CN104415028A - Application of benzopyrone compound in preparation of anti-tumor drugs - Google Patents
Application of benzopyrone compound in preparation of anti-tumor drugs Download PDFInfo
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- CN104415028A CN104415028A CN201310377457.XA CN201310377457A CN104415028A CN 104415028 A CN104415028 A CN 104415028A CN 201310377457 A CN201310377457 A CN 201310377457A CN 104415028 A CN104415028 A CN 104415028A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/539—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more oxygen atoms in the same ring, e.g. dioxazines
Abstract
The invention discloses an application of a benzopyrone compound represented by the general formula I in preparation of anti-tumor drugs, wherein in the formula, definitions of substituents are described the specification. The compound represented by the general formula I has a good anti-tumor activity, and especially has superior activity for resisting leukemia cell line HL-60, lung cancer A549, lung cancer H157, lung cancer H460, lung cancer H520, bladder cancer T24, bladder cancer J82, bladder cancer LNCap, prostate cancer PC-3 and the like.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of field of antineoplastic medicaments.Relate to the application of a kind of Benzofurantone compound as antitumor drug particularly.
Background technology
As Periodical and the Benzofurantone compound that patent reports containing methoxy acrylate structure have agricultural bactericidal activity: Pest Management Science, Volume:67, Issue:6, Pages:647-655; Natural ProductCommunications, Volume:6, Issue:12, Pages:1917-1920; Nongyao, Volume:50, Issue:2, Pages:90-92; Nongyaoxue Xuebao, Volume:12, Issue:4, Pages:453-457; Natural ProductCommunications, Volume:2, Issue:8, Pages:845-848; Chinese Chemical Letters, Volume:22, Issue:6, Pages:663-666; WO2005044813.
Journal of Medicinal Chemistry, Volume:50, Issue:12, Pages:2886-2895 report the following general formula compound containing benzopyrone structure and have anti-platelet activity.
In prior art, the compound simultaneously containing Structures of Natural Products fragment coumarin and methoxy acrylate only uses as disinfectant use in agriculture, and the compound of structure as shown in general formula I of the present invention has no the report as antitumor drug application.
Summary of the invention
The Benzofurantone compound of structure as shown in general formula I is the object of the present invention is to provide to prepare the application in antitumor drug.
Technical scheme of the present invention is as follows:
Benzofurantone compound is as the application preparing antitumor drug, and compound structure is as shown in general formula I:
In formula:
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows:
Q is selected from one of group shown in following Q1 to Q22:
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, amino, CHO, CO independently of one another respectively
2h, CO
2na, CO
2nH
4, C
1-C
12alkyl, halo C
1-C
12alkyl, C
3-C
8cycloalkyl, C
1-C
12alkoxyl, halo C
1-C
12alkoxyl, C
1-C
12alkylthio group, halo C
1-C
12alkylthio group, C
1-C
12alkoxy C
1-C
12alkyl, halo C
1-C
12alkoxy C
1-C
12alkyl, C
1-C
12alkoxy C
1-C
12alkoxyl, halo C
1-C
12alkoxy C
1-C
12alkoxyl, C
1-C
12alkylthio group C
1-C
12alkyl, halo C
1-C
12alkylthio group C
1-C
12alkyl, C
1-C
12alkyl amino, halo C
1-C
12alkyl amino, C
2-C
12dialkyl amido, halo C
2-C
12dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C
2-C
12thiazolinyl, halo C
2-C
12thiazolinyl, C
2-C
12alkynyl, halo C
2-C
12alkynyl, C
2-C
12alkene oxygen base, halo C
2-C
12alkene oxygen base, C
2-C
12alkynyloxy group, halo C
2-C
12alkynyloxy group, C
1-C
12alkyl sulphonyl, halo C
1-C
12alkyl sulphonyl, C
1-C
12alkyl sulphinyl, halo C
1-C
12alkyl sulphinyl, C
1-C
12alkyl-carbonyl, halo C
1-C
12alkyl-carbonyl, C
1-C
12alkyl-carbonyl oxygen base, C
1-C
12alkyl-carbonyl-amino, C
1-C
12alkyl sulphonyl oxygen base, C
1-C
12alkoxy carbonyl, halo C
1-C
12alkoxy carbonyl, C
1-C
12alkyl amino sulfonyl, C
1-C
12alkoxycarbonyl amino, C
1-C
12alkoxy carbonyl C
1-C
12alkyl, C
1-C
12alkoxy carbonyl C
1-C
12alkoxyl, amino C
1-C
12alkyl, C
1-C
12alkyl amino C
1-C
12alkyl, C
2-C
12dialkyl amido C
1-C
12alkyl, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11, SO
2nR
10r
11, C (=NOR
9) R
8or R
7; Or R
1with R
2between form five-membered ring, hexatomic ring or heptatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, phenoxy group, phenoxy group C
1-C
12alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C
1-C
12alkyl, phenyl C
1-C
12alkoxyl, phenyl C
1-C
12alkoxy C
1-C
12alkyl, naphthyl, naphthoxy, naphthoxy C
1-C
12alkyl, naphthyl carbonyl, naphthyl C
1-C
12alkyl, naphthyl C
1-C
12alkoxyl, naphthyl C
1-C
12alkoxy C
1-C
12alkyl, heteroaryl, heteroaryl oxygen base, heteroaryl C
1-C
12alkoxy C
1-C
12alkyl, heteroaryl oxygen base C
1-C
12alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C
1-C
12alkyl or heteroaryl C
1-C
12alkoxyl: halogen, nitro, cyano group, sulfydryl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
8cycloalkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, halo C
1-C
6alkylthio group, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
2-C
6alkynyl, C
3-C
6alkene oxygen base, halo C
3-C
6alkene oxygen base, C
3-C
6alkynyloxy group, halo C
3-C
6alkynyloxy group, C
1-C
6alkyl sulphinyl, halo C
1-C
6alkyl sulphinyl, C
1-C
6alkyl sulphonyl, halo C
1-C
6alkyl sulphonyl, C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkyl-carbonyl, halo C
1-C
6alkyl-carbonyl, C
1-C
6alkyl-carbonyl oxygen base, C
1-C
6alkyl-carbonyl-amino, C
1-C
6alkyl sulphonyl oxygen base, C
1-C
6alkoxy carbonyl, C
1-C
6alkoxy C
1-C
6alkoxyl, C
1-C
6alkoxy carbonyl C
1-C
6alkyl, C
1-C
6alkoxycarbonyl amino, C
1-C
6alkoxy carbonyl C
1-C
6alkoxyl, CHO, CO
2h, CO
2na, CO
2nH
4, NR
10r
11, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11or SO
2nR
10r
11;
R
8, R
9be selected from hydrogen, C respectively
1-C
6alkyl, aryl or aryl C
1-C
6alkyl;
R
10, R
11may be the same or different, be selected from hydrogen, C respectively
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, halo C
1-C
6alkylthio group or C
3-C
8cycloalkyl;
And stereoisomer.
When applying as antitumor drug in above-mentioned Benzofurantone compound, more preferably compound is: in general formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows;
Q is selected from Q
1, Q
2, Q
3, Q
4, Q
5, Q
6, Q
7, Q
8, Q
9, Q
19, Q
20, Q
21or Q
22;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, amino, CHO, CO independently of one another respectively
2h, CO
2na, CO
2nH
4, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, halo C
1-C
6alkylthio group, C
1-C
6alkoxy C
1-C
6alkyl, halo C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkoxy C
1-C
6alkoxyl, halo C
1-C
6alkoxy C
1-C
6alkoxyl, C
1-C
6alkylthio group C
1-C
6alkyl, halo C
1-C
6alkylthio group C
1-C
6alkyl, C
1-C
6alkyl amino, halo C
1-C
6alkyl amino, C
2-C
8dialkyl amido, halo C
2-C
8dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
2-C
6alkynyl, C
2-C
6alkene oxygen base, halo C
2-C
6alkene oxygen base, C
2-C
6alkynyloxy group, halo C
2-C
6alkynyloxy group, C
1-C
6alkyl sulphonyl, halo C
1-C
6alkyl sulphonyl, C
1-C
6alkyl sulphinyl, halo C
1-C
6alkyl sulphinyl, C
1-C
6alkyl-carbonyl, halo C
1-C
6alkyl-carbonyl, C
1-C
6alkyl-carbonyl oxygen base, C
1-C
6alkyl-carbonyl-amino, C
1-C
6alkyl sulphonyl oxygen base, C
1-C
6alkoxy carbonyl, halo C
1-C
6alkoxy carbonyl, C
1-C
6alkyl amino sulfonyl, C
1-C
6alkoxycarbonyl amino, C
1-C
6alkoxy carbonyl C
1-C
6alkyl, C
1-C
6alkoxy carbonyl C
1-C
6alkoxyl, amino C
1-C
6alkyl, C
1-C
6alkyl amino C
1-C
6alkyl, C
2-C
8dialkyl amido C
1-C
6alkyl, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11, SO
2nR
10r
11, C (=NOR
9) R
8or R
7; Or R
1with R
2between form five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, phenoxy group, phenoxy group C
1-C
6alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C
1-C
6alkyl, phenyl C
1-C
6alkoxyl, phenyl C
1-C
6alkoxy C
1-C
6alkyl, naphthyl, naphthoxy, naphthoxy C
1-C
6alkyl, naphthyl carbonyl, naphthyl C
1-C
6alkyl, naphthyl C
1-C
6alkoxyl, naphthyl C
1-C
6alkoxy C
1-C
6alkyl, heteroaryl, heteroaryl oxygen base, heteroaryl C
1-C
6alkoxy C
1-C
6alkyl, heteroaryl oxygen base C
1-C
6alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C
1-C
6alkyl or heteroaryl C
1-C
6alkoxyl: halogen, nitro, cyano group, sulfydryl, C
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
2-C
4thiazolinyl, halo C
2-C
4thiazolinyl, C
2-C
4alkynyl, halo C
2-C
4alkynyl, C
3-C
4alkene oxygen base, halo C
3-C
4alkene oxygen base, C
3-C
4alkynyloxy group, halo C
3-C
4alkynyloxy group, C
1-C
4alkyl sulphinyl, halo C
1-C
4alkyl sulphinyl, C
1-C
4alkyl sulphonyl, halo C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy carbonyl, C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxycarbonyl amino, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, CHO, CO
2h, CO
2na, CO
2nH
4, NR
10r
11, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11or SO
2nR
10r
11;
R
8, R
9be selected from hydrogen, C respectively
1-C
4alkyl, aryl or aryl C
1-C
4alkyl;
R
10, R
11may be the same or different, be selected from hydrogen, C respectively
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group or C
3-C
6cycloalkyl.
When applying as antitumor drug in above-mentioned Benzofurantone compound, preferred compound is further: in general formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows;
Q is selected from Q
1, Q
2, Q
3, Q
4, Q
5, Q
6, Q
7, Q
8, Q
9, Q
19, Q
20, Q
21or Q
22;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, amino, CHO, CO independently of one another respectively
2h, CO
2na, CO
2nH
4, C
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
1-C
4alkoxy C
1-C
4alkyl, halo C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkoxy C
1-C
4alkoxyl, halo C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkylthio group C
1-C
4alkyl, halo C
1-C
4alkylthio group C
1-C
4alkyl, C
1-C
4alkyl amino, halo C
1-C
4alkyl amino, C
2-C
6dialkyl amido, halo C
2-C
6dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C
2-C
4thiazolinyl, halo C
2-C
4thiazolinyl, C
2-C
4alkynyl, halo C
2-C
4alkynyl, C
2-C
4alkene oxygen base, halo C
2-C
4alkene oxygen base, C
2-C
4alkynyloxy group, halo C
2-C
4alkynyloxy group, C
1-C
4alkyl sulphonyl, halo C
1-C
4alkyl sulphonyl, C
1-C
4alkyl sulphinyl, halo C
1-C
4alkyl sulphinyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy carbonyl, halo C
1-C
4alkoxy carbonyl, C
1-C
4alkyl amino sulfonyl, C
1-C
4alkoxycarbonyl amino, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, amino C
1-C
4alkyl, C
1-C
4alkyl amino C
1-C
4alkyl, C
2-C
6dialkyl amido C
1-C
4alkyl, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11, SO
2nR
10r
11, C (=NOR
9) R
8or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, phenoxy group, phenoxy group C
1-C
4alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C
1-C
4alkyl, phenyl C
1-C
4alkoxyl, phenyl C
1-C
4alkoxy C
1-C
4alkyl, naphthyl, naphthoxy, naphthoxy C
1-C
4alkyl, naphthyl carbonyl, naphthyl C
1-C
4alkyl, naphthyl C
1-C
4alkoxyl, naphthyl C
1-C
4alkoxy C
1-C
4alkyl, heteroaryl, heteroaryl oxygen base, heteroaryl C
1-C
4alkoxy C
1-C
4alkyl, heteroaryl oxygen base C
1-C
4alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C
1-C
4alkyl or heteroaryl C
1-C
4alkoxyl: halogen, nitro, cyano group, sulfydryl, C
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
2-C
4thiazolinyl, halo C
2-C
4thiazolinyl, C
2-C
4alkynyl, halo C
2-C
4alkynyl, C
3-C
4alkene oxygen base, halo C
3-C
4alkene oxygen base, C
3-C
4alkynyloxy group, halo C
3-C
4alkynyloxy group, C
1-C
4alkyl sulphinyl, halo C
1-C
4alkyl sulphinyl, C
1-C
4alkyl sulphonyl, halo C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy carbonyl, C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxycarbonyl amino, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, CHO, CO
2h, CO
2na, CO
2nH
4, NR
10r
11, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11or SO
2nR
10r
11;
R
8, R
9be selected from hydrogen, C respectively
1-C
4alkyl, aryl or aryl C
1-C
4alkyl;
R
10, R
11may be the same or different, be selected from hydrogen, C respectively
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group or C
3-C
6cycloalkyl.
When applying as antitumor drug in above-mentioned Benzofurantone compound, further preferred compound is: in general formula I
Ar is selected from Ar1, Ar2 or Ar3;
Q is selected from Q
1, Q
2, Q
3, Q
4, Q
5, Q
6, Q
7or Q
8;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, C independently of one another respectively
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkyl amino, C
2-C
6dialkyl amido, C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy carbonyl or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, benzyl, phenethyl, heteroaryl: halogen, nitro, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl or halo C
1-C
4alkoxyl.
When applying as antitumor drug in above-mentioned Benzofurantone compound, preferred compound is further again: in general formula I
Ar is selected from Ar1, Ar2 or Ar3;
Q is selected from Q
1;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, C independently of one another respectively
1-C
4alkyl, halo C
1-C
4alkyl or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, benzyl, heteroaryl: halogen, nitro, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl or halo C
1-C
4alkoxyl.
When applying as antitumor drug in above-mentioned Benzofurantone compound, most preferred compound is: in general formula I
Ar is selected from Ar3;
Q is selected from Q1;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, C independently of one another respectively
1-C
4alkyl, halo C
1-C
4alkyl or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, benzyl, heteroaryl: halogen, nitro, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl or halo C
1-C
4alkoxyl.
In the definition of the compound of Formula I provided, collect the following substituent group of term general proxy used above:
Halogen: refer to fluorine, chlorine, bromine or iodine.Alkyl: straight or branched alkyl, such as methyl, ethyl, propyl group, isopropyl, normal-butyl or the tert-butyl group.Cycloalkyl: substituted or unsubstituted cyclic alkyl, such as cyclopropyl, cyclopenta or cyclohexyl.Substituent group is as methyl, halogen etc.Haloalkyl: straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom, such as, chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl etc.Alkoxyl: straight or branched alkyl, is connected in structure through oxygen atom key.Halogenated alkoxy: straight or branched alkoxyl, the hydrogen atom on these alkoxyls can partly or entirely replace by halogen atom.Such as, chlorine methoxyl group, dichloro methoxyl group, trichloromethoxy, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, chlorine fluorine methoxyl group, trifluoro ethoxy etc.Alkylthio group: straight or branched alkyl, is connected in structure through sulphur atom key.Halogenated alkylthio: straight or branched alkylthio group, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom.Such as, chloromethane sulfenyl, dichloromethane sulfenyl, trichloro-methylthio, fluorine methyl mercapto, difluoro methyl mercapto, trifluoromethylthio, chlorine fluorine methyl mercapto etc.Alkoxyalkyl: alkoxyl is connected in structure through alkyl.As-CH
2oCH
2,-CH
2oCH
2cH
3.Halogenated alkoxy alkyl: the hydrogen atom on the alkyl of alkoxyalkyl can partly or entirely replace by halogen atom.As-CH
2oCH
2cH
2cl.Alkyloxy-alkoxy: as-OCH
2oCH
2cH
3deng.Halogenated alkoxy alkoxyl: as-OCH
2oCH
2cH
2cl etc.Alkylthio alkyl: alkylthio group is connected in structure through alkyl.As-CH
2sCH
3.Haloalkylthioalkyl: halogenated alkylthio is connected in structure through alkyl.Alkyl amino: straight or branched alkyl, is connected in structure through nitrogen-atoms key.Haloalkylamino: straight or branched alkyl amino, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom.Dialkyl amido: as-N (CH
3)
2,-N (CH
2cH
3)
2.Halo dialkyl amido: dialkyl amido, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom.Thiazolinyl: straight or branched alkene class, such as vinyl, 1-acrylic, 2-acrylic and different cyclobutenyls, pentenyl and hexenyl isomers.Thiazolinyl also comprises polyenoid class, as 1,2-allene base and 2,4-hexadienyl.Haloalkenyl group: straight or branched alkene class, the hydrogen atom on these thiazolinyls can partly or entirely replace by halogen atom.Alkynyl: straight or branched alkynes class, such as acetenyl, 1-propinyl, 2-propynyl and different butynyl, pentynyl and hexynyl isomers.Alkynyl also comprises the group be made up of multiple triple bond, as 2,5-hexadiine base.Halo alkynyl: straight or branched alkynes class, the hydrogen atom on these alkynyls can partly or entirely replace by halogen atom.Alkene oxygen base: straight or branched alkene class, is connected in structure through oxygen atom key.Haloalkene oxygen base: straight or branched alkene oxygen base, the hydrogen atom on these alkene oxygen bases can partly or entirely replace by halogen atom.Alkynyloxy group: straight or branched alkynes class, is connected in structure through oxygen atom key.Halo alkynyloxy group: straight or branched alkynyloxy group, the hydrogen atom on these alkynyloxy groups can partly or entirely replace by halogen atom.Alkyl sulphonyl: straight or branched alkyl is through sulfonyl (-SO
2-) be connected in structure, as methyl sulphonyl.Halogenated alkyl sulfonyl: straight or branched alkyl sulphonyl, the hydrogen atom on its alkyl can partly or entirely replace by halogen atom.Alkyl sulphinyl: straight or branched alkyl is connected in structure, as methylsulfinyl through sulfinyl (-SO-).Alkylsulfinyl: straight or branched alkyl sulphinyl, the hydrogen atom on its alkyl can partly or entirely replace by halogen atom.Alkyl-carbonyl: alkyl is connected in structure, as-COCH through carbonyl
3,-COCH
2cH
3.Halogenated alkyl carbonyl: the hydrogen atom on the alkyl of alkyl-carbonyl can partly or entirely replace by halogen atom, as-COCF
3.Alkyl-carbonyl oxygen base: as-OCOCH
3,-OCOC (CH
3)
3.Alkyl-carbonyl-amino: as-NHCOCH
3,-NHCOC (CH
3)
3.Alkyl sulphonyl oxygen base: alkyl-O-S (O)
2.Alkoxy carbonyl: alkoxyl is connected in structure through carbonyl.As-COOCH
3,-COOCH
2cH
3.Halo alkoxy carbonyl: the hydrogen atom on the alkyl of alkoxy carbonyl can partly or entirely replace by halogen atom, as-COOCH
2cF
3,-COOCH
2cH
2cl etc.Alkyl amino sulfonyl: as-S (O)
2nHCH
3,-S (O)
2nHCH
2cH
3.Alkoxycarbonyl amino: as-NHCOOCH
3,-NHCOOCH
2cH
3.Alkoxy carbonyl alkyl: as-CH
2cOOCH
3,-CH
2cOOCH
2cH
3.Alkoxycarbonylalkoxy: as-OCH
2cOOCH
3,-OCH
2cOOCH
2cH
3.Aminoalkyl: as-CH
2nH
2,-CH
2cH
2nH
2.Alkylaminoalkyl group: as-CH
2nHCH
3,-CH
2nHCH
2cH
3.Dialkyl aminoalkyl: as-CH
2nH (CH
3)
2.Aryl moiety in (mixing) aryl, (mixing) aryloxy, (mixing) alkoxy aryl alkyl, (mixing) aromatic yloxy yl alkyl, (mixing) aryl carbonyl, (mixing) aryloxycarbonyl, (mixing) aromatic yl aminocarbonyl, (mixing) aryl alkyl or (mixing) alkoxy aryl comprises phenyl or naphthyl etc.Heteroaryl is containing the heteroatomic five-membered ring of one or more N, O, S or hexatomic ring.Such as pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, furyl, thiazolyl, quinolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiadiazolyl group, pyrazolyl, pyranose, triazolyl, tetrazole radical, benzothiazolyl, benzofuranyl etc.(mixing) aryloxy: as phenoxy group, pyridyloxy, 2-pyrimidinyl oxy, quinoline oxy etc.(mixing) alkoxy aryl alkyl: as-CH
2oCH
2ph, 6-chloropyridine-3-ylmethoxy etc.(mixing) aromatic yloxy yl alkyl: as-CH
2oPh, 4,6-dimethoxypyridin-2-base oxygen base ethyl etc.(mixing) aryl carbonyl: as benzoyl, 4-chlorobenzene formacyl etc.(mixing) aryloxycarbonyl: as phenyloxycarbonyl, 4-cHorophenoxycarbonyl, 4-nitrophenoxy carbonyl, naphthoxycarbonyl etc.(mixing) aromatic yl aminocarbonyl: as-CONHPh, pyridine-2-base amino carbonyl etc.(mixing) aryl alkyl: as benzyl, phenethyl, to chlorophenylmethyl, 6-chloropyridine 3-ylmethyl, 2-diuril azoles-5-ylmethyl etc.(mixing) alkoxy aryl: as-OCH
2ph ,-OCH
2ph-Cl-4.
In compound of the present invention, geometric isomer (respectively with Z and E to represent different configurations) can be formed because carbon-to-carbon double bond is connected different substituent groups with carbon-nitrogen double bond.The present invention includes the mixture of Z-type isomer and E-isomer and any ratio thereof.
Become oral with the Benzofurantone compound shown in general formula I for active fraction preparation or the form of parenteral route carries out the medicine of administration, or carry out the medicine of administration by the form of transplant medicine pump in body.
Further, be active fraction preparation treatment, prevention or the medicine of tumor remission with the Benzofurantone compound shown in general formula I, pharmaceutical dosage form is tablet, pill, capsule, electuary, syrup, injection or freeze-dried powder dosage form.
Further, be applied to preparation treatment, prevention or alleviate in colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer medicament.
Table 1 to list in general formula I R in Ar structure
1, R
2, R
3, R
4, R
5and R
6the concrete substituent group of part, but they are not limited only to these substituent groups.
Table 1R
1(R
2, R
3, R
4, R
5, R
6) substituent group
The compound that the present invention has anti-tumor activity is illustrated by the particular compound listed in table 2-table 53, but does not limit the present invention.
Q is selected from when Ar is selected from Ar1, Q
1time, representation compound 2-1 to 2-112 is in table 2.
Table 2 is ring substituents as Ar=Ar1
| Numbering | R 1 | R 3 | R 4 | R 5 | R 6 |
| 2-1 | H | H | H | H | H |
| 2-2 | CH 3 | H | H | H | H |
| 2-3 | C 2H 5 | H | H | H | H |
| 2-4 | i-C 3H 7 | H | H | H | H |
| 2-5 | n-C 3H 7 | H | H | H | H |
| 2-6 | n-C 4H 9 | H | H | H | H |
| 2-7 | t-C 4H 9 | H | H | H | H |
| 2-8 | OCH 3 | H | H | H | H |
| 2-9 | OC 2H 5 | H | H | H | H |
| 2-10 | CH 2Cl | H | H | H | H |
| 2-11 | CH 2NH 2 | H | H | H | H |
| 2-12 | CH 2CH 2NH 2 | H | H | H | H |
| 2-13 | CH 2CH 2CN | H | H | H | H |
| 2-14 | NH 2 | H | H | H | H |
| 2-15 | NO 2 | H | H | H | H |
| 2-16 | OH | H | H | H | H |
| 2-17 | CO 2H | H | H | H | H |
| 2-18 | F | H | H | H | H |
| 2-19 | Cl | H | H | H | H |
| 2-20 | Br | H | H | H | H |
| 2-21 | I | H | H | H | H |
| 2-22 | CH 2-CH=CH 2 | H | H | H | H |
| 2-38 | CH 2-C≡CH | H | H | H | H |
| 2-39 | H | CH 3 | H | H | H |
| 2-40 | H | C 2H 5 | H | H | H |
| 2-41 | H | i-C 3H 7 | H | H | H |
| 2-42 | H | n-C 3H 7 | H | H | H |
| 2-43 | H | n-C 4H 9 | H | H | H |
| 2-44 | H | t-C 4H 9 | H | H | H |
| 2-45 | H | OCH 3 | H | H | H |
| 2-46 | H | OC 2H 5 | H | H | H |
| 2-47 | H | CH 2Cl | H | H | H |
| 2-48 | H | CO 2H | H | H | H |
| 2-49 | H | F | H | H | H |
| 2-50 | H | Cl | H | H | H |
| 2-51 | H | Br | H | H | H |
| 2-52 | H | I | H | H | H |
| 2-53 | H | Ph | H | H | H |
| 2-54 | H | H | CH 3 | H | H |
| 2-55 | H | H | C 2H 5 | H | H |
| 2-56 | H | H | i-C 3H 7 | H | H |
| 2-57 | H | H | n-C 3H 7 | H | H |
| 2-58 | H | H | n-C 4H 9 | H | H |
| 2-59 | H | H | t-C 4H 9 | H | H |
| 2-60 | H | H | OCH 3 | H | H |
| 2-61 | H | H | OC 2H 5 | H | H |
| 2-62 | H | H | NH 2 | H | H |
| 2-63 | H | H | OH | H | H |
| 2-64 | H | H | CO 2H | H | H |
| 2-65 | H | H | F | H | H |
| 2-66 | H | H | Cl | H | H |
| 2-67 | H | H | Br | H | H |
| 2-68 | H | H | I | H | H |
| 2-69 | H | H | Ph | H | H |
| 2-70 | H | H | H | CH 3 | H |
| 2-71 | H | H | H | C 2H 5 | H |
| 2-72 | H | H | H | i-C 3H 7 | H |
| 2-73 | H | H | H | n-C 3H 7 | H |
| 2-74 | H | H | H | n-C 4H 9 | H |
| 2-75 | H7 | H | H | t-C 4H 9 | H |
| 2-76 | H | H | H | OCH 3 | H |
| 2-77 | H | H | H | OC 2H 5 | H |
| 2-78 | H | H | H | CH 2Cl | H |
| 2-79 | H | H | H | N(CH 3) 2 | H |
| 2-80 | H | H | H | OCOOCH 3 | H |
| 2-81 | H | H | H | OCOCH 3 | H |
| 2-82 | H | H | H | NH 2 | H |
| 2-83 | H | H | H | CN | H |
| 2-84 | H | H | H | OH | H |
| 2-85 | H | H | H | CO 2H | H |
| 2-86 | H | H | H | F | H |
| 2-87 | H | H | H | Cl | H |
| 2-88 | H | H | H | Br | H |
| 2-89 | H | H | H | I | H |
| 2-90 | H | H | H | CH 2-CH=CH 2 | H |
| 2-91 | H | H | H | CH 2-C≡CH | H |
| 2-92 | H | H | H | H | CH 3 |
| 2-93 | H | H | H | H | C 2H 5 |
| 2-94 | H | H | H | H | OCH 3 |
| 2-95 | H | H | H | H | CHO |
| 2-96 | H | H | H | H | F |
| 2-97 | H | H | H | H | Cl |
| 2-98 | H | H | H | H | Br |
| 2-99 | H | H | H | H | I |
| 2-100 | H | H | H | H | Ph |
| 2-101 | H | H | H | H | CH 2Ph |
| 2-102 | CH 3 | H | H | H | CH 3 |
| 2-103 | H | H | CH 3 | CH 3 | H |
| 2-104 | H | H | CH 3 | H | CH 3 |
| 2-105 | H | H | OCH 3 | H | OCH 3 |
| 2-106 | H | H | Cl | H | Cl |
| 2-107 | H | H | H | CH 3 | CH 3 |
| 2-108 | CH 3 | H | H | CH 3 | H |
| 2-109 | H | H | Cl | CH 3 | H |
| 2-110 | H | H | C 2H 5 | C 2H 5 | H |
| 2-111 | CH 3 | H | CH 3 | H | H |
| 2-112 | H | CH 3 | CH 3 | H | CH 3 |
Table 3: be selected from Q when Ar is selected from Ar1, Q
2time, representation compound 3-1 to 3-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 4: be selected from Q when Ar is selected from Ar1, Q
3time, representation compound 4-1 to 4-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 5: be selected from Q when Ar is selected from Ar1, Q
4time, representation compound 5-1 to 5-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 6: be selected from Q when Ar is selected from Ar1, Q
5time, representation compound 6-1 to 6-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 7: be selected from Q when Ar is selected from Ar1, Q
6time, representation compound 7-1 to 7-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 8: be selected from Q when Ar is selected from Ar1, Q
7time, representation compound 8-1 to 8-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 9: be selected from Q when Ar is selected from Ar1, Q
8time, representation compound 9-1 to 9-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 10: be selected from Q when Ar is selected from Ar1, Q
9time, representation compound 10-1 to 10-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 11: be selected from Q when Ar is selected from Ar1, Q
19time, representation compound 11-1 to 11-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 12: be selected from Q when Ar is selected from Ar1, Q
20time, representation compound 12-1 to 12-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 13: be selected from Q when Ar is selected from Ar1, Q
21time, representation compound 13-1 to 13-112 substituent group is consistent with table 2 compound 2-1 to 2-112;
Table 14: be selected from Q when Ar is selected from Ar1, Q
22time, representation compound 14-1 to 14-112 substituent group is consistent with table 2 compound 2-1 to 2-112.
Q is selected from when Ar is selected from Ar2, Q
1time, representation compound 15-1 to 15-121 is in table 15.
Table 15 is ring substituents as Ar=Ar2
Table 16: be selected from Q when Ar is selected from Ar2, Q
2time, representation compound 16-1 to 16-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 17: be selected from Q when Ar is selected from Ar2, Q
3time, representation compound 17-1 to 17-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 18: be selected from Q when Ar is selected from Ar2, Q
4time, representation compound 18-1 to 18-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 19: be selected from Q when Ar is selected from Ar2, Q
5time, representation compound 19-1 to 19-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 20: be selected from Q when Ar is selected from Ar2, Q
6time, representation compound 20-1 to 20-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 21: be selected from Q when Ar is selected from Ar2, Q
7time, representation compound 21-1 to 21-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 22: be selected from Q when Ar is selected from Ar2, Q
8time, representation compound 22-1 to 22-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 23: be selected from Q when Ar is selected from Ar2, Q
9time, representation compound 23-1 to 23-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 24: be selected from Q when Ar is selected from Ar2, Q
19time, representation compound 24-1 to 24-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 25: be selected from Q when Ar is selected from Ar2, Q
20time, representation compound 25-1 to 25-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 26: be selected from Q when Ar is selected from Ar2, Q
21time, representation compound 26-1 to 26-121 substituent group is consistent with table 15 compound 15-1 to 15-121;
Table 27: be selected from Q when Ar is selected from Ar2, Q
22time, representation compound 27-1 to 27-121 substituent group is consistent with table 15 compound 15-1 to 15-121.
Q is selected from when Ar is selected from Ar3, Q
1time, representation compound 28-1 to 28-131 is in table 28.
Table 28 is ring substituents as Ar=Ar3
Note: E is C (CH
3)=NOCH
3; M is C
6h
3-3,4-(OCH
3)
2.
Table 29: be selected from Q when Ar is selected from Ar3, Q
2time, representation compound 29-1 to 29-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 30: be selected from Q when Ar is selected from Ar3, Q
3time, representation compound 30-1 to 30-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 31: be selected from Q when Ar is selected from Ar3, Q
4time, representation compound 31-1 to 31-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 32: be selected from Q when Ar is selected from Ar3, Q
5time, representation compound 32-1 to 32-131 substituent group is consistent with table 2 compound 28-1 to 28-131;
Table 33: be selected from Q when Ar is selected from Ar3, Q
6time, representation compound 33-1 to 33-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 34: be selected from Q when Ar is selected from Ar3, Q
7time, representation compound 34-1 to 34-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 35: be selected from Q when Ar is selected from Ar3, Q
8time, representation compound 35-1 to 35-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 36: be selected from Q when Ar is selected from Ar3, Q
9time, representation compound 36-1 to 36-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 37: be selected from Q when Ar is selected from Ar3, Q
19time, representation compound 37-1 to 37-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 38: be selected from Q when Ar is selected from Ar3, Q
20time, representation compound 38-1 to 38-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 39: be selected from Q when Ar is selected from Ar3, Q
21time, representation compound 39-1 to 39-131 substituent group is consistent with table 28 compound 28-1 to 28-131;
Table 40: be selected from Q when Ar is selected from Ar3, Q
22time, representation compound 40-1 to 40-131 substituent group is consistent with table 28 compound 28-1 to 28-131.
Q is selected from when Ar is selected from Ar4, Q
1time, representation compound 41-1 to 41-116 is in table 41.
Table 41 is ring substituents as Ar=Ar4
Table 42: be selected from Q when Ar is selected from Ar4, Q
2time, representation compound 42-1 to 42-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 43: be selected from Q when Ar is selected from Ar4, Q
3time, representation compound 43-1 to 43-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 44: be selected from Q when Ar is selected from Ar4, Q
4time, representation compound 44-1 to 44-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 45: be selected from Q when Ar is selected from Ar4, Q
5time, representation compound 45-1 to 45-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 46: be selected from Q when Ar is selected from Ar4, Q
6time, representation compound 46-1 to 46-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 47: be selected from Q when Ar is selected from Ar4, Q
7time, representation compound 47-1 to 47-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 48: be selected from Q when Ar is selected from Ar4, Q
8time, representation compound 48-1 to 48-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 49: be selected from Q when Ar is selected from Ar4, Q
9time, representation compound 49-1 to 49-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 50: be selected from Q when Ar is selected from Ar4, Q
19time, representation compound 50-1 to 50-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 51: be selected from Q when Ar is selected from Ar4, Q
20time, representation compound 51-1 to 51-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 52: be selected from Q when Ar is selected from Ar4, Q
21time, representation compound 52-1 to 52-116 substituent group is consistent with table 41 compound 41-1 to 41-116;
Table 53: be selected from Q when Ar is selected from Ar4, Q
22time, representation compound 53-1 to 53-116 substituent group is consistent with table 41 compound 41-1 to 41-116.
The highly preferred compound of the present invention is as follows:
Compound 28-5: Turbo cornutus Solander bacterium ester.
Compound 28-72: SYP-3375 (coumoxystrobin).
Compound of Formula I involved in the present invention has been reported in the prior art, can obtain easily.Concrete preparation method can with reference to USP7642364, CNP1869032, Pest Manag.Sci.2011, and 67,647, Nat.Prod.Commun.2011,6,1917, Chin.Chem.Lett.2011,22,663, Chin.J.Pestic.2011,50,90.
The present invention includes the preparation that compound that above-mentioned general formula I comprises is the formulation ingredients that is mixed with of active component and its preparation composition.Formulation preparation method for: obtain formulation soln in compound dissolution the present invention contained to the surfactant of water miscible organic solvent, nonionic, water miscible lipoid, various cyclodextrin, fatty acid, fatty acid ester, phospholipid or its combination solvent; Add the carbohydrate that normal saline obtains 1-20%.Described organic solvent comprises Polyethylene Glycol (PEG), ethanol, the combination solvent of propylene glycol or these solvents.
The compound contained in general formula I of the present invention and stereoisomer and prodrug are for the preparation for the treatment of, prevention or alleviate antitumor drug or pharmaceutical preparation, and active constituents of medicine is the Benzofurantone compound shown in one or more general formula Is.Be particularly useful for the cancer that treatment or alleviation tissue or organ tumor cell cause.The preferred colon cancer of indication cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer etc.
The compound of the present invention's synthesis can be used for the active component of antitumor drug, can be used alone, also can with other antitumor, antiviral drugs drug combination.In the drug combination therapeutic process of indication of the present invention, comprise using together with at least one the compounds of this invention and one or more anti-tumor virus drugs of its reactive derivative and other and use to increase general curative effect.Dose during drug combination and administration time should be determined according to most rational therapy effect acquired when different.
The medicament compatibility contained comprises the effective dose of the compound in general formula I." effective dose " herein refers to the consumption that can produce this compound required for therapeutic effect for institute's treatment target.This effective dose or dosage can by there being experience person different according to the suggestion of different situations.Such as, the tumor class for the treatment of is different, and the usage of medicine is different; Whether share with other Therapeutic Method such as other antitumor drug or antiviral drugs, dosage all can change.Any spendable preparation formulation can be made.If some has alkalescence or acid compound also can form avirulent acid or salt, the form of the salt of this compound can be used.In pharmacy, spendable acylate comprises spendable anion salt on physiology, as toluenesulfonate, metilsulfate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or glycerophosphate etc.; Spendable inorganic salt comprises chloride, bromide, fluoride, iodide, sulfate, nitrate, bicarbonate, carbonate or phosphate etc.; The form of described salt can be made if any the compound of the alkalescence as amine and suitable acid; The compound of carboxylic acids can form spendable salt with alkali metal or alkaline-earth metal.
The compound contained in formula of I of the present invention is generally readily soluble in the mixed solvent of organic solvent, water-soluble solvent and organic solvent and water-soluble solvent and water.Water-soluble solvent preferred alcohols, poly ethylene glycol, N-methyl-2-pyrrolinone, N,N-dimethylacetamide, DMF, dimethyl sulfoxine, acetonitrile and its share.Described alcohol particular methanol, ethanol, isopropyl alcohol, glycerol or ethylene glycol.The compounds of this invention can mix with conventional preparations carrier and make preparation.Drug solution is obtained in compound dissolution to water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or in the mixed solvent of these solvents; Add the carbohydrate that normal saline obtains 1-20% again, as the aqueous solution of glucose.Preparation stabilization obtained therefrom for animal and clinical.
With the product medicine that compound in above-mentioned general formula I becomes for active fraction preparation, oral or parenteral administration can be passed through, also by transplant medicine pump in body and additive method administration, herein the parenteral administration of indication refer in subcutaneous Intradermal, intramuscular, intravenous, intra-arterial, atrium, in synovial membrane, in breastbone, in sheath, in wound site, intracranial injection or drip infusion technique etc.Use conventional method proportioning by technical staff, mixing finally becomes required pharmaceutical dosage form.Can be tablet, pill, capsule, electuary, syrup, injection, freeze-dried powder dosage form, Emulsion, powder, lyophilized powder, drop pill, emulsion suspension liquid, water hang solution, aqueous solution, colloid, colloid solution, slow releasing preparation, nanometer formulation or with other forms of dosage form for animal or clinical.
Compound in general formula I of the present invention is used for the treatment of or alleviates the preparation of cancer drug of a certain tissue or organ.Indication cancer comprises but is not only limited to colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer etc.
Detailed description of the invention
Following specific embodiment is used for further illustrating the present invention, but the present invention is not limited to these examples.
Antitumor cytolytic activity
The external test experience to inhibiting tumour cells effect is as follows:
Institute's employment tumor cell strain: bladder cancer J82, LNCap, T24, carcinoma of prostate PC-3, people pulmonary carcinoma A549, H157, H460, H520, human leukemia HL-60 etc.
Embodiment 1: to human bladder cancer cell J82, LNCap, T24, prostate gland cancer cell PC-3, the growth inhibition ratio of lung cell A549, H157, H460, H520, adopt Cell culture invitro technology, about 1000 to 3000 cell kinds are entered in 24 orifice plates, then more every hole add 1 milliliter well known to those skilled in the art can the cell culture fluid of culture experiment tumor cell line, (CO in cell culture incubator
25%, 370 DEG C) cultivate after 24 hours, then the contrast medicine of debita spissitudo and above-mentioned gained material medicine to be measured of preparing are added in hand-hole, note, the volume adding liquid is no more than 0.5% of cumulative volume.Allow cell continue to grow in cell culture incubator, after the week, by cell culture fluid sucking-off, wash once with cold 1 milliliter of PBS.Then, fix 10 minutes by the formalin room temperature of 1%, then wash once with cold 1 milliliter of PBS.Add the violet staining 30 minutes of 0.1%.Crystal violet recycling.The cell deionized water of dye lechery slowly rinses, and after room temperature is dried, preserves.Remaining cell by each concentration process calculates cell inhibitory rate with the remaining cell of the matched group without medicine process.Contrast medicament AZD6244, adopted name Selumetinib.
The remaining cell of suppression ratio=each concentration process/without remaining cell × 100% of the matched group of medicine process
Partial test the results are shown in Table 54:
The suppression ratio of table 54 pair human cancer cell growth
Note: 1. "/" representative is not surveyed.
2. bladder cancer J82, LNCap, T24, carcinoma of prostate PC-3, people pulmonary carcinoma A549, all strain cultures of H157, H460, H520 are RMPI-1640.
Embodiment 2: to the growth inhibition ratio of human leukemia HL-60 cell, measures test sample to the suppression ratio of each one growth of cancer cells with conventional mtt assay.Cell is taken out from incubator, with PBS liquid cleaning twice, with 0.25% trypsin solution digestion, add well known to those skilled in the art can the culture medium of culture experiment tumor cell line, each cell strain is made to stop digestion, centrifugal rear suction pipe piping and druming makes it to form cell suspension, and counts under inverted microscope.And with cultivating the culture medium of each tumor cell strain, cell is mixed with concentration is 5x10
4the cell suspension of/ml, cell 100 μ l is added in the 96 every holes of orifice plate, be positioned over 5% carbon dioxide, overnight incubation in 37 DEG C of humidified air, add the above-mentioned medicine to be measured being diluted to variable concentrations gradient, after making its effect 48h, add MTT, through reacting 4 hours, the reduction of MTT tetrazolium composition is produced formazan by living cells, add DMSO afterwards to dissolve formazan, finally 96 hole plate reader to be measured the light absorption value of 570nm.
Partial test the results are shown in Table 55:
The suppression ratio (%) that table 55 couple human leukemia cell HL60 grows
Note: human leukemia HL-60 culture medium is OPTI-MEM.
Claims (10)
1. Benzofurantone compound is as the application preparing antitumor drug, it is characterized in that compound structure is as shown in general formula I:
In formula:
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows:
Q is selected from one of group shown in following Q1 to Q22:
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, amino, CHO, CO independently of one another respectively
2h, CO
2na, CO
2nH
4, C
1-C
12alkyl, halo C
1-C
12alkyl, C
3-C
8cycloalkyl, C
1-C
12alkoxyl, halo C
1-C
12alkoxyl, C
1-C
12alkylthio group, halo C
1-C
12alkylthio group, C
1-C
12alkoxy C
1-C
12alkyl, halo C
1-C
12alkoxy C
1-C
12alkyl, C
1-C
12alkoxy C
1-C
12alkoxyl, halo C
1-C
12alkoxy C
1-C
12alkoxyl, C
1-C
12alkylthio group C
1-C
12alkyl, halo C
1-C
12alkylthio group C
1-C
12alkyl, C
1-C
12alkyl amino, halo C
1-C
12alkyl amino, C
2-C
12dialkyl amido, halo C
2-C
12dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C
2-C
12thiazolinyl, halo C
2-C
12thiazolinyl, C
2-C
12alkynyl, halo C
2-C
12alkynyl, C
2-C
12alkene oxygen base, halo C
2-C
12alkene oxygen base, C
2-C
12alkynyloxy group, halo C
2-C
12alkynyloxy group, C
1-C
12alkyl sulphonyl, halo C
1-C
12alkyl sulphonyl, C
1-C
12alkyl sulphinyl, halo C
1-C
12alkyl sulphinyl, C
1-C
12alkyl-carbonyl, halo C
1-C
12alkyl-carbonyl, C
1-C
12alkyl-carbonyl oxygen base, C
1-C
12alkyl-carbonyl-amino, C
1-C
12alkyl sulphonyl oxygen base, C
1-C
12alkoxy carbonyl, halo C
1-C
12alkoxy carbonyl, C
1-C
12alkyl amino sulfonyl, C
1-C
12alkoxycarbonyl amino, C
1-C
12alkoxy carbonyl C
1-C
12alkyl, C
1-C
12alkoxy carbonyl C
1-C
12alkoxyl, amino C
1-C
12alkyl, C
1-C
12alkyl amino C
1-C
12alkyl, C
2-C
12dialkyl amido C
1-C
12alkyl, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11, SO
2nR
10r
11, C (=NOR
9) R
8or R
7; Or R
1with R
2between form five-membered ring, hexatomic ring or heptatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, phenoxy group, phenoxy group C
1-C
12alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C
1-C
12alkyl, phenyl C
1-C
12alkoxyl, phenyl C
1-C
12alkoxy C
1-C
12alkyl, naphthyl, naphthoxy, naphthoxy C
1-C
12alkyl, naphthyl carbonyl, naphthyl C
1-C
12alkyl, naphthyl C
1-C
12alkoxyl, naphthyl C
1-C
12alkoxy C
1-C
12alkyl, heteroaryl, heteroaryl oxygen base, heteroaryl C
1-C
12alkoxy C
1-C
12alkyl, heteroaryl oxygen base C
1-C
12alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C
1-C
12alkyl or heteroaryl C
1-C
12alkoxyl: halogen, nitro, cyano group, sulfydryl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
8cycloalkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, halo C
1-C
6alkylthio group, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
2-C
6alkynyl, C
3-C
6alkene oxygen base, halo C
3-C
6alkene oxygen base, C
3-C
6alkynyloxy group, halo C
3-C
6alkynyloxy group, C
1-C
6alkyl sulphinyl, halo C
1-C
6alkyl sulphinyl, C
1-C
6alkyl sulphonyl, halo C
1-C
6alkyl sulphonyl, C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkyl-carbonyl, halo C
1-C
6alkyl-carbonyl, C
1-C
6alkyl-carbonyl oxygen base, C
1-C
6alkyl-carbonyl-amino, C
1-C
6alkyl sulphonyl oxygen base, C
1-C
6alkoxy carbonyl, C
1-C
6alkoxy C
1-C
6alkoxyl, C
1-C
6alkoxy carbonyl C
1-C
6alkyl, C
1-C
6alkoxycarbonyl amino, C
1-C
6alkoxy carbonyl C
1-C
6alkoxyl, CHO, CO
2h, CO
2na, CO
2nH
4, NR
10r
11, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11or SO
2nR
10r
11;
R
8, R
9be selected from hydrogen, C respectively
1-C
6alkyl, aryl or aryl C
1-C
6alkyl;
R
10, R
11may be the same or different, be selected from hydrogen, C respectively
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, halo C
1-C
6alkylthio group or C
3-C
8cycloalkyl;
And stereoisomer.
2. application according to claim 1, is characterized in that: in general formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows;
Q is selected from Q
1, Q
2, Q
3, Q
4, Q
5, Q
6, Q
7, Q
8, Q
9, Q
19, Q
20, Q
21or Q
22;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, amino, CHO, CO independently of one another respectively
2h, CO
2na, CO
2nH
4, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, halo C
1-C
6alkylthio group, C
1-C
6alkoxy C
1-C
6alkyl, halo C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkoxy C
1-C
6alkoxyl, halo C
1-C
6alkoxy C
1-C
6alkoxyl, C
1-C
6alkylthio group C
1-C
6alkyl, halo C
1-C
6alkylthio group C
1-C
6alkyl, C
1-C
6alkyl amino, halo C
1-C
6alkyl amino, C
2-C
8dialkyl amido, halo C
2-C
8dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, C
2-C
6alkynyl, halo C
2-C
6alkynyl, C
2-C
6alkene oxygen base, halo C
2-C
6alkene oxygen base, C
2-C
6alkynyloxy group, halo C
2-C
6alkynyloxy group, C
1-C
6alkyl sulphonyl, halo C
1-C
6alkyl sulphonyl, C
1-C
6alkyl sulphinyl, halo C
1-C
6alkyl sulphinyl, C
1-C
6alkyl-carbonyl, halo C
1-C
6alkyl-carbonyl, C
1-C
6alkyl-carbonyl oxygen base, C
1-C
6alkyl-carbonyl-amino, C
1-C
6alkyl sulphonyl oxygen base, C
1-C
6alkoxy carbonyl, halo C
1-C
6alkoxy carbonyl, C
1-C
6alkyl amino sulfonyl, C
1-C
6alkoxycarbonyl amino, C
1-C
6alkoxy carbonyl C
1-C
6alkyl, C
1-C
6alkoxy carbonyl C
1-C
6alkoxyl, amino C
1-C
6alkyl, C
1-C
6alkyl amino C
1-C
6alkyl, C
2-C
8dialkyl amido C
1-C
6alkyl, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11, SO
2nR
10r
11, C (=NOR
9) R
8or R
7; Or R
1with R
2between form five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, phenoxy group, phenoxy group C
1-C
6alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C
1-C
6alkyl, phenyl C
1-C
6alkoxyl, phenyl C
1-C
6alkoxy C
1-C
6alkyl, naphthyl, naphthoxy, naphthoxy C
1-C
6alkyl, naphthyl carbonyl, naphthyl C
1-C
6alkyl, naphthyl C
1-C
6alkoxyl, naphthyl C
1-C
6alkoxy C
1-C
6alkyl, heteroaryl, heteroaryl oxygen base, heteroaryl C
1-C
6alkoxy C
1-C
6alkyl, heteroaryl oxygen base C
1-C
6alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C
1-C
6alkyl or heteroaryl C
1-C
6alkoxyl: halogen, nitro, cyano group, sulfydryl, C
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
2-C
4thiazolinyl, halo C
2-C
4thiazolinyl, C
2-C
4alkynyl, halo C
2-C
4alkynyl, C
3-C
4alkene oxygen base, halo C
3-C
4alkene oxygen base, C
3-C
4alkynyloxy group, halo C
3-C
4alkynyloxy group, C
1-C
4alkyl sulphinyl, halo C
1-C
4alkyl sulphinyl, C
1-C
4alkyl sulphonyl, halo C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy carbonyl, C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxycarbonyl amino, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, CHO, CO
2h, CO
2na, CO
2nH
4, NR
10r
11, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11or SO
2nR
10r
11;
R
8, R
9be selected from hydrogen, C respectively
1-C
4alkyl, aryl or aryl C
1-C
4alkyl;
R
10, R
11may be the same or different, be selected from hydrogen, C respectively
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group or C
3-C
6cycloalkyl.
3. application according to claim 2, is characterized in that: in general formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows;
Q is selected from Q
1, Q
2, Q
3, Q
4, Q
5, Q
6, Q
7, Q
8, Q
9, Q
19, Q
20, Q
21or Q
22;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, amino, CHO, CO independently of one another respectively
2h, CO
2na, CO
2nH
4, C
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
1-C
4alkoxy C
1-C
4alkyl, halo C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkoxy C
1-C
4alkoxyl, halo C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkylthio group C
1-C
4alkyl, halo C
1-C
4alkylthio group C
1-C
4alkyl, C
1-C
4alkyl amino, halo C
1-C
4alkyl amino, C
2-C
6dialkyl amido, halo C
2-C
6dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C
2-C
4thiazolinyl, halo C
2-C
4thiazolinyl, C
2-C
4alkynyl, halo C
2-C
4alkynyl, C
2-C
4alkene oxygen base, halo C
2-C
4alkene oxygen base, C
2-C
4alkynyloxy group, halo C
2-C
4alkynyloxy group, C
1-C
4alkyl sulphonyl, halo C
1-C
4alkyl sulphonyl, C
1-C
4alkyl sulphinyl, halo C
1-C
4alkyl sulphinyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy carbonyl, halo C
1-C
4alkoxy carbonyl, C
1-C
4alkyl amino sulfonyl, C
1-C
4alkoxycarbonyl amino, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, amino C
1-C
4alkyl, C
1-C
4alkyl amino C
1-C
4alkyl, C
2-C
6dialkyl amido C
1-C
4alkyl, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11, SO
2nR
10r
11, C (=NOR
9) R
8or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, phenoxy group, phenoxy group C
1-C
4alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C
1-C
4alkyl, phenyl C
1-C
4alkoxyl, phenyl C
1-C
4alkoxy C
1-C
4alkyl, naphthyl, naphthoxy, naphthoxy C
1-C
4alkyl, naphthyl carbonyl, naphthyl C
1-C
4alkyl, naphthyl C
1-C
4alkoxyl, naphthyl C
1-C
4alkoxy C
1-C
4alkyl, heteroaryl, heteroaryl oxygen base, heteroaryl C
1-C
4alkoxy C
1-C
4alkyl, heteroaryl oxygen base C
1-C
4alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C
1-C
4alkyl or heteroaryl C
1-C
4alkoxyl: halogen, nitro, cyano group, sulfydryl, C
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
2-C
4thiazolinyl, halo C
2-C
4thiazolinyl, C
2-C
4alkynyl, halo C
2-C
4alkynyl, C
3-C
4alkene oxygen base, halo C
3-C
4alkene oxygen base, C
3-C
4alkynyloxy group, halo C
3-C
4alkynyloxy group, C
1-C
4alkyl sulphinyl, halo C
1-C
4alkyl sulphinyl, C
1-C
4alkyl sulphonyl, halo C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy carbonyl, C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxycarbonyl amino, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, CHO, CO
2h, CO
2na, CO
2nH
4, NR
10r
11, C (=O) NR
10r
11, OC (=O) NR
10r
11, C (=S) NR
10r
11or SO
2nR
10r
11;
R
8, R
9be selected from hydrogen, C respectively
1-C
4alkyl, aryl or aryl C
1-C
4alkyl;
R
10, R
11may be the same or different, be selected from hydrogen, C respectively
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group or C
3-C
6cycloalkyl.
4. application according to claim 3, is characterized in that: in general formula I
Ar is selected from Ar1, Ar2 or Ar3;
Q is selected from Q
1, Q
2, Q
3, Q
4, Q
5, Q
6, Q
7or Q
8;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, C independently of one another respectively
1-C
4alkyl, halo C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkylthio group, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkyl amino, C
2-C
6dialkyl amido, C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy carbonyl or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, benzyl, phenethyl, heteroaryl: halogen, nitro, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl or halo C
1-C
4alkoxyl.
5. application according to claim 4, is characterized in that:
Ar is selected from Ar1, Ar2 or Ar3;
Q is selected from Q
1;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, C independently of one another respectively
1-C
4alkyl, halo C
1-C
4alkyl or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, benzyl, heteroaryl: halogen, nitro, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl or halo C
1-C
4alkoxyl.
6. application according to claim 5, is characterized in that:
Ar is selected from Ar3;
Q is selected from Q1;
R
1, R
2, R
3, R
4, R
5, R
6may be the same or different, be selected from hydrogen, halogen, cyano group, C independently of one another respectively
1-C
4alkyl, halo C
1-C
4alkyl or R
7; Or R
1with R
2between form saturated five-membered ring or hexatomic ring;
R
7be selected from unsubstituted or that be independently selected from following group replace further by 1-5 phenyl, benzyl, heteroaryl: halogen, nitro, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl or halo C
1-C
4alkoxyl.
7. the application according to claim 1-6 any one, it is characterized in that: become oral with the Benzofurantone compound shown in general formula I for active fraction preparation or the form of parenteral route carries out the medicine of administration, or carry out the medicine of administration by the form of transplant medicine pump in body.
8. application according to claim 7, it is characterized in that: be active fraction preparation treatment, prevention or the medicine of tumor remission with the Benzofurantone compound shown in general formula I, pharmaceutical dosage form is tablet, pill, capsule, electuary, syrup, injection or freeze-dried powder dosage form.
9. application according to claim 8, is characterized in that: active constituents of medicine is the Benzofurantone compound shown in one or more general formula Is.
10. application according to claim 9, it is characterized in that, be applied to preparation treatment, prevention or alleviate in colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer medicament.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310377457.XA CN104415028B (en) | 2013-08-27 | 2013-08-27 | Application of benzopyrone compound in preparation of anti-tumor drugs |
| KR1020167005378A KR101885219B1 (en) | 2013-08-27 | 2014-08-22 | Applications of Substituent Benzyloxy Group Containing Ether Compounds for Preparing Antitumor Drugs |
| PCT/CN2014/084990 WO2015027863A1 (en) | 2013-08-27 | 2014-08-22 | Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs |
| AU2014314799A AU2014314799B2 (en) | 2013-08-27 | 2014-08-22 | Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs |
| JP2016537112A JP6178010B2 (en) | 2013-08-27 | 2014-08-22 | Application of substituted benzyloxy group-containing ether compounds for the production of antitumor drugs |
| EP14839919.9A EP3040073B1 (en) | 2013-08-27 | 2014-08-22 | Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs |
| CN201480042638.XA CN105431150B (en) | 2013-08-27 | 2014-08-22 | Ether compound containing substituted benzyloxy is used as the application for preparing antineoplastic |
| US14/909,124 US9895346B2 (en) | 2013-08-27 | 2014-08-22 | Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs |
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| CN201310377457.XA CN104415028B (en) | 2013-08-27 | 2013-08-27 | Application of benzopyrone compound in preparation of anti-tumor drugs |
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| CN104415028B CN104415028B (en) | 2017-05-03 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018171688A1 (en) * | 2017-03-22 | 2018-09-27 | Taipei Medical University | Atf3 induction compounds |
| CN112898260A (en) * | 2021-01-21 | 2021-06-04 | 中国药科大学 | 3-carbonyl-2H-benzopyran compound or pharmaceutically acceptable salt thereof, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1616448A (en) * | 2003-11-11 | 2005-05-18 | 沈阳化工研究院 | Benzopyrone compounds with pest killing and sterilizing activity and preparation and use |
| CN1869032A (en) * | 2005-05-26 | 2006-11-29 | 沈阳化工研究院 | Coumarin kind compound and its preparation and application |
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| CN1616448A (en) * | 2003-11-11 | 2005-05-18 | 沈阳化工研究院 | Benzopyrone compounds with pest killing and sterilizing activity and preparation and use |
| CN1869032A (en) * | 2005-05-26 | 2006-11-29 | 沈阳化工研究院 | Coumarin kind compound and its preparation and application |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018171688A1 (en) * | 2017-03-22 | 2018-09-27 | Taipei Medical University | Atf3 induction compounds |
| CN111201232A (en) * | 2017-03-22 | 2020-05-26 | 台北医学大学 | ATF3 inducing compounds |
| US11365200B2 (en) | 2017-03-22 | 2022-06-21 | Taipei Medical University | ATF3 induction compounds |
| CN112898260A (en) * | 2021-01-21 | 2021-06-04 | 中国药科大学 | 3-carbonyl-2H-benzopyran compound or pharmaceutically acceptable salt thereof, preparation method and application |
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| CN104415028B (en) | 2017-05-03 |
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