WO2005063689A1 - ベンズアミド誘導体 - Google Patents
ベンズアミド誘導体 Download PDFInfo
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- WO2005063689A1 WO2005063689A1 PCT/JP2004/019574 JP2004019574W WO2005063689A1 WO 2005063689 A1 WO2005063689 A1 WO 2005063689A1 JP 2004019574 W JP2004019574 W JP 2004019574W WO 2005063689 A1 WO2005063689 A1 WO 2005063689A1
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- alkyl
- alkoxy
- hydroxy
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/42—Y being a carbon atom of a six-membered aromatic ring
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- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention relates to novel benzamide derivatives and medicaments containing them as active ingredients, particularly to angiogenesis inhibitors useful as therapeutic agents for diseases such as malignant tumors involving angiogenesis.
- Angiogenesis is usually observed in adults during physiological phenomena such as endometrial hyperplasia and placental formation associated with the menstrual cycle, and is only observed during wound healing.
- pathological conditions include inflammation, rheumatoid arthritis, arteriosclerosis, diabetic retinopathy, and solid tumors, which often lead to the progression * exacerbation of these diseases.
- solid tumors the formation of vegetative blood vessels is essential for cancer tissue to grow beyond 1-2 mm in diameter (see Non-Patent Document 1). It is closely related to metastasis and the prognosis of cancer patients (see Non-Patent Documents 2 and 3).
- angiogenesis inhibitors are expected to be used as anticancer agents that cause less damage to normal tissues, unlike anticancer agents that exhibit cytotoxicity, and as postoperative adjuvant agents because of their inhibitory effects on cancer cell invasion and metastasis. .
- the process of angiogenesis is based on a multi-step process of destruction of the vascular basement membrane by activation of vascular endothelial cells forming the inside of blood vessels, sprouting and migration of vascular endothelial cells, proliferation, and tube formation.
- vascular endothelial cells involved in angiogenesis are also supplied from vascular endothelial progenitor cells present in peripheral blood and the like (see Non-Patent Document 5).
- Non-Patent Document 6 Non-Patent Document 7 reference.
- JP-A-2001-526255 Patent Document 1, Warner Lambert
- Patent Document 2 Ishihara Sangyo
- Patent Document 3 Emory Univ.
- WO02 / 059080 pamphlet Patent Document 4, Guilford Pharmaceuticals
- WO93Z23357 pamphlet Patent Document 5, Res. Corporation Tech. Inc.
- WO 02Z49632 pamphlet Patent Document 6, Institute for Designing Molecular Drugs discloses a compound having a chemical structure similar to that of the benzamide derivative of the present invention or a salt thereof, using an NFkB activity inhibitor, specifically, It is disclosed as an IKK inhibitor and its application suggests cancer, cancer metastasis, and vascular proliferative disease, but no specific fact is disclosed.
- KDR tyrosine kinase inhibitors for a review, see Non-Patent Document 8, Non-Patent Document 9, and Non-Patent Document 10). ;).
- KDR tyrosine kinase inhibitors for a review, see Non-Patent Document 8, Non-Patent Document 9, and Non-Patent Document 10).
- SU11248 Sugen / Pfizer, a compound having 3- (pyrroyl-2-ylmethylidene) -2-indolinone skeleton, see Patent Document 7
- PTK787 Noveartis, 1-rino (4 pyridyl
- a compound having a methyl) phthalazine skeleton see Patent Document 8.
- Patent Document 9 JP 2001-526255 A
- Patent Document 2 JP-A-2002-249473
- Patent Document 3 International Publication No. 02Z47679 pamphlet
- Patent Document 4 International Publication No.02Z59080 pamphlet
- Patent Document 5 International Publication No. 93Z23357 pamphlet
- Patent Document 6 International Publication No. 02Z49632 pamphlet
- Patent Document 7 International Publication No. 01Z37820 pamphlet
- Patent Document 8 U.S. Patent No. 6258812
- Patent Document 9 International Publication No. 01Z32651 pamphlet
- Patent Document 10 International Publication No. 99Z62890 pamphlet
- Non-Patent Document 1 Folkmann, J., J. Natul. Cancer Inst., Vol. 82, pp. 4-6, 1990
- Non-Patent Document 2 Weidner, N. et al., N. Engl.J. Med., Vol. 324, Pages 1-8, 1991
- Non-Patent Document 3 Bochner, BH et al., J. Natl. Cancer Inst., Vol. 87, pp. 1603-1612, 1995
- Patent Document 4 Klagsbrun, M. and Folkmann, J., Handbook of Experimental Pharmacology, Vol. 95, II, 549-586, 1990
- Non-Patent Document 5 Asahara, T. et al., Science, Vol. 275, pp. 964-967, 1997
- Non-Patent Document 6 Kabbinavar, F. et al., J. Clinical Oncology, Vol. 21, Vol. 60-65. , 2003
- Non-Patent Document 7 Laird, A.D. and Cherrington, J.M., Expert Opinion Investigational Drugs, Vol. 12, pp. 51-64, 2003
- Non-Patent Document 8 Boyer, S.J., Current Topics in Medicinal Chemistry, Volume 2, 973-1000, 2002
- Non-Patent Document 9 Glade—Bender, J., Kandel, J.J. and Yamashiro, D.J., Expert Opinion on Biological Therapy, Vol. 3, No. 2, pp. 263-276, 2003
- Non-Patent Document 10 Laird, AD and JM Cherrington, Expert Opinion Inv estigational Drugs, Vol. 12, No. 1, pp. 51-64, 2003
- the present invention provides a compound having a high angiogenesis inhibitory activity and useful as a therapeutic and prophylactic agent effective for diseases associated with pathological angiogenesis, for example, cancer and cancer metastasis, a method for producing the same, and a useful method for producing the same. It is an object of the present invention to provide novel intermediate compounds, and pharmaceutical compositions containing these compounds.
- the present inventors have conducted intensive studies with the aim of providing a therapeutic and prophylactic agent effective for a novel disease associated with pathological angiogenesis, for example, cancer and cancer metastasis. As a result, the compound of the present invention was obtained. The present inventors have found that they have a selective and high inhibitory activity on angiogenesis, and have further found a production method capable of easily synthesizing these compounds, thereby completing the present invention.
- A is C X or N
- A is C X or N, A is C X or N, A is C X or N, and
- A is C X or N
- R is hydrogen, C alkyl, halo C alkyl, C alkylcarbonyl or
- Aryl where the aryl is a halogen atom, C alkyl and C alcohol.
- Xica may also be substituted with one or more selected substituents;
- X, X, X, X and X each independently represent a hydrogen atom, a hydroxy, a halogen atom
- the above 19 groups may be substituted by one or more substituents selected from halogen, hydroxy, aryl, heteroaryl and cyano), aryl, aryloxy, arylcarbonyl, heteroaryl , Heteroaryloxy, heteroarylcarboyl and arylCalkyloxy (the above 7 groups are
- Atom, c-alkyl and C-alkoxy force selected one or more substitutions
- a group force, which is also substituted by a group, is also selected.
- Y is C alkyl, C cycloalkyl, C alkyl, C alkyl, C alkyl, C alkyl
- 2- 7 2-7 1-6 1-6 Rusulfonyl ⁇ the 15 or more groups are selected from saturated or unsaturated 3- to 7-membered carbocycles, one or more oxygen, nitrogen and sulfur atoms.
- 1-6 1-6 1-6 Phosphono force optionally substituted by one or more substituents selected), nitrogen atom, nitro, carboxyl and one or more oxygen atoms, nitrogen atoms Or unsaturated 3- to 7-membered heterocycle containing a heteroatom selected from and a sulfur atom (the heterocycle may be hydroxy, C alkyl, halo C alkyl, hydroxy C
- Z is a hydrogen atom, hydroxy, C alkyl, C cycloalkyl (the two or more
- Saturated or unsaturated 3- to 7-membered heterocycle containing selected heteroatoms Ring groups are derived from C alkyl, hydroxy C alkyl and C alkoxy C alkyl
- 1-6 1-6 1-6 1-6 optionally substituted by one or more substituents selected), a halogen atom, hydroxy, c alkoxy, hydroxy C alkoxy, C alkoxy C alkoxy,
- Cyano and aminoca may also be substituted by one or more substituents of choice), phosphono, C alkyl phosphono, di C alkyl phosphono, sulfonic acid, and
- R and R are each independently a hydrogen atom, C alkyl, C alkyl
- a saturated or unsaturated 3- to 7-membered heterocyclic ring containing one or more hetero atoms selected from oxygen, nitrogen and sulfur atoms (the above three groups are saturated or unsaturated 3 — 7-membered carbocycle, one or more oxygen, nitrogen and sulfur atoms Saturated or unsaturated, including selected heteroatoms 3—7-membered heterocycle, halogen, hydroxy, C alkoxy, hydroxy C Alkoxy, C alkoxy C alkoxy
- R is selected from the group consisting of
- z include hydrogen atom, methyl, ethyl, cyclopropyl, cyclopentyl, 2-hydroxyethyl, 2- (2-hydroxyethoxy) ethyl, 2-methoxyethyl, 2-cyanoethyl, and 4-pyridylmethyl.
- a Y force halogen atom in the above formula ( ⁇ ⁇ ) or (I), a Y force halogen atom, cyano, C alkyl, halo C alkyl, alkenyl, C alkyl, C alkyl,
- a compound of the above formula ( ⁇ ) or (I) or a prodrug thereof Provide their pharmaceutically acceptable salts.
- specific examples of Y include black mouth, bromo, thiomethyl, trifluoromethyl, ethyl, n-propyl, i-propyl, ethur, methoxy, trifluoromethoxy, cyclopropylmethoxy, 2-butyne 1 Includes yloxy, or 2-ethoxy ethoxy.
- A is C X or
- A is C X or N
- A is C X or N
- A is C X or
- N is A is C X or N;
- X, X, X, X and X 1S each independently represent a hydrogen atom, a halogen atom, a C
- X, X, X and X include a hydrogen atom, fluoro,
- A is CX or N, and A is CX or N
- A is C X or N, A is C X, A is C X, A, A and
- a pharmaceutical composition comprising the above compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- therapeutic and prophylactic agents for diseases involving angiogenesis such as cancer diseases including shaped tumors, and therapeutic and prophylactic agents for metastasis of solid tumors.
- halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
- halogen atom when the halogen atom is a substituent such as an aromatic carbon ring and an aromatic hetero ring, preferred halogen atoms include a chlorine atom and a bromine atom.
- halogen atom when the halogen atom is a substituent of an alkyl group or a group containing alkyl as a part thereof (alkoxy, alkenyl, unsaturated carbocycle, unsaturated heterocycle, etc.), preferred halogen atoms include And a fluorine atom.
- C alkyl is a straight-chain or branched-chain alkyl having 116 carbon atoms.
- a group for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylolebutinole, 1- Includes ethyl propyl, n-hexyl, 4-methynolepentinole, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl.
- C cycloalkyl refers to a cyclic or partially cyclic C3-9
- Alkyl group means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopropylmethyl, cyclohexylmethyl, cyclopropyl substituted with C alkyl group, C alkyl group Place
- C-alkyl refers to a linear or branched alkyl having 2 to 7 carbon atoms.
- kale group includes, for example, ether (Bulle), 1-probe, 2-probe (aryl), propene 2-yl, 3-butule (homoallyl) and the like. .
- C alkynyl is a straight-chain or branched-chain alkynyl having 2 to 7 carbon atoms.
- C alkoxy is one having 1 carbon atom already defined as an alkyl moiety.
- An alkyloxy group having sixteen straight or branched alkyl groups for example, For example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, This includes 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, and 2-ethylbutoxy.
- aryl means a C aromatic hydrocarbon group.
- heteroaryl refers to a 5- to 10-membered aromatic heterocyclic group containing one or more oxygen atoms, nitrogen atoms, and hetero atoms selected from sulfur atoms.
- heteroaryl refers to a 5- to 10-membered aromatic heterocyclic group containing one or more oxygen atoms, nitrogen atoms, and hetero atoms selected from sulfur atoms.
- C alkylcarbon has already been defined as an alkyl moiety.
- alkylcarbonyl group having a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and includes, for example, acetyl, propionyl, methylpropiol, and bivaloyl.
- C alkoxycarbol is already defined as an alkoxy moiety.
- Alkylcarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms for example, methoxycarbon, ethoxycarbon, n-propoxycarbonyl, i-propoxycanoleboninole, n-butoxy Carbonyl, s-butoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, 3-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, 1-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, n-hexyloxy Examples include carbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 1-methylpentoxycarbonyl, 3-ethylbutoxycarbonyl, and 2-ethylbutoxycarbonyl.
- C alkylthio refers to the number of carbon atoms already defined as the alkyl moiety. It means an alkylthio group having 1-6 linear or branched alkyl groups, for example, methylthio, ethylthio, npropylthio, ipropylthio, nbutylthio, s-butylthio, i-butylthio, t-butylthio, n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio, 1-ethylpropylthio, n- hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentyl Luthio, 3-ethylbutylthio, and 2-ethylbutylthio.
- C alkyl sulfol has already been defined as an alkyl moiety.
- alkylsulfonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms such as, for example, methylsulfol, ethylsulfol, n-propylsulfonyl, i-propinolesnorethol Ninore, n-butinores norehoninore, s-butinoresnorehoninore, i-butinore snorehoninore, t butinoresnorehoninore, n pentinoresnorenohonore, 3-methinolebutinoreshonore two Nole, 2-methinolebutinoresnorenolinole, 1-methinolebutinolesnorenolinole, 1-etchinolepropinole snorehoninole, n-hexinolesnorenolenorinole, 4-methylinolepentino
- C alkylamino refers to a carbon atom already defined as an alkyl moiety.
- di C alkylamino has already been defined as two alkyl moieties.
- dialkylamino group having a linear or branched alkyl group having 16 carbon atoms and the two alkyl portions may be the same or different.
- Examples of "1-6 amino" include, for example, di-n-propylamino-containing Examples include lumino, di-n-butylamido-containing methyl-n-butylamido-in-methyl-s-butylamino, methyl i-butylamido-in-methyl-t-butylamido-ethyl, n-butylamido-in-ethyl-s-butyramino, and ethyl-i-butylamido-in-ethyl-t-butylamido.
- saturated or unsaturated 3- to 7-membered carbocycle means a saturated or unsaturated bond-containing hydrocarbon ring having 3 to 7 carbon atoms, which is aromatic. Group hydrocarbon rings are also included.
- saturated or unsaturated 3-7 membered carbocycle includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, benzene and the like.
- saturated or unsaturated 5- to 7-membered carbocycle refers to a saturated or unsaturated bond-containing hydrocarbon ring having 5 to 7 carbon atoms, which is aromatic. Group hydrocarbon rings are also included.
- saturated or unsaturated 5- to 7-membered carbocycle includes, for example, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, benzene and the like.
- saturated or unsaturated 3-7 membered hetero ring refers to a saturated or unsaturated 3 to 7-membered hetero ring containing one or more oxygen atoms, nitrogen atoms and sulfur atoms.
- “Saturated or unsaturated 3-7 membered heterocycle” includes, for example, oxylane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, furan, thiophene, pyrrolyl, imidazole, pyrazole, oxazole, thiazole , Thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrosilane, 1,4-dioxane, morpholine, thiomorpholine and the like.
- the hetero ring when the “saturated or unsaturated 3-7 membered hetero ring” is bonded as a substituent to an aromatic carbon ring such as a benzene ring, the hetero ring is a nitrogen atom in the ring.
- a saturated or unsaturated 5- to 7-membered heterocyclic ring bonded to an aromatic carbocyclic ring for example, pyrrolidine-1-yl, piperidine-1-yl, morpholine-4-yl, piperazine-1-yl, Thiomorpholin-4yl, pyrroyl-1-yl, pyrazole-1-yl, imidazole-1-yl and the like are included.
- Preferred heterocycles are pyrrolidine 1-yl, piperidine 1-yl, morpholine 4-yl, and piperazine 1-yl.
- the term "saturated or unsaturated 5- to 7-membered heterocycle” refers to a saturated or unsaturated 5- or 7-membered heterocycle containing one or more oxygen atoms, nitrogen atoms and sulfur atoms.
- “Saturated or unsaturated 5- to 7-membered heterocycle” includes, for example, pyrrolidine, piperidine, piperazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxaziazole, Thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, morpholine, thiomorpholine and the like are included.
- C alkenyl has already been defined as an alkenyl moiety.
- alkenyloxy group having a linear or branched alkenyl group having 2 to 7 carbon atoms.
- C alkynyloxy has already been defined as an alkyl moiety.
- alkynyloxy group having a linear or branched alkynyl group having 2 to 7 carbon atoms.
- N—C alkylamino C alkoxy N, N—di C alkylamino C alkoxy
- the moiety means an alkyl group and an alkoxy group having 16 carbon atoms or an alkyl group having 217 carbon atoms as defined above.
- pyridyl C alkyl and “morpholino C alkyl”
- substitution position of the alkyl group on the pyridine ring or morpholine ring is not particularly limited.
- halo C alkyl refers to a carbon number already defined as an alkyl moiety.
- 1-6 has 1 or more halogen atoms as substituents
- 1-6 alkyl includes monohalo C alkyl, dihalo C alkyl, trihalo C alkyl and
- no-mouth C alkoxy refers to a carbon already defined as an alkoxy moiety.
- a straight or branched alkoxy group having a prime number of 1 to 6 means an alkoxy group substituted with a halogen atom, wherein the halogen atom is as defined above. Also Halo C
- the alkoxy may have one or more halogen atoms as a substituent.
- Halo c alkoxy includes monohalo C alkoxy, dihalo C alkoxy, trihalo C
- halo C alkylthio refers to a carbon already defined as an alkyl moiety.
- Alkyl may have one or more halogen atoms as a substituent.
- Halo c alkylthio includes monohalo C alkylthio, dihalo C alkylthio, trihalo
- aryloxycarbon means an aryloxycarbon having an aromatic hydrocarbon group defined previously as an aryl moiety.
- Nonoxycarbonyl, 1-naphthoxycarbonyl and 2-naphthoxycarbonyl are included.
- C alkylguadino refers to a guadinino group (—NHC (NH) NH 2)
- 1-6 means that one of the three nitrogen atoms contained in 2 is substituted with a C alkyl group.
- di C alkylgua-dino I refers to a guadinino group (—NHC (NH) NH ) 1S means those substituted with a C alkyl group at two positions on the nitrogen atom, for example, N
- di C alkylamidino refers to an amidino group (1-C (NH) NH 2)
- 1-6 means those substituted with a C alkyl group at two positions on the elementary atom, for example, C (NH)
- hydroxyaminocarbonyl means “1-C (O) NH-OHJ.
- hydroxyamidino means "1-C (NH ) NH—OH ”or tautomers thereof.
- C alkyl phosphono has C alkyl as defined above for the alkyl moiety
- sulfonic acid means "one SO OH”. Also, in the present invention! / ⁇
- C alkylsulfo has a C alkyl as defined above for an alkyl moiety.
- 3-9 3-9 2-7 2-7 '', ⁇ c alkylcarbonyl '' and ⁇ c alkoxycarbol '' may be
- aryl may be one or more in some cases. Substituted with the above halogen atom, C alkyl and C alkoxy
- the number of the substituents may be the maximum number possible in one chemical structure.
- the number of the substituents is, for example, 115, preferably 113.
- heteroaryl carboyl aryloxy carboyl, heteroaryl carbocarb, C alkoxy, Calkoxy, C alkyl
- the number of the substituents may be the maximum number possible in one chemical structure.
- the number of the substituents is, for example, 115, preferably 113.
- C alkyl and “C cycloalkyl” may be
- Nuclear Saturated or unsaturated 3-7 membered heterocycle containing selected heteroatoms The ring group may be c-alkyl, hydroxy C-alkyl and C-alkoxy C-alkyl.
- 1-6 1-6 1-6 1-6 may be substituted with one or more substituents selected from the following), halogen atom, hydroxy, C alkoxy, hydroxy C alkoxy, C alkoxy C alkoxy
- C alkylsulfonylca is substituted by one or more substituents.
- the number of the substituents may be the maximum number possible in one chemical structure.
- the number of the substituents is, for example, 115, preferably 113.
- a saturated or unsaturated 3- to 7-membered heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom may be a saturated or unsaturated 3- to 7-membered carbocycle, 1 or A saturated or unsaturated 3- to 7-membered hetero ring containing a hetero atom selected from the above oxygen, nitrogen and sulfur atoms, a halogen atom, hydroxy, C alkoxy,
- the number of substituents may be the maximum number possible per chemical structure.
- the number of the substituents is, for example, 115, preferably 113.
- the number of the substituents is from 1 to the maximum number that can be substituted in the chemical structure.
- the number of substituents is, for example, 117, typically 115, preferably 113.
- [0071] includes, for example, an aromatic carbocyclic group or an aromatic heterocyclic group as shown below:
- the present invention includes a salt of the compound represented by the formula (I) or ()) and a pharmaceutically acceptable salt of prodrug of the compound. These salts are produced by contacting the compound or a prodrug of the compound with an acid or base that can be used in the manufacture of a medicament.
- Such salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, phosphate, phosphonate, acetate, citrate, malate, salicylic acid Carboxylates such as salts, or alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts, alkylammonium salts, dialkylammonium salts And ammonium salts such as trialkylammonium salts and tetraalkylammonium salts.
- the "prodrug" of the present invention is converted to a compound of the formula (I) or ( ⁇ ) or a pharmaceutically acceptable salt thereof by enzymatic or non-enzymatic degradation under physiological conditions.
- Prodrugs may be inactive when administered to a patient, but will not form active compounds of formula (I) or (II) in vivo. It is something that is converted and exists.
- the prodrug may be inactive when administered to a patient, but is present in a living body after being converted into an active compound of the formula (1).
- the compound represented by formula ( ⁇ ) wherein L is —NH—C (O) — can be prepared, for example, by the method shown in Production Method 11, 1, 1-2, 1-3 or 14 Can be manufactured by
- A, Q, Q, Y, and Z are as defined in the formula ( ⁇ ), and Aa, Qa
- LG represents a leaving group applicable to the reaction, such as halogen or sulfonate.
- the amide (11C) can be produced by dehydrating and condensing the amine derivative (11A) and the benzoic acid derivative (11B). This reaction is carried out in the presence of an acid halogenating agent or dehydrating condensing agent, in the presence or absence of an active esterifying agent, in the presence or absence of a base, in an aprotic solvent, at 0 ° C to 180 ° C. It is done on condition.
- Examples of the acid halogenating agent include salted oxalyl, salted thiol, and the like.
- Examples of the dehydrating condensing agent include carbodiimide conjugates supported on polymers, (eg, N-cyclohexylcarbodiimide-N, monopropyloxymethyl polystyrene (PS-force rubodiimide), 1,3-dicyclohexylcarbodiimide (DCC), 2-ethoxy 1-ethoxycarbol-l, 2-dihydroquinoline (EEDQ), bromo-tris (pyrrolidino) phospho-dimethylhexafluorophosphato (PyBrOP), 1-ethyl-3- ( 3, -dimethylaminopro Pill) carbodiimide (EDC), (benzotriazole yloxy) tripyrrolidino phospho-dimethylhexafluorophosphato (PyBOP) and the like.
- polymers e
- Examples of the active esterifying agent include N-hydroxybenzotriazole (HOBt), di (N-succinimidyl) carbonate, carbodiimidazole and the like.
- Examples of the base include triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-indene (DBU) and the like.
- Examples of the aprotic solvent include carboxylic acid amides such as formamide or N, N-dimethylformamide, for example, halogenated hydrocarbons such as dichloromethane, tetrachloromethane, and chlorobenzene, and ketones such as acetone, for example, tetrahydrofuran. Or a cyclic ether such as dioxane, an ester such as ethyl acetate, or -tolyl such as acetonitrile, or a mixture thereof.
- LG represents a leaving group applicable to the reaction, such as a halogen atom or a sulfonate.
- Cyanation of a compound having a leaving group on the benzene ring can be carried out, for example, by appropriately applying the method described in Synthetic Communication, 887-90, 24 (6), (1994).
- the compound (1-1-C) is reacted in a solvent inert to the reaction, for example, in N, N-dimethylformamide in the presence of a catalytic amount of a palladium complex, for example, tetrakistriphenylphosphine palladium.
- a metal cyanide for example, zinc cyanide
- the corresponding cyanide (1-1D) can be obtained.
- Hydrolysis of the nitrile group to an amide is carried out, for example, by a method using hydrogen peroxide and an inorganic base (eg, Org. Syn. Coll. Vol. 2, 586-588 (1943)., J. Med. Chem., 43, 87 3-882 (2000).), In an aliphatic alcohol or dimethyl sulfoxide in the presence of an inorganic base (for example, JP-A-2000-86610, JP-A-2001-39936, etc.), or an acid. (For example, JP-A-6-239810), and the method described in these methods can be applied as appropriate.
- an inorganic base for example, JP-A-2000-86610, JP-A-2001-39936, etc.
- an acid for example, JP-A-6-239810, and the method described in these methods can be applied as appropriate.
- the method is a method of converting into amide (11E) using an aqueous hydrogen peroxide solution in the presence of an inorganic base such as potassium carbonate.
- an inorganic base such as potassium carbonate.
- dimethyl sulfoxide or the like can be used as a reaction solvent. Reaction time from about 10 minutes About 30 hours. Reaction temperatures range from about 10 ° C power to about 100 ° C.
- the compound (11F) as the final target product can be produced by performing a deprotection reaction and / or functional group modification in this step.
- a deprotection reaction for example, a hydroxyl group, an amino group, a halogen, a carboxyl group, a carbonyl group, a nitro group, a cyano group, a carbon
- the compound (11F) as the final target product can be produced by performing a deprotection reaction and / or functional group modification in this step.
- various known methods can be used.
- the selection and desorption operations of the protecting group can be performed, for example, by the method described in “Greene and Wuts,“ Protective Groups in Organic Sythesis ”” (2nd edition, John Wiley & Sons 1991).
- A, Q, Q, Y and Z are as defined in the formula (II), and Aa, Qa
- R represents a C alkyl group such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, and tert-butyl. Note that in the step 3
- Optically active compounds of the present invention can be obtained by using optically active amines as raw materials.
- a Q Q Y and Z are as defined in the formula ( ⁇ ), and Aa Qa
- a Q Q Y and Z are as defined in equation ( ⁇ ), and Aa Qa
- Step 2 (Nitrile hydrolysis) Production Method 1 1 Step 3 The same conditions as in -tolyl hydrolysis can be applied.
- LG represents a leaving group applicable to the reaction, such as halogen or sulfonate.
- W represents an O, O'-di-hydrocarbon-phosphono group or a triarylphospho-dim group. When W represents a triarylphospho-dimethyl group, part of the phenyl group in the phospho-dimethyl moiety may be polymerized.
- A, Q, Q, Y and Z are as defined in the formula (II), and Aa, Qa
- R represents a C alkyl group such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, and tert-butyl.
- W is 0,0, -G hydrocarbon-phosphono
- a triarylphospho-dum group When w represents a triarylphospho-dimethyl group, a part of the phenyl group in the phospho-dimethyl moiety may be polymerized.
- an optically active compound of the present invention can be obtained by using an optically active amine as a raw material.
- A, Q, Q, Y and Z are as defined in formula (II), and Aa, Qa
- w represents an o, o'-dihydrocarbon monophosphono group or a triarylphospho-dum group.
- W represents a triarylphospho-dimethyl group, a part of the phenyl group in the phospho-dimethyl moiety may be polymerized.
- A, Q, Q, Y and Z are as defined in the formula (II), and Aa, Qa
- w represents an o, o'-dihydrocarbon monophosphono group or a triarylphospho-dum group.
- W represents a triarylphospho-dimethyl group, a part of the phenyl group in the phospho-dimethyl moiety may be polymerized.
- A, Q, Q, Y and Z are as defined in the formula (II), and Aa, Qa
- w represents an o, o'-dihydrocarbon monophosphono group or a triarylphosphonium group.
- W represents a triarylphospho-dimethyl group, a part of the phenyl group in the phospho-dimethyl moiety may be polymerized.
- the compound in which L is represented by —NH—C (O) — in the formula (I) can be produced, for example, by the method shown in Production Method 3-1, 3-2, or 3-3.
- a, Xa, Xa, Xa, Xa, Y and Z are each X, X, X,
- LG is halogen, sulfonate
- An amide (3-1C) can be produced by dehydrating and condensing the aniline derivative (3-1A) and the benzoic acid derivative (3-1B). This reaction is carried out in the presence of an acid halogenating agent or dehydrating condensing agent, in the presence or absence of an active esterifying agent, in the presence or absence of a base, in an aprotic solvent, at 0 ° C to 180 ° C. Done in
- Examples of the acid halogenating agent include salted oxalil, salted thiol, and the like.
- Examples of the dehydration condensing agent include a carbodiimide conjugate carried on a polymer, (eg, N-cyclohexylcarbodiimide-N, monopropyloxymethyl polystyrene (PS-force rubodiimide)), 1,3-dicyclohexyl Carbodiimide (DCC), 2-ethoxy 1-eth Xicarbol-1,2-dihydroquinoline (EEDQ), bromo-tris (pyrrolidino) -phospho-dimethylhexafluorophosphoate (PyBrOP), 1-ethyl-3- (3-dimethylaminopropyl pill)
- Examples include carbodiimide (EDC), (benzotriazoleyloxy) tripyrrolidino-phospho-dimethylhexafluorophosphato (PyBOP) and the
- Examples of the active esterifying agent include N-hydroxybenzotriazole (HOBt), di (N-succinimidyl) carbonate, carbodiimidazole and the like.
- Examples of the base include triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-indene (DBU) and the like.
- aprotic solvent examples include carboxylic acid amides such as formamide or N, N-dimethylformamide; halogenated hydrocarbons such as dichloromethane, tetrachloroanilide or chlorobenzene; ketones such as acetone; Examples include cyclic ethers such as tetrahydrofuran or dioxane, esters such as ethyl acetate, or -tolyl such as acetonitrile, or mixtures thereof.
- LG represents a leaving group applicable to the reaction, such as a halogen atom or a sulfonate.
- Cyanation of a compound having a leaving group on the benzene ring can be carried out, for example, by appropriately applying the method described in Synthetic Communication, 887-90, 24 (6), (1994).
- compound (3-1-C) is reacted in a solvent inert to the reaction, for example, in N, N-dimethylformamide in the presence of a catalytic amount of a palladium complex, for example, tetrakistriphenylphosphine palladium.
- a metal cyanide for example, zinc cyanide
- Hydrolysis of the nitrile group to an amide is carried out, for example, by a method using hydrogen peroxide and an inorganic base (eg, Org. Syn. Coll. Vol. 2, 586-588 (1943)., J. Med. Chem., 43, 87 3-882 (2000).), In an aliphatic alcohol or dimethyl sulfoxide in the presence of an inorganic base (for example, JP-A-2000-86610, JP-A-2001-39936, etc.), or an acid. (For example, JP-A-6-239810), and the method described in these methods can be applied as appropriate.
- an inorganic base for example, JP-A-2000-86610, JP-A-2001-39936, etc.
- an acid for example, JP-A-6-239810, and the method described in these methods can be applied as appropriate.
- an inorganic base such as charcoal
- This is a method of converting into amide (3-1E) using hydrogen peroxide solution in the presence of potassium acid.
- a reaction solvent dimethyl sulfoxide or the like can be used. Reaction times are from about 10 minutes to about 30 hours. Reaction temperatures range from about 10 ° C power to about 100 ° C.
- the compound (3-1E) as the final target product can be produced by performing a deprotection reaction and / or functional group modification in this step.
- a deprotection reaction for example, a hydroxyl group, an amino group, a halogen, a carboxyl group, a carbonyl group, a nitro group, a cyano group
- various known methods can be used.
- the selection and desorption operations of the protecting group can be performed, for example, by the method described in “Greene and Wuts,“ Protective Groups in Organic Sythesis ”” (2nd edition, John Wiley & Sons 1991).
- Xa, Xa, Xa, Xa, Y and Z are each X, X, X in the definition of formula (I)
- X, Y and Z have the same definition, or by functional group modification or deprotection,
- X, X, X, X, Y and Z represent a group that can be converted.
- R is methyl, ethyl, propyl,
- Production Method 3-1 The same conditions as in the amidation in Step 1 can be applied.
- the hydrolysis of the ester group is carried out in an aqueous medium such as an alcohol solvent in the presence of an inorganic base.
- an aqueous medium such as an alcohol solvent
- an inorganic base for example, Corey, EJ; Szekely, I .; Shiner, CS Tetrah edron Lett. 3529, 1977
- a method for hydrolysis in the presence of an acid for example, Bry an, DB; Hall, RF; Holden, KG Fuffman, WF; Gleason, JG Am. Chem. Soc, 1977, 99, 2353
- the hydrolysis is performed using an aqueous solution of potassium hydroxide or sodium hydroxide in an alcohol solvent such as ethanol.
- the reaction time is about 10 minutes and about 30 hours, preferably about 30 minutes and about 3 hours.
- the reaction temperature is in the temperature range of 0 ° C and the boiling point of the solvent, preferably about 80 ° C to 100 ° C.
- amide (3-2-E) by dehydration-condensation of various amines such as ammonia, hydrazine, monosubstituted amine, substituted hydrazine and the like with a benzoic acid derivative (3-2-D).
- This reaction is carried out in the presence of an acid halogenating agent or a dehydrating condensing agent, in the presence or absence of an active esterifying agent, in the presence or absence of a base, in an aprotic solvent at 0 ° C to 180 ° C. It is done on condition.
- an optically active amine as a raw material, an optically active compound of the present invention can be obtained.
- Examples of the acid halogenating agent include salted oxalil, salted thiol, and the like.
- Examples of the dehydrating condensing agent include carbodiimide conjugates supported on a polymer (eg, N-cyclohexylcarbodiimide-N ′ propyloxymethyl polystyrene (PS carbodiimide)), 1,3-dicyclohexylcarbodiimide (DCC ), 2-ethoxy 1-ethoxy carbol-l, 2-dihydroquinoline (EEDQ), bromo-tris (pyrrolidino) phospho-dimethylhexafluorophosphato (PyBrOP), 1-ethyl 3- (3,- Examples thereof include (dimethylaminopropyl) carbodiimide (EDC) and (benzotriazoleyloxy) tripyrrolidino phospho-dimethylhexafluorophosphato (PyBOP).
- a polymer eg
- Examples of the active esterifying agent include N-hydroxybenzotriazole (HOBt), di (N-succinimidyl) carbonate, carbonyldiimidazole and the like.
- Examples of the base include triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-pandacene (DBU) and the like.
- aprotic solvents include carboxylic acid amides such as formamide or N, N-dimethylformamide, for example, dichlorometha Halogenated hydrocarbons such as tetrahydrofuran or chlorobenzene, ketones such as acetone, cyclic ethers such as tetrahydrofuran or dioxane, esters such as ethyl acetate, or -tolyl such as acetonitrile, or the like. And mixtures thereof.
- carboxylic acid amides such as formamide or N, N-dimethylformamide
- dichlorometha Halogenated hydrocarbons such as tetrahydrofuran or chlorobenzene
- ketones such as acetone
- cyclic ethers such as tetrahydrofuran or dioxane
- esters such as ethyl acetate, or -tolyl such as acetonitrile, or the like.
- esters such as
- the benzoic acid derivative ester derivative (3-2-C) obtained in step 1 can be converted to an amide (3-2-E) without undergoing the ester hydrolysis in step 2. That is, this reaction is carried out in the presence or absence of an activator such as a Lewis acid in a benzoic acid derivative ester derivative, or in the presence of various amines, for example, ammonia or an aliphatic amine, in an aprotic or protic solvent. The reaction is carried out at 0 ° C-180 ° C under normal pressure or under pressure.
- Xa, Xa, Xa, Xa, Y and Z are each X, X, X in the definition of formula (I)
- X, Y and Z have the same definition, or by functional group modification or deprotection,
- X, X, X, X, Y and Z represent a group that can be converted.
- Xa, Xa, Xa, Xa, Y and Z are each X, X, X in the definition of formula (I)
- X, Y and Z have the same definition, or by functional group modification or deprotection,
- X, X, X, X, Y and Z represent a group that can be converted.
- LG is halogen, sulfonate, etc.
- w represents an o, o'-di-hydrocarbon-phosphono group or a triarylphosphonium group.
- W represents a triarylphosphonium group
- part of the phenyl group in the phosphonium moiety may be polymerized.
- the dehydration condensation of the phosphorus compound (41A) and the aldehyde (41B) Stilbene derivative (4-1-C) can be produced.
- This reaction is carried out in a solvent in the presence of a base at a reaction temperature of -78 ° C solvent boiling point.
- the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, calcium hydride, pyridine, triethylamine, N, N-diisopropylethylamine, lithium diisopropylamide, and the like.
- Examples thereof include organic bases such as lithium hexamethyldisilazide, n-butyllithium, and sodium amide, and preferably include sodium hydride, lithium isopropylamide, and lithium hexamethyldisilazide.
- Examples of the solvent include non-reactive solvents. Examples include tetrahydrofuran, getyl ether, dioxane, methanol, ethanol, toluene, n-xane, and dimethylformamide. Tetrahydrofuran and getyl ether are preferred.
- Production method 3-1 The same conditions as in the cyanation in step 2 can be applied.
- Production Method 3-1 The same conditions as in 1-step 3 -tolyl hydrolysis can be applied.
- Xa, Xa, Xa, Xa, Y and Z are each X, X, X in the definition of formula (I)
- X, Y and Z have the same definition, or by functional group modification or deprotection,
- X, X, X, X, Y and Z represent a group that can be converted.
- R is methyl, ethyl, propyl,
- W represents a triarylphospho-pam group
- a part of the phosphoryl group of the phospho-pam moiety may be polymerized.
- an optically active compound of the present invention can be obtained.
- the benzoic acid derivative ester derivative obtained in Step 1 can be converted to an amide without undergoing Step 2 ester hydrolysis. That is, this reaction is carried out in the presence or absence of an activator such as a Lewis acid in a benzoic acid derivative ester derivative, or in the presence of various amines, for example, ammonia or an aliphatic amine, in an aprotic or protic solvent. The reaction is carried out at 0 ° C-180 ° C under normal pressure or under pressure.
- Xa, Xa, Xa, Xa, Y and Z are each X, X, X,
- X, X, X, Y, and z represent groups that can be converted.
- w is o, o, zy hydrocarbon-ho Represents a suphono group or a triarylphospho-dimethyl group.
- W represents a triarylphospho-dimethyl group, a part of the phenyl group in the phospho-dimethyl moiety may be polymerized.
- Production Method 4 1 The same conditions as in the condensation in step 1 can be applied.
- starting compounds of the compound of the present invention are novel compounds, and these compounds can be easily synthesized in the same manner as known starting materials or using methods known to those skilled in the art.
- Examples of amines that can be used as a raw material in the amidation step in Production Methods 12, 2, 2, 3, 2 and 42 include 2,4-dihydroxybutylamine, 2,3-dihydroxybutylamine, 2,3-dihydroxypropylamine, 2-hydroxy-1-methylethylamine, 1-methoxymethylpropylamine Amino acids such as homoserine, threon, tyrosine, lysine, glutamic acid, and aspartic acid.
- the carboxyl group of the amino acid and Z or the functional group contained in the amino acid residue may be protected by a protecting group. It may be subjected to group modification (for example, carboxyl group amidation).
- an example of the method for producing the compounds of the formula (I) and the formula (II) according to the present invention is as follows: Isolation of the target compound shown in the above reaction step It can be performed by applying ordinary chemical operations such as distillation, crystallization, filtration, recrystallization, and various types of chromatography.
- the compounds of the present invention and pharmaceutically acceptable salts thereof include all stereoisomers (for example, enantiomers, diastereomers (cis and trans geometries) of the compounds represented by formula (I) and formula ( ⁇ ). Including isomers;;)), racemic forms of the isomers, and other mixtures. Is included.
- the compound of the present invention may be a compound of the formula (I) or ( ⁇ ) in which Z may have one or more asymmetric points.
- the present invention provides a racemic mixture of such compounds, a diastereomer mixture , And enantiomers.
- the compounds of the present invention and pharmaceutically acceptable salts thereof can exist in several tautomeric forms, for example, enol and imine forms, keto and enamine forms, and mixtures thereof.
- Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer is usually predominant. Although one tautomer may be described, the present invention includes all tautomers of the compounds of the present invention.
- the compound of the present invention when obtained as a free form, it can be converted to a salt or a hydrate or solvate thereof which may be formed by the compound according to a conventional method.
- the compound according to the present invention When the compound according to the present invention is obtained as a salt, hydrate or solvate of the compound, it can be converted to a free form of the compound according to a conventional method.
- the compound according to the present invention or a pharmaceutically acceptable salt thereof has an excellent angiogenesis inhibitory action, is excellent in stability in the body and solubility in water, and is a prophylactic or therapeutic agent for a proliferative disease. (Especially a therapeutic agent).
- the compound according to the present invention or a pharmaceutically acceptable salt thereof includes breast cancer, colorectal cancer, ovarian cancer, lung cancer, spleen cancer, liver cancer, uterine cancer, brain cancer, prostate cancer, acute leukemia, It is also useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for diseases such as various cancers such as gastric cancer.
- the compounds of the present invention are useful as preventive or therapeutic agents (particularly therapeutic agents) for invasion and metastasis of solid cancer.
- the compounds of the present invention are also effective as prophylactic or therapeutic agents for other diseases associated with angiogenesis, such as Aluno, Ima's disease and HIV infection.
- the pharmaceutical composition of the present invention is used as an angiogenesis inhibitor, a therapeutic or prophylactic agent for a proliferative disease
- its administration method is oral, rectal, parenteral (intravenous, Intramuscular Topical, subcutaneous), intracisternal, vaginal, intraperitoneal, intravesical, topical (drip, powder, ointment, gel or cream) and inhalation (intraoral or nasal spray) .
- the dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and containers filled into individual doses. Parenteral solutions include. Dosage forms may also be adapted for various modes of administration, including controlled release formulations, such as subcutaneous implantation.
- compositions are produced by known methods using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, diluents and the like.
- additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, diluents and the like.
- excipients include starch such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.
- Examples of the coating agent include ethyl cellulose and hydroxypropyl cellulose.
- Hydroxypropyl methylcellulose shellac, talc, carnaupa wax, paraffin and the like.
- binder examples include polybutylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients.
- disintegrant examples include the same compounds as the above-mentioned excipients and chemically modified starch / cellulose such as croscarmellose sodium, sodium carboxymethyl starch, and cross-linked polybutylpyrrolidone. .
- Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenolethyl alcohol; benzalkonium chloride; and phenols such as phenol and tarezol. Anols; thimerosal; dehydroacetic acid; and sorbic acid.
- flavoring agent examples include, for example, commonly used sweeteners, sour agents, flavors and the like.
- a solvent for producing a liquid preparation ethanol, phenol, cresol, purified water, distilled water and the like can be used.
- the surfactant or emulsifier examples include polysorbate 80, polyoxystearate 40, lauromacrogol, and the like.
- the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof may vary depending on symptoms. , Age, weight, relative health, presence of other medications, administration method, etc.
- the generally effective amount is an effective component (a compound of the present invention represented by the formula (I) or ( ⁇ )) as an oral preparation.
- the daily dose is preferably 10-10 mg / kg for normal weight adult patients.
- the amount is preferably 0.1 to 1000 mg / kg of body weight per day, more preferably 10 to 800 mg / kg of body weight. It is desirable to administer this once or several times according to the symptoms
- the present invention provides a benzamide compound having a high angiogenesis inhibitory activity by a mechanism different from that of the existing NF-KB inhibitory effect and KDR tyrosine kinase activity inhibition. Further, according to the present invention, compounds useful for therapeutic and prophylactic agents effective for diseases associated with pathological angiogenesis such as cancer and cancer metastasis, production methods thereof, intermediate compounds useful for the production thereof, and these compounds A pharmaceutical composition is provided.
- FIG. 1 Changes in tumor volume when 600 mg Zkg of compound 111 of the present invention was administered to mice
- FIG. 2 is an example of the results of an antitumor test showing the change in tumor volume (A) and the rate of change in body weight (B) when 600 mg Zkg of Compound 2-1 1 of the present invention was administered to mice.
- the functional group was protected with a protecting group, if necessary, and after preparing the target molecule, the protecting group was removed.
- the selection and desorption operations of the protecting group were carried out, for example, by the method described in [Greene ana "uts, Protective Groups m Organic Synthesis” (No. 2
- Example 1-1-1 1—50 mg of 3-N— (4-chlorophenol) 4-methoxyisophthalamide obtained in Step E (di-animation compound 1-1-1-l) was added to 5 mL of dichloromethane. The suspension was suspended and stirred, and 0.16 M boron tribromide dichloromethane solution 1. OmL was added dropwise at room temperature. After stirring for 1 hour, 0.7 mL of a 0.16M boron tribromide dichloromethane solution was added dropwise at room temperature, and the mixture was further stirred for 30 minutes.
- reaction solution was diluted with 50 mL of ethyl acetate, washed with 0.1 M hydrochloric acid and then with saturated saline, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 44 mg of a colorless solid.
- lOmg and potassium carbonate 9mg were suspended in lmL of N, N-dimethylformamide. 3 ⁇ L of propyl iodide was added to the suspension and stirred at 70 ° C. for 1 hour.
- the reaction solution cooled to room temperature was diluted with 50 mL of ethyl acetate, washed with distilled water and then with saturated saline, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified using Waters 996-600E gradient high performance liquid chromatography with micromass (micromass ZMD) to give a white solid, 3-N- (4-clo-port) 4-propoxyisolate. 6 mg (52%) of phthalamide was obtained.
- Example 1-1-1-1 3-N- (4-chlorophenyl) 4-methoxyisophthalamide obtained in Step E, 2.56 g, was suspended in 136 mL of dichloromethane. A solution of boron bromide in dichloromethane was added dropwise at room temperature until the reaction was completed. The reaction solution was diluted with 500 mL of ethyl acetate, washed with 0.1 M hydrochloric acid and then with saturated saline, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 2. Og of a white solid.
- the solution was washed with distilled water and then with a saturated saline solution, and dried over anhydrous sodium sulfate.
- the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure.
- the residue was dissolved in 3 mL of methanol, and 20 mg of potassium carbonate was added to this solution, followed by stirring at room temperature for 1 hour.
- the reaction solution was diluted with 50 mL of ethyl acetate, washed with saturated sodium chloride ammonium, and dried over anhydrous sodium sulfate.
- the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure.
- the anhydrous sodium sulfate was separated by filtration and washed with ethyl acetate.
- the filtrate and washing solution were combined, and the ethyl acetate was distilled off under reduced pressure.
- the obtained residue was washed with a n-xane solution containing a small amount of getyl ether, dried under reduced pressure, and dried under reduced pressure. lg (96%) was obtained.
- N- (4 trifluoromethoxyphenyl) 4-methoxyisophthalamic acid ethyl obtained in Step E was dissolved in 2 mL of methanol, and 0.8 mL of a 20% aqueous potassium hydroxide solution was obtained. The solution was stirred at 80 ° C for 30 minutes, and then cooled to room temperature. After adjusting the pH to about 3 using 3 mL of 1 M hydrochloric acid, the aqueous solution was extracted with ethyl acetate. After combining the organic layers, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
- the obtained residue was purified by column chromatography (silica gel 5 g, aminopropyl-modified silica gel 2 g) using a 100: 1 mixture of dichloromethane and methanol as an eluting solvent to give 3-N- (4-trifluoromethoxyphenyl) 4-methoxy. 45 mg (96%) of isophthalamide were obtained.
- Example 1-2-1 According to the method described in Steps E, F and G, 4-tert-butyla-phosphoric acid was used instead of 4-chloroa-phosphoric acid.
- Example 1-mg of 4-methoxyisophthalate obtained in Step D and 2 L of N, N-dimethylformamide were dissolved in 5 mL of dichloromethane and cooled to 0 ° C. To this solution was added 59 L of Shiridani Oxalil little by little, and the mixture was stirred at 0 ° C for 20 minutes and then at room temperature for 16 hours. A pale yellow solid obtained by evaporating the reaction solution under reduced pressure and drying was dissolved in 3 mL of dichloromethane, and a solution of 63 mg of 4-chloroa-phosphine and 234 L of N, N-diisopropylethylamine dissolved in 2 mL of dichloromethane Added.
- N- (4-chlorophenol) ethyl 4-methoxyisophthalamate obtained in Step A was dissolved in 200 mL of methanol and 60 mL of a 20% aqueous potassium hydroxide solution. The solution was stirred at 80 ° C for 30 minutes, and then cooled to room temperature. After adjusting the pH to about 3 using 1M hydrochloric acid, the resulting precipitate is separated by filtration, washed with water, and dried under reduced pressure over calcium chloride, to give N- (4-chlorophenyl) 4-methoxyisophthalic acid. 10.7 g (99%) were obtained.
- Step B 140 mg of N- (4-chloromouth phenol) 4-methoxyisophthalic acid obtained in Step B was dissolved in 20 L of N, N-dimethylformamide and 4 mL of dichloromethane, and cooled to 0 ° C. To this solution, 60 L of Shiridani Oxalil was added little by little, and the mixture was stirred at 0 ° C for 20 minutes and then at room temperature for 30 minutes. The light yellow solid obtained by evaporating the reaction solution under reduced pressure and drying was 3 mL. Dissolved in dichloromethane.
- Example 1-2-1 By a similar operation to the production method described in Step G, it was synthesized using N- (4-chlorophenol) 4-methoxyisophthalic acid and methylamine hydrochloride.
- N- (4-chlorophenyl) was obtained in the same manner as in the production method described in Step 1-2, Step C.
- Example 1-2-3 Synthesized using N- (4-chlorophenyl) 4-methoxyisophthalic acid and cyclopropylamine in the same operation as in the production method described in Step C. [0339] ESI (LCZMS positive mode) mZz 345, 347 (M + H +); retention time 2.85 minutes
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AT04807929T ATE509905T1 (de) | 2003-12-26 | 2004-12-27 | Benzamidderivate |
US10/584,233 US7705053B2 (en) | 2003-12-26 | 2004-12-27 | Benzamide derivative |
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Cited By (4)
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US7754717B2 (en) | 2005-08-15 | 2010-07-13 | Amgen Inc. | Bis-aryl amide compounds and methods of use |
CN103342654A (zh) * | 2013-07-02 | 2013-10-09 | 扬州大学 | 腈基水解为酰胺基的新方法 |
JP2019506382A (ja) * | 2016-01-12 | 2019-03-07 | タイペイ メディカル ユニバーシティ | 癌及びウイルスを阻害するための化合物 |
JP2021535169A (ja) * | 2018-09-03 | 2021-12-16 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Teadモジュレーターとして有用なカルボキサミドおよびスルホンアミド誘導体 |
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CA2681850C (en) | 2007-04-20 | 2013-07-23 | Acucela Inc. | Styrenyl derivative compounds for treating ophthalmic diseases and disorders |
TWI490214B (zh) * | 2008-05-30 | 2015-07-01 | 艾德克 上野股份有限公司 | 苯或噻吩衍生物及該等作為vap-1抑制劑之用途 |
US8653086B2 (en) | 2008-10-21 | 2014-02-18 | Oregon Health & Science University | Naphthamides as anticancer agents |
LT2682382T (lt) * | 2009-02-16 | 2017-02-27 | Sumitomo Chemical Company, Limited | Fenilacetamido junginio gavimo būdas |
KR101642097B1 (ko) * | 2009-09-22 | 2016-07-25 | 주식회사유한양행 | 신규의 글루코키나제 활성화제 및 그의 제조방법 |
CN108276307A (zh) * | 2018-01-17 | 2018-07-13 | 常熟浸大科技有限公司 | 3-氰基-4-烃氧基苯甲酸酯的合成方法 |
US20220387359A1 (en) * | 2019-10-24 | 2022-12-08 | Oregon Health & Science University | Synergistic inhibitors of creb-mediated gene transcription |
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- 2004-12-24 TW TW093140633A patent/TW200529812A/zh unknown
- 2004-12-27 US US10/584,233 patent/US7705053B2/en active Active
- 2004-12-27 JP JP2005516699A patent/JP4844961B2/ja not_active Expired - Fee Related
- 2004-12-27 AT AT04807929T patent/ATE509905T1/de not_active IP Right Cessation
- 2004-12-27 WO PCT/JP2004/019574 patent/WO2005063689A1/ja not_active Application Discontinuation
- 2004-12-27 EP EP04807929A patent/EP1698618B1/en not_active Not-in-force
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2010
- 2010-03-23 US US12/730,093 patent/US8063046B2/en not_active Expired - Fee Related
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WO1997003967A1 (en) * | 1995-07-22 | 1997-02-06 | Rhone-Poulenc Rorer Limited | Substituted aromatic compounds and their pharmaceutical use |
WO2002059080A2 (en) * | 2001-01-25 | 2002-08-01 | Guilford Pharmaceuticals Inc. | Trisubstituted carbocyclic cyclophilin binding compounds and their use |
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US7754717B2 (en) | 2005-08-15 | 2010-07-13 | Amgen Inc. | Bis-aryl amide compounds and methods of use |
US8492404B2 (en) | 2005-08-15 | 2013-07-23 | Amgen Inc. | Bis-aryl amide compounds and methods of use |
CN103342654A (zh) * | 2013-07-02 | 2013-10-09 | 扬州大学 | 腈基水解为酰胺基的新方法 |
JP2019506382A (ja) * | 2016-01-12 | 2019-03-07 | タイペイ メディカル ユニバーシティ | 癌及びウイルスを阻害するための化合物 |
JP2021535169A (ja) * | 2018-09-03 | 2021-12-16 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Teadモジュレーターとして有用なカルボキサミドおよびスルホンアミド誘導体 |
JP7535500B2 (ja) | 2018-09-03 | 2024-08-16 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Teadモジュレーターとして有用なカルボキサミドおよびスルホンアミド誘導体 |
Also Published As
Publication number | Publication date |
---|---|
US8063046B2 (en) | 2011-11-22 |
US20070123493A1 (en) | 2007-05-31 |
ATE509905T1 (de) | 2011-06-15 |
EP1698618A4 (en) | 2007-03-21 |
US20100179326A1 (en) | 2010-07-15 |
US7705053B2 (en) | 2010-04-27 |
EP1698618A1 (en) | 2006-09-06 |
JPWO2005063689A1 (ja) | 2007-12-20 |
TW200529812A (en) | 2005-09-16 |
EP1698618B1 (en) | 2011-05-18 |
JP4844961B2 (ja) | 2011-12-28 |
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