WO2012031466A1 - 2-对辛基苯乙基-2-氨基丙二醇衍生物及其应用 - Google Patents

2-对辛基苯乙基-2-氨基丙二醇衍生物及其应用 Download PDF

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WO2012031466A1
WO2012031466A1 PCT/CN2011/070365 CN2011070365W WO2012031466A1 WO 2012031466 A1 WO2012031466 A1 WO 2012031466A1 CN 2011070365 W CN2011070365 W CN 2011070365W WO 2012031466 A1 WO2012031466 A1 WO 2012031466A1
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aminopropanediol
fty720
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day
compound
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李飞
叶霜
陈晓翔
季刚
王殿广
赵萍
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南京明生医药技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C225/18—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings the carbon skeleton containing also rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/31—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to 2-p-octylphenethyl-2-aminopropanediol derivatives and uses thereof.
  • 2-p-octylphenethyl-2-aminopropanediol (FTY720) (2-amino-2-(2-[4-octyl-phenyl]ethyl)-1,3-propanediol hydrochloride) is a novel immunosuppressive U, is a chemically synthesized analog of the natural extract of Ascomycete, Isaria sinclarii, which is similar in chemical structure to sphingosine and ceramide. It is structurally distinguished from fungal peptides such as FK506 (Plexigrid), cyclosporine A, and rapamycin.
  • FTY720 can significantly prolong the survival time of transplanted allogeneic skin, heart, liver and kidney, and the side effects are relatively rare.
  • the drug has been shown to be effective against multiple sclerosis and is expected to be marketed with the indication in the near future.
  • FTY720 is effective in the treatment of animal models of other autoimmune diseases, such as autoimmune diabetic mouse model, experimental autoimmune pigmented membrane-retinitis, autoimmune thyroiditis rats, experimental allergic cerebrospinal Membrane, adjuvant arthritis model rats, and MRL/lpr lupus animal models.
  • FTY720 also has many problems to be solved, especially for the nervous system with a large toxic side effect. Summary of the invention
  • the object of the present invention is to provide a higher activity of 2-p-octylphenethyl-2-aminopropanediol (FTY720) derivative: 2-(trans 4-methylcyclohexyl)formylphenethyl-2 - aminopropanediol and its analogs.
  • FY720 2-p-octylphenethyl-2-aminopropanediol
  • Another object of the present invention is to provide an application involving the 2-p-octylphenethyl-2-aminopropanediol derivative.
  • Ri R 2 and R 3 are independently selected from H or an acyl group; R 4 is selected from a methylene group, a carbonyl group,
  • R 5 is a trans 4-methylcyclohexyl group.
  • Ri, R 2 and R 3 are each independently an acyl group selected from H or C1 to C4, and more preferably independently selected from H or acetyl.
  • the 2-p-octylphenethyl-2-aminopropanediol derivative is preferably a compound of the formula: 2-(trans 4-methylcyclohexyl)formylphenethyl group represented by the formula (A-1).
  • a remarkable feature of 2-p-octylphenethyl-2-aminopropanediol is that its structure consists of a hydrophilic part.
  • the fraction (amino alcohol) and one lipophilic moiety (carbon chain) are the main factors for the toxicity and specific physicochemical properties of such compounds. Therefore, it is necessary to retain these two parts in the design of new compounds.
  • the function of different compounds of 2-amino 2-substituted-1,3-propanediol depends mainly on the position of the benzene ring in the side chain alkane; the optimal carbon chain length between the quaternary carbon and the benzene ring is two carbon atoms.
  • the substitution position on the benzene ring is preferably in the para position, and therefore, it is necessary to retain the benzene ring and to be substituted with a para position.
  • the length change of the alkyl chain only affects the toxicity.
  • the optimal carbon chain length between the quaternary carbon and the benzene ring is two carbon atoms, the activity is most obvious when the alkyl chain length is 8 carbon atoms.
  • the preparation route of the compound of the present invention is as follows:
  • the 2-p-octylphenethyl-2-aminopropanediol derivative of the present invention has an immunosuppressive and preventive and/or therapeutic effect on pulmonary fibrosis, and can be used in the preparation of a medicament for treating lung injury. It can be administered by two routes, oral or intravenous, and the doses for both purposes are between 0.2 and 10 mg/kg body weight.
  • the compound of the present invention is formulated into a tablet or an injection according to a conventional formulation process by adding an appropriate amount of a conventional pharmaceutical excipient such as starch, methyl or carboxymethylcellulose, water, polyvinylpyrrolidone and pvpp.
  • the present invention successfully synthesizes a series of 2-pairs including 2-(trans 4-methylcyclohexyl)formylphenethyl-2-aminopropanediol based on the structure-activity analysis of FTY720 Octyl phenylethyl-2-aminopropanediol derivative.
  • the compound of the present invention can inhibit the expression of pulmonary fibrosis-related genes such as VEGF, a-SMA, IL_1 ⁇ , and type I collagen, improve the pathology of pulmonary fibrosis induced by HE, reduce the staining of Mason fibers, and reduce the expression of TGF- ⁇ and a-SMA.
  • the curative effect is significantly better than FTY720, and the compound A-1 of the present invention can significantly prolong BLM compared with FTY720.
  • the invention can simultaneously act on resting lymph and activated lymph, and the rejection of organ transplantation not only has a good preventive effect, but also has a therapeutic effect.
  • the compounds of the present invention have superior immunosuppressive effects compared to FTY720 at different organ transplants.
  • the present invention can be used for the preparation of a medicament for the treatment of lung injury and/or pulmonary fibrosis, and/or an immunosuppressive drug, which provides a more effective and more effective treatment for the rejection of lung injury, pulmonary fibrosis and organ transplantation. Safe alternative medicine.
  • A is the HE staining of pulmonary fibrosis in the normal group (healthy mice not modeled by bleomycin); B is the HE staining of pulmonary fibrosis on the 7th day of bleomycin-induced mice; C is Bo HE staining of lung fibrosis on the 28th day of mice with phleomycin modeling; D is the HE staining of pulmonary fibrosis on day 28 of bleomycin-induced mice treated with FTY720; E is modeled by bleomycin The mice were treated with the compounds of the invention on day 28 for pulmonary fibrosis HE staining.
  • A is the normal group (healthy mice not modeled by bleomycin) Masson staining of pulmonary fibrosis;
  • B is the sonson staining of pulmonary fibrosis on the 7th day of bleomycin-induced mice;
  • C is Bo Masson staining of lung fibrosis on the 28th day of the mice with phagemycin;
  • D is the Masson staining of the pulmonary fibrosis on the 28th day of bleomycin-induced mice treated with FTY720;
  • E is Bo The Novomycin modelling mice were treated with the compounds of the invention for the 28th day of the Masson staining of pulmonary fibrosis.
  • FIG. 4 Immunohistochemical staining of TGF- ⁇ in lung fibrosis in mice.
  • A is the normal group (healthy mice not modeled by bleomycin). Immunohistochemical staining of lung fibrosis TGF- ⁇ ; B is the 7th day of bleomycin-induced lung fibrosis TGF- ⁇ immunohistochemical staining; C is a 28-day lung fibrosis TGF- ⁇ immunohistochemical staining of bleomycin-induced mice; D is a bleomycin-induced mouse treated with FTY720 on day 28 of the lung Partial fibrosis TGF- ⁇ immunohistochemical staining; E is a bleomycin modeled mouse treated with the compound of the invention on the 28th day of pulmonary fibrosis TGF- ⁇ immunohistochemical staining.
  • Figure 5 Immunohistochemical staining of ⁇ -SMA in lung fibrosis in mice.
  • A is the normal group (healthy mice not modeled by bleomycin) pulmonary fibrosis a-SMA immunohistochemical staining;
  • ⁇ is bleomycin model mice 7th day pulmonary fibrosis ⁇ - SMA immunohistochemical staining;
  • C is the 28th day of bleomycin-induced mouse lung fibrosis ⁇ -SMA immunohistochemical staining;
  • D is bleomycin modeling mice treated with FTY720 28th lung Partial fibrosis ⁇ -SMA immunohistochemical staining;
  • E is a bleomycin-induced mouse model of lung fibrosis ⁇ -SMA immunohistochemical staining on the 28th day of treatment with the compound of the present invention.
  • Figure 6 FTY720, Effect of the compounds of the invention on fibrosis-related gene expression.
  • A is FTY720, the compound of the present invention has an effect on the expression of t-SMA gene
  • B is FTY720, and the effect of the compound of the present invention on the expression of VEGF gene
  • C is FTY720, the effect of the compound of the present invention on the expression of type I collagen gene
  • D is FTY720 The effect of the compounds of the invention on the expression of the IL-1 ⁇ gene.
  • mice successfully modeled by BLM were divided into three groups, and the compound of the present invention 2-(trans 4-methylcyclohexyl)formylphenethyl-2- was administered from the next day from the group A-1 and the group of FTY720, respectively.
  • the untreated group was not administered.
  • the survival curve of the mice after administration is shown in Fig. 1. It can be seen from Fig. 1 that the compound A-1 of the present invention can significantly prolong the survival time of the lung fibrosis mice modeled by BLM, and the survival rate can reach 90% at 28 days.
  • the FTY720 is only about 33%, and the untreated group is completely dead. This indicates that the compound A-1 of the present invention can significantly prolong the survival time of the BLM-induced pulmonary fibrosis model mice compared with FTY720.
  • mice successfully modeled by BLM were divided into three groups, and the compound of the present invention 2-(trans 4-methylcyclohexyl)formylphenethyl-2- was administered from the next day from the group A-1 and the group of FTY720, respectively.
  • the untreated group was not administered. Healthy mice not modeled with bleomycin were also established as the normal group.
  • the right lower lung tissues of each group were routinely fixed, and after fixation, they were embedded in paraffin and made into pathological sections.
  • the sections were dewaxed in xylene for 5 to 10 minutes. Transfer to a mixture of xylene and pure alcohol (1:1) for about 5 minutes (such as dewaxing with secondary xylene, this step can be omitted). Into 100%, 95%, 85 %, 70% alcohol, all levels are 2 to 5 minutes. Finally, it is transferred to the dye liquor by distilled water. Sumujing staining for 5 to 15 minutes. Wash the excess dye on the slide, 0. 5 ⁇ 1 % hydrochloric acid (70% alcohol). Separate for a while. Microscopic examination until the chromatin in the nucleus and nucleus is clear, about 10 seconds.
  • Xylene is transparent (secondary) for about 10 minutes. Covering: Wipe off the excess xylene around the slice, do not dry it, quickly add a proper amount of neutral gum, and then cover it with a cover slip. Observed under light microscope, the results are shown in Figure 2.
  • the slices were dewaxed to water, and 1% potassium permanganate was oxidized for 5 min, washed with water, and bleached with oxalic acid for 1 min. Washed again, distilled water, celestite blue dyed for 5min water wash, drop the remaining liquid without washing with water, dyed Mayer's hematoxylin 3_5min, rinse with water 5-10mino Lichun red picric acid saturated liquid for 5min, 1% acetic acid aqueous solution, 1% The phosphomolybdic acid was differentiated and sliced for about 5 min, washed with distilled water, 1% light green or toluidine blue for 30 s, washed with 1% acetic acid aqueous solution, 95% alcohol differentiated, dehydrated with anhydrous alcohol, transparent with xylene, and sealed with neutral gum. Observed under light microscope, the results are shown in Figure 3.
  • each section was incubated with 1 drop of hydrogen peroxide solution for 10 minutes at room temperature to block endogenous peroxidase activity.
  • Rinse in PBS for 3x3min The PBS solution was removed, and 1 or 50 ⁇ l of anti-a-SMA antibody or anti-TGF- ⁇ antibody (DAK0) was added to each section and incubated at room temperature for 90 minutes.
  • Rinse in PBS for 3x5min The PBS solution was removed, and 1:10000 rabbit anti-rat-horseradish peroxidase (DAK0) 50 ⁇ l per section was incubated for 40 minutes at room temperature.
  • mRNA levels of VEGFA, a-SMA, type I collagen and IL_1 ⁇ were measured by Syber green dye I method. The results are shown in Fig. 6.
  • Reagents PrimeScript RT reagent Kit Perfect Real time was purchased from (Takara (code: DRR037A)o instrument using ABI PRISM 7900HT.
  • VEGF forward primer SEQ ID NO. 1
  • VEGF reverse primer SEQ ID NO. 2o
  • a - SMA forward primer SEQ ID N0. 3
  • a-SMA reverse primer SEQ ID N0. 4
  • IL -1 ⁇ forward primer SEQ ID N0. 5
  • IL- ⁇ ⁇ reverse primer SEQ ID NO. 6
  • Type I collagen forward primer SEQ ID NO. 7
  • Type I collagen reverse primer SEQ ID NO.
  • the heart of WKAH rats was transplanted into the neck of ACI rats to form a heart transplant model.
  • the test animals were divided into two groups. One group was orally administered with the compound A-1 of the present invention, which was called an experimental group, and the other group was administered with FTY720 orally, which was called a control group. Both groups were administered for 15 consecutive days from the date of transplantation; the first day of oral administration was counted as the 0th day on the first day of transplantation, and the first day after transplantation was counted as the first day on the second day after transplantation. Similarly, the 15th day of oral administration of drugs is counted as the 14th day.
  • the experimental results show that the number of days of survival of the transplanted heart in the recipient of the compound group of the present invention is correspondingly prolonged with the increase in the amount, and no side effects are observed despite the large amount.
  • the number of survival days of the control rats in the experimental dose range was not affected by the dose.
  • the survival days of the rats in each dose of the experimental group were significantly longer than those in the control rats, indicating that the compound of the present invention has a better immunosuppressive effect than FTY720.
  • Liver transplantation was performed on the rats, and the test animals were divided into two groups.
  • One group was orally administered with the compound A-1 of the present invention, which was called an experimental group, and the other group was administered with FTY720 orally, which was called a control group. Both groups were administered for 14 consecutive days from the day after transplantation.
  • the results showed that the compound of the present invention significantly prolonged the survival days of the recipient compared to FTY720, indicating that the compound of the present invention has a better immunosuppressive effect than FTY720.
  • the small bowel transplantation was performed on the rats, and the test animals were divided into two groups.
  • One group was orally administered with the compound A-1 of the present invention, which was called an experimental group, and the other group was administered with FTY720 orally, which was called a control group.
  • Both groups were administered for 15 consecutive days from the date of transplantation; the first day of oral administration of drugs was counted as the 0th day, and the second day after oral administration, the first day after transplantation, was counted as the first day. analogy, The 15th day of oral administration of drugs was counted as the 14th day.
  • the results showed that the compound of the present invention significantly prolonged the survival days of the recipient compared to FTY720, indicating that the compound of the present invention has a better immunosuppressive effect than FTY720.
  • Kidney transplantation was performed on Beagle dogs.
  • the test animals were divided into two groups.
  • One group was administered with the compound A_l of the present invention, which was called the experimental group, and the other group was administered with FTY720, which was called the control group. Both groups were dosed daily from the day of transplantation until the number of days of survival of the two groups of animals was significantly different.
  • the compound A-1 of the present invention can significantly prolong the survival days of the test dog compared with FTY720, indicating that the compound of the present invention also has an effect of inhibiting rejection in large animals.
  • Table 1 summarizes the experimental results of immunosuppression obtained when different amounts of the compounds A-1 and FTY720 of the present invention were administered to different organs of different animals.
  • the animals used in the examples of the embodiments of the present invention are all provided by the Experimental Animal Center of Jiangsu Province.

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Description

说明书
2-对辛基苯乙基 -2-氨基丙二醇衍生物及其应用 技术领域
本发明属于药物化学领域，具体涉及 2-对辛基苯乙基 -2-氨基丙二醇衍生物及其应用。
背景技术
2-对辛基苯乙基 -2-氨基丙二醇 （简称 FTY720 ) (2-amino-2-(2-[4-octyl-phenyl]ethyl) -1,3-propanediol hydrochloride) 是一个新型免疫抑制齐 U， 为子囊菌亚门 （ascomycete) 赤 僵菌（Isaria sinclarii)发酵菌丝体天然提取物的化学合成的类似物， 其化学结构类似于神 经鞘氨醇（sphingosine)和神经酰胺（ceramide) , 从结构上区别于 FK506 (普乐可复） ， 环孢霉素 A, 以及雷帕霉素等真菌多肽。 FTY720可以明显延长动物异体皮肤、 心脏、 肝 脏、 肾脏的移植存活时间， 并且毒副作用相对少见。 该药显示对多发性硬化疗效显著， 预 期近期可通过 FDA批准以该适应症上市。 FTY720治疗其他自身免疫性疾病动物模型有 效的报道多见， 如自身免疫性糖尿病小鼠模型， 实验性自身免疫性色素膜 -视网膜炎， 自 身免疫性甲状腺炎大鼠，实验性变应性脑脊髓膜炎，佐剂性关节炎模型大鼠，以及 MRL/lpr 狼疮动物模型。但 FTY720也有许多问题有待解决， 特别是对神经系统具有较大的毒副作 用。 发明内容
本发明的目的是提供一类活性更高的 2-对辛基苯乙基 -2-氨基丙二醇 （FTY720 )衍生 物： 2- (反式 4-甲基环己基） 甲酰基苯乙基 -2-氨基丙二醇及其类似物。
本发明的另一目的是提供涉及该 2-对辛基苯乙基 -2-氨基丙二醇衍生物的应用。
本发明的技术方案如下：
2-对辛基苯乙基 -2-氨基丙二醇衍生物， 结构如式 （1 ) 所示：
Figure imgf000004_0001
( 1 )
N一 OH 其中， Ri R2、 R3独立的选自 H或酰基； R4选自亚甲基、 羰基、
Figure imgf000004_0002
R5为反式 4-甲基环己基。
其中所述 Ri、 R2、 R3优选独立的选自 H或 C1~C4的酰基， 进一步优选独立的选自 H 或乙酰基。
所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物优选如下化合物： 结构式如（A-1 )所示 的 2- (反式 4-甲基环己基） 甲酰基苯乙基 -2-氨基丙二醇， 结构式如 （A-2)所示的 2- (反 式 4-甲基环己基） 甲酰基苯乙基 -2-乙酰氨基丙二醇二乙酸酯、 结构式如 （A-3) 所示的 2- (反式 4-甲基环己基） 甲基苯乙基 -2-氨基丙二醇、 结构式如 （A-4)所示的 2- (反式 4- 甲基环己基）羟甲基苯乙基 -2-氨基丙二醇或结构式如（A-5)所示的 2- (反式 4-甲基环己 基） 羟肟基苯乙基 -2-氨基丙二醇，
Figure imgf000004_0003
Figure imgf000004_0004
(A-5)
本发明化合物的设计思想：
1. 2-对辛基苯乙基 -2-氨基丙二醇 （FTY720) 的一个显著特点是其结构由 1个亲水部 分 (氨基醇)和 1个亲脂部分 (碳链)所组成， 而两性分子是这类化合物产生毒性和特殊理化 性质的主要原因， 因此， 在新化合物设计中保留这两部分是必需的。
2. 2-氨基 2-取代 -1,3-丙二醇不同化合物的作用功效主要依赖于侧链烷烃中苯环的位 置； 季碳和苯环之间的最佳碳链长度是两个碳原子， 苯环上取代位置以对位为宜， 因此， 保留苯环是必需的， 且以对位为取代。
3. 烷基链的长短变化仅对毒性有影响， 当季碳和苯环之间的最佳碳链长度是两个碳 原子， 烷基链长度为 8个碳原子时， 活性最明显。
基于以上构效关系的分析，我们着手对苯环对位的取代基进行改造，根据生物电子等 排原理， 我们将 FTY720中苯环 4位上的直碳链换为同碳原子数的取代环链， 之后， 再在 该碳链的苄位上增加羟基， 羰基， 肟基， 得到本发明新的化合物。
本发明化合物制备路线如下:
Figure imgf000005_0001
本发明所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物具有免疫抑制和预防和 /或治疗肺 纤维化的作用，可在制备治疗肺损伤的药物中的应用。可以经口服或静脉注射两个途径给 药， 两种用途给药剂量均在.0.2〜10mg/kg体重。 本发明的化合物加上适量的常规药用辅料， 如淀粉， 甲基或羧甲基纤维素， 水， 聚乙 烯吡洛烷酮和 pvpp等， 按照常规的制剂工艺制成片剂或注射剂。
本品 10〜500g
辅料 适量
制成 1000片或支
本发明的有益效果： 本发明基于对 FTY720 的构效分析， 成功合成了包括 2- (反式 4-甲基环己基） 甲酰基苯乙基 -2-氨基丙二醇在内的一系列 2-对辛基苯乙基 -2-氨基丙二醇 衍生物。本发明化合物能够抑制肺纤维化相关基因如 VEGF、 a -SMA、 IL_1 β、 I型胶原的 表达， 改善 H.E染色的肺部纤维化病理、 减少 Mason纤维染色、 减少 TGF- β和 a -SMA 的生成，对博来霉素诱导的炎症性肺损伤、坏死性胰腺炎引起的急性肺损伤均可起到保护 作用， 疗效显著优于 FTY720, 而且本发明化合物 A-1较之 FTY720能显著延长 BLM诱导 的肺纤维化模型小鼠的生存时间。本发明可同时作用于静息淋巴和已激活的淋巴，对器官 移植的排斥反应不仅有良好的预防效果， 同时还有治疗作用。在不同器官移植时， 本发明 化合物较之 FTY720具有更优越的免疫抑制作用。因此， 本发明可用于制备治疗肺损伤和 /或肺纤维化的药物和 /或免疫抑制剂类药物， 为治疗肺损伤、 肺纤维化和器官移植产生的 排斥反应提供了一种更加有效、 更加安全的可选药物。
附图说明
图 1 小鼠生存曲线图。
图 2 小鼠肺部纤维化 HE染色结果。
A为正常组（未经博来霉素造模的健康小鼠）肺部纤维化 HE染色图； B为博来霉素造模小 鼠第 7日肺部纤维化 HE染色图； C为博来霉素造模小鼠第 28日肺部纤维化 HE染色图； D 为博来霉素造模小鼠经 FTY720治疗第 28 日肺部纤维化 HE染色图； E为博来霉素造模小 鼠经本发明化合物治疗第 28日肺部纤维化 HE染色图。
图 3 小鼠肺部纤维化 Mas son染色结果。
A为正常组（未经博来霉素造模的健康小鼠）肺部纤维化 Masson染色图； B为博来霉素造 模小鼠第 7日肺部纤维化 Masson染色图; C为博来霉素造模小鼠第 28日肺部纤维化 Masson 染色图； D为博来霉素造模小鼠经 FTY720治疗第 28日肺部纤维化 Masson染色图； E为博 来霉素造模小鼠经本发明化合物治疗第 28日肺部纤维化 Masson染色图。
图 4 小鼠肺部纤维化 TGF- β免疫组化染色结果。
A为正常组 （未经博来霉素造模的健康小鼠） 肺部纤维化 TGF- β免疫组化染色图； B为博 来霉素造模小鼠第 7 日肺部纤维化 TGF- β免疫组化染色图； C为博来霉素造模小鼠第 28 日肺部纤维化 TGF- β免疫组化染色图； D为博来霉素造模小鼠经 FTY720治疗第 28日肺部 纤维化 TGF- β免疫组化染色图； E为博来霉素造模小鼠经本发明化合物治疗第 28 日肺部 纤维化 TGF- ø免疫组化染色图。
图 5 小鼠肺部纤维化 α -SMA免疫组化染色结果。
A为正常组（未经博来霉素造模的健康小鼠）肺部纤维化 a -SMA免疫组化染色图； Β为博 来霉素造模小鼠第 7日肺部纤维化 α -SMA免疫组化染色图； C为博来霉素造模小鼠第 28 日肺部纤维化 α -SMA免疫组化染色图； D为博来霉素造模小鼠经 FTY720治疗第 28 日肺 部纤维化 α -SMA免疫组化染色图； E为博来霉素造模小鼠经本发明化合物治疗第 28日肺 部纤维化 α -SMA免疫组化染色图。
图 6 FTY720, 本发明化合物对纤维化相关的基因表达的影响。
A 为 FTY720、本发明化合物为对 t -SMA基因表达的影响； B为 FTY720、本发明化合物对 VEGF基因表达的影响； C 为 FTY720、 本发明化合物对 I型胶原基因表达的影响； D 为 FTY720、 本发明化合物对 IL-1 β基因表达的影响。
具体实施方式
实施例 1
2-苯乙醇甲磺酸酯（B-1 ) 的制备
将 2-苯乙醇 （100.0g， 0.82 mol)、 三乙胺 (102.0g， 1.0 mol)和二氯甲烷 (500mL)投入 反应瓶中， 在 5 °C左右 （0~10°C ) 滴加甲磺酰氯 (119.0 g， 1.14mol)， 滴毕 0~10°C反应 3 h; 将反应混合物倒入水中， 分出有机相， 有机相用水洗至中性， 用无水硫酸镁干燥， 浓 縮， 得 B-1 (155.8 g, 95.0%)
2-苯基碘乙烷（B-2) 的制备
将正丁酮 (500 mLl)， 碘化钠 (157.0g, 2.85mol)和 B-1 ( 125.0g, 0.38mol)， 加入反应瓶 中， 室温反应 5 h， 回收正丁酮， 将浓縮物缓慢倒入冰水混合物中， 弃去水层， 固体溶于 二氯甲烷中， 水洗， 有机相用无水硫酸镁干燥， 浓縮， 得 B-2(83.8g, 95.0% )， GC-MS(m /z):232(M+), 51， 77, 105， 127。
2-乙酰氨基 2-(2-苯基乙基)丙二酸二乙酯 (B-3)的制备
将无水乙醇 (800mL)投入反应瓶中， 分批缓慢加入金属钠 (20.0g， 0.87mol)， 待金属钠 全部反应后， 在 60°C~65°C温度下， 加入乙酰氨基丙二酸二乙酯 (172.0g， 0.8mol), 反应 1 h， 加入 B-2(65.0g, 0.28 mol)， 反应 7 h， 回收乙醇， 浓縮物溶于二氯甲烷中， 水洗至中 性， 有机相用无水硫酸镁干燥， 浓縮， 结晶， 得 B-3(62.9 g, 70.0 %) , 熔点 112.4 °C~11 2.8 °C， GC-MS(m/z):276(M-45), 91， 143， 171， 217， 276。
2-乙酰氨基 2-(2-苯基乙基 )-1,3-丙二醇 (B-4)的制备
将四氢呋喃 (400mL)， 硼氢化锂 (12.0g， 0.56mol)投入反应瓶中， 回流反应 1 h， 降至 室温， 加入 B-3 (44.9g， 0.14 mol)， 回流反应 6 h， 缓慢滴加饱和氯化铵溶液， 滴毕， 分出有机相， 水洗至中性， 无水硫酸镁干燥， 浓縮， 得 B-4(24.9 g, 75.0 %)。 GC-MS(m/ z):219(M+)， 73， 91， 115， 129， 146， 188。
2-乙酰氨基 2-(2-苯基乙基) - 1 ,3-丙二醇二乙酸酯 (B-5)的制备
依次将吡啶 (300mL)， 醋酐 (250.0g， 2.45mol) 和 B-4(33.2g, 0.14mol)投入反应瓶中， 4 5°C下反应 10 h， 将反应物倒入水中， 弃去水相， 溶于二氯甲烷中， 水洗至中性， 干燥， 浓縮， 结晶， 得 B-5(22.5 g, 50.0 %) , 熔点 106.5 °C~108.3 °C。 GC-MS(m/z):321(M+), 9 7， 129， 146， 157， 164， 188， 206， 248， 261。
2-乙酰氨基 2-[2-(4-对甲基环己基甲酰基苯基)乙基 ]-1,3-丙二醇二乙酸酯 (A-2)的制备
0 °C~5°C， 依次将对甲基环己基甲酰氯 （340.0 g, 2.12 mol)， 三氯化铝 (555.4 g, 4. 16 mol)和二氯甲烷 (250 mL)投入反应瓶中， 搅拌反应 0.5 h后， 缓慢滴加 B-5 ( 166.9 g， 0.52 mol) 的溶液，滴加完毕， 室温反应 8h， 将反应混合物慢慢倒入 5 %的盐酸冰水溶液 中， 分出有机层， 用饱和氯化钠溶液洗至中性， 无水硫酸镁干燥， 浓縮， 结晶， 得 A-2(6 9.4 g， 30.0%)
A-2:
白色结晶： mp: 108.5~110.5°C。 IR(KBr， υ ,cm-丄)：
3310.47, 2945.03， 1749.63, 1558.33， 1246.10, 1223.65， 1040.31。
1HNMR(400MHz,DMSO-J6)( δ ,ppm):
7.88(d,J=8.0Hz,2H,ArH), 7.71(s,lH,NH), 7.32(d,J=8.0Hz,2H, ArH), 4.28(d,J=10.8Hz,2H,0- CH2)， 4.18(d,J=10.8Hz,2H,0-CH2), 3.36(s,lH,羰基 α位- CH), 2.59(t,J=8.4Hz,2H,苄基 a位- CH2)， 2.03 1.99(m，9H，CH3X 3)， 1.792-1.716(m,2H,CH2), 1.65(s，H，CH)， 1.40~1.30(m,8H, 环己基 -CH2)， 0.91(d,J=6.8Hz,3H,CH3)。
13CNMR(400MHz,DMSO-J6)( δ ,ppm):
202.99， 170.30, 147.75, 133.90， 128.86， 128.51， 125.99， 63.41， 44.33， 42.42， 34.09， 32.61， 31.98， 29.26， 26.87， 23.52， 22.74， 20.84。
MS(FAB M/Z):444 (M+-l).
2-氨基 2-[2-(4-对甲基环己基甲酰基苯基)乙基] -1,3-丙二醇 (A-l)的制备
将氢氧化锂 (17.0g, 0.4mol)和甲醇 (200mL)投入反应瓶中， 加入 A-2(20.0g， 0.046mol), 回流 h， 减压蒸除甲醇， 结晶， 得 A-l g,
A-l:
白色结晶， mp: 133.5~135.5°C。
IR(KBr， υ ,cm l):
3349.82， 3290.12, 2945.03， 1670.18, 1019.89。
1HNMR(400MHz,DMSO-J6)( δ ,ppm):
7.86(d,J=8.0Hz,2H, ArH), 7.32(d,J=8.0Hz,2H, ArH), 4.49(s，2H，NH2)， 3.25(t，4H，0-CH2)， 2.69~2.65(m,2H,苄基 CH2), 1.798~1.714(m,2H, CH2)， 1.54-1.49, 1.37-1.31, 1.14~1.11(9H, 环己基)， 0.91(d,J=6.4Hz,3H,-CH
13CNMR(400MHz,DMSO-J6)( δ ,ppm):
202.99， 149.42， 133.60， 128.77, 128.42， 65.56， 55.66， 44.33， 36.59， 34.11, 31.99， 29.30， 29.26， 22.73。
MS(FAB M/Z):320 (M++l)。 本发明化合物对肺纤维化模型的治疗效应 2. 1博来霉素致小鼠肺纤维化模型的建立
8-12周龄 C57B1/6小鼠， SPF级层流架无菌饮食喂养， 经气管软骨环间隙向心端注射 0. 05-0. 075 units ( 2-3 units/kg 体重） 博来霉素（以下简称 BLM, 购自 Gensia Sicor Pharmaceuticals)， 注射时体位直立， 注射后旋转体位以保证博来霉素在肺内均匀分布。 2. 2生存曲线测定
将 BLM造模成功的小鼠分为三组， A-1组和 FTY720组分别从第二天开始给予本发明 化合物 2- (反式 4-甲基环己基） 甲酰基苯乙基 -2-氨基丙二醇 （A-1 ) lmg/kg 和 FTY720 0. 5mg/kg, 每天尾静脉注射一次。 未处理组不给药。
给药后小鼠生存曲线见图 1， 由图 1可看出本发明化合物 A-1能显著延长 BLM造模的 肺纤维化小鼠的生存时间，在 28d时的生存率可达 90%, 而 FTY720则只有 33%左右，未处理 组完全死亡。 这说明本发明化合物 A-1较之 FTY720能显著延长 BLM诱导的肺纤维化模型 小鼠的生存时间。
2. 3对肺部纤维化的病理改变
将 BLM造模成功的小鼠分为三组， A-1组和 FTY720组分别从第二天开始给予本发明 化合物 2- (反式 4-甲基环己基） 甲酰基苯乙基 -2-氨基丙二醇 （A-1 ) lmg/kg 和 FTY720 0. 5mg/kg, 每天尾静脉注射一次。未处理组不给药。另设立未经博来霉素造模的健康小鼠 作为正常组。
各组小鼠右下肺组织常规固定后， 经固定后， 常规石蜡包埋， 制成病理切片。
2. 3. 1. HE染色
切片在二甲苯中脱蜡 5〜10分钟。移入二甲苯和纯酒精（1 : 1 )混合液中 5分钟左右 (如经二次二甲苯脱蜡， 此步可略）。 入 100%、 95 %、 85 %、 70%酒精， 各级为 2〜5分 钟。最后经蒸馏水转入染液。 苏木精染液染色 5〜15分钟。水洗玻片上多余染液， 0. 5〜1 %盐酸酒精 （70%酒精配制） 分色片刻。 镜检控制， 直至细胞核及核内染色质清晰为止， 约数 10秒钟。流水冲洗 15〜30分钟， 或者在碳酸锂饱和液中短时间碱化或蓝化， 即细胞 核呈蓝色， 蒸馏水短洗。 0. 1〜0. 5 %伊红染液染色 1〜5分钟， 若着色困难， 可在每 100 毫升染液中加入 1〜2滴冰醋酸， 使易着色且不易脱色。 依次经 70%、 85 %、 95 %、 100 %酒精脱水，各级为 2〜3分钟，在 95 %以下浓度的酒精中伊红易脱色，应适当縮短时间。 二甲苯透明 （二次）， 共约 10分钟。 封片： 擦去切片周围多余二甲苯， 切勿干涸， 迅速滴 加适量中性树胶， 再加盖玻片封固。 光镜下观察， 结果见图 2
2. 3. 2 Masson染色
切片脱蜡至水， 1%高锰酸钾氧化切片 5min， 水洗， 草酸漂白 lmin。 再水洗， 蒸馏水 洗， 天青石蓝染 5min水洗， 摔去余液不用水洗， 滴染 Mayer氏苏木素 3_5min， 流水冲洗 5-10mino丽春红苦味酸饱和液染 5min， 1%醋酸水溶液洗， 1%磷钼酸分化切片约 5min， 蒸 馏水洗， 1%淡绿或者甲苯胺蓝滴染 30s， 1%醋酸水溶液洗切片， 95%酒精分化， 无水酒精 脱水， 二甲苯透明， 中性树胶封固。 光镜下观察， 结果见图 3
2. 3. 3 TGF- β , α -SMA免疫组化染色
切片脱蜡和水化后， 用 PBS (pH7. 4)冲洗三次， 每次 3min。 如果有必要， 每张切片加 1滴过氧化氢液室温下孵育 10分钟，以阻断内源性过氧化物酶的活性。 PBS冲洗 3x3min。 除去 PBS液， 每张切片加 1滴或 50 μ 1的抗 a -SMA抗体、 或抗 TGF- β抗体（DAK0公司）， 室温下孵育 90分钟。 PBS冲洗 3x5min。 除去 PBS液， 每张切片 1： 10000的兔抗大鼠-辣 根过氧化物酶（DAK0公司） 50 μ 1， 室温下孵育 40分钟。 PBS冲洗 3x3min。 除去 PBS液， 每张切片加 1滴或 50 μ 1新鲜配制的 DAB或 AEC溶液，显微镜下观察 3_5分钟。 自来水冲 洗， 苏木素复染， 用 0. 1%HC1分化， 自来水冲洗， PBS返蓝， 中性树胶封固， 封片。 光镜 下观察， 结果见图 5 。
病理结果显示 FTY720和本发明化合物 A-1均能有效地改善 H. E染色的肺部纤维化病 理、 减少 Mason纤维染色、 减少 TGF- β和 a -SMA的生成， 且本发明化合物 A-1效果较之 FTY720更为显著， 提示本发明化合物 A-1对治疗 BLM诱导的肺纤维化模型有效。
2. 4 对肺纤维化相关的基因表达的影响
使用 Syber green dye I法检测小鼠 VEGFA、 a -SMA、 I型胶原和 IL_1 β的 mRNA水 平， 结果见图 6。 试剂 PrimeScript RT reagent Kit Perfect Real time购自 （Takara ( code : DRR037A)o 仪器使用 ABI PRISM 7900HT。
引物序列： VEGF正向引物: SEQ ID NO. 1； VEGF反向引物 SEQ ID NO. 2o a - SMA 正 向引物： SEQ ID N0. 3; a -SMA 反向引物： SEQ ID N0. 4; IL-1 β正向引物： SEQ ID N0. 5; IL-Ι β反向引物： SEQ ID NO. 6； I型胶原正向引物： SEQ ID NO. 7； I型胶原反向引物： SEQ ID NO. 8。
50mg小鼠肺组织，按 Trizol法抽提 mRNA后，逆转录成为 cDNA。 SYBR Premix Ex Taq (2x) lOul , PCR 正向引物 0. 8 ul， PCR反向引物 0. 8ul ( 50mg/ml ) , ROX Reference dye 0. 4ul, RT 反应液 2ul, ddH20 6ul配至 20 ul反应体系。 反应过程： 95. 0°C变性 30秒， 95. 0°C 5秒 60. 0°C 34秒， 95. 0°C 15秒， 40个循环； 后 60. 0°C 1分， 95. 0°C 15秒。
结果显示： 与未经造模的正常组小鼠相比， 经 BLM处理以后小鼠的 a -SMA、 VEGFA、 IL-1 β、 I型胶原基因的 mRNA水平显著升高， 但 Fty720和本发明化合物 A-1均能显著 下调上述基因的 mRNA水平，而本发明化合物 A-1在下调上述基因的 mRNA水平方面的活性 较之 Fty720更强。 实施例 3 本发明化合物免疫抑制效果考察
实验方法：
将 WKAH大鼠的心脏移植到 ACI大鼠的颈部，形成心脏移植模型。 受试动物分为两组， 一组口投本发明化合物 A-1 , 称为实验组， 另一组口投 FTY720, 称为对照组。 两组均从移 植当日起连续 15日给药； 口投药物第一日即移植当日计为第 0日， 口投药物第二日即移 植后的第 1天依次计为第 1 日，以此类推， 口投药物第 15日计为第 14日。实验结果显示， 本发明化合物组随着用量的增加移植心脏在受者中的生存日数得到相应的延长，尽管用量 很大也没有发现副作用。而对照组大鼠在实验剂量范围内其生存日数不受剂量影响。且各 剂量的实验组大鼠的生存日数较之对照组大鼠的生存日数显著延长，表明本发明化合物较 之 FTY720有更好的免疫抑制效果。
对大鼠做肝脏移植， 受试动物分为两组， 一组口投本发明化合物 A-1 , 称为实验组， 另一组口投 FTY720, 称为对照组。 两组均从移植次日开始连续 14 d给药。 结果显示， 本 发明化合物较之 FTY720能显著延长受者的生存日数，表明本发明化合物较之 FTY720有更 好的免疫抑制效果。
对大鼠做小肠移植， 受试动物分为两组， 一组口投本发明化合物 A-1 , 称为实验组， 另一组口投 FTY720, 称为对照组。 两组均从移植当日起连续 15日给药； 口投药物第一日 即移植当日计为第 0日， 口投药物第二日即移植后的第 1天依次计为第 1 日， 以此类推， 口投药物第 15日计为第 14日。 结果显示， 本发明化合物较之 FTY720能显著延长受者的 生存日数， 表明本发明化合物较之 FTY720有更好的免疫抑制效果。
对 Beagle犬做肾脏移植， 受试动物分为两组， 一组口投本发明化合物 A_l， 称为实 验组， 另一组口投 FTY720, 称为对照组。 两组均从移植当日起每日给药， 直至两组动物 的生存日数出现显著不同。本发明化合物 A-1较之 FTY720能明显延长受试狗的生存日数， 表明本发明化合物对大动物也同样有抑制排斥反应的效果。
表 1总结了本发明化合物 A-1与 FTY720的不同用量对不同动物的不同器官移植时， 所得到的免疫抑制的实验结果。
表 1
Figure imgf000013_0001
从上表看出，实验组本发明化合物在不同器官移植时，免疫抑制的作用均优于对照组
FTY720。
本发明实施例部分所用动物均由江苏省实验动物中心提供。

Claims

权利要求书
1、 2-对辛基苯乙 -2-氨基丙二醇衍生物， 结构如式 （1 ) 所示：
Figure imgf000014_0001
( 1 ) 其中， 、 R2、 R3独立的选自 H或酰基； R4选自亚甲基、 羰基、
Figure imgf000014_0002
R5为反式 4-甲基环己基。
2、根据权利要求 1所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物，其特征在于所述 、 R2、 R3可独立的选自 H或 C1~C4的酰基。
3、根据权利要求 2所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物，其特征在于所述 、 R2、 R3可独立的选自 H或乙酰基。
4、 根据权利要求 1~3中任一项所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物， 其特征在于 所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物为： 结构式如 （A-1 ) 所示的 2- (反式 4-甲 基环己基） 甲酰基苯乙基 -2-氨基丙二醇， 结构式如（A-2)所示的 2- (反式 4-甲基环己基） 甲酰基苯乙基 -2-乙酰氨基丙二醇二乙酸酯、 结构式如 （A-3 )所示的 2- (反式 4-甲基环己 基） 甲基苯乙基 -2-氨基丙二醇、 结构式如 （A-4) 所示的 2- (反式 4-甲基环己基） 羟甲基 苯乙基 -2-氨基丙二醇或结构式如 （A-5 )所示的 2- (反式 4-甲基环己基）羟肟基苯乙基 -2- 氨基丙二醇，
Figure imgf000015_0001
(A-5)
5、权利要求 1所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物在制备治疗肺损伤和 /或肺纤维 化的药物中的应用。
6、 权利要求 1所述的 2-对辛基苯乙基 -2-氨基丙二醇衍生物在制备免疫抑制剂药物中的应 用。
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