CN107663202A - 3- (urea groups-methyl) -4- aryl-pyridine derivatives and preparation method thereof and the application as medicines resistant to liver cancer - Google Patents
3- (urea groups-methyl) -4- aryl-pyridine derivatives and preparation method thereof and the application as medicines resistant to liver cancer Download PDFInfo
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- CN107663202A CN107663202A CN201610621149.0A CN201610621149A CN107663202A CN 107663202 A CN107663202 A CN 107663202A CN 201610621149 A CN201610621149 A CN 201610621149A CN 107663202 A CN107663202 A CN 107663202A
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- 0 Cc1c(C*)cncc1 Chemical compound Cc1c(C*)cncc1 0.000 description 3
- DMMMFFINBMGHBI-UHFFFAOYSA-N CC(C)(C)OC(NCc(cncc1)c1-c1c[s]cc1)=O Chemical compound CC(C)(C)OC(NCc(cncc1)c1-c1c[s]cc1)=O DMMMFFINBMGHBI-UHFFFAOYSA-N 0.000 description 1
- YUUJHIGBSXUBLK-UHFFFAOYSA-N NCc(cncc1)c1-c1ccc[s]1 Chemical compound NCc(cncc1)c1-c1ccc[s]1 YUUJHIGBSXUBLK-UHFFFAOYSA-N 0.000 description 1
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
3 (ureidomethy) 4 aryl pyridine derivative and preparation method thereof and the application as medicines resistant to liver cancer.The invention discloses the compound shown in a kind of formula I or its pharmaceutically acceptable salt, crystal formation, solvate：Wherein, X is O or S；N is 0~3 integer；R1、R2、R3、R4、R5Separately selected from H, cyano group, COOR11、C1~C4Alkyl, C1~C4Alkoxy, trifluoromethyl, amino, nitro, hydroxyl, sulfydryl or halogen, R11Selected from H or C1~C4Alkyl.Meanwhile the invention also discloses the preparation method of compound shown in formula I.Half-inhibition concentration (the IC of the compounds of this invention50) smaller, there is good inhibiting effect to liver cancer cells；Moreover, the preparation method of the compounds of this invention is easy, reaction condition is gentle, and easy to operation and control, energy consumption is small, and yield is high, and cost is low, can be adapted to industrialization production.
Description
Technical field
The present invention relates to 3- (urea groups-methyl) -4- aryl-pyridine derivatives and preparation method thereof and as medicines resistant to liver cancer
Application.
Background technology
Tumour is to threaten one of principal element of human life, wherein liver cancer be a kind of characteristic of disease occurred frequently in global range and
High lethal malignant tumour.Due to by hepatitis type B virus (HBV), HCV (HCV) and alcoholic fatty liver
Influence, China's onset of liver cancer rate and the death rate are occupied first of the whole world, and serious threat the life and health of our people.But due to lacking
The effective ways of liver cancer are early diagnosed, the middle and advanced stage stage is generally in when patient clinical is made a definite diagnosis, operation is lost and cures most
Good chance so that drug therapy occupies critical role in the therapeutic process of mid and late liver cancer.
At present, the medicine clinically mainly applied includes traditional cell toxicant based chemotherapy medicine and the in recent years table in clinic
The small molecule targeted drug of existing positive therapeutic.Conventional cell poison class medicine is played in the systemic treatment of mid and late liver cancer to pass
Important effect, but most mid and late liver cancer patients are simultaneously with hepatic sclerosis, liver function damage and thrombopenia, these trouble
Person is generally poor to the tolerance of classic chemotherapy medicine, therefore the use of conventional cell cytotoxic chemotherapeutic drugs is extremely restricted.Closely
Nian Lai, with many further investigations such as the pathogenesis to liver cancer, the Molecular Biology Mechanism, for the small molecule target of liver cancer
Substantial progress is achieved to drug research, becomes one kind effectively selection of liver cancer treatment.However, so far clinically
The small molecule targeted drug used only has the Mutiple Targets small-molecule drug Sorafenib (Sorafenib) of U.S. FDA approval, the medicine
Using expensive, and the shortcomings of offer limited effectiveness and resistance be present.Therefore researched and developed also urgently for the small molecule targeted drug of liver cancer
It is pending.
The content of the invention
It is an object of the invention to provide a kind of new 3- (urea groups-methyl) -4- aryl-pyridines with medical value to spread out
Biology：Compound shown in formula I.
Compound or its pharmaceutically acceptable salt, crystal formation, solvate shown in formula I provided by the invention：
Wherein,
X is O or S；
N is 0~3 integer；
R1、R2、R3、R4、R5Separately selected from H, cyano group, COOR11、C1~C4Alkyl, C1~C4Alkoxy, fluoroform
Base, amino, nitro, hydroxyl, sulfydryl or halogen, R11Selected from H or C1~C4Alkyl.
Further, X S；N is 0,1 or 2.
Further, described R1、R2、R3、R4、R5All H.
Further, described compound is：
Further, described R1、R2、R3、R4、R5In, at least one is cyano group, COOCH3Or COOCH2CH3, remaining
Be selected from H, methyl, ethyl, methoxyl group, ethyoxyl, trifluoromethyl or halogen；
Preferably, described R1、R2、R3、R4、R5In, there is one or two for cyano group, COOCH3Or COOCH2CH3, remaining
Be selected from H, methyl or ethyl；
It is furthermore preferred that described R1、R2、R3、R4、R5In, only one is cyano group, COOCH3Or COOCH2CH3, remaining
For H.
Further, described compound is：
Present invention also offers a kind of method for preparing above-claimed cpd, it comprises the following steps：Compound 5 and compound
7
React, separate in organic solvent, purifying, obtain the compound shown in Formulas I：
Wherein,
X is O or S；
N is 0~3 integer；
R1、R2、R3、R4、R5Separately it is selected from H, C1~C4Alkyl, C1~C4Alkoxy, trifluoromethyl, COOR11, cyanogen
Base, amino, nitro, hydroxyl, sulfydryl or halogen, R11Selected from H or C1~C4Alkyl；
The mol ratio of the compound 5 and compound 7 is 1：1~1.5；The temperature of the reaction is 0 DEG C~60 DEG C；
The organic solvent in dichloromethane, tetrahydrofuran, toluene, ethyl acetate, second cyanogen any one or two
More than kind.
Further, the compound 5 is prepared by following steps：
1., the amino of 3- pyridyl-methanamines is protected, obtain compound 2；
2., compound 2 and halogen simple substance react, obtain compound 3；
3., compound 3 withReaction, obtains compound 4；
4. compound 4 sloughs amino protecting group, compound 5 is obtained；
Wherein,
RaFor tertbutyloxycarbonyl, benzyloxycarbonyl group, fluorenylmethyloxycarbonyl, methoxycarbonyl group, carbethoxyl group, allyloxycarbonyl, front three
Base silicon carbethoxyl group, phthalyl, p-toluenesulfonyl, trifluoroacetyl group, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulphonyl
Base, pivaloyl group, benzoyl, trityl, benzyl, 2,4- veratryls or to methoxybenzyl；
Halogen simple substance is fluorine simple substance, elemental chlorine, bromine simple substance or elemental iodine；
RbFor fluorine, chlorine, bromine or iodine；
X is O or S.
Present invention also offers above-claimed cpd or its pharmaceutically acceptable salt, crystal formation, solvate to prepare treatment
And/or the application in the medicine to prevent liver cancer.
Treated and/or the pharmaceutical composition that prevents liver cancer present invention also offers a kind of, it be with above-claimed cpd or its
Pharmaceutically acceptable salt, crystal formation, solvate are active component, the preparation being prepared plus pharmaceutically conventional auxiliary material.
Half-inhibition concentration (the IC of the compounds of this invention50) smaller, there is good inhibiting effect to liver cancer cells；And
And the preparation method of the compounds of this invention is easy, reaction condition is gentle, and easy to operation and control, energy consumption is small, and yield is high, cost
It is low, industrialization production can be adapted to.
The compound and derivative provided in the present invention can according to IUPAC (IUPAC) or
CAS (chemical abstracts service, Columbus, OH) naming system is named.
The definition using term on the present invention：Unless otherwise indicated, what group or term herein provided is initial
The group or term of definition suitable for entire description；For the term being not specifically defined herein, it should according to open
Content and context, their implication can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value of carbon content and maximum are represented by prefix in hydrocarbon group, for example, prefix Ca~CbAlkyl table
Bright any alkyl for including " a " to " b " individual carbon atom.Thus, for example, C1~C4Alkyl refers to the alkane for including 1~4 carbon atom
Base, in other words, C1~C4Alkyl includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or the salt formed is usual
In chemistry or physically with forming the other compatible into split-phase of certain pharmaceutical dosage form, and physiologically compatible with by body phase.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its stereoisomer, with inorganic and/or organic acid
The acid and/or basic salt formed with alkali, also including amphion salt (inner salt), in addition to quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be directly obtained in being finally separating and purify of compound.Can also be by by above-claimed cpd, or it is vertical
Body isomers, it is obtained by mixing with a number of acid or alkali appropriate (such as equivalent).These salt may be in the solution
Form precipitation and collected with filter method, or reclaim and obtain after the solvent evaporates, or be freeze-dried after being reacted in aqueous medium
It is made.Heretofore described salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, the hydrogen of compound
Fluorate, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleic acid
Salt, tartrate or trifluoroacetate.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes
(but being not limited to)：Orally, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound mixes with least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mix：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) bond
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, example
Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, tristearin (i)
Sour magnesium, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also include
Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can use coating and shell material to prepare, such as casing and
Other materials well known in the art.They can include opacifying agent, also, reactive compound or compound in this composition
Release can be discharged in certain part in alimentary canal in a delayed fashion.The example of adoptable embedding component is polymeric material
And Wax.If necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, such as water or other solvents, increase
Solvent and emulsifying agent, example know, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials
Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste
Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and the mixture of Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
Composition for parenteral injection can include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
The formulation of the compounds of this invention for being locally administered includes ointment, powder, patch, propellant and inhalant.
Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary may need
Propellant be mixed together.
Pharmaceutically acceptable auxiliary material of the present invention, refer to the material being included in addition to the active ingredient (s in formulation.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but the addition of the composition
Leading position of the aforementioned pharmaceutical compositions in treatment of diseases will not be changed, and only play auxiliary effect, these auxiliary
Effect is only the utilization to the composition known activity, is the usual adjuvant treatment modality of field of medicaments.If will be above-mentioned complementary
Composition is used cooperatively with pharmaceutical composition of the present invention, still falls within the scope of protection of the invention.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Brief description of the drawings
Fig. 1 is the compounds of this invention 8b's1H NMR scheme.
Fig. 2 is the compounds of this invention 8d's1H NMR scheme.
Fig. 3 is the compounds of this invention 8i's1H NMR scheme.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
Wherein,
Compound 5 can be obtained by buying commercially available prod, can also be prepared by the following method to obtain：
(1) compound 2 (N- tertbutyloxycarbonyl -3- pyridyl-methanamines) is synthesized
Compound 1：Amine, the commercially available product of uncommon love (Shanghai) the chemical conversion industry Development Co., Ltd of ladder；
DMAP：DMAP；PE：Petroleum ether；EA：Ethyl acetate；
At room temperature, compound 1 (1.08g, 10mmol) is dissolved in acetonitrile (40ml), adds di-tert-butyl dicarbonate
It is complete through TCL detection raw material reactions after (2.40g, 11mmol) and DMAP (0.12g, 1mmol) stirring at normal temperature 2h, it is concentrated under reduced pressure
Crude product is through column chromatography (PE afterwards：EA=5：1) colorless oil compound 2 (1.25g, yield 60%) is purified to obtain.
(2) compound 3 (the iodo- 3- pyridyl-methanamines of N- tertbutyloxycarbonyls -4-) is synthesized
THF：Tetrahydrofuran；tert-BuLi：Tert-butyl lithium；
Compound 2 (0.954g, 4.59mmol) THF (8ml) solution is cooled to -78 DEG C, and will at -78 DEG C
Tert-BuLi (10.6ml, 13.77mmol) is added, and I is added after stirring reaction 30min2The THF of (1.746g, 6.88mmol)
(7ml) solution, the stirring reaction 1h at -78 DEG C, after be slowly increased to -20 DEG C of 0.5~2h of reaction, it is complete through TLC detection reactions, use
Saturation Na2S2O3The unnecessary I of solution washes away2, through ethyl acetate extraction three times, the anhydrous MgSO of organic layer4Dry, after being concentrated under reduced pressure
Yellow oily compound 3 (0.31g, yield 20%) is obtained through column chromatography.
(3) compound 4 is synthesized
A, compound 4a (N- tertbutyloxycarbonyls -4- (3- thiophene) -3- pyridyl-methanamines) is synthesized
3 thienylboronic acid：The commercially available product of lark prestige Science and Technology Ltd.；
Pd(PPh3)4：Tetrakis triphenylphosphine palladium, the commercially available product in Shanghai Ying Gong bio tech ltd；
By compound 3 (0.10g, 0.31mmol) and 3 thienylboronic acid (0.048g, 0.37mmol), potassium carbonate
(57.05mg, 0.413mmol) is dissolved in toluene (3ml) and ethanol (1ml), and the 10min that deaerates, then by Pd (PPh3)4
(35.8mg, 0.031mmol) is added thereto, and back flow reaction is overnight, complete through TCL detection reactions, is filtered to remove inorganic salts, then subtract
Crude product is through column chromatography (PE after pressure concentration：EA=8：1) yellow solid compound 4a (0.08g, yield 93%) is purified to obtain.
B, compound 4b (N- tertbutyloxycarbonyls -4- (2- thiophene) -3- pyridyl-methanamines) is synthesized
According to above-claimed cpd 4a synthetic method, the 3 thienylboronic acid in raw material is replaced with 2- thienyl boric acids, is prepared into
To compound 4b (yield 89%)；
(4) compound 5 is synthesized
A, compound 5a ((4- (thiene-3-yl) pyridin-3-yl) methylamine) is synthesized
Compound 4a (0.21g, 0.74mmol) is dissolved in 5M HCl ethyl acetate solution (EA.HCl) (20ml), room
Warm stirring reaction is stayed overnight, after TCL detection raw material reactions completely, with saturation NaHCO3Alkalescence is adjusted to, ethyl acetate extracts 3 times,
Organic layer obtains yellow oily compound 5a (0.12g, yield 86%) after drying, concentration.
B, compound 5b is synthesized
According to above-claimed cpd 5a synthetic method, using compound 4b as raw material, compound 5b is prepared.
C, compound 5c is synthesized
According to above-claimed cpd 5a synthetic method, using compound 4c as raw material, compound 5c is prepared.
Compound 7 can be obtained by buying commercially available prod (such as:Phenyl isocyanate can be by buying Hunan De Jia
The commercially available prod of biochemical technology Co., Ltd obtains), it can also be prepared by the following method to obtain：
A, compound 7a (phenyl isocyanate) is synthesized
DCM：Dichloromethane；
Aniline (0.12g, 1.25mmol) is added into reaction bulb and is dissolved with DCM (5ml), adds saturation NaHCO3
(8.75ml) solution, is cooled to 0 DEG C, adds trichloromethyl carbonate (0.12g, 0.41mmol) and stirring reaction 15min, warp afterwards
After TCL detection display reactions completely, with dichloromethane extraction three times, organic layer obtains colourless liquid chemical combination after drying, concentration
Thing 7a.
B, compound 7b is synthesized
According to above-mentioned similar method, the aniline in raw material is replaced with gavaculine ethyl ester, compound is prepared
7b。
C, compound 7c is synthesized
According to above-mentioned similar method, the aniline in raw material is replaced with ethylaminobenzoate, compound is prepared
7c。
D, compound 7d is synthesized
According to above-mentioned similar method, (amino-methyl benzoic acid and ethanol can be passed through with an amino-methyl benzoic acid ethyl ester
Reaction obtain) replace raw material in aniline, compound 7d is prepared.
E, compound 7e is synthesized
According to above-mentioned similar method, the aniline in raw material is replaced with paraaminomethyl benzoic acid ethyl ester, chemical combination is prepared
Thing 7e.
Embodiment 1, synthesis compound 8a (1- phenyl -3- ((4- (thiene-3-yl) pyridin-3-yl) methyl) urea)
Compound 5a (0.14g, 0.74mmol), compound 7a (0.13g, 1.11mmol) are dissolved in dichloromethane (4ml)
In, it is placed in 0 DEG C of stirring reaction overnight, after TLC detection reactions completely, crude product is through column chromatography (CH after being concentrated under reduced pressure2Cl2：
CH3OH=20：1) compound as white solid 8a (0.12g, yield 53%), LC-MS m/z are purified to obtain:310.09[M+H].Implement
Example 2, synthesis compound 8b (3- (3- ((4- (thiene-3-yl) pyridin-3-yl) methyl) urea groups) benzoic acid)
According to the similar method of embodiment 1, the compound 7a in raw material is replaced with compound 7b, compound is prepared
8ba (yield 51%).
Compound 8ba (0.5g, 1.30mmol) is dissolved in the mixed liquor of ethanol (15ml) and water (15ml), adds NaOH
100 DEG C of 1~2h of back flow reaction afterwards, complete through TLC detection reactions, the HCl solution for adding 1N adjusts PH to acidity, by the solid of precipitation
Filtering, vacuum drying, obtains compound as white solid 8b (0.42g, yield 92%).
1H NMR(400MHz,DMSO-d6):δ12.81(s,br 1H),8.86(s,1H),8.63(s,1H),8.50(d,J
=4.8Hz, 1H), 8.05 (t, J=1.6Hz, 1H), 7.83 (dd, J=1.2Hz, 1.6Hz, 1H), 7.76-7.74 (m, 1H),
7.60-7.58 (m, 1H), 7.49 (dt, J=1.2Hz, 1.2Hz, 1H), 7.40 (dd, J=1.2Hz, 1.2Hz, 1H), 7.38-
7.32 (m, 2H), 6.76-6.75 (m, 1H), 4.42 (d, J=5.6Hz, 2H) ppm, are shown in Fig. 1；LC-MS m/z:352.09[M-
H]。
Embodiment 3, synthesis compound 8c (4- (3- ((4- (thiene-3-yl) pyridin-3-yl) methyl) urea groups) benzoic acid)
According to the similar method of embodiment 2, the compound 7b in raw material is replaced with compound 7c, compound 8c is prepared
(yield 55%).
1H NMR(400MHz,DMSO-d6):δ 12.50 (s, 1H), 9.01 (s, 1H), 8.63 (s, 1H), 8.50 (d, J=
4.0Hz, 1H), 7.83-7.75 (m, 3H), 7.50-7.40 (m, 3H), 6.83 (s, 1H), 4.43 (d, J=4.8Hz, 2H) ppm,
LC-MS m/z:352.09[M-H]。
Embodiment 4, synthesis compound 8d (3- ((3- ((4- (thiene-3-yl) pyridin-3-yl) methyl) urea groups) methyl) benzene
Formic acid)
According to the similar method of embodiment 2, the compound 7b in raw material is replaced with compound 7d, compound 8d is prepared
(yield 53%).
1H NMR(400MHz,DMSO-d6):δ 12.92 (s, br 1H), 8.58 (s, 1H), 8.48 (d, J=5.2Hz,
1H),7.87(s,1H),7.82-7.78(m,2H),7.73-7.71(m,1H),7.51-7.42(m,2H),7.38-7.35(m,
2H), 6.68-6.64 (m, 2H), 4.34 (d, J=8.0Hz, 2H), 4.29 (d, J=8.0Hz, 2H) ppm, are shown in Fig. 2；LC-MSm/
z:366.09.08[M-H]。
Embodiment 5, synthesis compound 8e (4- ((3- ((4- (thiene-3-yl) pyridin-3-yl) methyl) urea groups) methyl) benzene
Formic acid)
According to the similar method of embodiment 2, the compound 7b in raw material is replaced with compound 7e, compound 8e is prepared
(yield 52%).
1H NMR(400MHz,DMSO-d6):δ 12.85 (S, 1H), 8.59 (s, 1H), 8.48 (d, J=5.2Hz, 1H),
7.89 (d, J=8.0Hz, 2H), 7.80-7.79 (m, 1H), 7.73-7.71 (m, 1H), 7.39-7.35 (m, 4H), 6.70 (s,
2H), 4.34 (d, J=6.0Hz, 2H), 4.30 (d, J=6.4Hz, 2H) ppm, LC-MS m/z:366.09.08[M-H].
Embodiment 6, synthesis compound 8f (1- (3- cyano-phenyls) -3- ((4- (thiene-3-yl) pyridin-3-yl) methyl)
Urea)
M-aminophenyl formonitrile HCN (0.08g, 0.69mmol) is dissolved in THF (7ml), addition triethylamine (0.14g,
0 DEG C is cooled to after 1.37mmol), trichloromethyl carbonate (0.07g, 0.23mmol) is added at 0 DEG C and reacts 3h afterwards, in 0 DEG C
Room temperature reaction is moved to after lower addition compound 5a (0.09g, 0.46mmol) overnight, it is complete through TLC detection reactions, be concentrated under reduced pressure through
Column chromatography (CH2Cl2：CH3OH=10：1) purifying obtains compound as white solid 8f (0.07g, yield 44%).
1H NMR(400MHz,DMSO-d6):δ 8.98 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=4.8Hz, 1H),
7.93 (t, J=1.6Hz, 1H), 7.83-7.82 (m, 1H), 7.76-7.74 (m, 1H), 7.61-7.58 (m, 1H), 7.46-7.34
(m, 4H), 6.87 (t, J=5.6Hz, 1H), 4.43 (d, J=5.6Hz, 2H) ppm, LC-MS m/z:335.08[M+H].
Embodiment 7, synthesis compound 8g (1- (4- cyano-phenyls) -3- ((4- (thiene-3-yl) pyridin-3-yl) methyl)
Urea)
According to the similar method of embodiment 6, the compound 6f in raw material is replaced with compound 6g, compound 8g is prepared
(yield 38%), LC-MS m/z:335.08[M+H].
Embodiment 8, synthesis compound 8h (1- phenyl -3- ((4- (thiophene -2- bases) pyridin-3-yl) methyl) urea)
According to the similar method of embodiment 1, the compound 5a in raw material is replaced with compound 5b, compound 8h is prepared
(yield 56%).
1H NMR(400MHz,DMSO-d6):δ 8.63 (d, J=12.4Hz, 2H), 8.51 (d, J=5.2Hz, 1H), 7.81
(dd, J=1.2,0.8Hz, 1H), 7.48 (dd, J=1.2,1.2Hz, 1H), 7.46 (d, J=5.2Hz, 1H), 7.40-7.38
(m, 2H), 7.27-7.20 (m, 3H), 6.92-6.88 (m, 1H), 6.66 (t, J=5.6Hz, 1H), 4.50 (d, J=5.6Hz,
2H) ppm, LC-MS m/z:310.09[M+H].
Embodiment 9, synthesis compound 8i (4- (3- ((4- (thiophene -2- bases) pyridin-3-yl) methyl) urea groups) benzoic acid)
According to the similar method of embodiment 2, the compound 5a in raw material is replaced with compound 5b, is replaced with compound 7c former
Compound 7b in material, compound 8i (yield 48%) is prepared.
1H NMR(400MHz,DMSO-d6):δ 12.46 (s, 1H), 9.08 (d, J=19.2Hz, 1H), 8.65 (s, 1H),
8.51 (d, J=4.8Hz, 1H), 7.83-7.80 (m, 3H), 7.51-7.48 (m, 3H), 7.46 (d, J=5.2Hz, 1H) 7.28-
7.26 (m, 1H), 6.87-6.85 (m, 1H) 4.51 (d, J=8.0Hz, 2H) ppm, are shown in Fig. 3；LC-MS m/z:352.09[M-H].
Embodiment 10, synthesis compound 8j (4- ((3- ((4- (thiene-3-yl) pyridin-3-yl) methyl) urea groups) methyl)
Ethyl benzoate)
According to the similar method of embodiment 1, the compound 7a in raw material is replaced with compound 7e, compound 8j is prepared
(yield 63%), LC-MS m/z:396.12[M+H].
Embodiment 11, synthesis compound 8k (1- (3- cyano-phenyls) -3- ((4- (thiophene -2- bases) pyridin-3-yl) methyl)
Urea)
According to the similar method of embodiment 6, the compound 5a in raw material is replaced with compound 5b, compound 8k is prepared
(yield 33%).
1H NMR(400MHz,DMSO-d6):δ 9.02 (s, 1H), 8.64 (s, 1H), 8.51 (d, J=4.8Hz, 1H),
7.94 (t, J=1.6Hz, 1H), 7.82 (dd, J=1.2Hz, 1.2Hz, 1H), 7.61-7.58 (m, 1H), 7.49-7.42 (m,
3H), 7.37-7.34 (m, 1H), 7.28-7.26 (m, 1H), 6.88 (t, J=5.6Hz, 1H), 4.51 (d, J=5.6Hz, 2H)
Ppm, LC-MS m/z:335.08[M+H].
Embodiment 12, synthesis compound 8l (1- (4- cyano-phenyls) -3- ((4- (thiophene -2- bases) pyridin-3-yl) methyl)
Urea)
According to the similar method of embodiment 6, the compound 6f in raw material is replaced with compound 6g, is replaced with compound 5b former
Compound 5a in material, compound 8l (yield 30%) is prepared.
1H NMR(400MHz,DMSO-d6):δ 9.19 (s, 1H), 8.64 (s, 1H), 8.52 (d, J=5.2Hz, 1H),
7.82 (dd, J=1.2Hz, 1.2Hz, 1H), 7.69-7.66 (m, 2H), 7.59-7.57 (m, 2H), 7.49-7.46 (m, 2H),
7.27-7.25 (m, 1H), 6.91 (t, J=5.6Hz, 1H), 4.51 (d, J=5.6Hz, 2H) ppm, LC-MS m/z:335.08[M
+H]。
Illustrate the beneficial effect of the compounds of this invention below by way of test example.
Test example 1, the compounds of this invention are tested to the inhibitory activity of liver cancer cell lines (Huh7 and SMMC7721)
(1) experiment material
Main agents：
RPMI-1640, hyclone, pancreatin etc. purchased from Gibco BRL companies (Invitrogen Corporation,
USA)；
IMDM culture mediums are purchased from ATCC (American Type Culture Collection)；
Tetramethyl azo azoles salt (MTT), dimethyl sulfoxide (DMSO) (DMSO) are Sigma companies (USA) product；
Bel7402 Huh7 and SMMC7721.
When the compounds of this invention carries out experiment in vitro, 10mM storing liquids are configured to 100%DMSO, -20 DEG C of refrigerators is put and keeps away
Light saves backup, and faces the used time and is diluted to required concentration with complete culture solution.
(2) experimental method
It is 1~2 × 10 with cell complete culture solution adjustment cell concentration4Individual/mL cell suspension, 96 orifice plates are inoculated in,
Per the μ l cell suspensions of hole 200, overnight incubation.Next day, suction are abandoned supernatant (drawing supernatant after suspension cell centrifugation), then used respectively
The compounds of this invention (Sorafenib is as positive control) the processing cell of gradient concentration.The negative right of not drug containing is set simultaneously
According to group and isometric solvent control group, DMSO concentration is 0.1%, and each dosage group sets 3 multiple holes, at 37 DEG C, 5%CO2Bar
Cultivated under part.After 72 hours, the μ l of MTT reagents 20 that concentration is 5mg/mL are added per hole, after being further cultured for 2-4h, abandon supernatant, per hole
The μ L of DMSO 150 are added, vibration mixes 15min, and absorbance (A) value (A values and living cells is determined with ELIASA (λ=570nm)
Number is directly proportional), take its average value.Relative cell proliferation inhibiting rate=(negative control group A570- experimental group A570)/negative control group
A 570× 100%.Experiment is at least repeated 3 times.
(3) experimental result
Half-inhibition concentration (IC of the compounds of this invention to Bel7402 Huh7 and SMMC772150), it is shown in Table 1.
Table 1, the compounds of this invention are to Huh7 and SMMC7721 half-inhibition concentration (IC50)
The above results show, the half-inhibition concentration (IC of the compounds of this invention50) smaller, have to liver cancer cells good
Inhibitory action.
In summary, the half-inhibition concentration (IC of the compounds of this invention50) smaller, have to liver cancer cells and suppress well
Effect；Moreover, the preparation method of the compounds of this invention is easy, reaction condition is gentle, and easy to operation and control, energy consumption is small, yield
Height, cost is low, can be adapted to industrialization production.
Claims (10)
1. compound or its pharmaceutically acceptable salt, crystal formation, solvate shown in formula I：
Wherein,
X is O or S；
N is 0~3 integer；
R1、R2、R3、R4、R5Separately selected from H, cyano group, COOR11、C1~C4Alkyl, C1~C4Alkoxy, trifluoromethyl, ammonia
Base, nitro, hydroxyl, sulfydryl or halogen, R11Selected from H or C1~C4Alkyl.
2. compound according to claim 1 or its pharmaceutically acceptable salt, crystal formation, solvate, it is characterised in that：
X is S；N is 0,1 or 2.
3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, crystal formation, solvate, its feature exist
In：Described R1、R2、R3、R4、R5All H.
4. compound according to claim 3 or its pharmaceutically acceptable salt, crystal formation, solvate, it is characterised in that：
Described compound is：
5. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, crystal formation, solvate, its feature exist
In：Described R1、R2、R3、R4、R5In, at least one is cyano group, COOCH3Or COOCH2CH3, remaining is selected from H, methyl, second
Base, methoxyl group, ethyoxyl, trifluoromethyl or halogen；
Preferably, described R1、R2、R3、R4、R5In, there is one or two for cyano group, COOCH3Or COOCH2CH3, remaining choosing
From H, methyl or ethyl；
It is furthermore preferred that described R1、R2、R3、R4、R5In, only one is cyano group, COOCH3Or COOCH2CH3, remaining is H.
6. compound according to claim 5 or its pharmaceutically acceptable salt, crystal formation, solvate, it is characterised in that：
Described compound is：
A kind of 7. method for preparing compound described in claim 1~6 any one, it is characterised in that：It comprises the following steps：
Compound 5 is reacted in organic solvent with compound 7, is separated, and purifying, obtains the compound shown in formula I；
Wherein,
X is O or S；
N is 0~3 integer；
R1、R2、R3、R4、R5Separately it is selected from H, C1~C4Alkyl, C1~C4Alkoxy, trifluoromethyl, COOR11, cyano group, ammonia
Base, nitro, hydroxyl, sulfydryl or halogen, R11Selected from H or C1~C4Alkyl；
The mol ratio of the compound 5 and compound 7 is 1：1~1.5；The temperature of the reaction is 0 DEG C~60 DEG C；
Any one or two kind of the organic solvent in dichloromethane, tetrahydrofuran, toluene, ethyl acetate, second cyanogen with
On.
8. according to the method for claim 7, it is characterised in that：The compound 5 is prepared by following steps：
1., the amino of 3- pyridyl-methanamines is protected, obtain compound 2；
2., compound 2 and halogen simple substance react, obtain compound 3；
3., compound 3 withReaction, obtains compound 4；
4. compound 4 sloughs amino protecting group, compound 5 is obtained；
Wherein,
RaFor tertbutyloxycarbonyl, benzyloxycarbonyl group, fluorenylmethyloxycarbonyl, methoxycarbonyl group, carbethoxyl group, allyloxycarbonyl, trimethyl silicane second
Oxygen carbonyl, phthalyl, p-toluenesulfonyl, trifluoroacetyl group, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, spy
Valeryl, benzoyl, trityl, benzyl, 2,4- veratryls or to methoxybenzyl；
Halogen simple substance is fluorine simple substance, elemental chlorine, bromine simple substance or elemental iodine；
RbFor fluorine, chlorine, bromine or iodine；
X is O or S.
9. prepared by compound described in claim 1~6 any one or its pharmaceutically acceptable salt, crystal formation, solvate
Application in the medicine treated and/or prevented liver cancer.
A kind of 10. pharmaceutical composition treated and/or prevented liver cancer, it is characterised in that：It is any one with claim 1~6
The item compound or its pharmaceutically acceptable salt, crystal formation, solvate are active component, plus pharmaceutically conventional auxiliary material
The preparation being prepared.
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