CN101092384A - A category of compound of alpha - amido - N - substituent amide, its composition, and application - Google Patents
A category of compound of alpha - amido - N - substituent amide, its composition, and application Download PDFInfo
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Abstract
This invention relates to a novel alpha-amino-N-substituted amide compound, its composition and its application. The alpha-amino-N-substituted amide compound is shown in structural formula I. The compound has such advantages as simple preparation and high anti-tumor activity.
Description
Technical field
The present invention relates to a class alpha-amido-N-substituted amide compound and salt thereof, comprise their pharmaceutical composition and in the purposes of preparation in the antitumor drug.
Background technology
Cancer is a big killer who threatens human health.From world wide, have every year to surpass 1,000 ten thousand newly-increased cases of cancer, 7,000,000 patients that have an appointment can be devitalized by cancer.Along with the rising of economic level, the increase of human mean lifetime, estimation is after following 20 years, and annual cancer mortality number will rise to 1,000 ten thousand.Therefore, scientist attempts that always this treatment of diseases is obtained some and breaks through, and makes great efforts the therapy that exploitation is suitable for treating and preventing human cancer.But because the pathogenesis of cancer is comparatively complicated, kinds of Diseases are various, and so far for it, the mankind still can't effectively treat wherein most diseases.According to statistics, since nineteen ninety the incidence of some common cancers (as lung cancer, cancer of the stomach etc.) has improved 22%, and its mortality ratio has increased this ratio equally.Therefore, how effectively treating this disease, is the severe challenge that will face human future.
In the chemotherapy field of tumour, scientist is studying the antineoplastic agent that can effectively resist all kinds cancer for a long time always.But unfortunately, the cancer therapy drug of having developed is effectively usually producing big toxicity to normal cell in the kill cancer cell, symptoms such as the user shows as weight loss, feels sick, illusion, appetite stimulator.
In addition, existing tumor chemical therapy reagent be not very desirable aspect antineoplastic validity, broad spectrum.Therefore, pressing for invention can more effective antagonism all kinds cancer, the chemical treatment reagent with highly selective, high efficiency.
Bengamides is the natural product that has remarkable anti-tumor activity from a class of ocean.After this compound in 1986 was separated from the cavernous body of ocean, owing to have wide biological activity, a plurality of groups had carried out study on the synthesis to it.Wherein, the antitumous effect of bengamide B is the most outstanding, and it all reaches the nmole level in external everyone the activity of tumor cells test of carrying out, and significantly suppresses the growth of MDA-MB-435S human breast carcinoma heterograft in vivo.There are reasons such as poorly soluble, synthetic difficulty owing to this compound, Novartis carries out the study on the synthesis of bengamide analogue in calendar year 2001, this natural product analogue: the LAF389 suitable with bengamide B that found that a kind of solvability is better, the inside and outside is active.Although this compound shows good prospects for application in the early stage, after calendar year 2001 enters clinical study, find to exist side effect such as sense of taste disorder, the dimness of vision and do not have desired therapeutic effect and can't further develop.
Summary of the invention
The invention provides the antineoplastic agent based on the Bengamide skeleton, they can effectively resist various cancer cells, and some compounds have well water-soluble (reaching 20mg/ml), and all compounds process for production thereof are simple, have very strong drug development prospect.Alpha-amido-N-substituted amide compounds of the present invention has great potential in the oncotherapy field.
A class alpha-amido-N-substituted amide compound of the present invention has the structure of formula I.
Wherein:
X is (CH
2)
mOr O, m is 0,1,2,3,4;
Y is H; C
2-C
5The straight or branched thiazolinyl; The C that aromatic base replaces
2-C
5Alkenyl; The C that hydroxyl, amino, alkoxyl group replace
2-C
5Alkyl and C
2-C
4The C that replaces of acyloxy
2-C
5Alkyl; Structural formula is
Methylene radical furans or structural formula be
Methylene radical tetrahydrofuran (THF), structural formula be
Methylene radical pyridine or structural formula be
Or methylene radical hexahydropyridine; The C that aryl replaces
1-C
5Alkyl; The C that substituted aryl replaces
1-C
5Alkyl; Structure is
Substituted acyl, wherein, R
1Be C
1-C
5Alkyl, the C that aryl replaces
1-C
5Alkyl, C
3-C
6Cycloalkyl, hydroxyl, C
1-C
5Alkoxyl group, the C that aryl replaces
1-C
5Alkoxyl group, the C that substituted aryl replaces
1-C
5Alkoxyl group, structural formula is
Amine, wherein, R
2, R
3Independent respectively is H, C
1-C
5The C that alkyl, aryl replace
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl, piperidyl, pyrryl;
N is in 0,1,2,3,4;
And comprise that 3 reach the possible steric isomer of the institute that is caused by 1 replacement;
If contain acidity or basic functionality in the compound, comprise its pharmacy acceptable salt.
According to compound of the present invention, as n=0,1,2,3, m is 1 o'clock, has the structure shown in the following general formula I I:
Wherein,
R
4Be H; C
1-C
5Alkyl; The C that aryl replaces
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl;
And comprise 3 all steric isomers;
If contain acidic functionality in the compound, comprise its pharmacy acceptable salt.
Perhaps, when n=4, compound according to the present invention has the structure shown in the following general formula III:
Wherein, the definition of X, Y is the same, but as X=(CH
2)
mThe time, do not comprise m=0, Y=H and m=1, the compound of Y=H.
Further, for above-claimed cpd, when X is (CH
2)
m, the Y structure be as
Substituted acyl the time, have the structure shown in the general formula III a.
Wherein, m is 0,1,2,3,4;
R
5Be C
1-C
5Alkyl; The C that aryl replaces
1-C
5Alkyl; C
3-C
6Cycloalkyl; Hydroxyl; C
1-C
5Alkoxyl group; The C that aryl replaces
1-C
5Alkoxyl group; The C that substituted aryl replaces
1-C
5Alkoxyl group; Structural formula is
Amine, wherein, R
2, R
3Independent respectively is H, C
1-C
5The C that alkyl, aryl replace
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl, piperidyl, pyrryl;
And comprise all steric isomers of 3 generations;
If contain acidic functionality in the compound, comprise its pharmacy acceptable salt.Perhaps, when X be (CH
2)
m, do not contain in the Y structure as
Substituted acyl the time, above-claimed cpd has the structure shown in the general formula III b.
Wherein, m is 0,1,2,3,4;
R
6Be H, C
2-C
5The straight or branched thiazolinyl, the C that aromatic base replaces
2-C
5Alkenyl, the C that hydroxyl, amino, alkoxyl group replace
2-C
5Alkyl and C
2-C
4The C that replaces of acyloxy
2-C
5Alkyl, structural formula is
Methylene radical furans or structural formula be
The methylene radical tetrahydrofuran (THF), structural formula is
Methylene radical pyridine or structural formula be
The methylene radical hexahydropyridine, the C that aryl replaces
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl;
And comprise all steric isomers of 3 generations;
Perhaps, when X is O, do not contain in the Y structure as
Substituted acyl the time, above-claimed cpd has the structure shown in the general formula III c.
Wherein, R
7Be H, C
2-C
5The C that straight or branched thiazolinyl, aryl replace
1-C
5Alkyl;
And comprise all steric isomers of 3 generations;
In the above-mentioned definition: 1) C
1-C
5Alkyl be straight or branched, latter's example comprises sec.-propyl, isobutyl-, the tertiary butyl, neo-pentyl etc.; The C that aryl replaces
1-C
5Alkyl is an aromatic nucleus unsubstituted alkyl substituting group, as styroyl, benzene butyl etc.;
2) C of substituted aryl replacement
1-C
5Alkyl is as to the fluorobenzene ethyl, to the anisole ethyl, to chlorobenzene butyl or the like;
3) C
1-C
5Alkoxyl group comprises straight or branched, as oxyethyl group, butoxy, isopropoxy, tert.-butoxy etc.; The C that substituted aryl replaces
1-C
5The alkyl of alkoxyl group is a straight chain, as to the fluorobenzene oxyethyl group, to methoxy benzene oxyethyl group, to chlorobenzene butoxy etc.; The C that aryl replaces
1-C
5The alkyl of alkoxyl group is a straight chain, as benzyloxy, benzene butoxy etc.
The present invention implements through the following steps:
(a) NaEH, THF, 2 hydroxy pyrimidine; (b) DIEA, i-PrOH refluxes; (c) TFA/THF/H
2O; (d) 1NHCl, THF
The steps include: 1) couplings take place and obtain compound 3 in compound 1 and 2; 2) compound 3 removes the ketal protection and obtains target product 4.
Wherein, the definition of X, Y is the same.
For structure shown in general formula I I, the III, compound 2 adopts following method preparation respectively.
Structure shown in the mutual-through type II:
When n=0, adopt following method preparation.
(a) EDC, HOBt, DMAP, CH
2Cl
2(b) HCl/AcOEt or HCl/ dioxane
Compound 5 and 6 obtains 7 through linked reaction, removes the Boc protecting group with HCl/AcOEt or HCl/ dioxane system again, obtains compound 8.
When n=1, adopt following method preparation.
(a) TiCl
3, MeOH, H
2O; (b) THF, LIHMDS or NaH, DMF; (c) HCl/AcOEt or HCl/ dioxane
When n=2, adopt following method preparation.
(a) EDC, HOBT, DMAP, CH
2Cl
2(b) HCl/AcOEt or HCl/ dioxane
When n=3, adopt following synthetic method.
(e) EDC, HOBT, DMAP, CH
2Cl
2(f) HCl/AcOEt or HCl/ dioxane
Structure shown in the mutual-through type III:
When X is (CH
2) m, contain in the Y structure just like
Substituted acyl the time, mutual-through type IIIa
Shown in structure, lactam compound 2 adopts following method synthetic:
(a) (Boc)
2O, NaHCO
3, THF/H
2O; (b) THF, LIHMDS or NaH, DMF; (c) HCl/AcOEt orHCl/ dioxane
When 3 configurations of compound 23 were uncertain, its raceme 23 ' adopted the literature method preparation.
When X is (CH
2) m, do not contain in the Y structure as
Substituted acyl the time, structure shown in the mutual-through type IIIb, compound 2 is prepared as follows.
(a) LiHMDS, THF or NaH, DMF; (b) HCl/AcOEt or HCl/ dioxane
When 3 configurations were uncertain, synthetic with 23 ' raw material, its condition was same as described above.
When X is O, do not contain in the Y structure as
Substituted acyl the time, the structure shown in the mutual-through type IIIc, compound 2 is synthetic with the following method:
(a) HBF
4, CH
2Cl
2(b) the following document of the synthetic method of some compounds reference among the present invention of HCl/AcOEt or HCl/ dioxane:
1. the universal synthesis method of the preparation of lactone side chain 1 and compound 3,4 is seen document J.Med.Chem, 2001,44, and 3692-3699 and Org.Process.Res.Dev., 2003,7,856-865;
2. compound 9 synthetic sees document J.Org, Chem, 1980,45,410-415;
3. compound 14 synthetic sees document J.Org, Chem, 1982,47,104-109;
4. compound 18 synthetic sees document J.Med.Chem., 1996,39,4531-4536;
Compound 23 and 23 ' syntheticly see document Tetra.Lett., 1995,3,439-440 and document Tetra.Lett., 1980,2443-2446;
6. the synthesized reference document Bioorg.Med.Chem. of compound 40,2003,11,3193-3204;
7. the synthesized reference document Tetrahedron:Asymmetry of compound 43,2003,14,2081-2085 and Org.Syn.Coll, 1973,5,245;
The present invention also provides the pharmaceutical composition that comprises above-claimed cpd, and said composition as active ingredient, and can also have one or more acceptable accessories with compound of the present invention.
In addition, the present invention also provides the application of above-claimed cpd in the preparation antitumor drug.
The present invention design with synthesized the new antitumoral compounds that a class contains the alpha-amido-N-substituted amide structure, such compound is simple, the overwhelming majority all has stronger anti-tumor activity, the water-soluble 20mg/ml that reaches of compound L 458B wherein, external activity reaches 74Nm, and confirms to have activity in vivo preferably through experimentation on animals.Since the skeleton structure of this compounds come from be proved to be have in the excellent body, the marine natural product Bengamids of anti tumor activity in vitro, so compound provided by the present invention has huge antitumor drug potentiality to be exploited.
Figure of description
Fig. 1 is that L-458B is to human breast carcinoma MDA-MB-435S Nude Mice Growth Inhibition accompanying drawing.
Embodiment
Preparation embodiment
The present invention is further elaborated below in conjunction with specific embodiment, and the present invention is not limited to these embodiment.
In the following preparation example, the Mercury-Vx 300M Instrument measuring that NMR produces with Varian, NMR calibration: δ H/C 7.26/77.0ppm (CDCl3); Reagent is mainly provided by Shanghai chemical reagents corporation, and purifying products is mainly used column chromatography, silica gel (200-300 order), and the used silica gel model of column chromatography is thick empty (ZLX-II), is produced by subsidiary factory of Haiyang Chemical Plant, Qingdao.
The preparation of embodiment 1-4a (L404)
(a) EDC, HOBT, DMAP, CH
2Cl
2(b) HCl/AcOEt; (c) 1, Sodium isooctanoate (NaEH), THF; (i) THF/1N HCl.
Get compound 5 (175mg 1mmol) is dissolved in the 8ml methylene dichloride, add 6a (139mg, 1mmol), EDCI (300mg, 1.56mmol), HOBT (150mg, stirred overnight at room temperature 1.11mmol) and behind the 5mgDMAP, a small amount of 4 molecular sieves.Next day, to filter, filtrate directly adds the 50ml methylene dichloride, extraction, washing (10ml), saturated common salt washing (10ml), dried over sodium sulfate obtains compound 7a (182.2mg, productive rate 70%).Get this compound 60mg and be dissolved among the 5ml HCl/AcOEt, stirring at room 1h handles, and concentrates, and is spin-dried for solvent and obtains compound 8a crude product.This compound is dissolved among the THF, add compound 1 (50mg, 0.18mmol) and Sodium isooctanoate 170mg, stirred overnight at room temperature, TLC analyzed and reacted completely next day.Processing is spin-dried for solvent, adds ethyl acetate (70ml), extraction, and washing (10ml), saturated common salt washing (10ml), anhydrous sodium sulfate drying, the column chromatography separation obtains compound 3a (65mg, productive rate 63.5%).Compound 3a (65mg) is dissolved in 3ml1NHCl/THF (V/V=1: 1) in the solution, be spin-dried for column purification behind the stirring 2h under the room temperature, and obtained compound 4a (L404) (44mg, productive rate 86.5%).
1H NMR(CDCl
3，300MHz)：δ7.75(t，1H)，7.05(t，1H)，5.79(d，1H)，5.40(dd，1H)，4.42(m，1H)，4.15(m，3H)，4.03(d，1H)，3.97(d，1H)，3.82(m，2H)，3.62-3.57(m，2H)，3.41(s，3H)，1.23(t，3H)，0.97(s，9H).
The preparation of embodiment 2-4b (L458B).
(a) LiHMDS, THF; (b) HCl/AcOEt; (c) 1, diisopropyl ethyl amine (DIEA), i-PrOH refluxes;
(d)TFA/THF/H
2O.
(1.0g 4.4mmo1) is dissolved among the THF compound 23, and ice bath adds the 1M THF solution of 6.6mmolLiHMDS down, adds compound 24b (4.4mmol), removes ice bath stirring at room 8h aftertreatment.Add 1ml water, be spin-dried for solvent, ethyl acetate extraction (50ml * 2), washing (10ml), saturated common salt washing (10ml), dried over sodium sulfate, the column chromatography separation obtains compound 26b (1.1g, productive rate 80%).Compound 26b (160mg 0.51mmol) is dissolved in 10ml 2NHCl/EtOAc, stirring at room 1h, and TLC analyzes has not had raw material, concentrates, and is spin-dried for and obtains compound 27b.Compound 27b and 1 (72mg, 0.26mmol), diisopropyl ethyl amine (178 L, 1.02mmol), after i-PrOH mixes, 90 ℃ of oil baths are stirred 10h and are handled, and concentrate, be spin-dried for, column chromatography separate compound 3b (115mg, 45%).Compound 3b (76mg) is dissolved among the THF, and stirring at room 1h aftertreatment concentrates and is spin-dried for all solvents, and the column chromatography separation obtains compound 4b (L458B) (40mg, productive rate 57%).
1H NMR(CDCl
3，300MHz)：δ8.09(d，1H)，5.80(d，1H)，5.40(dd，1H)，4.64(m，1H)，4.35-4.00(m，5H)，4.80-4.65(m，4H)，3.56(s，3H)，3.28(m，2H)，2.05-1.6(m，6H)，1.26(t，3H)，1.00(s，9H).
Embodiment 3-4e (L520), 4f (L444), the preparation of 4g (L472-2)
(a)NaOH，H2O，THF；(b)EDC，HOBt，DMAP，ROH(47e，47f，47g)；(c)HCl/AcOEt；
(d) 1, Sodium isooctanoate (NaEH), THF; (e) THF/1N HCl.
Compound 26b is dissolved in the mixing solutions of second alcohol and water (V/V=1/1), and 0 ℃ adds down solid NaOH (2eq), stirs 1h, conditioned reaction liquid pH=2～3 after rising to room temperature, add ethyl acetate, extraction, separatory, the organic layer drying, be spin-dried for crude product 46 (productive rate 90%), need not be further purified.Be dissolved among the exsiccant DCM 46, add EDC (1.5eq), HOBt (1.5eq), DMAP (1.5eq) and corresponding pure 47e, 47f or 47g (10eq), stirred overnight at room temperature, next day dichloromethane extraction, saturated common salt washing, drying is spin-dried for, and crosses post and gets compound 26e-26g (yield 60～83%).
8a in employing and the example 1,3a, the similar synthetic method of 4a obtains compound 4e-4g (yield 40%-85%).
Structural formula and NMR data see Table 1.
Embodiment 4-4c, 4d, 4k, 41,4m, 4n, 4o, the preparation of 4p
(a) NaH, DMF; (b) HCl/AcOEt; (c) 1, Sodium isooctanoate (NaEH), THF; (d) THF/1N HCl.
Under 0 ℃ of the nitrogen protection, compound 23 is dissolved among the DMF, adds NaH (1.2eq); keep 0 ℃ to stir 1h, add bromo-derivative 38c-38d, 38k-38p (1.5eq); reaction system rises to room temperature gradually, and stirring is spent the night, and adds frozen water cancellation reaction next day; ethyl acetate extraction, washing, saturated common salt washing; anhydrous sodium sulfate drying is spin-dried for, and crosses post and gets compound 26c-26d; 26k-26p, productive rate 40～60%.
8a in employing and the example 1,3a, the similar synthetic method of 4a obtains compound 4c-4d, 4k-4p (yield 30%-85%).
Structural formula and NMR data see Table 1.
The preparation of embodiment 5-4i
(a) LiHMDS, THF; (b) HCl/AcOEt; (c) 1, Sodium isooctanoate (NaEH), THF; (d) THF/1N HCl.
N
2Protection, under 0 ℃, (100mg 0.44mmol) is dissolved among the exsiccant THF10ml with compound 23; the THF solution (1.2eq) of the LiHMDS of adding 1M (0.5ml, 0.5mmol), 0 ℃ is stirred 1h; add compound 48, reaction system rises to room temperature gradually, and stirring is spent the night; add frozen water cancellation reaction next day, ethyl acetate extraction, washing; the saturated common salt washing, dried over sodium sulfate, solvent is spin-dried for; cross post and get compound 26i (110mg, productive rate 76%).
8a in employing and the example 1,3a, the similar synthetic method of 4a obtains compound 4i (yield 60%).
Structural formula and NMR data see Table 1.
The preparation of embodiment 6-4j
(a) O
3, NaOH, EtOH, CH
2Cl
2,-78 ℃; (b) HCl/AcOEt; (c) 1, Sodium isooctanoate (NaEH), THF; (d) THF/1N HCl.
(200mg, (V/V=1: 4), system is cooled to-78 ℃, feeds O 0.675mmol) to be dissolved in the mixing solutions of 2.5N NaOH (5eq) ethanolic soln and methylene dichloride with compound 26c (seeing example 4)
3, system becomes blueness by yellow behind about 30min, stops logical O
3, add ether and water, the extraction separatory, washing, the saturated common salt washing, dried over sodium sulfate was spin-dried for post, got compound 26j (154mg, productive rate 67%).
8a in employing and the example 1,3a, the similar synthetic method of 4a obtains compound 4j (yield 55%).
Structural formula and NMR data see Table 1.
The preparation of embodiment 7-4q
(a) 2 furan carboxyaldehyde, triethylamine, EtOH, then NaBH
4, room temperature; (b) EDC, HOBT, CH
2Cl
2, room temperature;
(c) methylene dichloride, Grubbs cat., 40 ℃; (d) Pd (OH)
2/ C (20wt%), 1atm H
2, MeOH; (e) HCl/AcOEt; (f) 1, Sodium isooctanoate (NaEH), THF; (g) THF/1N HCl.
(750mg 6.17mmol) is dissolved in the 15ml exsiccant ethanol compound 49 hydrochlorides, and ice bath adds triethylamine (1.72ml down, 12.33mmol), stir moments later, add 2 furan carboxyaldehyde (593mg, 6.17mmol), stir 5h under the room temperature, add NaBH after being cooled to 0 ℃ in batches
4(467mg, 12.3mmol), stirred overnight at room temperature adds the frozen water cancellation next day and reacts, and adds ethyl acetate extraction, washing, the saturated common salt washing, dried over sodium sulfate is spin-dried for solvent, crosses post, gets compound 50 (540mg, productive rate 53%).N
2Protection is dissolved in 50 (130mg) in the 5ml exsiccant methylene dichloride down, adds compound 32 (210mg; 1.2eq), EDC (1.2eq), HOBt (1.2eq); DMAP (catalyzer), stirred overnight at room temperature, use ethyl acetate extraction after the frozen water cancellation reaction next day; washing; the saturated common salt washing, dried over sodium sulfate is spin-dried for; cross post and get compound 51 (147mg, productive rate 66%).Set up in the there-necked flask of reflux condensing tube in one, (70mg 0.20mmol) is dissolved in dry methylene chloride (100ml), seals each mouthful with the rubber plug, the oxygen in the Ar gas displacement eliminating system to get compound 51.Start stirring, enclose in Ar atmosphere and add down the solution that Grubbs catalyzer (5%mmol) is dissolved in the 80ml methylene dichloride, after adding, the sealing of maintenance system, be warming up to 40 ℃ stir 15h after, the TLC monitoring has transformed fully.Most solvents are removed in decompression, and column chromatography for separation gets compound 52 (55mg, productive rate 90%).In a 100ml single port bottle, (55mg 0.18mmol) is dissolved among the 40ml MeOH, adds 20%wt Pd (OH) to get compound 52
2/ C (10mg, 20%wt), sealing system, H
2Stir under the atmosphere and spend the night.Filter, concentrate reduzate (productive rate 99%).(57mg 0.18mmol) in 10ml single port bottle, adds 3ml 2N HCl/EtOAc under the ice bath, stirring at room reaction 1.5h handles, and concentrates and is spin-dried for solvent, gets compound 27q (48mg, Quantitative yield) to get this compound.
3a in employing and the example 1, the similar synthetic method of 4a obtains compound 4q (yield 50%).
Structural formula and NMR data see Table 1.
Table 1
The preparation of embodiment 8. compound 4r (L388)
(a) TsCl, pyridine; (b) BnONHBoc, NaH, DMF; (c) (trifluoroacetic acid) TFA, CH
2Cl
2(d) EDC.HCl, HOBT, DMAP, CH
2Cl
2(e) toluene, Grubbs cat., 90 ℃; (f) Pd (OH)
2/ C (20wt%), 1atm H
2, MeOH; (g) HCl/ dioxane; (h) 1, NaEH, THF; (i) THF/1N HCl
(0.5ml 4.8mmol) is dissolved in the 15ml pyridine compound 28, and (1.8g 9.6mmol), stirs the 6h aftertreatment to add Tosyl chloride.Add frozen water, the AcOEt extraction (2 * 25ml), organic layer pickling (5ml), washing (2 * 10ml), the saturated common salt washing (1 * 15ml), Na
2SO
4Drying, concentrate compound 29 (1.1g, productive rate 96%).Benzyloxy amine (the BnONHBoc) (428mg of Boc protection; 1.84mol) be dissolved among the 2.5mlDMF; ice bath adds NaH (170mg down; 7.08mml); after stirring 20min, (369mg 1.54mmol) is dissolved in the solution of 3ml DMF to add compound 29; after stirring 10min, system moves to and stirs the 20h aftertreatment in 80 ℃ of oil baths.Pour in the frozen water, and petroleum ether extraction (2 * 50ml), organic layer washing (10ml), saturated common salt washing (10ml), anhydrous Na
2SO
4Drying, column chromatography purifying get compound 30 (420mg, productive rate 94%).(179mg 0.61mmol) is dissolved in 8ml CH to compound 30
2Cl
2In, adding 2ml TFA, stirring at room 2h handles.Concentrate and to revolve most of TFA, EtOAc dilute (50ml), and washing (2 * 5ml), saturated common salt washing (10ml), concentrated 31 crude products (123mg) are directly used in next step reaction.Compound 31 (0.61mmol) is dissolved in 20ml CH
2Cl
2In, add under the room temperature compound 32 (147mg, 0.73mol), EDC (139.0mg, 0.73mmol), HOBT (82.4mg, 0.73mmol) and behind the 4 molecular sieves, stirring at room 10h aftertreatment.Filter dichloromethane extraction (80ml), washing (10ml), saturated common salt washing (10ml), column chromatography (sherwood oil: ethyl acetate=4: 1) obtain compound 33 (61.4mg, 2 step productive rates 38.4%).A bite in a there-necked flask is set up reflux condensing tube, and (59mg 0.16mmol) is dissolved in dry toluene (150ml), seals each mouthful with the rubber plug, the oxygen in the Ar gas displacement eliminating system to get compound 33.Start stirring, enclose in Ar atmosphere and add down the solution that Grubbs catalyzer (12%mmol) is dissolved in 100ml toluene, after adding, the sealing of maintenance system, be warming up to 80 ℃ stir 15h after, the TLC monitoring has transformed fully.Most solvents are removed in decompression, and column chromatography for separation gets compound 34 (24mg, productive rate 45%).In a 250ml single port bottle, (24mg 0.07mmol) is dissolved among the 40ml MeOH, adds 20%wt Pd (OH) to get compound 34
2/ C (20mg, 20%wt), sealing system, H
2Stir under the atmosphere and spend the night.Filter, concentrate reduzate (productive rate 99%).(40mg 0.16mmol) in 10ml single port bottle, adds 3ml 2NHCl/EtOAc under the ice bath, stirring at room reaction 1.5h handles, and concentrates and is spin-dried for solvent, gets compound 27r (33mg, Quantitative yield) to get this compound.Get compound 27r (33mg) in a 50ml single port bottle, and adding 20ml THF and Sodium isooctanoate (106.0mg, 0.64mmol) stirring makes the solution clarification, and (41mg, 0.15mmol), stirring at room moments later moves to 45 ℃ of stirring 40h processing down to add compound 1.Concentrate and be spin-dried for solvent, institute's excess shifts (50ml) with EtOAc, extraction, washing (2 * 5ml), saturated common salt washing (5ml), anhydrous sodium sulfate drying concentrates, and column chromatography for separation gets compound 3r.(15mg 0.035mmol) in a 10ml single port bottle, adds 0.5mlTHF and 1ml hydrochloric acid (1N) under the room temperature, stirring at room 2.5h aftertreatment adds several ammoniacal liquor neutralizations, is spin-dried for all solvents, and the surplus residue of institute is with CHCl to get compound 3r
3Dissolving back column chromatography for separation gets target compound 4r (L388) (7.5mg, productive rate 55.0%).
1H NMR(CDCl
3，300MHz)：δ7.97(d，1H)，6.12(m，1H)，5.83(d，1H)，5.41(dd，1H)，4.57(m，1H)，4.23(t，1H)，3.81-3.74(m，2H)，3.60(t，1H)，3.54 and 3.55(each s，3H)，3.29(m，2H)，2.03(m，2H)，1.88-1.60(m，4H)，1.02(s，9H)。
Embodiment 9. compound 4s (L430-2)
(a)EDC，HOB T，DMAP，CH
2Cl
2；(b) HCl/AcOEt；(c)1，NaEH，THF；(d) THF/1NHCl
Compound 14 (50mg 0.19mmol) is dissolved in the methylene dichloride, adds EDC (0.20mmol) under the room temperature, HOBT (0.19mmol), and DMAP (3mg), 4 molecular sieves, stirring at room 8h handles.Filtration, filtrate is washed (10ml) with dichloromethane extraction (80ml), saturated common salt washing (10ml), anhydrous sodium sulfate drying concentrates, and the column chromatography separation obtains compound 16s (40mg, yield 74%).Compound 16s (40mg) is dissolved among the 5ml 2N HCl/AcOEt, behind the stirring at room 1h, concentrates and is spin-dried for the crude product that solvent obtains compound 17s, is directly used in next step reaction.3a in compound 17s employing and the example 1, the similar synthetic method of 4a obtains compound 4s (L430-2) (50%).
1H NMR(CDCl
3，300MHz)：δ7.32(d，1H)，5.83(d，1H)，5.41(dd，1H)，4.57(m，1H)，4.22(m，3H)，4.13(q，2H)，3.82-3.79(m，2H)，3.61(m，1H)，3.59-3.54(m，4H)，3.42(m，2H)，3.19(m，1H)，2.66(m，1H)，2.02(m，1H)，1.86(m，1H)，1.25(t，3H)，1.02(s，9H)。
Experimental example
Experimental example 1: cell levels anti-tumor activity test experiments
1. experiment purpose:
Carry out the anti-tumor activity test of synthetic compound of the present invention, by measuring compound comes assessing compound to the proliferation inhibition activity of people source breast cancer cell MDA-MB-435S anti tumor activity in vitro.
2. test philosophy:
Adopt mtt assay, this analytical procedure is reduced 3-with metabolism, and (4,5-dimethylthylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) be basic.Have the desaturase relevant with NADP in the plastosome of viable cell, xanchromatic MTT can be reduced to insoluble hepatic Formazan, this enzyme of dead cell disappears, and MTT is not reduced.With available microplate reader behind the DMSO dissolving Formazan in 550/690nm wavelength place measuring light density.
3. experimental procedure:
Take the logarithm vegetative period, cell growth state good attached cell MDA-MB-435S through 0.05% trysinization, and counting is made into cell suspension with substratum, the counting back by 3000 cells in every hole, 100 μ L culture medium inoculateds in 96 orifice plates; 96 orifice plates that inoculation is good move into 37 ℃, 5%CO
2Incubator in spend the night and treat cell attachment; Beginning dosing in second day, dosing fore portion control wells directly adds MTT solution (5mg/ml) 20 μ L (need not inhale substratum) effect and read A550/690 as initial cell concentration afterwards in 3 hours, every hole, medicine hole adds the substratum that 100 μ L contain 2 μ L compounds, with DMSO is the background contrast, equally also be the DMSO of the interior 2 μ L of adding of substratum of every hole 100 μ L, and each experiment all have the positive control Zorubicin.Placed in 37 ℃, the incubator of 5%,CO2 72 hours, each compound is done three multiple holes (draw 6 μ L compounds in the eppendorf of the bacterium of going out pipe, add 300 μ L substratum mixings then add respectively in three holes), and each compound is done six concentration gradients; (72 hours) every hole directly adds MTT solution (5mg/ml) 40 μ L (need not inhale substratum) after three days, puts into incubator and takes out after three hours hole liquid is blotted, and adds 100 μ L DMSO again, and slight vibration is fully dissolved crystallisate; (550/690) detects the absorbance value in each hole as the cell density after the drug effect on enzyme connection detector.The propagation of breast cancer cell MDA-MB-435S is suppressed medicine and cytotoxicity reflects with clean growth rate of percentage and cell survival rate respectively, from percentage grow only/cell survival-compound concentration functional arrangement measures IC
50Value.Calculation formula
The clean growth rate of percentage=[the initial A550/690 of (cell+medicine) A550/690-]/[(cell+pharmaceutical carrier DMSO) the initial A550/690 of A550/690-] * 100%
Cell survival rate=[(cell+medicine) A550/690/ (cell+pharmaceutical carrier DMSO) A550/690] * 100%
4. experimental result:
Table 2
| Entry | The clean growth rate IC of cell 50(μM) | Cell survival rate IC 50(μM) | Entry | The clean growth rate IC of cell 50(μM) | Cell survival rate IC 50(μM) |
| L404 (4a) | 2.42 | 13.57 | L462 (4k) | 0.40 | 1.89 |
| L458B (4b) | 0.074 | 0.50 | L476 (4l) | 0.29 | 1.30 |
| L440 (4c) | 0.35 | 2.87 | L490 (4m) | 1.31 | ＞2 |
| L486-2 (4d) | 0.34 | 3.10 | L504 (4n) | 0.28 | 1.63 |
| L520 (4e) | 0.29 | 1.79 | L494 (4o) | 0.56 | ＞2 |
| L444 (4f) | 0.31 | 2.44 | L506 (4p) | 0.27 | 1.56 |
| L472-2 (4g) | 0.42 | 3.19 | L456 (4q) | 0.25 | ＞2 |
| L458D (4h) | 1.61 | ＞2 | L388 (4r) | 0.44 | 2.27 |
| L472-1 (4i) | 2.11 | ＞2 | L430-2 (4s) | 0.36 | 4.05 |
| L486-1 (4j) | 1.12 | ＞2 |
Annotate: 1. activity data is the external activity of example pharmaceuticals to the MDA-MB-435S human breast cancer cell in the table;
2.IC
50Example pharmaceuticals concentration when value is 50% growth-inhibiting;
Experimental example 2: the horizontal active testing of animal
1. experiment purpose: select the L458B in the above-claimed cpd to carry out intravenous injection, observe I458B human breast carcinoma MDA-MB-435S Nude Mice is had or not experimental therapeutic action and action intensity, with the activity in vivo of test compounds.
2. make a summary: experimental result shows that the I458B intravenously administrable has certain growth-inhibiting effect to human breast carcinoma MDA-MB-435S Nude Mice.T/C (%) is 76 during I458B intravenously administrable 50mg/kg dosage, and T/C during 200mg/kg dosage (%) is 50.5.
Be subjected to the reagent thing:
Title: I458B
Animal: source, kind system, strain: the BALB/cA nude mouse is provided by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences nude mouse laboratory.The conformity certification numbering: Shanghai is moving closes the card word No. 122.
Age in days: 40-45 days
Body weight: 16-18g
Sex: female
Every treated animal number: 12 of control groups, 6 of administration groups.
Dosage is provided with: high and low two dosage groups are established in the I458B experiment, are respectively 50mg/kg and 200mg/kg.
Transplanted tumor: human breast carcinoma MDA-MB-435S Nude Mice, it is subcutaneous and set up to be inoculated in nude mouse by human breast carcinoma MDA-MB-435S cell strain, and the cell inoculation amount is 5 * 10
6, inoculation is used after forming and passing for 3 generations again in the nude mouse body behind the transplanted tumor.
Experimental technique:
The tumor tissue of getting the growth animated period cuts into 1.5mm
3About, under aseptic condition, it is subcutaneous to be inoculated in nude mouse right side armpit.Nude Mice treats that with vernier caliper measurement transplanted tumor diameter tumor growth is to 100-300mm
3Back (the 13rd day, reject transplanted tumor nude mouse excessive, too small and that do not grow) is with the animal random packet.Use the method for measuring the knurl footpath, dynamic observe the antineoplastic effect of tested thing.The measurement number of times of diameter of tumor is 2 times weekly.Experimental group is intravenously administrable 3 pins weekly, totally 3 weeks.(negative control group is given equivalent physiological saline to positive controls simultaneously for mitomycin, MMC) intravenously administrable totally 1 pin.The calculation formula of gross tumor volume (TV) is: TV=1/2 * a * b
2, wherein a, b represent length and width respectively.Calculate relative tumour volume (RTV) according to the result who measures, calculation formula is: RTV=V
t/ V
0V wherein
0(d during for minute cage administration
0) measurement gained gross tumor volume, V
tGross tumor volume when measuring each time.The evaluation index of anti-tumor activity is relative tumor proliferation rate T/C (%), and calculation formula is as follows:
T
RTV: treatment group RTV; C
RTV: negative control group RTV.
Result and discussion:
I458B sees Table the experimental treatment result of human breast carcinoma MDA-MB-435S Nude Mice and schemes.Experimental result shows that T/C (%) is 49.5 during intravenously administrable 200mg/kg dosage, and human breast carcinoma MDA-MB-435S Nude Mice is had than the obvious growth restraining effect.Toxic reaction does not appear in nude mouse after the administration, does not have dead the generation yet.Test-results sees Table 3.
Table 3.L458B is to the experimental therapy effect of human breast carcinoma MDA-MB-435S Nude Mice
| Group | Dosage | Number of animals | Body weight (g) | TV(mm 3) | RTV | T/C (％) | |||
| Beginning | At last | Beginning | At last | d 0 | d 21 | ||||
| Control | 0.2ml/ only | 12 | 12 | 16.8 | 19.6 | 135±61 | 1494± 105 | 11±4.9 | |
| MMC | 5mg/kg， d1 | 6 | 6 | 16.5 | 17.3 | 122±43 | 231± 124 | 1.8±0.4 | 16.2 |
| L458B | 200mg/kg | 6 | 6 | 18 | 18.8 | 145±65 | 779± 576 | 5.5±3.7 | 49.5 |
| L458B | 50mg/kg | 6 | 6 | 17.3 | 20.3 | 133±62 | 1190± 956 | 8.5±4.3 | 76 |
Annotate: administering mode is intravenous injection.
Claims (12)
1, following alpha-amido-N-substituted amide compound and the pharmacy acceptable salt thereof of a class formation formula:
Wherein:
X is (CH
2)
mOr O, m is 0,1,2,3 or 4;
Y is H; C
2-C
5The straight or branched thiazolinyl; The C that aromatic base replaces
2-C
5Alkenyl; The C that hydroxyl, amino, alkoxyl group replace
2-C
5Alkyl and C
2-C
4The C that replaces of acyloxy
2-C
5Alkyl; Structural formula is
Methylene radical furans or structural formula be
Methylene radical tetrahydrofuran (THF), structural formula be
Methylene radical pyridine or structural formula be
Or methylene radical hexahydropyridine; The C that aryl replaces
1-C
5Alkyl; The C that substituted aryl replaces
1-C
5Alkyl; Structure is
Substituted acyl, wherein, R
1Be C
1-C
5Alkyl, the C that aryl replaces
1-C
5Alkyl, C
3-C
6Cycloalkyl, hydroxyl, C
1-C
5Alkoxyl group, the C that aryl replaces
1-C
5Alkoxyl group, the C that substituted aryl replaces
1-C
5Alkoxyl group, structural formula is
Amine, wherein, R
2, R
3Be H, C independently respectively
1-C
5The C that alkyl, aryl replace
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl, piperidyl, pyrryl;
N is in 0,1,2,3 and 4;
And comprise that 3 reach the possible steric isomer of the institute that is caused by 1 replacement;
If contain acidity or basic functionality in the compound, comprise its pharmacy acceptable salt.
2, alpha-amido-N-substituted amide compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that:
As n=0,1,2 or 3, m is 1 o'clock, has the structure shown in the following general formula I I:
Wherein:
R
4Be H; C
1-C
5Alkyl; The C that aryl replaces
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl;
And comprise 3 all steric isomers;
If contain acidic functionality in the compound, comprise its pharmacy acceptable salt.
3, alpha-amido-N-substituted amide compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that:
When n=4, have the structure shown in the following general formula III:
Wherein, the definition of X, Y is with claim 1, but as X=(CH
2)
mThe time, do not comprise m=0, Y=H and m=1, the compound of Y=H.
4, alpha-amido-N-substituted amide compound according to claim 3 and pharmacy acceptable salt thereof is characterized in that:
When X is (CH
2)
m, in the Y structure be as
Substituted acyl the time, have general formula III a
Shown structure:
Wherein, m is 0,1,2,3 or 4;
R
5Be C
1-C
5Alkyl; The C that aryl replaces
1-C
5Alkyl; C
3-C
6Cycloalkyl; Hydroxyl; C
1-C
5Alkoxyl group; The C that aryl replaces
1-C
5Alkoxyl group; The C that substituted aryl replaces
1-C
5Alkoxyl group; Structural formula is
Amine, wherein, R
2, R
3Be H, C independently respectively
1-C
5The C that alkyl, aryl replace
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl, piperidyl, pyrryl;
And comprise all steric isomers of 3 generations;
If contain acidic functionality in the compound, comprise its pharmacy acceptable salt.
5, alpha-amido-N-substituted amide compound according to claim 3 and pharmacy acceptable salt thereof is characterized in that:
When X is (CH
2)
m, do not contain in the Y structure as
Substituted acyl the time, have the structure shown in the general formula III b:
Wherein, m is 0,1,2,3 or 4;
R
6Be H, C
2-C
5The straight or branched thiazolinyl, the C that aromatic base replaces
2-C
5Alkenyl, the C that hydroxyl, amino, alkoxyl group replace
2-C
5Alkyl and C
2-C
4The C that replaces of acyloxy
2-C
5Alkyl, structural formula is
Methylene radical furans or structural formula be
The methylene radical tetrahydrofuran (THF), structural formula is
Methylene radical pyridine or structural formula be
The methylene radical hexahydropyridine, the C that aryl replaces
1-C
5The C that alkyl or substituted aryl replace
1-C
5Alkyl;
And comprise all steric isomers of 3 generations.
6, alpha-amido-N-substituted amide compound according to claim 3 and pharmacy acceptable salt thereof is characterized in that:
When X is O, do not conform in the Y structure as
Substituted acyl the time, have the structure shown in the general formula III c,
Wherein, R
7Be H, C
2-C
5The C that straight or branched thiazolinyl, aryl replace
1-C
5Alkyl;
And comprise all steric isomers of 3 generations.
7, alpha-amido-N-substituted amide compound and pharmacy acceptable salt thereof according to claim 2 is characterized in that, during n=0, and R
4Be ethyl; During n=2, R
4Be ethyl.
8, alpha-amido-N-substituted amide compound according to claim 4 and pharmacy acceptable salt thereof is characterized in that, during m=1, and R
5Be methoxyl group, oxyethyl group, benzyloxy, isopropoxy; During m=2, R
5Be oxyethyl group; During m=3, R
5Be oxyethyl group.
9, alpha-amido-N-substituted amide compound according to claim 5 and pharmacy acceptable salt thereof is characterized in that, during m=0, and R
7For phenmethyl, styroyl, hydrocinnamyl, benzene butyl, to the fluorobenzene ethyl, to anisole ethyl, methylene radical tetrahydrofuran (THF), pentenyl, acetoxyl group butyl.
10, alpha-amido-N-substituted amide compound according to claim 6 and pharmacy acceptable salt thereof is characterized in that R
8Be hydrogen.
11, a kind of pharmaceutical composition comprises that each described compound of claim 1～6 and pharmacy acceptable salt thereof are as active ingredient.
12, described alpha-amido-N-substituted amide compound of claim 1 and pharmacy acceptable salt thereof the application in the preparation antitumor drug.
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| PCT/CN2007/001470 WO2008000131A1 (en) | 2006-06-22 | 2007-04-29 | α-AMINO-N-SUBSTITUTED AMIDE COMPOUNDS, COMPOSITIONS AND USES THEREOF |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009074020A1 (en) * | 2007-12-11 | 2009-06-18 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Alpha-amino-n-substituted amides, pharmaceutical composition containing them and uses thereof |
| CN105037192A (en) * | 2015-06-25 | 2015-11-11 | 西安嘉宏能源化工科技有限公司 | One-step method for synthesizing p-formylamino benzene alkyl ether as octane booster |
| CN112851749A (en) * | 2019-11-12 | 2021-05-28 | 中国科学院上海药物研究所 | alpha-amino-N-substituted amide compounds, pharmaceutical compositions containing the same and their use in antibacterials |
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| US6545148B2 (en) * | 2001-03-12 | 2003-04-08 | Novartis Ag | Process for preparing certain substituted caprolactams |
| JP2006528611A (en) * | 2003-07-25 | 2006-12-21 | ノバルティス アクチエンゲゼルシャフト | Substituted lactams and their use as anticancer agents |
| FR2878528B1 (en) * | 2004-11-29 | 2008-05-16 | Aventis Pharma Sa | 2-ALCOXY-3,4,5-TRIHYDROXY-ALKYLAMIDES, PREPARATION THEREOF, COMPOSITIONS CONTAINING SAME AND USE THEREOF |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009074020A1 (en) * | 2007-12-11 | 2009-06-18 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Alpha-amino-n-substituted amides, pharmaceutical composition containing them and uses thereof |
| US8470763B2 (en) | 2007-12-11 | 2013-06-25 | Shanghai Institute Of Materia Medica Chinese Academy Of Sciences | Alpha-amino-N-substituted amides, pharmaceutical composition containing them and uses thereof |
| CN105037192A (en) * | 2015-06-25 | 2015-11-11 | 西安嘉宏能源化工科技有限公司 | One-step method for synthesizing p-formylamino benzene alkyl ether as octane booster |
| CN105037192B (en) * | 2015-06-25 | 2017-05-31 | 西安嘉宏能源化工科技有限公司 | One-step method octane rating promoter is to formamido alkyl ether benzene synthetic method |
| CN112851749A (en) * | 2019-11-12 | 2021-05-28 | 中国科学院上海药物研究所 | alpha-amino-N-substituted amide compounds, pharmaceutical compositions containing the same and their use in antibacterials |
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