, splashes into 0.1ml (6N) hydrochloric acid; Stirring at room 24 hours is added 0.78g (7.5mmol) 2; Continued stirring at room 24 hours, and added the 4.0g soda ash light, stirred 2 hours, filter; Concentrate to remove and desolvate, resistates is through silica gel column chromatography (sherwood oil: ETHYLE ACETATE=15: 1), obtain colourless liquid 2.059g, yield 67%.
Embodiment 22-aldehyde-base-5,5-dimethyl--1,3-dioxane (1)
With 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane 2.04g (10.0mmol) add in the 50ml second eyeball; Add 98mg (0.43mmol) DDQ and 5ml water again, in 50 ℃ of stirred in water bath 2 hours, TLC showed that raw material disappears basically; Take out cold to room temperature, add 200ml water, with dichloromethane extraction (50ml * 6); Extraction liquid filters through anhydrous sodium sulfate drying, revolves to steam to remove to desolvate; Resistates is through silica gel column chromatography (sherwood oil (30-60 ℃): ether=4: 1), obtain colourless liquid 1.27g, yield 80%.ESI-MS(m/e)：159.3[M+H]
+，181.4[M+Na]
+
Method is led in the preparation of 318 kinds of L-amino acid methyl esters of embodiment hydrochloride 2a-r
The 50ml anhydrous methanol is dripping thionyl chloride 3.75ml (50mmol) under ice bath, after dropwising in the 30min, adds L-amino acid 42mmol, stirring at room 24h, TLC (CHCl in batches
3: MeOH=2: 3) monitor to raw material disappearance termination reaction.Water pump is taken the intact sulfur oxychloride SOCl of unreacted away
2And HCl, with ether grind repeatedly white solid, methyl alcohol-ether recrystallization, L-amino acid methyl ester hydrochloride be white solid (proline methyl ester hydrochloride is colourless sticking oil).Logical according to this method has been synthesized HClPhe-OMe, HClAla-OMe, HClGly-OMe, HClArg-OMe, HClAsp-(OMe)
2, HClLeu-OMe, HClMet-OMe, HClSer-OMe, HClTyr-OMe, HClThr-OMe, HClIle-OMe, HClTrp-OMe, HClVal-OMe, HClPro-OMe, HClHis-OMe, HClGlu-(OMe)
2, HClArg (NO
2)-OMe, HClAsn-OMe, HClGln-OMe, yield be at 85-99%, physical constants such as fusing point, optically-active and the data consistent of having reported.
Method is led in the preparation of embodiment 4N-acetoacetyl-L-amino acid methyl ester 3a-r
L-amino acid methyl ester hydrochloride 30mmol is added in the 50ml methyl alcohol, add triethylamine 5ml (35.6mmol), after the stirring and dissolving, be transferred in the ice bath; Under 0-5 ℃ of condition, splash into ketene dimer 2.646g (31.5mmol), added in about 10 minutes, solution becomes orange-yellow; Continue to stir 15 minutes, moved to room temperature reaction again 1 hour, rotation is steamed and is removed methyl alcohol; After cold slightly, colourless needle crystal can occur in the bottle, add amount of ethyl acetate; Filter, filter cake repeatedly washs with amount of ethyl acetate, to filter cake and 2%FeCl
3Color reaction does not take place in ethanolic soln, will filtrate to concentrate, and small amount of crystalline can occur again; Come again the operation of front, the rotation evaporate to dryness is with chloroform or acetone solution resistates; Add 1.2～1.5 times of silica gel dry method and mix appearance,, adopt petroleum ether-ethyl acetate system gradient elution with the decompression column chromatography for separation to thick product; At sherwood oil: during ETHYLE ACETATE=3: 1 wash-outs, obtain product L-amino acid methyl ester acetoacetyl product.
The preparation of embodiment 5N-acetoacetyl-L-glycine methyl ester (3a)
According to the logical method of preparation, obtaining 3a is light yellow oil, yield 89.7%.ESI-MS(m/e)：346[2M+H]
+，369[2M+Na]
+。
The preparation of embodiment 6N-acetoacetyl-L-alanine methyl ester (3b)
According to the logical method of preparation, obtaining 3b is light yellow oil, yield 90.74%; ESI-MS (m/e): 188.0 [M+H]
+
The preparation of embodiment 7N-acetoacetyl-L-valine methyl ester (3c)
According to the logical method of preparation, obtaining 3c is light yellow oil, yield 88.7%; ESI-MS (m/e): 216 [M+H]+, 238 [M+Na]
+
The preparation of embodiment 8N-acetoacetyl-L-leucine methyl esters (3d)
According to the logical method of preparation, obtaining 3d is light yellow oil, yield 90.8%; ESI-MS (m/e): 230 [M+H]
+
The preparation of embodiment 9N-acetoacetyl-L-Isoleucine methyl esters (3e)
According to the logical method of preparation, obtaining 3e is light yellow oil, yield 79-9%; ESI-MS (m/e): 230 [M+H]
+
The preparation of embodiment 10N-acetoacetyl-L-phenylalanine methyl ester (3f)
According to the logical method of preparation, obtaining 3f is light yellow oil, yield 90.7%; ESI-MS (m/e): 287 [M+Na]
+
The preparation of embodiment 11N-acetoacetyl-L-L-Tyrosine methyl ester (3g)
According to the logical method of preparation, obtaining 3g is light yellow oil, yield 84.3%; ESI-MS (m/e): 302 [M+Na]
+
The preparation of embodiment 12N-acetoacetyl-L-serine methylester (3h)
According to the logical method of preparation, obtaining 3h is clear crystal, yield 81.2%; ESI-MS (m/e): 204 [M+H]
+
The preparation of embodiment 13N-acetoacetyl-L-Threonine methyl esters (3i)
According to the logical method of preparation, obtaining 3i is light yellow oil, puts for a long time and separates out crystal, yield 82.7%; ESI-MS (m/e): 216 [M-H]
+
The preparation of embodiment 14N-acetoacetyl-L-aspartic acid dimethyl ester (3j)
According to the logical method of preparation, obtaining 3j is light yellow oil, yield 65.22%; ESI-MS (m/e): 246 [M+H]
+
Embodiment 15N-acetoacetyl-L-glutamic acid dimethyl ester (3 preparation
According to the logical method of preparation, obtaining 3k is light yellow oil, yield 82.74%; ESI-MS (m/e): 541 [2M+Na]
+
The preparation of embodiment 16N-acetoacetyl-L-tryptophan methyl ester (3l)
According to the logical method of preparation, obtaining 3l is light yellow oil, yield 92.35%; ESI-MS (m/e): 303 [M+H]
+
The preparation of embodiment 17N-acetoacetyl-L-methionine(Met) methyl esters (3m)
According to the logical method of preparation, obtaining 3m is light yellow oil, yield 80.8%; ESI-MS (m/e): 287 [M+K]
+
The preparation of embodiment 18N-acetoacetyl-L-arginine methyl esters (3n)
According to the logical method of preparation, obtaining 3n is reddish brown oily compound, yield 56%; ESI-MS (m/e): 274 [M+H]
+
The preparation of embodiment 19N-acetoacetyl-altheine methyl esters (3o)
According to the logical method of preparation, obtaining 3o is light yellow oil, yield 65%, ESI-MS (m/e): 231 [M+H]
+
The preparation of embodiment 20N-acetoacetyl-L-glutamine methyl esters (3p)
According to the logical method of preparation, obtaining 3o is light yellow oil, yield 83%, ESI-MS (m/e): 245 [M+H]
+
The preparation of embodiment 21N '-N-diacetyl ethanoyl-L-cystine dimethyl (3q)
According to the logical method of preparation, obtaining 3q is light yellow oil, yield 80.2%; ESI-MS (m/e): 437 [M+H]
+
Embodiment 22N, the preparation of N ε-acetoacetyl-L-lysine methyl ester (3r)
According to the logical method of preparation, the feed ratio of lysine methyl ester and ketene dimer is 1: 2.1, and obtaining 3r is light yellow oil, yield 90.29%; ESI-MS (m/e): 329 [M+H]
+
Embodiment 23N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-(1, the preparation of 3-two carbonyl butyls-L-amino acid methyl ester 4a-r
In the 100ml round-bottomed flask, add N-acetoacetyl-L-glycine methyl ester 4.469mmol, 2-aldehyde-base-5,5-dimethyl--1; 3-dioxane 938mg (5.936mmol) newly steams toluene 30ml, and anhydrous magnesium sulfate 8.0g connects reflux condensing tube; Drying tube, stirring reaction is 72 hours in 100 ℃ of oil baths, stops heating, takes out cooled and filtered; Use amount of ethyl acetate drip washing, concentrate, steaming desolventizes, with 1.2～1.5 times of silica gel mixed samples of resistates; The decompression column chromatography, gradient elution (ETHYLE ACETATE-sherwood oil system) obtains light yellow oil.
The preparation of embodiment 24N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-glycine methyl ester (4a)
According to the logical method of preparation, obtaining 4a is light yellow oil, yield 36.9%.FAB-MS(m/e)：314[M+H]
+。
The preparation of embodiment 25N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-alanine methyl ester (4b)
According to the logical method of preparation, obtaining 4b is light yellow oil, yield 37.6%; FAB-MS (m/e): 328 [M]
+.
The preparation of embodiment 26N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-valine methyl ester (4c)
According to the logical method of preparation, obtaining 4c is light yellow oil, yield 40.2%; ESI-MS (m/e): 357 [M+H]
+
The preparation of embodiment 27N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-leucine methyl esters (4d)
According to the logical method of preparation, obtaining 4d is light yellow oil, yield 24.3%; ESI-MS (m/e): 371 [M+H]
+
The preparation of embodiment 28N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-Isoleucine methyl esters (4e)
According to the logical method of preparation, obtaining 4e is light yellow oil, yield 37.4%; ESI-MS (m/e): 371 [M+H]
+
The preparation of embodiment 29N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-phenylalanine methyl ester (4f)
According to the logical method of preparation, obtaining 4f is light yellow oil, yield 33.8%; FAB-MS (m/e): 401 [M]
+
The preparation of embodiment 30N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-L-Tyrosine methyl ester (4g)
According to the logical method of preparation, obtaining 4g is light yellow oil, yield 33.1%; FAB-MS (m/e): 420 [M]
+.
The preparation of embodiment 31N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-serine methylester (4h)
According to the logical method of preparation, obtaining 4h is light yellow oil, yield 19.4%; ESI-MS (m/e): 366 [M+Na]
+
The preparation of embodiment 32N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-Threonine methyl esters (4i)
According to the logical method of preparation, obtaining 4i is light yellow oil, yield 42..8%; ESI-MS (m/e): 380 [M+Na]
+.
The preparation of embodiment 33N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-aspartic acid dimethyl ester (4j)
According to the logical method of preparation, obtaining 4j is light yellow oil, yield 29.4%; FAB-MS (m/e): 385 [M]
+.
The preparation of embodiment 34N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-glutamic acid dimethyl ester (4k)
According to the logical method of preparation, obtaining 4k is light yellow oil, yield 40.7%; FAB-MS (m/e): 423 [M+H+Na]
+.
The preparation of embodiment 35N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-tryptophan methyl ester (4l)
According to the logical method of preparation, obtaining 4l is light yellow oil, yield 36.4%; FAB-MS (m/e): 443 [M+H]
+.
The preparation of embodiment 36N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-methionine(Met) methyl esters (4m)
According to the logical method of preparation, obtaining 4m is light yellow oil, yield 52.8%; FAB-MS (m/e): 388 [M+H]
+.
Embodiment 37N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-N
G-(NO
2The preparation of)-L-l-arginine Bian ester (4n)
According to the logical method of preparation, obtaining 4n is light yellow oil, yield 16.8%; ESI-MS (m/e): 534 [M+H]
+.
The preparation of embodiment 38N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-altheine methyl esters (4o)
According to the logical method of preparation, obtaining 4o is light yellow oil, yield 33%, ESI-MS (m/e): 371 [M+H]
+.
The preparation of embodiment 39N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-glutamine methyl esters (4p)
According to the logical method of preparation, obtaining 4p is light yellow oil, yield 43%, ESI-MS (m/e): 385 [M+H]
+.
Embodiment 40N ', the preparation of N-two-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-cystine dimethyl (4q)
According to the logical method of preparation, obtaining 4q is light yellow oil, yield 16.4%; ESI-MS (m/e): 718 [M+H]
+
The preparation of embodiment 41N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-lysine methyl ester (4r)
According to the logical method of preparation, obtaining 4r is light yellow oil, yield 16%, ESI-MS (m/e): 623 [M+H]
+.
Embodiment 42 preparation (S)-2-replace-(the logical method of methyl acetate (5a-r) of 3 '-ethanoyl-2 '-pyridone-1 '-yl)
2.58mmolN-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-amino acid methyl ester added be equipped with in the round-bottomed flask of 8ml 1,4 dioxane, add 0.4M H
2SO
44ml, with argon shield good after, in 60 ℃ of reactions 16 hours, TLC showed that raw material disappears, and takes out cooling, used 5%NaHCO adding under the ice bath
3Be neutralized to neutrality, add 30ml water, ethyl acetate extraction (15ml x 3) after the extraction liquid drying, concentrates, and silica gel column chromatography gets light yellow oil.
Embodiment 43 (3 '-ethanoyl-2 '-pyridone-1 '-yl) the preparation of methyl acetate (5a)
According to the logical method of preparation, obtaining 5a is clear crystal, yield 47.3%; ESI-MS (m/e): 210 [M+H]
+
Embodiment 44 (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl) preparation of methyl propionate (5b)
According to the logical method of preparation, obtaining 5b is light yellow oil, yield 50.4%; FAB-MS (m/e): 224 [M]
+.
Embodiment 45 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-methyl-methyl-butyrate (5c)
According to the logical method of preparation, obtaining 5c is light yellow oil, yield 64.8%; ESI-MS (m/e): 252 [M+H]
+.
Embodiment 46 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-methyl-methyl valerate (5d)
According to the logical method of preparation, obtaining 5d is light yellow oil, yield 64%, ESI-MS (m/e): 266 [M+H]
+.
Embodiment 47 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-methyl-methyl valerate (5e)
According to the logical method of preparation, obtaining 5e is light yellow oil, yield 55.9%, ESI-MS (m/e): 266 [M+H]
+
Embodiment 48 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-phenyl-methyl propionate (5f)
According to the logical method of preparation, obtaining 5f is clear crystal, yield 57.3%, FAB-MS (m/e): 300 [M]
+.
Embodiment 49 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-(4 "-hydroxyl-phenyl)-methyl propionate (5g)
According to the logical method of preparation, obtaining 5g is light yellow oil, yield 65.9%, ESI-MS (m/e): 316 [M+H]
+.
Embodiment 50 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-hydroxyl-methyl propionate (5h)
According to the logical method of preparation, obtaining 5h is light yellow oil, yield 36%, ESI-MS (m/e): 240 [M+H]
+.
Embodiment 51 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-hydroxyl-methyl-butyrate (5i)
According to the logical method of preparation, obtaining 5i is light yellow oil, yield 57%, ESI-MS (m/e): 254 [M+H]
+.
Embodiment 52 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-methoxycarbonyl-methyl propionate (5j)
According to the logical method of preparation, obtaining 5j is light yellow oil, yield 35%, ESI-MS (m/e): 282 [M+H]
+.
Embodiment 53 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-methoxycarbonyl-methyl-butyrate (5k)
According to the logical method of preparation, obtaining 5k is light yellow oil, yield 35%, ESI-MS (m/e): 296 [M+H]
+.
Embodiment 54 (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-(preparation of indoles-3 '-yl)-methyl propionate (5l)
According to the logical method of preparation, obtaining 5l is light yellow oil, yield 49%, ESI-MS (m/e): 339 [M+H]
+.
Embodiment 55 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-methyl mercapto-methyl-butyrate (5m)
According to the logical method of preparation, obtaining 5m is light yellow oil, yield 47.9%, FAB-MS (m/e): 284 [M]
+.
Embodiment 56 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-5-nitro guanidine radicals-methyl valerate (5n)
According to the logical method of preparation, obtaining 5n is light yellow oil, yield 36.9%, ESI-MS (m/e): 430 [M+H]
+
Embodiment 57 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-aminocarboxyl methyl propionate (5o)
According to the logical method of preparation, obtaining 5o is light yellow oil, yield 33%, ESI-MS (m/e): 267 [M+H]
+.
Embodiment 58 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-aminocarboxyl methyl-butyrate (5p)
According to the logical method of preparation, obtaining 5p is light yellow oil, yield 33%, ESI-MS (m/e): 281 [M+H]
+.
Embodiment 59 (2S, 2S ')-3,3 '-two sulphur-2, the 2-two (preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-propionic acid dimethyl ester (5q)
According to the logical method of preparation, obtaining 5q is light yellow oil, yield 34%, ESI-MS (m/e): 509 [M+H]
+.
Embodiment 60 preparation (2S)-2, the 6-two (preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-methyl caproate (5r)
According to the logical method of preparation, obtaining 5r is light yellow oil, yield 26%, ESI-MS (m/e): 401 [M+H]
+.
Embodiment 61 preparation (S)-2-replace-(the logical method of acetate 6a-r of 3 '-ethanoyl-2 '-pyridone-1 '-yl)
1mmol (S)-2-is replaced-(3 '-ethanoyl-2 '-pyridone-1 '-yl) methyl acetate is dissolved in the 5ml methyl alcohol, and under the condition of ice bath, adding 2NNaOH to pH value is 13.Reacted 3 hours, TLC shows the raw material completely dissolve, and 2NHCl adjust pH to 7 is removed the methyl alcohol in the reaction solution with Rotary Evaporators.Use 2N HCl adjust pH to 3 again, ethyl acetate extraction (15ml x 3) merges the ester layer, washes ester layer (15ml) with saturated NaCl solution collection, and the ester layer is used anhydrous sodium sulfate drying, concentrates, and silica gel column chromatography gets the title compound colorless solid.
Embodiment 62 (the S)-2-replacement-(3 '-ethanoyl-2 '-pyridone-1 '-yl) preparation of acetate (6a)
According to the logical method of preparation, obtaining 6a is colorless solid, yield 62%, ESI-MS (m/e): 196 [M]
+
Embodiment 63 (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl) preparation of propionic acid (6b)
According to the logical method of preparation, obtaining 6b is colorless solid, yield 45%, ESI-MS (m/e): 211 [M]
+.
Embodiment 64 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-methyl-butyric acid (6c)
According to the logical method of preparation, obtaining 6c is faint yellow solid, yield 70%, ESI-MS (m/e): 238 [M+H]
+.
Embodiment 65 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-methyl-valeric acid (6d)
According to the logical method of preparation, obtaining 6d is faint yellow solid, yield 76%, ESI-MS (m/e): 252 [M+H]
+.
Embodiment 66 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-methyl-valeric acid (6e)
According to the logical method of preparation, obtaining 6e is faint yellow solid, yield 71%, ESI-MS (m/e): 252 [M+H]
+.
Embodiment 67 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-phenyl-propionic acid (6f)
According to the logical method of preparation, obtaining 6f is colorless solid, yield 68.5%, ESI-MS (m/e): 286.3 [M+H]
+
Embodiment 68 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-(4 "-hydroxyl-phenyl)-propionic acid (6g)
According to the logical method of preparation, obtaining 6g is faint yellow solid, yield 75%, ESI-MS (m/e): 302 [M+H]
+
Embodiment 69 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-hydroxyl-propionic acid (6h)
According to the logical method of preparation, obtaining 6h is faint yellow solid, yield 51%, ESI-MS (m/e): 226 [M+H]
+.
Embodiment 70 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-hydroxyl-butyric acid (6i)
According to the logical method of preparation, obtaining 6i is faint yellow solid, yield 65.2%, ESI-MS (m/e): 240 [M+H]
+
Embodiment 71 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-methoxycarbonyl-propionic acid (6j)
According to the logical method of preparation, obtaining 6j is faint yellow solid, yield 55%, ESI-MS (m/e): 254 [M+H]
+.
Embodiment 72 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-methoxycarbonyl-butyric acid (6k)
According to the logical method of preparation, obtaining 6k is yellow oil, yield 52%, ESI-MS (m/e): 268 [M+H]
+.
Embodiment 73 (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-(preparation of indoles-3 '-yl)-propionic acid (6l)
According to the logical method of preparation, obtaining 6l is yellow oil, yield 74%, ESI-MS (m/e): 325 [M+H]
+.
Embodiment 74 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-methyl mercapto-butyric acid (6m)
According to the logical method of preparation, obtaining 6m is faint yellow solid, yield 60%, ESI-MS (m/e): 270 [M+H]
+
The preparation of embodiment 75 (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl)-5-nitro guanidine radicals-methyl valerate (6n ')
According to the logical method of preparation, obtain 6n ' and be yellow oil, yield 52%, ESI-MS (m/e): 340 [M+H]
+..
Embodiment 76 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-5-nitro guanidine radicals-valeric acid (6n)
In 25ml eggplant bottle, add (294mg, 1.0mmol) (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl)-5-nitro guanidine radicals-methyl valerate, ethanol (8ml), water (2ml), Pd/C (1.0g, 5%) and formic acid (30 μ l), feeding H
2Gas reacted 4 hours, TLC shows does not have (2S)-2-(3 '-ethanoyl-2 '-pyridone-1 '-yl)-5-nitro guanidine radicals-methyl valerate residue.Filter, the evaporate to dryness of will filtrating, residuum is worn away with ether repeatedly, until the 6n colourless powder 280mg that obtains, yield 95%, ESI-MS (m/e): 295 [M+H]
+.
Embodiment 77 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-aminocarboxyl-propionic acid (6o)
According to the logical method of preparation, obtaining 6o is yellow solid, yield 52%, ESI-MS (m/e): 253 [M+H]
+.
Embodiment 78 (2S)-2-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-4-aminocarboxyl-butyric acid (6p)
According to the logical method of preparation, obtaining 6p is faint yellow solid, yield 53%, ESI-MS (m/e): 267 [M+H]
+.
Embodiment 79 (2S, 2S ')-3,3 '-two sulphur-2, the 2 '-(preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-propionic acid (6q)
According to the logical method of preparation, obtaining 6q is faint yellow solid, yield 50%, ESI-MS (m/e): 481 [M+H]
+.
Embodiment 80 (2S)-2, the 6-two (preparation of 3 '-ethanoyl-2 '-pyridone-1 '-yl)-caproic acid (6r)
According to the logical method of preparation, obtaining 6r is yellow oil, yield 60%, ESI-MS (m/e): 387 [M+H]
+.
The active evaluation experimental of iron drive row of experimental example 1 The compounds of this invention
1) given the test agent: prepared compound 6a-r among the embodiment; PBS with containing 1%DMSO is mixed with desired concn.
2) laboratory animal: ICR male mice, body weight 18-22g.
3) animal model preparation and experimental technique: laboratory animal is divided into groups by 12 every group, and the physiological salt soln 0.2ml that experimental group adopts abdominal injection 2mgkg-1 of ferrodextranum every day injects twice every day, injects continuously five days.Treatment group abdominal injection every day (S)-2-replaces-(50% the DMSO solution of the acetate 6a-r of 3 '-ethanoyl-2 '-pyridone-1 '-yl); The DMSO (50% of positive controls abdominal injection every day 0.3mmolkg-1; 0.2ml) solution; Negative control group abdominal injection every day DMSO (50%, 0.2ml) solution.After administration every day two hours, collect urine in 5 hours, collect the fecal sample in 24 hours.Successive administration 5 days after the last administration 24, takes by weighing body weight, eyeball and gets blood, takes off cervical vertebra and put to death mouse, get liver, kidney, brain, spleen, heart, left side femur.All biological specimens use all that HNO3: HClO4 (3: 1) is nitrated on hot plate to be occurred to the adularescent solid; With redistilled water dissolving and be transferred to constant volume in the volumetric flask; Content with atomic absorption spectrophotometer iron; Adopt the Excel software data processing, the test of significance user difference analysis of each group difference and t check.Represent with
.
4) experimental result is seen table 1.
The active evaluation experimental result of the iron drive row of table 1 The compounds of this invention
A) data are with X ± SD μ g iron/g tissue, n=12; The H.M.=healthy mice, N.C.=blank, P.C.=positive control; B) with positive control ratio, p＜0.01; C) with positive control ratio, p＜0.01; D) with positive control ratio, p＜0.05; E) with positive control ratio, p＜0.05; F) with positive control ratio, p＜0.05; G) with positive control ratio, p＜0.05.
Experimental result shows that The compounds of this invention has excellent iron expulsion action, and the toxinicide when can be used as iron poisoning is clinically used.
Claims (6)
- (S)-2-replace-(acetic acid compound of 3 '-ethanoyl-2 '-pyridone-1 '-yl), its structural formula is shown in formula I, formula II or the formula III:
Formula I formula II formula IIIWherein, R is selected from hydrogen, CH 3, CH (CH 3) 2, CH 2CH (CH 3) 2, CH (CH 3) C 2H 5, CH 2C 6H 5, CH 2C 6H 4-OH-p, CH 2OH, CH (CH 3) OH, CH 2CO 2CH 3, CH 2CH 2CO 2CH 3, CH 2CH 2SCH 3, CH 2CONH 2Or CH 2CH 2CONH 2 - 2. method for preparing the said formula I of claim 1 compound may further comprise the steps:(1) changes L-amino acid into the L-amino acid methyl ester;(2) with 1,1,3,3-tetramethoxy propane and 2 carry out the acetal shift reaction, generate 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane;(3) with 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1, the hydrolysis of 3-dioxane generates 2-aldehyde-base-5,5-dimethyl--1,3-dioxane;(4) L-amino acid methyl ester and dicthenone condensation prepared N-acetoacetyl-L-amino acid methyl ester that step (1) is prepared;(5) with N-acetoacetyl-L-amino acid methyl ester and 2-aldehyde-base-5,5-dimethyl--1, the reaction of 3-dioxane, generation N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-acetoacetyl-L-amino acid methyl ester;(6) at H 2SO 4Have down with dioxane that (1,3-two carbonyl butyls-L-amino acid methyl ester generates (S)-2-and replace-(the methyl acetate of 3 '-ethanoyl-2 '-pyridone-1 '-yl) with N-[2-(5,5-dimethyl--1,3 dioxane-2 base-) vinyl]-N-;(7) (S)-2-is replaced-(3 '-ethanoyl-2 '-pyridone-1 '-yl) methyl acetate saponification promptly gets;Described L-amino acid is: L-glycocoll, L-L-Ala, L-Xie Ansuan, L-leucine, L-Isoleucine, L-phenylalanine(Phe), L-tyrosine, L-Serine, L-Threonine, L-aspartic acid, L-L-glutamic acid, L-methionine(Met), altheine or L-glutamine.
- 3. method for preparing the said formula II of claim 1 compound may further comprise the steps:(1) changes the L-halfcystine into the L-acthiol-J;(2) with 1,1,3,3-tetramethoxy propane and 2 carry out the acetal shift reaction, generate 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane;(3) with 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1, the hydrolysis of 3-dioxane generates 2-aldehyde-base-5,5-dimethyl--1,3-dioxane;(4) with L-acthiol-J and dicthenone condensation prepared N ', N-two (acetoacetyl)-L-cystine dimethyl;(5) with N ', N-two (acetoacetyl)-L-cystine dimethyl and 2-aldehyde-base-5,5-dimethyl--1; The reaction of 3-dioxane generates N ', and N-two-[2-(5; 5-dimethyl--1,3 dioxane-2 base-) vinyl]-N ', N-two (acetoacetyl)-L-cystine dimethyl;(6) with N ', N-two-[2-(5,5-dimethyl--1; 3 dioxane-2 base-) vinyl]-N '; Intramolecular aldol reaction takes place in N-two (acetoacetyl)-L-cystine dimethyl, generates (2S, 2S ')-3; 3 '-two sulphur-2, and 2-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-3-propionic acid dimethyl ester;(7) with (2S, 2S ')-3,3 '-two sulphur-2, and 2-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-saponification of 3-propionic acid dimethyl ester, promptly get.
- 4. method for preparing the said formula III of claim 1 compound may further comprise the steps:(1) changes L-Methionin into the L-lysine methyl ester;(2) with 1,1,3,3-tetramethoxy propane and 2 carry out the acetal shift reaction, generate 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1,3-dioxane;(3) with 2-(2 ', 2 '-dimethoxy-ethyl)-5,5-dimethyl--1, the hydrolysis of 3-dioxane generates 2-aldehyde-base-5,5-dimethyl--1,3-dioxane;(4) with L-lysine methyl ester and dicthenone condensation prepared N, N ε-two (acetoacetyl)-L-lysine methyl ester;(5) with N, N ε-two (acetoacetyl)-L-lysine methyl ester and 2-aldehyde-base-5,5-dimethyl--1; The reaction of 3-dioxane generates N, and [2-(5 for N ε-two; 5-dimethyl--1,3 dioxane-2 base-) vinyl]-N, N ε-two (acetoacetyl)-L-lysine methyl ester;(6) with N, and N ε-two [2-(5,5-dimethyl--1; 3 dioxane-2 base-) vinyl]-N; Intramolecular aldol reaction takes place in N ε-acetoacetyl-L-lysine methyl ester, generates (2S)-2, and 6-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-methyl caproate;(7) with (2S)-2, and 6-two (3 '-ethanoyl-2 '-pyridone-1 '-yl)-the methyl caproate saponification, promptly get.
- 5. the pharmaceutical composition of a drive row heavy metal, by described (the S)-2-of the claim 1 of significant quantity replace-(acetic acid compound of 3 '-ethanoyl-2 '-pyridone-1 '-yl) and pharmaceutically acceptable carrier are formed, and described heavy metal is an iron.
- Described (the S)-2-of claim 1 replace-(purposes of acetic acid compound in preparation drive row heavy metal medicine of 3 '-ethanoyl-2 '-pyridone-1 '-yl), described heavy metal is an iron.
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|---|---|---|---|---|
| CN1151399A (en) * | 1995-09-29 | 1997-06-11 | 西巴-盖尔基股份公司 | Novel hydroxylpyridinones |
| US20060211680A1 (en) * | 2003-09-17 | 2006-09-21 | Yoshitaka Tomigahara | Cinnamoyl compound and use of the same |
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| CN1151399A (en) * | 1995-09-29 | 1997-06-11 | 西巴-盖尔基股份公司 | Novel hydroxylpyridinones |
| US20060211680A1 (en) * | 2003-09-17 | 2006-09-21 | Yoshitaka Tomigahara | Cinnamoyl compound and use of the same |
Non-Patent Citations (2)
| Title |
|---|
| SHEILA GARRATT,et al.The Reaction of Diketene with Glycine.《Journal of Organic Chemistry》.1963,第28卷1372-1373. * |
| 吴世德等.去铁酮对铝染毒小鼠脑、肝、肾、骨组织中钙、锌、镁含量的影响.《食品与药品》.2006,第8卷(第07A期),33-35. * |
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