CN115703754A - Dehydrocostuslactone carbamate derivatives and salts thereof, pharmaceutical compositions and uses thereof - Google Patents
Dehydrocostuslactone carbamate derivatives and salts thereof, pharmaceutical compositions and uses thereof Download PDFInfo
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Abstract
The invention relates to a dehydrocostuslactone carbamate derivative, a pharmaceutical composition, a preparation method and application thereof, belongs to the field of pharmacy, and particularly relates to a compound shown as a formula (I), a pharmaceutical composition and a preparation method thereofAnd uses, in particular the use of compounds of formula (I) for the treatment of rheumatoid arthritis and for the treatment of cancer.
Description
Technical Field
The invention relates to dehydrocostunolide derivatives, salts thereof, drugs which are used as active ingredients and used for treating rheumatoid arthritis or assisting in treating rheumatoid arthritis, and application of the compounds and compositions in preparing anti-cancer drugs or drugs assisting in treating cancers. Belongs to the field of pharmaceutical chemistry.
Background
Sesquiterpene lactones (SQL) are a natural product of plant origin and have a wide range of biological activities, including anti-inflammatory, antiviral and antiproliferative properties. Such compounds typically have an α -methylene- γ -lactone ring structure that is critical to their activity. Radix aucklandiae is dried root of Aucklandia lappa Decne of Compositae, and is named Saussurea costus (falc.) Lipech. The main extraction components of radix aucklandiae are costunolide and dehydrocostuslactone. As shown in formula II, dehydrocostuslactone is a sesquiterpene lactone extracted from Chinese medicinal wood, and has antiinflammatory, antiviral, and antioxidant pharmacological activities. In addition, dehydrocostunolide has been found to have cytotoxic activity against various human cancer cells such as liver cancer, leukemia, ovarian cancer, etc. Therefore, dehydrocostus lactone can be a potential cancer treatment drug and is expected to be developed and researched.
Due to the promising activity of dehydrocostunolide as an anti-leukemia and anti-cancer agent, there is an increasing interest in modifying the hydrogen costunolide backbone to increase its cytotoxicity and selectivity towards cancer cells. Dehydrocostunolide involves two main reaction sites: one is a double bond in the α -methylene- γ -lactone ring, which is capable of Michael addition to the nucleophilic reagent to give the corresponding amine product. Another important chemical modification site is the double bond. This site can undergo allylic oxidation reactions and can add secondary alcohol structures alongside the double bond. Dehydrocostuslactone not only has a variety of pharmacological actions (Bioorganic & Medicinal Chemistry Letters 2013,23,6087-6092), it itself can be used as an important synthon to synthesize complex natural products (+) -ainsliadamer a, (-) -gochnatolides a-C, (-) -ainsliatamers a-B (j.am. Chem. Soc.,2012, 134,12414-12417 chemical science,2013,4,1163-1167 wo 2015/161824 Al.
Carbamates are compounds in which an amino group or an amino group is directly linked to the carbonyl group of a formate, and the general formula is RNHCOOR'. Urethane bonds provide superior hydrolytic stability compared to ester bonds, while acting as hydrogen bond donors and hydrogen bond acceptors. Because of these properties, carbamate functionality finds wide application in pharmaceutical chemistry, and is an integral part of many commercially available drugs. The Peter a crooks topic group reported a series of carbamate analogs of parthenolide and evaluated these derivatives for anti-cancer activity against 60 human cancer cell lines (Bioorganic & Medicinal Chemistry Letters,2014,24,3499-3502). Some of the carbamate compounds of parthenolide showed better activity in leukemia, non-small cell lung cancer, renal cancer and breast cancer.
Rheumatoid Arthritis (RA) is a systemic autoimmune disease. The clinical manifestations are mainly inflammatory synovitis, polyarticular, symmetrical and aggressive arthritis. The incidence population of rheumatoid arthritis is middle-aged, and female patients are more. The pathology of the patient is manifested by chronic inflammation of the synovial membrane of the joints, cartilage and bone destruction of the joints, which can ultimately lead to joint deformity and loss of function. Rheumatoid arthritis patients are often accompanied by the increase of Rheumatoid Factors (RF) and inflammatory factors such as TNF, IL-6, interferon-gamma, IL-12 p70, etc. Therefore, rheumatoid arthritis is a disease of the immune system. Traditional drugs for treating rheumatoid arthritis include nonsteroidal anti-inflammatory drugs, glucocorticoids and the like, and are often accompanied by serious toxic and side effects. Therefore, the development of effective and safe therapeutic drugs is very urgent.
Disclosure of Invention
1. A dehydrocostuslactone carbamate derivative of the following formula (I) and its salt,
wherein R1 represents alkyl, alkylaryl, aryl; wherein R is 1 Expressed as alkyl, alkylaryl, aryl; when R is 2 When it is hydrogen, R 3 Represents
R 5 Represents various amine compounds such as alkylamine, arylamine, dialkylamine, diarylamine, cyclic amine, heterocyclic amine and the like; r 5 Represents an alkyl thiol, an aryl thiol, an alkoxy group or an aryloxy group.
2. The method comprises the following specific steps: the starting material 1 (1 equivalent) was added to dichloromethane (2 mL), then the amine compound 2 (1 equivalent) was added at 0 ℃, and the mixture was stirred at room temperature for 8-12 hours. When the reaction was complete (monitored by thin layer chromatography), water was added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (3 x 15ml). The organic layer was then washed with brine solution, dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give crude product as an oil. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to afford the carbamate analogue 5.
3. The dehydrocostunolide derivative or salt thereof is preferably compound 5a-5e as shown in formula (I):
4. the invention also provides application of the dehydrocostuslactone derivative or the salt thereof in treating cancers or assisting in treating the cancers, wherein the cancers comprise leukemia, breast cancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, colorectal cancer, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer and the like, and the preferred type of the cancers is leukemia.
5. The invention also provides a medicament for treating rheumatoid arthritis, which comprises an effective amount of the dehydrocostuslactone derivative shown in the formula (I) and a pharmaceutically acceptable carrier or a composition of the dehydrocostuslactone derivative and other medicaments for treating the rheumatoid arthritis.
6. The pharmaceutically acceptable carrier or excipient is one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical adjuvants. The medicine of the invention can be administered by two forms of injection and oral administration, such as intravenous injection and intramuscular injection, and the oral administration polarity can be tablets and capsules.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 3;
FIG. 2 is a carbon spectrum of Compound 3;
FIG. 3 is a hydrogen spectrum of Compound 5 a;
FIG. 4 is a carbon spectrum of compound 5 a;
FIG. 5 is a high resolution mass spectrum of compound 5 a;
FIG. 6 is a hydrogen spectrum of Compound 5 b;
FIG. 7 is a carbon spectrum of Compound 5 b;
FIG. 8 is a high resolution mass spectrum of compound 5 b;
FIG. 9 is a hydrogen spectrum of Compound 5 c;
FIG. 10 is a carbon spectrum of Compound 5 c;
FIG. 11 is a high resolution mass spectrum of compound 5 c;
FIG. 12 is a hydrogen spectrum of Compound 5 d;
FIG. 13 is a carbon spectrum of compound 5 d;
FIG. 14 is a high resolution mass spectrum of compound 5 d;
FIG. 15 is a hydrogen spectrum of Compound 5 e;
figure 16 is a carbon spectrum of compound 5 e;
FIG. 17 is a high resolution mass spectrum of compound 5 e;
Detailed Description
To further illustrate the technical means and effects adopted by the present invention, the present invention will be described in detail with reference to specific embodiments. The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited thereto. The organic reagents, and solvents used in the present invention were all commercially available.
Preparation of raw material 1:
dissolving dehydrocostuslactone (1 mmol) in appropriate amount of dichloromethane (5 mL), adding SeO 2 (0.2 mmol) was stirred at room temperature, then TBHP (tert-butyl hydroperoxide) (2 mmol) was diluted with a small amount of dichloromethane and added dropwise over 5 minutes. Monitoring after 30minThe reaction was terminated. The reaction was quenched with saturated sodium thiosulfate (10 mL) and worked up with dichloromethane (3 × 15ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then carrying out column chromatography separation to obtain a pure product. Using petroleum ether: ethyl acetate =15, the unreacted starting material was recovered with an eluent of petroleum ether: ethyl acetate =3:1 to give compound 1. 1 H NMR(400MHz,CDCl 3 ):δ＝6.22(s,1H),5.50(s,2H),5.35 (s,1H),4.92(s,1H),4.78(s,1H),4.69(t,J＝6.0Hz,1H),3.90(t,J＝8.6 Hz,1H),3.09(t,J＝11.3Hz,2H),2.86(t,J＝7.6Hz,1H),2.58–2.48(m, 1H),2.27–2.16(m,2H),1.90–1.84(m,2H),1.46–1.33(m,1H),1.24-1.22 (m,1H). 13 C NMR(100MHz,CDCl 3 ):δ＝170.1,154.1,148.5,139.4, 120.5,113.2,113.1,84.9,74.5,49.5,45.5,44.1,39.8,36.7,30.9.
Preparation of compound 3:
compound 1 (1 equivalent) and triethylamine (1.2 equivalents) were dissolved in dichloromethane (2 mL) and p-nitrophenyl chloroformate 2 (1 equivalent) was added at 0 ℃. The reaction mixture was stirred at room temperature for 17 hours, and when the reaction was complete, water was added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (3 × 10ml). The organic layer was washed with water, then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. And (5) performing column chromatography separation to obtain a pure product. Using petroleum ether: ethyl acetate =5:1 to give p-nitrophenoxycarbonyl ester 3. Yellow solid, yield 67%. 1 H NMR(400MHz,CDCl 3 ):δ＝8.31-8.24(m,2H),7.45-7.35 (m,2H),6.25(d,J＝3.5Hz,1H),5.68-5.66(m,2H),5.62(s,1H),5.54 (d,J＝3.1Hz,1H),4.98(s,1H),4.81(s,1H),3.95(t,J＝9.1Hz,1H), 3.27-3.11(m,2H),2.94-2.87(m,1H),2.57-2.51(m,1H),2.37-2.24(m, 2H),2.20-2.12(m,2H),1.49-1.39(m,1H). 13 C NMR(100MHz,CDCl 3 ): δ＝170.0,155.5,152.2,147.6,145.4,139.0,125.3,121.8,120.9,117.7, 115.6,113.7,84.5,81.8,49.5,45.3,44.8,36.9,36.2,30.9.
Synthesis of Compounds 5a-5 e:
compound 3 (1 equivalent) was added to dichloromethane (2 mL), then amine compound 4 (1 equivalent) was added at 0 ℃, and the mixture was stirred at room temperature for 8-12 hours. When the reaction was complete (monitored by thin layer chromatography), water was added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (3 x 15ml). The organic layer was then washed with brine solution, dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give the crude product as an oil. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to afford the carbamate analog (5 a-5 e).
Example 1
5a, yellow oil, 84% yield. 1 H NMR(400MHz,CDCl 3 ):δ＝ 6.24(d,J＝3.5Hz,1H),5.61(t,J＝5.8Hz,1H),5.57-5.42(m,3H),5.21 (s,1H),4.95(s,1H),4.83(s,1H),3.92(t,J＝9.1Hz,1H),3.70(s,4H), 3.31-3.30(m,2H),3.13-2.98(m,2H),2.91-2.85(m,1H),2.51-2.41(m, 6H),2.36-2.20(m,2H),2.15-2.06(m,1H),2.01-1.93(m,1H),1.47-1.36 (m,1H),1.25-1.23(m,1H). 13 C NMR(100MHz,CDCl 3 ):δ＝170.1, 156.2,149.5,148.0,139.2,120.6,115.2,113.5,85.2,66.9,57.4,53.3, 49.8,45.2,44.5,37.6,37.1,36.9,31.0,13.2.HRMS(ESI):m/z[M+H] + calcd for C 22 H 31 N 2 O 5 :403.2233；found:403.2226.
Example 2
5b, yellow oil, 54% yield; 1 H NMR(400MHz,CDCl 3 ):δ＝6.22 (d,J＝3.5Hz,1H),5.59(t,J＝5.9Hz,1H),5.54-5.43(m,3H),5.34(s, 1H),4.93(s,1H),4.82(s,1H),3.91(t,J＝9.1Hz,1H),3.30(d,J＝5.7 Hz,2H),3.08-3.01(m,2H),2.89-2.83(m,1H),2.61-2.51(m,6H), 2.32-2.21(m,2H),2.15-2.07(m,1H),2.00-1.91(m,1H),1.76(s,4H), 1.45-1.37(m,1H),1.23(d,J＝7.0Hz,1H). 13 C NMR(100MHz, CDCl 3 ):δ＝170.1,156.3,149.5,148.0,139.3,120.5,115.2,113.5,85.1, 76.3,54.9,53.8,49.8,45.2,44.4,39.5,37.5,36.8,30.9,23.4.HRMS (ESI):m/z[M+H] + calcd for C 22 H 31 N 2 O 4 :387.2284；found:387.2282.
example 3
5c, yellow oil, yield 81%; 1 H NMR(400MHz,CDCl 3 ):δ＝6.22 (d,J＝3.5Hz,1H),5.66-5.58(m,2H),5.52(s,1H),5.50(d,J＝3.1Hz, 1H),5.40(s,1H),4.94(s,1H),4.82(s,1H),3.90(t,J＝9.1Hz,1H), 3.71-3.68(m,4H),3.27-3.24(m,2H),3.09-3.00(m,2H),2.89-2.83(m, 1H),2.54-2.50(m,1H),2.43-2.40(m,6H),2.32-2.21(m,2H),2.15-2.07 (m,1H),1.96-1.89(m,1H),1.71-1.65(m,2H),1.45-1.34(m,1H). 13 C NMR(100MHz,CDCl 3 ):δ＝170.0,156.3,149.6,148.0,139.2,120.6, 114.9,113.4,85.2,76.1,66.9,57.2,53.6,49.8,45.2,44.4,40.3,37.5, 36.9,30.9,25.8.HRMS(ESI):m/z[M+H] + calcd for C 23 H 33 N 2 O 5 : 417.2389；found:417.2383.
example 4
5d, yellow oil, 66% yield; 1 H NMR(400MHz,CDCl 3 ):δ＝7.48 (s,1H),7.03(s,1H),6.93(s,1H),6.22(d,J＝3.5Hz,1H),5.58(s,1H), 5.52-5.50(m,2H),5.41(s,1H),5.26(d,J＝21.0Hz,1H),4.93(s,1H), 4.78(s,1H),4.00(t,J＝7.0Hz,2H),3.90(t,J＝9.1Hz,1H),3.31-3.16 (m,2H),3.08-2.99(m,2H),2.90-2.84(m,1H),2.55-2.49(m,1H),2.33- 2.21(m,2H),2.14-2.07(m,1H),2.01-1.93(m,3H),1.44-1.34(m, 1H). 13 C NMR(100MHz,CDCl 3 ):δ＝170.0,156.5,149.4,147.9,139.2, 137.1,129.5,120.6,118.8,115.1,113.4,85.1,49.8,45.1,44.4,44.3, 38.0,37.5,36.9,31.5,30.9.HRMS(ESI):m/z[M+H] + calcd for C 22 H 28 N 3 O 4 :398.2080；found:398.2077.
example 5
5e, yellow oil, 66% yield; 1 H NMR(400MHz,CDCl 3 ):δ＝7.33- 7.19(m,10H),5.59(t,J＝6.4Hz,1H),5.45(s,1H),5.38(s,1H),4.91(s, 1H),4.78(s,1H),3.88(t,J＝9.2Hz,1H),3.47-3.43(m,2H),2.98-2.94 (m,3H),2.91-2.78(m,7H),2.51-2.46(m,1H),2.38-2.34(m,1H),2.31- 2.21(m,2H),2.09-2.05(m,1H),2.00-1.87(m,2H),1.29-1.26(m, 5H). 13 C NMR(400MHz,CDCl 3 ):δ＝177.6,156.2,149.8,148.6,139.9, 128.8,128.7,128.6,128.4,126.5,126.1,114.7,112.8,85.5,76.3,51.6, 49.7,47.6,47.2,45.1,44.0,42.1,37.9,37.4,36.3,36.0,32.6,29.7. HRMS(ESI):m/z[M+H]+calcd for C 32 H 39 N 2 O 4 :515.2910；found: 515.2909.
example 6:
anticancer action of dehydrocostuslactone derivatives:
preparing KG-1a leukemia cell into 4.5X 10 4 Adding each/mL cell suspension into 96-well cell culture plate at a concentration of 100 μ L per well, culturing for 24 hr, adding compounds at different concentrations, setting 6 multiple wells per test concentration, placing at 37 deg.C, and 5% 2 Culturing for 72 hours under saturated humidity condition, adding 10 mu LCCK-8 into each hole, incubating for 1-4 hours at 37 ℃, measuring absorbance (A) value by an enzyme-linked detector at the wavelength of 450nm, and calculating the inhibitory action of the compound on tested cancer cells.
TABLE 1 EXAMPLE 1 preparation of compound vs KG1a (highly CD34 +)Acute myeloid leukemia cell line) inhibitory Activity of cancer cells (IC) 50 ，μM)
| Compound | IC 50 ，μM |
| 5a | 3.78 |
| 5b | 7.51 |
| 5c | 2.19 |
| 5d | 15.96 |
| 5e | 5.82 |
| 1 | 11.11 |
From the above table, it is clear that most dehydrocostunolide derivatives have increased anticancer activity compared to the parent natural product 1.
Example 7: anti-rheumatoid arthritis bioactivity test of compounds 5a-5e
The height of inflammatory factors IL-1 beta, TNF-alpha, IL-6 and IL-17 at focus positions is an important index for evaluating rheumatoid arthritis. For example, IL-1 β can induce joint synovial cell proliferation, interstitial degradation and bone destruction, promote neutrophil, macrophage and lymphocyte accumulation, and cause local inflammatory response. TNF-alpha stimulates synovial cells and chondrocytes to synthesize prostaglandin E2 and collagenase, causing destruction of bone and cartilage resorption, promoting fibroblast synovial cell proliferation. Animal experimental data have been used in a number of literature to examine the efficacy of drugs in the treatment of rheumatoid arthritis by testing their effects on factors which are secreted by synovial cells. These documents are: [1] huang Qingchun, zhang Shengpeng, xu Qiuying, effects of compound Danshen on type II collagen induced synovial cell secretion and tumor necrosis factor in rat model, modern healing, 2001,5 (10): 54-55. [2] Huang Qingchun, zhang Shengpeng, huang Weiyi, etc., the effect of compound Danshen injection on IL-1 beta mRNA expression of CIA rat synovial cells, anhui college of traditional Chinese medicine, 2002,21 (5): 39-41.
The compounds 5a to 5e obtained by the method of the present invention were used for model preparation, drug grouping, and preparation of culture medium supernatant of rat synovial cells according to the method provided in reference [1 ].
The effect of compounds 5a to 5e on TNF-. Alpha.and PEG2 secretion by synovial cells was examined according to the method provided in reference [1], and the effect of compounds 5a to 5e on IL-1. Beta. By synovial cells was examined according to the method provided in reference [2 ].
All the operations were carried out according to the methods provided in references [1] and [2 ].
TABLE-content of TNF-. Alpha.IL-1. Beta.and PEG2 in synovial cell culture supernatant (x. + -. S, ng/mL)
| Group of | TNF-α | IL-1β | PEG2 |
| Blank group | 0.46±0.071 | 0.35±0.126 | 9.31±0.29 |
| Saline water group | 0.87±0.062 | 0.76±0.073 | 35.73±4.87 |
| Compound 5a | 0.63±0.085 | 0.45±0.201 | 23.21±4.59 |
| Compound 5b | 0.67±0.052 | 0.47±0.041 | 27.21±2.46 |
| Compound 5c | 0.64±0.046 | 0.47±0.041 | 25.21±3.11 |
| Compound 5d | 0.58±0.061 | 0.53±0.087 | 29.21±1.54 |
| Compound 5e | 0.69±0.057 | 0.57±0.056 | 27.21±0.22 |
The invention establishes a rat rheumatoid arthritis animal model, researches the influence of the compounds 5a-5e on inflammatory factors TNF-alpha, IL-1 beta and PEG2 by adopting a synovial cell primary culture method, and the result shows that the compounds 5a-5e can obviously reduce the contents of the inflammatory factors TNF-alpha, IL-1 beta and PEG2, thereby achieving the effect of treating rheumatoid arthritis
Example 3: injection solution
After the compounds 5a to 5e prepared in example 1 were dissolved in a small amount of DMSO, water for injection was added as usual, followed by fine filtration, potting and sterilization to prepare an injection.
Example 4: tablet formulation
The compounds 5a-5e prepared in example 1 and excipients were added to 5:1 by weight ratio, granulated and tableted to obtain tablets.
Example 5: capsule
The compounds 5a-5e prepared in example 1 and excipients were added to the excipients in a weight ratio of 5:1 and made into capsules.
The compounds, uses and methods of the invention have been described by way of specific examples. All such substitutions and modifications are intended to be included within the scope of the present invention.
Claims (4)
1. A dehydrocostuslactone carbamate derivative of the following formula (I) and its salt,
wherein R is 1 Expressed as alkyl, alkylaryl, aryl; when R is 2 When it is hydrogen, R 3 Represents
R 5 Represents various amine compounds such as alkylamine, arylamine, dialkylamine, diarylamine, cyclic amine, heterocyclic amine and the like; r 5 Represents alkylthioAlcohols, arylthiols, alkoxy or aryloxy.
2. The molecule of claim 1, prepared by a method comprising the steps of: compound 1 (1 equivalent) was added to dichloromethane (2 mL), then amine compound 2 (1 equivalent) was added at 0 ℃, and the mixture was stirred at room temperature for 8-12 hours. When the reaction was complete (monitored by thin layer chromatography), water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (3 × 15ml). The organic layer was then washed with brine solution, dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give crude product as an oil. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to give the carbamate analogs (5 a-5 d),
3. the invention also provides the use of the compounds of formulae 5a-5e in the preparation of a medicament for the treatment of rheumatoid arthritis and cancer.
4. The invention also provides the use of the compounds of formulae 5a-5e in the preparation of an adjuvant medicament for the treatment of rheumatoid arthritis and cancer.
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