GB2494595A - Phenylbutyryl curcumin derivatives and uses for preparing anti-tumor drugs thereof - Google Patents

Phenylbutyryl curcumin derivatives and uses for preparing anti-tumor drugs thereof Download PDF

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GB2494595A
GB2494595A GB1223251.8A GB201223251A GB2494595A GB 2494595 A GB2494595 A GB 2494595A GB 201223251 A GB201223251 A GB 201223251A GB 2494595 A GB2494595 A GB 2494595A
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tumors
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Jianhua Xu
Yang Liu
Lixan Wu
Yanfang Lin
Zhijuin Wu
Xiaodan Guo
Min Wu
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Fujian Medical University
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    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

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Abstract

Provided are phenylbutyryl curcumin derivatives, their preparation methods, pharmaceutical compositions containing said derivatives and uses thereof for preparing anti-tumor drugs. Said curcumin derivatives are specifically 4-[bis(2-chloroethyl)amino]phenylbutyryl curcumin and 4,4'-bis[bis(2-chloroethyl)amino]phenylbutyryl curcumin, and their pharmaceutically acceptable salts. The curcumin derivatives are effective on inhibiting various animal tumor cell transplantation models in vivo, and do not have serious toxicity in mouse.

Description

Phenylbutyryl Curcumin Derivatives and Use Thereof iii Manufacturing Medicarnents for Preventing Tumors
Field of the Invention
This present invention relates to tile pharmaceutical field and particularly relates to phenylbutyryl Curcumin derivatives and methods for manufacturing them, and use of the derivatives hi manufacturing medicaments for preventhig tumors.
Description of the Prior art
Curcumin (Cur for short) is an effective component extracted from rhizomes of the plants of genus Curcuma, such as curcurna longa, curcuma zedoary, curcurna aroniatica and so on. The Curcumin has effects on preventing tumors, inflammatory, Human imniunodeficiency virus, cholesterol, and oxidation and has good potential of clinical application. But Cur is unstable, low bioavailability and difficult to reach effective concentration in vivo and metabolizes quickly in vivo, thus Cur is difficult to be applied in manufacturing effective anti-tumor medicarnents. It is important to synthesize Curcumin derivatives to improve bioavailabil ity, and prolong biological half-life t112 by structure modification.
Summary of the Invention
One of the objects of the invention is to provide 4-[bis (2-chloroethyl) amino] phenylbutyiyl Curc umin, 4,4' -[bis(2-chloroethyl)arnino]diphenylbutyryl Curcumin, and pharmaceutically acceptable salts thereof Another object of the invention is to provide methods for manufacturing 4-[bis(2-chloroethyl)amino]phenylbutyryl Curc umin. 4,4' -[bis(2-chloroethyl) amino]diphenylbutyryl Curcumin and pharnrnceutically acceptable salts thereof In order to attain the objects of the invention, technical solutions are as follows.
The structural formula of 4-[bis(2-ch1oroetliyamino]pheny1butyryl Curcurnin of the invention is shown as following compound 1, and the structural fonnula of 4,4 -[bis(2-chloroethyl)amino] diphenylbutyryl Curcumin is shown as following compoulld 2, and the salts of the phenylbutyryl Curcumin derivatives of the invention are pharmaceutically acceptable salts of compound 1 and compouid 2 respectively. o a
i-13C0 It Cl O OH compound 1 Cl: o o 1 1 Cl 00 0 ci conipound2 N ci The pharmaceutically acceptable salts comprise alkali metal salts, alkaline earth metal salts, and the salts containilig organic bases. The pharmaceutically acceptable salts further comprise calcium salts, magnesium salts, ammoniuin salts, triethyl amine salts, and ethanolamine salts.
The methods for manufacturing the Curcumin derivatives of the invention and salts thereof comprise the following steps: dissolving Curcurnir in dried dichloromethane, adding catalytic amount of DMA P (N,N-4-dimethyl aminopyridine), then adding 4-[bis(2-cliloroethyl)anñno] phenylbutyric acid dissolved in dichloromethane for esterification, then separating and purifying the products by column chromatography. In the method of the invention, dehydrant DCC (N,N-dicyclohexylcarbodiimide) or EDCI (1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiirnide hydrochloride) can be added in advance, and then conventional catalytic amount of DMAP is added.
The Curcunrin derivatives having the structure of compound 1 or compound 2 have been identified by nuclear magnetic resonance spectrum (NMR), infra-red spectrum (IR), ultraviolet spectrum (UV), and liquid chromatography-mass spectrornetry (HPLC-Mass). Compound 1 and compound 2 can be manufactured to suitably pharmaceutical dosage forms after identification.
The invention claims medicaments of compound I or compound 2, or pharmaceutically acceptable salts thereof, or medicaments comprising compound I or compound 2, or pharmaceutical compositions or preparations consisting of the pharmaceutically acceptable salts thereof.
In manufacturing pharmaceutical forms, carriers of the medicaments can be selected from conventional carriers in tile art, such as diluents. excipients. fillers, adhesives, disintegrating agents, surfactants, lubricants and so on. The medicaments can be made in forms of oral administration and other pharmaceutical forms, such as oral liquid, suspension, capsule, tablet, pilula, granula, injecta and so on. The medicarnents of the invention can be manufactured by conventional methods in the art, and comprise 0.1 wt% -99.5 wt% of active ingredient of compound 1 or compound 2, or pharmaceutical compositions contaning 0.1 wt% -99.5 wt% of compound 1 or compound 2. These are technique s which can be obtained by a skilled person in the art.
The dosages of the medicanients in the invention can be determined according to the ways of administration of the inedicaments, ages of patients, weights of patients, types of diseases, and severity of diseases. The dosages may be 0.00 1-10 g/kg (weight of a patient), and the medicaments can be administered once or more.
Another object of the invention is to provide use of 4-[bis(2-chloroethyflamino] phenylbutyryl Curcumin and 4,4'-[bis(2-cIi loroethyl)amino]diphenylbutyryl Curcumin in manufacturing medicaments for preventing tumors.
The Curcumin derivatives can be used in manufacturing the medicaments for treating leukemia, skin cancer, gastric cancer, colon cancer, liver calicer, breast cancer, or prostate cancer, but not limited in them. To leukemia, Human chronic myeloid leukemia is preferred.
The advantages of the invention are as follows: compound 1 (Curcumin 4-[bis(2-chl oroethyl)aminojphenylbutyrate) of the invention significantly inhibits various animal tumor cell transplantation models in vivo. The rate of theinhibition to transplanted tumors of Human chronic myeloid leukemia cells K562 in nude mice is tip to 60%, and the weights of the mice change insignificantly, and none of the mice is dead. Compound 1 also prolongs the life span of NOD-SCID mice into which the Human chronic myeloid leukemia cells 1(562 are transplanted, and no severe toxic reactions are shorn on the mice. The rate of the inhibition of liver cancer 1-122 of mice is 40-75% in viva Compound 2 has the similar structure to compound 1, thus compound 2 has equal effects to compound 1 which are also proved by tests. Thus, these compounds have better effects on preventing tumors than Curcumin has.
Brief Description of the Drawin2s
Figure 1 is a diagram of inhibition to transplanted hepatocarcinoma H22 tumor of the mice by intravenous administration of compound 1.
Figure 2 is a diagram of inhibition to transplanted hepatocarcinoma H22 tumor of the mice by oral administration of compound 1.
Figure 3 is a diagram of growth curve of transp'anted tumors of Human chronic myeloid leukemia cells K562 in nude mice effected by compound 1.
Figure 4 is a diagram of effects of compound 1 on transplanted tumors of Human chronic niyeloid leukemia cells K562 in nude mice.
Figure 5 is an anatomical diagram of a mouse model of Human chronic myeloid leukemia.
Figure 6 is a diagram of marrow bcr-abl gene expression of a mouse model of Human chronic myeloid leukemia.
Figure 7 is a diagram of peripheral hemogram of Human chronic myeloid leukemia mice model in NS group.
Figure 8 is a diagram of effects of compound 1 on peripheral hemograrn of Human chronic myeloid leukemia mice model.
Figure 9 is a diagrani of inhibitory effects of compound 2 on transplanted hepatocarcinoma H22 tumors of mice.
As shown in Figure 1, the mice with transplanted hepatocarcinoma H22 tumor is established and normal saline (control group) arid compound 1 (50 mg/kg and 70 mg/kg, medication group) are intravenously administered separately. The rate of the inhibition to the transplanted tumors of the mice is up to 60%.
As shown in Figure 2, the mice with transplanted hepatocarcinoma H22 tumor is established and saline (control group), compound I (50 mg/kg, 75 mg/kg and 100 mg/kg, medication group), and Curcumin (50 mg/kg, Curcumin control group) are orally administered normal separately. The rates of inhibition of the tumors of the mice in medication group are 41.21%, 52.93% and 75.06% separately. The rate of inhibition of the tumors of the mice in Curcumin control group (equimolar to 100 mg/kg of compound 1) is only 16.58%. The inhibitory effects of the compound 1 on the tumors are more significant than that of Curcumin.
As shown in Figure 3, the nude mice with transplanted tumor of Human chronic myeloid leukemia cells K562 is established and normal saline (control group) and compound 1 (40 mg/kg and 60 mg/kg, medication group) are orally administered separately. Then at the 0, 4 th, 8 th, and 11th day, the length, width and height of the tumors of the mice are measured by vernier caliper. The volume of the tumor = length x width x height x 1/2. The percent of the increase (%) = ((average volume of the tumors in experimental groups) -(average volume of the tumors in the control group)) / (average volume of the tumors in the control group) x 100%. It can be seen from Figure 3 that the growth of the tumors of the mice in medication group is significantly inhibited.
As shown iii Figure 4, the nude mice with transplanted tumor of Human chronic myeloid leukemia cells K562 is established and normal saline (control group) and compound 1 (40 mg/kg and 60 mg/kg, medication group) are orally administered separately. The rates of the inhibition of the tumors of the mice are 66.6% and 56.7% separately.
As shown in Figure 5 and Figure 6, the NOD-SCID mouse of Human chronic myeloid leukemia in control group is dissected, and there are a lot of bloody ascites and solid tumors in the abdominal cavity. The bcr-abl gene of Human chronic rnyeloid leukemia is found in marrow cells of the mouse by RT-PCR. thus it shows that Human chronic myeloid leukemia cells K562 home in the marrow of the NOD-SCID mouse.
As shown in Figure 7 and Figure 8, the NOD-SCID mice of Human chronic myeloid leukemia are orally administered normal saline (control group) and compound 1 (60 mg/kg, medication group), separately. The immature cells in peripheral hemogram of the mice in tile medication group are obviously less than the mice in the control group.
As shown in Figure 9, the mice are orally administered normal saline (control group), compound 2 (35 mg/kg, 50 mg/kg, 75 mg/kg and 115 mg/kg, medication group) and Curcumin (50 mg/kg, Curcumin control group), separately. The rates of the inhibition of the tumors are 27.43%, 32.25%, 62.60% and 58.39% separately.
The rate of the inhibition of the tumors of the mice i11 Curcumin control group (equimolar to 100 mg/kg of the compound) is only 13.42%. The inhibitory effects of compound 2 on the tumors are more significant than that of Curcumin.
Detailed Description of the Preferred Embodiments
The invention is described in details by tile combination of tile drawings and the following embodiments.
Enthodiment 1: synthesis of 4-[bis(2-chloroethyl)amino]phenylbutyryl Curcumin (compound 1) EDCT l.92g (lOmmol) was dissolved in 200nil of anhydrous dicliloromethane and stirred in ice-bath. Then. Curcumin 7.36g (2Ommol) and DMAP 0.244 g (2 mmol) were added. Then 200m1 dichioromethane containing 3.04g( 1 Ommol) 4-[bis(2-chloroethyl)amino] phenylbutyric acid was slowly dropped. The mixture was stirred for 6 hours at room temperature. Organic phase was dried by anhydrous magnesium sulfate after being washed by distilled water, and then filtered and concentrated to obtain crude product. The crude product was separated by preparative chromatography of medium pression, with C 18 reversed phase column, and eluted with the mixture of methanol and water (50%-> 100%, volume percent) to obtain purified 4-[bis(2-chloroethyl)amino]phenylbutyryl Curcumin (1.30 g). The production was in 20% yield, and tile structure formula of the product is as follows: 0 OH H3C0><t Cl::OH compound I c 1 The molecular formula is C351-137C11N07, mp 100-102°C 1H NMR (D6-DMSO): 5 1.88 (t, 2 H, -COCH2CH2CH2Ph), 2.51 ft 2 H, -COCH2CH3CH2Ph), 2.58 (In, 2 1-1, -COCI-I2CH2CH2Ph), 3.62 (t, 4 H, -NCH2CH2CI), 3.71 (t, 4 H, -NCH3CH2CI), 3.85 (s, 6 H, 2Ar-OCH3), 6.14 (s, 1 H, -COCH=C(OH)-), 630 (d, 2 H, 2-CHCH-Ar, 6.78-6.99 (in, 2 H), T13-7.19 (in, 2 H), 7.33 (rn, 2 H), 7.51 (d, 2 H), 7.58 (d, 2 H), 7.62 (d, 2 H, 2Ar-CH=), 9.72 (s, 1 H, Ar-OH); H PLC-MS rn/z: 654.2 (M + 1).
Embodiment 2: syiithesis of 4,4'-[bi s(2-chloroethyl)amiiio]diphenylbutyryl Curcumin (compound 2) EDCI 1.92 g (10 minol) was dissolved in lOOinI anhydrous dichlorornethane and stirred in ice-bath. Curcumin 1.84 g (5 mrnol) and DMAP 0.122 g (1 rnmo) were added. Then 200m1 dichloromethane containing 3.04g( I Omrnol) 4-[b is(2-chloroethyl)aminopheny1butyric acid was slowly dropped. The mixture was stirred for 6 hours at room temperature. Organic phase was dried by anhydrous magnesium sulfate after washed by distilled water, and then filtered and concentrated to obtain crude product. The crude product was separated by chromatography of medium pression. with Cl 8 reversed phase column, and elued with the mixture of methanol and water (5O%_*100%, volume percent) to obtain purified 4,4'-[bis(2-chloroethyl)amino]diphenylbutyryl Curcumin (1.88 g, compound 2). The production was in 40% yield. The structural formula of the product is as follows: 0 OH HaCO:,H] ii J I ci / 0 0 / compound 2 N a C49H54C14N1O, mp. 58-60°C, H NMR (CDC13): 3 2.04 (m, 4 H, -COCH2CH1CH2Ph), 2.29 (t, 4 H, -COCH2CH2CH1PIi). 2.60 (rn, 4 H, -COCH2CH2CH-,Ph), 3.63 (t, 4 H, -NCI-LCH2C1), 3.70 (t, 4 Ii, -NCH2CFI2CI), 3.87 (s, 6 H, 2Ar-OCH3), 6.58 (d, 2 H, .1 = 16 Hz, 2-CH=CH-Ar), 6.63 (d, 4 H, J 8 Hz), 6.66 (s, 1 H, -COCH=C(OH)-), 7.03 (s, 2 H), 7.05 (rn, 2 H), 7.08 (m, 2 H), 7.12 (d, 4 H, J= 8 Hz). 7.17(m, 2 H), 7.51 (d, 2 H), 7.53 (d, 2 H), 7.62 (d, 2 H, J= 16 Hz, 2Ar-CHj; HPLC-MS nih: 941.3 (M + 1).
Embodiment 3: effects of compound I on the mice with transplanted hepatocarcinoma H22 tumor 1' 3.1 Materials 8-12 weeks old female healthy mice of Kunming species were selected, and the weight of each mouse was (20 2) g. The mice were obtained from the laboratory animal center of Fujian Medical University (certificate of conformity is SCXK (fujian) 200420002). The mouse liver cancer cell was H22. Compound 1 of required concentration was prepared before being used.
3.2 Method 3.2.1 Building tumor-bearing mice model The tumor cells H22 was subcultured for more than two generations. The amount of the cells was adjusted to 107/mL. Then the cells (0.2 mL per mouse) were inoculated into the subcutaneous regions of right forelimbs of two mice. After about two weeks, the tumors were taken out and homogenized. and then inoculated into other eighty mice.
3.2.2 Grouping A: 24h later after being inoculated with the tumor cells, the mice were divided into three groups randomly. Group I was a control group of normal saline. Compound I in this embodiment and in the following embodiments was manufactured by the methods in the above embodiments. Group II was a low-dose group of compound 1(50mg/kg of compound 1). Group 111 was a high-dose group of compound 1(70 mg/kg). The compound (0.1 mL/i0 g) or the normal saline (0.1 mL/I0 g) was administrated by caudal vein injection.
B: 24h later after being inoculated with the tumor cells, the mice were divided into five groups randomly. Group I was a control group of normal saline (i.e. tumors control group). Group II was a low-dose group of compound 1 (50 mg/kg). Group III was a high-dose group of compound 1 (75 mg/kg). Group IV was a high-dose group of compound 1 (I 00 mg/kg). Group V was a Cur group (50 mg/kg, equimolar to group TV). The way of administration was caudal vein injection, and the dosage was 0.1 mL/l0 g.
3.2.3 Rate of inhibition of the tumors The tumors were taken out of the bodies of the mice and weighed. The rate of the inhibition of the tumors is calculated. The rate of the inhibition of the tumors (%) = ((average weight of the mice in the control group) -(average weight of the mice in experimental group)) / (average weight of the tumors of the mice in the control group) x 100%.
3.3 Results 3.3.1 Inhibitory effects of compound 1 on the tumors by intravenous administration The inhibitory effects of compound I with various dosages on the tumors were observed. The inhibitory etrects of compound 1 on the transplanted hepatocarcinoma 1-122 tumor of the mice were significant (see table 1 and Figure 1).
Table 1 Inhibitory effects of compound 1 on the transplanted hepatocarcinoma H22 tumor of the mice by intravenous administration Dosage Amount of Weight of Rate of Group mouse tumor (g) inhibition mg/kg x day before/after + s) NS 0 10 10/10 1.01 ±0.47 0 Low-dosage 50)< 7 10/9 0.40+ 0.15 60.84** group High-dose 70 x 5 10/6 0.335 ± 0.16 66.83** group Note: NS (normal saline control group), compared with NS, * P < 0.05, ** P < 0.01.
3.3.2 Inhibitory effects of compound 1 on the tumors by oral administration.
The mice were orally administrated for six days and then the inhibitory effects on the tumors were observed. The rate of the inhibition of the tumors gradually improved as the dosage was increased and good dose-effect relationship was shown. The inhibitory effects of the medication group (100 mg/kg) on the tumors were more significantly improved than that of the Curcumin control group (50 mg/kg). Compound I was so safe that none of the mice was dead at large dosage (see table 2 and Figure 2).
Table 2 Inhibitory effects of oral administration on the transplanted hepatocarcinoma H22 tumor of the mice amount of wcight(y + s) weight of rate of group mouse tumor (g) inhibition of tumors before/after before / after (i ± s) (%) NS 10/10 20.26 + 1.68 / 26.43 ± 4.00 1.60+0.24 0 compoundl 10/10 20.79 + 1.63 / 22.12 ± 2.48 0.94± 0.33 41.21" (50mg/kg) compoundi 10/10 21.02 ± 1.54 / 22.00 ± 3.98 0.76± 0.26 52.93" (75mg/kg) compoundl 10/10 21.10+1.57/18.64±1.91 0.40±0.15 75.06" (100mg/kg) Curcumin 10/10 21.17+ 1.62/26.61 ±3.67 1.34± 0.25 16.58 mg/kg Note: compared with NS, * P <0.05; ** P <0.01. Cur is CurciLmin Embodiment 4: Effects of compound I on nude mouse with transplanted tumors of Human chronic niyeloid leukemia cells K562 4.1 Materials 4-6 weeks old male SPF mice were provided by Shanghai Slac Laboratory Animal Inc. (certificate of conformity is SCXX (shanghai) 2007-0005), and the mice were raised in SPF laboratory. The T-Iuman chronic myeloid leukemia cells K562 were provided by the cell bank of Shanghai Insitute of Biochemistry and Cell Biology, CAS (ICBC). Compound I of required concentration was preparedbefore being used.
4.2 Method 4.2.1 Building tumor-bearing mice model The tumor cells K562 had been subcultured for more than two generations. The amount of the cells was adjusted to 5 X 107/mL. Then the cells (0.2 mL per mouse) were inoculated into the subcutaneous regions of right forelimbs of thirty nude mice.
4.2.2 Grouping Six days later after inocu'ation of the tumor cefls, the mice were divided into three groups randomly. according to the volume of the tumors. Group I was a control group of normal saline. Group II was a low-dose group of compound 1 (40 mg/kg).
Group III was a high-dose group of compound 1 (60 mg/kg). The way of administration was intragastric administration, and the dosage was 0.1 inL/l0 g.
4.2.3 Rate of increase of the tumors The length, the height and the width of the tumors were measured by vernier caliper at 0, the 4 th, the 8 th and the 11th day respectively. The volume of the tumor = length x width X height >< 1/2, and the rate of the increase of the tumor (%) = ((average volume of the tumors in experimental group) -(average volume of the tumors in the control group)/ (average volume of the tumors in the contro' group) x 100%.
4.2.4 Rate of inhibition of the tumors The tumors were taken out of the bodies of the mice and weighed. The rate of the inhibition of the tumors was calculated. The rate of the inhibition of the tumors (%) = ((average weight of the tumors of the mice in the control group) -(average weight of the tumors of the mice in experimenta' group))! (average weight of the tumors of the mice in the control group) x 100%.
4.3 Results 4.3.1 Rate of increase of the tumors The growth of the tumors of the mice can be seen in Figure 3. The rate of increase of the tumors in the medication group was lower than in the NS control group.
4.3.2 Inhibitory effects of oral administration on the tumors Inhibitory effects on the tumors were observed after 11 days of oral administration.
The inhibitory effects of compound I on the nude mice transplanted tumors of K562 were significant. The rates of the inhibition of the tumors were 66.6% and 56.7%, respectively. They are obviously different hi statistic analysis (t test) and there is a dosage effect relationship (see table 3 and Figure 4). The weight of the nude mice in the medication group changes unobviously, and none of the nude mice was dead, compared with the mice in the control group. The toxicity of the compound did not rise when the compound was appiled to prevent the tumors. It can be seeii from the above that the inhibitory effects of compound I oii the nude mice with transplanted tumors of Human chronic rnyeloid leukemia cells K562 were significant.
Table 3 Inhibitory effects of oral administration on tile mide mice with transplanted tumors of Human chronic myeloid leukemia cells K562 amount Weight of mouse (Y + Weight of Rate of group of mice s) lumor (g) inhibitio n before! before! after ( + s) (%) after NS 6!6 19.9+ 1.8!21.1 ± 1.0 1.36+1.19 0 eompoundl (4Omg!kg) 6!6 19.6+ 1.9!20.6± 1.6 0.46+0.17 65.90** compoundl (60 mg!kg) 6!6 20.7+ 1.6!21.5 + 1.2 0.50+0.40 57.70 Note: compared with NS group, P < 0.05, ** P < 0.01.
Enibodiment 5 Effects of compound 1 on mice model of Human chronic myeloid leukemia 5.1 Materials 5.1.1 NOD-SCID mice 4-6 weeks old female and male mice were provided by the Institute of laboratory animal, Chinese Academy of Medical Sciences (certificate of conformity is SCXK (beijing) 2005-0013), and weight of each mouse was 18-22 g. NOD-SCID mice is were raised in cover box on laminar flow rack in SPF laboratory (conforming to the standard of SPF). Standard particle feed, drink, litter and all products contact with mice were sterilized.
5.1.2 Human chronic myeloid leukemia cells (K562) The cells 1(562 were provided by the cell bank of Shanghai Institute of cell biology, Chinese Academy of Sciences. The cells of conventional subculture in logarithmic growth phase were transplanted into animals.
5.1.3 Compound 1 of required concentration was preparedbefore being used.
5.2 Method 5.2.1 Building up mice model of chronic myeloid leukemia NOD-SCID mice were irradiated all over the body by 2.0 Gy X. Then, the cells K562 in logarithmic growth phase were transplanted at the next day and lx io cell/mouse was injected into the caudal vein.
5.2.2 Effects of compound 1 on NOD-SCID mice model of chronic myeloid leukemia The NOD-SCID mice into which cells K562 are transplanted were divided into several groups randomly. There were four mice in each of groups (a normal saline control group and a medication group). Normal saline was given to the mice in the control group by lavage, and the dosage was 0.2 mL/mouse. Compound 1 was administrated to the mice in the medication group by lavage, and the dosage was mg/kg. It was an interval of 5 days between 5 days and 8 days of continuous administration of compound 1, two weeks later after the transplantation.
Conditions, weights and appetites of the mice were observed during the period of administration, and toxicity of compound 1 and endurance of the mice were evaluated for adjusting the administration. Survival time was recorded in a period of three months. More than two months of survival time of the mice with transplanted cells K562 was long tenn survival.
5.2.3 Peripheral blood smear and leukocyte count Blood was collected from caudal veins of the mice in each group before and after 1, 2, 3, 4 and S weeks of transplantation. Blood smears were prepared, and the amount of leukocyte was counted by oil immersion lens via Giemsa staining.
5.3 Results 5.3. 1 Building up NOD-SCID mice model of Human chronic myeloid leukemia After the Human chronic myeloid leukemia cells K562 were transplanted into the mice in the control group of normal saline, the survival time was 32.5 + 9.0 days, and the fur of the mice was wrinkled, and the mice were torpid, limping and gradual weight loss. Three weeks later after transplantation, the amount of leukocyte in peripheral blood increased obviously and reached to 2-10 times of pretransplant. A lot ofjuvenile cells can be seen in peripheral blood smears. There were a lot of bloody ascites and solid tumors in the abdominal cavity. Splenauxe was unobvious (see Figure 5). Human gene bcr-abl was found in the marrow cells of NOD-SCID mice by RT-PCR (see Figure 6), which showed that Human chronic myeloid leukemia cells K562 home in the marrow of NOD-SCID, and the model of Human chronic rnyeloid leukemia is built up successftilly.
5.3.2 Effects of oral administration on the mice of Human chronic myeloid leukemia Two mice in the medication group survived for 85 days (long-term survival), and the other mice survived longer than the control group. The amount of leukocyte in peripheral blood of the mice in the medication group was far less than the control group (see TaMe 4, 5 and Figure7, 8). II can be seen from the above that compound I synthesized in Embodiment 1 was effective to the mice of Human chronic myeloid leukemia.
Table 4 Effects of oral administration on the survival time of the mice of Human chronic myeloid leukemia dosage weight of mouse long term survival time prolonging group before/after survival (d) rate of survival time (mg/kg) (i + s) (i ± s) (%) NS 0 26.3 ± 2.5 / 28 0/4 32.5 ± 9.0 0 compound 1 60 25.5 + 2.1 / 23.3 ± 2/4 68.5 ± 24.4 110.77* 0.6 *: P < 0.05, vs NS group.
Table 5 The amount of leulcocyte in peripheral blood of the mice in each group (xl 091L) Group time (week) after inoculation of cell K562 0 1 2 3 4 5 NS 4.02 + 1.02 3.31 th 1.34 4.68 + 1.52 14.03 + 5.52 8.91 ± 2.66 dead Compound 1 3.92 ± 0.34 2.53 + 0.70 2.52 + 1.27 7.86 + 2.52 7.35 + 3.! I 6.47 + 3.86 Embodiment 6. Inhibitory effects of compound 2 on the transplanted hepatocarcinoma 1-122 tumor of the mice Compound 2 was synthesized by the above methods. Test method iii this embodiment was the same as compound I. Compound 2 of required concentration was prepared before being applied. The tumors were taken out of the bodies of the mice under aseptic conditions, and the well grown tissue of the tumors was selected and made into single cell suspension by homogenate and filtering. The amount of the cells was adjusted to I x 107/mL. Then the cells (0.2 mL per mouse) were inoculated into the subcutaneous regions of right forelimbs of the mice, and the transplanted tumors H22 bearing mice model was built up. At the next day, the mice were divided into several groups randomly. There were nine mice in each group, and weight of each mouse was recorded before administration of compound 2. The mice were orally administered compound 2 (0.2 inL/10 g of weight) once a day for 8 days. The tumors were taken out 24 h later after last administration and photographed and weighed (see table 6 and Figure 9). The average weight of the tumors and rate of inhibition were calculated. Rate of inhibition of tumors (%) = ((average weight of the tumors in the control group) (average weight of the tumors in experimental groups))! (average weight of the tumors in the control group) 100%.
Table 6 Inhibitory effects of compound 2 on the transplanted hepatocarcinorna H22 tumor of the mice amount of weight of mouse (±s) weight of rate of group mouse before/after tumor (g) iithbition before/after ( + s) (%) NS 9/9 20.08+1.03/28.9±3.15 1.24+0.64 Curcumin / 19.83±0.96/30.08+3.77 1.08±0.33 13.42 mg/kg x 8 positive control 9/9 19.96±1.19/21.56+3.28 0.90±0.20 27.25 mgikgx8 compound 2 9/9 20.52+1.23/26.23+3.41 0.90+0.36 27.43 mgikgx8 com ound 2 9/8 20.38+1.24/23.74+1.85 0.84+0.42 32.25 mg'kgx8 compound 2 9/9 20.56±1.82/21.08±1.01 0.46±0.26 62.60** mg'kg8 compound 2 9/9 20.14+1.52/18.69±2.55 0.52+0.16 58.39** mg/kgxS Note: compared with NS group, P C 0.05; *9) C 0.01.
Compound 1. compound 2, or pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising Compound 1, compound 2, or pharmaceutically acceptable salts thereof were proved to have similar effects by above methods. The pharmaceutically acceptable salts comprise alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as calcium salts or magnesium salts), salts containing organic base (such as ammonium salts), or salts containing organic base (such as triethylamine salts or ethano lamine salts).
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