CN102757477B - Allyl cysteinyl amino acid methyl ester derivative and synthesis method and application thereof - Google Patents
Allyl cysteinyl amino acid methyl ester derivative and synthesis method and application thereof Download PDFInfo
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- -1 Allyl cysteinyl amino acid methyl ester Chemical class 0.000 title abstract description 9
- 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 31
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 17
- 235000001014 amino acid Nutrition 0.000 claims abstract description 12
- 230000001760 anti-analgesic effect Effects 0.000 claims abstract description 9
- 150000001413 amino acids Chemical class 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 102
- 238000006243 chemical reaction Methods 0.000 claims description 83
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an allyl cysteinyl amino acid methyl ester 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, wherein pharmacokinetic properties of the parent nucleus are improved through structural modification, so as to improve the biological activity of the parent nucleus and obtain the allyl cysteinyl amino acid methyl ester derivative shown as a formula I. Pharmacological and pharmacodynamic experiments show that the allyl cysteinyl amino acid methyl ester 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 methyl ester derivative, relate in particular to allyl cysteine methyl ester derivative and the synthetic method thereof with anti-inflammatory or analgesic activities, the invention further relates to them in the application of preparing in anti-inflammatory or analgesic, the invention belongs to allyl cysteine amino acid derivative field.
Background technology
Inflammation is many major diseases, for example the major incentive of cancer, cardiovascular disorder and presenile dementia.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, has the pharmacologically actives such as the body's immunity of raising, anti-inflammatory, antibacterial, 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 various pathogens as the diplococcus of staphylococcus, meningitis, pneumonia, suis and diphtheria, dysentery, intestinal bacteria, typhoid fever, paratyphoid, Whooping cough, tubercule bacillus and vibrio cholerae etc.Can treat acute bacillary dysentery, Whooping cough, infantile diarrhea, lobar pneumonia, pulmonary tuberculosis, wound suppuration, trachoma etc.The antibacterial principle of garlicin is to breed sulphur atom in necessary halfcystine molecule and combine and suppressed the Growth and reproduction of bacterium due to the sulphur atom of sulfocompound in garlic and bacterial growth.2009, Yung-Hyun Cho found that garlic can reduce bacterial growth in the time for the treatment of chronic bacterial prostatitis, amelioration of inflammation reaction, and in the time using, can work in coordination with effectiveness with its generation together with Ciprofloxacin, reach better antiphlogistic effects.
Summary of the invention
One of object of the present invention is to provide a class and has the allyl cysteine methyl ester derivative of anti-inflammatory and antalgic activity;
Two of object of the present invention is to provide a kind of method of synthetic above-mentioned allyl cysteine methyl ester derivative;
Three of the object of the invention is that described allyl cysteine methyl ester derivative is prepared into anti-inflammatory or analgesic medicine.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
Have the allyl cysteine methyl ester derivative of anti-inflammatory and antalgic activity, its structural formula is 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 reacts with 3-bromopropylene and obtains allyl cysteine (SAC);
2) allyl cysteine (SAC) with (BOC)
2reaction, obtains Boc-SAC;
3) amino acid reacts and obtains HClAA-OMe with methyl alcohol;
4) Boc-SAC and HClAA-OMe condensation obtain Boc-SAC-AA-OMe;
5) Boc-SAC-AA-OMe is sloughed to Boc, to obtain final product.
Wherein, preferred, step 1) in Cys reacted at 0 DEG C with 3-bromopropylene in ammoniacal liquor within three hours, form allyl cysteine (SAC);
Step 2) in preferably containing SAC (allyl cysteine) in the dioxane of alkalescent water with (BOC)
2reaction, obtains Boc-SAC;
Step 3) in preferably under the effect of sulfur oxychloride, amino acid reacts and obtains HClAA-OMe with methyl alcohol; 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) in preferably in the ethyl acetate of containing hydrogen chloride Boc-SAC-AA-OMe remove Boc and generate SAC-AA-OMe.
It is parent nucleus that the present invention utilizes most important activeconstituents allyl cysteine in garlic, carry out amino acid modified to it, obtain the allyl cysteine methyl ester 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 methyl ester derivative of the present invention has excellent anti-inflammatory or analgesic activities, can be prepared into anti-inflammatory or analgesic.
The present invention also provides a kind of anti-inflammatory or analgesic pharmaceutical composition, and this pharmaceutical composition forms by treating allyl cysteine methyl ester derivative and the pharmaceutically acceptable carrier shown in the formula I of upper significant quantity.Described carrier includes but not limited to: glucose, salt solution, glycerine, ethanol, distilled water etc.; Described pharmaceutical composition can be prepared into injection or oral preparations according to conventional drug formulation process.For example, can be that carrier is prepared into injection formulations with physiological saline or the aqueous solution that contains glucose; Or be prepared into oral preparations according to conventional oral preparations method, for example: 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.
Brief description of the drawings
The structural formula of Fig. 1 allyl cysteine methyl ester derivative of the present invention.
Fig. 2 allyl cysteine methyl ester derivative of the present invention synthetic route schematic diagram: i) 3-bromopropylene and ammoniacal liquor; Ii) (Boc)
2o and 2N NaOH iii) DCC, HOBt, NMM and amino acid methyl ester; Iv) 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
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.
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative completely, and they are only used for the present invention to be specifically described, and not should be understood to limitation of the present invention.
Embodiment 1 prepares allyl cysteine (SAC)
In reaction flask, add 9g (74.3mmol) Cys, the NH that is 2M by 200ml concentration
4oH adds 14g (115.7mmol) 3-bromopropylene after dissolving, and at 0 DEG C, reflects 3h.Be concentrated into dryly, 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 prepares Boc-SAC
Take 640mg SAC in reaction flask, add 8ml water dissolution, under condition of ice bath, slowly drip 1N NaOH4ml, will be dissolved with 1.040mg (Boc)
2the dioxane of O is slowly poured into wherein, and adjusting reaction solution pH is 9, and reaction 72h, takes out CO in reaction system every 3h with single-pass during this time
2once.TLC detection reaction completely after, adjusting reaction solution pH is 7, revolve except dioxane, then to adjust reaction solution pH is 2, be extracted with ethyl acetate reaction solution three times, the ethyl acetate layer obtaining extracts and washes three times with saturated NaCl again, obtains ethyl acetate layer anhydrous Na SO
4dried overnight, removes by filter NaSO
4, be spin-dried for ethyl acetate and obtain title compound.ESI-MS(m/e):282[M+H]
+.
Embodiment 3 prepares HCl ﹒ Gly-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, 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 prepares HCl ﹒ Ala-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, 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 prepares HCl ﹒ Val-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, 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 prepares HCl ﹒ Ile-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, 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 prepares HCl ﹒ Leu-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, 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 prepares HCl ﹒ Tyr-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, 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 prepares HCl ﹒ Thr-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, 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 prepares HCl ﹒ Pro-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, 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 prepares HCl ﹒ Glu-OMe
2(1i)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmolL-Glu is added in reaction system, reaction 36h, 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 prepares HCl ﹒ Ser-OMe (1j)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmolL-Ser is added in reaction system, reaction 24h, 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 prepares HCl ﹒ Lys-OMe (1k)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmolL-Lys is added in reaction system, reaction 24h, 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 prepares HCl ﹒ Asp-OMe
2(1l)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl
2, activation 30min.10mmolL-Asp is added in reaction system, reaction 24h, 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 prepares HCl ﹒ Trp-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, 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 prepares HCl ﹒ Met-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, 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 prepares HCl ﹒ Phe-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, 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 prepares Boc-SAC-Gly-OMe (2a)
Take 2.61g Boc-SAC in reaction flask, with a small amount of anhydrous THF dissolving, under condition of ice bath, add 1-hydroxy benzo triazole (HoBt) 1.45g, after 5min, add again N, N '-dicyclohexylcarbodiimide (DCC), is adjusted to 9 anhydrous THF and pours in reaction system being dissolved with 10mmol HCl ﹒ Gly-OMe and pH NMM after 20min.Reaction 12h, after the reflection completely of TLC detection display, by reacting liquid filtering, filtrate is spin-dried for rear with acetic acid ethyl dissolution, 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 obtaining 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:47.2-48.1℃.
IR(KBr):3313.71,3003.17,2972.31,1761.01,1101.35,985.62,925.83,705.95
1HNMR(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 prepares Boc-SAC-Ala-OMe (2b)
According to the method for embodiment 18, Boc-SAC reacts with HClAla-OMe, obtains title compound.ESI-MS(m/e):369[M+Na]
+.Mp:64.2-64.5℃.
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.
Embodiment 20 prepares Boc-SAC-Val-OMe (2c)
According to the method for embodiment 18, Boc-SAC reacts with HClVal-OMe, obtains title compound.ESI-MS(m/e):397[M+Na]
+.Mp:112.4-113.6℃.
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)
13CNMR(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.
Embodiment 21 prepares Boc-SAC-Ile-OMe (2d)
According to the method for embodiment 18, Boc-SAC reacts with HClIle-OMe, obtains title compound.ESI-MS(m/e):411[M+Na]
+.Mp:91.8-93.2℃.
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.
Embodiment 22 prepares Boc-SAC-Leu-OMe (2e)
According to the method for embodiment 18, Boc-SAC reacts with HClLeu-OMe, obtains title compound.ESI-MS(m/e):411[M+Na]
+.Mp:98.1-98.3℃.
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 prepares Boc-SAC-Tyr-OMe (2f)
According to the method for embodiment 18, Boc-SAC reacts with HClTyr-OMe, obtains title compound.ESI-MS(m/e):461[M+Na]
+.
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 prepares Boc-SAC-Thr-OMe (2g)
According to the method for embodiment 18, Boc-SAC reacts with HClThr-OMe, obtains title compound.ESI-MS(m/e):376[M+Na]
+.Mp:64.3-65.2℃.
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 prepares Boc-SAC-Pro-OMe (2h)
According to the method for embodiment 18, Boc-SAC reacts with HClPro-OMe, obtains title compound.ESI-MS(m/e):395[M+Na]
+.
IR(KBr):2980.02,1747.51,1733.861710.86,1647.21,1519.91,1488.111438.90,1365.60,1166.93,1045.42
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,3H),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 prepares Boc-SAC-Glu-OMe (2i)
According to the method for embodiment 18, Boc-SAC reacts with HClGlu-OMe, obtains title compound.ESI-MS(m/e):441[M+Na]
+.Mp:105.2-105.8℃
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 prepares Boc-SAC-Ser-OMe (2j)
According to the method for embodiment 18, Boc-SAC reacts with HClSer-OMe, obtains title compound.ESI-MS(m/e):364[M+H]
+.
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=4.8Hz3H),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 prepares 2 (Boc-SAC)-Lys-OMe (2k)
According to the method for embodiment 18, Boc-SAC reacts with HClLys-OMe, obtains title compound.ESI-MS(m/e):669[M+Na]
+.
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 prepares Boc-SAC-Asp-OMe
2(2l)
According to the method for embodiment 18, Boc-SAC and HClAsp-OMe
2reaction, obtains title compound.ESI-MS(m/e):547[M+Na]
+.Mp:106.3-107.5℃
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 prepares Boc-SAC-Trp-OMe (2m)
According to the method for embodiment 18, Boc-SAC reacts with HClTrp-OMe, obtains title compound.ESI-MS(m/e):464[M+H]
+.Mp:113.4-114.8℃
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 prepares Boc-SAC-Met-OMe (2n)
According to the method for embodiment 18, Boc-SAC reacts with HClMet-OMe, obtains title compound.ESI-MS(m/e):407[M+H]
+.Mp:65.4-65.6℃
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 prepares Boc-SAC-Phe-OMe (2o)
According to the method for embodiment 18, Boc-SAC reacts with HClPhe-OMe, obtains title compound.ESI-MS(m/e):445[M+Na]
+.Mp:79.8-80.2℃
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 prepares SAC-Gly-OMe (3a)
Take Boc-SAC-Gly-OMe600mg in reaction flask, with a small amount of anhydrous ethyl acetate dissolving, under ice bath, slowly drip the hydrochloric ethyl acetate 10ml of 4N, reaction process keeps cryodrying, reaction 2.5h, after TLC monitoring reaction finishes, liquid in reaction system is drained, then added a small amount of dry ethyl acetate to drain, three times repeatedly, add subsequently a small amount of ether, drain, three times repeatedly.Obtain title compound.ESI-MS(m/e):255[M+Na]
+.
IR(KBr):2922.16,1747.51,1672.28,1483.26,1215.15,983.70
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)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=170.07,168.37,134.47,118.36,52.31,51.99,41.14,34.38,31.62.
Embodiment 34 prepares SAC-Ala-OMe (3b)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Ala-OMe.ESI-MS(m/e):230[M-H
2O]
+.Mp:122.6-123.0℃.
IR(KBr):3344.57,2833.43,1730.15,1662.64,1546.91,1471.69,1408.04,1346.31,1230.58
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)
13CNMR(75MHz,DMSO-d
6):δ/ppm=172.67,167.47,134.46,118.34,52.49,51.86,48.21,34.39,31.84,17.29.
Embodiment 35 prepares SAC-Val-OMe (3c)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Val-OMe.ESI-MS(m/e):275[M+H]
+.Mp:110.8-111.1℃.
IR(KBr):3265.49,1687.71,1541.12,1213.23,1143.79,989.48,732.95
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),1.00-0.75(t,J=6.0Hz,5H)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=171.48,155.68,134.88,117.64,78.70,57.71,54.36,52.18,34.35,32.79,28.60,18.53.
Embodiment 36 prepares SAC-Ile-OMe (3d)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Ile-OMe.ESI-MS(m/e):289[M+H]
+.
IR(KBr):3309.85,1751.36,1687.71,1529.55,1436.97,1288.45,1165.00,1053.13,927.76,634.58
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),1.00-0.75(m,5H)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=173.72,172.25,135.06,117.54,56.44,54.44,52.17,37.13,36.25,35.24,25.16,15.84,15.52,11.59.
Embodiment 37 prepares SAC-Leu-OMe (3e)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Leu-OMe.ESI-MS(m/e):289[M+H]
+.Mp:110.1-110.3℃.
IR(KBr):2870.08,1973.18,1726.29,1683.86,1560.41,1444.68,1355.36,1147.65,935.48,678.94
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),1.00-0.75(m,5H)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.58,167.95,134.49,118.28,52.14,52.01,51.10,34.42,31.68,24.50,23.17,21.83,21.55.
Embodiment 38 prepares SAC-Tyr-OMe (3f)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Tyr-OMe.ESI-MS(m/e):339[M+H]
+.Mp:145.8-145.1℃.
IR(KBr):3211.48,3014.74,1737.86,1662.64,1577.77,1517.98,1217.08,1153.43,
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)
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 39 prepares SAC-Thr-OMe (3g)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Thr-OMe.ESI-MS(m/e):299[M+Na]
+.Mp:161.1-161.4℃.
IR(KBr):3170.97,1737.86,1685.79,1550.77,1475.54,1294.24,1211.30,997.20,686.66,632.65
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)
13CNMR(75MHz,DMSO-d
6):δ/ppm=170.89,168.30,168.22,134.50,118.32,66.63,58.81,58.71,52.43,51.76,34.28,31.84,20.55.
Embodiment 40 prepares SAC-Pro-OMe (3h)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Pro-OMe.ESI-MS(m/e):273[M+H]
+.Mp:87.9-88.3℃
IR(KBr):2877.79,1745.58,1653.00,1477.47,1361.74,1174.65,1097.50,995.27,923.90
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,3H)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.08,166.78,134.69,118.50,59.41,52.42,50.54,47.48,30.44,29.08,25.11.
Embodiment 41 prepares SAC-Glu-OMe
2(3i)
According to the method for embodiment 33, by Boc-SAC-Glu-OMe
2prepare title compound.ESI-MS(m/e):319[M+H]
+.
IR(KBr):3008.95,2501.67,1726.29,1676.14,1487.12,1444.68,1406.11,1226.73,1174.65,1109.07,929.69,
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-.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=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 41 prepares SAC-Ser-OMe (3j)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Ser-OMe.ESI-MS(m/e):264[M+H]
+.Mp:165.4-166.4℃
IR(KBr):3325.28,2889.37,1745.58,1658.78,1554.63,1496.76,1367.53,1340.53,1234.44,1033.85
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),3.70-3.65(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)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=170.68,167.75,134.43,118.37,61.31,52.50,51.81,34.26,31.52.
Embodiment 42 prepares 2SAC-Lys-OMe (3k)
According to the method for embodiment 33, prepare title compound by 2 (Boc-SAC)-Lys-OMe.ESI-MS(m/e):447[M+H]
+.Mp:103.4-103.8℃
IR(KBr):3205.69,2953.02,1743.65,1672.28,1560.41,1489.05,1436.47,1213.23,1132.21,991.41,923.90,738.74
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),1.30-1.20(m,2H)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.19,167.93,167.35,134.47,134.35,118.43,118.36,65.37,52.75,52.63,52.44,34.33,34.20,31.60,31.25,30.66,28.55,22.96,21.50.
Embodiment 43 prepares SAC-Asp-OMe
2(3l)
According to the method for embodiment 33, by Boc-SAC-Asp-OMe
2prepare title compound.ESI-MS(m/e):448[M+H]
+.Mp:126.4-126.8℃
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=171.39,170.95,169.09,168.60,134.56,118.14,118.08,52.75,52.71,39.13,34.56,31.72,31.47.
Embodiment 44 prepares SAC-Trp-OMe (3m)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Trp-OMe.ESI-MS(m/e):362[M+Na]
+.Mp:147.1-147.5℃
IR(KBr):2915.09,2835.36,1737.86,1361.74,1338.60,1249.87,1217.06,927.76,746.45
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)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=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.
Embodiment 45 prepares SAC-Met-OMe (3n)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Met-OMe.ESI-MS(m/e):307[M+H]
+.Mp:154.3-154.8℃
IR(KBr):3327.21,2883.58,1726.29,1670.35,1550.77,1462.04,1309.67,1276.67,1266.56,1238.30,1170.79,1055.06,1033.12,979.84,644.22
1HNMR(300MHz,DMSO-d
6):δ/ppm=8.30-8.20(d,J=7.8Hz1H),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)
13CNMR(75MHz,DMSO-d
6):δ/ppm=171.93,168.05,134.43,118.39,52.58,52.04,51.57,34.33,31.48,30.83,29.79,14.91.
Embodiment 46 prepares SAC-Phe-OMe (3o)
According to the method for embodiment 33, prepare title compound by Boc-SAC-Phe-OMe.ESI-MS(m/e):323[M+H]
+.
IR(KBr):3327.21,2916.37,2850.79,2812.21,2787.14,2711.92,1730.15,1550.77,1406.11,1228.66,777.89
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)
13C?NMR(75MHz,DMSO-d
6):δ/ppm=172.40,171.50,167.72,137.25,134.49,129.62,128.81,128.68,127.16,118.30,54.59,54.48,52.43,51.79,34.43,31.76,25.80,21.53.
The anti-inflammatory activity evaluation experimental of experimental example 1 compound 3a-o of the present invention
The compounds of this invention 3a-o (embodiment 33-46 is prepared), acetylsalicylic acid are used respectively physiological saline wiring solution-forming (2 μ mol/ml); Male ICR mouse (20 ± 2g) is divided into blank group, acetylsalicylic acid group and 3a-o group at random, every group of 15 mouse.Gavage gave the compounds of this invention 3a-o (dosage is 20 μ mol/kg), acetylsalicylic acid (dosage is 165 μ mol/kg) administration after 30 minutes respectively, was coated with 0.03ml dimethylbenzene toward the left ear gabarit of small white mouse.After 2 hours, small white mouse cervical vertebra dislocation is put to death, the two ears punch tool of diameter 7mm is got circular auricle, weigh, two weight differences of justifying auricles as swelling.Result is listed table 1 in.
The restraining effect of table 1 the compounds of this invention 3a-o to mice ear
N=15; A) compare P<0.05 with NS group; .
The anti-inflammatory activity evaluation experimental of experimental example 2 various dose the compounds of this invention 3h
According to the method for experimental example 1, the compounds of this invention 3h is pressed to 2 μ mol/kg, 20 μ mol/kg, 200 μ mol/kg Three doses to male ICR mouse gavage, the weight difference of two circle auricles is listed table 2 in.
The restraining effect of table 2 various dose 3h to mouse swelling
N=15; A) compare P<0.01 with NS group; B) compare with 20 μ mol/kg groups,, P<0.01
The hot tail-flick method of experimental example 3 mouse optical radiation is evaluated the analgesic activity experiment of the compounds of this invention 3a-o
Male ICR mouse (20 ± 2g) is raised one day before experiment under experimental temperature.Mouse is packed in special stationary magazine creel, outside afterbody is exposed to.Survey the light beam irradiates mouse tail that when pain produces with baby spot, start to whipping response latency (tail flick latency, TFL) from irradiating with stopwatch meter.Regulating spot light lamp and mouse back range is 2 – 6s from making to irritate the comparatively sensitive TFL of intensity.When experiment starts, first survey 3 times, every minor tick 5min, gets average as Basic Pain Threshold.Compound 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 physiological saline group and is made parallel control.For preventing skin scald, illumination 15s dead line, interval 30min repetition measurement TFL is to observe 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-Basic Pain Threshold value after AAPT=administration).The result obtaining is listed table 3 in.Result shows that the compounds of this invention 3a-o all has clear and definite analgesic activity.
The analgesic activity of table 3 the compounds of this invention 3a-o
Threshold of pain increase rate represents with mean ± SD%, n=15; A) with relatively P<0.001 of NA group; B) with relatively P<0.01 of NS group; C) with relatively P<0.05 of NS group.
The analgesic activity experiment of experimental example 4 the compounds of this invention 3h various dose
Adopt experimental example 3 the hot whipping model evaluation of mouse optical radiation the analgesic activity of the compounds of this invention 3h2 μ mol/kg, 20 μ mol/kg and 200 μ mol/kg Three doses.Result is listed table 4 in.
Experimental result shows, the compounds of this invention 3h has dose-dependent analgesic activity.
The analgesic activity of 3h under table 4 different dosing dosage
Threshold of pain increase rate represents with mean ± SD%, n=10; A) with relatively P<0.001 of NS group; B) with relatively P>0.05 of NS group.
Claims (9)
1. have the allyl cysteine methyl ester derivative of anti-inflammatory and antalgic activity, its structural formula is 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.
2. the method for allyl cysteine methyl ester derivative described in synthetic claim 1, the method comprises:
1) Cys reacts and obtains allyl cysteine with 3-bromopropylene;
2) allyl cysteine with (BOC)
2o reaction, obtains Boc-SAC;
3) amino acid reacts and obtains HClAA-OMe with methyl alcohol, and wherein, described amino acid is selected from Gly, Ala, Val, Ile, Leu, Tyr, Thr, Pro, Glu, Ser, Lys, Asp, Trp, Met or Phe;
4) Boc-SAC and HClAA-OMe condensation obtain Boc-SAC-AA-OMe;
5) Boc-SAC-AA-OMe is removed to Boc, to obtain final product.
3. it is characterized in that: step 1 in accordance with the method for claim 2) in Cys is reacted at 0 DEG C with 3-bromopropylene in ammoniacal liquor three hours form allyl cysteine.
4. it is characterized in that: step 2 in accordance with the method for claim 2) in containing allyl cysteine in the dioxane of alkalescent water with (BOC)
2o reaction, obtains Boc-SAC.
5. in accordance with the method for claim 2, it is characterized in that: step 3) under the effect of sulfur oxychloride, amino acid reacts and obtains HClAA-OMe with methyl alcohol.
6. 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.
7. it is characterized in that: step 5 in accordance with the method for claim 2) in the ethyl acetate of containing hydrogen chloride, Boc-SAC-AA-OMe is removed to Boc.
8. allyl cysteine methyl ester derivative claimed in claim 1 is in the purposes of preparing in anti-inflammatory or analgesic.
9. anti-inflammatory or an analgesic pharmaceutical composition, is characterized in that: be made up of the upper significant quantity allyl cysteine methyl ester derivative claimed in claim 1 for the treatment of and pharmaceutically acceptable carrier.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110106706.2A CN102757477B (en) | 2011-04-27 | 2011-04-27 | Allyl cysteinyl amino acid methyl ester derivative and synthesis method and application thereof |
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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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