CN110016011B - Amide derivative and medical use thereof - Google Patents
Amide derivative and medical use thereof Download PDFInfo
- Publication number
- CN110016011B CN110016011B CN201810009807.XA CN201810009807A CN110016011B CN 110016011 B CN110016011 B CN 110016011B CN 201810009807 A CN201810009807 A CN 201810009807A CN 110016011 B CN110016011 B CN 110016011B
- Authority
- CN
- China
- Prior art keywords
- reference example
- yield
- acid
- referring
- instead
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to an amide compound with an anti-tumor effect, which has a structure shown in a formula I:
in the formula I, X is CH or N; when X is CH, R 1 Is halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; when X is N, R 1 Is H, halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; r 1 And CN is a substituent on the benzene ring or the pyridine ring; the substituted phenyl or pyridyl group is attached to the thiophene ring by a single bond. The compounds have selective inhibition effect on tumor cells.
Description
Technical Field
The present invention relates to amide derivatives having antitumor activity.
Background
Tumors are a serious disease that seriously threatens human health. The cytotoxic drugs have wide anti-tumor spectrum but large toxic and side effects; compared with the traditional cytotoxic antitumor drugs, the selective tyrosine kinase inhibitor antitumor drugs have the advantages of effective oral administration and small toxic and side effects; however, the anti-tumor spectrum is narrow, and drug resistance is easy to generate. How to overcome the toxic and side effects while maintaining the antitumor effect is a bottleneck in the research and development of antitumor drugs.
Chinese invention patent CN106986854A discloses a compound C1 with the structural formula shown below:
the compound shows selective inhibition effect on breast cancer cells, cervical cancer cells and ovarian cancer cells. However, its antitumor activity is yet to be improved.
Disclosure of Invention
The present invention provides amide derivatives of formula I:
in the formula I, X is CH or N; when X is CH, R 1 Is halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; when X is N, R 1 Is H, halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; r 1 And CN is a substituent on the benzene ring or the pyridine ring; substituted phenyl or pyridyl radicalsIs connected to the thiophene ring by a single bond.
The present invention provides amide derivatives of formula Ia:
in the formula Ia, R 1 Is halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; r 1 And CN is a substituent on the benzene ring.
The present invention provides amide derivatives of formula Ib:
in the formula Ib, R 1 Is halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; r 1 And CN is a substituent on the benzene ring.
The present invention provides an amide derivative represented by formula Ic:
in the formula Ic, R 1 Is H, halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; r 1 And CN is a substituent on the pyridine ring.
The present invention provides an amide derivative represented by the formula Id:
in the formula Id, R 1 Is H, halogen, CF 3 Or an alkyl group of 1 to 3 carbon atoms, R 2 Is alkyl with 1-3 carbon atoms; r 1 And CN is a substituent on the pyridine ring.
The amide derivatives provided by the invention are selected from the following structures:
the invention provides a pharmaceutical composition of an amide derivative represented by formula I, ia, ib, ic or Id as an active ingredient, together with one or more pharmaceutically acceptable carriers or excipients.
The invention provides an amide derivative shown as a formula I, ia, ib, ic or Id as an active ingredient, and application of a pharmaceutical composition thereof in preparing an anti-tumor medicament; these pharmaceutical compositions may be in the form of tablets, such as immediate release tablets, sustained release tablets, controlled release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, sublingual tablets, and the like; capsules such as hard capsules, soft capsules, etc.; the injection can be sterile or bacteriostatic aqueous injection, oily injection, lyophilized powder for injection, injection microsphere, etc.
Detailed Description
The following examples are intended to specifically explain the present invention, however, the scope of the present invention is not limited to the following examples. The target compound was prepared according to the following synthetic route:
substituted phenylboronic acid or pyridineboronic acid with 4-bromo-2-thiophenecarboxaldehyde or 5-bromo-2-thiophenecarboxaldehyde in Pd (Ph) 3 P) 4 Under the action, the Suzuki reaction is carried out to prepare a product ia or ib with a benzene ring connected with the 4-position or 5-position of the thiophene ring, or a product ic or id with a pyridine ring connected with the 4-position or 5-position of the thiophene ring; ia. ib, ic or id and substituted malonic acid are respectively condensed by Knoevenagel reaction to prepare propyleneAcid derivatives iia, iib, iic, or iid; iia, iib, iic or iid reacts with thionyl chloride to prepare an acyl chloride intermediate, and the acyl chloride intermediate directly reacts with ammonia water without separation to prepare the target compounds Ia, ib, ic or Id.
Reference example 1 preparation of (E) -2-methyl-3- (4- (4-cyanophenyl) thiophen-2-yl) acrylamide (C1)
Reference example 1.1 preparation of 4- (4-cyanophenyl) -thiophene-2-carbaldehyde (ia-0)
To a mixed solvent of 15mL of dioxane and 5mL of water, 0.38g (2 mmol) of 4-bromo-2-thiophenecarboxaldehyde, 0.36g (2.4 mmol) of 4-cyano-phenylboronic acid and 0.17g of Cs were added in this order with stirring 2 CO 3 (5 mmol), stirred at room temperature for 5 minutes; then 0.12g Pd (Ph) is added 3 P) 4 The reaction mixture was refluxed for 4.5 hours under nitrogen. Cooled to room temperature and 20mL CH added 2 Cl 2 Separating the aqueous layer from CH 2 Cl 2 Extraction (3X 15 mL), combining the organic phases and adding Na 2 SO 4 Drying overnight, filtering to remove solid, evaporating to dryness under reduced pressure, separating the residue by silica gel column chromatography, eluting with mixed solvent of ethyl acetate and petroleum ether (1: 10), collecting the desired components, and evaporating to dryness under reduced pressure to obtain ia-0.34g.
Reference example 1.2 preparation of (E) -2-methyl-3- (4- (4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-0)
To 5ml of pyridine were added 0.21g (1 mmol) of ia-0 and 0.14g (1.2 mmol) of methylmalonic acid, 3 drops of piperidine, and refluxed for 3 hours; after cooling, decompressing and evaporating to dryness; adding 5ml of water, carrying out ice bath, and adding 10M hydrochloric acid with stirring until the pH is =5; extraction with ethyl acetate (3X 10 mL); mixing extractive solutions, and washing with water to neutral. With Na 2 SO 4 Drying overnight, filtering to remove solid, evaporating to dryness under reduced pressure, separating the residue by silica gel column chromatography, eluting with mixed solvent of dichloromethane and methanol petroleum ether (50: 1), collecting the desired components, and evaporating to dryness under reduced pressure to obtain iia-0.15g.
Reference example 1.3 preparation of (E) -2-methyl-3- (4- (4-cyanophenyl) thiophen-2-yl) acrylamide (C1)
To 20mL of dry was added 0.27g (1 mmol) of iia-0,0.1ml of thionyl chloride, 5 drops of DMF and refluxed for 2h; cooling to room temperature, reducingAnd (5) evaporating to dryness under pressure. The residue was dissolved in 20mL of dry THF, stirred in an ice bath and 0.6mL of concentrated aqueous ammonia was added dropwise. Stirred at 0 ℃ for 2h, then poured into 10mL of ice water, extracted with dichloromethane (3X 15 mL) 2 SO 4 Drying overnight, filtering to remove solid, evaporating to dryness under reduced pressure, separating the residue by silica gel column chromatography, eluting with mixed solvent of ethyl acetate and petroleum ether (1: 10), collecting the desired components, and evaporating to dryness under reduced pressure to obtain reference compound C1.13 g. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.31(s，1H)；8.01-7.91(m，4H)；7.85(s，1H)；7.59(br s，1H)；7.53(m，1H)；7.14(br s，1H)；2.14(d，3H)。
EXAMPLE 1 preparation of (E) -2-methyl-3- (4- (3-fluoro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ia-1)
Referring to the method of reference example 1.1, 4- (3-fluoro-4-cyanophenyl) -thiophene-2-carbaldehyde (ia-1) was prepared in 73% yield by reacting 3-fluoro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (4- (3-fluoro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-1) was obtained in 59% yield by reacting ia-1 instead of ia-0 with methylmalonic acid.
Referring to the method of reference example 1.3, iia-1 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ia-1 in 41% yield. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.26(s，1H)；7.91(m，1H)；7.82(s，1H)；7.80(d，1H)；7.73(m，1H)；7.56(br s，1H)；7.52(m，1H)；7.12(br s，1H)；2.13(d，3H)。
Example 2 preparation of (E) -2-methyl-3- (4- (2-fluoro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ia-2)
Referring to the method of reference example 1.1, 4- (2-fluoro-4-cyanophenyl) -thiophene-2-carbaldehyde (ia-2) was prepared in 62% yield by reacting 4-cyano-phenylboronic acid with 2-fluoro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid.
Referring to the method of reference example 1.2, ia-2 was reacted with methylmalonic acid, instead of ia-0, to obtain (E) -2-methyl-3- (4- (2-fluoro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-2) in 48% yield.
Referring to the method of reference example 1.3, iia-2 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without isolation to prepare the target compound Ia-2 in 39% yield. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.27(s，1H)；8.10(m，1H)；7.81(s，1H)；7.66(m，1H)；7.56(br s，1H)；7.50(m，1H)；7.31(d，1H)；7.14(br s，1H)；2.15(d，3H).
Example 3 preparation of (E) -2-methyl-3- (4- (3-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylamide (Ia-3)
Referring to the method of reference example 1.1, 4- (3-trifluoromethyl-4-cyanophenyl) -thiophene-2-carbaldehyde (ia-3) was prepared in 82% yield by reacting 3-trifluoromethyl-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, ia-3 was reacted with methylmalonic acid instead of ia-0 to obtain (E) -2-methyl-3- (4- (3-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-3) in 55% yield.
Referring to the method of reference example 1.3, iia-3 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ia-3 in 31% yield. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.42(d，1H)；8.30(s，1H)；7.92(q，1H)；7.85(s，1H)；7.71(q，1H)；7.57(br s，1H)；7.51(m，1H)；7.15(br s，1H)；2.16(d，3H)。
EXAMPLE 4 preparation of (E) -2-methyl-3- (4- (2-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylamide (Ia-4)
Referring to the method of reference example 1.1, 4- (2-trifluoromethyl-4-cyanophenyl) -thiophene-2-carbaldehyde (ia-4) was prepared in 75% yield by reacting 4-cyano-phenylboronic acid with 2-trifluoromethyl-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (4- (2-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-4) was obtained in 41% yield by reacting ia-4 with methylmalonic acid instead of ia-0.
Referring to the procedure of reference example 1.3, iia-4 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ia-4 in a yield of 26%. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.52(d，1H)；8.29(s，1H)；8.10(q，1H)；7.91(q，1H)；7.84(s，1H)；7.56(br s，1H)；7.52(m，1H)；7.15(br s，1H)；2.17(d，3H)。
Example 5 preparation of (E) -2-methyl-3- (4- (3-chloro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ia-5)
Referring to the method of reference example 1.1, 4- (3-chloro-4-cyanophenyl) -thiophene-2-carbaldehyde (ia-5) was prepared in 69% yield by reacting 3-chloro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, ia-5 was used instead of ia-0 to react with methylmalonic acid to obtain (E) -2-methyl-3- (4- (3-chloro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-5) in 51% yield.
Referring to the method of reference example 1.3, iia-5 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ia-5 in a yield of 32%. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.34-8.31(m，2H)；7.85-7.73(m，3H)；7.59(br s，1H)；7.53(m，1H)；7.14(br s，1H)；2.15(d，3H)。
EXAMPLE 6 preparation of (E) -2-methyl-3- (4- (2-chloro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ia-6)
Referring to the method of reference example 1.1, 4- (2-chloro-4-cyanophenyl) -thiophene-2-carbaldehyde (ia-6) was prepared in 62% yield by reacting 2-chloro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (4- (2-chloro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-6) was obtained in 48% yield by reacting ia-6 instead of ia-0 with methylmalonic acid.
With reference to the method of reference example 1.3, using iia-6Replacing iia-0, reacting with thionyl chloride to obtain an acyl chloride intermediate, and reacting with concentrated ammonia water without separation to obtain the target compound Ia-6 with the yield of 29%. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.25(s，1H)；8.02(q，1H)；7.85(s，1H)；7.81(d，1H)；7.691(s，1H)；7.59(br s，1H)；7.50(m，1H)；7.13(br s，1H)；2.11(d，3H)。
Example 7 preparation of (E) -2-methyl-3- (5- (3-fluoro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ib-1)
Referring to the method of reference example 1.1, 5- (3-fluoro-4-cyanophenyl) -thiophene-2-carbaldehyde (ib-1) was prepared in 80% yield by reacting 3-fluoro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
By reacting ib-1 instead of ia-0 with methylmalonic acid according to the method of reference example 1.2, (E) -2-methyl-3- (5- (3-fluoro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iib-1) was obtained in 53% yield.
Referring to the method of reference example 1.3, the target compound Ib-1 was prepared in 46% yield by reacting with thionyl chloride using iib-1 instead of iia-0 to prepare an acid chloride intermediate, which was then reacted with concentrated aqueous ammonia without separation. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.26(d，1H)；8.01(d，1H)；7.95(m，1H)；7.81(m，1H)；7.68(m，1H)；7.55(br s，1H)；7.50(m，1H)；7.14(br s，1H)；2.14(d，3H).
Example 8 preparation of (E) -2-methyl-3- (5- (2-fluoro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ib-2)
Referring to the method of reference example 1.1, 5- (2-fluoro-4-cyanophenyl) -thiophene-2-carbaldehyde (ib-2) was prepared in 77% yield by reacting 2-fluoro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (5- (2-fluoro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iib-2) was obtained in 46% yield by reacting ib-2 instead of ia-0 with methylmalonic acid.
Referring to the method of reference example 1.3, by using iib-2 instead of iia-0, an acid chloride intermediate was prepared by reacting with thionyl chloride, and a concentrated aqueous ammonia was prepared without separationThe target compound Ib-2, yield 31%. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.30(d，1H)；8.01(d，1H)；7.95(m，1H)；7.81(m，1H)；7.68(m，1H)；7.59(br s，1H)；7.54(m，1H)；7.15(br s，1H)；2.16(d，3H).
Example 9 preparation of (E) -2-methyl-3- (5- (3-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylamide (Ib-3)
Referring to the method of reference example 1.1, 5- (3-trifluoromethyl-4-cyanophenyl) -thiophene-2-carbaldehyde (ib-3) was prepared in 81% yield by reacting 3-trifluoromethyl-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (5- (3-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylic acid (iia-1) was obtained in 48% yield by reacting ib-3 instead of ia-0 with methylmalonic acid.
Referring to the method of reference example 1.3, iib-3 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ib-3 in a yield of 35%. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.43(d，1H)；8.32(d，1H)；8.01(d，1H)；7.86(d，1H)；7.73(q，1H)；7.59(br s，1H)；7.53(m，1H)；7.14(br s，1H)；2.18(d，3H).
Example 10 preparation of (E) -2-methyl-3- (5- (2-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylamide (Ib-4)
Referring to the method of reference example 1.1, 5- (2-trifluoromethyl-4-cyanophenyl) -thiophene-2-carbaldehyde (ib-4) was prepared in 85% yield by reacting 2-trifluoromethyl-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (5- (2-trifluoromethyl-4-cyanophenyl) thiophen-2-yl) acrylic acid (iib-4) was obtained in 47% yield by reacting ib-4 instead of ia-0 with methylmalonic acid.
Referring to the method of reference example 1.3, iib-4 was used instead of iia-0 to react with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ib-4 in 4 yield1 percent. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.49(d，1H)；8.33(d，1H)；8.01-7.92(m，3H)；7.59(br s，1H)；7.53(m，1H)；7.14(br s，1H)；2.14(d，3H).
EXAMPLE 11 preparation of (E) -2-methyl-3- (5- (3-chloro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ib-5)
Referring to the method of reference example 1.1, 5- (3-chloro-4-cyanophenyl) -thiophene-2-carbaldehyde (ib-5) was prepared in 91% yield by reacting 3-chloro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (5- (3-chloro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iib-5) was obtained in 47% yield by reacting ib-5 instead of ia-0 with methylmalonic acid.
Referring to the method of reference example 1.3, iiib-5 was used instead of iia-0, and reacted with thionyl chloride to prepare an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without separation to prepare the target compound Ib-5 in a yield of 35%. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.30-8.27(m，2H)；8.01(d，1H)；7.74-7.71(m，2H)；7.59(br s，1H)；7.53(m，1H)；7.14(br s，1H)；2.18(d，3H).
Example 12 preparation of (E) -2-methyl-3- (5- (2-chloro-4-cyanophenyl) thiophen-2-yl) acrylamide (Ib-6)
Referring to the method of reference example 1.1, 5- (2-chloro-4-cyanophenyl) -thiophene-2-carbaldehyde (ib-6) was prepared in 77% yield by reacting 2-chloro-4-cyano-phenylboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (5- (2-chloro-4-cyanophenyl) thiophen-2-yl) acrylic acid (iib-6) was obtained in 52% yield by reacting ib-6 instead of ia-0 with methylmalonic acid.
Referring to the method of reference example 1.3, the target compound Ib-6 was prepared in 34% yield by reacting with thionyl chloride using iib-6 instead of iia-0 to prepare an acid chloride intermediate, which was then reacted with concentrated aqueous ammonia without separation. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.27(d，1H)；8.01(d，1H)；7.95(m，1H)；7.81(d，1H)；7.67(d，1H)；7.59(br s，1H)；7.50(m，1H)；7.12(br s，1H)；2.16(d，3H).
Example 13 preparation of (E) -2-methyl-3- (4- (6-cyanopyridin-3-yl) thiophen-2-yl) acrylamide (Ic-1)
Referring to the method of reference example 1.1, 4- (6-cyanopyridin-3-yl) -thiophene-2-carbaldehyde (ic-1) was prepared in 62% yield by reacting 6-cyano-3-pyridineboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (4- (6-cyanopyridin-3-yl) thiophen-2-yl) acrylic acid (iic-1) was obtained in 39% yield by reacting ic-1 with methylmalonic acid instead of ia-0.
Referring to the procedure of reference example 1.3, ic-1 was reacted with thionyl chloride instead of iia-0 to give an acid chloride intermediate which was reacted with concentrated aqueous ammonia without isolation to give Ic-1 in 28% yield. Nuclear magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：9.05(d，1H)；8.31(s，1H)；8.28(m，1H)；7.84(s，1H)；7.63(d，1H)；7.57(br s，1H)；7.53(m，1H)；7.16(br s，1H)；2.14(d，3H).
Example 14 preparation of (E) -2-methyl-3- (4- (5-fluoro-6-cyanopyridin-3-yl) thiophen-2-yl) acrylamide (Ic-2)
Referring to the method of reference example 1.1, 4- (5-fluoro-6-cyanopyridin-3-yl) -thiophene-2-carbaldehyde (ic-2) was prepared in 61% yield by reacting 5-fluoro-6-cyano-3-pyridineboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, by reacting ic-2 instead of ia-0 with methylmalonic acid, (E) -2-methyl-3- (4- (5-fluoro-6-cyanopyridin-3-yl) thiophen-2-yl) acrylic acid (iic-2) was obtained in 47% yield.
Referring to the procedure of reference example 1.3, ic-2 was reacted with thionyl chloride in place of iia-0 to give an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without isolation to give Ic-2 in 33% yield. Magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：9.01(s，1H)；8.30(s，1H)；8.09(s，1H)；7.87(s，1H)；7.589(br s，1H)；7.54(m，1H)；7.15(br s，1H)；2.12(d，3H).
Example 15 preparation of (E) -2-methyl-3- (4- (5-trifluoromethyl-6-cyanopyridin-3-yl) thiophen-2-yl) acrylamide (Ic-3)
Referring to the method of reference example 1.1, 4- (5-trifluoromethyl-6-cyanopyridin-3-yl) -thiophene-2-carbaldehyde (ic-3) was prepared in 55% yield by reacting 5-trifluoromethyl-6-cyano-3-pyridineboronic acid instead of 4-cyano-phenylboronic acid with 4-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, (E) -2-methyl-3- (4- (5-trifluoromethyl-6-cyanopyridin-3-yl) thiophen-2-yl) acrylic acid (iic-3) was obtained in 38% yield by reacting ic-3 instead of ia-0 with methylmalonic acid.
Referring to the procedure of reference example 1.3, ic-3 was reacted with thionyl chloride in place of iia-0 to give an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without isolation to give Ic-3 in 45% yield. Magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：9.01(s，1H)；8.30(s，1H)；8.28(s，1H)；7.82(s，1H)；7.56(br s，1H)；7.51(m，1H)；7.11(br s，1H)；2.14(d，3H).
EXAMPLE 16 preparation of (E) -2-methyl-3- (5- (6-cyanopyridin-3-yl) thiophen-2-yl) acrylamide (Id-1)
Referring to the method of reference example 1.1, 5- (6-cyanopyridin-3-yl) -thiophene-2-carbaldehyde (id-1) was prepared in 82% yield by reacting 6-cyano-3-pyridineboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, using id-1 instead of ia-0, reaction with methylmalonic acid gave (E) -2-methyl-3- (5- (6-cyanopyridin-3-yl) thiophen-2-yl) acrylic acid (iid-1) in 41% yield.
Referring to the procedure of reference example 1.3, using iia-1 instead of iia-0, an acid chloride intermediate was prepared by reaction with thionyl chloride, and Id-1 was prepared in 36% yield by reaction with concentrated aqueous ammonia without isolation. Magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：9.00(s，1H)；8.27(d，1H)；8.10(s，1H)；7.97(d，1H)；7.59(br s，1H)；7.54(m，1H)；7.12(br s，1H)；2.15(d，3H).
Example 17 preparation of (E) -2-methyl-3- (5- (5-fluoro-6-cyanopyridin-3-yl) thiophen-2-yl) acrylamide (Id-2)
Referring to the method of reference example 1.1, 5- (5-fluoro 6-cyanopyridin-3-yl) -thiophene-2-carbaldehyde (id-2) was prepared in 65% yield by reacting 5-fluoro-6-cyano-3-pyridineboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the procedure of reference example 1.2, (E) -2-methyl-3- (5- (5-fluoro-6-cyanopyridin-3-yl) thiophen-2-yl) acrylic acid (iid-2) was obtained in 40% yield by reacting id-1 instead of ia-0 with methylmalonic acid.
Referring to the procedure of reference example 1.3, using iia-2 instead of iia-0, an acid chloride intermediate was prepared by reaction with thionyl chloride, and Id-2 was prepared in 31% yield by reaction with concentrated aqueous ammonia without isolation. Magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：8.96(s，1H)；8.26(d，1H)；8.05(s，1H)；8.02(d，1H)；7.55(br s，1H)；7.52(m，1H)；7.13(br s，1H)；2.12(d，3H).
EXAMPLE 18 preparation of (E) -2-methyl-3- (5- (5-trifluoromethyl-6-cyanopyridin-3-yl) thiophen-2-yl) acrylamide (Id-3)
Referring to the procedure of reference example 1.1, 5- (5-trifluoromethyl-6-cyanopyridin-3-yl) -thiophene-2-carbaldehyde (id-3) was prepared in 61% yield by reacting 5-trifluoromethyl-6-cyano-3-pyridineboronic acid instead of 4-cyano-phenylboronic acid with 5-bromo-2-thiophenecarboxaldehyde.
Referring to the method of reference example 1.2, using id-3 instead of ia-0, reaction with methylmalonic acid gave (E) -2-methyl-3- (5- (5-trifluoromethyl-6-cyanopyridin-3-yl) thiophen-2-yl) acrylic acid (iid-3) in 47% yield.
Referring to the method of reference example 1.3, using iid-3 instead of iia-0, reacted with thionyl chloride to produce an acid chloride intermediate, which was reacted with concentrated aqueous ammonia without isolation to produce Id-3 in 25% yield. Magnetic resonance hydrogen spectrum delta (400MHz, DMSO-d) 6 )：9.01(s，1H)；8.29(d，1H)；8.28(s，1H)；8.01(d，1H)；7.56(br s，1H)；7.50(m，1H)；7.13(br s，1H)；2.16(d，3H).
Example 19 evaluation of antitumor Activity in vitro
The antitumor activity of the target compound was evaluated by measuring the cytotoxicity of breast cancer cells (MCF-7), cervical cancer cells (HeLa), ovarian cancer cells (H08910), lung cancer cells (A549), bladder cancer cells (T24), gastric cancer cells (BGC-823) and mouse embryonic fibroblasts (NIH 3T 3).
Each 100. Mu.l of the tumor cell suspension (cell number: 5X 10) 4 ) Inoculating into 96-well plate, placing CO 2 Incubating in an incubator until the cell density reaches 80%, discarding the culture solution, adding new culture solution containing drugs to be detected with different concentrations, and setting 3 parallel holes; the culture medium was changed every 2 days. On day 3 post-dose, add 5mg/mL thiazole blue (MTT) solution 10. Mu.L/well, continue incubation at 37 ℃ for 4h, discard solution, add 100. Mu.L DMSO per well, shake at room temperature for 10min to dissolve MTT crystals completely. Measuring the absorbance of each hole by the enzyme-linked immunosorbent assay detector at the wavelength of 550nm, and calculating the inhibition rate according to the formula:
inhibition (%) = (solvent group OD value-administration group OD value)/solvent group OD value) × 100%
Results are expressed as mean ± SD, n =3.
The half Inhibitory Concentration (IC) of each test substance on the growth of various tumor cells was calculated by SPSS software 50 )。
TABLE 1 evaluation results of in vitro antitumor Activity
Claims (7)
1. An amide derivative selected from the structures:
2. a pharmaceutical composition comprising the amide derivative as claimed in claim 1 as an active ingredient, together with one or more pharmaceutically acceptable carriers or excipients.
3. Use of an amide derivative as claimed in claim 1 for the manufacture of a medicament for the treatment of cancer.
4. Use of an amide derivative Ia-1, ia-3, ic-3 or Id-3 according to claim 1 for the preparation of a medicament for the treatment of a cancer selected from breast cancer, ovarian cancer, cervical cancer.
5. Use of an amide derivative Ia-1, ia-3, ic-3, id-3 or Ib-3 as claimed in claim 1 in the manufacture of a medicament for the treatment of a cancer selected from breast cancer.
6. Use of an amide derivative Ia-1, ia-3, ic-3 or Id-3 as claimed in claim 1 for the preparation of a medicament for the treatment of a cancer selected from ovarian cancer.
7. Use of an amide derivative Ia-1, ia-3, ic-3, id-3 or Ic-2 according to claim 1 for the preparation of a medicament for the treatment of a cancer selected from cervical cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810009807.XA CN110016011B (en) | 2018-01-05 | 2018-01-05 | Amide derivative and medical use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810009807.XA CN110016011B (en) | 2018-01-05 | 2018-01-05 | Amide derivative and medical use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110016011A CN110016011A (en) | 2019-07-16 |
| CN110016011B true CN110016011B (en) | 2023-02-03 |
Family
ID=67187292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810009807.XA Active CN110016011B (en) | 2018-01-05 | 2018-01-05 | Amide derivative and medical use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110016011B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112245424B (en) * | 2020-10-19 | 2021-09-21 | 中国医学科学院医药生物技术研究所 | Application of bisabolane sesquiterpene structural analogue in preparation of anti-coronavirus medicines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986854B (en) * | 2016-01-21 | 2019-02-01 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of bisabolane sequiterpene analogue and the preparation method and application thereof |
-
2018
- 2018-01-05 CN CN201810009807.XA patent/CN110016011B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110016011A (en) | 2019-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106916101A (en) | Double target spot inhibitor of NAMPT/HDAC and preparation method thereof | |
| WO2018086547A1 (en) | 2-substituted aromatic ring-pyrimidine derivative, and preparation and application thereof | |
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| CN108864111A (en) | A kind of Tr*ger ' s base class compound and the preparation method and application thereof containing benzimidazole | |
| CN110372703A (en) | Five-ring heterocycles miazines compound and application thereof | |
| CN110016011B (en) | Amide derivative and medical use thereof | |
| CN114751891A (en) | (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound and application thereof | |
| CN110156735B (en) | Formononetin derivative and preparation method and application thereof | |
| CN113563340B (en) | Matrine pyrimidine derivative and preparation method and application thereof | |
| CN108864089B (en) | Indolopyridone drug molecule and preparation method and application thereof | |
| WO2022089604A1 (en) | New crystalline forms of a kras g12c inhibitor compound | |
| CN105906678B (en) | Fluorine substitution triazole norcantharidin derivative of structure containing glucoside and preparation method and application | |
| EP4063361A1 (en) | Crystal forms of fused ring compound, and composition thereof, preparation method therefor and application thereof | |
| CN104211712B (en) | Artemisinin derivative containing heteroaryl piperidine, its preparation method and application | |
| CN101139305B (en) | 4'-amido diphenyl ethylene alkyl derivative | |
| CN106967146A (en) | Oleanolic acid terazole derivatives and its production and use | |
| CN112209884B (en) | 1-H benzimidazole derivative, preparation method and application thereof | |
| CN106083967B (en) | Triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof | |
| CN106083966B (en) | Fluorine replaces triazole norcantharidin derivative of structure containing galactoside and the preparation method and application thereof | |
| CN112898271B (en) | N- (pyridine-3-yl) pyrrolidine-2-formamide compound and preparation method and application thereof | |
| CN117069696B (en) | Double-target small molecule inhibitor and preparation method and application thereof | |
| WO2019115709A1 (en) | Mitochondrial inhibitors for the treatment of proliferation disorders | |
| CN115109083B (en) | Pyridostatin compound, preparation method and application thereof, and pharmaceutical composition | |
| CN114031623B (en) | C 14 Amino-substituted tetrandrine derivative and preparation and application thereof | |
| CN115572247B (en) | Vitamin K 3 Derivatives and medical use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20201118 Address after: 100070 Beijing Fengtai District Branch Road No. nine Room 303 Applicant after: BEIJING MEIBEITA DRUG RES Co.,Ltd. Address before: 225300 new drug development base 1, drug Town Road, Taizhou, Jiangsu two phase D building 707. Applicant before: TAIZHOU HUAYUAN MEDICINAL TECH Co.,Ltd. |
|
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |