CN104262352B - Camptothecin derivative and its medical usage - Google Patents
Camptothecin derivative and its medical usage Download PDFInfo
- Publication number
- CN104262352B CN104262352B CN201410440442.8A CN201410440442A CN104262352B CN 104262352 B CN104262352 B CN 104262352B CN 201410440442 A CN201410440442 A CN 201410440442A CN 104262352 B CN104262352 B CN 104262352B
- Authority
- CN
- China
- Prior art keywords
- camptothecin
- ethyl
- piperazine
- methyl
- oxygen carbonyls
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 CCC(C(C=C1N2Cc3c1nc(ccc(OC(NC(CC(N1CCN(C)CC1)=O)C(N1CCN(C)CC1)=*)=O)c1)c1c3CC)=C(COCO)C2=O)=* Chemical compound CCC(C(C=C1N2Cc3c1nc(ccc(OC(NC(CC(N1CCN(C)CC1)=O)C(N1CCN(C)CC1)=*)=O)c1)c1c3CC)=C(COCO)C2=O)=* 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Abstract
The camptothecin derivative and its avirulent pharmaceutically acceptable salt, hydrate or solvate represented the object of the present invention is to provide Formulas I.In Formulas I, R1、R4Represent the alkyl of H or C1 C5；R2The alkyl side chain of L-type or D type amino acid is represented, including H, CH3, CH (CH3)2, CH2CH(CH3)2Or CH (CH3)CH2CH3；R3Represent H or CH2N(CH3)2；N is 0 or 16 integer.
Description
Technical field
The present invention relates to new water soluble camptothecin derivatives and its atoxic pharmaceutically acceptable salts.The derivative
Object and its atoxic pharmaceutically acceptable salt can be used as tumour and cancer treatment drugs.
Background technology
Camptothecine (Camptothecin, CPT) and 10-hydroxycamptothecine are that clinical practice is most wide, are had potent anti-swollen
The natural plant biological alkali of knurl effect.Camptothecin analogues mechanism of action is unique, using DNA topoisomerase Is as effect target
Mark, inhibits the synthesis of DNA in organism, and plays antitumor action.Camptothecine is to gastric cancer, liver cancer, carcinoma of urinary bladder and white
The malignant tumours such as blood disease have a better effect.But natural camptothecine compounds water solubility is very poor, clinical practice is limited
System.
By carrying out structure of modification to camptothecine or 10-hydroxycamptothecine, it was found that the water-soluble camptothecin drug of a batch,
Such as topotecan, Irinotecan.
But there are two shortcomings for Irinotecan (Irinotecan, CPT-11).First deficiency be its have compared with
The effect of strong acetylcholine esterase inhibition, and then lead to the side effect of the cholinergics syndrome such as diarrhea；Second deficiency is for she
It is vertical low for the conversion ratio of from health to active form SN-38, and there is larger individual differences.
Invention content
In order to overcome above-mentioned deficiency, better antitumor drug is found, the present inventor passes through shown in numerous studies discoverable type I
Camptothecin derivative has antitumor action more stronger than Irinotecan, and weaker to the inhibiting effect of cholinesterase.
In Formulas I, R1、R4Represent the alkyl of H or C1-C5；R2The alkyl side chain of L-type or D type amino acid is represented, including H ,-
CH3,-CH (CH3)2,-CH2CH(CH3)2Or-CH (CH3)CH2CH3；R3Represent H or-CH2N(CH3)2；N is the integer of 0 or 1-6.
The alkyl of the C1-C5 includes but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle
Butyl, n-pentyl, tertiary pentyl, neopentyl.
Therefore, the camptothecin derivative shown in present invention offer Formulas I and its non-toxic pharmaceutically acceptable salt are as anti-
The purposes of tumour medicine.
Another aspect of the present invention provides a kind of pharmaceutical composition, and it includes tree alkali derivant of the present invention or its non-poison
The pharmaceutically acceptable salt and suitable excipients, these pharmaceutical compositions of property can be solution, tablet, capsule or note
Penetrate agent；These pharmaceutical compositions can pass through injection administration or oral medication.
Camptothecin derivative shown in Formulas I provided by the invention, is selected from：
N- [(7- Ethyl-camptothecin -10- oxygen carbonyls amino) acetyl group]-N '-methyl piperazine (I1),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl]-N '-methyl piperazine (I2),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- methyl-butrylaminos]-N '-methyl piperazine (I3),
N- [4- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- (N- (N '-methyl piperazine) carbonyl-butyryl]-N '-first
Base piperazine (I4),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- methyl-valeryl]-N '-methyl piperazine (I5),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- methyl-valeryl]-N '-methyl piperazine (I6),
N- [(S) -3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- (N- (N '-methyl piperazine) carbonyl-propionyl] -
N '-methyl piperazine (I7),
N- [(R) -3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- (N- (N '-methyl piperazine) carbonyl-propionyl] -
N '-methyl piperazine (I8),
N- [3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl]-N '-methyl piperazine (I9),
N- [4- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) butyryl]-N '-methyl piperazine (I10),
N- [6- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) hexanoyl]-N '-methyl piperazine (I11),
N- [(7- Ethyl-camptothecin -10- oxygen carbonyls amino) acetyl] piperazine (I12),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl] piperazine (I13),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I14),
N- [2- (camptothecine -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I15),
Or its atoxic pharmaceutically acceptable salt, hydrate or solvate.
Specific embodiment
It is further illustrated the present invention below by specific embodiment, it should be understood, however, that, these embodiments are only
It is used for specifically describing in more detail, and is not to be construed as limiting the present invention in any form.
The present invention carries out the material and test method that are arrived used in experiment general and/or specific description.Though
So to realize the present invention many materials and operating method used in purpose be it is known in the art that still the present invention still herein
It is described in detail as far as possible.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and
Operating method is well known in the art.
Target compound can be prepared according to following synthetic route:
The amino acid hydrochloride salt or tosilate of benzyl protection are with triphosgene (BTC) in saturation NaHCO3+ dichloromethane
Reaction generation isocyanates in alkane two phase liquid, then by isocyanates and camptothecin derivative in THF, Et3Life is reacted under the conditions of N
Into carbamate structures, and after dissociate carboxyl through the protection of catalytic hydrogenation debenzylation, then acted in condensing agent HBTU and DIEA
Under, free carboxy with N methyl piperazine/piperazine is connected through acylation reaction, finally salt is reacted into hydrochloric ethyl acetate, obtains
Target compound.
In reaction equation, R1、R4Represent the alkyl of H or C1-C5；R2The alkyl side chain of L-type or D type amino acid is represented, including
H ,-CH3,-CH (CH3)2,-CH2CH(CH3)2Or-CH (CH3)CH2CH3；R3Represent H or-CH2N(CH3)2；N is the whole of 0 or 1-6
Number.
1 N- of embodiment [(7- Ethyl-camptothecin -10- oxygen carbonyls amino) acetyl group]-N '-methyl piperazine (I1) synthesis
The glycine benzyl hydrochloride (H-Gly-OBzlHCl) of 1.23g (6.12mmol) is dissolved in 100mL unsaturated carbonates
Triphosgene 668mg (2.25mmol) is added in after 5min is stirred in mixed solution in hydrogen sodium and 100mL dichloromethane, at 0 DEG C, is stirred
Stop reaction after mixing 15min.Reaction solution is extracted four times with dichloromethane, anhydrous sodium sulfate drying.Filtering, filtrate decompression is steamed
It is dry, obtain isocyanate derivates (II1), it is directly used in the next step.
600mg (1.53mmol) 7-Ethyl-10-hydroxycamptothecin (SN-38) is dissolved in 150mL tetrahydrofurans, is added in
0.85mL(6.12mmol)Et330min is stirred at room temperature in N；By II1After being dissolved with 2mL dichloromethane, add in above-mentioned reaction solution,
It is reacted overnight at 40 DEG C；TLC is monitored after reaction, evaporated under reduced pressure, with silica gel medium pressure column chromatography for separation, with dichloromethane：Third
Ketone (5：1) mixed solvent elutes, and obtains yellow solid III1782mg, yield 87.7%.
By 782mg (1.34mmol) III1It is dissolved in tetrahydrofuran：Ethyl alcohol (7：4) in the mixed solvent adds in 313mg Pd/
C, at room temperature catalytic hydrogenation.Reaction overnight, filters off Pd/C, filtrate decompression is evaporated, with silica gel medium pressure column chromatography for separation, with dichloro
Methane：Acetone：Formic acid (300：100：1) mixed solvent elutes, and obtains yellow solid IV1455mg, yield 70.0%.
By 455mg (0.92mmol) IV1It is dissolved in 120mL dichloromethane, N methyl piperazine 0.20mL is added in into reaction
(1.84mmol), HBTU 523mg (1.38mmol), DIEA0.64mL (3.68mmol), are stirred overnight at room temperature.Reaction solution is used
Water washing, anhydrous sodium sulfate drying.Anhydrous sodium sulfate is filtered off, filtrate decompression is evaporated, with silica gel medium pressure column chromatography for separation, with two
Chloromethanes：Methanol (20：1) mixed solvent elutes, and obtains faint yellow solid I1398mg, yield 75.1%.1H-NMR(400MHz,
DMSO-d6):δppm 0.87-0.90(t,3H),1.28-1.32(t,3H),1.86-1.90(m,2H),2.19(s,3H),
2.28-2.32(m,4H),3.18-3.20(q,2H),3.44-3.48(m,4H),4.00-4.01(d,2H),5.35(s,2H),
5.44 (s, 2H), 6.52 (s, 1H), 7.33 (s, 1H), 7.62-7.65 (dd, 1H), 7.95-7.96 (d, 1H), 7.98-8.01
(t,1H),8.18-8.20(d,1H)。
2 N- of embodiment [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl]-N '-methyl piperazine (I2) synthesis
With reference to embodiment 1, H-Gly-OBzlHCl is replaced to be reacted with triphosgene with l-Alanine benzyl ester hydrochloride, be made
Isocyanate derivates (the II of l-Alanine benzyl ester2), it is directly used in the next step.
By SN-38 and II2Intermediate III is made in reaction2, yield 93.8%.
By III2Intermediate compound IV is made in catalytic hydrogenation2, yield 87.6%.
By IV2It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made2, yield 74.7%.1H-NMR(400MHz,DMSO-d6):δppm 0.87-0.90(t,3H),1.27-1.31(m,6H),1.86-1.89(m,2H),
2.22(s,3H),2.32-2.38(m,4H),3.17-3.19(q,2H),3.43-3.52(m,4H),4.60-4.64(m,1H),
5.33(s,2H),5.44(s,2H),6.56(s,1H),7.33(s,1H),7.60-7.63(dd,1H),7.92-7.93(d,1H),
8.17-8.19(d,1H),8.24-8.26(d,1H)。
3 N- of embodiment [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- methyl-butrylaminos]-N '-methyl piperazine
(I3) synthesis
With reference to embodiment 1, H-Gly-OBzlHCl is replaced to be reacted with triphosgene with Valine benzyl ester hydrochloride, be made
Isocyanate derivates (the II of Valine benzyl ester3), it is directly used in the next step.
By SN-38 and II3Intermediate III is made in reaction3, yield 94.8%.
By III3Intermediate compound IV is made in catalytic hydrogenation3, yield 68.5%.
By IV3It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made3, yield 73.8%.1H-NMR(400MHz,DMSO-d6):δ ppm 0.86-0.90 (t, 3H), 0.92-0.94 (d, 3H), 0.97-0.99 (d, 3H),
1.27-1.31 (t, 3H), 1.83-1.91 (m, 2H), 2.05-2.06 (m, 1H), 2.18 (s, 3H), 2.26-2.33 (m, 4H),
3.18-3.22(q,2H),3.52-3.59(m,4H),4.36-4.40(m,1H),5.35(s,2H),5.45(s,2H),6.56(s,
1H),7.32(s,1H),7.60-7.63(dd,1H),7.93-7.94(d,1H),8.18-8.23(m,2H)。
4 N- of embodiment [4- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- (N- (N '-methyl piperazine) carbonyls-fourth
Acyl]-N '-methyl piperazine (I4) synthesis
With reference to embodiment 1, H-Gl is replaced with Pidolidone benzyl ester hydrochloridey- OBzlHCl is reacted with triphosgene, is made
Isocyanate derivates (the II of Pidolidone benzyl ester4), it is directly used in the next step.
By SN-38 and II4Intermediate III is made in reaction4, yield 97.9%.
By III4Intermediate compound IV is made in catalytic hydrogenation4, yield 54.0%.
By IV4It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made4, yield 61.8%.1H-NMR(400MHz,DMSO-d6):δppm 0.87-0.90(t,3H),1.27-1.31(t,3H),1.86-1.92(m,2H),
2.15-2.44(m,18H),3.16-3.21(q,2H),3.34-3.68(m,8H),4.58-4.64(m,1H),5.32(s,2H),
5.44(s,2H),6.57(s,1H),7.31(s,1H),7.60-7.63(dd,1H),7.93-7.94(d,1H),8.16-8.19
(d,1H),8.22-8.24(d,1H)。
5 N- of embodiment [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- methyl-valeryl]-N '-methyl piperazine
(I5) synthesis
With reference to embodiment 1, H-Gly-OBzlHCl is replaced to be reacted with triphosgene with L-Leu benzyl ester hydrochloride, be made
Isocyanate derivates (the II of L-Leu benzyl ester5), it is directly used in the next step.
By SN-38 and II5Intermediate III is made in reaction5, yield 97.3%%.
By III5Intermediate compound IV is made in catalytic hydrogenation5, yield 69.7%.
By IV5It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made5, yield 70.8%.1H-NMR(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),0.93-0.96(m,6H),1.27-1.31(t,3H),
1.39-1.46(m,1H),1.58-1.65(m,1H),1.73-1.76(m,1H),1.84-1.93(m,2H),2.19(s,3H),
2.28-2.35(m,4H),3.16-3.22(q,2H),3.46-3.56(m,4H),4.53-4.59(m,1H),5.34(s,2H),
5.44 (s, 2H), 6.55 (s, 1H), 7.32 (s, 1H), 7.59-7.62 (dd, 2.6,1H), 7.92-7.93 (d, 1H), 8.17-
8.19(d,1H),8.29-8.31(d,1H)。
6 N- of embodiment [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- methyl-valeryl]-N '-methyl piperazine
(I6) synthesis
With reference to embodiment 1, H-Gly-OBzlHCl is replaced to be reacted with triphosgene with l-Isoleucine benzyl ester hydrochloride, made
Obtain the isocyanate derivates (II of l-Isoleucine benzyl ester6), it is directly used in the next step.
By SN-38 and II6Intermediate III is made in reaction6, yield 98.7%.
By III6Intermediate compound IV is made in catalytic hydrogenation6, yield 71.9%.
By IV6It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made6, yield 68.9%.1H-NMR(400MHz,DMSO-d6):δppm 0.86-0.91(m,9H),1.18-1.30(m,4H),1.57-1.62(m,1H),
1.81-1.92(m,3H),2.18(s,3H),2.23-2.32(m,4H),3.16-3.21(q,2H),3.52-3.60(m,4H),
4.39-4.43(t,1H),5.33(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.59-7.62(dd,1H),
7.92-7.92(d,1H),8.17-8.19(d,1H),8.25-8.27(d,1H)。
7 N- of embodiment [(S) -3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- (N- (N '-methyl piperazine) carbonyls
Base-propionyl]-N '-methyl piperazine (I7) synthesis
With reference to embodiment 1, H-Gly-OBzlHCl is replaced to be reacted with triphosgene with (S)-aspartic acid benzyl ester hydrochloride,
Isocyanate derivates (the II of (S)-aspartic acid benzyl ester is made7), it is directly used in the next step.
By SN-38 and II7Intermediate III is made in reaction7, yield 98.1%.
By III7Intermediate compound IV is made in catalytic hydrogenation7, yield 73.3%.
By IV7It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made7, yield 64.3%.1H-NMR(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),1.27-1.31(t,3H),1.84-1.91(m,2H),
2.16-2.34(m,14H),2.65-2.69(m,1H),2.87-2.99(m,1H),3.16-3.21(q,2H),3.35-3.64(m,
8H),4.93-4.94(m,1H),5.34(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.60-7.63(dd,
2.6,1H),7.91-7.92(d,1H),8.18-8.20(d,1H),8.46-8.49(d,1H)。
8 N- of embodiment [(R) -3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- (N- (N '-methyl piperazine) carbonyls
Base-propionyl]-N '-methyl piperazine (I8) synthesis
With reference to embodiment 1, H-Gly-OBzlHCl is replaced to be reacted with triphosgene with (R)-aspartic acid benzyl ester hydrochloride,
Isocyanate derivates (the II of (R)-aspartic acid benzyl ester is made8), it is directly used in the next step.
By SN-38 and II8Intermediate III is made in reaction8, yield 94.7%.
By III8Intermediate compound IV is made in catalytic hydrogenation8, yield 73.5%.
By IV8It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made8, yield 62.7%.1H-NMR(400MHz,DMSO-d6):δppm 0.87-0.90(t,3H),1.28-1.31(t,3H),1.82-1.93(m,2H),
2.17-2.35(m,14H),2.64-2.70(m,1H),2.94-2.99(m,1H),3.17-3.19(q,2H),3.37-3.62(m,
8H),4.91-4.96(m,1H),5.34(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.60-7.63(dd,
2.6,1H),7.91-7.92(d,1H),8.18-8.20(d,1H),8.47-8.49(d,1H)。
9 N- of embodiment [3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl]-N '-methyl piperazine (I9) synthesis
Beta-alanine 1.34g (15mmol) is dissolved in 100mL benzene, benzyl alcohol 15mL is added in into reaction, to toluene sulphur
Sour 3.43g (18mmol), 105 DEG C are heated to reflux 5h, while the water of reaction generation is separated with water knockout drum.It will reaction after the completion of reaction
Object is cooled to room temperature, and is then poured into ether, is placed, and after having solid precipitation, filters out solid, ether washing, vacuum
It is dry, obtain Beta-alanine benzyl ester tosilate 4.97g, yield 94.1%.
With reference to embodiment 1, replace H-Gly-OBzlHCl anti-with triphosgene with Beta-alanine benzyl ester tosilate
Should, the isocyanate derivates (II of obtained Beta-alanine benzyl ester9), it is directly used in the next step.
By SN-38 and II9Intermediate III is made in reaction9, yield 98.8%.
By III9Intermediate compound IV is made in catalytic hydrogenation9, yield 52.1%.
By IV9It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made9, yield 76.8%.1H-NMR(400MHz,DMSO-d6):δppm 0.87-0.90(t,3H),1.27-1.31(t,3H),1.82-1.93(m,2H),
2.19(s,3H),2.25-2.33(m,4H),2.58-2.62(t,2H),3.16-3.21(t,2H),3.32-3.37(m,2H),
3.44-3.48(m,4H),5.33(s,2H),5.44(s,2H),6.54(s,1H),7.32(s,1H),7.63-7.66(dd,2.4,
1H),7.91-7.94(m,2H),8.16-8.18(d,1H)。
10 N- of embodiment [4- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) butyryl]-N '-methyl piperazine (I10) conjunction
Into
With reference to embodiment 9, replace the effect of Beta-alanine p-methyl benzenesulfonic acid is lower to be reacted with benzyl alcohol with 4-Aminobutanoicacid, obtain
4-Aminobutanoicacid benzyl ester tosilate, yield 94.4%.
With reference to embodiment 1, replace H-Gly-OBzlHCl anti-with triphosgene with 4-Aminobutanoicacid benzyl ester tosilate
Should, the isocyanate derivates (II of obtained 4-Aminobutanoicacid benzyl ester10), it is directly used in the next step.
By SN-38 and II10Intermediate III is made in reaction10, yield 95.9%.
By III10Intermediate compound IV is made in catalytic hydrogenation10, yield 59.8%.
By IV10It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made10, yield 68.0%.1H-NMR(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),1.27-1.31(t,3H),1.72-1.77(m,2H),
1.84-1.91(m,2H),2.17(s,3H),2.22-2.31(m,4H),2.38-2.42(t,2H),3.12-3.22(m,4H),
3.45(m,4H),5.34(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.64-7.66(dd,2.4,1H),
7.95-8.00(m,2H),8.16-8.18(d,1H)。
11 N- of embodiment [6- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) hexanoyl]-N '-methyl piperazine (I11) conjunction
Into
With reference to embodiment 9, replace the effect of Beta-alanine p-methyl benzenesulfonic acid is lower to be reacted with benzyl alcohol with 6-aminocaprolc acid, obtain
6-aminocaprolc acid benzyl ester tosilate, yield 87.6%.
With reference to embodiment 1, replace H-Gly-OBzlHCl anti-with triphosgene with 6-aminocaprolc acid benzyl ester tosilate
Should, the isocyanate derivates (II of obtained 6-aminocaprolc acid benzyl ester11), it is directly used in the next step.
By SN-38 and II11Intermediate III is made in reaction11, yield 94.9%.
By III11Intermediate compound IV is made in catalytic hydrogenation11, yield 59.6%.
By IV11It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made11, yield 67.8%.1H-NMR(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),1,27-1.38(m,5H),1.48-1.56(m,4H),
1.84-1.91(m,2H),2.16(s,3H),2.21-2.23(t,2H),2.27-2.33(m,4H),3.09-3.22(m,4H),
4.43(m,4H),5.34(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.63-7.66(dd,2.4,1H),
7.94-7.98(m,2H),8.16-8.18(d,1H)。
12 N- of embodiment [(7- Ethyl-camptothecin -10- oxygen carbonyls amino) acetyl] piperazine (I12) synthesis
By intermediate compound IV1462mg (0.94mmol) is dissolved in 120mL dichloromethane, and piperazine 162mg is added in into reaction
(1.88mmol), HBTU 535mg (1.41mmol), DIEA0.65mL (3.76mmol), are stirred overnight at room temperature.Reaction solution is used
Distill water washing, anhydrous sodium sulfate drying.Anhydrous sodium sulfate is filtered off, filtrate decompression is evaporated, with silica gel medium pressure column chromatography for separation,
Use dichloromethane：Methanol (20：1) mixed solvent elution, obtains yellow solid I12258mg, yield 48.6%.1H-NMR
(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),1.00-1.03(t,1H),1.28-1.31(t,3H),1.84-
1.91(m,2H),2.68-2.73(m,4H),3.16-3.22(q,2H),3.41-3.44(m,4H),3.99-4.00(d,2H),
5.34(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.62-7.65(dd,2.6,1H),7.56-7.96(d,
1H),8.00-8.03(t,1H),8.18-8.20(d,1H)。
13 N- of embodiment [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl] piperazine (I13) synthesis
By compound intermediate IV2617mg (1.22mmol) is dissolved in 120mL dichloromethane, and piperazine is added in into reaction
210mg (2.44mmol), HBTU 694mg (1.83mmol), DIEA 0.85mL (4.88mmol), are stirred overnight at room temperature.It will be anti-
Liquid is answered to be washed with distilled water, anhydrous sodium sulfate drying.Anhydrous sodium sulfate is filtered off, filtrate decompression is evaporated, with silica gel medium pressure column layer
Analysis separation, uses dichloromethane：Methanol (20：1) mixed solvent elution, obtains yellow solid I13258mg, yield 43.1%.1H-
NMR(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),1.03-1.05(m,1H),1.27-1.31(m,6H),
1.82-1.93(m,2H),2.68-2.74(m,4H),3.16-3.21(q,2H),3.40-3.46(m,4H),4.57-4.64(m,
1H),5.33(s,2H),5.44(s,2H),6.55(s,1H),7.32(s,1H),7.60-7.62(dd,2.2,1H),7.92-
7.93(d,1H),8.16-8.19(d,1H),8.24-8.25(d,1H)。
14 N- of embodiment [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I14) conjunction
Into
By intermediate compound IV5579mg (1.05mmol) is dissolved in 120mL dichloromethane, and piperazine 181mg is added in into reaction
(2.10mmol), HBTU 599mg (1.58mmol), DIEA 0.73mL (4.20mmol), are stirred overnight at room temperature.Reaction solution is used
Distill water washing, anhydrous sodium sulfate drying.Anhydrous sodium sulfate is filtered off, filtrate decompression is evaporated, with silica gel medium pressure column chromatography for separation,
Use dichloromethane：Methanol (20：1) mixed solvent elution, obtains yellow solid I14258mg, yield 39.6%.1H-NMR
(400MHz,DMSO-d6):δppm 0.86-0.90(t,3H),0.93-0.95(m,6H),1.27-1.31(t,3H),1.40-
1.45(m,1H),1.58-1.65(m,1H),1.73-1.76(m,1H),1.84-1.91(m,2H),2.66-2.73(m,4H),
3.16-3.22(q,2H),3.40-3.50(m,4H),4.53-4.58(m,1H),5.34(s,2H),5.44(s,2H),6.55(s,
1H),7.32(s,1H),7.59-7.62(dd,2.4,1H),7.92-7.93(d,1H),8.17-8.19(d,1H),8.27-8.29
(d,1H)。
15 N- of embodiment [2- (camptothecine -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I15) synthesis
With reference to embodiment 1,10-hydroxycamptothecine is replaced into SN-38, with II5Intermediate III is made in reaction15, yield
92.5%.
By III15Intermediate compound IV is made in catalytic hydrogenation15, yield 61.4%.
By IV15It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made15, yield 60.2%.1H-NMR(400MHz,DMSO-d6):δppm 0.83-0.89(t,3H),0.91-0.94(m,6H),1.35-1.41(m,1H),
1.52-1.60(m,1H),1.70-1.73(m,1H),1.81-1.90(m,2H),2.18(s,3H),2.25-2.33(m,4H),
3.44-3.52(m,4H),4.50-4.56(m,1H),5.31(s,2H),5.42(s,2H),6.52(s,1H),7.30(s,1H),
7.55-7.60 (dd, 2.6,1H), 7.90-7.91 (d, 1H), 8.14-8.17 (d, 1H), 8.26-8.30 (d, 1H), 8.31 (s,
1H)。
16 N- of embodiment [2- (topotecan -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I16) synthesis
With reference to embodiment 1, topotecan is replaced into SN-38, with II5Intermediate III is made in reaction16, yield 90%.
By III16Intermediate compound IV is made in catalytic hydrogenation16, yield 61.7%.
By IV16It is reacted under HBTU and DIEA effects with N methyl piperazine, target compound I is made16, yield 45.2%.1H-NMR(400MHz,DMSO-d6):δppm 0.85-0.92(t,3H),0.95-0.99(m,6H),1.39-1.45(m,1H),
1.55-1.63(m,1H),1.73-1.76(m,1H),1.84-1.93(m,2H),2.17(s,3H),2.21(s,3H),2.23(s,
3H),2.26-2.34(m,4H),3.46-3.54(m,4H),4.52-4.58(m,1H),5.34(s,2H),5.45(s,2H),
6.52 (s, 1H), 7.33 (s, 1H), 7.58-7.63 (d, 2.6,1H), 8.16-8.19 (d, 1H), 8.28-8.32 (d, 1H),
8.33(s,1H)。
17 external inhibiting activity of acetylcholinesterase of embodiment is tested
17.1 instruments and reagent
Ultraviolet specrophotometer Japan Shimadzu UV-2550；Detection wavelength:412mμ；Cuvette capacity 1ml；Make 0.01M by oneself
PBS buffer solution, 0.1M pH7.3 phosphate buffers, 0.1M pH7.0 phosphate buffers；Acetylthiocholine AlfaAesar
(Tianjin) Chemical Co., Ltd.；5,5- dimercaptos-bis--(2- nitrobenzoic acids) AlfaAesar (Tianjin) Chemical Co., Ltd.；Electricity
Eel acetylcholinesterase Sigma-Aldrich (Shanghai) trade Co., Ltd.
17.2 test methods
The inhibiting activity of acetylcholinesterase of compound is measured using Ellman methods：It is respectively that 20 each target compounds of μ L are molten
Liquid and 20 μ L AChE (4 UmL-1) it is added to 2.5mL 0.1molL-1In (pH 7.3) phosphate buffer, 37 DEG C of incubations
Then 1min sequentially adds 100 μ L 0.01molL-1DTNB, 100 μ L 0.075molL-1Reaction starts after ATch, whirlpool
Revolve 10 s.Under 412nm, absorbance is tested with ultraviolet specrophotometer, interval 15s reads a data, reads 3min altogether, ask
Slope.Each sample is parallel to be surveyed 3 times, is averaged.Experimental result is shown in Table 1.
In experimental implementation, sky is done with the solution of target compound containing equivalent, DTNB and ATch in another cuvette of timing
White control, then deducted drug background color, so not needing to deduct again in calculating.
Data process computing formula：
Control：With enzyme, DTNB, ATch and buffer solution system
Blank1：With DTNB, ATch and buffer solution system
Dosing：With enzyme, drug, DTNB, ATch and buffer solution system
Blank2：With drug, DTNB, ATch and buffer solution system
The inhibiting effect evaluation test result of 1 acetylcholinesterase of table
18 antitumor activity evaluation of embodiment
Compound is tested to human colon cancer cell strain (SW1116), human lung adenocarcinoma cell line (A549) and people with mtt assay
Stomach cancer cell line (SGC-7901)：It is about 2.5 × 10 to prepare concentration4μg·mL-1Cell suspension, be inoculated in 96 holes culture
Plate, 100.0uL/ holes put 37 DEG C, 5%CO2It is incubated 24 hours in incubator；The tested material of various concentration is added to the swollen of culture
In 96 orifice plates of oncocyte, continue culture 72 hours；Culture solution is discarded, 100.0 μ L of 0.05%MTT applications liquid, training are added in per hole
It supports 4 hours；Culture solution is discarded, 100 μ L DMSO are added in per hole, vibrates 5 minutes Shi Jia Za grain dissolutions, measures cell in 490nm
The absorbance at place.
Processing for Data Analysis in Physics is as follows：
Control：With cell, MTT solution without the absorbance in the hole of drug
Blank：With culture medium and MTT solution without the absorbance in the hole of cell
Dosing：The absorbance in the hole with cell, MTT solution and drug solution
Half-inhibition concentration (IC of each tested material to various growth of tumour cell is finally calculated by respective handling software50)。
It the results are shown in Table 2：
2 antitumor activity evaluation result of the test of table
Claims (7)
1. camptothecin derivative or its atoxic pharmaceutically acceptable salt shown in Formulas I：
In Formulas I, R1、R4Represent the alkyl of H or C1-C5；R2Selected from H ,-CH3,-CH (CH3)2,-CH2CH(CH3)2Or-CH (CH3)
CH2CH3；R3Represent H or-CH2N(CH3)2；N is the integer of 0 or 1-6.
2. the camptothecin derivative of claim 1, is selected from：
N- [(7- Ethyl-camptothecin -10- oxygen carbonyls amino) acetyl group]-N '-methyl piperazine (I1),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl]-N '-methyl piperazine (I2),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- methyl-butrylaminos]-N '-methyl piperazine (I3),
N- [4- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- (N- (N '-methyl piperazine) carbonyl-butyryl]-N '-methyl piperazine
Piperazine (I4),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- methyl-valeryl]-N '-methyl piperazine (I5),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- methyl-valeryl]-N '-methyl piperazine (I6),
N- [(S) -3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- (N- (N '-methyl piperazine) carbonyl-propionyl]-N '-first
Base piperazine (I7),
N- [(R) -3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -3- (N- (N '-methyl piperazine) carbonyl-propionyl]-N '-first
Base piperazine (I8),
N- [3- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl]-N '-methyl piperazine (I9),
N- [4- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) butyryl]-N '-methyl piperazine (I10),
N- [6- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) hexanoyl]-N '-methyl piperazine (I11),
N- [(7- Ethyl-camptothecin -10- oxygen carbonyls amino) acetyl] piperazine (I12),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) propionyl] piperazine (I13),
N- [2- (7- Ethyl-camptothecin -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I14),
N- [2- (camptothecine -10- oxygen carbonyls amino) -4- methyl-valeryl] piperazine (I15),
Or its atoxic pharmaceutically acceptable salt.
3. containing camptothecin derivative and its atoxic pharmaceutically acceptable salt described in claims 1 or 2 is used as activity
The pharmaceutical composition that ingredient and suitable excipients are formed.
4. the pharmaceutical composition described in claim 3, described pharmaceutical composition is solution, tablet, capsule or injection.
5. the pharmaceutical composition described in claim 3, described pharmaceutical composition passes through injection administration or oral medication.
6. camptothecin derivative or its atoxic pharmaceutically acceptable salt described in claims 1 or 2 prepare it is antitumor
Purposes in drug.
7. contain the camptothecin derivative described in claims 1 or 2 or its atoxic pharmaceutically acceptable salt is used as activity
Purposes of the pharmaceutical composition of ingredient in antitumor drug is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410440442.8A CN104262352B (en) | 2014-09-01 | 2014-09-01 | Camptothecin derivative and its medical usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410440442.8A CN104262352B (en) | 2014-09-01 | 2014-09-01 | Camptothecin derivative and its medical usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104262352A CN104262352A (en) | 2015-01-07 |
| CN104262352B true CN104262352B (en) | 2018-06-15 |
Family
ID=52153963
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410440442.8A Active CN104262352B (en) | 2014-09-01 | 2014-09-01 | Camptothecin derivative and its medical usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104262352B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397256A (en) * | 2015-07-27 | 2017-02-15 | 新钰生技股份有限公司 | Synthesis method of compound 3(2-acetamido-acetamido)-propionic acid for inhibiting melanin production |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1982313A (en) * | 2005-12-13 | 2007-06-20 | 深圳市天和医药科技开发有限公司 | Camptothecin compound containing multiple organic hydroxy-acid group on 10-bit substituent, its production and composition |
| WO2013093931A2 (en) * | 2011-09-19 | 2013-06-27 | Sun Pharma Advanced Research Company Ltd. | Novel prodrugs of phenolic drugs |
| CN103848840A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
-
2014
- 2014-09-01 CN CN201410440442.8A patent/CN104262352B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1982313A (en) * | 2005-12-13 | 2007-06-20 | 深圳市天和医药科技开发有限公司 | Camptothecin compound containing multiple organic hydroxy-acid group on 10-bit substituent, its production and composition |
| WO2013093931A2 (en) * | 2011-09-19 | 2013-06-27 | Sun Pharma Advanced Research Company Ltd. | Novel prodrugs of phenolic drugs |
| CN103848840A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104262352A (en) | 2015-01-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105153122B (en) | [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application | |
| CN104903334A (en) | Tenofovir prodrug and pharmaceutical uses thereof | |
| CN107382966B (en) | Piperlongumine-ligustrazine heterocomplex, preparation method and medical application | |
| CN106866572B (en) | Nitric oxide donator type β elemene derivatives and its production and use | |
| JP7326622B2 (en) | Spiro compounds and their use as ERK inhibitors | |
| EP3626709A1 (en) | Indazole compound for use in inhibiting kinase activity, composition and application thereof | |
| ES2772682T3 (en) | Imidazooxazine crystal, pharmaceutical composition containing said crystal, and method of producing said crystal | |
| CN110452176A (en) | Indazole analog derivative and its preparation method and application | |
| CN104262352B (en) | Camptothecin derivative and its medical usage | |
| RU2485121C1 (en) | Novel crystalline forms of adefovir dipivoxil and methods for production thereof | |
| WO2021004391A1 (en) | C-myc protein inhibitor, and preparation method therefor and use thereof | |
| CN106317050B (en) | A kind of phenyl thiazole derivant and the preparation method and application thereof | |
| CN102952151B (en) | 3 double β carbolines alkaloid compounds, its preparation method and its pharmaceutical composition and purposes | |
| CN109836477B (en) | Phenylalanine derivative containing benzothiadiazine-3-ketone 1, 1-dioxide and preparation method and application thereof | |
| CN109956896B (en) | Spiro [ cyclopropane-1, 3-indoline ] framework, crystal thereof, preparation method and application thereof | |
| CN101928323A (en) | 23-hydroxy betulinic acid derivative with modified sites 3, 23 and 28 as well as preparation method, preparation and application thereof | |
| CN106045972B (en) | Carbazole-rivastigmine dyad and its pharmaceutical composition and application | |
| WO2007067071A1 (en) | Dioxolane derivates for the treatment of cancer | |
| CN112724104B (en) | Selenium-containing melphalan derivative and preparation method and application thereof | |
| CN114149392B (en) | Curcumene nitrogen-containing derivative, preparation and application thereof | |
| CN102838652B (en) | A kind of oleanolic acid derivate with anticarcinogenesis and its production and use | |
| RU2800042C1 (en) | Spiro compounds as erk inhibitors and their use | |
| CN115073547B (en) | Steroid carboline derivative, preparation method and application thereof, and anti-tumor pharmaceutical composition | |
| JP7348214B2 (en) | Crystal forms of HDAC6 selective inhibitors and uses thereof | |
| CN108164528B (en) | A kind of amide derivatives and its application in hypertension, hyperlipidemia and atherosclerosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |