CN109305972B - A kind of dihydropyranopyrazole compound and its preparation method and application - Google Patents
A kind of dihydropyranopyrazole compound and its preparation method and application Download PDFInfo
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- CN109305972B CN109305972B CN201811133143.4A CN201811133143A CN109305972B CN 109305972 B CN109305972 B CN 109305972B CN 201811133143 A CN201811133143 A CN 201811133143A CN 109305972 B CN109305972 B CN 109305972B
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- acid
- dihydropyranopyrazole
- compound
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- -1 dihydropyranopyrazole compound Chemical class 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 108010065942 Prostaglandin-F synthase Proteins 0.000 claims abstract description 29
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- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000003112 inhibitor Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 10
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
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- LGSWWSDRTMRRNH-UHFFFAOYSA-N 1,2-dihydropyrano[3,2-c]pyrazole Chemical class C1=COC2=CNNC2=C1 LGSWWSDRTMRRNH-UHFFFAOYSA-N 0.000 abstract description 2
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- C07D491/04—Ortho-condensed systems
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- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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Abstract
本发明公开了一种二氢吡喃并吡唑类化合物及其制备方法和应用。所述化合物具有式（I）所示的结构或其药学上可接受的盐；其中，R1选自氢、C1‑6直链烷基、C1‑6环烷基、C1‑6卤代烷基、环状或直链C1‑6烷氧基、取代或非取代苯基、取代或非取代2‑吡啶基；R2选自C1‑10烷基、C1‑10卤代烷基、芳基取代C1‑6烷基或含环烷基的C3‑12烷基；R3、R4、R5、R6、R7各自独立地选自氢、卤素、羟基、硝基、取代或非取代C1‑6烷基、取代或非取代C1‑6烷氧基。本发明所述二氢吡喃并吡唑类化合物结构新颖，制备方法简单，且对于AKR1C3具有明显的抑制作用，甚至明显优于阳性对照药物甲氯酚那酸，可作为AKR1C3抑制剂使用，可制备成为AKR1C3相关疾病的药物应用，尤其是制备成为治疗前列腺癌的药物进行应用。 The invention discloses a dihydropyranopyrazole compound and a preparation method and application thereof. The compound has the structure shown in formula (I) or a pharmaceutically acceptable salt thereof; wherein, R 1 is selected from hydrogen, C 1-6 straight-chain alkyl, C 1-6 cycloalkyl, C 1-6 Haloalkyl, cyclic or straight-chain C 1-6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 2-pyridyl; R 2 is selected from C 1-10 alkyl, C 1-10 haloalkyl, Aryl-substituted C 1-6 alkyl or cycloalkyl-containing C 3-12 alkyl; R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, hydroxyl, nitro, Substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy. The dihydropyranopyrazole compounds of the present invention have novel structures, simple preparation methods, and have obvious inhibitory effect on AKR1C3, which is even significantly better than that of the positive control drug, mclofenac, and can be used as AKR1C3 inhibitors. The preparation is used as a medicine for AKR1C3-related diseases, especially the preparation and application of a medicine for the treatment of prostate cancer. 
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a dihydropyranopyrazole compound and a preparation method and application thereof.
Background
Prostate cancer has become the 3 rd most malignant tumor threatening the health of men in China, and is also referred to as a silent killer, which is not easy to be found in early stage and usually develops to late stage when diagnosed. Prostate cancer is a hormone-dependent malignant tumor, and androgen plays an important role in the process of prostate cancer occurrence and development. Endocrine therapy with the aim of lowering serum androgen levels and antagonizing androgen receptors is therefore a first-line treatment for advanced prostate cancer. However, almost all patients will develop castration-resistant prostate cancer (CRPC) gradually after a median time of 14-30 months, with a remaining median survival of only 1-2 years. The pathogenesis of CRPC is extremely complex, and no ideal therapeutic drug exists at present. Chemotherapy based on Docetaxel (Docetaxel ) is the current standard first-line treatment for CRPC. Although chemotherapy of this drug can delay the progression of the disease, adverse effects of chemotherapy also severely affect the quality of life of patients, and only 25-50% of patients respond well to chemotherapy. Novel endocrine therapeutic drugs are recently marketed (androgen synthesis inhibitor Abiraterone, Abiraterone, 2011; androgen receptor antagonist Enzalutamide, Enzalutamide, 2012), but have shortcomings of treatment resistance and the like.
Human aldehyde-ketone reductase 1C3(AKR1C3), a member of family 1C subfamily 3 of aldehyde-ketone reductases (AKR), belongs to a monomeric cytosolic protein, contains 323 amino acid residues, and is approximately 37kDa in size. AKR1C3 encodes 17 β hydroxysteroid dehydrogenase 5(17 β -HSD5), which reduces the carbonyl group at position 17 of steroids, and is a key enzyme in the synthesis of testosterone (T) and Dihydrotestosterone (DHT). The success of new endocrine treatment drugs has revealed the fact that androgen signalling pathways still play a central role in the progression of CRPC. As an important class of 17 β hydroxysteroid dehydrogenases, AKR1C3 is a potential new target for the treatment and prevention of CRPC. Compared to abirtadone, AKR1C3 inhibitors have the following advantages: (1) the AKR1C3 inhibitor acts on the downstream of androgen synthesis path, and will not affect the conversion of other important hormones, so the side effect is less. (2) The AKR1C3 inhibitor has double functions of androgen synthesis inhibition and androgen receptor antagonism, and can produce stronger antitumor effect than single-target drugs. (3) The AKR1C3 inhibitor can reverse the drug resistance of novel androgen receptor antagonist enzalutamide, and can be used as a drug partner to enhance the curative effect. Studies have shown that high expression and gene mutation of AKR1C3 are closely related to the development and progression of prostate cancer and CRPC, and that inhibitors thereof have shown good efficacy in preclinical studies.
Therefore, the development and research of the novel AKR1C3 inhibitor are a new hotspot in the research field of CRPC resistant medicaments, and have great development prospect and application value.
Disclosure of Invention
The invention aims to overcome the application defects of dihydropyranopyrazole compounds in the prior art and provide a dihydropyranopyrazole compound.
The invention also aims to provide a preparation method of the dihydropyranopyrazole compound.
The invention further aims to provide application of the dihydropyranopyrazole compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating AKR1C3 related diseases.
The above object of the present invention is achieved by the following scheme:
a dihydropyranopyrazole compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is1Selected from hydrogen, C1-6Chain alkyl, C1-6Halogenated chain alkyl group, C3-6Cycloalkyl radical, C3-6Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 2-pyridyl;
R2is selected from C1-10Chain alkyl, C1-10Halogenated chain alkyl and aryl substituted C1-6Chain alkyl or C containing cycloalkyl3-12An alkyl group;
R3、R4、R5、R6、R7each independently selected from hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-6Chain alkyl, substituted or unsubstituted C1-6An alkoxy group; the substituent is halogen or C1-4A linear alkyl group.
As a preferable mode, in the compound of the structure shown in the formula (I), R is1Selected from hydrogen, C1-4Chain alkyl, C3-6Cycloalkyl, furan-3-yl, halophenyl, halo 2-pyridyl;
the R is2Is selected from C1-10Chain alkyl, C1-10Halogenated chain alkyl, phenyl substituted C1-6Chain alkyl or C3-6C of cycloalkyl3-12An alkyl group;
the R is3、R4、R5、R6、R7Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, methyl, ethyl, methoxy or ethoxy.
As a preferable mode, the R is1Selected from hydrogen, methyl, cyclopentyl, furan-3-yl, pyridin-2-yl or 2-fluorophenyl;
R2selected from methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, (3-methyl) butyl, (4-methyl) pentyl, (2, 2-dimethyl) propyl, (2-cyclopentyl) ethyl, (2-cyclohexyl) ethyl or (3-phenyl) propyl;
R3、R4、R5、R6、R7independently selected from hydrogen, hydroxy, methoxy, nitro or fluoro.
As a more preferable mode, the dihydropyranopyrazole compound is selected from any one of the following compounds:
as a preferred embodiment, the pharmaceutically acceptable salts of the dihydropyranopyrazoles are salts of the compounds of formula (I) with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid, or glutamic acid.
The invention also provides a preparation method of the dihydropyranopyrazole compound, which comprises the following steps:
dissolving the compounds 1, 2 and 3 and the alkaline substance in a solvent for reaction, separating and purifying after the reaction is finished to obtain the target product.
Preferably, the reaction is carried out at normal temperature or under heating reflux. More preferably, the temperature of the heating reflux is 30-120 ℃; the reaction time is 1-12 h.
Preferably, the solvent is one or more of tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1, 4-dioxane, benzene, toluene or xylene.
Preferably, the basic substance is one or more of piperidine, pyrrole, pyridine, triethylamine, diisopropylethylamine, sodium acetate, sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate.
As a preferred scheme, the specific reaction process is as follows: in a solvent, the compounds 1, 2 and 3 react for 1 to 12 hours at room temperature or at the temperature of between 30 and 120 ℃ under the action of alkaline substances by stirring until the raw materials react completely, then the reaction product is cooled to the room temperature, partial solvent is removed by concentration, and the precipitated solid is filtered, washed by the solvent and dried to obtain the target product.
The application of the dihydropyranopyrazole compound or the pharmaceutically acceptable salt thereof as an AKR1C3 inhibitor is also within the protection scope of the invention.
The application of the dihydropyranopyrazole compound or the pharmaceutically acceptable salt thereof in preparing the medicine for treating AKR1C3 related diseases is also within the protection scope of the invention.
As a preferred embodiment, the AKR1C 3-related disease is prostate cancer.
As a preferable scheme, the medicament is prepared into a clinically acceptable dosage form by adding conventional auxiliary materials according to a conventional process.
As a more preferable scheme, the medicament is in the form of tablets, pills, capsules, intramuscular injection, intravenous injection, powder injection, oral liquid or liniment.
Compared with the prior art, the invention has the following beneficial effects:
the dihydropyranopyrazole compound has a novel structure and a simple preparation method, has an obvious inhibiting effect on AKR1C3, is even obviously superior to a positive control drug, namely meclofenamic acid, can be used as an AKR1C3 inhibitor, has a potential application value in treating diseases related to AKR1C3, can be prepared into a drug application of the diseases related to AKR1C3, and especially can be prepared into a drug for treating prostate cancer.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
The following are the starting compounds according to the present example:
EXAMPLE 1 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -1-methyl-3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P1)
1-methyl-3-propyl-1H-pyrazol-5 (4H) -one (1a) (140mg,1.0mol), malononitrile (2) (66mg,1.0mmol), 3-methoxy-4-hydroxy-5-nitrobenzaldehyde (3a) (197mg,1.0mmol) were dissolved in 5.0mL of ethanol, followed by addition of piperidine (91. mu.L, 1.0mmol) and stepwise ramp-up to reflux for 1 hour. After the reaction is completed, the reaction product is cooled to room temperature, and the precipitated solid is subjected to suction filtration, ethanol washing and drying to obtain a product P1 which is a yellow solid with the yield of 68%.
1H NMR(400MHz,DMSO–d6)δ10.35(br s,2H),7.25(d,J＝1.8Hz,1H),7.14(s,1H),7.10(s,2H),4.68(s,1H),3.84(s,3H),3.62(s,3H),2.12–1.97(m,2H),1.38–1.12(m,2H),0.69(t,J＝7.3Hz,3H).
EXAMPLE 2 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -1-cyclopentyl-3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P2)
The starting materials were replaced by reactions 1b, 2 and 3a and the product was obtained as a yellow solid in 71% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ10.36(br s,1H),7.24(d,J＝1.3Hz,1H),7.14(s,1H),7.08(s,2H),4.68(s,1H),4.56(dt,J＝14.6,7.2Hz,1H),3.84(s,3H),2.16–1.92(m,5H),1.89–1.74(m,4H),1.65–1.49(m,3H),0.69(t,J＝7.3Hz,3H).
EXAMPLE 3 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -1- (tetrahydrofuran-3-yl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P3)
The starting materials were replaced by reactions 1c, 2 and 3a and the product was obtained as a yellow solid in 65% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.24(s,1H),10.45(br s,1H),7.31(s,1H),7.17(s,2H),6.99(s,1H),4.90(s,1H),4.74(s,1H),4.14–3.91(m,2H),3.89(s,3H),3.77–3.58(m,2H),2.46–2.25(m,2H),2.25–1.97(m,2H),1.40–1.17(m,2H),0.83–0.59(m,3H)；HRMS(ESI)m/z calcd C21H24N5O6 +[M+H]+442.1721,found 442.1718.
EXAMPLE 4 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -1- (pyridin-2-yl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P4)
The product was obtained as a yellow solid in 68% yield according to the procedure of example 1, substituting starting materials for 1d, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.58(s,1H),10.50(br s,1H),8.46(d,J＝4.2Hz,2H),8.15–7.91(m,1H),7.83(s,1H),7.78(s,1H),7.34–7.23(m,1H),4.77(d,J＝11.3Hz,1H),3.87(s,3H),2.75–2.58(m,2H),1.68–1.47(m,2H),0.90(t,J＝7.2Hz,3H)；HRMS(ESI)m/z calcd C22H21N6O5 +[M+H]+449.1568,found 449.1560.
EXAMPLE 5 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -1- (2-fluorophenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P5)
The starting materials were replaced by reaction of 1e, 2 and 3a and the product was obtained as a yellow solid in 73% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ10.42(br s,1H),7.64(t,J＝7.8Hz,1H),7.60–7.52(m,1H),7.51–7.44(m,1H),7.39(t,J＝7.6Hz,1H),7.34(s,1H),7.20(s,1H),7.12(s,2H),4.80(s,1H),3.86(s,3H),2.26–2.07(m,2H),1.43–1.22(m,2H),0.74(t,J＝7.3Hz,3H)；HRMS(ESI)m/z calcd C23H21FN5O5 +[M+H]+466.1521,found 466.1521.
EXAMPLE 6 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3-methyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P6)
The product was obtained as a yellow solid in 72% yield following the procedure of example 1 substituting starting materials for 1f, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.15(s,1H),10.35(br s,1H),7.24(d,J＝1.7Hz,1H),7.11(d,J＝1.6Hz,1H),6.95(s,2H),4.69(s,1H),3.84(s,3H),1.87(s,3H)；HRMS(ESI)m/z calcd C15H14N5O5 +[M+H]+344.0989,found 344.0986.
EXAMPLE 7 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3-ethyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P7)
The product was obtained as a yellow solid in 74% yield according to the procedure of example 1, substituting 1g of starting material, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.18(s,1H),7.23(s,1H),7.08(s,1H),6.91(s,2H),4.70(s,1H),3.82(s,3H),2.23(dt,J＝14.3,7.3Hz,2H),0.85(t,J＝7.5Hz,3H)；13C NMR(101MHz,DMSO–d6)δ161.32,155.13,150.17,141.85,137.11,121.07,115.85,114.81×2,99.98,96.51,57.19,57.13,36.02,18.32,12.97；HRMS(ESI)m/z calcd C16H16N5O5 +[M+H]+358.1146,found 358.1141.
EXAMPLE 8 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3-butyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P8)
The product was obtained as a yellow solid in 69% yield following the procedure of example 1 substituting starting materials for 1h, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.16(s,1H),10.34(br s,1H),7.25(d,J＝2.0Hz,1H),7.10(d,J＝1.9Hz,1H),6.92(s,2H),4.69(s,1H),3.82(s,3H),2.31–2.08(m,2H),1.31–1.17(m,2H),1.08–1.01(m,2H),0.69(t,J＝7.1Hz,3H)；HRMS(ESI)m/z calcd C18H20N5O5 +[M+H]+386.1459,found 386.1451.
EXAMPLE 9 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3-pentyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P9)
The product was obtained as a yellow solid in 78% yield following the procedure of example 1 substituting starting materials for 1i, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.16(s,1H),7.26(s,1H),7.10(s,1H),6.92(s,2H),4.69(s,1H),3.83(s,3H),2.33–2.21(m,1H),2.21–2.10(m,1H),1.31–1.13(m,1H),1.13–1.00(m,3H),1.00–0.87(m,2H),0.72(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO–d6)δ161.35,155.05,150.05,142.08,140.74,137.17,136.06,121.08,115.99,114.94,96.90,57.15×2,36.17,31.12,27.85,24.78,22.07,14.10；HRMS(ESI)m/z calcd C19H22N5O5 +[M+H]+400.1615,found 400.1617.
EXAMPLE 10 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3-hexyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P10)
The starting materials were replaced by 1j, 2 and 3a and the product was obtained as a yellow solid in 75% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.16(s,1H),7.25(s,1H),7.07(s,1H),6.94(s,2H),4.68(s,1H),3.81(s,3H),2.27–2.14(m,2H),1.27–1.19(m,4H),1.04–0.92(m,4H),0.77(t,J＝7.1Hz,3H)；HRMS(ESI)m/z calcd C20H24N5O5 +[M+H]+414.1772,found 414.1767.
EXAMPLE 11 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3-heptyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P11)
The product was obtained as a yellow solid in 73% yield following the procedure of example 1 substituting starting materials for 1k, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.17(s,1H),10.38(br s,1H),7.25(s,1H),7.09(s,1H),6.94(s,2H),4.69(s,1H),3.82(s,3H),2.26(ddd,J＝14.8,8.7,6.1Hz,1H),2.15(ddd,J＝14.7,8.5,6.4Hz,1H),1.30–1.13(m,4H),1.09–0.93(m,6H),0.81(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO–d6)δ161.34,155.07,150.04,142.14,140.76,137.08,136.04,121.07,116.01,114.92,96.85,57.19,57.14,36.17,31.48,28.89,28.62,28.17,24.82,22.41,14.30；HRMS(ESI)m/z calcd C21H26N5O5 +[M+H]+428.1928,found 428.1926.
EXAMPLE 12 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3- (3-methylbutyl) -1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P12)
The product was obtained as a yellow solid in 78% yield according to the procedure of example 1, substituting 1l of starting material, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.15(s,1H),10.33(br s,1H),7.25(d,J＝1.9Hz,1H),7.10(d,J＝1.9Hz,1H),6.91(s,2H),4.69(s,1H),3.82(s,3H),2.25(ddd,J＝15.8,10.3,5.7Hz,1H),2.20–2.09(m,1H),1.28–1.13(m,2H),0.87(ddd,J＝18.9,9.1,4.4Hz,1H),0.71–0.64(m,6H)；HRMS(ESI)m/z calcd C19H22N5O5 +[M+H]+400.1615,found 400.1610.
EXAMPLE 13 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3- (4-methylpentyl) -1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P13)
The product was obtained as a yellow solid in 72% yield according to the procedure of example 1, substituting starting materials for 1m, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.15(s,1H),10.34(s,1H),7.26(s,1H),7.10(s,1H),6.93(s,2H),4.69(s,1H),3.82(s,3H),2.33–2.10(m,2H),1.33–1.17(m,2H),1.09–0.98(m,1H),0.89–0.79(m,2H),0.69(dd,J＝7.4,5.2Hz,6H)；13C NMR(101MHz,DMSO–d6)δ161.34,155.00,150.04,142.11,140.76,137.11,136.10,121.07,115.95,114.92,96.93,57.14×2,38.24,36.16,27.50,26.12,25.02,22.69,22.62；HRMS(ESI)m/z calcd C20H24N5O5 +[M+H]+414.1772,found 414.1771.
EXAMPLE 14 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3- (2, 2-dimethylpropyl) -1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P14)
The product was obtained as a yellow solid in 73% yield following the procedure of example 1 substituting starting materials for 1n, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.14(s,1H),10.38(br s,1H),7.20(d,J＝1.3Hz,1H),7.07(s,1H),6.93(s,2H),4.63(s,1H),3.83(s,3H),2.19(d,J＝14.0Hz,1H),1.85(d,J＝14.0Hz,1H),0.80(s,9H)；13C NMR(101MHz,DMSO–d6)δ161.11,154.99,150.03,141.97,138.46,137.25,135.50,120.99,116.13,115.05,97.87,57.52,57.21,38.49,36.78,32.49,29.76×3；HRMS(ESI)m/z calcd C19H22N5O5 +[M+H]+400.1615,found 400.1613.
EXAMPLE 15 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3- (2-cyclopentylethyl) -1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P15)
The product was obtained as a yellow solid with 71% yield according to the procedure of example 1, substituting starting materials for 1o, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.22(s,1H),7.31(s,1H),7.15(s,1H),6.97(s,2H),4.75(s,1H),3.88(s,3H),2.35–2.18(m,2H),1.61–1.40(m,6H),1.39–1.25(m,2H),1.11–0.98(m,1H),0.94–0.80(m,2H)；13C NMR(101MHz,DMSO–d6)δ161.26,155.08,150.05,142.12,140.87,137.13,135.98,121.05,116.04,115.02,96.73,57.23,57.14,36.15,34.63,32.24,32.07,25.14,25.07,25.06,24.14；HRMS(ESI)m/z calcd C21H24N5O5 +[M+H]+426.1772,found 426.1771.
EXAMPLE 16 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3- (2-cyclohexylethyl) -1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P16)
The product was obtained as a yellow solid in 68% yield according to the procedure of example 1, substituting starting materials for 1p, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.16(s,1H),10.29(br s,1H),7.26(s,1H),7.09(s,1H),6.92(s,2H),4.68(s,1H),3.82(s,3H),2.32–2.21(m,1H),2.21–2.11(m,1H),1.59–1.50(m,3H),1.41(dd,J＝25.4,12.4Hz,2H),1.21–1.12(m,1H),1.10–0.97(m,3H),0.93–0.82(m,2H),0.73–0.55(m,2H)；13C NMR(101MHz,DMSO–d6)δ161.33,155.06,150.08,142.13,141.00,137.14,136.01,121.07,116.00,115.04,96.77,57.19,57.13,37.01,36.21,35.66,32.70×2,26.49,26.06,26.03,22.36；HRMS(ESI)m/z calcd C22H26N5O5 +[M+H]+440.1928,found 440.1923.
EXAMPLE 17 Synthesis of 6-amino-4- (3-methoxy-4-hydroxy-5-nitrophenyl) -3- (3-phenylpropyl) -1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P17)
The product was obtained as a yellow solid in 66% yield according to the procedure of example 1, substituting starting materials for 1q, 2 and 3 a.
1H NMR(400MHz,DMSO–d6)δ12.22(s,1H),7.23(s,1H),7.20(d,J＝7.4Hz,2H),7.13(t,J＝7.2Hz,1H),7.06(s,1H),6.99(d,J＝7.4Hz,2H),6.92(s,2H),4.68(s,1H),3.80(s,3H),2.34(t,J＝7.7Hz,2H),2.30–2.13(m,2H),1.70–1.50(m,1H),1.50–1.32(m,1H)；13C NMR(101MHz,DMSO–d6)δ161.28,155.14,150.03,142.18,141.58,140.40,137.07,135.89,128.66×2,128.44×2,126.20,121.05,115.96,114.86,96.93,57.25,57.15,36.11,35.07,29.81,24.60；HRMS(ESI)m/z calcd C23H22N5O5 +[M+H]+448.1615,found 448.1615.
EXAMPLE 18 Synthesis of 6-amino-4- (3-nitro-4-hydroxyphenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P18)
The starting materials were replaced by 1r, 2 and 3b and the product was obtained as a yellow solid in 75% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.16(s,1H),10.89(br s,1H),7.72(d,J＝2.2Hz,1H),7.35(dd,J＝8.6,2.3Hz,1H),7.11(d,J＝8.6Hz,1H),6.92(s,2H),4.69(s,1H),2.22(ddd,J＝15.0,8.5,6.7Hz,1H),2.10(ddd,J＝14.7,8.5,6.5Hz,1H),1.33–1.23(m,1H),1.21–1.11(m,1H),0.64(t,J＝7.3Hz,3H)；HRMS(ESI)m/z calcd C16H16N5O4 +[M+H]+342.1197,found 342.1198.
Example 19.6 Synthesis of amino-4- (3-nitrophenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P19)
The starting materials were replaced by 1r, 2 and 3c and the product was obtained as a yellow solid in 78% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.24(s,1H),8.13(d,J＝7.7Hz,1H),8.03(s,1H),7.67(dt,J＝15.4,7.6Hz,2H),7.04(s,2H),4.89(s,1H),2.26–2.14(m,1H),2.13–2.01(m,1H),1.33–1.03(m,3H),0.60(t,J＝7.3Hz,3H)；HRMS(ESI)m/z calcd C16H16N5O3 +[M+H]+326.1248,found 326.1244.
EXAMPLE 20 Synthesis of 6-amino-4- (3-methoxy-4-hydroxyphenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P20)
The starting materials were replaced by 1r, 2 and 3d and the product was obtained as a yellow solid in 69% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.06(s,1H),8.83(s,1H),6.77(s,2H),6.71(d,J＝0.7Hz,1H),6.69(s,1H),6.55(dd,J＝8.1,1.9Hz,1H),4.49(s,1H),3.70(s,3H),2.20(ddd,J＝14.9,8.5,6.8Hz,1H),2.08(ddd,J＝14.6,8.4,6.5Hz,1H),1.34–1.07(m,2H),0.65(t,J＝7.3Hz,3H)；HRMS(ESI)m/z calcd C17H19N4O3 +[M+H]+327.1452,found 327.1440.
Example 21.6 Synthesis of amino-4- (3, 4-dihydroxyphenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P21)
The starting materials were replaced by 1r, 2 and 3e and the product was obtained as a yellow solid in 72% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.04(s,1H),8.78(br s,1H),8.67(br s,1H),6.73(s,2H),6.63(d,J＝7.9Hz,1H),6.49(d,J＝2.0Hz,1H),6.46(dd,J＝8.0,2.0Hz,1H),4.38(s,1H),2.20(ddd,J＝14.9,8.3,6.9Hz,1H),2.09(ddd,J＝14.6,8.4,6.6Hz,1H),1.31–1.18(m,2H),0.68(t,J＝7.3Hz,3H)；HRMS(ESI)m/z calcd C16H17N4O3 +[M+H]+313.1295,found 313.1296.
Example 22.6 Synthesis of amino-4- (4-hydroxyphenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P22)
The starting materials were replaced by 1r, 2 and 3f and the product was obtained as a yellow solid in 77% yield according to the procedure of example 1.
1H NMR(400MHz,DMSO–d6)δ12.04(s,1H),9.24(s,1H),6.95(d,J＝8.5Hz,2H),6.74(s,2H),6.69(d,J＝8.5Hz,2H),4.47(s,1H),2.18(ddd,J＝14.9,8.4,6.7Hz,1H),2.06(ddd,J＝14.7,8.5,6.5Hz,1H),1.30–1.16(m,2H),0.65(t,J＝7.3Hz,3H)；13C NMR(101MHz,DMSO–d6)δ160.96,156.52,155.14,140.22,135.62,128.91×2,121.29,115.56×2,98.22,58.64,36.22,26.72,21.42,13.81；HRMS(ESI)m/z calcd C16H17N4O2 +[M+H]+297.1346,found 297.1340.
EXAMPLE 23 Synthesis of 6-amino-4- (4-fluorophenyl) -3-propyl-1, 4-dihydropyran [2,3-c ] pyrazole-5-carbonitrile (P23)
The product was obtained as a yellow solid in 78% yield by substituting 1r, 2 and 3g of starting materials for the reaction according to example 1.
1H NMR(400MHz,DMSO–d6)δ12.14(s,1H),7.21(tt,J＝5.0,2.5Hz,2H),7.17–7.10(m,2H),6.88(s,2H),4.64(s,1H),2.22–1.99(m,2H),1.28–1.09(m,2H),0.63(t,J＝7.3Hz,3H)；HRMS(ESI)m/z calcd C16H16FN4O+[M+H]+299.1303,found 299.1304.
Example 24
Test molecules and buffers containing 0.1M phosphate(pH 6.0), 8. mu.M of a mixed solution of 9, 10-phenanthrenequinone and 0.15mM NADPH, incubated at 30 ℃ for 10 minutes, added with recombinant AKR1C3 protein (the recombinant protein was prepared by the method described in chemical-Biological Interactions, 2015, Vol.240, page: 310-
3 multifunctional microplate reader to detect the effect of compounds on the rate of coenzyme NADPH consumption, measured at least three times per molecule. IC for inhibiting AKR1C3 protein activity50Values were calculated by concentration testing and non-linear regression.
The test data of the inhibitory activity of the compound of the present invention on AKR1C3 enzyme are shown in Table 1 (under the same conditions, the inhibitory activity IC of the positive control Meclofenamic acid on AKR1C3 enzyme500.516 μ M):
table 1: data sheet for compounds and for the inhibition activity test of AKR1C3 enzyme (IC)50Unit is mu M)
The results show that the 4-aryl dihydropyrane pyrazole compound has good inhibitory activity on AKR1C3, and has wide application space as AKR1C3 inhibitor; even better than the positive controls meclofenamic acid, especially compounds P1, P7, P8, P9, P10, P15, P16, P17 and P18, in particular compounds P7, P8, P9, P10, P15, P16 and P18, the inhibitory effect on AKR1C3 is significant due to the positive control drugs.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (6)
1. A dihydropyranopyrazole compound having the structure:
2. the dihydropyranopyrazole compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt of the compound according to claim 1 with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, succinic acid, malic acid, or glutamic acid.
3. Use of the dihydropyranopyrazole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of AKR1C3 inhibitors.
4. Use of the dihydropyranopyrazole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of a medicament for the treatment of AKR1C 3-related diseases.
5. The use of claim 4, wherein the AKR1C 3-associated disease is prostate cancer.
6. The use of claim 4, wherein the medicament is in the form of a tablet, pill, capsule, intramuscular injection, intravenous injection, powder for injection, oral liquid, or varnish.
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