CN109111459B - Cephalotaxine salicylate derivative, its preparation method and application - Google Patents
Cephalotaxine salicylate derivative, its preparation method and application Download PDFInfo
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Abstract
A compound containing a cephalotaxine salicylate derivative, wherein the cephalotaxine salicylate derivative has the following general formula (I):
Description
Technical Field
The invention relates to a cephalotaxine salicylate derivative, a preparation method and application thereof, in particular to a cephalotaxine salicylate derivative used for treating cancer, chronic myelocytic leukemia, acute myelocytic leukemia and lupus erythematosus diseases.
Background
The cephalotaxine is a main active component in cephalotaxus fortunei components, and has various pharmacological activities of resisting cancer, chronic myelocytic leukemia, acute myelocytic leukemia, lupus erythematosus and the like. Cephalotaxine has good pharmacological activity, but its clinical application is limited due to its strong side effects, such as gastrointestinal reaction, bone marrow suppression, cardiotoxicity, hypotension, alopecia, rash, etc. In addition, further studies have found that cephalotaxine is not sufficiently active in vivo, is poorly absorbed, is rapidly metabolized, and has low bioavailability, which further limits its use. At present, the structural modification of cephalotaxine mainly focuses on the following aspects: 1. modifying hydroxyl; 2. varying the alkyl side chain length; 3. the biological electron isostere is used for modification.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel cephalotaxine ester derivative containing salicylic acid to meet the requirements of the field of medicine.
The technical scheme for realizing the aim of the invention is as follows: in order to enhance the activity and improve the side effect of the cephalotaxine compounds, the inventor introduces salicylic acid groups into the cephalotaxine compounds to obtain a novel cephalotaxine ester derivative containing salicylic acid, so as to improve the biological activity and the side effect of the cephalotaxine compounds and meet the requirement of clinical medication.
According to the present invention, there is provided a cephalotaxine salicylate-containing derivative compound having the following general formula (I):
wherein:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 may be the same or different and are each independently or are each independently selected from: hydrogen, carbonyl, hydroxy, C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Acid alkoxy radical, C2-C6Alkynyl, C2-C6Alkenyl radical, C3-C9Cycloalkyl radical, C7-C9Aralkyl, phenyl, cyano C1-C8Alkyl, nitro C1-C8Alkyl, carboxyl, C1-C8Haloalkyl, mono-or polyhydroxy C1-C8Alkyl radical, C1-C4Alkylthio of C1-C4Alkyl radical, C1-C4Alkyl sulfonyl C1-C4Alkyl radical, C1-C6Acyloxy C1-C4Alkyl radical, C1-C6Acyl radical C1-C4Alkyl, sulfonic acid group, however, at least one of R1, R2, R3, R4 and R5 is R.
Preferably, in the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 may be the same or different and are each independently or each independently selected from: hydrogen, carbonyl, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Acid alkoxy radical, C2-C4Alkynyl, C2-C4Alkenyl radical, C3-C7Cycloalkyl radical, C7-C8Aralkyl, phenyl, cyano C1-C4Alkyl, nitro C1-C4Alkyl, carboxyl, C1-C4Haloalkyl, mono-or polyhydroxy C1-C4Alkyl radical, C1-C3Alkylthio of C1-C3Alkyl radical, C1-C3Alkyl sulfonyl C1-C3Alkyl radical, C1-C3Acyl oxygenRadical C1-C3Alkyl radical, C1-C3Acyl radical C1-C3Alkyl, sulfonic acid group, however, at least one of R1, R2, R3, R4 and R5 is R.
More preferably, the cephalotaxine salicylate-containing derivative is:
compound 01:
(1S,3aR) -2-methoxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 02:
(1S,3aS) -2-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 03:
(S) -2-oxo-2, 3,5,6,8, 9-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 04:
(3aR) -2-methoxy-6-oxo-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 05:
(3aS) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 06:
(3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 07:
(3aR) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-3-yl 2-hydroxybenzoate;
compound 08:
(1S,3aR) -2-methoxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 09:
(1S,3aS) -2-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 10:
(S) -2-oxo-2, 3,5,6,8, 9-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 11:
(3aR) -2-methoxy-6-oxo-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 12:
(3aS) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 13:
(3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
or
Compound 14:
(3aR) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-3-yl 2-acetoxybenzoate.
According to the invention, the preparation method of the cephalotaxine salicylate derivative is also provided, and the method comprises the following steps:
1) subjecting a benzoic acid compound of general formula (a) to an acyl chlorination reaction with a chlorinating agent or an acyl chlorinating agent in the presence of an organic solvent to obtain a benzoyl chloride of general formula (B):
wherein R6, R7, R8, R9, R10 may be the same or different and are each independently or are each independently selected from: hydrogen, carbonyl, hydroxy, C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Acid alkoxy radical, C2-C6Alkynyl, C2-C6Alkenyl radical, C3-C9Cycloalkyl radical, C7-C9Aralkyl, phenyl, cyano C1-C8Alkyl, nitro C1-C8Alkyl, carboxyl, C1-C8Haloalkyl, mono-or polyhydroxy C1-C8Alkyl radical, C1-C4Alkylthio of C1-C4Alkyl radical, C1-C4Alkyl sulfonyl C1-C4Alkyl radical, C1-C6Acyloxy C1-C4Alkyl radical, C1-C6Acyl radical C1-C4Alkyl, or, sulfonic acid group;
2) reacting a benzoyl chloride of general formula (B) with a compound of general formula (C) in the presence of an organic solvent to obtain an aqueous cephalotaxin ester derivative of general formula (I):
wherein:
in formula (C), R1, R2, R3, R4, R5 may be the same or different and are each independently or are each independently selected from: hydrogen, carbonyl, hydroxy, C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Acid alkoxy radical, C2-C6Alkynyl, C2-C6Alkenyl radical, C3-C9Cycloalkyl radical, C7-C9Aralkyl, phenyl, cyano C1-C8Alkyl, nitro C1-C8Alkyl, carboxyl, C1-C8Haloalkyl, mono-or polyhydroxy C1-C8Alkyl radical, C1-C4Alkylthio of C1-C4Alkyl radical, C1-C4Alkyl sulfonyl C1-C4Alkyl radical, C1-C6Acyloxy C1-C4Alkyl radical, C1-C6Acyl radical C1-C4Alkyl, or, sulfonic acid group; however, at least one of R1, R2, R3, R4 and R5 is R.
Preferably, the reaction of step 1) is carried out in the presence of a catalyst, wherein the catalyst is one or more of Dimethylformamide (DMF), triethylamine or pyridine.
Preferably, the reaction of step 2) is carried out in the presence of a catalyst, wherein the catalyst is Dicyclohexylcarbodiimide (DCC)/4-pyrrolidinopyridine (PP).
Preferably, in step 1) of the above production method, the chlorinating agent or the acid chlorinating agent is phosphorus trichloride or phosphorus chloride. In step 1), the organic solvent is dichloromethane or dimethylsulfoxide.
Preferably, in step 2) of the above production method, the organic solvent is chloroform;
preferably, in step 1) of the above preparation process, the reaction temperature is 50 to 100 ℃, preferably 60 to 80 ℃, e.g., 70 ℃.
Preferably, in step 2) of the above preparation process, the reaction temperature is 0 to 100 ℃, preferably 20 to 50 ℃, e.g. 25 ℃.
According to the present invention, there is also provided a pharmaceutical composition for anticancer, anti-chronic myelogenous leukemia, anti-acute myelogenous leukemia, anti-lupus erythematosus disease, which comprises the above-mentioned compound or a pharmaceutically acceptable salt thereof.
According to the invention, the use of the above derivative compounds for the preparation of a medicament for the treatment of cancer, chronic myelogenous leukemia, acute myelogenous leukemia and/or lupus erythematosus.
The technical scheme for realizing the above purpose of the invention is as follows: and (3) obtaining the compound with the general formula B from the commercial product A under the action of a catalyst and a solvent. The reaction temperature is 0 to 100 ℃ and preferably 70 ℃. The reaction time is from 1 to 24 hours, preferably 2 hours. The solvent is one or a mixture of a dichloromethane solution containing phosphorus trichloride, a dichloromethane solution containing phosphorus pentachloride or thionyl chloride, and the thionyl chloride is preferred. The catalyst is one or a mixture of DMF, triethylamine or pyridine, and pyridine is preferred.
And (3) reacting the compound with the general formula B and a commercial product C under the action of a catalyst and a solvent to obtain the compound with the general formula (I). The reaction temperature is from 0 to 100 ℃ and preferably 25 ℃. The reaction time is 2 to 4 days, preferably 3 days. The solvent is anhydrous chloroform. The catalyst is Dicyclohexylcarbodiimide (DCC)/4-pyrrolidinylpyridine (PP).
The reaction formula is as follows:
the invention also aims to provide the application of the cephalotaxine ester derivative containing salicylic acid.
The technical scheme for realizing the above purpose of the invention is as follows: the application of the cephalotaxine salicylate derivative in preparing medicine for treating cancer, chronic myelocytic leukemia, acute myelocytic leukemia, lupus erythematosus and other diseases.
The further technical scheme of the invention is as follows: pharmaceutically acceptable salts of the cephalotaxine salicylate derivative compounds, pharmaceutical preparations thereof and pharmaceutical uses thereof.
The invention further adopts the technical scheme that: the application of the compound containing the salicylic acid cephalotaxine ester derivative comprises resisting cancer, chronic myelocytic leukemia, acute myelocytic leukemia and lupus erythematosus.
The following pharmacological experiments were performed on the compounds of the invention:
and (3) in the anticancer aspect: the MTT method and the SRB method are adopted to determine that the compound with the general formula (I) has obvious cytotoxicity effect. The compound of the general formula (I) is injected into the abdominal cavity of a lymphoma mouse, the growth of the lymphoma can be obviously inhibited for nine consecutive days, and the inhibition rate is 90.2%.
Against chronic myelogenous leukemia: when 24 rats with chronic myelogenous leukemia were intravenously injected with 0.02-0.04mg/d of the compound of formula (I) for 7-9 days, the number of leukocytes was significantly reduced, and the results showed 7 complete hematologic remissions (29.2%), 18 partial hematologic remissions (75.0%), and 20 total hematologic remissions (83.3%).
Anti-acute myeloid leukemia: the compound of the general formula (I) is injected into 29 rats suffering from acute myelocytic leukemia for treatment by 0.01mg/d and 0.20-0.50mg/d of cytarabine in combination with 1.50-3.00 mu g/d of granulocyte colony stimulating factor (HAG), and the scheme has obvious curative effect on the acute myelocytic leukemia, and the result shows that the acute myelocytic leukemia is completely relieved by 79 percent.
Lupus erythematosus resistant diseases: injecting 0.80-1.00 mg/(kg. d) glucocorticoid prednisone into 35 cases of rats with lupus erythematosus disease-1) After 4-8 weeks, the dosage is reduced to 0.10-0.20mg/d, 0.01mg of the compound with the general formula (I) and 5ml of 0.9% sodium chloride are injected, 5-7 days are taken as a treatment course, 2-4 weeks are separated, and 3-7 treatment courses are total, the scheme has obvious curative effect on the lupus erythematosus diseases, and the result shows that the score of the lupus score table is reduced from 12.67 to 4.96 before treatment.
Pharmacological experiments prove that the compound has different degrees of anticancer, chronic myelocytic leukemia resistance, acute myelocytic leukemia resistance and lupus erythematosus resistance.
Therefore, the compound and the salt thereof can be used for preparing the medicines for resisting cancers, chronic myelocytic leukemia, acute myelocytic leukemia and lupus erythematosus diseases.
The compounds of the present invention may be administered to a patient in need of treatment either alone or in a composition comprising a therapeutically effective amount of a compound of the present invention and salts thereof and a pharmaceutically acceptable carrier.
The technical scheme disclosed by the invention shows that the compound has excellent pharmacological effects of resisting cancers, chronic myelocytic leukemia, acute myelocytic leukemia and lupus erythematosus, is easy to prepare, is convenient for industrial production, and can meet the requirements of the field of medicines. The compound of the invention has higher curative effect.
Drawings
FIG. 1 is the structural formula of Compound 1;
FIG. 2 is the structural formula of Compound 2;
FIG. 3 is the structural formula of Compound 3;
FIG. 4 is the structural formula of Compound 4;
FIG. 5 is the structural formula of Compound 5;
FIG. 6 is the structural formula of Compound 6;
FIG. 7 is the structural formula of Compound 7;
FIG. 8 is the structural formula of Compound 8;
FIG. 9 is the structural formula of Compound 9;
FIG. 10 is the structural formula of Compound 10;
FIG. 11 is the structural formula of Compound 11;
FIG. 12 is the structural formula of Compound 12;
FIG. 13 is a structural formula of Compound 13;
FIG. 14 is the structural formula of Compound 14.
Detailed Description
EXAMPLE 1 Synthesis of Compound 01
(1S,3aR) -2-methoxy-1, 5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate (Compound 01)
0.02mol of salicylic acid is reacted with 4ml of thionyl chloride at 70 ℃,4 drops of catalyst pyridine are added, after 2 hours of reaction, excess SOCl2 is removed by suction filtration under reduced pressure, dissolved in 10ml of dichloromethane and stirred under ice bath. Dissolving 0.01mol of cephalotaxine in anhydrous chloroform, then dissolving 0.02mol of DDC and 0.002mol of PP in anhydrous chloroform, adding into the reaction solution under the protection of nitrogen, and stirring at room temperature for reaction for three days. Using ethyl acetate: petroleum ether is 1: 3, performing column chromatography to obtain a target product. The relevant data are as follows:
compound 01EI-MS m/z 435.4; anal, calcd, for C25H25NO6: C, 68.95; h, 5.79; n, 3.22; found C, 68.97; h, 5.81; n,3.24
EXAMPLE 2 Synthesis of Compound 02
(1S,3aS) -2-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [1,2-a ] azepin-1-yl 2-hydroxybenzoate (Compound 02)
The desired product was obtained by following the procedure of example 1 using 0.01mol of (1S,3aS) -1-hydroxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [1,2-a ] azepin-2 (3H) -one instead of cephalotaxine. The relevant data are as follows:
compound 02EI-MS m/z: 421.1; anal, calcd, for C24H23NO6: C, 68.40; h, 5.50; n, 3.32; found C, 68.42; h, 5.52; n,3.30
EXAMPLE 3 Synthesis of Compound 03
(S) -2-oxo-2, 3,5,6,8, 9-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate (Compound 03)
The desired product was obtained by following the procedure of example 1 using 0.01mol of (S) -1-hydroxy-5, 6,8, 9-tetrahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] aza-2 (3H) -one instead of cephalotaxine. The relevant data are as follows:
compound 03EI-MS m/z: 419.4; anal, calcd, for C24H21NO6: C, 68.73; h, 5.05; n, 3.34; found C, 68.71; h, 5.07; n,3.36
EXAMPLE 4 Synthesis of Compound 04
(3aR) -2-methoxy-6-oxo-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate (Compound 04)
The desired product was obtained by following the procedure of example 1 using 0.01mol of (3aR) -1-hydroxy-2-methoxy-1, 4,5,8,9,14 b-hexahydro-6H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-6-one instead of cephalotaxine. The relevant data are as follows:
compound 04EI-MS m/z: 449.4; anal, calcd, for C25H23NO7: C, 66.81; h, 5.16; n, 3.12; found C, 66.83; h, 5.18; n,3.14
EXAMPLE 5 Synthesis of Compound 05
(3aS) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate (Compound 05)
The procedure of example 1 was followed using 0.01mol of (3aS) -1-hydroxy-2, 2-dimethoxy-1, 2,3,4,5,8,9,14 b-octahydro-6H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] aza-6-one in place of cephalotaxine to obtain the desired product. The relevant data are as follows:
compound 05EI-MS m/z: 481.1; anal, calcd, for C26H27NO8: C, 64.86; h, 5.56; n, 2.91; found C, 64.88; h, 5.54; n,2.93
EXAMPLE 6 Synthesis of Compound 06
(3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate (Compound 06)
The desired product was obtained by following the procedure of example 1 using 0.01mol of (3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-ol in place of cephalotaxine. The relevant data are as follows:
compound 06EI-MS m/z: 467.1; anal, calcd, for C26H29NO7: C, 66.80; h, 6.25; n, 3.00; found C, 66.82; h, 6.23; n,3.02
EXAMPLE 7 Synthesis of Compound 07
(3aR) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-3-yl 2-hydroxybenzoate (Compound 07)
The title product was obtained by following the procedure of example 1 using 0.01mol of (3aR) -3-hydroxy-2, 2-dimethoxy-1, 2,3,4,5,8,9,14 b-octahydro-6H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] aza-6-one instead of cephalotaxine. The relevant data are as follows:
compound 07EI-MS m/z: 481.2; anal, calcd, for C26H29NO7: C, 64.86; h, 5.65; n, 2.91; found C, 64.88; h, 5.67; n,2.89
EXAMPLE 8 Synthesis of Compound 08
(1S,3aR) -2-methoxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate (Compound 08)
The procedure of example 1 was followed using 0.01mol of acetylsalicylic acid instead of salicylic acid to obtain the desired product. The relevant data are as follows:
compound 08EI-MS m/z: 477.1; anal.calcd.for C27H27NO7: C, 67.91; h, 5.70; n, 2.93; found C, 67.93; h, 5.72; n,2.91
EXAMPLE 9 Synthesis of Compound 09
(1S,3aS) -2-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [1,2-a ] azepin-1-yl 2-acetoxybenzoate (Compound 09)
The desired product was obtained by following the procedure of example 8 using 0.01mol of (1S,3aS) -1-hydroxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [1,2-a ] azepin-2 (3H) -one in place of cephalotaxine. The relevant data are as follows:
compound 09EI-MS m/z: 463.1; anal, calcd, for C26H25NO7: C, 67.38; h, 5.44; n, 3.02; found C, 67.36; h, 3.04; n,3.00
EXAMPLE 10 Synthesis of Compound 10
(S) -2-oxo-2, 3,5,6,8, 9-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] aza-1-yl 2-acetoxybenzoate (Compound 10)
The desired product was obtained by following the procedure of example 8 using 0.01mol of (S) -1-hydroxy-5, 6,8, 9-tetrahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] aza-2 (3H) -one in place of cephalotaxine. The relevant data are as follows:
compound 10EI-MS m/z: 461.1; anal, calcd, for C26H23NO7: C, 67.67; h, 5.02; n, 3.04; found C, 67.69; h, 5.04; n,3.02
EXAMPLE 11 Synthesis of Compound 11
(3aR) -2-methoxy-6-oxo-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate (Compound 11)
The title product was obtained by following the procedure of example 8 using 0.01mol of (3aR) -1-hydroxy-2-methoxy-1, 4,5,8,9,14 b-hexahydro-6H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-6-one instead of cephalotaxine. The relevant data are as follows:
compound 11EI-MS m/z: 491.1; anal.calcd.for C27H25NO8: C, 65.98; h, 5.13; n, 2.85; found C, 65.96; h, 5.15; n,2.83
EXAMPLE 12 Synthesis of Compound 12
(3aS) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate (Compound 12)
The procedure of example 8 was followed using 0.01mol of (3aS) -1-hydroxy-2, 2-dimethoxy-1, 2,3,4,5,8,9,14 b-octahydro-6H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] aza-6-one in place of cephalotaxine to obtain the desired product. The relevant data are as follows:
compound 12EI-MS m/z: 523.1; anal, calcd, for C28H29NO9: C, 64.24; h, 5.58; n, 2.68; found C, 64.26; h, 5.56; n,2.70
EXAMPLE 13 Synthesis of Compound 13
(3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate (Compound 13)
The title product was obtained by following the procedure of example 8 using 0.01mol of (3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-ol in place of cephalotaxine. The relevant data are as follows:
compound 13EI-MS m/z 509.2; anal, calcd, for C28H31NO8: C, 66.00; h, 6.13; n, 2.75; found C, 66.02; h, 6.15; n,2.73
EXAMPLE 14 Synthesis of Compound 14
(3aR) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-3-yl 2-acetoxybenzoate (Compound 14)
The procedure of example 8 was followed using (3aR) -3-hydroxy-2, 2-dimethoxy-1, 2,3,4,5,8,9,14 b-octahydro-6H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-6-one in place of cephalotaxine to provide the desired product. The relevant data are as follows:
compound 14EI-MS m/z: 523.2; anal, calcd, for C28H31NO8: C, 64.24; h, 5.58; n, 2.68; found C, 64.26; h, 5.56; n,2.66
Example 15
The results of the cytotoxicity of the compounds of the present invention (concentration 100. mu.g/ml, control cisplatin, DDP) measured by MTT colorimetry are shown in Table 1.
TABLE 1 inhibition of 4 cancer cells by 14 compounds in the examples
Example 16
The 14 compounds of the example were screened in vitro using murine leukemia P388, the results of which are shown in Table 2.
TABLE 2 inhibition of leukemia P388 by 14 compounds of the example
Example 17
The 14 compounds in the example were screened in vitro using mouse lupus erythematosus LE and the results are shown in Table 3.
TABLE 3 integral Table of the 14 compounds in the example against lupus
Claims (3)
1. A cephalotaxine salicylate-containing ester derivative, said cephalotaxine salicylate-containing ester derivative being:
compound 01:
(1S,3aR) -2-methoxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 02:
(1S,3aS) -2-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 03:
(S) -2-oxo-2, 3,5,6,8, 9-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 04:
(3aR) -2-methoxy-6-oxo-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 05:
(3aS) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 06:
(3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-hydroxybenzoate;
compound 07:
(3aR) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-3-yl 2-hydroxybenzoate;
compound 08:
(1S,3aR) -2-methoxy-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 09:
(1S,3aS) -2-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 10:
(S) -2-oxo-2, 3,5,6,8, 9-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 11:
(3aR) -2-methoxy-6-oxo-1, 5,6,8,9,14 b-hexahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 12:
(3aS) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
compound 13:
(3aS) -2, 2-dimethoxy-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-1-yl 2-acetoxybenzoate;
or
Compound 14:
(3aR) -2, 2-dimethoxy-6-oxo-1, 2,3,5,6,8,9,14 b-octahydro-4H- [1,3] dioxole [4',5':4,5] benzo [1,2-d ] cyclopenta [ b ] pyrrolo [1,2-a ] azepin-3-yl 2-acetoxybenzoate.
2. A pharmaceutical composition against lymphoma, chronic myelogenous leukemia, acute myelogenous leukemia, or lupus erythematosus comprising the cephalotaxine salicylate derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
3. Use of the cephalotaxine salicylate derivative according to claim 1 for the preparation of a medicament for anti-lymphoma, anti-chronic myelogenous leukemia, anti-acute myelogenous leukemia or anti-lupus erythematosus disease.
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Non-Patent Citations (2)
| Title |
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| Synthesis of cephalotaxine esters and correlation of their structures with antitumor activity;Mikolajczak, Kenneth L.等;《Journal of Medicinal Chemistry》;19771231;第20卷(第3期);第328-332页，Chart I，Table II，Table I，第332页左栏第14-47行 * |
| 三尖杉属植物中生物碱的研究 IX. 三尖杉酯碱类似物的半合成及其抗白血病活性;王定志，等;《药学学报》;19921231;第27卷(第3期);第178-184页，尤其是Fig 1、Tab1，第179页第1-2段 * |
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