CN109678785A - A kind of compound and its preparation method and application - Google Patents
A kind of compound and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of compounds, and shown in the structural formula of the compound such as formula (1), wherein R is H or CH3.The present invention also provides the methods of preparation above compound.The present invention also provides the application of above compound or its pharmaceutically acceptable salt, solvate or medicinal composition in the drug that disease relevant to the activation of hedgehog pathway is treated in preparation.Above compound provided by the invention can be used in the drug that relevant to the activation of hedgehog pathway disease is treated in preparation, which can be used for preparing the drug for treating medulloblastoma related disease more particularly to inhibit the growth of medulloblastoma well.
Description
Technical field
The present invention relates to a kind of compounds and its preparation method and application.
Background technique
Medulloblastoma is the most common brain tumor of children, accounts about the 30% of pediatric tumor.Medulloblastoma is pernicious
The highest intracranial tumors of degree, are mainly manifested in: growth is extremely rapid；Operation is not easy complete resection；Tumour cell has along brain ridge
Marrow generates the tendency of sowing property plantation.Treatment method generally used now includes operation, chemotherapy and radiotherapy, but is still had very
More patients die of this disease, even if surviving, can also leave various sequelae, including cognitive defect and endocrine disturbance, so
People need to improve in a hurry the strategy process for the treatment of medulloblastoma.Data show that nearly 30% medulloblastoma patient is
Due to the abnormal activation of hedgehog (hedgehog) access, the activation of hedgehog (hedgehog) access is also found in other pernicious
In tumour, including basal-cell carcinoma, glioma and cancer of pancreas.2012 and 2015, vismodegib and Sony De Ji
Two hedgehog (hedgehog) pathway inhibitors are ratified by FDA for treating basal-cell carcinoma respectively.
Although clinical experimental stage shows that preferable inhibition marrow is female to the two hedgehog (hedgehog) inhibitor in the early stage
The effect of cytoma, but develop drug resistance quickly, it is often more important that, both inhibitor do not have cancer cell and normal cell
It is selective, lead to serious toxic side effect, especially permanent bone injury, for these reasons, both drugs are gone back at present
It is not approved for the treatment for medulloblastoma.
Summary of the invention
The purpose of the present invention is to provide a kind of compounds and its preparation method and application, to solve to lack currently on the market
The problem for the treatment of the active drug of medulloblastoma, the compound of offer of the invention can be used in preparation treatment and hedgehog pathway
The relevant disease of activation drug, which can be used for making more particularly to inhibit the growth of medulloblastoma well
The drug of standby treatment medulloblastoma related disease.
In order to achieve the above objectives, the invention provides the following technical scheme:
On the one hand, the present invention provides a kind of compounds, shown in the structural formula of the compound such as formula (1),
Formula (1)
Wherein: R is H or CH3。
On the other hand, the present invention also provides a kind of preparation method of the compound of structure shown in above-mentioned formula (1), this method
Include:
(1) formula (3) compound: formula (2) compound represented ethyl isobutyrate and 2 is synthesized, the reaction of 3- dichloropropylene obtains
Formula (3) compound represented, reaction equation is as follows,
(2) it synthesizes formula (4) compound: step (1) resulting formula (3) compound represented being reacted with bromine, is obtained
Formula (4) compound represented, reaction equation is as follows,
(3) it synthesizes formula (5) compound: step (2) resulting formula (4) compound represented and tert-butyl mercaptan being carried out anti-
It answers, obtains formula (5) compound represented, reaction equation is as follows,
(4) formula (6) compound is synthesized: by LiAlH4It is reacted, is obtained shown in formula (6) with formula (7) compound represented
Compound, reaction equation is as follows,
(5) it synthesizes formula (8) compound: step (4) resulting formula (6) compound represented being reacted with MsCl, is obtained
To formula (8) compound represented, reaction equation is as follows,
(6) formula (10) compound is synthesized: by chemical combination shown in step (5) resulting formula (8) compound represented and formula (9)
Object is reacted, and formula (10) compound represented is obtained, and reaction equation is as follows,
(7) formula (11) compound is synthesized: step (6) resulting formula (10) compound represented and step (3) is resulting
Formula (5) compound represented is reacted, and formula (11) compound represented is obtained, and reaction equation is as follows,
(8) it synthesizes formula (1-1) compound: step (7) resulting formula (11) compound represented is reacted with LiOH,
Formula (1-1) compound represented is obtained, reaction equation is as follows,
(9) it synthesizes formula (12) compound: step (7) resulting formula (11) compound represented and tert-butyl mercaptan is carried out
Reaction, obtains formula (12) compound represented, and reaction equation is as follows,
(10) it synthesizes formula (1-2) compound: step (9) resulting formula (12) compound represented and LiOH being carried out anti-
It answers, obtains formula (1-2) compound represented, reaction equation is as follows,
Further, in the step (6), the mole dosage of formula (9) compound represented and formula (8) compound represented
Than for 1:0.1-3.
Further, in the step (6), in the presence of triethylamine and tetrabutylammonium bromide, shown in formula (8)
Compound and formula (9) compound represented are reacted.
Further, formula (9) compound represented, formula (8) compound represented, triethylamine and tetrabutylammonium bromide are rubbed
Your amount ratio is 1:0.1-3:0.5-6:0.01-1.
Further, in the step (6), formula (8) compound represented and formula (9) compound represented are reacted
Time is 3-30h.
In another aspect, the present invention also provides the compound of structure shown in above-mentioned formula (1) or its pharmaceutically acceptable salt,
The application of solvate or medicinal composition in the drug that disease relevant to the activation of hedgehog pathway is treated in preparation.
Further, the relevant disease of the activation to hedgehog pathway is the relevant tumour of activation with hedgehog pathway.
Further, the relevant tumour of the activation to hedgehog pathway is medulloblastoma.
The present invention still further provides a kind of pharmaceutical composition, described pharmaceutical composition include as active constituent as
The compound of above-mentioned formula (1), and at least one pharmaceutically acceptable excipient.
For the purposes of the present invention, the pharmaceutically acceptable salt of the compound of the invention such as above-mentioned formula (1) can be
Last purifying or separation when system is reacted by carboxyl and suitable alkali, such as the hydroxide of metal cation or ammonium
Object, carbonate perhaps bicarbonate or organic base is primary, secondary, tertiary amine, the cation of pharmaceutically-acceptable salts includes but is not limited to
Lithium, sodium, potassium, calcium, magnesium and aluminium and nontoxic quaternary ammonium cation, such as ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, front three
Amine, triethylamine, diethylamine, ethamine, tri-n-butylamine, pyridine, N, accelerine, N- methyl piperidine and N-methylmorpholine.
For the purposes of the present invention, the solvate of the invention such as the compound of above-mentioned formula (1) refers to a kind of physics
In conjunction with 1-3 kind is organic or inorganic solvent molecule, the combination of this physics includes hydrogen bond, in specific condition, solvent molecule meeting
Be inserted into the lattice of crystalline compounds, these solvents include but is not limited to water known to those of ordinary skill, ethyl alcohol, methanol and
Isopropanol.
The beneficial effects of the present invention are: the compound of above-mentioned formula (1) provided by the invention can be used in preparation treatment with
The drug of the relevant disease of activation of hedgehog pathway, the compound, can more particularly to inhibit the growth of medulloblastoma well
To be used to prepare the drug for the treatment of medulloblastoma related disease.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, below with presently preferred embodiments of the present invention explanation as after.
Specific embodiment
With reference to embodiment, the embodiment of the present invention is furthur described in detail.Following embodiment is used for
Illustrate the present invention, but is not intended to limit the scope of the invention.
Embodiment one
(1) lithium diisopropylamine (LDA, 150mL, 2mol, in tetrahydrofuran) is added drop-wise to tetrahydrofuran (500mL)
In, -78 DEG C are cooled to, is added dropwise ethyl isobutyrate (formula (2), 33 grams, 0.284mol), reaction mixture is protected at -70 to -65 DEG C
It holds 20 minutes, 2,3- dichloropropylene (31 grams, 0.279mol) is then added dropwise, after being added dropwise, reaction solution is gradually warming up to room temperature
18h is reacted, is quenched after completion of the reaction with saturated ammonium chloride, is extracted 2 times with methylene chloride (2x 300mL), combined organic layer is used
Anhydrous sodium sulfate dries, filters revolving and obtains grease compound 4-chloro -2,2- dimethyl -4- pentenoic acid ethyl ester (formula of brown
(3), 59 grams, 0.279mol, 93% yield), it is directly used in and reacts in next step.Formula (3)1H NMR(400MHz,CDCl3):δ
(ppm)1.24-1.28(m,9H),2.65(s,2H),4.15(q,4H),5.13(s,1H),5.24(s,1H)。
(2) by chloro- 2, the 2- dimethyl -4- pentenoic acid ethyl ester of step (1) resulting 4- (formula (3), 59 grams, 0.279 mole)
It is added in the mixture of ethyl alcohol (300 milliliters) and water (200 milliliters), at -5-0 DEG C, is added dropwise bromine (48 grams, 0.300 mole),
After being added dropwise, reaction mixture reacts 2 hours at room temperature, after completion of the reaction, with methylene chloride (300 milliliters of 3x) extraction 3
Secondary, combined organic phase is washed with 5% sodium bicarbonate solution, and organic phase is dried, filtered with anhydrous sodium sulfate, is obtained after concentration
Bromo- 2, the 2- dimethyl -4- carbonyl ethyl valerate of brown oil compound 5- (formula (4), 78 grams, 0.279 mole, 100% yield),
It is directly used in and reacts in next step.Formula (4)1H NMR(400MHz,CDCl3):δ(ppm)1.18-1.25(m,9H),2.59(s,2H),
3.85 (s, 2H), 4.11 (q, J=7.2Hz, 2H).
(3) by bromo- 2, the 2- dimethyl -4- carbonyl ethyl valerate of step (2) resulting 5- (formula (4), 78g, 0.279mol)
At 0-5 DEG C, it is added in tetrahydrofuran (500mL), is added dropwise to triethylamine (TEA, 45mL, 0.324mol) and tert-butyl sulphur respectively
Alcohol (t-BuSH, 35mL, 0.310mol), reaction solution is in room temperature reaction 18h, after completion of the reaction, petroleum ether (300mL) and mistake is added
Solid is filtered out, silica gel column purification is used after filtrate revolving, obtains brown oil compound 5- (tert .- butylthio) -2,2- diformazan
Base -4- carbonyl ethyl valerate (formula (5), 71.2g, 0.273mol, 98% yield).Formula (5)1H NMR(400MHz,CDCl3):δ
(ppm) 1.24-1.20 (m, 9H), 1.31 (s, 9H), 2.94 (s, 2H), 3.27 (s, 2H), 4.11 (q, J=6.8Hz, 2H).
(4)LiAlH4(LAH, 251mg, 6.62mmol) is placed in tetrahydrofuran (10mL), is slowly added into 4- at 0 DEG C
In tetrahydrofuran (10mL) solution of methoxyl methyl benzoate (formula (7), 1.0g, 6.02mmol), reaction solution is anti-at 20 DEG C
2h is answered, is quenched after fully reacting with NaOH solution (6.25mol), is then extracted 2 times with ethyl acetate (2x 50mL), it is anhydrous
Na2SO4It dries, filters and is spin-dried for obtaining white solid 4- methoxyl group benzylalcohol (formula (6), 800mg, 5.59mmol, yield 96%), directly
It connects for reacting in next step.Formula (6)1H NMR(400MHz,CDCl3): δ (ppm) 3.81 (s, 3H), 4.62 (d, J=5.6Hz,
2H), 6.89 (d, J=7.2Hz, 2H), 7.29 (d, J=8.8Hz, 2H).
(5) the resulting 4- methoxyl group benzylalcohol of step (4) (formula (6), 600mg, 4.34mmol) is placed in tetrahydrofuran
In (12mL), be added at 0 DEG C triethylamine (TEA, 1.10g, 10.68mmol) and MsCl (methylsufonyl chloride, 547mg,
4.78mol), 3h is stirred at room temperature in reaction mixture, and saturation NH is added after fully reacting4Cl solution (5mL), with EtOAc (second
Acetoacetic ester, 3x 30mL) extraction 3 times, by washing, saturated common salt water washing, anhydrous Na2SO4Dry, organic phase is concentrated to obtain
Yellow oil product 4- methoxy methyl sulfonic acid benzyl ester (formula (8), 540mg, 2.50mmol, 57.5% yield).
(6) by the resulting 4- methoxy methyl sulfonic acid benzyl ester of step (5) (formula (8), 503.9mg, 2.33mmol) and (4- isopropyl
Base phenyl) hydrazinobenzene hydrochloride salt (formula (9), 350mg, 2.33mmol) is placed in toluene (10mL), be added triethylamine (TEA, 707mg,
6.99mmol) and tetrabutylammonium bromide (TBAB, 25mg, 0.08mmol), reaction mixture react 15h at reflux, so
Temperature is slowly down to room temperature afterwards, ethyl acetate extraction is added after concentration, successively washing, saturated common salt water washing and anhydrous slufuric acid
Sodium is dry.Organic phase after concentration is with silica gel column purification (mobile phase: EA (ethyl acetate): PE (petroleum ether)=100:1-20:1)
Obtain yellow oil product 1- (4- isopropyl phenyl) -1- (4- methoxy-benzyl) phenylhydrazine (formula (10), 240mg, 0.89mmol,
Yield 38.0%).In other embodiments, (4- isopropyl phenyl) hydrazinobenzene hydrochloride salt (formula (9)), 4- methoxy methyl sulfonic acid benzyl
The mole dosage ratio of ester (formula (8)), triethylamine and tetrabutylammonium bromide may be 1:0.1:0.5:0.01, and reaction mixture exists
3h is reacted under reflux state.Really, (4- isopropyl phenyl) hydrazinobenzene hydrochloride salt (formula (9)), 4- methoxy methyl sulfonic acid benzyl ester (formula
(8)), the mole dosage of triethylamine and tetrabutylammonium bromide ratio may be 1:3:6:1, and reaction mixture is anti-at reflux
Answer 30h.
(7) by step (6) resulting 1- (4- isopropyl phenyl) -1- (4- methoxy-benzyl) phenylhydrazine (formula (10), 228mg,
0.85mmol) and step (3) resulting 5- (tert .- butylthio) -2,2- dimethyl -4- carbonyl ethyl valerate (formula (5), 220mg,
0.85mmol) in toluene (8mL), acetic acid (HOAc, 1mL) is added, reaction mixture reacts 16h, fully reacting at room temperature
Afterwards, concentration of reaction solution obtains 3- with silica gel column purification (mobile phase: EA (ethyl acetate): PE (petroleum ether)=1:100-1:50)
(3- (tert .- butylthio) -5- isopropyl -1- (4- methoxy-benzyl) -1 hydrogen-indoles -2- base) -2,2- ethyl dimethyl
(formula (11), 180mg, 0.36mmol, yield 43%).Formula (11):1H NMR(400MHz,CDCl3):δ(ppm)1.17-1.21
(m, 9H), 1.26 (s, 9H), 1.29 (d, J=6.8Hz, 6H), 2.98-3.02 (m, 1H), 3.29 (s, 2H), 3.74 (s, 3H),
4.05-4.10 (m, 2H), 5.32 (s, 2H), 6.76 (s, 2H), 6.99 (d, J=8.4Hz, 1H), 7.08 (d, J=8.4Hz,
1H),7.62(s,1H)；MS(ESI):m/z 496.4[M+1]+。
(8) by step (7) resulting 3- (3- (tert .- butylthio) -5- isopropyl -1- (4- methoxy-benzyl) -1 hydrogen-Yin
Diindyl -2- base) -2,2-Dimethylpropionic acid ethyl ester (formula (11), 80mg, 0.161mmol) is placed in THF (tetrahydrofuran, 3mL), MeOH
(methanol, 3mL) and H2In the mixed liquor of O (3mL), LiOH.H is added2O (34.0mg, 0.86mmol), reaction mixture is at 60 DEG C
Lower reaction 16h, is concentrated after completion of the reaction, with hydrochloric acid tune pH=6 after adding water (5mL) to dilute, then with EtOAc (ethyl acetate,
It 2x20mL) extracts 2 times, combined organic phase is dry with anhydrous sodium sulfate, obtains white solid product by preparation purifying chromatography
3- (3- (tert .- butylthio) -5- isopropyl -1- (4- methoxy-benzyl) -1 hydrogen-indoles -2- base) -2,2- neopentanoic acid (formula
(1-1), 10mg, 0.02mmol, yield 13.3%).Formula (1-1):1H NMR(400MHz,DMSO-d6):δ(ppm)1.10(s,
6H), 1.20 (s, 9H), 1.23 (d, J=6.4Hz, 6H), 2.94-2.98 (m, 1H), 3.21 (s, 2H), 3.68 (s, 3H), 5.40
(s,2H),6.78-6.83(m,4H),6.96-6.99(m,1H),7.27-7.30(m,1H),7.46(s,1H),12.93(s,
1H)；MS(ESI):m/z 468.4[M+1]+。
Embodiment two
According to method described in embodiment one, method described in the present embodiment two is different from the institute of method described in embodiment one
Be, using following step (9) and step (10) replace embodiment one in step (8):
(9) by step (7) resulting 3- (3- (tert .- butylthio) -5- isopropyl -1- (4- methoxy-benzyl) -1 hydrogen-Yin
Diindyl -2- base) -2,2-Dimethylpropionic acid ethyl ester (formula (11), 1.5g, 3mmol) and tert-butyl mercaptan (t-BuSH, 2.7g,
30mmol) it is dissolved in CH2Cl2AlCl is added portionwise in 5 minutes at 0 DEG C in (40mL)3(2.0g, 15mmol), reaction mixture
2h is reacted at this temperature, is poured into ice water after completion of the reaction, and the HCl of 1 equivalent is added, is extracted with dichloromethane 2 times, organic phase
Successively be washed with water, salt washing and anhydrous sodium sulfate it is dry, silica gel column purification (EA (ethyl acetate): PE (petroleum ether) is used after concentration
=10:1) obtain white solid product 3- (3- (tert .- butylthio) -5- isopropyl -1- (4- hydroxybenzyl) -1 hydrogen-indoles -2-
Base) -2,2-Dimethylpropionic acid ethyl ester (formula (12), 500mg, 1mmol, yield: 33.3%).Formula (12):1H NMR(400MHz,
CDCl3):
(ppm) 1.14-1.27 (m, 18H), 1.29 (d, J=7.2Hz, 6H), 2.99-3.02 (m, 1H), 3.29 (s, 2H),
4.05-4.10 (m, 1H), 5.30 (s, 2H), 6.67-6.73 (m, 4H), 7.01 (d, J=8.4Hz, 1H), 7.07 (d, J=
8.4Hz,1H),7.62(s,1H)；MS(ESI):m/z 482.4[M+1]+。
(10) by step (9) resulting 3- (3- (tert .- butylthio) -5- isopropyl -1- (4- hydroxybenzyl) -1 hydrogen-Yin
Diindyl -2- base) -2,2-Dimethylpropionic acid ethyl ester (200mg, 0.42mmol) is placed in tetrahydrofuran (5mL) and methanol (5mL), adds
Enter water (10mL) and LiOH.H2O (175mg, 4.2mmol), reaction mixture react 5h at 60 DEG C, then use hydrochloric acid (1mol)
PH=4 is adjusted, is extracted 2 times with DCM (methylene chloride, 2x10mL), organic phase washed with water is washed, salt is washed, and with anhydrous sulphur
Sour sodium is dry, obtains product 3- (3- (tert .- butylthio) -5- isopropyl -1- (4- hydroxyl benzyl with preparing chromatogram purification after concentration
Base) -1 hydrogen-indoles -2- base) -2,2-Dimethylpropionic acid (formula (1-2), 112mg, 0.25mmol, yield 83.3%).Formula 1-2:1H
NMR (400MHz, DMSO-d6): (ppm) 1.09 (s, 6H), 1.18 (s, 9H), 1.22 (d, J=7.2Hz, 6H), 2.91-2.98
(m, 1H), 3.22 (s, 2H), 5.30 (s, 2H), 6.61 (d, J=8.4Hz, 1H), 6.61 (d, J=8.4Hz, 1H), 6.70 (d, J
=8.4Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 7.29 (d, J=8.8Hz, 1H), 7.45 (s, 1H), 9.32 (s, 1H),
12.5(s,1H)；MS(ESI):m/z 454.4[M+1]+。
Embodiment three
The embodiment is for illustrating the compound pair of formula of the invention (1) tumor proliferation relevant to the activation of hedgehog pathway
Influence.
Test method and result: extracting medulloblastoma from Patch1 deficient mice, then that these tumours are thin
Born of the same parents cultivate in test tube, the compound of the present invention co-incubation of various concentration are added 48 hours, are tested with MTT experiment method thin
The survival condition of born of the same parents calculates the IC of each compound with statistical software Prism50Value, test result are as follows: the compound of formula (1-1)
IC50For 9 μm of ol, the IC of the compound of formula (1-2)50For 15.5 μm of ol.
As seen from the experiment, the compound of structure shown in formula (1) provided by the invention all has inhibits marrow female well
The effect of cytoma growth.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. a kind of compound, which is characterized in that shown in the structural formula of the compound such as formula (1),
Formula (1)
Wherein: R is H or CH3。
2. a kind of method for preparing compound described in claim 1, which is characterized in that this method comprises:
(1) formula (3) compound: formula (2) compound represented ethyl isobutyrate and 2 is synthesized, the reaction of 3- dichloropropylene obtains formula
(3) compound represented, reaction equation is as follows,
(2) it synthesizes formula (4) compound: step (1) resulting formula (3) compound represented being reacted with bromine, obtains formula (4)
Compound represented, reaction equation is as follows,
(3) it synthesizes formula (5) compound: step (2) resulting formula (4) compound represented is reacted with tert-butyl mercaptan,
Formula (5) compound represented is obtained, reaction equation is as follows,
(4) formula (6) compound is synthesized: by LiAlH4It is reacted with formula (7) compound represented, obtains chemical combination shown in formula (6)
Object, reaction equation is as follows,
(5) it synthesizes formula (8) compound: step (4) resulting formula (6) compound represented being reacted with MsCl, obtains formula
(8) compound represented, reaction equation is as follows,
(6) synthesize formula (10) compound: by step (5) resulting formula (8) compound represented and formula (9) compound represented into
Row reaction, obtains formula (10) compound represented, and reaction equation is as follows,
(7) formula (11) compound is synthesized: by step (6) resulting formula (10) compound represented and step (3) resulting formula (5)
Compound represented is reacted, and formula (11) compound represented is obtained, and reaction equation is as follows,
(8) it synthesizes formula (1-1) compound: step (7) resulting formula (11) compound represented being reacted with LiOH, is obtained
Formula (1-1) compound represented, reaction equation is as follows,
(9) it synthesizes formula (12) compound: step (7) resulting formula (11) compound represented and tert-butyl mercaptan being carried out anti-
It answers, obtains formula (12) compound represented, reaction equation is as follows,
(10) it synthesizes formula (1-2) compound: step (9) resulting formula (12) compound represented being reacted with LiOH, is obtained
To formula (1-2) compound represented, reaction equation is as follows,
3. preparation method according to claim 2, which is characterized in that in the step (6), formula (9) compound represented
Mole dosage ratio with formula (8) compound represented is 1:0.1-3.
4. preparation method according to claim 2, which is characterized in that in the step (6), in triethylamine and tetrabutyl bromine
In the presence of changing ammonium, formula (8) compound represented and formula (9) compound represented are reacted.
5. the preparation method according to claim 4, which is characterized in that change shown in formula (9) compound represented, formula (8)
The mole dosage ratio for closing object, triethylamine and tetrabutylammonium bromide is 1:0.1-3:0.5-6:0.01-1.
6. preparation method according to claim 2, which is characterized in that in the step (6), formula (8) compound represented
It is 3-30h with the time that formula (9) compound represented is reacted.
7. compound described in claim 1 or its pharmaceutically acceptable salt, solvate or medicinal composition are controlled in preparation
Treat the application in the drug of disease relevant to the activation of hedgehog pathway.
8. application according to claim 7, which is characterized in that the relevant disease of the activation to hedgehog pathway is and thorn
The relevant tumour of the activation of hedgehog access.
9. application according to claim 8, which is characterized in that the relevant tumour of the activation to hedgehog pathway is that marrow is female
Cytoma.
10. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes as active constituent such as claim 1
Described in formula (1) compound, and at least one pharmaceutically acceptable excipient.
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| CN (1) | CN109678785A (en) |
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| WO2020003119A1 (en) * | 2018-06-25 | 2020-01-02 | Suzhou Mednes Pharma Tech Co., Ltd. | Compounds and methods for treatment of hedgehog pathway associated conditions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020003119A1 (en) * | 2018-06-25 | 2020-01-02 | Suzhou Mednes Pharma Tech Co., Ltd. | Compounds and methods for treatment of hedgehog pathway associated conditions |
| US11718614B2 (en) | 2018-06-25 | 2023-08-08 | Suzhou Mednes Pharma Tech Co., Ltd. | Compounds and methods for treatment of hedgehog pathway associated conditions |
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