WO2023071895A1 - 羟脯氨酰基-丝氨酸化合物及其制备方法和应用 - Google Patents

羟脯氨酰基-丝氨酸化合物及其制备方法和应用 Download PDF

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WO2023071895A1
WO2023071895A1 PCT/CN2022/126293 CN2022126293W WO2023071895A1 WO 2023071895 A1 WO2023071895 A1 WO 2023071895A1 CN 2022126293 W CN2022126293 W CN 2022126293W WO 2023071895 A1 WO2023071895 A1 WO 2023071895A1
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compound
hydroxyprolyl
serine
preparation
acid
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姜琪坤
马宏达
邱诗
何仲贵
孙进
王永军
张天虹
徐秋驰
李鹏艳
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苏州裕泰医药科技有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
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Definitions

  • the invention belongs to the technical field of medicine, relates to a hydroxyprolyl-serine compound and a preparation method thereof, and also relates to a pharmaceutical composition containing the compound and its application in treating inflammatory bowel disease.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • IBD treatment is to control mucosal inflammation and suppress excessively activated immune responses.
  • Inhibitors such as cyclosporine, tacomus, etc.
  • the above-mentioned drugs all have disadvantages such as long medication time, low overall response rate and serious side effects. Therefore, it is very necessary to develop highly effective and low toxic IBD drugs.
  • Trans-L-Hydroxyprolyl-L-serine is an antihepatitis drug The dipeptide isolated in the injection has certain anti-inflammatory activity.
  • Trans-L-hydroxyprolyl-L-serine has hepatoprotective effect on cholestatic hepatitis caused by ⁇ -naphthyl isothiocyanate (ANIT), and its mechanism of action is as follows: (1) Enhance liver tissue free radical Clearing ability, inhibiting liver cell lipid peroxidation damage; (2) reducing the accumulation of inflammatory cells in areas of inflammation and tissue damage; (3) inhibiting the release of inflammatory cytokines.
  • Trans-L-hydroxyprolyl-L-serine is composed of two amino acids, trans-L-hydroxyproline and L-serine, in which hydroxyproline and serine share 3 chiral carbon atoms, and there are 8 stereo isomer.
  • the present invention provides hydroxyprolyl-serine compounds of different stereoconfigurations and their preparation methods and pharmaceutical compositions containing the compounds, as well as the hydroxyprolyl-serine compounds of different stereoconfigurations.
  • the present invention firstly provides a hydroxyprolyl-serine compound or a salt thereof with the following structure:
  • the present invention further provides a hydroxyprolyl-serine compound or a salt thereof with the following structure:
  • the present invention also provides a preparation method of the hydroxyprolyl-serine compound:
  • the preparation method of the hydroxyprolyl-serine compound comprises the following steps:
  • Step 1 Dissolve compound I, compound II, and N,N'-dicyclohexylcarboimide (DCC) in the reaction solvent, fill with nitrogen, react at 25-30°C, and rotate to evaporate to obtain compound III; compound The molar ratio of I and compound II is 0.1-10:1.
  • Step 2 Dissolve compound III and compound IV in a reaction solvent containing N,N-diisopropylethylamine (DIPEA), and react at 25-30°C for 2-24 hours to obtain compound V; compound III and compound IV
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Compound V is dissolved in different acids to obtain the target compound M.
  • reaction solvent described in the first step is one or two or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide combination.
  • the reaction solvent described in the second step is one or a combination of two or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide .
  • the acid described in the third step is one or a combination of two or more of hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid.
  • the synthetic route is as follows:
  • N,N'-dicyclohexylcarboimide DCC
  • reaction solvent diichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylethane amides
  • DIPEA N,N-diisopropylethylamine
  • reaction solvent diichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-dimethylacetamide
  • Acids hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid.
  • the present invention also provides a pharmaceutical composition, comprising the above-mentioned hydroxyprolyl-serine compound or its salt and a pharmaceutically acceptable carrier or excipient.
  • the invention provides the application of the hydroxyprolyl-serine compound or its salt in the preparation of medicine for treating inflammatory bowel disease.
  • the invention also provides the application of the pharmaceutical composition in the preparation of medicines for treating inflammatory bowel disease.
  • the inflammatory bowel disease is colitis.
  • the beneficial effects of the present invention are as follows: based on the fact that hydroxyproline has 2 chiral carbon atoms and serine has 1 chiral carbon atom, due to the difference in stereoselectivity in the interaction between the chiral drug and the body, the Stereo configuration is closely related to pharmacodynamics.
  • 4 different configurations of compound III are reacted with 2 different configurations of compound IV to form 8 different configurations of hydroxyprolyl-serine, and the effects of different enantiomers in treating IBD are investigated.
  • each compound has the effect of improving the disease state of colitis to varying degrees, wherein, the compound of Example 1, the compound of Example 2, the compound of Example 4
  • Both the compound and the compound of Example 8 can effectively improve the disease state of colitis, specifically manifested as improving the weight loss caused by the disease, improving the survival rate, reducing the disease activity index (DAI) score, and prolonging the length of the colon.
  • DAI disease activity index
  • the compound of Example 8 shows the most excellent pharmacodynamic effect, which provides the possibility for the treatment of IBD induced by DSS.
  • Figure 1 is a single crystal X-ray diffraction characterization diagram of the compound of Example 1.
  • Fig. 2 is a diagram of the pharmacodynamic administration scheme of the compounds of Examples 1-8.
  • Fig. 3 is a graph showing changes in body weight of mice before and after treating IBD with compounds of Examples 1-8.
  • Fig. 4 is a graph showing the DAI scores of mice treated with the compounds of Examples 1-8 for IBD in mice.
  • Fig. 5 is a graph comparing the colon length of mice treated with the compounds of Examples 1-8 for IBD in mice.
  • Step 1 Dissolve compound I-1, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotary evaporate to obtain compound III-1 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-1 and compound IV-1 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-1;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Dissolve compound V-1 in hydrochloric acid, suction filter, wash, and lyophilize to obtain compound A (trans-4-L-hydroxyprolyl-L-serine).
  • Step 1 Dissolve compound I-1, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotary evaporate to obtain compound III-1 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-1 and compound IV-2 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-2;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Compound V-2 was dissolved in hydrochloric acid, suction filtered, washed, and freeze-dried to obtain Compound B (trans-4-L-hydroxyprolyl-D-serine).
  • Step 1 Dissolve compound I-2, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotate to evaporate to obtain compound III-2 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-2 and compound IV-1 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-3;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Dissolve compound V-3 in hydrochloric acid, filter with suction, wash, and lyophilize to obtain compound C (trans-4-D-hydroxyprolyl-L-serine).
  • Step 1 Dissolve compound I-2, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotate to evaporate to obtain compound III-2 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-2 and compound IV-2 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-4;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Dissolve compound V-4 in hydrochloric acid, filter with suction, wash, and lyophilize to obtain compound D (trans-4-D-hydroxyprolyl-D-serine).
  • Embodiment 5 the preparation of cis-4-L-hydroxyprolyl-L-serine (compound E):
  • Step 1 Dissolve compound I-3, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotate to obtain compound III-3 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-3 and compound IV-1 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-5;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Compound V-5 was dissolved in hydrochloric acid, filtered with suction, washed, and freeze-dried to obtain Compound E (cis-4-L-hydroxyprolyl-L-serine).
  • Embodiment 6 the preparation of cis-4-L-hydroxyprolyl-D-serine (compound F):
  • Step 1 Dissolve compound I-3, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotate to obtain compound III-3 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-3 and compound IV-2 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-6;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Dissolve compound V-6 in hydrochloric acid, filter with suction, wash, and lyophilize to obtain compound F (cis-4-L-hydroxyprolyl-D-serine).
  • Step 1 Dissolve compound I-4, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotate to obtain compound III-4 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-4 and compound IV-1 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-7;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Dissolve compound V-7 in hydrochloric acid, filter with suction, wash, and lyophilize to obtain compound G (cis-4-D-hydroxyprolyl-L-serine).
  • Step 1 Dissolve compound I-4, compound II, and N,N'-dicyclohexylcarboimide (DCC) in tetrahydrofuran, fill with nitrogen, react at 25°C for 2 hours, and rotate to obtain compound III-4 ;
  • DCC N,N'-dicyclohexylcarboimide
  • Step 2 Dissolve compound III-4 and compound IV-2 in dichloromethane containing N,N-diisopropylethylamine (DIPEA), react at 25°C for 2h, evaporate the solvent under reduced pressure, and the residue is Dilute with dichloromethane, wash with 5% phosphoric acid aqueous solution, aqueous solution, and saturated saline successively, filter with suction, mix the filtrate with silica gel, and perform gradient elution with dichloromethane and methanol (100:1-1:100) through silica gel column chromatography , collecting the column chromatography and concentrating to obtain compound V-8;
  • DIPEA N,N-diisopropylethylamine
  • Step 3 Compound V-8 was dissolved in hydrochloric acid, suction filtered, washed, and freeze-dried to obtain Compound H (cis-4-D-hydroxyprolyl-D-serine).
  • Healthy C57BL/6 mice were used as model animals, randomly divided into 8 mice in each group, and modeled with dextran sodium sulfate (DSS, 3%). Except for the blank group, the other groups were free to drink 3% DSS solution was used for 5 days to establish a mouse model of experimental colitis, and the administration scheme was shown in Figure 2.
  • the experiment was divided into 11 groups, which were the blank group, the model group, the positive drug sulfasalazine group, the compound group of Example 1, the compound group of Example 2, the compound group of Example 3, the compound group of Example 4, and the compound group of Example 4. 5 compound group, Example 6 compound group, Example 7 compound group, Example 8 compound group.
  • sulfasalazine 250 mg/kg was orally administered once a day
  • the compounds of Examples 1-8 25 mg/kg were orally administered twice a day.
  • Both the normal control group and the model group were administered to C57BL/6 mice with an equal amount of normal saline instead of the compound of the example.
  • mice were weighed every day during the experiment. Calculate the rate of change in mouse body weight.
  • Mouse body weight change rate (%) (mouse body weight-mouse initial body weight)/mouse initial body weight ⁇ 100%
  • the DAI index is the sum of the weight loss score, stool consistency score, and bloody stool score. Among them, the score of blood in stool is scored based on the color development status measured by the fecal occult blood kit.
  • the specific steps are as follows: first, pick a mung bean-sized stool sample and place it on a white board, and then add 2 drops (about 0.1 mL) of O-tolidine Solution to different positions of the stool. . Then add 2 drops (about 0.1 mL) of the freshly prepared oxidant dropwise, immediately time and observe the color change, and judge according to the color change within 2 minutes.
  • the main feature of the DSS-induced ulcerative colitis model is the shortening of the colon accompanied by edema. Colon length can be used as an index to reflect the severity of inflammation to a certain extent.
  • the specific steps are as follows: quickly open the abdominal cavity, free colon and distal ileum, take out the entire intestinal segment from the anus to the end of the cecum, and measure the length of the entire intestinal segment from the anus to the end of the cecum in each group.
  • Embodiment 1-8 compound treats ulcerative colitis experimental result
  • each compound has a certain therapeutic effect on IBD.
  • the compound of Example 1, the compound of Example 2, the compound of Example 4, and the compound of Example 8 can effectively improve the disease state of colitis, and the specific performance is to improve the weight loss caused by the disease (Fig. 3), improve Survival, reduced disease activity index (DAI) score (Fig. 4), and prolonged colon length (Fig. 5).
  • the compound of Example 8 shows the most excellent pharmacodynamic effect, which provides the possibility for the treatment of IBD induced by DSS.

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Abstract

属于医药技术领域，涉及羟脯氨酰基-丝氨酸化合物及其制备方法，还涉及包含该化合物的药物组合物和其在治疗炎症性肠病中的应用。提供了不同立体构型的羟脯氨酰基-丝氨酸化合物及其制备方法和含有该化合物的药物组合物，以及所述的不同立体构型的羟脯氨酰基-丝氨酸在制备治疗IBD药物中的应用。所述的羟脯氨酰基-丝氨酸化合物或其盐的结构式如下（M）。

Description

羟脯氨酰基-丝氨酸化合物及其制备方法和应用 技术领域
本发明属于医药技术领域，涉及羟脯氨酰基-丝氨酸化合物及其制备方法，还涉及包含该化合物的药物组合物和其在治疗炎症性肠病中的应用。
背景技术
炎症性肠病(IBD)是一种慢性、特发性肠炎，可影响整个胃肠道，增加肠癌的风险。IBD主要包括溃疡性结肠炎(UC)和克罗恩病(CD)两种类型，临床主要表现为腹泻、腹痛、黏液脓血便、体重减轻等，并伴随着肠外疾病，如关节炎、结节性红斑、虹膜炎、强直性脊柱炎、硬化性胆管炎等。
目前，IBD的治疗重点是控制粘膜炎症和抑制过度激活的免疫反应，常见用药主要包括氨基水杨酸类(如柳氮磺吡啶)、糖皮质激素类(如甲基泼尼松龙)和免疫抑制剂类(如环孢菌素、他可莫司等)。上述药物均存在用药时间长、总体响应率低且副作用严重等缺点。因此，非常有必要开发高效和低毒的IBD药物。
反-L-羟脯氨酰基-L-丝氨酸是从抗肝炎药物
Figure PCTCN2022126293-appb-000001
注射剂中分离的二肽，具有一定的抗炎活性。反-L-羟脯氨酰基-L-丝氨酸对α-萘基异硫氰酸酯(ANIT)所引起的胆汁淤积性肝炎具有肝保护作用，其作用机制如下：(1)增强肝组织自由基清除能力、抑制肝细胞脂质过氧化损伤；(2)减少炎性细胞在炎症和组织损伤区域的聚集；(3)抑制炎性细胞因子的释放。目前，未发现关于反-L-羟脯氨酰基-L-丝氨酸用于治疗IBD的报道。
近年来，手性药物的研究已成为新药研发的热点。手性药物的立体构型与药物疗效密切相关，研究手性药物对映体之间的药效差异显得尤为重要。反-L-羟脯氨酰基-L-丝氨酸是由反-L-羟脯氨酸和L-丝氨酸两个氨基酸组成，其中羟脯氨酸和丝氨酸共有3个手性碳原子，存在8种立体异构体。现有技术中并没有将立体异构体化合物用于治疗IBD的报道。并且由于化合物的构型不同，其对于IBD的治疗效果也是不同的。
发明内容
针对现有技术的缺陷，本发明提供了不同立体构型的羟脯氨酰基-丝氨酸化合物及其制备方法和含有该化合物的药物组合物，以及所述的不同立体构型的羟脯氨酰基-丝氨酸在制备治疗IBD药物中的应用。
本发明是通过如下技术方案实现的：
本发明首先提供了具有如下结构的羟脯氨酰基-丝氨酸化合物或其盐：
Figure PCTCN2022126293-appb-000002
本发明进一步提供了如下结构的羟脯氨酰基-丝氨酸化合物或其盐：
Figure PCTCN2022126293-appb-000003
本发明还提供了所述的羟脯氨酰基-丝氨酸化合物的制备方法：
所述羟脯氨酰基-丝氨酸化合物的制备方法包括如下步骤：
第一步：将化合物Ⅰ、化合物Ⅱ、N,N'-二环己基碳酰亚胺(DCC)溶于反应溶剂中，充入氮气，25-30℃反应，旋蒸，得化合物Ⅲ；化合物Ⅰ和化合物Ⅱ的摩尔比为0.1-10:1。
第二步：将化合物Ⅲ与化合物Ⅳ溶于含有N,N-二异丙基乙胺(DIPEA)的反应溶剂中，25-30℃反应2-24h，得化合物Ⅴ；化合物Ⅲ和化合物Ⅳ的摩尔比为0.1-10:1。
第三步：将化合物Ⅴ溶于不同的酸，即得目标化合物M。
其中，第一步所述的反应溶剂为二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、 N,N-二甲基乙酰胺中一种或两种及以上的组合。
第二步所述的反应溶剂为二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、N,N-二甲基乙酰胺中的一种或两种及以上的组合。
第三步所述的酸为盐酸、醋酸、甲酸、马来酸、乳酸、碳酸、三氟乙酸、磷酸、对甲苯磺酸中的一种或两种及以上的组合。
合成路线如下：
Figure PCTCN2022126293-appb-000004
Figure PCTCN2022126293-appb-000005
为
Figure PCTCN2022126293-appb-000006
Figure PCTCN2022126293-appb-000007
为
Figure PCTCN2022126293-appb-000008
a：N,N'-二环己基碳酰亚胺(DCC)，反应溶剂(二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、N,N-二甲基乙酰胺)；
b：N,N-二异丙基乙胺(DIPEA)，反应溶剂(二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、N,N-二甲基乙酰胺)；
c：酸：盐酸、醋酸、甲酸、马来酸、乳酸、碳酸、三氟乙酸、磷酸、对甲苯磺酸。
根据其反应物构型不同，分别得到如下化合物：(A)所示的反-4-L-羟脯氨酰基-L-丝氨酸、(B)所示的反-4-L-羟脯氨酰基-D-丝氨酸、(C)所示的反-4-D-羟脯氨酰基-L-丝氨酸、(D)所示的反-4-D-羟脯氨酰基-D-丝氨酸、(E)所示的顺-4-L-羟脯氨酰基-L-丝氨酸、(F)所示的 顺-4-L-羟脯氨酰基-D-丝氨酸、(G)所示的顺-4-D-羟脯氨酰基-L-丝氨酸、(H)所示的顺-4-D-羟脯氨酰基-D-丝氨酸中的一种：
Figure PCTCN2022126293-appb-000009
本发明还提供了一种药物组合物，包括上述的羟脯氨酰基-丝氨酸化合物或其盐和药学上可接受的载体或赋形剂。
本发明提供了所述的羟脯氨酰基-丝氨酸化合物或其盐在制备治疗炎症性肠病药物中的应用。
本发明还提供了所述的药物组合物在制备治疗炎症性肠病药物中的应用。
所述的炎症性肠病为结肠炎。
本发明的有益效果如下：基于羟脯氨酸有2个手性碳原子，丝氨酸有1个手性碳原子，由于手性药物与机体间的相互作用存在立体选择性差异，导致手性药物的立体构型与药效学关系紧密。本发明分别将4种不同构型的化合物Ⅲ与2种不同构型的化合物Ⅳ反应，形成8种不同构型的羟脯氨酰基-丝氨酸，并考察不同对映体治疗IBD的效果。在葡聚糖硫酸钠(DSS)造成的小鼠炎症性肠病模型中，各化合物均有不同程度改善结肠炎的疾病状态的作用，其中，实施例1化合物、实施例2化合物、实施例4化合物、实施例8化合物均可以有效改善结肠 炎的疾病状态，具体表现为改善疾病造成的体重减轻、提高生存率，降低疾病活动指数(DAI)评分，延长结肠长度。其中，实施例8化合物显示出最为优异的药效学作用，为治疗DSS诱导的IBD提供可能性。
附图说明
图1为实施例1化合物的单晶X-射线衍射表征图。
图2为实施例1-8化合物的药效学给药方案图。
图3为实施例1-8化合物对小鼠IBD治疗前后的小鼠体重变化图。
图4为实施例1-8化合物对小鼠IBD治疗后的小鼠DAI评分图。
图5为实施例1-8化合物对小鼠IBD治疗后的小鼠结肠长度比较图。
具体实施方式
实施例1：反-4-L-羟脯氨酰基-L-丝氨酸(化合物A)的制备：
Figure PCTCN2022126293-appb-000010
第一步：将化合物I-1、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-1；
第二步：将化合物III-1与化合物IV-1溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-1；
第三步：将化合物V-1溶于盐酸，抽滤，洗涤，冻干即得化合物A(反-4-L-羟脯氨酰基-L-丝氨酸)。
实施例2：反-4-L-羟脯氨酰基-D-丝氨酸(化合物B)的制备：
Figure PCTCN2022126293-appb-000011
第一步：将化合物I-1、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-1；
第二步：将化合物III-1与化合物IV-2溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-2；
第三步：将化合物V-2溶于盐酸，抽滤，洗涤，冻干即得化合物B(反-4-L-羟脯氨酰基-D-丝氨酸)。
实施例3：反-4-D-羟脯氨酰基-L-丝氨酸(化合物C)的制备：
Figure PCTCN2022126293-appb-000012
第一步：将化合物I-2、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-2；
第二步：将化合物III-2与化合物IV-1溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲 烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-3；
第三步：将化合物V-3溶于盐酸，抽滤，洗涤，冻干即得化合物C(反-4-D-羟脯氨酰基-L-丝氨酸)。
实施例4：反-4-D-羟脯氨酰基-D-丝氨酸(化合物D)的制备：
Figure PCTCN2022126293-appb-000013
第一步：将化合物I-2、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-2；
第二步：将化合物III-2与化合物IV-2溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-4；
第三步：将化合物V-4溶于盐酸，抽滤，洗涤，冻干即得化合物D(反-4-D-羟脯氨酰基-D-丝氨酸)。
实施例5：顺-4-L-羟脯氨酰基-L-丝氨酸(化合物E)的制备：
Figure PCTCN2022126293-appb-000014
第一步：将化合物I-3、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-3；
第二步：将化合物III-3与化合物IV-1溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-5；
第三步：将化合物V-5溶于盐酸，抽滤，洗涤，冻干即得化合物E(顺-4-L-羟脯氨酰基-L-丝氨酸)。
实施例6：顺-4-L-羟脯氨酰基-D-丝氨酸(化合物F)的制备：
Figure PCTCN2022126293-appb-000015
第一步：将化合物I-3、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-3；
第二步：将化合物III-3与化合物IV-2溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-6；
第三步：将化合物V-6溶于盐酸，抽滤，洗涤，冻干即得化合物F(顺-4-L-羟脯氨酰基-D-丝氨酸)。
实施例7：顺-4-D-羟脯氨酰基-L-丝氨酸(化合物G)的制备：
Figure PCTCN2022126293-appb-000016
第一步：将化合物I-4、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-4；
第二步：将化合物III-4与化合物IV-1溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-7；
第三步：将化合物V-7溶于盐酸，抽滤，洗涤，冻干即得化合物G(顺-4-D-羟脯氨酰基-L-丝氨酸)。
实施例8：顺-4-D-羟脯氨酰基-D-丝氨酸(化合物H)：
Figure PCTCN2022126293-appb-000017
第一步：将化合物I-4、化合物II、N,N'-二环己基碳酰亚胺(DCC)溶于四氢呋喃中，充入氮气，25℃反应2h，旋蒸，得化合物III-4；
第二步：将化合物III-4与化合物IV-2溶于含有N,N-二异丙基乙胺(DIPEA)的二氯甲烷中，25℃反应2h，减压蒸去溶剂，残余物以二氯甲烷稀释，依次用5％磷酸水溶液、水溶液、饱和食盐水洗，抽滤，滤液用硅胶拌样，经硅胶柱层析，二氯甲烷和甲醇(100：1-1：100)梯度洗脱，收集柱层析物，浓缩，得化合物V-8；
第三步：将化合物V-8溶于盐酸，抽滤，洗涤，冻干即得化合物H(顺-4-D-羟脯氨酰基-D-丝氨酸)。
实施例1-8化合物的鉴定信息见表1：
表1.实施例1-8化合物的相关信息
Figure PCTCN2022126293-appb-000018
Figure PCTCN2022126293-appb-000019
实施例9：C57BL/6小鼠体内药效学研究
给药方案
以健康的C57BL/6小鼠为模型动物，随机分组，每组8只，采用葡聚糖硫酸钠(DSS，3％)进行造模，除空白组自由饮水外，其余组均自由饮用3％DSS溶液5天，建立小鼠实验性结肠炎模型，给药方案如图2所示。该实验共分为11组，分别为空白组、模型组、阳性药物柳氮磺胺吡啶组、实施例1化合物组、实施例2化合物组、实施例3化合物组、实施例4化合物组、实施例5化合物组、实施例6化合物组、实施例7化合物组、实施例8化合物组。其中，口服给予柳氮磺吡啶(250mg/kg)一日一次、口服给予实施例1-8化合物(25mg/kg)一日两次。正常对照组和模型组均以等量生理盐水替代实施例化合物给予C57BL/6小鼠。
检测指标和方法
体重变化率
在实验过程中每天称量小鼠体重。计算小鼠体重变化率。
小鼠体重变化率(％)＝(小鼠体重-小鼠初始体重)/小鼠初始体重×100％
疾病活动指数评分
实验期间每天观察小鼠体重、粪便性状以及血便情况，并且进行评分，评分要求如表2所示。DAI指数为体重下降分数、粪便性状分数与血便分数之和。其中血便分数以粪便隐血试剂盒测定显色状况为依据进行评分，具体步骤如下：首先挑取绿豆大小粪便样本置于白板上，滴加O-tolidine Solution 2滴(约0.1mL)于粪便不同位置。随后滴加临用新配的氧化剂2滴(约0.1mL)，立即计时并观察颜色变化，2min内根据颜色变化判读。
表2.疾病活动指数评分
Figure PCTCN2022126293-appb-000020
结肠长度的测定
DSS诱导溃疡性结肠炎模型的主要特征为结肠的缩短并伴随着水肿。结肠长度在一定程度上可以作为反映炎症严重程度的指标。具体步骤如下：迅速剖开腹腔，游离结肠和远端回肠，取出肛门至盲肠末端的整个肠段，测量各组肛门至盲肠末端的整个肠段长度。
统计学处理
用GraphPad Prism5.0处理数据，采用独立样本t检验进行数据分析。结果如图3、图4和图5所示，###，与空白组相比p<0.005；*，与造模组相比p<0.05；**，与造模组相比p<0.01；***，与造模组相比p<0.005。
结果
表3.实施例1-8化合物治疗溃疡性结肠炎实验结果
Figure PCTCN2022126293-appb-000021
Figure PCTCN2022126293-appb-000022
结论
结果如图3、4、5所示，由结果可知，当给予实施例1-8化合物后，各化合物对IBD均有一定治疗效果。与模型组相比，实施例1化合物、实施例2化合物、实施例4化合物、实施例8化合物均可以有效改善结肠炎的疾病状态，具体表现为改善疾病造成的体重减轻(图3)、提高生存率，降低疾病活动指数(DAI)评分(图4)，延长结肠长度(图5)。其中，实施例8化合物显示出最为优异的药效学作用，为治疗DSS诱导的IBD提供可能性。

Claims (10)

  1. 具有如下结构的羟脯氨酰基-丝氨酸化合物或其盐：
    Figure PCTCN2022126293-appb-100001
  2. 权利要求1的羟脯氨酰基-丝氨酸化合物或其盐，其结构式如下：
    Figure PCTCN2022126293-appb-100002
  3. 如权利要求1所述的羟脯氨酰基-丝氨酸化合物的制备方法，其特征在于：
    第一步：将化合物Ⅰ、化合物Ⅱ、N,N'-二环己基碳酰亚胺溶于反应溶剂中，充入氮气，反应，旋蒸，得化合物Ⅲ；
    第二步：将化合物Ⅲ与化合物Ⅳ溶于含有N,N-二异丙基乙胺的反应溶剂中，反应，得化合物Ⅴ；
    第三步：将化合物Ⅴ溶于酸，即得目标化合物M；
    Figure PCTCN2022126293-appb-100003
    其中，
    Figure PCTCN2022126293-appb-100004
    为
    Figure PCTCN2022126293-appb-100005
    Figure PCTCN2022126293-appb-100006
    为
    Figure PCTCN2022126293-appb-100007
  4. 如权利要求3所述的制备方法，其特征在于，第一步或第二步反应所述的反应溶剂为二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、N,N-二甲基乙酰胺中的一种或两种及以上的组合。
  5. 如权利要求3所述的制备方法，其特征在于，第三步所述的酸为盐酸、醋酸、甲酸、马来酸、乳酸、碳酸、三氟乙酸、磷酸、对甲苯磺酸。
  6. 如权利要求3所述的制备方法，其特征在于，第一步中，化合物Ⅰ和化合物Ⅱ的摩尔比为0.1-10：1。
  7. 如权利要求3所述的制备方法，其特征在于，第二步中，化合物Ⅲ和化合物Ⅳ的摩尔比为0.1-10：1。
  8. 一种药物组合物，包含权利要求1或2所述的羟脯氨酰基-丝氨酸化合物或其盐中的一种或几种和其药学上可以接受的载体或赋形剂。
  9. 一种药物制剂，包含权利要求1或2所述的羟脯氨酰基-丝氨酸化合物或其盐中的一种或几种或权利要求8所述的药物组合物。
  10. 权利要求1或2所述的羟脯氨酰基-丝氨酸化合物中的一种或几种或权利要求8所述的药物组合物或权利要求9所述的药物制剂在制备治疗炎症性肠病药物中的应用。
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