CN109678781B - Hedgehog pathway inhibitor - Google Patents
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- 229940121827 Hedgehog pathway inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 208000000172 Medulloblastoma Diseases 0.000 claims abstract description 15
- 241000289669 Erinaceus europaeus Species 0.000 claims abstract description 14
- 230000037361 pathway Effects 0.000 claims abstract description 13
- 230000004913 activation Effects 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 19
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- 238000003786 synthesis reaction Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
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- 239000007818 Grignard reagent Substances 0.000 claims description 3
- HWWVAHCWJLGKLW-UHFFFAOYSA-N n,n-dimethylhydroxylamine;hydron;chloride Chemical compound Cl.CN(C)O HWWVAHCWJLGKLW-UHFFFAOYSA-N 0.000 claims description 3
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
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- 230000035484 reaction time Effects 0.000 claims description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- FQOSZELLQXJGPI-UHFFFAOYSA-N n-methoxy-n-methyl-2-[4-(2-methylpropyl)phenyl]propanamide Chemical compound CON(C)C(=O)C(C)C1=CC=C(CC(C)C)C=C1 FQOSZELLQXJGPI-UHFFFAOYSA-N 0.000 description 2
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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- 206010018338 Glioma Diseases 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- 241000699670 Mus sp. Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a compound with inhibiting effect on activation of hedgehog pathway, the structural formula of the compound is shown as formula (1), wherein R is H or CH3. The invention also provides a method for preparing the compound. The invention also provides the application of the compound or the pharmaceutically acceptable salt, solvate or drug compound thereof in preparing a medicine for treating diseases related to the activation of the hedgehog pathway. The compound provided by the invention can be used for preparing a medicine for treating diseases related to activation of hedgehog pathway, particularly can well inhibit growth of medulloblastoma, and can be used for preparing a medicine for treating diseases related to medulloblastoma.
Description
Technical Field
The present invention relates to a hedgehog pathway inhibitor.
Background
Medulloblastoma is the most common brain tumor in children, accounting for approximately 30% of tumors in children. Medulloblastoma is the most malignant intracranial tumor, mainly expressed in: the growth is extremely rapid; the operation is not easy to completely cut off; tumor cells tend to colonize the cerebrospinal fluid. The current treatment options available include surgery, chemotherapy and radiation therapy, but many patients still die of the disease and, if they survive, leave behind various sequelae, including cognitive deficits and endocrine disorders, and there is an urgent need for improved strategies for treating medulloblastoma. The data show that nearly 30% of medulloblastoma patients are due to abnormal activation of the hedgehog pathway, which is also found in other malignancies, including basal cell carcinoma, glioma, and pancreatic carcinoma. In 2012 and 2015, two hedgehog pathway inhibitors, vismodegib and sonydigil, were FDA approved for the treatment of basal cell carcinoma, respectively.
Although these two hedgehog inhibitors showed good effect in inhibiting medulloblastoma in the initial clinical trial phase, they rapidly become resistant, and more importantly, they are not selective for cancer cells and normal cells, resulting in severe toxic side effects, especially permanent bone damage, for which reason these two drugs are not currently approved for the treatment of medulloblastoma.
Disclosure of Invention
The invention aims to provide a hedgehog pathway inhibitor, a preparation method and an application thereof, aiming at solving the problem that effective medicines for treating medulloblastoma are lacked in the current market.
In order to achieve the purpose, the invention provides the following technical scheme:
on one hand, the invention provides a compound, the structural formula of which is shown as a formula (1),
formula (1)
Wherein: r is H or CH3。
In another aspect, the present invention also provides a method for preparing a compound having a structure represented by formula (1) above, the method comprising:
(1) synthesis of a Compound of formula (3): reacting the compound shown in the formula (2) with dimethylhydroxylamine hydrochloride to obtain a compound shown in a formula (3), wherein the reaction formula is as follows,
(2) synthesis of a Compound of formula (4): reacting the compound shown in the formula (3) obtained in the step (1) with a methyl Grignard reagent to obtain a compound shown in a formula (4), wherein the reaction formula is as follows,
(3) synthesis of a Compound of formula (6): reacting the compound shown in the formula (5) with o-chlorobenzyl chloride to obtain the compound shown in the formula (6), wherein the reaction formula is as follows,
(4) synthesis of a Compound of formula (1-1): reacting the compound shown in the formula (6) obtained in the step (3) with the compound shown in the formula (4) obtained in the step (2) to obtain the compound shown in the formula (1-1), wherein the reaction formula is as follows,
(5) synthesis of a Compound of formula (1-2): reacting the compound shown in the formula (1-1) obtained in the step (4) with tert-butyl mercaptan to obtain a compound shown in a formula (1-2), wherein the reaction formula is as follows,
further, in the step (4), the compound represented by the formula (6) and the compound represented by the formula (4) are reacted in the presence of acetic acid and a solvent medium.
Further, the solvent medium is toluene.
Further, in the step (4), the conditions for reacting the compound represented by the formula (6) with the compound represented by the formula (4) include: the reaction time is 2-50 h.
Further, in the step (4), the conditions for reacting the compound represented by the formula (6) with the compound represented by the formula (4) include: the reaction temperature is 10-50 ℃.
In still another aspect, the present invention further provides a use of the compound having the structure represented by the above formula (1) or a pharmaceutically acceptable salt, solvate or pharmaceutical complex thereof in preparing a medicament for treating a disease associated with activation of the hedgehog pathway.
Further, the disease associated with activation of the hedgehog pathway is a tumor associated with activation of the hedgehog pathway.
Further, the tumor associated with activation of the hedgehog pathway is medulloblastoma.
The present invention still further provides a pharmaceutical composition comprising a compound of formula (1) as described above as an active ingredient, together with at least one pharmaceutically acceptable excipient.
For the purpose of the present invention, the pharmaceutically acceptable salts of the compounds of formula (1) as described above according to the present invention can be prepared at the time of final purification or isolation by reacting the carboxyl group with a suitable base, such as metal cations or ammonium hydroxide, carbonate or bicarbonate, or organic bases primary, secondary or tertiary amines, the cations of the pharmaceutically acceptable salts including, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum, and non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine and N-methylmorpholine.
For the purposes of the present invention, a solvate of a compound of formula (1) as described above according to the present invention refers to a physical association of 1-3 molecules of organic or inorganic solvents, including hydrogen bonds, and in particular cases, solvent molecules inserted into the crystal lattice of the crystalline compound, including but not limited to water, ethanol, methanol and isopropanol, as is well known to those of ordinary skill.
The invention has the beneficial effects that: the compound of the formula (1) having an inhibitory effect on the activation of the hedgehog pathway provided by the invention can be used for preparing a medicament for treating diseases related to the activation of the hedgehog pathway, particularly can well inhibit the growth of medulloblastoma, and can be used for preparing a medicament for treating diseases related to the medulloblastoma.
The foregoing is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clear and clear, and to implement the technical solutions according to the content of the description, the following is a description of preferred embodiments of the present invention.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example one
The abbreviation HATU in this example refers to a compound of formula I
Formula (I)
(1)2- (4-isobutylphenyl) propionic acid (formula (2), 10g, 49mmol) was taken in tetrahydrofuran (100mL), dimethylhydroxylamine hydrochloride (5g, 49mmol), triethylamine (15g, 150mmol) and HATU (23g, 60mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours, concentrated and purified with silica gel column (mobile phase PE (petroleum ether): EA (ethyl acetate) ═ 20:1) to give 2- (4-isobutylphenyl) -N-methoxy-N-methylpropanamide (formula (3), 10g, 40mmol) as a colorless oily product. LCMS (ESI) of formula (3) M/z250.1[ M +1 ]]+。
(2) Adding the 2- (4-isobutylphenyl) -N-methoxy-N-methylpropionamide (formula (3), 11g, 44.2mmol) obtained in the step (1) into tetrahydrofuran (200mL), dropwise adding a methyl Grignard reagent (14.7mL, 3mol/L) at 0 ℃, reacting the reaction mixture at 0 ℃ for 0.5h after the dropwise adding is finished, quenching the reaction mixture by using a saturated ammonium chloride solution, extracting the reaction mixture by using ethyl acetate, and concentrating the extraction solution to obtain a colorless oily compound, namely 3- (4-isobutylphenyl) butyl-2-ketone (formula (4), 7.7g, 37.7 mmol). Formula (4)1H NMR(400MHz,CDCl3):δ(ppm)0.89(s，1H)0.91(s，1H)1.37(d，2H)1.81-1.88(m,1H),2.04(s,2H)2.45(d,2H),3.72(q,1H),7.11(s,4H)。
(3) P-methoxybenzyl hydrazine hydrochloride (formula (5), 10g, 57.3mmol) was taken up in toluene (toluene, 100mL), o-chlorobenzyl chloride (9.2g, 57.5mmol) and triethylamine (TEA, 17.4g, 171.9mmol) were added, the reaction mixture was stirred at room temperature for 12 hours, after completion of the reaction, it was extracted 2 times with ethyl acetate (2 × 50mL), the organic layers were combined, concentrated and purified with silica gel column to give 1- (2-chlorobenzyl) -1- (4-methoxyphenyl) hydrazine (formula (6), 6.0g, 22.9mmol) as a yellow oily product.
(4) 1- (2-chlorobenzyl) -1- (4-methoxyphenyl) hydrazine (formula (6), 1.02g, 5mmol) obtained in step (3) and 3- (4-isobutylphenyl) butyl-2-one (formula (4)) obtained in step (2) were dissolved in toluene (40mL), acetic acid (20mL) was added, the reaction mixture was stirred at 25 ℃ for 18h, and after completion of the reaction, the reaction solution was concentrated and purified by preparative chromatography to give the oily product of formula (1-1) (0.4g, 0.95 mmol). In other embodiments, the reaction conditions may also be such that the reaction mixture is stirred at 10 ℃ for 2 h. Indeed, the reaction conditions may also be such that the reaction mixture is stirred for 50h at 50 ℃. LCMS (ESI) of formula (1-1) M/z 432.3[ M +1 ]]+；1H NMR(400MHz,CDCl3):δ(ppm)0.88(s，3H)0.90(s，3H)1.81(s，3H)1.81-1.88(m,1H),2.44(d,2H),3.70(s,1H),3.83(d，1H)4.80(s，2H)6.38(d，1H)6.64(s，2H)7.07-7.40.(m,8H)。
Example two
According to the method of the first embodiment, the method of the second embodiment is different from the method of the first embodiment in that the method further comprises the following step (5):
(5) the compound of formula (1-1) (0.35g, 0.83mmol) obtained in step (4) in example one was taken in dichloromethane (20ml), tert-butylmercaptan (720mg) was added, aluminum trichloride was added at 0 ℃ for reaction, the temperature was gradually raised to room temperature after 2 hours of reaction, after quenching with water, extraction was performed with dichloromethane, concentration was performed, and purification was performed by preparative chromatography to give an oily product of formula (1-2) (0.3g, 0.72 mmol). LCMS (ESI) of formula (1-2) M/z418.3[ M +1 ]]+；1H NMR(400MHz,DMSO):δ(ppm)0.88(s，3H)0.90(s，3H)1.81(s，3H)1.81-1.88(m,1H),2.44(d,2H),5.72(s，2H)6.75(d，2H)6.93(m，2H)7.10-7.22.(m,6H)7.37(m，1H)7.41(m，1H)7.47(m，1H)。
EXAMPLE III
This example serves to illustrate the effect of the compounds of formula (1) of the present invention on tumor proliferation associated with activation of the hedgehog pathway.
Test methods and results: extracting medulloblastoma from Patch1 gene-deficient mice, culturing the tumor cells in test tubes, adding different concentrations of the compound of formula (1) of the present invention, co-culturing for 48 hours, testing the survival of the cells by MTT assay, calculating the IC of each compound by statistical software Prism50The test results show that the compounds with the structure shown in the formula (1) have good effect of inhibiting the growth of medulloblastoma, particularly the compounds with the formula (1-2) have better inhibiting effect, and the IC of the compounds with the formula (1-2) is tested506. mu. mol.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (8)
1. A compound is characterized in that the structural formula of the compound is shown as a formula (1),
formula (1)
Wherein: r is H or CH3。
2. A process for preparing a compound of claim 1, comprising:
(1) synthesis of a Compound of formula (3): reacting the compound shown in the formula (2) with dimethylhydroxylamine hydrochloride to obtain a compound shown in a formula (3), wherein the reaction formula is as follows,
(2) synthesis of a Compound of formula (4): reacting the compound shown in the formula (3) obtained in the step (1) with a methyl Grignard reagent to obtain a compound shown in a formula (4), wherein the reaction formula is as follows,
(3) synthesis of a Compound of formula (6): reacting the compound shown in the formula (5) with o-chlorobenzyl chloride to obtain the compound shown in the formula (6), wherein the reaction formula is as follows,
(4) synthesis of a Compound of formula (1-1): reacting the compound shown in the formula (6) obtained in the step (3) with the compound shown in the formula (4) obtained in the step (2) to obtain the compound shown in the formula (1-1), wherein the reaction formula is as follows,
(5) synthesis of a Compound of formula (1-2): reacting the compound shown in the formula (1-1) obtained in the step (4) with tert-butyl mercaptan to obtain a compound shown in a formula (1-2), wherein the reaction formula is as follows,
3. the production method according to claim 2, wherein in the step (4), the compound represented by the formula (6) and the compound represented by the formula (4) are reacted in the presence of acetic acid and a solvent medium.
4. A method as claimed in claim 3, wherein said solvent medium is toluene.
5. The method according to claim 2, wherein in the step (4), the conditions for reacting the compound represented by the formula (6) with the compound represented by the formula (4) include: the reaction time is 2-50 h.
6. The method according to claim 2, wherein in the step (4), the conditions for reacting the compound represented by the formula (6) with the compound represented by the formula (4) include: the reaction temperature is 10-50 ℃.
7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating medulloblastoma associated with activation of the hedgehog pathway.
8. A pharmaceutical composition comprising, as active principle, a compound of formula (1) as defined in claim 1, and at least one pharmaceutically acceptable excipient.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1427825A (en) * | 2000-04-03 | 2003-07-02 | 圣诺菲-合成实验室公司 | Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands |
| WO2014151451A1 (en) * | 2013-03-15 | 2014-09-25 | Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center | Inhibition of leukotriene synthesis and activity in the treatment of sonic hedgehog-associated medulloblastoma |
| WO2016191911A1 (en) * | 2015-05-29 | 2016-12-08 | Wuhu Eastinno Biotechnologies Co., Ltd. | Pharmaceutical composition and use thereof and methods of treating diseases mediated by hedgehog signaling pathway |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1427825A (en) * | 2000-04-03 | 2003-07-02 | 圣诺菲-合成实验室公司 | Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands |
| WO2014151451A1 (en) * | 2013-03-15 | 2014-09-25 | Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center | Inhibition of leukotriene synthesis and activity in the treatment of sonic hedgehog-associated medulloblastoma |
| WO2016191911A1 (en) * | 2015-05-29 | 2016-12-08 | Wuhu Eastinno Biotechnologies Co., Ltd. | Pharmaceutical composition and use thereof and methods of treating diseases mediated by hedgehog signaling pathway |
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