CN102757478B - Allyl cysteinyl amino acid derivative and synthesis method and application thereof - Google Patents
Allyl cysteinyl amino acid derivative and synthesis method and application thereof Download PDFInfo
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- -1 Allyl cysteinyl amino acid derivative Chemical class 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title abstract 3
- AMPHKYRLSOPVBX-YFKPBYRVSA-N allylcysteine Chemical compound OC(=O)[C@H](CS)NCC=C AMPHKYRLSOPVBX-YFKPBYRVSA-N 0.000 claims abstract description 17
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 17
- 230000001760 anti-analgesic effect Effects 0.000 claims abstract description 10
- 235000001014 amino acid Nutrition 0.000 claims abstract description 8
- 150000001413 amino acids Chemical class 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 107
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 61
- 238000000034 method Methods 0.000 claims description 56
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Abstract
The invention discloses an allyl cysteinyl amino acid derivative and a synthesis method and application thereof. The synthesis method comprises the following steps: taking the most important active component allyl cysteine in garlic as a parent nucleus; performing amino acid modification on the parent nucleus to obtain the allyl cysteinyl amino acid derivative shown as a formula I, wherein pharmacokinetic properties of the parent nucleus are improved through structural modification, so as to improve the biological activity of the parent nucleus. Pharmacological and pharmacodynamic experiments show that the allyl cysteinyl amino acid derivative has excellent anti-inflammatory or analgesic activity and can be prepared into anti-inflammatory or analgesic medicines.
Description
Technical field
The present invention relates to oligopeptides, relate in particular to allyl cysteine amino acid derivative and synthetic method thereof with anti-inflammatory and analgesic activities, the invention further relates to their application in preparing anti-inflammatory or analgesic, belong to allyl cysteine amino acid derivative field.
Background technology
Inflammation is the major incentive of many major diseases (such as cancer, cardiovascular disorder and presenile dementia etc.).Preventing inflammation is early stage step and the committed step of the described major disease of prevention, and finding outstanding anti-inflammatory drug is one of focus of new drug research.
The garlic food and medicament dual-purpose effect history of existing several thousand, have the pharmacologically actives such as the body's immunity of raising, anti-inflammatory, antibiotic, hypotensive, reducing blood-fat in recent years along with the deep discovery garlicin of garlic pharmacology activity research.Wherein the anti-inflammatory action of garlic causes international concern gradually.Garlic has obvious inhibition or killing action to diplococcus of various pathogens such as staphylococcus, meningitis, pneumonia etc., can treat the inflammatory diseasess such as lobar pneumonia, pulmonary tuberculosis, wound suppuration, trachoma.The principle of garlicin antimicrobial antiphlogistic is because the sulphur atom of sulfocompound in garlic combines and suppressed the Growth and reproduction of bacterium with sulphur atom in the necessary halfcystine molecule of bacterial growth breeding.2009, Yung-Hyun Cho found that garlic can reduce bacterial growth when the treatment chronic bacterial prostatitis, the amelioration of inflammation reaction, and, when together with Ciprofloxacin, using, can work in coordination with effectiveness with its generation, reach better antiphlogistic effects.
Summary of the invention
One of purpose of the present invention is to provide the allyl cysteine amino acid derivative that a class has anti-inflammatory and antalgic activity;
Two of purpose of the present invention is to provide a kind of method of synthetic above-mentioned allyl cysteine amino acid derivative;
Three of the object of the invention is that described allyl cysteine amino acid derivative is prepared into to anti-inflammatory or analgesic medicine.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
Allyl cysteine amino acid derivative with anti-inflammatory and antalgic activity, its structural formula are shown in formula I:
Wherein, R is selected from hydrogen, CH
3, CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH (CH
3)
2, CH
2C
6H
4-OH-p, CH (OH) CH
3, Indole-5-yl-CH
2, CH
2CH
2CO
2CH
3, CH
2OH, CH
2CH
2CH
2CH
2NHCOCH (NH
2) CH
2SCH
2CHCH
2, CH
2CO
2CH
3, Imidazole-4-yl-CH
2, CH
2CH
2SCH
3Or CH
2C
6H
5.
Two of the object of the invention is to provide a kind of method of synthetic above-mentioned allyl cysteine amino acid derivative, and the method comprises:
1) Cys and the reaction of 3-bromopropylene obtain allyl cysteine (SAC);
2) allyl cysteine (SAC) with (BOC)
2Reaction, obtain Boc-SAC;
3) amino acid and methyl alcohol reaction obtain HClAA-OMe;
4) Boc-SAC and HClAA-OMe condensation obtain Boc-SAC-AA-OMe;
5) Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA;
6) Boc-SAC-AA is removed to Boc, obtain.
Wherein, preferred, step 1), Cys react to three hours formation allyl cysteines (SAC) in ammoniacal liquor under 0 ℃ with the 3-bromopropylene;
Step 2) in preferred in containing the dioxane of alkalescent water SAC (allyl cysteine) with (BOC)
2Reaction, obtain Boc-SAC;
Step 3) preferred under the effect of sulfur oxychloride in, amino acid and methyl alcohol reaction obtain HClAA-OMe; Wherein, described amino acid is selected from Gly, Ala, Val, Ile, Leu, Tyr, Thr, Pro, Glu, Ser, Lys, Asp, Trp, Met or Phe;
Step 4) in, preferably under DCC and HOBt exist, Boc-SAC is condensed into Boc-SAC-AA-OMe with HClAA-OMe in anhydrous THF;
Step 5) preferred in containing the basic solution of NaOH in, Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA;
Step 6) in preferred in the ethyl acetate of containing hydrogen chloride Boc-SAC-AA remove Boc and generate SAC-AA.
The present invention utilizes most important activeconstituents allyl cysteine in garlic to be parent nucleus, to it, carry out amino acid modified, obtain the allyl cysteine amino acid derivative shown in formula I, by its structural modification is improved to its medicine for character, and then improve the biological activity of parent nucleus.Pharmacology pharmacodynamic is tested and is shown, allyl cysteine amino acid derivative of the present invention has excellent anti-inflammatory or analgesic activities, it can be prepared into to anti-inflammatory or analgesic.
The present invention also provides a kind of anti-inflammatory or analgesic pharmaceutical composition, and this pharmaceutical composition is comprised of compound and the pharmaceutically acceptable carrier shown in the formula I of the upper significant quantity for the treatment of.Described carrier includes but not limited to: glucose, salt solution, glycerine, ethanol, distilled water etc.; Described pharmaceutical composition can be prepared into according to the drug formulation process of routine injection or oral preparations.For example, can be that carrier is prepared into injection formulations by it with physiological saline or the aqueous solution that contains glucose; Or according to the oral preparations method of routine, it is prepared into to oral preparations, and such as: the various oral preparations such as enteric coated capsule, colon site-specific drug.
The dosage of pharmaceutical composition of the present invention is the significant quantity in treatment, and concrete dosage should be with reference to factors such as route of administration and patient health situations, as a reference: every day about 3-120 microgram/Kg body weight, be preferably 35 micrograms/Kg body weight.
The accompanying drawing explanation
The structural formula of Fig. 1 allyl cysteine amino acid derivative of the present invention.
Fig. 2 allyl cysteine synthetic route of the present invention schematic diagram: i) 3-bromopropylene and ammoniacal liquor; Ii) (Boc)
2O and 2N NaOH; Iii) DCC, HOBt, NMM and amino acid methyl ester; Iv) 4N NaOH; V) hydrogenchloride ethyl acetate solution (4N); R is selected from hydrogen, CH
3, CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH (CH
3)
2, CH
2C
6H
4-OH-p, CH (OH) CH
3, Indole-5-yl-CH
2, CH
2CH
2CO
2CH
3, CH
2OH, CH
2CH
2CH
2CH2NHCOCH (NH
2) CH
2SCH
2CHCH
2, CH
2CO
2CH
3, Imidazole-4-yl-CH
2, CH
2CH
2SCH
3Or CH
2C
6H
5.
Embodiment
In order further to set forth the present invention, below provide a series of embodiment.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
In reaction flask, adding 9g (74.3mmol) Cys, is the NH of 2M with 200ml concentration
4OH adds 14g (115.7mmol) 3-bromopropylene after dissolving, and under 0 ℃, reflects 3h.Be concentrated into driedly, obtain colorless solid.Water-ethyl alcohol recrystallization obtains title compound.ESI-MS(m/e):162[M+H]
+.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=5.85-5.65(m,1H),5.05-5.20(m,2H),3.75-3.85(m,1H),3.05-3.18(d,J=7.2Hz,2H),2.80-3.05(m,2H).
Embodiment 2 preparation Boc-SAC
Take 640mg SAC in reaction flask, add the 8ml water dissolution, under condition of ice bath, slowly drip 1N NaOH 4ml, will be dissolved with 1.040mg (Boc)
2The dioxane of O is slowly poured into wherein, and adjusting reaction solution pH is 9, reaction 72h, during every 3h, with single-pass, take out CO in reaction system
2Once.The TLC detection reaction fully after, adjusting reaction solution pH is 7, revolve except dioxane, then to adjust reaction solution pH is 2, with ethyl acetate extraction reaction solution three times, the ethyl acetate layer that obtains extracts and washes three times with saturated NaCl again, obtains ethyl acetate layer anhydrous Na SO
4Dried overnight, remove by filter NaSO
4, be spin-dried for ethyl acetate and obtain title compound.ESI-MS(m/e):282[M+H]
+.
Embodiment 3 preparation HClGly-OMe (1a)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Gly is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):89[M+H]
+
Embodiment 4 preparation HClAla-OMe (1b)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Ala is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):104[M+H]
+
Embodiment 5 preparation HClVal-OMe (1c)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Val is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):132[M+H]
+
Embodiment 6 preparation HCl HClIle-OMe (1d)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Ile is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):146[M+H]
+
Embodiment 7 preparation HCl HClLeu-OMe (1e)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Leu is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):146[M+H]
+
Embodiment 8 preparation HClTyr-OMe (1f)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Tyr is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):196[M+H]
+
Embodiment 9 preparation HClThr-OMe (1g)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Thr is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):134[M+H]
+
Embodiment 10 preparation HClPro-OMe (1h)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Pro is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):130[M+H]
+
Embodiment 11 preparation HClGlu-OMe
2(1i)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Glu is added in reaction system, reaction 36h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):176[M+H]
+
Embodiment 12 preparation HClSer-OMe (1j)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Ser is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):120[M+H]
+
Embodiment 13 preparation HClLys-OMe (1k)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Lys is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):161[M+H]
+
Embodiment 14 preparation HClAsp-OMe
2(1l)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Asp is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):162[M+H]
+
Embodiment 15 preparation HClTrp-OMe (1m)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Trp is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):219[M+H]
+
Embodiment 16 preparation HClMet-OMe (1n)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Met is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):164[M+H]
+
Embodiment 17 preparation HClPhe-OMe (1o)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmol L-Phe is added in reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass, reaction solution is drained, and adds a small amount of methyl alcohol to drain, and 3 times repeatedly, then add a small amount of ether to drain, three times repeatedly, obtain title compound.ESI-MS(m/e):180[M+H]
+
Embodiment 18 preparation Boc-SAC-Gly-OMe (2a)
Take 2.61g Boc-SAC in reaction flask, with a small amount of anhydrous THF, dissolve, under condition of ice bath, add 1-hydroxy benzo triazole (HoBt) 1.45g, after 5min, add again N, N '-dicyclohexylcarbodiimide (DCC), will be dissolved with 10mmol HClGly-OMe and pH and with NMM, be adjusted to 9 anhydrous THF and pour in reaction system after 20min.Reaction 12h, after the reflection fully of TLC detection display, by reacting liquid filtering, filtrate is spin-dried for the rear acetic acid ethyl dissolution of using, and uses successively 5%NaHCO
3Solution, saturated NaCl solution, 5%KHSO
4Solution, saturated NaCl solution, saturated NaHCO
3Solution, saturated NaCl solution extraction is washed three times, the ethyl acetate layer that obtains anhydrous Na SO
4Dried overnight.Remove by filter NaSO
4, filtrate being spin-dried for obtains title compound.ESI-MS(m/e):355[M+Na]
+.Mp:48℃
(c=0.51,CH
3OH).IR(KBr):3313.71,3003.17,2972.31,1761.01,1101.35,985.62,925.83,705.95.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.45-8.25(t,J=5.4Hz,1H),7.05-6.95(d,J=8.4Hz,1H)5.85-5.65(m,1H),5.05-5.20(m,2H),4.10-4.00(m,1H),3.95-3.75(m,2H),3.70-3.55(s,3H),3.25-3.05(d,J=6.9Hz,1H),2.95-2.50(m,2H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.67,170.53,155.74,134.87,117.66,78.71,55.58,54.17,28.65,25.79,24.92.
Embodiment 19 preparation Boc-SAC-Ala-OMe (2b)
According to the method for embodiment 18, Boc-SAC and HClAla-OMe reaction, obtain title compound.ESI-MS(m/e):369[M+Na]
+.Mp:64℃.
(c=0.53,CH
3OH).IR(KBr):3446.79,3319.49,3082.25,1749.44,1543.05,1166.93,1049.28,678.94.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.45-8.25(d,J=7.2Hz,1H),7.00-6.85(d,J=8.1Hz,1H),5.85-5.65(m,1H),5.05-5.20(m,2H),4.40-4.20(m,1H),4.10-4.00(m,1H),3.95-3.75(m,2H),3.60(s,3H),3.35-3.15(d,J=4.5Hz,2H),2.85-2.65(m,1H),2.60-2.45(m,2H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=173.24,171.06,155.71,134.91,117.64,78.66,54.22,52.33,48.03,34.40,33.12,28.63,17.38.Elem.
Embodiment 20 preparation Boc-SAC-Val-OMe (2c)
According to the method for embodiment 18, Boc-SAC and HClVal-OMe reaction, obtain title compound.ESI-MS(m/e):397[M+Na]
+.Mp:114℃.
(c=0.51,CH
3OH).IR(KBr):3323.35,2970.38,1751.36,1681.93,1649.14,1535.34,1290.38,1056.99,1022.27.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.15-8.05(d,J=8.4Hz,1H),7.05-6.95(d,J=8.7Hz,1H)5.85-5.65(m,1H),5.25-5.05(m,2H),4.30-4.10(m,2H),3.70-3.55(s,3H),3.25-3.05(d,J=8.1Hz,2H),2.95-2.50(m,3H),2.15-1.95(m,1H),1.40(s,9H),1.00-0.75(t,J=6.0Hz,5H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.17,171.48,155.68,134.88,117.64,78.70,57.71,54.36,52.18,34.35,32.79,30.52,28.60,19.31,18.53.Elem.
Embodiment 21 preparation Boc-SAC-Ile-OMe (2d)
According to the method for embodiment 18, Boc-SAC and HClIle-OMe reaction, obtain title compound.ESI-MS(m/e):411[M+Na]
+.Mp:93℃.
(c=0.49,CH
3OH).IR(KBr):3321.42,1747.51,1649.14,1556.55,1286.52,1172.72,927.76.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.15-8.00(d,J=8.1Hz,1H),7.05-6.95(d,J=8.4Hz,1H)5.85-5.65(m,1H),5.25-5.05(m,2H),4.30-4.10(m,2H),3.70-3.55(s,3H),3.25-3.05(d,J=6.9Hz,2H),2.80-2.65(m,1H),2.15-1.95(m,3H),1.90-1.70(m,1H),1.40(s,9H),1.00-0.75(m,5H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.13,171.33,155.66,134.92,128.82,128.26,117.58,78.76,56.72,54.39,52.10,36.89,34.43,31.03,15.77,11.50.Elem.
Embodiment 22 preparation Boc-SAC-Leu-OMe (2e)
According to the method for embodiment 18, Boc-SAC and HClLeu-OMe reaction, obtain title compound.ESI-MS(m/e):411[M+Na]
+.Mp:98℃.
(c=0.51,CH
3OH).IR(KBr):3338.78,2980.02,1759.08,1683.86,2525.69,1367.53,1249.87,1155.36.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.15-8.00(d,J=8.1Hz,1H),7.05-6.95(d,J=8.4Hz,1H)5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.20(m,1H),4.20-4.05(m,1H),3.70-3.55(s,3H),3.25-3.05(d,J=8.2Hz,2H),2.80-2.65(m,1H),2.15-1.95(m,3H),1.90-1.70(m,1H),1.40(s,9H),1.00-0.75(m,5H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=173.12,171.26,155.63,134.87,117.63,78.68,54.35,52.29,50.64,34.38,32.83,28.59,24.51,23.25,21.69.
Embodiment 23 preparation Boc-SAC-Tyr-OMe (2f)
According to the method for embodiment 18, Boc-SAC and HClTyr-OMe reaction, obtain title compound.ESI-MS(m/e):461[M+Na]
+.
(c=0.49,CH
3OH).IR(KBr):3475.73,1753.29,1726.29,1446.61,1367.53,1269.16,1051.20,840.96.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.30-8.10(d,J=7.5Hz,1H),7.15-6.95(m,3H),6.75-6.50(d,J=8.4Hz,2H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.20(m,1H),4.20-4.05(m,1H),3.70-3.55(s,3H),3.50-3.25(m,2H),3.25-3.05(d,J=8.2Hz,2H),2.80-2.65(m,2H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.16,171.12,156.65,155.62,134.83,130.45,127.15,117.65,115.54,78.74,54.26,52.24,36.39,34.36,33.07,28.62.
Embodiment 24 preparation Boc-SAC-Thr-OMe (2g)
According to the method for embodiment 18, Boc-SAC and HClThr-OMe reaction, obtain title compound.ESI-MS(m/e):376[M+Na]
+.Mp:65℃.
(c=0.51,CH
3OH).IR(KBr):3485.37,2517.10,1720.50,1670.35,1575.84,1506.41,1282.66,1195.87,1136.07.
1HNMR(300MHz,DMSO-d
6):δ/ppm=7.90-7.75(d,J=8.7Hz,1H),7.20-7.05(d,J=8.7Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.70-3.55(s,3H),3.45(s,1H),3.25-3.10(m,2H),2.80-2.65(m,1H),2.60-2.45(m,2H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.69,171.33,155.76,134.95,117.62,78.77,66.71,58.07,54.47,52.33,34.32,32.83,28.62,20.47.
Embodiment 25 preparation Boc-SAC-Pro-OMe (2h)
According to the method for embodiment 18, Boc-SAC and HClPro-OMe reaction, obtain title compound.ESI-MS(m/e):395[M+Na]
+.
(c=0.52,CH
3OH).IR(KBr):2980.02,1747.51,1733.86?1710.86,1647.21,1519.91,1488.11?1438.90,1365.60,1166.93,1045.42.
1HNMR(300MHz,DMSO-d
6):δ/ppm=7.20-7.05(d?J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,2H),4.20-4.05(m,1H),3.70-3.55(s,3H),3.45(s,1H),3.45-3.10(m,3H),2.80-2.65(m,1H),2.60-2.45(m,1H),2.40-2.05(m,1H),2.05-1.75(m,3),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.57,169.67,155.31,135.01,117.55,78.60,59.07,46.98,40.85,40.29,34.66,33.09,25.02.
Embodiment 26 preparation Boc-SAC-Glu-OMe (2i)
According to the method for embodiment 18, Boc-SAC and HClGlu-OMe reaction, obtain title compound.ESI-MS(m/e):441[M+Na]
+.Mp:105℃
(c=0.52,CH
3OH).IR(KBr):3315.63,1749.44,1726.29,1656.85,1517.98,1436.97,1161.15,1112.93,920.05.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=8.5Hz,1H),7.05-6.90(d,J=8.1Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.70-3.65(s,3H),3.65-3.55(s,3H),3.45(m,1H),3.25-3.10(m,2H),2.80-2.65(m,1H),2.60-2.45(m,1H),2.45-2.30(t,J=7.5Hz,1H),2.15-1.95(m,1H),1.95-1.75(m,1H),1.40(s,9H),1.15-1.05(t,J=7.5Hz,1H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=173.02,171.71,168.00,134.39,118.26,65.35,52.49,52.10,51.85,48.99,34.38,31.54,29.92,26.47,15.53.
Embodiment 27 preparation Boc-SAC-Ser-OMe (2j)
According to the method for embodiment 18, Boc-SAC and HClSer-OMe reaction, obtain title compound.ESI-MS(m/e):364[M+H]
+.
(c=0.52,CH
3OH).IR(KBr):3599.64,2998.95,1651.57,1435.55,1431.12,1334.09,1128.73,1205.49,1005.26,994.66.
1HNMR(300MHz,DMSO-d
6):δ/pp=8.40-8.20(d,J=7.5Hz,1H),7.05-6.90(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.75-3.25(m,1H),3.70-3.65(s,3H),3.45-3.30(m,1H),3.25-3.10(d,J=4.8Hz?3H),2.80-2.65(m,1H),2.60-2.45(m,1H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.37,171.24,155.53,134.92,117.62,78.71,63.33,61.63,55.62,55.06,54.24,53.24,52.34,49.05,39.08,33.14,28.61.
Embodiment 28 preparation 2 (Boc-SAC)-Lys-OMe (2k)
According to the method for embodiment 18, Boc-SAC and HClLys-OMe reaction, obtain title compound.ESI-MS(m/e):669[M+Na]
+.
(c=0.48,CH
3OH).IR(KBr):3275.13,2931.80,1747.51,1639.49,1699.67,1533.41,1249.87,1172.72,1049.28,1022.27,920.77.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=8.5Hz,1H),7.95-7.85(t,J=4.8Hz,1H),6.95-6.90(d,J=8.7Hz,1H),6.95-6.80(d,J=8.1Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.20-4.15(m,1H),4.15-4.08(m,1H),4.05-4.00(m,1H),3.70-3.65(s,3H),3.30(s,1H),3.20-3.10(t,J=8.2Hz,4H),2.80-2.60(m,2H),2.60-2.55(m,4H),1.80-1.55(m,2H),1.40(s,20H),1.30-1.20(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.74,171.29,170.75,155.66,134.88,134.84,117.64,78.69,52.30,52.27,34.41,34.28,33.01,28.95,28.62,22.91.
Embodiment 29 preparation Boc-SAC-Asp-OMe
2(2l)
According to the method for embodiment 18, Boc-SAC and HClAsp-OMe
2Reaction, obtain title compound.ESI-MS(m/e):547[M+Na]
+.Mp:107℃
(c=0.52,CH
3OH).IR(KBr):3354.21,2933.73,1795.08,1649.14,1521.84,1436.97,1367.53,1166.93,1056.99,929.69.
1HNMR(300MHz,DMSO-d
6):δ/ppm=7.45-7.55(d,J=5.4Hz,1H),6.65-6.55(d,J=7.5Hz,1H),6.15-6.00(d,J=5.1Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),5.25-5.05(m,4H),4.85-4.65(m,2H),4.65-4.45(m,1H),3.85-3.75(s,3H),3.75-3.65(s,3H),3.55-3.45(m,3H),3.25-3.10(m,4H),2.55-2.75(m,1H),1.95-1.75(m,1H),1.40(s,9H),1.30-1.15(t,J=6.9Hz,4H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.04,170.87,133.71,133.63,117.97,117.83,65.81,52.62,52.53,52.10,35.09,35.07,32.60,32.43,28.32,15.24.
Embodiment 30 preparation Boc-SAC-Trp-OMe (2m)
According to the method for embodiment 18, Boc-SAC and HClTrp-OMe reaction, obtain title compound.ESI-MS(m/e):464[M+H]
+.Mp:115℃
(c=0.52,CH
3OH).IR(KBr):3311.78,2915.09,2835.36,1737.86,1361.74,1338.60,1249.87,1217.06,927.76
1HNMR(300MHz,DMSO-d
6):δ/ppm=10.95-10.85(s,1H),8.30-8.20(m,1H),7.55-7.45(d,J=7.5Hz,1H),7.40-7.35(d,J=8.1Hz,1H),7.20-7.15(s,1H),7.15-6.90(m,3H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.65-3.55(s,3H),3.25-3.10(m,4H),2.80-2.65(m,1H),2.60-2.45(m,1H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/pp=172.40,171.20,155.68,136.55,134.84,127.53,124.16,121.44,118.91,118.42,117.64,111.89,109.52,78.77,54.32,53.50,52.28,34.38,33.13,28.61,27.47.
Embodiment 31 preparation Boc-SAC-Met-OMe (2n)
According to the method for embodiment 18, Boc-SAC and HClMet-OMe reaction, obtain title compound.ESI-MS(m/e):407[M+H]
+.Mp:65℃.
(c=0.53,CH
3OH).IR(KBr):3547.09,3116.97,1907.60,1707.60,1761.01,1558.48,1521.84,1290.38,1274.95,775.68.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.30-8.20(d,J=7.8Hz,1H),7.05-6.95(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.65(s,3H),3.25-3.10(d,J=7.2Hz,2H),2.80-2.65(m,1H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.41,171.42,155.67,154.81,134.80,117.69,78.70,54.36,52.43,51.25,34.34,32.67,30.96,29.82,28.60,15.02.
Embodiment 32 preparation Boc-SAC-Phe-OMe (2o)
According to the method for embodiment 18, Boc-SAC and HClPhe-OMe reaction, obtain title compound.ESI-MS(m/e):445[M+Na]
+.Mp:80℃
(c=0.50,CH
3OH).IR(KBr):3348.42,2980.02,2360.87,2339.65,1739.79,1656.85,1525.69,1392.61,1022.27,700.16.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=7.5Hz,2H),6.95-6.85(d,J=8.4Hz,2H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.65(s,3H),3.50-3.35(s,3H),3.25-3.10(d,J=7.2Hz,2H),3.10-3.00(m,2H),2.80-2.65(m,2H),1.40(s,9H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.05,171.17,155.59,137.41,134.83,129.56,128.69,127.01,117.65,78.71,54.32,53.91,52.31,37.08,34.36,33.06,28.62.
Embodiment 33 preparation Boc-SAC-Gly (3a)
Take Boc-SAC-Gly-OMe 800mg in reaction flask, with a small amount of tetrahydrofuran (THF), dissolve, under ice bath, slowly drip the NaOH solution of 2N until reaction solution pH is 13, reaction process keeps ice bath, reaction 2.5h.The TLC monitoring reaction is used saturated KHSO after finishing
4Conditioned reaction liquid pH is 7, revolves except tetrahydrofuran (THF), then is 2 by the reaction solution pH regulator, with the ethyl acetate extraction, washes reaction solution three times, and the ethyl acetate layer that obtains, with saturated NaCl washing three times, spends the night with anhydrous sodium sulfate drying subsequently.Filtering sodium sulfate, revolve and namely obtain title compound except ethyl acetate.
Embodiment 34 preparation Boc-SAC-Ala (3b)
Method according to embodiment 33, prepare title compound by Boc-SAC-Ala-OMe.
Embodiment 35 preparation Boc-SAC-Val (3c)
Method according to embodiment 33, prepare title compound by Boc-SAC-Val-OMe.
Embodiment 36 preparation Boc-SAC-Ile (3d)
Method according to embodiment 33, prepare title compound by Boc-SAC-Ile-OMe.
Embodiment 37 preparation Boc-SAC-Leu (3e)
Method according to embodiment 33, prepare title compound by Boc-SAC-Leu-OMe.
Embodiment 38 preparation Boc-SAC-Tyr (3f)
Method according to embodiment 33, prepare title compound by Boc-SAC-Tyr-OMe.
Embodiment 39 preparation Boc-SAC-Thr (3g)
Method according to embodiment 33, prepare title compound by Boc-SAC-Thr-OMe.
Embodiment 40 preparation Boc-SAC-Pro (3h)
Method according to embodiment 33, prepare title compound by Boc-SAC-Pro-OMe.
Embodiment 41 preparation Boc-SAC-Glu (3i)
According to the method for embodiment 33, by Boc-SAC-Glu-OMe
2Prepare title compound.
Embodiment 41 preparation Boc-SAC-Ser (3j)
Method according to embodiment 33, prepare title compound by Boc-SAC-Ser-OMe.
Embodiment 42 preparation 2 (Boc-SAC)-Lys (3k)
According to the method for embodiment 33, by 2 (Boc-SAC)-Lys-OMe, prepare title compound.
Embodiment 43 preparation Boc-SAC-Asp (3l)
According to the method for embodiment 33, by Boc-SAC-Asp-OMe
2Prepare title compound.
Embodiment 44 preparation Boc-SAC-Trp (3m)
Method according to embodiment 33, prepare title compound by Boc-SAC-Trp-OMe.
Embodiment 45 preparation Boc-SAC-Met (3n)
Method according to embodiment 33, prepare title compound by Boc-SAC-Met-OMe.
Embodiment 46 preparation Boc-SAC-Phe (3o)
Method according to embodiment 33, prepare title compound by Boc-SAC-Phe-OMe.
Embodiment 46 preparation SAC-Gly (4a)
Take 600mg Boc-SAC-Gly in reaction flask, with a small amount of anhydrous ethyl acetate, dissolve, under condition of ice bath, slowly drip 4N hydrochloric ethyl acetate 9ml, reaction continues 2h under the condition of drying, ice bath.The TLC monitoring reaction finishes, and reaction solution is drained with water pump, adds a small amount of dry ethyl acetate repeatedly to drain three times, then adds a small amount of anhydrous diethyl ether to drain, three times repeatedly.Namely obtain title compound.ESI-MS(m/e):219[M+H]
+.Mp:89℃
(c=0.49,CH
3OH).IR(KBr):2935.66,1680.00,1579.70,1519.91,1398.39,1249.87,993.34,933..55.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.45-8.25(t,J=5.4Hz,1H),7.05-6.95(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.05-5.20(m,2H),4.10-4.00(m,1H),3.95-3.75(m,2H),3.25-3.05(d,J=6.9Hz,1H),2.95-2.50(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=170.07,168.37,134.47,51.99,41.14,34.38,31.62.
Embodiment 47 preparation SAC-Ala (4b)
Method according to embodiment 46, prepare title compound by Boc-SAC-Ala.ESI-MS(m/e):233[M+H]
+.Mp:127℃.
(c=0.51,CH
3OH).IR(KBr):2924.09,1735.93,1674.21,1562.34,1489.05,1213.23,1138.00,991.41,923.90.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.45-8.25(d,J=7.2Hz,1H),7.00-6.85(d,J=8.1Hz,1H),5.85-5.65(m,1H),5.05-5.20(m,2H),4.40-4.20(m,1H),4.10-4.00(m,1H),3.95-3.75(m,2H),3.35-3.15(d,J=4.5Hz,2H),2.85-2.65(m,1H),2.60-2.45(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=173.68,172.43,167.34,134.44,118.33,51.94,48.29,48.19,34.36,31.56,21.21,17.24.
Embodiment 48 preparation SAC-Val (4c)
Method according to embodiment 46, prepare title compound by Boc-SAC-Val.ESI-MS(m/e):261[M+H]
+.
(c=0.51,CH
3OH).IR(KBr):2488.17,1687.71,1541.12,1213.23,1143.79,989.48,921.97.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.15-8.05(d,J=8.4Hz,1H),7.05-6.95(d,J=8.7Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.30-4.10(m,2H),3.25-3.05(d,J=8.1Hz,2H),2.95-2.50(m,3H),2.15-1.95(m,1H),1.00-0.75(t,J=6.0Hz,5H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.60,167.99,134.45,118.31,58.09,51.98,34.46,31.84,30.47,19.53,18.48.
Embodiment 49 preparation SAC-Ile (4d)
Method according to embodiment 46, prepare title compound by Boc-SAC-Ile.ESI-MS(m/e):275[M+H]
+.
(c=0.48,CH
3OH).IR(KBr):3271.27,2922.16,1654.92,1527.62,1367.53,1166.93,921.97.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.15-8.00(d,J=8.1Hz,1H),7.05-6.95(d,J=8.4Hz,1H)5.85-5.65(m,1H),5.25-5.05(m,2H),4.30-4.10(m,2H),3.25-3.05(d,J=6.9Hz,2H),2.80-2.65(m,1H),2.15-1.95(m,3H),1.90-1.70(m,1H),1.00-0.75(m,5H).
13CNMR(75MHz,DMSO-d
6):δ/ppm=172.58,167.86,134.41,57.10,51.92,37.02,34.39,31.74,25.12,15.98,11.86.
Embodiment 50 preparation SAC-Leu (4e)
Method according to embodiment 46, prepare title compound by Boc-SAC-Leu.ESI-MS(m/e):275[M+H]
+.
(c=0.49,CH
3OH).IR(KBr):2922.16,1722.43,1672.28,1550.77,1471.69,1201.65,92.05.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.15-8.00(d,J=8.1Hz,1H),7.05-6.95(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.30-4.10(m,2H),3.25-3.05(d,J=6.9Hz,2H),2.80-2.65(m,1H),2.15-1.95(m,3H),1.90-1.70(m,1H),1.00-0.75(m,5H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.58,167.86,134.41,57.10,51.92,37.02,34.39,31.74,25.12,15.98,11.86.
Embodiment 51 preparation SAC-Tyr (4f)
Method according to embodiment 46, prepare title compound by Boc-SAC-Tyr.ESI-MS(m/e):325[M+H]
+.
(c=0.51,CH
3OH).IR(KBr):2783.28,1722.43,1516.05,1228.66,1105.21,925.83,839.03,734.88,542.00.
1H?NMR(300MHz,DMSO-d
6):δ/ppm=8.30-8.10(d,J=7.5Hz,1H),7.15-6.95(m,3H),6.75-6.50(d,J=8.4Hz,2H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.20(m,1H),4.20-4.05(m,1H),3.50-3.25(m,2H),3.25-3.05(d,J=8.2Hz,2H),2.80-2.65(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.65,167.90,156.68,134.48,130.54,127.05,118.32,115.64,65.38,54.83,52.40,51.09,36.28,34.43,15.64.
Embodiment 52 preparation SAC-Thr (4g)
Method according to embodiment 46, prepare title compound by Boc-SAC-Thr.ESI-MS(m/e):263[M+H]
+.
(c=0.53,CH
3OH).IR(KBr):3080.32,1681.93,2785.21,1942.32,1558.48,1463.97,1377.17,1207.44?1132.21,1055.06.
1HNMR(300MHz,DMSO-d
6):δ/ppm=7.90-7.75(d,J=8.7Hz,1H),7.20-7.05(d,J=8.7Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.45(s,1H),3.25-3.10(m,2H),2.80-2.65(m,1H),2.60-2.45(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.44,171.81,168.17,134.49,118.32,66.72,58.50,51.89,34.32,31.99,20.84.
Embodiment 53 preparation SAC-Pro (4h)
Method according to embodiment 46, prepare title compound by Boc-SAC-Pro.ESI-MS(m/e):258[M+H]
+.Mp:114.9-115.2℃
(c=0.53,CH
3OH).IR(KBr):2891.30,1616.35,1409.96,1369.46,1224.80,1190.08,991.41,918.12,738.74
1HNMR(300MHz,DMSO-d
6):δ/ppm=7.20-7.05(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,2H),4.20-4.05(m,1H),3.45(s,1H),3.45-3.10(m,3H),2.80-2.65(m,1H),2.60-2.45(m,1H),2.40-2.05(m,1H),2.05-1.75(m,3H)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.37,169.48,134.75,118.42,60.22,47.00,39.35,32.18,30.49,28.62,22.25.
Embodiment 54 preparation SAC-Glu (4i)
Method according to embodiment 46, prepare title compound by Boc-SAC-Glu.ESI-MS(m/e):290[M+H]
+.
(c=0.49,CH
3OH).IR(KBr):3300.20,2432.24,1737.86,1666.50,1558.48,1487.12,1408.04,1228.66,1116.78,991.41,921.97.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=8.5Hz,1H)7.05-6.90(d,J=8.1Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.45(m,1H),3.25-3.10(m,2H),2.80-2.65(m,1H),2.60-2.45(m,1H),2.45-2.30(t,J=7.5Hz,1H),2.15-1.95(m,1H),1.95-1.75(m,1H),1.15-1.05(t,J=7.5Hz,1H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=1174.12,172.86,167.84,134.44,118.35,51.94,34.41,31.64,30.41,26.88,21.54.
Embodiment 55 preparation SAC-Ser (4j)
Method according to embodiment 46, prepare title compound by Boc-SAC-Ser.ESI-MS(m/e):249[M+H]
+.
(c=0.50,CH
3OH).IR(KBr):3194.12,1720.50,1672.28,1552.70,1490.97,1384.89,1205.51,1124.50,1047.35,991.41,927.76,738.74.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=7.5Hz,1H),7.05-6.90(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.75-3.25(m,1H),3.45-3.30(m,1H),3.25-3.10(d,J=4.8Hz,3H),2.80-2.65(m,1H),2.60-2.45(m,1H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.53,167.72,134.43,128.70,128.17,118.38,61.46,60.24,51.91,34.42,34.26,21.22,14.54.
Embodiment 56 preparation 2SAC-Lys (4k)
According to the method for embodiment 46, by 2 (Boc-SAC) Lys-OH, prepare title compound.ESI-MS(m/e):433M+H]
+.
(c=0.48,CH
3OH).IR(KBr):2924.09,2532.54,1674.21,1562.34,1458.18,1379.10,1217.08,1128.36,991.41,923.90.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=8.5Hz,1H),7.95-7.85(t,J=4.8Hz,1H),6.95-6.90(d,J=8.7Hz,1H),6.95-6.80(d,J=8.1Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.20-4.15(m,1H),4.15-4.08(m,1H),4.05-4.00(m,1H),3.30(s,1H),3.20-3.10(t,J=8.2Hz,4H),2.80-2.60(m,2H),2.60-2.55(m,4H),1.80-1.55(m,2H),1.30-1.20(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=173.12,172.40,167.88,134.46,134.33,118.45,118.38,60.23,51.91,34.37,34.20,31.73,31.29,28.62,21.48,21.22.
Embodiment 57 preparation SAC-Asp (4l)
Method according to embodiment 46, prepare title compound by Boc-SAC-Asp.ESI-MS(m/e):420[M+H]
+.Mp:124℃
(c=0.52,CH
3OH).IR(KBr):3369.64,2926.01,1734.01,1651.07,1523.76,1440.83,1402.25,1321.34,1062.78,933.555.
1HNMR(300MHz,DMSO-d
6):δ/ppm=7.45-7.55(d,J=5.4Hz,1H),6.65-6.55(d,J=7.5Hz,1H),6.15-6.00(d,J=5.1Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.85-4.65(m,2H),4.65-4.45(m,1H),3.85-3.75(s,3H),3.75-3.65(s,3H),3.55-3.45(m,3H),3.25-3.10(m,4H),2.55-2.75(m,1H),1.95-1.75(m,1H),1.30-1.15(t,J=6.9Hz,4H).
13CNMR(75MHz,DMSO-d
6):δ/ppm=172.16,171,76,169.01,168.40,133.64,134.60,118.08,118.01,52.54,35.79,34.63,34.59,31.95,31.74.
Embodiment 58 preparation SAC-Trp (4m)
Method according to embodiment 46, prepare title compound by Boc-SAC-Trp-OH.ESI-MS(m/e):348[M+H]
+.Mp:123℃
(c=0.53,CH
3OH).IR(KBr):2920.23,2814.14,2771.71,1489.05,1338.60,1228.66,1207.44,929.69,742.59.
1HNMR(300MHz,DMSO-d
6):δ/ppm=10.95-10.85(s,1H),8.30-8.20(m,1H),7.55-7.45(d,J=7.5Hz,1H),7.40-7.35(d,J=8.1Hz,1H),7.20-7.15(s,1H),7.15-6.90(m,3H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.25-3.10(m,4H),2.80-2.65(m,1H),2.60-2.45(m,1H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.53,167.62,134.43,128.86,128.34,118.38,60.24,55.46,51.91,34.42,31.56,21.22,14.54.
Embodiment 59 preparation SAC-Met (4n)
Method according to embodiment 46, prepare title compound by Boc-SAC-Met-OH.ESI-MS(m/e):293[M+H]
+.
(c=0.52,CH
3OH).IR(KBr):3331.07,3001.24,3205.69,3028.24,2771.71,2445.74,1739.79,1668.43,1174.65,929.69.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.30-8.20(d,J=7.8Hz,1H),7.05-6.95(d,J=8.4Hz,1H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.25-3.10(d,J=7.2Hz,2H),2.80-2.65(m,1H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.88,172.40,167.86,134.46,118.34,65.36,60.21,34.42,33.78,31.64,31.19,29.98,25.81,24.88,21.21,15.62.
Embodiment 60 preparation SAC-Phe (4o)
Method according to embodiment 46, prepare title compound by Boc-SAC-Phe.ESI-MS(m/e):309[M+H]
+.
(c=0.53,CH
3OH).IR(KBr):2875.86,2333.87,1726.29,1672.28,1548.84,1496.76,1406.11,1215.15,1109.07,991.41,923.90.
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.40-8.20(d,J=7.5Hz,2H),6.95-6.85(d,J=8.4Hz,2H),5.85-5.65(m,1H),5.25-5.05(m,2H),4.40-4.25(m,1H),4.20-4.05(m,1H),3.65(s,3H),3.25-3.10(d,J=7.2Hz,2H),3.10-3.00(m,2H),2.80-2.65(m,2H).
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.44,167.82,137.66,134.54,129.74,128.73,127.02,118.27,54.49,51.95,37.02,34.47,32.00,21.56.
The anti-inflammatory activity evaluation experimental of experimental example 1 compound 4a-o of the present invention
The compound 4a-o (embodiment 46-60 is prepared) that the embodiment of the present invention is prepared and acetylsalicylic acid physiological saline wiring solution-forming (2 μ mol/ml); (20 ± 2g) are divided into blank group, acetylsalicylic acid group and 4a-o group, every group of 15 mouse to male ICR mouse at random.Gavage gave compound 4a-o (dosage is 20 μ mol/kg) or acetylsalicylic acid (dosage is 165 μ mol/kg) administration after 30 minutes respectively, toward the left ear gabarit of small white mouse, was coated with 0.03ml dimethylbenzene.After 2 hours, small white mouse cervical vertebra dislocation execution, two ears are got to circular auricle, weigh, justified the weight difference of auricles to two as swelling with the punch tool of diameter 7mm.Result is listed table 1 in.
The restraining effect of table 1 compound 4a-o to mice ear
N=15; A) with the NS group, compare P<0.05; .; .
The anti-inflammatory activity evaluation experimental of experimental example 2 the compounds of this invention 4h various dose
According to the method for experimental example 1 by 4h by 2 μ mol/kg, 20 μ mol/kg ,/00 μ mol/kg Three doses is to the male ICR mouse gavage, the weight differences of two circle auricles are listed table 2 in.
The restraining effect of table 2 various dose 4h to mouse swelling
N=15; A) with the NS group, compare P<0.01; B) with 20 μ mol/kg groups, compare,, P<0.01
The hot tail-flick method of experimental example 3 mouse optical radiation is estimated the analgesic activity of 4a-o
Male ICR mouse (20 ± 2g), before experiment, under experimental temperature, raised one day.Mouse is packed in special stationary magazine creel, outside afterbody is exposed to.The light beam irradiates mouse tail that produces with baby spot while surveying pain, start to whipping response latency (tail flick latency, TFL) from irradiation with the stopwatch meter.Regulating spot light lamp and mouse back range is 2-6s from making the comparatively sensitive TFL of stimulus intensity.When experiment starts, first survey 3 times, every minor tick 5min, get average as Basic Pain Threshold.Compound 4a-o of the present invention is mixed with in the 2 μ mol/ml aqueous solution, gastric infusion, each gavage amount is 0.2ml, dosage is 20 μ mol/kg.Each test is established the physiological saline group and is made parallel control.For preventing skin scald, illumination 15s dead line, interval 30min repetition measurement TFL is to observe the medicine analgesic time-effect relationship.With threshold of pain increase rate evaluation medicine analgesic intensity: PTV=AAPT/BPT (PTV=threshold of pain increase rate, BPT=Basic Pain Threshold value, threshold of pain after the AAPT=administration-Basic Pain Threshold value).The result that obtains is listed table 3 in.
Experimental result shows that compound 4a-o of the present invention all has clear and definite analgesic activity
The analgesic activity of table 3 the compounds of this invention 4a-o
Threshold of pain increase rate represents with mean ± SD%, n=15; A) with the NA group, compare P<0.001; B) with the NS group, compare P<0.01; C) with the NS group, compare P<0.05.
The analgesic activity experiment of experimental example 4 the compounds of this invention 4h various dose
Adopt experimental example 3 the hot whipping model evaluation of mouse optical radiation the analgesic activity of 2 μ mol/kg, 20 μ mol/kg and 200 μ mol/kg Three doses 4h.Result is listed table 4 in.
Experimental result shows that the compounds of this invention 4h has dose-dependent analgesic activity.
The analgesic activity of 4h under table 4 different dosing dosage
Threshold of pain increase rate represents with mean ± SD%, n=10; A) with the NS group, compare P<0.001; B) with the NS group, compare P>0.05.
Claims (9)
1. the allyl cysteine amino acid derivative that has anti-inflammatory and antalgic activity, its structural formula are shown in the formula I:
The formula I
Wherein, R is selected from hydrogen, CH
3, CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH (CH
3)
2, CH
2C
6H
4-OH-p, CH (OH) CH
3, Indole-5-yl-CH
2, CH
2CH
2CO
2CH
3, CH
2OH, CH
2CH
2CH
2CH
2NHCOCH (NH
2) CH
2SCH
2CHCH
2, CH
2CO
2CH
3, Imidazole-4-yl-CH
2, CH
2CH
2SCH
3Or CH
2C
6H
5.
2. synthesize the method for the described allyl cysteine amino acid derivative of claim 1, the method comprises:
1) Cys and the reaction of 3-bromopropylene obtain allyl cysteine;
2) allyl cysteine with (BOC)
2The O reaction, obtain Boc-SAC;
3) under the sulfur oxychloride effect, amino acid and methyl alcohol reaction obtain HClAA-OMe;
4) Boc-SAC and HClAA-OMe condensation obtain Boc-SAC-AA-OMe;
5) Boc-SAC-AA-OMe sloughs methyl esters and generates Boc-SAC-AA;
6) Boc-SAC-AA is removed to Boc, obtain;
Wherein, described amino acid is selected from Gly, Ala, Val, Ile, Leu, Tyr, Thr, Pro, Glu, Ser, Lys, Asp, Trp, Met or Phe.
3. it is characterized in that in accordance with the method for claim 2: in step 1), Cys is reacted under 0 ° of C with the 3-bromopropylene in ammoniacal liquor and formed allyl cysteine in three hours.
4. it is characterized in that: step 2 in accordance with the method for claim 2) in containing the dioxane of alkalescent water allyl cysteine with (BOC)
2Reaction, obtain Boc-SAC.
5. in accordance with the method for claim 2, it is characterized in that: step 4) under DCC and HOBt exist, Boc-SAC is condensed into Boc-SAC-AA-OMe with HClAA-OMe in anhydrous THF.
6. in accordance with the method for claim 2, it is characterized in that: step 5) in containing the basic solution of NaOH, Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA.
7. it is characterized in that: step 6 in accordance with the method for claim 2) in the ethyl acetate of containing hydrogen chloride Boc-SAC-AA remove Boc and generate SAC-AA.
8. the purposes of allyl cysteine amino acid derivative claimed in claim 1 in preparing anti-inflammatory or analgesic.
9. an anti-inflammatory or analgesic pharmaceutical composition, is characterized in that: the upper significant quantity allyl cysteine amino acid derivative claimed in claim 1 for the treatment of and pharmaceutically acceptable carrier, consist of.
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CN101467991A (en) * | 2007-08-02 | 2009-07-01 | 复旦大学 | Uses of allyl cysteine and analogue thereof in preparing medicament for treating myocardial damage |
CN101880315A (en) * | 2009-05-08 | 2010-11-10 | 北京大学 | Branch oligopeptide with analgesic activity, preparation method and application thereof |
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CN101880315A (en) * | 2009-05-08 | 2010-11-10 | 北京大学 | Branch oligopeptide with analgesic activity, preparation method and application thereof |
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