CN107266468A - The preparation and application of the thiapyran miazines compound of the structure containing pyrazoline - Google Patents
The preparation and application of the thiapyran miazines compound of the structure containing pyrazoline Download PDFInfo
- Publication number
- CN107266468A CN107266468A CN201710597504.XA CN201710597504A CN107266468A CN 107266468 A CN107266468 A CN 107266468A CN 201710597504 A CN201710597504 A CN 201710597504A CN 107266468 A CN107266468 A CN 107266468A
- Authority
- CN
- China
- Prior art keywords
- dihydro
- pyrazol
- thiopyrano
- pyrimidine
- morpholino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims description 14
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 239000000651 prodrug Substances 0.000 claims abstract description 10
- 229940002612 prodrug Drugs 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 238000011282 treatment Methods 0.000 claims abstract description 5
- 230000002062 proliferating effect Effects 0.000 claims abstract description 3
- -1 thiopyranopyrimidine compound Chemical class 0.000 claims description 74
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 45
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
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- MYWWWNVEZBAKHR-UHFFFAOYSA-N methyl 3-(3-methoxy-3-oxopropyl)sulfanylpropanoate Chemical compound COC(=O)CCSCCC(=O)OC MYWWWNVEZBAKHR-UHFFFAOYSA-N 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- RLLPVAHGXHCWKJ-UHFFFAOYSA-N permethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 RLLPVAHGXHCWKJ-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 150000003230 pyrimidines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the thiapyran miazines compound of the structure containing pyrazoline shown in formula I, its geometric isomer and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein Ar1、Ar2, n and substituent R1With the implication provided in the description.The invention further relates to purposes of the compounds of formula I in the medicine for the treatment of and/or pre- anti-cancer and other proliferative diseases is prepared.
Description
Technical Field
The invention relates to a pyrazoline structure-containing thiopyranopyrimidine compound, a geometric isomer thereof, a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, a preparation method thereof and a pharmaceutical composition containing the compound.
Background
Malignant tumors are a disease that seriously jeopardizes human health and life. Human malignancies cause mortality second to cardiovascular, ranked second.
The nature of cellular carcinogenesis is a deregulation of the cellular signaling system, resulting in rapid growth and unlimited proliferation of cancer cells. Since the PI3K pathway plays an important role in the occurrence and development of tumors, small molecule inhibitors targeting key molecules in the PI3K/Akt signal pathway have become hot spots in the research of current antitumor drugs, and recently, with the deep research of PI3K pathway inhibitors, a batch of alicyclic pyrimidine compounds are proved to have good PI3K/mTOR inhibitory activity and good in-vivo and pharmacokinetic activity. BMCL-200908069-1 is a triazine selective mTOR inhibitor obtained by virtual compound screening of KuDOS pharmaceutical company, the inhibitory activity of the inhibitor on mTOR is 0.27 mu M, the inhibitory activity on PI3K kinase is more than 10 mu M, and good antitumor activity is shown. In addition, the recently designed and synthesized thiopyranopyrimidine derivatives 7e of the subject group also have excellent antitumor activity (Design, synthesis, anticancer and gating students of novel 4-morpholino-7, 8-dihydro-5H-thiophanato [4,3-d ] pyrimidine derivatives as mTOR inhibitors [ J ]. Bioorganic & medicinal chemistry,2014,22(24):6746 and 6754.). A series of Novel pyrazoline derivatives are reported in the literature (Synthesis and pharmacological testing of 4, 5-dipyrazolines carrying pyridine mobility [ J ]. Europan journal of medical Chemistry,55(2012) 467-. The chemical formulas of BMCL-200908069-1, thiopyranopyrimidine derivatives 7e and compounds A, B and C are as follows:
the invention designs and synthesizes a series of pyrazoline structure-containing thiopyranopyrimidine compounds, the series of compounds retain the main structure of thiopyranopyrimidine and introduce pyrazoline active groups, and various pyrazoline structure-containing thiopyranopyrimidine compounds are designed and synthesized. The invention mainly researches the antitumor activity of different substituted thiopyranopyrimidine compounds containing pyrazoline structures so as to screen antitumor drugs with better activity and selectivity. The result of screening the anti-tumor activity of a plurality of PI3K/mTOR inhibitor high-expression cell strains in vitro shows that the compounds have stronger anti-tumor activity and selectivity, and a plurality of compounds are also tested for the in vivo activity of PI3K alpha and mTOR kinase. Experiments show that some compounds have high antitumor activity.
Disclosure of Invention
The invention provides a thiopyranopyrimidine compound containing a pyrazoline structure, as shown in a general formula I, a geometric isomer thereof, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the general formula I is as follows:
wherein
n＝0、1、2；
R1Is selected from H or-CH3；
Ar1、Ar2Respectively represents phenyl, naphthyl, pyridyl and thienyl, wherein the phenyl, naphthyl, pyridyl and thienyl have 1 to 4 same or different R2Substitution;
R21 to 4 same or different hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, mercapto, C1～C4) Alkyl radical, C3～C6Cycloalkyl radical, C1～C4Alkenyl radical, C1～C4Alkynyl, C1～C4Alkoxy radical, C1～C4Alkylthio, allyl, (2-methyl) allyl, C1～C4Alkoxymethyl group, C1～C4Alkyl acyl or C1～C3A substituent of an alkylenedioxy group;
the present invention preferably relates to compounds of the general formula I as described above, geometric isomers thereof, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
n＝0、1、2；
R1is H;
Ar1、Ar2respectively represents phenyl, naphthyl, pyridyl and thienyl, wherein the phenyl, naphthyl, pyridyl and thienyl have 1 to 4 same or different R2Substitution;
R2is 1 to 4 same or different groups selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, mercapto, methyl, ethyl, tert-butyl, propenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, formyl, acetyl, propionyl or cycloproponyl;
the pyrazoline structure-containing thiopyranopyrimidine compound of the general formula I is one selected from the following compounds, but these compounds are not meant to limit the present invention in any way:
(1)4- (2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(2)4- (2- (5- (3, 4-dichlorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(3)4- (2- (5- (3, 4-dichlorophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(4)4- (2- (3- (4-bromophenyl) -5- (3, 4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(5)4- (2- (5- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(6)4- (2- (5- (3, 4-dichlorophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(7)4- (2- (5- (4-fluorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(8)4- (2- (3, 5-bis (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
(9)4- (2- (5- (4-bromophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
(10)4- (2- (5- (4-bromophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(11)4- (2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(12)4- (2- (3- (4-methoxyphenyl) -5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
(13) 4-morpholin-4-yl-2- [3- (6-trifluoromethoxy-naphthalen-2-yl) -5- (6-vinyl-naphthalen-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine
(14)1- (4- (1- (4- ((S) -3-methylmorpholino) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-2-yl) -3-p-ran-2-yl) -4, 5-dihydro-1H-pyrazol-5-yl) cyclohexyl) ethan-1-one
(15)2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(16)2- (5- (3, 4-dichlorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(17)2- (5- (3, 4-dichlorophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(18)2- (3- (4-bromophenyl) -5- (3, 4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(19)2- (5- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine 6, 6-dioxide
(20)2- (5- (3, 4-dichlorophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(21)2- (5- (4-fluorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(22)2- (3, 5-bis (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(23)2- (5- (4-bromophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(24)2- (5- (4-bromophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(25)2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine 6, 6-dioxide
(26)2- (3- (4-methoxyphenyl) -5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(27)6- (3- (5- (((methylthio) methyl) thio) pyridin-2-yl) -1- (4-morpholino-6, 6-dioxo-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-2-yl) -4, 5-dihydro-1H-pyrazol-5-yl) nicotinonitrile
The following synthetic scheme illustrates the preparation of the pyrazoline structure-containing thiopyranopyrimidine compounds of general formula I according to the invention, all starting materials being prepared by the means described in the synthetic scheme, by methods which are well known to those skilled in the art of organic chemistry or are commercially available. All of the final thiopyranopyrimidines of the present invention are prepared by the methods described in the synthetic schemes or by analogous methods thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in the synthetic route are as defined below or in the claims.
Scheme 1 synthetic route to the subject compounds
The invention firstly synthesizes intermediates A6 and A7, and then cyclizes with different substituted micromolecule chalcone to obtain the target compound.
The pyrazoline structure-containing thiopyranopyrimidines of the general formula I in the present invention may be used to form pharmaceutically acceptable salts with acids according to conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are those of formula I above which may themselves be less active or even inactive, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The compound can be prepared into a composition by mixing the compound containing the pyrazoline structure of the thiopyranopyrimidine compound shown in the general formula I and pharmaceutically acceptable salts, hydrates or solvates thereof serving as active ingredients with a pharmaceutically acceptable carrier or excipient, and can be prepared into a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The clinical dosage of the pyrazoline structure-containing thiopyranopyrimidine compounds of the general formula I for patients can be determined according to the following formula: the therapeutic efficacy and bioavailability of the active ingredients in vivo, their metabolic and excretory rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10 to 500mg, preferably 50 to 300 mg. Therefore, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, 10 to 500mg, preferably 50 to 300mg, of the pyrazoline structure-containing thiopyranopyrimidine compound of the above general formula I should be contained per unit formulation in consideration of the above effective dose. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The active compounds of the present invention or their pharmaceutically acceptable salts and solvates thereof may be used alone as the sole anti-proliferative agent or in combination with anti-proliferative agents now on the market for the treatment and/or prevention of proliferative diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
The compound of the invention has the activity of inhibiting the growth of tumor cells in vitro, so the compound can be used for preparing medicaments for treating and/or preventing cancers, such as lung cancer, liver cancer, prostate cancer and the like.
Through in vitro inhibition activity tests of lung cancer cells A549, human prostate cancer cells PC-3 and liver cancer cells HepG2, the compound has a remarkable inhibition effect on lung cancer cells, prostate cancer cells and liver cancer cells, and is particularly used for preparing medicines for treating and/or preventing prostate cancer, lung cancer and liver cancer.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicament cisplatin, camptothecin medicament irinotecan, vinca base medicament novinova, deoxycytidine medicament gemcitabine, etoposide, taxol and the like) on the market at present. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
Detailed Description
The present invention will be further described in detail with reference to specific examples for explaining the present invention more specifically, but they are not to be construed as limiting the present invention.
The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the derivatives was measured by BrukeraRx-400 and mass spectrometry by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
A thiopyranopyrimidine compound containing a pyrazoline structure of the general formula I:
the structural formulas of examples 1 to 27 of the present invention are shown in Table 1 below
TABLE 1 structural formulas of examples 1 to 27
Step A preparation of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (A1)
2.7098g NaH (60%) was put into a 250mL dry three-necked flask, 40mL anhydrous Tetrahydrofuran (THF) was added, the mixture was stirred at room temperature for 10min, then a solution of dimethyl 3,3' -thiodipropionate (10.1015g,0.049mol) in THF (30mL) was slowly added dropwise over about 1h, then 10mL THF was added to rinse the dropping funnel, and the reaction was continued for 1-2h, after which the reaction was completed. The reaction solution was adjusted to pH 6-7 with 2% dilute hydrochloric acid, then dichloromethane was added for extraction (50mL x 3), the organic layers were combined and washed with saturated sodium chloride solution (50mL x 3), the collected organic layers were dried over sufficient anhydrous sodium sulfate and filtered, and the filtrate was decompressed to remove the solvent to give 8.52 as a yellow oily liquid with a yield of 99.9%.
1H NMR(400MHz,CDCl3)3.73(s,3H),3.67(s,1H),3.27(s,2H),2.75(t,J＝6.0Hz,2H),2.52(t,J＝5.9Hz,2H).
Step B preparation of 7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine-2, 4-diol (A2)
Adding sodium metal (16.2252g,0.7mol) into 300mL of absolute ethyl alcohol, stirring in an ice bath until the sodium metal is dissolved, adding urea (32.7178g,0.54mol), heating to 80 ℃, adding 31.3050g (0.18mol) of intermediate A1 after the urea is dissolved, stopping the reaction after about 24 hours of reaction, cooling to room temperature, removing the solvent under reduced pressure, adding ice water into residues, adjusting the pH of the residues to 6-7 with acetic acid in an ice bath, separating out a white solid, performing suction filtration, washing a filter cake with ice water, and drying to obtain 13.6333g of a white powdery solid, wherein the yield is: 41.2 percent;
m.p.：>300℃。ESI-MS m/z:[M-H]-:183.2；1H NMR(400MHz,CDCl3)3.81(s,2H),3.23(t,J＝5.9Hz,2H),2.96(t,J＝6.0Hz,2H).
step C preparation of 2, 4-dichloro-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine (A3)
3.0293g (0.016mol) of intermediate A2 were added to a dry 50mL round bottom flask, followed by 20mL of phosphorus oxychloride, stirred and heated, and after refluxing at 110 ℃ for 3h, the reaction was stopped and cooled to room temperature. Slowly adding the reaction solution into crushed ice, violently stirring to separate out yellow granular solid, performing suction filtration, washing a filter cake with a large amount of water, and drying to obtain 3.1174g of yellow granular solid with the yield of 85.7%;
m.p.：87.1-87.9℃。ESI-MS m/z:[M+H]+:185.2,1H NMR(400MHz,CDCl3)3.81(s,2H),3.23(t,J＝5.9Hz,2H),2.96(t,J＝6.0Hz,2H).
step D preparation of 2-chloro-4-morpholine-7, 8-dihydro-5H-thiopyrano [4,3-D ] pyrimidine (A4)
4.5765g (0.02mol) of intermediate A3 were placed in 90mL of methanol, 5mL of morpholine were slowly added dropwise at room temperature over 5min, and after the addition was complete, the reaction was carried out at room temperature for 1 h. After the reaction, the mixture was filtered, and the filter cake was washed with water and dried to obtain 4.2265g of an off-white solid. The yield is 75.2%;
m.p.：161.1-162.4℃。ESI-MS m/z:[M+H]+:272.1；1H NMR(400MHz,CDCl3)3.81(s,2H),3.23(t,J＝5.9Hz,2H),2.96(t,J＝6.0Hz,2H).
step preparation of E2-chloro-4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide (A5)
4.0300g (0.015mol) of Compound A4 and 60mL of methanol were added to a 250mL round-bottom flask and stirred at room temperature, then 0.4473g (0.001mol) of sodium tungstate was weighed and dissolved in 5mL of 30% hydrogen peroxide, and then slowly added dropwise to the reaction solution and stirred at room temperature for 2 to 3 hours. After the reaction was completed, the mixture was filtered by suction to obtain 3.9190g of a pale yellow solid, yield: 87.0 percent;
m.p.：145.7-146.8℃。ESI-MS m/z:[M+Na]+:326.1；1H NMR(400MHz,DMSO)4.38(s,2H),3.77–3.69(m,4H),3.56(t,J＝6.6Hz,2H),3.45–3.39(m,4H),3.31(t,J＝6.7Hz,2H).
step F Synthesis of 2-hydrazino-4-morpholine-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine (A6)
3.4725g (0.013mol) of intermediate A4 is weighed and placed in a 250mL three-necked bottle, 110mL of 80% hydrazine hydrate is added, the mixture is heated and stirred, the reflux reaction is carried out for 1h, the reaction is stopped, a white solid is precipitated after the mixture is cooled to room temperature, the mixture is filtered, washed for 2 times by cold water, and the white solid 1.7310g is obtained after drying, so that the yield is: 50.7 percent;
m.p.：172.1-173.2℃。ESI-MS m/z:[M+H]+:268.2；1H NMR(400MHz,DMSO)7.66(s,1H),4.07(s,2H),3.73–3.66(m,4H),3.54(s,2H),3.18(s,4H),2.89(t,J＝6.1Hz,2H),2.82(t,J＝6.0Hz,2H).
step G Synthesis of 2-hydrazino-4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide (A7)
Weighing 3.4018g (0.011mol) of intermediate A5, placing the intermediate A5 in a 250mL three-necked bottle, adding 70mL of ethanol and 70mL of 80% hydrazine hydrate, heating and stirring, carrying out reflux reaction for 1h, stopping the reaction, cooling to room temperature, separating out a white solid, carrying out suction filtration, washing with cold water for 2 times, and drying to obtain 2.5384g of a white solid, wherein the yield is as follows: 75.7 percent;
m.p.：230.2-231.9℃。ESI-MS m/z:[M+H]+:300.1；1H NMR(400MHz,DMSO)7.95(s,1H),4.13(s,2H),4.10(s,2H),3.70(s,4H),3.43(t,J＝6.4Hz,2H),3.17(s,4H),3.11(t,J＝6.7Hz,2H).
step H4- (2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
Chalcone (0.001mol) and 4- (2-hydrazino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine (0.001mol) are dissolved in 13mL ethanol, 1mL of 10% NaOH solution is dropwise added, the reaction is carried out for 15min, and the reaction is stopped after TLC detection.
Adding appropriate amount of water into the reaction solution, adjusting pH to 6-7 with dilute hydrochloric acid solution, separating out solid, stirring for 10min, vacuum filtering, and drying the filter cake.
Example 1
4- (2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
Intermediate a6 was synthesized according to steps a-d, d-f and finally intermediate a6 was reacted with chalcone via step E to give 4- (2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine.
1H NMR(400MHz,DMSO)8.19(s,2H),7.48–7.42(m,6H),7.15(s,2H),5.51(s,1H),4.02(s,1H),3.87(s,2H),3.77–3.56(m,5H),3.55–3.45(m,4H),3.26(d,J＝16.6Hz,2H),2.95(s,2H).
According to the method of example 1, an intermediate A6 is synthesized according to steps a-d, d-f, and finally the intermediate A6 is reacted with chalcones containing different substituents through step E to respectively prepare the compounds of examples 2-14.
Example 2
4- (2- (5- (3, 4-dichlorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,CDCl3)7.84(d,J＝8.7Hz,2H),7.61(d,J＝7.7Hz,2H),7.25(d,J＝8.3Hz,1H),7.07(d,J＝8.7Hz,2H),5.67(dd,J＝11.7,6.2Hz,1H),3.96(dd,J＝18.1,11.8Hz,1H),3.83(s,3H),3.62–3.52(m,5H),3.47–3.40(m,6H),3.04(s,2H),2.94(d,J＝5.9Hz,2H).
Example 3
4- (2- (5- (3, 4-dichlorophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,DMSO)7.75(d,J＝6.9Hz,2H),7.54(d,J＝8.3Hz,2H),7.46–7.40(m,3H),7.18(d,J＝8.3Hz,1H),5.63(dd,J＝12.2,6.2Hz,1H),3.90–3.76(m,2H),3.54(dd,J＝18.2,7.8Hz,6H),3.21–3.06(m,4H),2.88(s,4H).
Example 4
4- (2- (3- (4-bromophenyl) -5- (3, 4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,DMSO)7.68(d,J＝8.3Hz,2H),7.63(d,J＝8.4Hz,2H),7.54(d,J＝8.3Hz,2H),7.17(d,J＝8.2Hz,1H),5.63(dd,J＝12.0,6.1Hz,1H),3.84(dd,J＝17.5,12.5Hz,1H),3.56(s,3H),3.52(s,2H),3.48–3.39(m,2H),3.18(d,J＝5.9Hz,1H),3.11(d,J＝14.3Hz,2H),2.88(s,4H).
Example 5
4- (2- (5- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,DMSO)7.64(d,J＝7.2Hz,2H),7.53(d,J＝11.8Hz,2H),7.25(d,J＝7.4Hz,2H),7.17(d,J＝7.3Hz,1H),5.61(s,1H),3.88–3.75(m,1H),3.59–3.44(m,7H),3.12(s,4H),2.88(s,4H).
Example 6
4- (2- (5- (3, 4-dichlorophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,DMSO)7.79(dd,J＝8.6,5.6Hz,2H),7.54(d,J＝8.2Hz,2H),7.27(t,J＝8.8Hz,2H),7.17(dd,J＝8.3,1.8Hz,1H),5.62(dd,J＝12.2,6.2Hz,1H),3.84(dd,J＝17.9,12.3Hz,1H),3.56(t,J＝7.4Hz,2H),3.53–3.44(m,3H),3.41(d,J＝9.2Hz,1H),3.19(d,J＝6.2Hz,1H),3.17–3.06(m,3H),2.89(d,J＝13.0Hz,4H),2.48(s,3H).
Example 7
4- (2- (5- (4-fluorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,CDCl3)8.13(d,J＝8.2Hz,2H),7.23(s,2H),7.00(dd,J＝20.6,8.2Hz,4H),5.52(s,1H),3.93–3.87(m,1H),3.85(s,3H),3.82–3.75(m,1H),3.61(s,3H),3.51(d,J＝15.6Hz,2H),3.44(d,J＝8.4Hz,1H),3.37(s,4H),3.22(d,J＝13.2Hz,2H),2.96(s,2H).
Example 8
4- (2- (3, 5-bis (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
1H NMR(400MHz,DMSO)7.79(dd,J＝8.6,5.6Hz,2H),7.25(dt,J＝8.9,7.2Hz,4H),7.10(t,J＝8.8Hz,2H),5.64(dd,J＝12.1,5.7Hz,1H),3.84(dd,J＝17.8,12.2Hz,1H),3.61–3.40(m,6H),3.09(dd,J＝17.6,5.5Hz,3H),3.00–2.90(m,2H),2.86(d,J＝20.0Hz,4H).
Example 9
4- (2- (5- (4-bromophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
1H NMR(400MHz,DMSO)7.93(d,J＝3.6Hz,2H),7.56–7.46(m,5H),7.24(d,J＝8.3Hz,2H),5.68(dd,J＝11.7,6.0Hz,1H),4.00(dd,J＝18.2,11.9Hz,1H),3.63–3.48(m,7H),3.32(d,J＝6.0Hz,2H),3.28(d,J＝5.9Hz,2H),3.07(s,2H),2.91(t,J＝5.9Hz,2H).
Example 10
4- (2- (5- (4-bromophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,DMSO)7.64(d,J＝7.2Hz,2H),7.47(d,J＝7.2Hz,2H),7.24(d,J＝7.4Hz,2H),7.15(d,J＝7.2Hz,2H),5.60(d,J＝6.1Hz,1H),3.82(dd,J＝16.9,11.9Hz,1H),3.57(s,3H),3.53(s,3H),3.44(s,1H),3.07(s,4H),2.87(s,4H),2.32(s,3H).
Example 11
4- (2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
1H NMR(400MHz,DMSO)7.79(s,2H),7.48(s,2H),7.27(s,2H),7.17(s,2H),5.63(s,1H),3.89–3.79(m,1H),3.55(d,J＝15.2Hz,6H),3.44(s,1H),3.09(d,J＝12.2Hz,4H),2.87(s,4H).
Example 12
4- (2- (3- (4-methoxyphenyl) -5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
1H NMR(400MHz,CDCl3)7.72(d,J＝8.4Hz,2H),7.28(d,J＝7.0Hz,2H),7.21(d,J＝7.6Hz,3H),7.01(d,J＝8.5Hz,2H),5.63(s,1H),3.86(d,J＝17.3Hz,1H),3.81(s,3H),3.57(d,J＝15.0Hz,3H),3.53–3.39(m,7H),3.10(s,1H),2.90(s,4H).
Example 13
4- (2- (3- (6- (trifluoromethoxy) naphthalen-2-yl) -5- (6-vinylnaphthalen-2-yl) -4, 5-dihydro-1H-pyrazol-1-yl) -8H-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
ESI-MS[M+H]+m/z:667.7
Example 14
1- (4- (1- (4- ((S) -3-methylmorpholino) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-2-yl) -3-p-ran-2-yl) -4, 5-dihydro-1H-pyrazol-5-yl) cyclohexyl) ethan-1-one
ESI-MS[M+H]+m/z:570.73
Step I2- (3, 5-Diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
Chalcone (0.001mol) and 2-hydrazino-4-morpholino-7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine 6, 6-dioxide (0.001mol) are dissolved in 13mL ethanol, 1mL of 10% NaOH solution is dropwise added, the reaction is carried out for 15min after the addition is finished, and the reaction is stopped after the TLC detection reaction is completed.
Adding appropriate amount of water into the reaction solution, adjusting pH to 6-7 with dilute hydrochloric acid solution, separating out solid, stirring for 10min, vacuum filtering, and drying the filter cake.
Example 15
2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
Intermediate a7 was formed first according to steps a-E, E-g and finally intermediate a7 was reacted with chalcone via step E to give 2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide.
1H NMR(400MHz,CDCl3)7.90(d,J＝6.3Hz,2H),7.40(d,J＝7.3Hz,4H),7.28(d,J＝3.2Hz,2H),7.23(d,J＝7.6Hz,2H),5.60(dd,J＝11.9,6.2Hz,1H),3.84(dd,J＝17.3,12.1Hz,1H),3.62(d,J＝6.5Hz,2H),3.52(d,J＝15.3Hz,3H),3.41(d,J＝14.8Hz,1H),3.21(dd,J＝26.0,8.3Hz,5H),2.96(dd,J＝23.3,17.1Hz,4H).
According to the method of the embodiment 1, the intermediate A7 is synthesized according to the steps a-E and E-g, and finally the intermediate A7 is reacted with chalcones with different substituents through the step E to respectively prepare the compounds of the embodiments 15-28.
Example 16
2- (5- (3, 4-dichlorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.81(s,1H),7.48(d,J＝8.2Hz,2H),7.32–7.26(m,2H),7.17(d,J＝8.5Hz,2H),5.63(s,1H),4.09(d,J＝4.7Hz,3H),3.53(d,J＝17.8Hz,4H),3.15(d,J＝4.4Hz,10H).
Example 17
2- (5- (3, 4-dichlorophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.70(d,J＝8.6Hz,2H),7.56–7.51(m,2H),7.09(dd,J＝65.5,8.3Hz,4H),5.62(dd,J＝12.0,5.6Hz,1H),4.10(dd,J＝40.6,15.5Hz,2H),3.90–3.83(m,1H),3.56(s,2H),3.51(s,2H),3.42(s,3H),3.16(dd,J＝12.3,5.6Hz,3H),3.03(d,J＝33.1Hz,3H).
Example 18
2- (3- (4-bromophenyl) -5- (3, 4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.71(d,J＝8.2Hz,2H),7.65(d,J＝8.4Hz,2H),7.58–7.53(m,2H),7.18(d,J＝8.5Hz,1H),5.65(dd,J＝12.1,6.0Hz,1H),4.12(dd,J＝39.1,15.5Hz,2H),3.87(dd,J＝18.0,12.4Hz,1H),3.55(s,3H),3.49(s,2H),3.21(dd,J＝17.5,6.2Hz,4H),3.09(s,2H),3.00(s,2H).
Example 19
2- (5- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.84–7.79(m,2H),7.57–7.53(m,2H),7.29(t,J＝8.8Hz,2H),7.18(d,J＝8.3Hz,1H),5.65(dd,J＝12.0,5.9Hz,1H),4.46(s,1H),4.12(dd,J＝39.9,15.5Hz,2H),3.93–3.77(m,2H),3.55(s,6H),3.24(d,J＝6.0Hz,2H),3.16(d,J＝30.3Hz,4H).
Example 20
2- (5- (3, 4-dichlorophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.60(dd,J＝45.3,8.4Hz,4H),7.28–7.13(m,3H),5.61(s,1H),4.10(s,16H),2.33(s,3H).
Example 21
2- (5- (4-fluorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.70(d,J＝8.7Hz,2H),7.23(dd,J＝8.5,5.5Hz,2H),7.12–7.07(m,2H),6.99(d,J＝8.8Hz,2H),5.61(dd,J＝11.9,5.4Hz,1H),4.11(dt,J＝43.3,12.9Hz,2H),3.89–3.82(m,1H),3.78(s,3H),3.67(s,1H),3.54(s,3H),3.49(s,3H),3.17(s,2H),3.07(dd,J＝17.9,5.6Hz,4H).
Example 22
2- (3, 5-bis (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.86(dd,J＝31.4,25.2Hz,2H),7.39–7.21(m,4H),7.13(dd,J＝20.1,11.5Hz,2H),5.92–5.44(m,1H),4.59–3.41(m,16H).
Example 23
2- (5- (4-bromophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.76(d,J＝6.7Hz,2H),7.46(dd,J＝18.6,7.9Hz,5H),7.18(d,J＝8.2Hz,2H),5.65(dd,J＝12.0,5.3Hz,1H),4.17(d,J＝15.4Hz,1H),4.04(d,J＝15.6Hz,1H),3.88(dd,J＝17.7,12.1Hz,1H),3.48(dd,J＝47.2,13.3Hz,7H),3.17(dd,J＝10.6,5.6Hz,2H),3.09(d,J＝11.7Hz,2H),2.97(s,2H).
Example 24
2- (5- (4-bromophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.99–7.76(m,1H),7.71(s,1H),7.53(dd,J＝21.8,7.9Hz,2H),7.37–7.13(m,4H),5.63(s,1H),4.61–3.42(m,16H),2.49(s,3H).
Example 25
2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,CDCl3)7.81(s,2H),7.48(d,J＝8.2Hz,2H),7.28(t,J＝8.3Hz,2H),7.17(d,J＝8.2Hz,2H),5.69–5.58(m,1H),4.17(d,J＝15.9Hz,1H),4.04(d,J＝15.1Hz,1H),3.87(dd,J＝17.5,12.1Hz,1H),3.56(s,2H),3.51(s,3H),3.42(d,J＝5.8Hz,2H),3.16(s,2H),3.10(s,1H),3.06(s,1H),2.97(s,2H).
Example 26
2- (3- (4-methoxyphenyl) -5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
1H NMR(400MHz,DMSO)7.70(d,J＝8.0Hz,2H),7.26(d,J＝6.8Hz,2H),7.18(d,J＝6.8Hz,3H),6.99(d,J＝7.8Hz,2H),5.59(d,J＝6.3Hz,1H),4.23–3.98(m,2H),3.86(d,J＝18.0Hz,1H),3.78(s,3H),3.68(d,J＝11.1Hz,2H),3.50(d,J＝11.9Hz,4H),3.18(s,3H),3.09(d,J＝5.1Hz,2H),3.03(d,J＝8.4Hz,2H).
Example 27
6- (3- (5- (((methylthio) methyl) thio) pyridin-2-yl) -1- (4-morpholino-6, 6-dioxo-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-2-yl) -4, 5-dihydro-1H-pyrazol-5-yl) nicotinonitrile
ESI-MS[M+H]+m/z:608.7
In vitro cytotoxic Activity
The thiopyranopyrimidine compound derivative containing a pyrazoline structure is subjected to in vitro activity screening for inhibiting lung cancer cells A549, prostate cancer PC-3 and liver cancer cells HepG2, and a reference product GDC-0941 is prepared according to a method described in the literature (J.Med.chem.,2008,51(18), pp 5522-5532).
1) After the cells were revived and passaged for 2-3 times for stabilization, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
3) The drug-containing culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 100 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 4h, the MTT solution is discarded, and 100 mu L of dimethyl sulfoxide is added. Oscillating on a magnetic oscillator to fully dissolve the survival cells and the MTT reaction products, and placing the mixture into a microplate reader for measuring results. Determination of drug IC by Bliss method50The value is obtained.
The results of the activity of the compound on liver cancer cells HepG2, lung cancer cells A549 and prostate cancer PC-3 are shown in Table 2.
The results of the experiment are shown in table 2. IC in Table 150>80% by weight, indicated as "+++", 80%>IC50>60% by weight, 60% by "+ +", and>IC50>40%, denoted "+", IC50<40%, indicated by "-", "NA" indicates no activity, and "ND" indicates not tested.
TABLE 2 antitumor Activity of the target Compounds in vitro
From the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity.
The compounds of general formula I of the present invention can be administered alone, but usually administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms, e.g., tablets, capsules, injections, aerosols, suppositories, films, drops, liniments for external use and ointments, using such compounds.
Application example 1: tablet formulation
12g of the compound in example 2 is added with 24g of auxiliary materials according to a general tabletting method in pharmacy, and the mixture is pressed into 200 tablets, wherein each tablet is 200 mg.
Application example 2: capsule preparation
Mixing 15g of the compound in example 6 with 30g of auxiliary materials according to the requirement of a pharmaceutical capsule, and filling the mixture into hollow capsules, wherein each capsule weighs 200 mg.
Application example 3: injection preparation
20g of the compound obtained in example 9 was adsorbed by activated carbon in accordance with a conventional pharmaceutical procedure, filtered through a 0.65 μm microporous membrane, and then filled in a nitrogen tank to prepare a hydroinjection preparation, each containing 2mL, in a total of 200 bottles.
Application example 4: aerosol formulation
30g of the compound in example 14 is dissolved in a proper amount of propylene glycol, and then distilled water and other additives are added to prepare 200mL of clear solution.
Application example 5: suppository
The compound 10g of the compound of the example 17 is ground into powder and added with proper amount of glycerol, the mixture is evenly ground and added with the melted glycerol gelatin, the mixture is evenly ground and poured into a model coated with a lubricant, and 30 suppositories are prepared
Application example 6: film agent
10g of the compound obtained in example 17 was swelled with polyvinyl alcohol, medicinal glycerin, water, etc. under stirring, dissolved by heating, filtered through a 80-mesh screen, and dissolved by adding the compound obtained in example 14 to the filtrate under stirring, and 100 films were formed on a film-coating machine.
Application example 7: drop pills
20g of the compound in example 19 and 60g of a matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1200 pills.
Application example 8: external liniment
20g of the compound in example 20 is mixed with 5g of auxiliary materials such as emulsifier and the like according to a conventional pharmaceutical method, ground and added with distilled water to 400 mL.
Application example 9: ointment formulation
Prepared by grinding 10g of the compound of example 24, and then uniformly grinding the ground compound with 500g of oil-based substances such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (7)
1. A thiopyranopyrimidine compound containing a pyrazoline structure is characterized in that: the general formula is:
wherein
n＝0、1、2；
R1Is selected from H or-CH3；
Ar1、Ar2Is phenyl, naphthyl, 5-to 10-membered heteroaryl, 5About 10 membered saturated or partially saturated heterocyclic group, and
Ar1、Ar2optionally 1 to 4 identical or different R2Substitution;
R2are respectively selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, sulfhydryl and (C)1～C4) Alkyl, (C)3～C6) Cycloalkyl group, (C)2～C4) Alkenyl, (C)2～C4) Alkynyl, (C)1～C4) Alkoxy group, (C)1～C4) Alkylthio, allyl, (2-methyl) allyl, (C)1～C4) Alkoxymethyl group, (C)1～C4) Alkyl acyl or (C)1～C3) A substituent of an alkylenedioxy group.
2. The pyrazoline structure-containing thiopyranopyrimidine compound according to claim 1, wherein: n is 0, 1, 2;
R1is H;
Ar1、Ar2respectively represents phenyl, naphthyl, pyridyl and thienyl, wherein the phenyl, naphthyl, pyridyl and thienyl have 1 to 4 same or different R2Substitution;
R2each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, mercapto, methyl, ethyl, tert-butyl, propenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, formyl, acetyl, propionyl or cyclopropoyl.
3. The pyrazoline structure-containing thiopyranopyrimidine compound according to claim 1, wherein: the method specifically comprises the following steps:
(1)4- (2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(2)4- (2- (5- (3, 4-dichlorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(3)4- (2- (5- (3, 4-dichlorophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(4)4- (2- (3- (4-bromophenyl) -5- (3, 4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(5)4- (2- (5- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(6)4- (2- (5- (3, 4-dichlorophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(7)4- (2- (5- (4-fluorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(8)4- (2- (3, 5-bis (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
(9)4- (2- (5- (4-bromophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
(10)4- (2- (5- (4-bromophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-4-yl) morpholine
(11)4- (2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) morpholine
(12)4- (2- (3- (4-methoxyphenyl) -5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-d ] -4-yl) morpholine
(13) 4-morpholin-4-yl-2- [3- (6-trifluoromethoxy-naphthalen-2-yl) -5- (6-vinyl-naphthalen-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine
(14)1- (4- (1- (4- ((S) -3-methylmorpholino) -7,8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-2-yl) -3-p-ran-2-yl) -4, 5-dihydro-1H-pyrazol-5-yl) cyclohexyl) ethan-1-one
(15)2- (3, 5-diphenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(16)2- (5- (3, 4-dichlorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(17)2- (5- (3, 4-dichlorophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(18)2- (3- (4-bromophenyl) -5- (3, 4-dichlorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(19)2- (5- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine 6, 6-dioxide
(20)2- (5- (3, 4-dichlorophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(21)2- (5- (4-fluorophenyl) -3- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(22)2- (3, 5-bis (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(23)2- (5- (4-bromophenyl) -3-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(24)2- (5- (4-bromophenyl) -3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(25)2- (5- (4-bromophenyl) -3- (4-fluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine 6, 6-dioxide
(26)2- (3- (4-methoxyphenyl) -5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl) -4-morpholino-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidine 6, 6-dioxide
(27)6- (3- (5- (((methylthio) methyl) thio) pyridin-2-yl) -1- (4-morpholino-6, 6-dioxo-7, 8-dihydro-5H-thiopyrano [4,3-d ] pyrimidin-2-yl) -4, 5-dihydro-1H-pyrazol-5-yl) nicotinonitrile.
4. A pharmaceutical composition comprising a compound of any one of claims 1 to 3, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient together with a pharmaceutically acceptable excipient.
5. The use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claims 1 to 3, for the manufacture of a medicament for the treatment and/or prophylaxis of proliferative diseases.
6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claims 1 to 3, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
7. Use of a compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition according to claims 1 to 3, for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer, prostate cancer, liver cancer.
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| CN113880859A (en) * | 2021-11-16 | 2022-01-04 | 江西科技师范大学 | 2-aryl-4-arylmethylamino pyrimidine compound and application thereof |
| CN113880859B (en) * | 2021-11-16 | 2022-06-21 | 江西科技师范大学 | 2-aryl-4-arylmethylamino pyrimidine compound and application thereof |
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