CN113272295A - Piperazinone-containing quinazoline dione compound, preparation method, pharmaceutical composition and application thereof - Google Patents
Piperazinone-containing quinazoline dione compound, preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- CN113272295A CN113272295A CN201980088459.2A CN201980088459A CN113272295A CN 113272295 A CN113272295 A CN 113272295A CN 201980088459 A CN201980088459 A CN 201980088459A CN 113272295 A CN113272295 A CN 113272295A
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- Prior art keywords
- substituted
- unsubstituted
- membered aromatic
- straight
- aromatic heterocycle
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- -1 quinazoline dione compound Chemical class 0.000 title claims abstract description 77
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 32
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 229910052794 bromium Inorganic materials 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 16
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 claims description 9
- 101710144590 Poly [ADP-ribose] polymerase 2 Proteins 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 6
- 150000008515 quinazolinediones Chemical class 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
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- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
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- GHEFZYZTGHKBBI-UHFFFAOYSA-N methyl 5-(bromomethyl)-2-fluorobenzoate Chemical class COC(=O)C1=CC(CBr)=CC=C1F GHEFZYZTGHKBBI-UHFFFAOYSA-N 0.000 claims description 4
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
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- MLPMRZNSRNHAOY-UHFFFAOYSA-N 3-[(2,4-dioxoquinazolin-1-yl)methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CN2C(NC(=O)C3=CC=CC=C32)=O)=C1 MLPMRZNSRNHAOY-UHFFFAOYSA-N 0.000 claims description 2
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 2
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
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Abstract
The invention relates to a piperazinone-containing quinazoline-2, 4-dione salt compound as a PARP1/2 inhibitor and a preparation method thereof, a pharmaceutical composition containing the compound, and combined application of the compound as a medicament, in particular as an anti-tumor medicament or as a tumor medicament sensitizer and an anti-tumor medicament.
Description
The invention relates to a piperazinone-containing quinazoline-2, 4-dione salt compound as a PARP1/2 inhibitor and a preparation method thereof, a pharmaceutical composition containing the compound, and combined application of the compound as a medicament, in particular as an anti-tumor medicament or as a tumor medicament sensitizer and an anti-tumor medicament.
Polyadenylated Ribose (Poly ADP Ribose Polymerase, PARP) is widely present in eukaryotic cells and is a cellular ribozyme capable of catalyzing nuclear saccharification of Poly ADP. The enzyme was first reported by Chambon et al in 1963 and has important functions of maintaining the integrity of chromosome structure, participating in the replication and transcription of DNA, and maintaining gene stability [ D' Amours D.Et al. Biochemical Journal,1999,342, 249-268 ]. The PARP family contains at least 17 subtypes, of which PARP-1 is the most widely studied. [ Ame J.C.et al.Bioessays,2004,26, 882-. Most chemotherapy drugs have the effect of killing tumor cells by directly or indirectly damaging DNA chains, and the inhibition of the activity of PARP-1 can effectively block the repair of damaged DNA, so that the chemotherapy drugs and the drugs have a synergistic anti-tumor effect. PARP-1 inhibitors are more sensitive to cells with mutations in the genes susceptible to breast cancer (BRCA-1, BRCA-2) and can be used alone for the treatment of BRCA-mutated tumors [ Bryant, H.E.et al.Nature 2005,434,913 ] 917].
Among the PARP families, PARP-2 and PARP-1 have the highest homology [ Kutuzov, M.M.et al.molecular Biology 48,485-495 ]. It is both similar and different from PARP-1 in biological function. Like PARP-1, PARP-2 is also activated by damaged DNA [ Ame, J.C.et al.J Biol Chem 1999,274,17860-8 ]. Through observation of a PARP-2 gene knockout model, mice are found to have increased sensitivity to ionizing radiation and methylation reagents and increased genomic instability. In addition, PARP-2 also has unique physiological functions. Downregulation of the PARP-2 gene prevents cardiomyocyte hypertrophy [ Geng, B.et al. Biochemical and Biophysical Research Communications 430,944-950 ]. In mouse models of colitis, deletion of the PARP-2 gene improves inflammatory conditions and promotes the restoration of colon function [ Popoff, I.et. al. journal of Pharmacology and Experimental Therapeutics 2002,303,1145-1154 ].
Most PARP-1 inhibitors known at present also have inhibitory effect on PARP-2 and the activity is comparable. Until now, three PARP-1/2 inhibitors, olaparib, licarpanib and nilapanib, have been marketed as antitumor agents in 2014, 2016 and 2017, respectively [ Nature Reviews Drug Discovery,2017,16, 229; lin k.y.et al.cell,2017,169,183; nature Biotechnology,2017,35,398 ].
Compared with an original compound without salt, the compound has better in-vivo antitumor activity and oral bioavailability, and aims to provide a new and better substance basis for treating diseases related to PARP-1/2.
Disclosure of Invention
The invention aims to provide a piperazinone-containing quinazoline-2, 4(1H,3H) -dione salt derivative shown in formula I, a preparation method thereof, a pharmaceutical composition, application thereof in preparation of PARP-1/2 inhibitor and potential drugs thereof, and application thereof in preparation of antitumor drugs or antitumor drug sensitizers.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides piperazinone-containing quinazoline dione salt derivatives shown in a general formula I:
in the formula I, the compound is shown in the specification,
R 1、R 2、R 3、R 4and R5Independently selected from H, F, Cl, Br;
R 6selected from the following atoms or groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, C1-4 straight chain or branched chain alkyl, cyclopropyl, cyclopropylmethylene and cyclobutyl, wherein Ar is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched chain alkyl, halogen-substituted C1-4 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or poly-substitutedSubstitution; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-to 8-membered rings, substituted or unsubstituted azacycloalkyl with 3-to 8-membered rings, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
m is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
In the general formula I, R is5Independently preferably from F.
Preferred compounds of the present invention according to formula I of the present invention include, but are not limited to, compounds represented by formula I-A:
in the formula I-A, the compound of formula I-A,
R 1、R 2、R 3and R4Independently selected from H, F, Cl, Br;
R′ 6selected from the following atoms or groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, C1-4 straight chain or branched chain alkyl, cyclopropyl, cyclopropylmethylene and cyclobutyl, wherein Ar is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched chain alkyl, halogen-substituted C1-4 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said benzene ring containsThe nitrogen hexabasic aromatic heterocycle and the pentabasic aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-to 8-membered rings, substituted or unsubstituted azacycloalkyl with 3-to 8-membered rings, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
m is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
In the general formula I-A, R is1、R 2、R 3、R 4Independently preferably from H, F.
Preferred compounds of the present invention according to formula I of the present invention include, but are not limited to, compounds represented by formula I-B:
in the formula I-B, the compound of formula I-B,
R 1、R 2、R 3、R 4independently selected from H, F, Cl, Br;
ar is selected from the group consisting of atoms or groups or structural fragments comprising
Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
m is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
In the general formula I-B, R is1、R 2、R 3、R 4、R 5Independently preferably from H, F.
For the purposes of the present invention, preferred compounds include, but are not limited to:
1- (3- (4-Pentane-3' -yl-3-oxopiperazine) -1-formyl-4-fluoro-benzyl) quinazoline-2, 4(1H,3H) -dione sodium salt
In a second aspect of the present invention, there is provided a process for the preparation of a compound of the first aspect, which comprises the steps of: r1-R 4Substituted different quinazolinediones and containing R5The substituted 3-methoxycarbonylbromobenzyl respectively undergoes selective alkylation reaction under the action of HMDS, and contains R after hydrolysis1-R 5The substituted different 3- ((2, 4-dioxo-3, 4-dihydroquinazolin-1 (2H) -yl) methyl) benzoic acid is then reacted with a compound comprising R6Piperidones of (A)Condensing the derivative to obtain a 1-benzyl quinazoline diketone compound, and finally carrying out acid-base reaction with different bases to obtain a base addition salt of the 1-benzyl quinazoline diketone compound. Wherein R is1、R 2、R 3、R 4、R 5、R 6M is as defined for the compound according to the first aspect of the invention.
The reagent and the reaction condition are (a) urea, 140 ℃ and 6 h; (b) i) lithium Hexamethyldisilazide (HMDS), concentrated sulfuric acid, toluene, reflux, 2h, ii) substituted methyl 5- (bromomethyl) -2-fluorobenzoate, 145 ℃,3h, iii) methanol, hexane, 70 ℃,30 min; (c) LiOH, MeOH, H2O, THF,55 ℃ and 2 h; (d)2- (7-azobenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), 1-Hydroxybenzotriazole (HOBT), Diisopropylethylamine (DIEA), DMF (N, N-dimethylformamide), overnight; (e) MOH/H2O/40℃；
Wherein R is1、R 2、R 3、R 4、R 5、R 6And M is as defined for the compounds according to the first aspect of the invention.
In addition, the starting materials and intermediates in the above reactions are readily available, and the reactions in each step can be readily synthesized according to reported literature or by conventional methods in organic synthesis to those skilled in the art. The compounds of formula I may exist in the form of solvates or non-solvates, and crystallization using different solvents may give different solvates.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier.
The composition comprises at least one compound of the invention and a pharmaceutically acceptable carrier. The medicine composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various particle delivery systems. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable dosage range per day for a compound of the invention is from 0.1 to 1000mg/Kg body weight, preferably from 1 to 500mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The fourth aspect of the technical scheme of the invention provides an application of the compound of the first aspect of the invention in preparing PARP-1/2 inhibitor, in preparing a medicament for preventing and/or treating diseases related to PARP-1/2, in preparing an anti-tumor medicament, and in preparing a medicament for treating diseases related to tumor, wherein the tumor is selected from melanoma, gastric cancer, lung cancer, breast cancer, renal cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, and glioma.
The beneficial technical effects are as follows:
the compound of the patent application shows very strong in-vivo anti-tumor activity at low dose; and the compounds of the present patent application have higher oral bioavailability compared to the non-salified compounds.
The present invention will be further illustrated with reference to the following examples, but the scope of the present invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or High Resolution Mass Spectrometry (HRMS). NMR was measured using a Varian marcry 300 or Varian marcry 400 solvent in CDCl3、DMSO-d 6、acetone-d 6、CD 3OD, internal standard TMS, chemical shifts are given in ppm. m.p. is the melting point given in ° c, the temperature is uncorrected. Silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.
List of abbreviations:
TLC, thin layer chromatography;
CDCl 3: deuterated chloroform; DIEA: diisopropylethylamine; TFA: trifluoroacetic acid; TEA: triethylamine
DMF: n, N-dimethylformamide; THF: tetrahydrofuran; PE: petroleum ether; EA: ethyl acetate
min: the method comprises the following steps of (1) taking minutes; r.t. room temperature; DCM: dichloromethane; h: hours; et (Et)3N: triethylamine
EDC or EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
NBS: n-bromosuccinimide; DMAP: 4-dimethylaminopyridine
AIBN: azobisisobutyronitrile; boc: tert-butyloxycarbonyl radical
HMDS: lithium hexamethyldisilazide
HBTU: o-benzotriazole-tetramethylurea hexafluorophosphate
HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid;
Et 3n: triethylamine; HOBt: 1-hydroxybenzotriazole;NaH: sodium hydride;
CCl 4: carbon tetrachloride; DMSO-d6: deuterated dimethyl sulfoxide; acetone-d6: deuterated acetone
CD 3OD: deuterated methanol; TMS: tetramethyl silicon
Preparation of an intermediate:
preparation of (mono) 5- ((2, 4-dioxo-3, 4-dihydroquinazolin-1 (2H) -yl) methyl) -2-fluorobenzoic acid
a) 2-fluoro-5-bromomethylbenzoic acid methyl ester
Methyl 2-fluoro-5-methylbenzoate (6.72g,40mmol) was added to the reaction flask, CCl was added4(100mL), NBS (7.47g,42mmol), AIBN (1.29g,8mmol), acetonitrile (20mL), heated to reflux, stopped after 1.5h, DCM (100mL) was added, washed with saturated NaCl (50mL × 3), dried over anhydrous magnesium sulfate, and column chromatographed (EA: P ═ 1:150) to give 6.4g of a white solid in 65% yield.
1H NMR(300MHz,CDCl 3)δ(ppm):7.96-7.99(1H,m),7.53-7.58(1H,m),7.10-7.17(1H,m),4.48(2H,s),3.94(3H,s).
b)5- ((2, 4-dioxo-3, 4-dihydroquinazolin-1 (2H) -yl) methyl) -2-fluorobenzoic acid methyl ester
Adding quinazoline-2, 4(1H,3H) -diketone (2g,12.3mmol) into a reaction bottle, adding toluene (40mL), adding HMDS (10.4mL,61.6mmol) and concentrated sulfuric acid (20 drops), heating and refluxing for reaction, clarifying a reaction solution after 5H, concentrating, adding methyl 2-fluoro-5-bromomethylbenzoate into reaction residues, heating to 140 ℃ for reaction, stopping the reaction after 4H, cooling to 100 ℃, adding dioxane (15mL) and methanol (10mL), stirring at 70 ℃ for 30min, cooling to 0 ℃, and performing suction filtration to obtain 3.3g of white solid with the yield of 81.8%.
1H NMR(300MHz,DMSO-d 6)δ(ppm):11.47(brs,1H),8.02(d,J＝5.7Hz,1H),7.86(d,J＝4.5Hz,1H),7.66(t,J＝5.7Hz,1H),7.58-7.61(m,1H),7.23-7.34(m,3H),5.34(s,2H),3.83(s,3H)；m.p.212-214℃.
c) Methyl 5- ((2, 4-dioxo-3, 4-dihydroquinazolin-1 (2H) -yl) methyl) -2-fluorobenzoate (2g,6.1mmol) was added to methanol (30mL), THF (15mL), lithium hydroxide (421mg,18.3mmol) was dissolved in water (15mL) and added to a reaction flask, the temperature was raised to 50 ℃ for reaction, the reaction was stopped after 30min, concentration was carried out, the aqueous layer was adjusted to pH 2 with dilute HCl solution, suction filtration was carried out, and the filter cake was washed with water to give 1.4g of a white solid in 73.2% yield.
1H NMR(300MHz,DMSO-d 6)δ(ppm):13.31(s,1H),11.76(s,1H),8.02(d,J＝5.7Hz,1H),7.82(d,J＝4.2Hz,1H),7.66(t,J＝5.7Hz,1H),7.55-7.57(m,1H),7.23-7.31(m,3H),5.33(s,2H).m.p.>250℃
Preparation of (di) N-benzyloxycarbonyl-3-oxopiperazines
Piperazine 2-one (1g,10mmol) was added to ethyl acetate (40mL), water (20mL), and K was added with stirring at room temperature2CO 3(6.9g,50mmol), benzyloxycarbonyl chloride (2.1mL,15mmol) was added dropwise to the reaction flask, and after completion of the addition, the reaction was stirred at room temperature, and the reaction was stopped the next day, followed by separation, washing of the organic layer with 20 mL. times.2 of a saturated NaCl solution, drying over anhydrous magnesium sulfate, and column chromatography (D: M75: 1) gave 1.4g of a white solid in 59.8% yield.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.32-7.40(m,5H),6.94(brs,1H),5.16(s,2H),4.16(s,2H),3.70(t,J＝4.8Hz,2H),3.40(brs,2H)
Example 1
1- (3- (4-Pentane-3' -yl-3-oxopiperazine) -1-formyl-4-fluoro-benzyl) quinazoline-2, 4(1H,3H) -dione sodium salt
a) Benzyl 4-pentyl 3' -yl-3-oxopiperazine-1-carboxylate
N-benzyloxycarbonyl-3-oxopiperazine (8g,10.25mmol) was added to DMF (80mL), NaH (2.7g,68.33mmol) was added at room temperature under an argon atmosphere, the mixture was stirred at room temperature for 1h, 3-bromopentane (10.56mL,84.29mmol) was added, the reaction was warmed to 50 ℃ and stopped after 3d, water was added, extraction was performed with 200mL of ethyl acetate, the organic layer was washed with a saturated NaCl solution (50 mL. times.2), dried over anhydrous magnesium sulfate, and column chromatography was performed to give 4.6g of a product with a yield of 44.3%.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.28-7.36(m,5H),5.16(s,1H),4.45-4.50(m,1H),4.19(s,2H),3.68(t,J＝5.2Hz,2H),3.16(brs,2H),1.35-1.58(m,4H),0.85(t,J＝7.6Hz,6H),
b) 1-Pentane-3' -ylpiperazin-2-ones
Benzyl 4-pentyl 3' -yl-3-oxopiperazine-1-carboxylate (4.5g), EtOH (60mL), 10% Pd/C (1.35g) were added, hydrogenation was carried out at normal temperature and pressure for 4h, the reaction was stopped, and the mixture was filtered and concentrated to give 2.5g of a colorless oil with a yield of 99.6%.
c)1- (3- (4-Pentane-3' -yl-3-oxopiperazine) -1-formyl-4-fluoro-benzyl) quinazoline-2, 4(1H,3H) -dione (Compound P)
To 5- ((2, 4-dioxo-3, 4-dihydroquinazolin-1 (2H) -yl) methyl) -2-fluorobenzoic acid (3.14g,10mmol), DMF (60mL), EDC (3.84g,20mmol), HOBt (2.7g,20mmol), DIEA (5.23mL,30mmol) and the compound 1-pentan-3' -ylpiperazin-2-one (2.5g,14.7mmol) were added, the reaction was stirred at room temperature, stopped the next day, water was added, extraction was performed with a mixture of MeOH: DCM ═ 1:10, the organic layer was washed with water (50mL × 2), a saturated NaCl solution (50mL × 2), dried over anhydrous magnesium sulfate, recrystallized from ethyl acetate, methanol and n-hexane to give 3.25g of the product, and the total yield was 69.7%.
1H-NMR(400MHz,CDCl 3)δ(ppm):10.80(s,0.4H),10.67(s,0.6H),8.46(d,J＝6.8Hz,1H),7.69-7.81(m,3H),7.32-7.39(m,2H),7.04(t,J＝9.2Hz,1H),4.42-4.51(m,2H),4.28(s,2H),4.04(s,1H),3.96(s,1H),3.52(s,1H),3.24(t,J＝5.2Hz,1H),3.11(s,1H),1.37-1.59(m,4H),0.82-0.86(m,6H).
d)1- (3- (4-Pentane-3' -yl-3-oxopiperazine) -1-formyl-4-fluoro-benzyl) quinazoline-2, 4(1H,3H) -dione sodium salt (Compound from example 1)
The compound 1- (3- (4-pentane-3' -yl-3-oxopiperazine) -1-formyl-4-fluoro-benzyl) quinazoline-2, 4(1H,3H) -dione (1g,2.14mmol) was placed in a reaction flask, NaOH (93.3mg,2.33mmol) was dissolved in 2mL water, added to the reaction flask, warmed to 40 ℃ for reaction for 1H until the reaction solution was clear, concentrated to dryness, dissolved with ethyl acetate and a small amount of methanol, filtered, the filtrate was concentrated, and recrystallized with ethyl acetate, methanol and n-hexane to give 720mg of a white solid with a yield of 68.9%.
1H-NMR(400MHz,DMSO-d 6)δ(ppm):7.87-7.91(m,1H),7.35-7.45(m,2H),7.22-7.30(m,2H),6.97-7.03(m,2H),5.27(s,2H),4.17-4.27(m,2H),3.80-3.83(m,1H),3.19-3.21(m,1H),2.94-2.97(m,1H),2.49-2.51(m,2H),1.09-1.47(m,4H),0.74(t,J＝7.6Hz,6H).
Pharmacological experiments:
experimental example 1: animal in vivo pharmacodynamic experiment:
(one) inhibitory Effect of the Compound of example 1 on human Breast cancer MDA-MB-436 subcutaneous transplantation tumor
The experimental method comprises the following steps:
1. step (ii) of
Collecting human breast cancer MDA-MB-436 tumor cells under aseptic condition, adjusting cell density to 1 × 10 with sterilized normal saline7Taking 0.2ml per ml, inoculating to the subcutaneous layer of the axillary back of the nude mouse, taking out under aseptic condition when the tumor grows to the size of 1cm in diameter, cutting into tumor blocks of 1mm multiplied by 1mm, and uniformly inoculating to the subcutaneous layer of the axillary back of the nude mouse. 7 days later, the tumor grows to 100-300 mm3Thereafter, animals were randomized and dosing was initiated (day 0). Olaparib and the compound of example 1 were administered orally daily. Body weights were weighed twice weekly and tumor lengths and widths were measured with a vernier caliper, nude mice were dislocated 23 days after dosing, tumor tissues were stripped off, and weighed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.
2. Grouping
A blank control group, a positive drug oarapanib group (100mg/kg), an example 1 compound (1.1mg/kg) group, an example 1 compound (3.3mg/kg) group and an example 1 compound (10mg/kg) group.
3. Pharmaceutical formulation
Olaparib was suspended in 0.5% sodium carboxymethylcellulose solution and the compound of example 1 was dissolved in sterile water.
4. Calculation method
Tumor Volume (TV): v1/2 × a × b2And a and b represent tumor length and width, respectively.
And (3) tumor inhibition rate: inhibition (%) is (1-T/C) × 100, T is the treatment group TV or tumor weight, C is the negative control group TV or tumor weight.
The experimental results are as follows:
the compound of example 1 has significant inhibitory activity against human breast cancer MDA-MB-436, and the results are shown in Table 1.
TABLE 1 growth inhibition of human breast cancer MDA-MB-436 by the compound of example 1 in subcutaneous xenograft tumors in nude mice
P <0.01 in comparison with control group
NA is not applicable
EXAMPLE 1 inhibition of the Primary Compound P on human Breast cancer MDA-MB-436 subcutaneous transplantation tumor in nude mice
The experimental method comprises the following steps:
1. step (ii) of
Collecting human breast cancer MDA-MB-436 tumor cells under aseptic condition, adjusting cell density to 1 × 10 with sterilized normal saline7Taking 0.2ml per ml, inoculating to the subcutaneous layer of the axillary back of the nude mouse, taking out under aseptic condition when the tumor grows to the size of 1cm in diameter, cutting into tumor blocks of 1mm multiplied by 1mm, and uniformly inoculating to the subcutaneous layer of the axillary back of the nude mouse. 7 days later, the tumor grows to 100-300 mm3Thereafter, animals were randomized and dosing was initiated (as secondDay 0). Olaparib and compound P were administered orally daily. Body weights were weighed twice weekly and tumor lengths and widths were measured with a vernier caliper, and 18 days after dosing nude mice were dislocated and sacrificed, tumor tissues were stripped off, and weighed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.
2. Grouping
A blank control group, a positive drug olaparib group (100mg/kg), a compound P (25mg/kg) group, a compound P (50mg/kg) group, and a compound P (100mg/kg) group.
3. Pharmaceutical formulation
All compounds were suspended in 0.5% sodium carboxymethyl cellulose solution.
4. Calculation method
Tumor Volume (TV): v1/2 × a × b2And a and b represent tumor length and width, respectively.
And (3) tumor inhibition rate: inhibition (%) is (1-T/C) × 100, T is the treatment group TV or tumor weight, C is the negative control group TV or tumor weight.
The experimental results are as follows: compound P can inhibit MDA-MB-436 tumor growth in a dose-dependent manner.
TABLE 2 growth inhibition of human breast cancer MDA-MB-436 in nude mice subcutaneous xenograft tumor by Compound P
P <0.001 in comparison with control group
NA is not applicable
Experimental example 2 drug experiment
Experimental methods
1. Establishment of plasma sample Standard Curve
Example 1 a prototype compound P stock solution (2.5mg/mL) was diluted with acetonitrile containing propranolol as an internal standard to working solutions at concentrations of 5, 10, 25, 50, 100, 250, 500, 1000 ng/mL.
30 μ L of the working solution of the prototype compound of example 1 and 30 μ L of acetonitrile containing an internal standard (propranolol, 0.2 μ g/mL) were added to 30 μ L of blank mouse plasma, and centrifuged (14000 rpm. times.5 min) twice after the mixing and spinning, and 5 μ L of the supernatant was taken for LC/MS/MS analysis.
2. Plasma pharmacokinetic study of mice orally/intravenously injected with prototype Compound P of example 1 and Compound of example 1
Example 1 prototype compound P and example 1 compound were formulated as a 2.5mg/mL suspension with 0.5% CMC (containing tween) for oral administration and example 1 compound was formulated as a 0.25mg/mL solution with 10% DMSO saline for intravenous injection.
26 mice were orally administered with 5 mice per group and 3 mice per group in the venous group, and a stepwise blood sampling method was used. Fasting is carried out for 12h before administration, and water is freely drunk. Mice were bled from the orbital venous plexus 5, 15, 30min, 1,2, 4, 6,8, 12h after oral administration of the prototype compound of example 1 and the compound of example 1 (25 mg/kg). Mice were bled from the orbital venous plexus 2, 5, 15, 30min, 1,2, 4, 6,8, 12h after intravenous injection of the compound of example 1 (2.5mg/10 mL/kg). 30 mu L of plasma is separated, 60 mu L of acetonitrile containing the internal standard propranolol is added, after the mixed rotation, the plasma is centrifuged (14000rpm is multiplied by 5min) twice, and 5 mu L of supernatant is taken for LC/MS/MS analysis. The reticle samples were measured after dilution.
LC/MS/MS conditions
A chromatographic column: zomax C18(100 mm. times.2.1 mm, 3.5 μm); column temperature: at the temperature of 37 ℃ and the like,
mobile phase: an acetonitrile/water (containing 0.1% formic acid) gradient; flow rate: 0.2 mL/min; MRM positive ion mode detection m/z 467.2 → 304.9(YHP1318), m/z 260 → 183 (internal propranolol).
4. Data analysis
Plasma pharmacokinetic parameters were calculated using WinNonlin software.
The experimental results are as follows:
1. plasma sample standard curve
According to LC/MS/MS spectra of each sample, the peak area ratio of the compound to be detected and the internal standard is taken as the ordinate, the concentration of the compound to be detected is taken as the abscissa, correlation analysis is carried out, the correlation relationship between the concentration of the prototype compound P (5-1000ng/mL) in the example 1 in the plasma sample and the peak area ratio of the chromatogram is good, and the correlation coefficient is more than 0.99.
2. Plasma pharmacokinetic study of mice orally/intravenously injected with prototype Compound P of example 1 and Compound of example 1
The pharmacokinetic parameters of the mice after oral and intravenous injection of prototype compound P of example 1 and example 1 are shown in table 3. The bioavailability of the compound of example 1 orally in mice was higher than that of its prototype compound P.
TABLE 3 plasma pharmacokinetic parameters of oral and intravenous injection of the Compound of example 1 and Compound P in mice
Claims (11)
- The piperazinone-containing quinazoline diketone salt compound shown in the general formula I,
in the formula I, the compound is shown in the specification,R 1、R 2、R 3、R 4and R5Independently selected from H, F, Cl, Br;R 6selected from the following atoms or groups or structural fragments:(1) hydrogen, substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, wherein Ar isIndependently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-to 8-membered rings, substituted or unsubstituted azacycloalkyl with 3-to 8-membered rings, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;(3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;m is independently selected from alkali metals or alkaline earth metals. - The piperazinone-containing quinazolinedione salt compounds of claim 1, wherein said quinazolinedione salt compounds are represented by formula IA,
in the formula IA,R 1、R 2、R 3and R4Independently selected from H, F, Cl, Br;R′ 6selected from the following atoms or groups or structural fragments:(1) hydrogen, substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar wherein Rc is1、Rc 2、Rc 3、Rd 1Is independently selected fromH. C1-4 straight chain or branched chain alkyl, cyclopropyl, cyclopropylmethylene and cyclobutyl, wherein Ar is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched chain alkyl, halogen-substituted C1-4 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-to 8-membered rings, substituted or unsubstituted azacycloalkyl with 3-to 8-membered rings, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORc1、SRc 2、NRc 3Rd 1Cyclopropyl, cyclopropylmethylene, cyclobutyl, wherein Rc is1、Rc 2、Rc 3、Rd 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;m is independently selected from alkali metals or alkaline earth metals. - The piperazinone-containing quinazolinedione salt compounds of claim 1, wherein said quinazolinedione salt compounds are represented by formula IB
In the formula IB, the compound represented by the formula IB,R 1、R 2、R 3、R 4independently selected from H, F, Cl, Br;ar is selected from the group consisting of atoms or groups or structural fragments comprisingSubstituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′ 2、NRa′ 3Rb′ 1Wherein Ra'1、Ra′ 2、Ra′ 3、Rb′ 1Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylene, cyclobutyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;m is independently selected from alkali metals or alkaline earth metals. - A piperazinone containing quinazolinedione salt compound according to any of claims 1-3, wherein M is selected from the group consisting of lithium, sodium, potassium, cesium, calcium, magnesium, barium.
- The piperazinone-containing quinazolinedione salt compounds according to claim 1, said quinazolinedione salt compounds are as follows:1- (3- (4-pentan-3' -yl-3-oxopiperazine) -1-formyl-4-fluoro-benzyl) quinazoline-2, 4(1H,3H) -dione sodium salt.
- A process for the preparation of piperazinone containing quinazolinedione salt compounds according to any of claims 1-5, comprising the steps of:R 1-R 4substituted different quinazolinediones and containing R5The substituted 3-methoxycarbonylbromobenzyl respectively undergoes selective alkylation reaction under the action of HMDS, and contains R after hydrolysis1-R 5The substituted different 3- ((2, 4-dioxo-3, 4-dihydroquinazolin-1 (2H) -yl) methyl) benzoic acid is then reacted with a compound comprising R6Condensing the piperidone derivative to obtain a 1-benzyl quinazoline diketone compound, and finally carrying out acid-base reaction with different bases to obtain a base addition salt of the 1-benzyl quinazoline diketone compound; wherein R is1、R 2、R 3、R 4、R 5、R 6M is as defined in any one of claims 1 to 5,
the reagent and the reaction condition are (a) urea, 140 ℃ and 6 h; (b) i) lithium Hexamethyldisilazide (HMDS), concentrated sulfuric acid, toluene, reflux, 2h, ii) substituted methyl 5- (bromomethyl) -2-fluorobenzoate, 145 ℃,3h, iii) methanol, hexane, 70 ℃,30 min; (c) LiOH, MeOH, H2O, THF,55 ℃ and 2 h; (d)2- (7-azobenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), 1-Hydroxybenzotriazole (HOBT), Diisopropylethylamine (DIEA), DMF (N, N-dimethylformamide), overnight; (e) MOH/H2O/40℃；Wherein R is1、R 2、R 3、R 4、R 5、R 6M is as defined in any one of claims 1 to 5. - A pharmaceutical composition comprising an effective amount of the piperazinone containing quinazolinedione compounds of any one of claims 1-5 and a pharmaceutically acceptable carrier.
- Use of piperazinone containing quinazolinedione salts according to any of claims 1 to 5 in the preparation of PARP-1/2 inhibitors.
- Use of the piperazinone containing quinazolinedione salt compounds of any one of claims 1-5 in the preparation of medicaments for preventing and/or treating PARP-1/2 related diseases.
- Use of piperazinone containing quinazolinedione compounds according to any of claims 1 to 5 for the preparation of anti-tumor drugs or anti-tumor drug sensitizers.
- The use according to claim 10, wherein the tumor is selected from the group consisting of melanoma, gastric cancer, lung cancer, breast cancer, triple negative breast cancer, kidney cancer, liver cancer, oral epidermoid cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, glioma.
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| CN106083741A (en) * | 2016-02-22 | 2016-11-09 | 南京中医药大学 | 2 sulfur are for quinazolinedione derivatives |
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