Quinazoline compounds

专利摘要:
The present invention relates to compounds of formula (I). [Formula I] In the above formula, Ring A is phenyl or a 5- or 6-membered heterocyclic ring as defined herein, Z is -O-, -NH- or -S-, m is an integer containing 0 to 5, R 1 is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or —NR 5 R 6 (where R 5 And R 6 may be the same or different and is hydrogen or C 1-3 alkyl), R 2 is hydrogen, hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, amino or nitro, R 3 is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro, ring A is 5- or 6- At least one R 3 when it is a heterocyclic ring is either hydroxy or halogeno, X 1 is -O-, -CH 2- , -S-, -SO-, -SO 2- , -NR 7- , -NR 7 CO-, -CONR 7- , -SO 2 NR 7 -or -NR 7 SO 2- , wherein R 7 is hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, R 4 is selected from a number of groups defined herein comprising C 2-5 alkylene, C 3-5 alkenylene or C 3-5 alkynylene chains, wherein each methylene group is a (methylene group of α-carbon Are optionally substituted by one substituent each selected from hydroxy, halogeno, amino and C 1-4 alkanoyloxy, the conditions being as defined herein. The invention also provides a pharmaceutical composition comprising a compound of formula (I), the use of a compound of formula (I) in the manufacture of a medicament for use in causing antiangiogenic and / or vascular permeability reducing effects in warm blooded animals, and warm blooded animals in need of treatment To anti-angiogenic and / or vascular permeability-reducing effects. The compounds are useful for disease states such as cancer, rheumatoid arthritis and psoriasis.
公开号:KR20020084295A
申请号:KR1020027013364
申请日:2001-04-03
公开日:2002-11-04
发明作者:에네껭로렝프랑스와앙드레；스토크일레인소피일리저버쓰
申请人:아스트라제네카 아베；
IPC主号:

专利说明:

Quinazolin compounds {QUINAZOLINE COMPOUNDS}
[2] Normal angiogenesis plays an important role in a variety of processes, including various components of fetal development, wound healing and female reproduction. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atherosclerosis, Kaposi's sarcoma and hemangioma (Fan et al , 1995, Trends Pharmacol. Sci. 16: 57-66, Folkman, 1995, Nature Medicine 1: 27-31). Alteration of vascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al , 1993, Endocrinology 133: 829-837, Senger et al , 1993, Cancer and Metastasis Reviews, 12: 303324). Several polypeptides with in vitro endothelial cell growth promoting activity have been identified, including acidic and basic fibroblast growth factor (aFGF & bFGF) and vascular endothelial growth factor (VEGF). In contrast to the growth factor activity of FGFs due to the limited expression of these receptors, the growth factor activity of VEGF is relatively specific for endothelial cells. Recent evidence indicates that VEGF is normal and pathological angiogenesis (Jakeman et al , 1993, Endocrinology, 133: 848-859, Kolch et al , 1995, Breast Cancer Research and Treatment, 36: 139-155) and vascular permeability (Connolly). et al , 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of VEGF action by removal of VEGF with antibodies can lead to inhibition of tumor growth (Kim et al , 1993, Nature 362: 841-844).
[3] Tyrosine kinase receptors (RTKs) are important for the transmission of biochemical signals across the plasma membrane of cells. These membrane transfer molecules are characterized by an extracellular ligand binding domain that is linked to intracellular tyrosine kinase domains through fragments in the plasma membrane. The binding of a ligand to a receptor stimulates receptor related tyrosine kinase activity to phosphorylate tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signal cascade that causes a variety of cellular responses. To date, at least 19 distinct RTK subgroups defined by amino acid sequence homology have been identified. One of these subgroups consists of the current fms-like tyrosine kinase receptor Flt or Flt1, the kinase insertion domain containing receptor KDR (also called Flk-1) and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Flt and KDR, have been shown to bind VEGF with high affinity (De Vries et al , 1992, Science 255: 989-991, Terman et al , 1992, Biochem. Biophys. Res. Comm. 1992 187: 1579-1586). The binding of VEGF to these receptors expressed in heterologous cells was associated with changes in tyrosine phosphorylation and calcium flow of cellular proteins.
[1] The present invention relates to quinazoline derivatives, methods for their preparation, pharmaceutical compositions containing them as active ingredients, methods for treating vaginal conditions associated with angiogenesis and / or increased vascular permeability, antiangiogenesis and / or in warm-blooded animals such as humans It relates to their use as a medicament for the development of a vascular permeability reducing effect and their use in the manufacture of a medicament.
[4] Compounds of the present invention include cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atherosclerosis, arterial restenosis, autoimmune disease, acute inflammation, excessive scarring It inhibits the effects of VEGF, which has properties useful for the treatment of disease conditions associated with formation and adhesion, endometriosis, uterine bleeding of dysfunction, and retinal vascular proliferation.
[5] The compounds of the present invention have some activity against EGF receptor tyrosine kinases while greater potency against VEGF receptor tyrosine kinases. In addition, the compounds of the present invention are substantially more potent on VEGF receptor tyrosine kinases than on EGF receptor tyrosine kinases or FGF R1 receptor tyrosine kinases.
[6] According to the present invention there is provided a quinazoline derivative or a pharmaceutically acceptable salt of formula (I) or a prodrug thereof.
[7]
[8] In the above formula,
[9] Ring A may be saturated, partially saturated, unsaturated, aromatic or non-aromatic and a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 ring heteroatoms selected from O, N and S Or a phenyl ring,
[10] Z is -0-,-NH- or -S-,
[11] m is an integer from 0 to 5,
[12] R ¹ is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio or —NR ⁵ R ⁶ (where R ⁵ And R ⁶ may be the same or different and is hydrogen or C _1-3 alkyl,
[13] R ² is hydrogen, hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, trifluoromethyl, amino or nitro,
[14] R ³ is hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro, ring A is 5- or 6- At least one R ³ when it is a heterocyclic ring is one of hydroxy or halogeno,
[15] X ¹ is -O-, -CH _2- , -S-, -SO-, -SO _2- , -NR ^7- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ⁷ -or -NR ⁷ SO _2- , wherein R ⁷ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl,
[16] R ⁴ is selected from one of the following groups,
[17] 1) -Y ¹ X ² COR ⁸ wherein -Y ¹ -is C _2-5 alkylene and each methylene group (except for the methylene group of α-carbon) is optionally hydroxy, halogeno, amino and C _1- X ² is —O— or —NR ⁹ — where R is substituted by one substituent each selected from ₄ alkanoyloxy, and there are one or more than three substituents on the C _2-5 alkylene chain; ⁹ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl, and R ⁸ is C _1-3 alkyl, -NR ¹⁰ R ¹¹ or -OR ¹² , wherein R ^l0 , R ^l1 And R ¹² may be the same or different and is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl.
[18] 2) -Y ² -X ³ R ¹³ wherein -Y ² -is C _2-5 alkylene, C _3-5 alkenylene or C _3-5 alkynylene, wherein each methylene group (a-carbon of except methylene groups), when there are optionally hydroxy, halogeno, amino and C _1-4 alkanoyl and each selected from oxy, alkylene, alkenylene or alkynylene of substituents on the chain at least one to three X ³ Is -O-, -S-, -SO-, -SO _2- , -OCO-, -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ⁷ -Wherein R ⁷ is as described above and R ¹³ is hydrogen or C _1-3 alkyl, wherein the C _-3 alkyl group is one selected from oxo, hydroxy, halogeno and Cl _-4 alkoxy or May have two substituents],
[19] 3) -Y ¹ -X ⁶ C _1-5 alkyl R ¹⁴ wherein Y ¹ is as described above and X ⁶ is —O—, —S—, —SO—, —SO ₂ —, —NR ⁷ CO— , -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- (where R ⁷ is as described above) and R ¹⁴ is 3 or less selected from O, S and N, respectively C _3-7 cycloalkyl or a _3-7 membered saturated or partially saturated heterocyclic group containing a ring heteroatom of wherein the carbocyclic group or heterocyclic group is optionally oxo, hydroxy, halogeno , C _1-4 alkyl, wherein the C _1-4 alkyl group is optionally hydroxy, cyano, halogeno, amino, nitro, morpholino, C _3-5 cycloalkyl, piperidin-1-yl and piperazine Substituted with one or two substituents selected from -1-yl), C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, carbamoyl, C _1-3 alkylcarbamoyl, N, N -di (C _1-3 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 alkoxycarbonyl, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N- C _1-3 alkyl-C _2-4 Alkanoylamino, N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino and N- C _1-3 alkyl-C _1- Substituted by one or two substituents selected from ₃ alkanesulfonylamino,
[20] Or R ¹⁴ is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms each selected from O, N and S, wherein a pyridone group, a phenyl group or a heterocyclic group group optionally halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _l-4 alkyl, hydroxy, C _1-4 alkyl amino C _1-4 alkylamino, C _1-4 hydroxy alkoxy, carboxy, Cyano, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfa Moyl, C _1-3 alkanesulfonylamino, N- C _1-3 alkyl-C _1-3 alkanesulfonylamino, -CONR ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ , wherein R ¹⁰ and R ¹¹ are as described above. Substituted with up to 5 substituents selected from
[21] 4) -Y ¹ -X ⁴ C _1-5 alkylX ⁵ R ¹⁵ wherein Y ¹ is as described above and X ⁴ and X ⁵ may be the same or different and each is -O-, -S-, -SO -, -SO _2- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , NR ⁷ SO ₂ -or -NR ^7- (wherein R ⁷ is as described above and R ¹⁵ is hydrogen or C _1-3 alkyl),
[22] 5) -Y ¹ -OC _1-3 alkyl, wherein X ¹ is as described above when X ¹ is -O-, -S-, -SO- or -SO _2- ;
[23] 6) -Y ² -R ¹⁶ {wherein -Y ² -is as described above and R ¹⁶ is saturated or partially saturated and contains 3-7 members containing up to 3 hetero atoms selected from O, S and N Heterocyclic ring, wherein the heterocyclic ring is optionally oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl, wherein , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl are optionally substituted by ₃ alkanoyloxy, trifluoromethyl, amino, nitro and R ¹⁴ described above is), C _l-4 alkoxy, carbamoyl, C _1-4 alkyl-carbamoyl, NN - di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 alkoxycarbonyl , C _3-7 cycloalkyl, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N- C _1-3 alkyl-C _{2- 4} alkanoylamino, N -C _1-3 alkyl sulfamoyl, N, N - di - [C _1-3 alkyl] sulfamoyl, C _l-3 alkane Sulfonyl amino, N -C _1-3 alkyl, -C _1-3 substituted by up to three substituents selected from the alkane sulfonyl amino, or R ¹⁶ is one to be selected from the flutes dongi, a phenyl group or a O, N and S 3 A 5 or 6-membered aromatic heterocyclic group containing 2 ring hetero atoms, wherein the pyridone group, phenyl group or heterocyclic group is optionally halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _{1- 4} hydroxyalkyl, C _l-4 alkyl, amino, C _1-4 alkylamino, C _1-4 hydroxy alkoxy, carboxy, cyano, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _{1- 4} alkylsulfonyl, N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino, N- C _1-3 alkyl-C _{1 Is} substituted by up to 5 substituents selected from _-3 alkanesulfonylamino, -CONR ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ , wherein R ¹⁰ and R ^ll are as described above],
[24] 7) -Y ² -X ⁶ -R ¹⁴ , wherein Y ² , X ⁶ and R ¹⁴ are as described above,
[25] 8) -Y ² -NR ¹⁷ R ¹⁸ wherein Y ² is as described above and R ¹⁷ and R ¹⁸ are each hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-3 alkoxycarbonyl C _1-6 alkyl (wherein, R ¹⁷ or R ¹⁸ is any alkyl group of hydroxy, halogeno, C _l-3 alkyl, C _l-3 alkoxy, C _l-3 alkanoyloxy, trifluoromethyl Is optionally substituted with up to two substituents selected from rommethyl, cyano, amino or nitro).
[26] 9) -Y ³ -R ^a , wherein Y ³ is C _1-5 alkylene, C _2-5 alkenylene or C _2-5 alkynylene, wherein each methylene group (excluding the methylene group of α-carbon) is Optionally substituted by one substituent each selected from hydroxy, halogeno, amino and C _1-4 alkanoyloxy, provided that there are no more than three substituents on the alkylene, alkenylene or alkynylene chain R ^a is substituted by one substituent selected from hydroxy, amino and halogeno on the ring carbon linked to Y ³ and optionally substituted with oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, carbamoyl, C _1-4 alkylcarbamoyl, NN -di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 Alkoxycarbonyl and C _3-7 cycloalkyl, wherein C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl are optionally hydroxy, halogeno, cyano, C _1-3 alkyl, Up to ₃ substituents selected from C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and up to 3 substituents selected from R ¹⁴ described above) Is C _3-7 cycloalkyl which is further substituted by
[27] m is an integer of 1 to 3,
[28] R ¹ is methoxy, R ² is hydrogen, Z is -NH-,
[29] R ³ is halogeno or Ci _-3 alkyl, and
[30] X ^l is -O-,
[31] R ⁴ is not selected from one of the following three groups,
[32] a) -C _2-5 alkylR ¹⁹ , wherein R ¹⁹ represents one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy It can be piperidin-4-yl),
[33] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[34] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above,
[35] Wherein any alkylene, alkenylene or alkynylene chain in the groups a) to c) is optionally substituted by one or more substituents selected from hydroxy, halogeno and amino.
[36] According to another aspect of the present invention, there is provided a quinazoline derivative or pharmaceutically acceptable salt of formula (I) or a prodrug thereof.
[37] [Formula I]
[38]
[39] In the above formula,
[40] Ring A may be phenyl or saturated, partially saturated or unsaturated, may be aromatic or non-aromatic, and contains 5 or 6 containing 1, 2 or 3 ring heteroatoms selected from O, N and S A membered heterocyclic ring,
[41] Z is -O-, -NH- or -S-,
[42] m is an integer containing 0 to 5,
[43] R ¹ is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, or —NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ may be the same or different and are hydrogen or C _1-3 alkyl),
[44] R ² is hydrogen, hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, trifluoromethyl, amino or nitro,
[45] R ³ is hydroxy, halogeno, C _l-3 alkyl, C _l-3 alkoxy, C _1-3 alkanoyloxy, trifluoromethyl, cyano, and amino, or nitro, the ring A 5- or 6- At least one R ^{3 when it} is a heterocyclic ring is either hydroxy or halogeno,
[46] X ¹ is -O-, -CH ^2- , -S-, -SO-, -SO ² , -NR ⁷ -,-NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ⁷ -or -NR ⁷ S0 _2- , wherein R ⁷ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl,
[47] R ⁴ is selected from one of the following groups:
[48] 1) -Y ¹ X ² COR ⁸ wherein -Y ¹ -is a C _2-5 alkylene chain wherein each methylene group (α- is less than 1 to 3 substituents on the C _2-5 alkylene chain The methylene group of carbon is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, X ² is —O— or —NR ⁹ — (R ⁹ is hydrogen, C _1-3 alkyl or C _l-3 alkoxyC _2-3 alkyl) and R ⁸ is C _1-3 alkyl, —NR ¹⁰ R ¹¹ or —OR ¹² , wherein R ¹⁰ , R ¹¹ and R ¹² may be the same or different and hydrogen a C _l-3 alkyl, or C _1-3 alkoxy is C _2-3 alkyl)],
[49] 2) -Y ² -X ³ R ¹³ wherein -Y ² -is C _2-5 alkylene, C _3-5 alkenylene or C _3-5 alkynylene, wherein alkylene, alkenylene or alkynylene chain When there are 1 to 3 substituents on the phase, each methylene group (except for the methylene group of α-carbon) is optionally substituted by one substituent independently selected from hydroxy, halogeno and amino, and X ³ is -O- , -S-, -SO-, -SO _2- , -OCO-, -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- (where R ⁷ is as described above), and R is hydrogen or C ^l3 _l3 alkyl, wherein, C _1-3 alkyl group is one or two substituents selected from oxo, hydroxy, halogeno and C _l-4 alkoxy Can hold],
[50] 3) -Y ¹ -X ⁶ C _1-5 alkyl R ¹⁴ wherein Y ¹ is as described above and X ⁶ is —O—, —S—, —SO—, —SO ₂ —, —NR ⁷ CO -, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- , where R ⁷ is as described above, R ¹⁴ is C _3-7 cycloalkyl or O, A 3-7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms each selected from S and N, wherein the carbocyclic group or heterocyclic group is oxo, hydroxy, halogeno , C _1-4 alkyl, wherein the C _1-4 alkyl group is hydroxy, cyano, halogeno, amino, nitro, morpholino, C _3-5 cycloalkyl, piperidin-1-yl and piperazine- by 1 or 2 substituents selected from 1-1 optionally substituted), C _2-4 alkenyl, C _2-4 alkynyl, C _l-4 alkyl, hydroxy, C _1-4 alkoxy, carbamoyl, C _1-3 alkyl-carbamoyl, N, N - di (C _1-3 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 Al Brassica Viterbo carbonyl, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N -C _1-3 alkyl, -C _2-4 alkanoylamino , N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino and N- C _1-3 alkyl-C _1-3 alkanesul Optionally substituted by 1 or 2 substituents selected from phenylamino, or R ¹⁴ is a pyridone group, a phenyl group or a 5 or 6-membered aromatic containing 1 to 3 ring heteroatoms each selected from O, N and S Heterocyclic group wherein a pyridone, phenyl or heterocyclic group is halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 aminoalkyl, C _{1 -4} alkylamino, C _{l-4-hydroxy-alkoxy,} carboxy, cyano, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, N -C _1-3 alkyl sulfamoyl , N, N - di - [C _1-3 alkyl] sulfamoyl, C _1-3 alkane sulfonyl amino, N -C _1-3 Kill -C _1-3 alkane sulfonyl amino, -CONR ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ is optionally substituted by substituents selected from 5 or less (wherein, R ^l0 and R ^ll are as defined above); ,
[51] 4) -Y ¹ -X ⁴ C _1-5 alkylX ⁵ R ¹⁵ [wherein Y 1 is as described above, X ⁴ and X ⁵ may be the same or different and each is —O—, —S—, —SO -, -SO ^2- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , NR ⁷ SO ₂ -or -NR ^7- (wherein R ⁷ is as described above and R ^l5 is hydrogen or Cl 3 alkyl),
[52] 5) -Y ¹ -OC _1-3 alkyl, wherein X ¹ is as described above when X ¹ is -0-, -S-, -SO- or -SO ₂ ;
[53] 6) -Y ² -R ¹⁶ {wherein -Y ² -is as described above and R ¹⁶ is a saturated or partially saturated 3 to 7 membered group containing up to 3 heteroatoms selected from O, S and N; Heterocyclic ring, wherein the heterocyclic ring is oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl, wherein C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl itself is hydroxy, halogeno, cyano, C _l-3 alkyl, Cl-3 alkoxy, C _{l- 3} alkanoyloxy, trifluoromethyl, amino, nitro and up to 3 substituents selected from R ¹⁴ described above), C _1-4 alkoxy, carbamoyl, C _1-4 alkylcarba Moyl, NN -di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 alkoxycarbonyl, C _3-7 cycloalkyl, C _1-4 alkylthio, C _1-4 alkyl Sulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N- C _1-3 alkyl-C _2-4 alkanoylamino, N -C _1-3 alkyl sulfamoyl, N, N-di - [C _1-3 alkyl] sulfamoyl, C _{l-3-amino-alkane-sulfonyl} and N -C _1-3 alkyl- Optionally substituted with up to 3 substituents selected from C _1-3 alkanesulfonylamino, or R ¹⁶ contains a pyridone group, a phenyl group or 1 to 3 ring heteroatoms each selected from O, N and S A 5 or 6-membered aromatic heterocyclic group wherein the pyridone group, phenyl group or heterocyclic group is halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _{1- 4} aminoalkyl, C _1-4 alkylamino, C _1-4 hydroxyalkoxy, carboxy, cyano, C _1-4 alkylthio, _C1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, N- C _{1 -3-alkyl} sulfamoyl, N, N - di - [C _1-3 alkyl] sulfamoyl, C _1-3 alkane sulfonyl amino, N -C _1-3 alkyl, -C _1-3 alkane sulfonyl amino, -CONR to ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ (wherein, R ¹⁰ and R ¹¹ are as defined above) By the following five substituents selected arbitrarily substituted]},
[54] 7) -Y ² -X ⁶ -R ¹⁴ , wherein Y ² , X ⁶ and R ¹⁴ are as described above, and
[55] 8) -Y ² -NR ¹⁷ R ¹⁸ wherein Y ² is as described above and R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _{1 -3} alkoxyC _1-6 alkyl, wherein any alkyl group in R ¹⁷ or R ¹⁸ is hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoro Each optionally substituted with up to 2 substituents selected from methyl, cyano, amino or nitro).
[56] 9) -Y ³ -R ^a , wherein Y ³ is C _1-5 alkylene, C _2-5 alkenylene or C _2-5 alkynylene, wherein three on the alkylene, alkenylene or alkynylene chain In the case of the following substituents, each methylene group (excluding the methylene group of α-carbon) is optionally substituted by one substituent each selected from hydroxy, halogeno and amino, and R ^a is on a ring carbon linked to Y ³ Substituted by one substituent selected from hydroxy amino and halogeno and optionally substituted with oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy , carbamoyl, C _l-4 alkyl-carbamoyl, NN - di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C1-4 alkoxycarbonyl, and C _3-7 cycloalkyl (wherein , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl itself are hydroxy, halogeno, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, bit Is further substituted by a methyl, cyano, amino, nitro and the three selected from the following are substituted by a substituent of up to three) substituents selected from the above-mentioned R ¹⁴ fluoro],
[57] m is an integer of 1 to 3,
[58] R ¹ is methoxy, R ² is hydrogen, Z is -NH-,
[59] R ³ is halogeno or Ci _-3 alkyl, and
[60] X ¹ is -O-,
[61] R ⁴ is not selected from one of the following three.
[62] a) -C _2-5 alkyl, R ¹⁹ (wherein, R ^l9 is one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _l-4 alkyl and hydroxy-C _l-4 alkoxy It can be piperidin-4-yl),
[63] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[64] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above.
[65] According to another aspect of the present invention, there is provided a quinazoline derivative or pharmaceutically acceptable salt of formula (I) or a prodrug thereof.
[66] [Formula I]
[67]
[68] In the above formula,
[69] Z is -O-, -NH- or -S-,
[70] m is an integer containing 0 to 5,
[71] R ¹ is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio or —NR ⁵ R ⁶ (where R ⁵ And R ⁶ may be the same or different and is hydrogen or C _1-3 alkyl),
[72] R ² is hydrogen, hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, trifluoromethyl, amino or nitro,
[73] R ³ is hydroxy, halogeno, Cl _1-3 alkyl, Cl _1-3 alkoxy, Cl _1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro,
[74] X ^l is -O-, -CH _2- , -S-, -SO-, -SO _2- , -NR ^7- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ⁷ -or -NR ⁷ SO _2- , wherein R ⁷ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl,
[75] R ⁴ is selected from the following groups,
[76] 1) -Y ¹ X ² COR ⁸ wherein -Y ¹ -is a C _2-5 alkylene chain wherein each methylene group (α- is less than 1 to 3 substituents on the C _2-5 alkylene chain The methylene group of carbon is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, X ² is —O— or —NR ⁹ — (R ⁹ is hydrogen, C _1-3 alkyl or C _l-3 alkoxyC _2-3 alkyl) and R ⁸ is C _1-3 alkyl, —NR ¹⁰ R ¹¹ or —OR ¹² , wherein R ¹⁰ , R ¹¹ and R ¹² may be the same or different and hydrogen a C _l-3 alkyl, or C _1-3 alkoxy is C _2-3 alkyl)],
[77] 2) -Y ² -X ³ R ¹³ wherein -Y ² -is C _2-5 alkylene, C _3-5 alkenylene or C _3-5 alkynylene, wherein the alkylene, alkenylene or alkynylene chain When there are 1 to 3 substituents on the phase, each methylene group (except for the methylene group of α-carbon) is optionally substituted by one substituent independently selected from hydroxy, halogeno and amino, and X ³ is -O- , -S-, -SO-, -SO _2- , -OCO-, -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- (where R ⁷ is as described above hanba) and R is hydrogen or C ^l3 _l3 alkyl, wherein, C _1-3 alkyl group is one or two substituents selected from oxo, hydroxy, halogeno and C _l-4 alkoxy Can hold],
[78] 3) -Y ¹ -X ⁶ C _1-5 alkyl R ¹⁴ wherein Y ¹ is as described above and X ⁶ is —O—, —S—, —SO—, —SO ₂ —, —NR ⁷ CO -, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- , where R ⁷ is as described above, R ¹⁴ is C _3-7 cycloalkyl or O, A 3-7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms each selected from S and N, wherein the carbocyclic group or heterocyclic group is oxo, hydroxy, halogeno , C _1-4 alkyl, wherein the C _1-4 alkyl group is hydroxy, cyano, halogeno, amino, nitro, morpholino, C _3-5 cycloalkyl, piperidin-1-yl and piperazine- by 1 or 2 substituents selected from 1-1 optionally substituted), C _2-4 alkenyl, C _2-4 alkynyl, C _l-4 alkyl, hydroxy, C _1-4 alkoxy, carbamoyl, C _1-3 alkyl-carbamoyl, N, N - di (C _1-3 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 Al Brassica Viterbo carbonyl, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N -C _1-3 alkyl, -C _2-4 alkanoylamino , N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino and N- C _1-3 alkyl-C _1-3 alkanesul Optionally substituted by 1 or 2 substituents selected from phenylamino, or R ¹⁴ is a pyridone group, a phenyl group or a 5 or 6-membered aromatic containing 1 to 3 ring heteroatoms each selected from O, N and S Heterocyclic group wherein a pyridone, phenyl or heterocyclic group is halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 aminoalkyl, C _{1 -4} alkylamino, C _{l-4-hydroxy-alkoxy,} carboxy, cyano, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, N -C _1-3 alkyl sulfamoyl , N, N - di - [C _1-3 alkyl] sulfamoyl, C _1-3 alkane sulfonyl amino, N -C _1-3 Kill -C _1-3 alkane sulfonyl amino, -CONR ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ is optionally substituted by substituents selected from 5 or less (wherein, R ^l0 and R ^ll are as defined above); ,
[79] 4) -Y ¹ -X ⁴ C _1-5 alkylX ⁵ R ¹⁵ [wherein Y ¹ is as described above, X ⁴ and X ⁵ may be the same or different and each is —O—, —S—, — SO-, -SO ^2- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , NR ⁷ SO ₂ -or -NR ^7- (where R ⁷ is as described above and R ^l5 is hydrogen Or Cl-3 alkyl),
[80] 5) -Y ¹ -OC _1-3 alkyl, wherein X ¹ is as described above when X ¹ is -0-, -S-, -SO- or -SO ₂ ;
[81] 6) -Y ² -R ¹⁶ {wherein -Y ² -is as described above and R ¹⁶ is a saturated or partially saturated 3 to 7 membered group containing up to 3 heteroatoms selected from O, S and N; Heterocyclic ring, wherein the heterocyclic ring is oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl, wherein C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl itself is hydroxy, halogeno, cyano, C _l-3 alkyl, Cl-3 alkoxy, C _{l- 3} alkanoyloxy, trifluoromethyl, amino, nitro and up to 3 substituents selected from R ¹⁴ described above), C _1-4 alkoxy, carbamoyl, C _1-4 alkylcarba Moyl, NN -di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 alkoxycarbonyl, C _3-7 cycloalkyl, C _1-4 alkylthio, C _1-4 alkyl Sulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N- C _1-3 alkyl-C _{2 -4} alkanoylamino, N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, Cl _-3 alkanesulfonylamino and N- C _1-3 alkyl-C Optionally substituted with up to 3 substituents selected from _1-3 alkanesulfonylamino, or R ¹⁶ is a pyridone group, a phenyl group or 5 containing 1 to 3 ring heteroatoms each selected from O, N and S Or a 6-membered aromatic heterocyclic group wherein the pyridone group, phenyl group or heterocyclic group is halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 Aminoalkyl, C _1-4 alkylamino, C _1-4 hydroxyalkoxy, carboxy, cyano, C _1-4 alkylthio, _C1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, N- C _{1- 3} alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino, N- C _1-3 alkyl-C _1-3 alkanesulfonylamino, -CONR ¹⁰ At R ¹¹ and —NR ¹⁰ COR ¹¹ , wherein R ¹⁰ and R ¹¹ are as described above Optionally substituted with up to 5 substituents selected]},
[82] 7) -Y ² -X ⁶ -R ¹⁴ , wherein Y ² , X ⁶ and R ¹⁴ are as described above, and
[83] 8) -Y ² -NR ¹⁷ R ¹⁸ wherein Y ² is as described above and R ¹⁷ and R ¹⁸ are hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _{1 -3} alkoxyC _1-6 alkyl, wherein any alkyl group in R ¹⁷ or R ¹⁸ is hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoro Each optionally substituted with up to 2 substituents selected from methyl, cyano, amino or nitro).
[84] 9) -Y ³ -R ^a , wherein Y ³ is C _1-5 alkylene, C _2-5 alkenylene or C _2-5 alkynylene, wherein three on the alkylene, alkenylene or alkynylene chain In the case of the following substituents, each methylene group (excluding the methylene group of α-carbon) is optionally substituted by one substituent each selected from hydroxy, halogeno and amino, and R ^a is on a ring carbon linked to Y ³ Substituted by one substituent selected from hydroxy amino and halogeno and optionally substituted with oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy , carbamoyl, C _l-4 alkyl-carbamoyl, NN - di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C1-4 alkoxycarbonyl, and C _3-7 cycloalkyl (wherein , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl itself are hydroxy, halogeno, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, bit Is further substituted by a methyl, cyano, amino, nitro and the three selected from the following are substituted by a substituent of up to three) substituents selected from the above-mentioned R ¹⁴ fluoro],
[85] m is an integer of 1 to 3,
[86] R ¹ is methoxy, R ² is hydrogen, Z is -NH-,
[87] R ³ is halogeno or Ci _-3 alkyl, and
[88] X ¹ is -O-,
[89] R ⁴ is not selected from one of the following three.
[90] a) -C _2-5 alkyl, R ¹⁹ (wherein, R ^l9 is one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _l-4 alkyl and hydroxy-C _l-4 alkoxy It can be piperidin-4-yl),
[91] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[92] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above,
[93] Wherein any alkylene, alkenylene or alkynylene chain in groups a) to c) is optionally substituted by one or more substituents selected from hydroxy, halogeno and amino.
[94] As used herein, the general term "alkyl" includes both straight and branched chain alkyl groups. However, for individual alkyl groups, such as "propyl", only specific for the straight chain form, for individual branched alkyl groups, such as "isopropyl", only for the branched chain form.
[95] Insofar as certain compounds of the formula (I) as defined above may be present in optically active or racemic form by one or more asymmetric carbon atoms, the present invention is directed to any optically active or racemic having the activity described above in its definition. It is to be understood to include the form. Synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of racemic forms. Similarly, the above-mentioned activity can be assessed using standard laboratory techniques mentioned later.
[96] In the above formula (I), hydrogen is present at the 2 and 8 positions of the quinazoline group.
[97] The illustrations herein may represent only one of the possible tautomeric forms. It is to be understood that the present invention includes any tautomeric forms that inhibit VEGF receptor tyrosine kinase activity and are not limited to simply any tautomeric forms used within the chemical formula.
[98] It is also to be understood that certain quinazolines of formula I and their salts may exist in solvated as well as unsolvated forms, such as hydrated forms. It is also to be understood that the present invention encompasses all these solvated forms that inhibit VEGF receptor tyrosine kinase activity.
[99] To avoid uncertainty, when X ¹ is a group of the formula —NR ⁷ CO— the nitrogen atom has an R ⁷ group attached to the quinazoline ring and the carbonyl (CO) group is attached to R ⁴ , while X ¹ is For example, in the case of the group -CONR ^7- , it is understood that the carbonyl group is attached to the quinazoline ring and the nitrogen atom bearing the R ⁷ group is attached to R ⁴ . Similar rules apply to the remaining two atom X ¹ bond groups. When X ¹ is NR ⁷ , the nitrogen atom has a R ⁷ group bonded to the quinazoline ring and R ⁴ . Similar provisions apply to other flags. In addition, when X ¹ is —NR ⁷ — and R ⁷ is C _1-3 alkoxyC _2-3 alkyl, the C _2-3 alkyl moiety is bonded to the nitrogen atom of X ¹ and similar provisions apply to other groups.
[100] The α-carbon of the alkylene, alkenylene or alkynylene chain in Y ¹ and Y ² is the carbon atom of the chain bonded to X ¹ . β-carbon is a carbon atom of a carbon chain bonded to α-carbon.
[101] Preferred values for Y ¹ include 2-acetoxypropylene, 2-hydroxyethylene, 2-hydroxypropylene, 3-hydroxypropylene, 2-hydroxybutylene, 3-hydroxybutylene and 4-hydroxy Butylene.
[102] Suitable values for Y ¹ include 2-hydroxyethylene, 2-hydroxypropylene, 3-hydroxypropylene, 2-hydroxybutylene, 3-hydroxybutylene and 4-hydroxybutylene.
[103] Suitable values for Y ² include those described above for Y ¹ and 2-hydroxybut-3enylene, 2-hydroxypent-3-enylene, 4-hydroxybut-2-enylene and 3- Hydroxypent-4-enylene.
[104] More preferred values for Y ¹ are 2-hydroxypropylene and 2-acetoxypropylene.
[105] More preferred values for Y ² are 2-hydroxypropylene and 2-acetoxypropylene. Morpholine, thiomorpholine, (tetrahydro-1,4-thiazine), thiazolidine, 1,2,6-tetrahydropyridine, tetrahydrofuran, tetrahydropyran, 1,1-dioxotetrahydro- 1,4-thiazine, homopiperazine dihydropyridine, tetrahydropyridine, dihydropyrimidine and tetrahydropyrimidine.
[106] Examples of 5- or 6-membered aromatic heterocyclic groups for ring A include furan, pyrrole, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, oxadiazole, thiadiazole, tria Sol, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, indole.
[107] Examples of suitable 3-7 membered saturated or partially saturated heterocyclic groups for R ¹⁴ and R ¹⁶ include pyrrolidine, piperidine, aziridine, azetidine, piperazine, homopiperidine, pyrroline , Morpholine, thiomorpholine, (tetrahydro-1,4-thiazine), thiazolidine, 1,2,6-tetrahydropyridine, tetrahydrofuran, tetrahydropyran, 1,1-dioxotetrahydro 1,4-thiazine, homopiperazine dihydropyridine, tetrahydropyridine, dihydropyrimidine and tetrahydropyrimidine.
[108] Examples of suitable C _3-7 cycloalkyl groups in R ¹⁴ , R ¹⁶ and R ^a are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, in particular cyclopropyl, cyclopentyl and cyclohexyl.
[109] Examples of 5 or 6 membered aromatic heterocyclic groups for R ¹⁴ and R ¹⁶ include furan, pyrrole, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, oxadiazole, thia Diazoles, triazoles, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5triazine, indole.
[110] Preferred 5 or 6 membered aromatic heterocyclic groups for R ¹⁴ and R ¹⁶ are pyridine, imidazole, thiophene, triazole, and pyridazine. More preferred are pyridine, imidazole or triazole.
[111] Suitable values for any of the 'R' groups (R ¹ to R ¹⁹ ) or suitable values for the various substituents on the ring system or alkyl chain in R ⁴ include the following.
[112] For halogeno, fluoro, chloro, bromo and iodo,
[113] Methyl, ethyl, propyl, isopropyl and t -butyl for C _1-6 alkyl
[114] Vinyl, allyl and but-2-enyl, for C _2-5 alkenyl,
[115] For C _2-5 alkynyl ethynyl, 2-propynyl and but-2-ynyl,
[116] For C _1-6 alkoxy, methoxy, ethoxy, propoxy, isopropoxy and butoxy,
[117] For C _2-6 alkenyloxy, vinyloxy and allyloxy,
[118] For C _2-6 alkynyloxy, ethynyloxy and 2-propynyloxy,
[119] For C _1-4 alkylthio, methylthio, ethylthio and propylthio,
[120] Methylsulfinyl and ethylsulfinyl for C _1-4 alkylsulfinyl,
[121] Methylsulfonyl and ethylsulfonyl for Cl ₄ alkylsulfonyl,
[122] For C _1-4 alkylamino, methylamino, ethylamino, propylamino, isopropylamino and butylamino,
[123] Dimethylamino, diethylamino, N -ethyl- N -methylamino and diisopropylamino, for di- [C _1-4 alkyl] amino,
[124] For C _1-4 alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and t -butoxycarbonyl,
[125] N -C _1-4 alkyl carbamic respect to gather N - methylcarbamoyl, N - ethyl-carbamoyl and N - propyl-carbamoyl,
[126] For N, N -di- [C _1-4 alkyl] carbamoyl N, N -dimethylcarbamoyl, N -ethyl- N -methylcarbamoyl and N, N -diethylcarbamoyl,
[127] Acetyl and propynyl for C _2-4 alkanoyl,
[128] For C _1-4 alkanoyloxy, acetoxy and propynyloxy,
[129] For C _2-4 alkanoylamino, acetamido and propionamido,
[130] FIG methyl propionamide amino-methyl-acetamido, and N-N -C _1-3 alkyl, -C _2-4 N with respect to alkanoylamino
[131] N -C _1-3 N with respect to alkyl-sulfamoyl-methyl-sulfamoyl, and N-ethyl sulfamoyl,
[132] As for N, N -di- [C _1-3 alkyl] sulfamoyl, N, N -dimethylsulfamoyl,
[133] For _Cl-3 alkanesulfonylamino, methanesulfonylamino and ethanesulfonylamino,
[134] For N- C _1-3 alkyl-C _1-3 alkanesulfonylamino, N -methylmethanesulfonylamino and N -methylethanesulfonylamino are suitable.
[135] R ¹⁴ and R ¹⁶ a saturated or preferred groups for partially cyclic saturated heterocyclic substituent of the Examples of oxo, hydroxy, halogeno, C _1-4 alkyl (where, C _l-4 alkyl group is hydroxy, cyano, halogeno , Amino, nitro, morpholino, C _3-5 cycloalkyl, piperidin-1-yl and piperazin-1-yl), C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 Alkoxy, carbamoyl, C _1-3 alkylcarbamoyl, N, N -di (C _1-3 alkyl) carbamoyl, C _2-4 alkanoyl and C _1-4 alkoxycarbonyl. Wherein the C _1-4 alkyl group is selected from hydroxy, cyano, halogeno, amino, morpholino, C _3-5 cycloalkyl, piperidin-1-yl and piperazin-1-yl Optionally substituted by 2 substituents), C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, carbamoyl, C _1-3 alkylcarbamoyl, N, N -di (C _1-3 alkyl) carbamoyl, C _2-4 alkanoyl and C _1-4 alkoxycarbonyl.
[136] More preferred substituents for the saturated or partially saturated heterocyclic groups in R ¹⁴ and R ¹⁶ include oxo, hydroxy, halogeno, C _1-4 alkyl (optionally hydroxy, cyano, morpholino, cyclopentyl, pi piperidine there is piperazin-1-yl or substituted by 1-yl), allyl, C _1-4 alkoxy, C _2-4 alkanoyl or C _l-4 alkoxycarbonyl.
[137] More preferred substituents for the saturated or partially saturated heterocyclic groups in R ¹⁴ and R ^{16 are} oxo, hydroxy, fluoro, chloro, bromo, methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, 3- Hydroxypropyl, 2-morpholinoethyl, cyclopropyl, allyl, methoxy, acetyl and methoxycarbonyl.
[138] Preferred substituents for the ring carbon atoms in the saturated or partially saturated heterocyclic groups in R ¹⁴ and R ¹⁶ are hydroxy, bromo and methyl. Most preferred ring carbon atoms in the saturated or partially saturated heterocyclic groups in R ¹⁴ and R ¹⁶ are unsubstituted.
[139] Preferred substituents for the ring NH group in the saturated or partially saturated heterocyclic group in R ¹⁴ and R ¹⁶ include C _1-4 alkyl (optionally substituted as described above), C _2-5 alkyl, C _2-4 alkoxy Noyl or C _1-4 alkoxycarbonyl. Cl-4 alkyl (optionally hydroxy, fluoro, chloro, bromo, cyclopentyl, morpholino, piperazin-1-yl or piperidin-1-yl), acetyl, allyl or methoxycarbonyl More preferred.
[140] It is preferable that the aromatic group in R <^14> and R <^16> is substituted by 3 or less substituents, and it is more preferable to substitute by 2 or less substituents.
[141] Preferred substituents for the aromatic groups in R ¹⁴ and R ¹⁶ include halogeno, C _1-4 alkyl, amino, C _1-4 alkoxy, hydroxyC _1-4 alkyl or C _1-4 hydroxyalkoxy. More preferred substituents include fluoro, chloro, bromo, methyl, ethyl, methoxy, hydroxymethyl and 2-hydroxyethyl.
[142] Ring A is preferably a 5-6 membered heteroaromatic moiety containing 1 to 3 heteroatoms each selected from phenyl or O, N and S.
[143] Ring A is more preferably a 6-membered heteroaromatic moiety containing 1 to 3 heteroatoms each selected from phenyl or O, N and S.
[144] However, it is more preferred that Ring A is phenyl or pyridyl.
[145] Most preferably, ring A is phenyl.
[146] In another aspect Ring A is pyridyl.
[147] It is preferable that m is an integer containing 1-5. It is more preferable that m is 2 or 3. m is most preferably 2.
[148] R ^l is hydrogen, hydroxy, cyano, nitro, trifluoromethyl, C _l-3 alkyl, C _1-3 alkoxy, or amino.
[149] R ¹ is more preferably hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy. More preferably R ¹ is hydrogen, methyl or methoxy. Most preferably R ¹ is hydrogen or methoxy, in particular methoxy.
[150] R ² is preferably hydrogen, fluoro, amino or nitro. Most preferably R ² is hydrogen. R ³ is preferably hydroxy, halogeno, Cl _-2 alkyl, Cl _-2 alkoxy, trifluoromethyl, cyano, amino or nitro.
[151] R ³ is more preferably fluoro, chloro, bromo, methyl or methoxy.
[152] Specific values for ring A having (R ³ ) _m are 2-fluoro-4-chloro-5-hydroxyphenyl, 2fluoro-4-bromo-5-hydroxyphenyl, 2-fluoro- 4-chlorophenyl or 2-fluoro-4-bromophenyl.
[153] When ring A is phenyl, it is preferred that m is 2 and the phenyl ring is substituted in the 2- and 4- positions.
[154] When ring A is phenyl, m is 2 and the phenyl ring is preferably substituted at the 2- and 4-positions by substituents selected from fluoro, chloro and bromo, respectively.
[155] More preferably, ring A having (R ³ ) _m is 2-fluoro-4-chlorophenyl or 2-fluoro-4bromophenyl. In another aspect, ring A having (R ³ ) _m is 2-chloro-3-methoxyphenyl, 2-bromo-3-chlorophenyl, 2,3-dibromophenyl, 2,3 -Dichlorophenyl 2,4-dichlorophenyl, 2-bromo-4-chlorophenyl, 2-chloro-3-methylphenyl, 2-bromo-4-methylphenyl, 2-chloro-3-methoxyphenyl or 3-chloro -4-fluorophenyl.
[156] -NR ⁷ CO X ¹ is -0-, -S-, -, - NR 7 S0 2 - or -NR ⁷ - (wherein, R ⁷ is hydrogen, C _l-2 alkyl or C _l-2 alkoxyethyl) Is preferably.
[157] X ¹ is preferably -O-, -S-, -NR ⁷ CO- or -NR ⁷ SO ^2- , wherein R ⁷ is hydrogen, methyl or ethyl.
[158] More preferably, X ¹ is —O—, —S—, —NR ⁷ CO—, wherein R ⁷ is hydrogen or methyl.
[159] Further, X ¹ is more preferably -O- or -NHCO- or -S-. Further, X ¹ is more preferably -O- or -S-. Most preferably, X ¹ is -O-.
[160] X ² is —O— or —NR ⁹ —, wherein R ⁹ is hydrogen, C _1-3 alkyl or C _1-2 alkoxyethyl.
[161] X ³ is -O-, -S-, -SO-, -SO _2- , -NR ⁷ CO-, -NR ⁷ SO ₂ -or -NR ^7- (wherein R ⁷ is hydrogen, C _1-2 alkyl Or C _1-2 alkoxyethyl).
[162] X ³ is _{-O-, -S-, -SO-, -SO 2} - or -NR ⁷ - it is more preferably a (wherein, R ⁷ is hydrogen, C _1-2 alkyl or C _l-2 alkoxyethyl) Do.
[163] Further, X ³ is more preferably -O- or -NR ^7- , wherein R ⁷ is hydrogen, methyl or ethyl.
[164] X ⁴ and X ⁵ may be the same or different and each is —O—, —S—, —SO—, SO ₂ — or —NR ₇ —, where R ⁷ is hydrogen, C _1-3 alkyl or C _{1 -2} alkoxyethyl).
[165] X ⁴ and X ⁵ may be the same or different and more preferably are each -O-, -S- or -NR ^7- , wherein R ⁷ is hydrogen, methyl, ethyl or C _1-2 alkoxyethyl Do.
[166] X ⁴ and X ⁵ may be the same or different and each is more preferably —0- or —NH—.
[167] X ⁶ is preferably -O-.
[168] R ⁴ is preferably selected from one of the following groups.
[169] 1a) -Y ¹ -X ² COR ⁸ , wherein Y ¹ , X ² and R ⁸ are as described above,
[170] 2a) -Y ¹ -X ³ R ¹³ , wherein Y ¹ , X ² and R ^l3 are as described above,
[171] 3a) -Y ¹ -R ²⁰ wherein Y ¹ is as described above and R ²⁰ is a 3-7 membered saturated or partially saturated hetero containing 1 or 2 ring atoms selected from O, S and N, respectively Cyclic group, which heterocyclic group is selected from oxo, hydroxy, halogeno, C _1-4 alkyl (optionally hydroxy, halogeno, cyano, C _5-7 cycloalkyl or O, S and N, respectively) Substituted by a 5 or 6 membered saturated heterocyclic group containing 1 or 2 ring heteroatoms), C _2-5 alkenyl, C _2-5 alkynyl, C _1-4 alkoxy, carbamoyl, C _1-4 alkyl-carbamoyl, N, N - di (C _1-4 alkyl) carbamoyl, C _1-4 alkanoyl and C _1-4 to hold one or two substituents, selected from alkoxy-carbonyl Can be
[172] 4a) -Y ¹ -X ⁴ C _1-5 alkylX ⁵ R ¹⁵ , wherein Y ¹ , X ⁴ , X ⁵ and R ¹⁵ are as described above,
[173] 5a) C _1-3 alkoxy-Y ^1- , wherein X ¹ is as described above when X ¹ is -O-, -S-, -SO- or -SO _2- ;
[174] 6a) -Y ¹ -X ⁶ C _1-5 alkyl R ²¹ wherein Y ¹ and X ⁶ are as described above and R ²¹ is 1 or 2 selected from cyclopentyl, cyclohexyl or O, S and N, respectively A 5 or 6 membered saturated heterocyclic group containing 2 ring heteroatoms, wherein the cyclopentyl, cyclohexyl or heterocyclic group is oxo, hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxide Oxyalkyl, C _1-4 alkoxy, carbamoyl, C _1-4 alkylcarbamoyl, N, N -di (C _1-4 alkyl) carbamoyl, C _1-4 alkanoyl and C _1-4 alkoxy May have 1 or 2 substituents selected from carbonyl),
[175] 7a) -Y ¹ X ⁶ R ²¹ , wherein Y ¹ , X ⁶ and R ²¹ are as described above, and
[176] 8a) -Y ¹ -NR ¹⁷ R ¹⁸ , wherein Y ¹ , R ¹⁷ and R ¹⁸ are as described above.
[177] More preferred R ⁴ is selected from one of the following groups.
[178] 1b) -Y ¹ -R ²⁰ ,
[179] 2b) C _1-3 alkoxy-Y ^1- ,
[180] 3b) -Y ¹ -X ⁶ -R ²¹ ,
[181] 4b) -Y ¹ -NR ¹⁷ R ¹⁸ ,
[182] In the formula, Y ^1, X ^6, R ^a, R ^17, R ^l8, R ²⁰ and R ²¹ are as defined above, Y ⁴ is a C _2-5 alkylene chain, in which on the C _2-5 alkylene chain When there are three or less substituents, each methylene group (except for the α-carbon) is optionally substituted by one substituent each selected from hydroxy, halogeno and amino.
[183] Further preferred R ⁴ is selected from one of the following groups.
[184] 1c) -Y ¹ -R ₂₂ ,
[185] 2c) C _1-3 alkoxy-Y ^1- ,
[186] 3c) Y ¹ -X ⁶ -R ²² ,
[187] 4c) -Y ¹ -NR ¹⁷ R ¹⁸ ,
[188] In the above formula, Y ¹ , Y ⁴ , X ⁶ , R ^a , R ¹⁷ and R ¹⁸ are as described above, and R ²² is cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, azetidinyl, pipe Ferrazinyl, homopiperidinyl, pyrrolyl, morpholino, thiomorpholino, morpholinyl, thiomorpholinyl, thiazolidinyl and 1,2,6-tetrahydropyridyl, each of which is described above The system is 1 or 2 selected from oxo, hydroxy, halogeno, C _1-4 alkyl, C _1-4 alkoxy, hydroxyC _1-4 alkyl, C _2-4 alkanoyl and C _1-4 alkoxycarbonyl Optionally substituted by a substituent.
[189] The alkylene, alkenylene or alkynylene group of Y ¹ or Y ² in R ⁴ is preferably substituted on the β-carbon by a hydroxy, halogeno, amino or C _1-4 alkanoyloxy group.
[190] The alkylene, alkenylene or alkynylene group of Y ¹ or Y ² in R ⁴ is preferably substituted on the β-carbon by hydroxy, halogeno or amino group.
[191] The alkylene, alkenylene or alkynylene group of Y ¹ or Y ² in R ⁴ is preferably substituted by hydroxy or acetoxy.
[192] Y ² in R ⁴ is C _2-5 alkylene where each methyl group (except for α-carbon) is hydroxy, halogeno when there are 1-3 substituents on the alkylene, alkenylene or alkynylene chain It is preferably substituted by one substituent each selected from, amino and C _1-4 alkanoyloxy.
[193] Y ² in R ⁴ is C _2-5 alkylene where each methyl group (except for α-carbon) is hydroxy, halogeno when there are 1-3 substituents on the alkylene, alkenylene or alkynylene chain And optionally substituted with one substituent each selected from amino.
[194] Y ¹ or Y ² in R ⁴ is preferably substituted by only one substituent selected from hydroxy, halogeno, amino and acetoxy. More preferably Y ¹ or Y ² in R ⁴ is C _2-5 alkylene substituted on the β-carbon by one substituent selected from hydroxy, halogeno, amino and acetoxy. More preferably, Y ¹ or Y ² in R ⁴ is 2-hydroxypropylene, 2-acetoxypropylene, or 2-hydroxybutylene. It is particularly preferable that Y ¹ or Y ² in R ⁴ is 2-hydroxypropylene or 2acetoxypropylene.
[195] Y ¹ or Y ² in R ⁴ is preferably substituted by only one substituent selected from hydroxy, halogeno and amino. More preferably, Y ¹ or Y ² in R ⁴ is C _2-5 alkylene substituted on the β-carbon by one substituent selected from hydroxy, halogeno and amino. More preferably, Y ¹ or Y ² in R ⁴ is 2-hydroxypropylene or 2-hydroxybutylene. Most preferably Y ¹ or Y ² in R ⁴ is 2-hydroxypropylene.
[196] Y ³ is C _1-5 alkylene where each methylene group (except for α-carbon) has one substituent each selected from hydroxy, halogeno and amino when there are no more than two substituents on the alkylene chain It is preferably substituted by More preferably, Y ³ in R ⁴ is unsubstituted or substituted by one substituent selected from hydroxy, halogeno or amino. In addition, Y ³ in R ⁴ is more preferably methylene, ethylene or propylene. Most preferably Y ³ in R ⁴ is methylene.
[197] R ⁴ is formula ^{-Y 2 -R 16, -Y 2 -NR} 17 R 18 or -Y ³ -R ^a, wherein is described above, ^{Y 2, Y 3, R a} , R 16, R l7 and ^l8 R The same is preferable.
[198] R ⁴ is of the formula -Y ¹ -R ¹⁶ , -Y ² -NR ¹⁷ R ¹⁸ or -Y ³ -R ^a , wherein Y ¹ and Y ³ are as defined above and R ¹⁶ is O, S and N Is a 4-7 membered saturated or partially saturated heterocyclic group containing 1 or 2 ring heteroatoms each selected from which is optionally substituted as described above and R ^a , R ¹⁷ And R ¹⁸ is more preferably as described above.
[199] R ¹⁶ is a 4-7 membered saturated or partially saturated heterocyclic group containing one nitrogen atom and optionally containing one additional ring heteroatom selected from O, S and N, wherein this heterocy The click ring is linked to -Y ² -via a ring nitrogen atom, where this heterocyclic ring is optionally substituted as described above.
[200] Preferred heterocyclic groups for R ¹⁶ include pyrrolidine, piperidine, azetidine, piperazine, homopiperidine, pyrroline, morpholine, thiomorpholine, thiazolidine and 1,2,6 tetrahydro Pyridine.
[201] Examples of R ¹⁶ in any of the preferred substituent groups for the heterocyclic oxo, hydroxy, C _l-4 alkyl, C _l-4 hydroxyalkyl, C _l-4 alkoxy, C _l-4 alkanoyl, C _2-5 cycloalkyl There is a 5- or 6-membered saturated or partially saturated heterocyclic ring containing alkyl or one or two ring heteroatoms selected from O, S and N.
[202] Optional substituents more preferred for the heterocyclic group in R ^{16 are} oxo, hydroxy, methyl, ethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl, 3 -Hydroxypropyl, methoxy, ethoxy, acetyl, cyclopropyl, vinyl, allyl and 2-morpholinoethyl.
[203] Preferred optional substituents for the ring carbon atom in the heterocyclic group of R ¹⁶ are methyl and hydroxy. Preferred substituents for the ring nitrogen atom in the heterocyclic group of R ¹⁶ include C _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-5 alkenyl, C _2-5 substituted with a heterocyclic group Alkanoyl, C _2-5 alkynyl, C _2-5 cycloalkyl and C _1-3 alkyl. Optional substituents more preferred for the ring nitrogen atom in the heterocyclic group of R ¹⁶ are methyl, 2-hydroxyethyl, allyl, 2-hydroxyethyl, 3-hydroxypropyl, cyclopropyl and 2-morpholinoethyl There is this. Preferably, the heterocyclic group of R ¹⁶ is unsubstituted.
[204] R ^a is C _3-7 cycloalkyl, wherein the ring is linked to —Y ³ — via a ring carbon atom substituted by hydroxy, amino or halogeno, which ring is optionally further defined as described above It is preferable that there is a substitution.
[205] R ^a is C _3-7 cycloalkyl, wherein the ring is linked to —Y ³ — via a ring carbon atom substituted by hydroxy, which ring further optionally has further substitution as described above desirable.
[206] R ^a is hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, wherein the hydroxy group is a substituent on a ring carbon atom linked to Y ³ , which ring is oxo, hydroxy, C _1-4 Alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _2-5 cycloalkyl, or 5 containing 1 or 2 ring heteroatoms selected from 0, S and N Or optionally further substituted by one or two substituents selected from a six-membered saturated or partially saturated heterocyclic ring.
[207] Most preferably, R ^a is 1-hydroxycyclopentyl or 1-hydroxycyclohexyl.
[208] Preferred substituents for R ^a are as defined above for R ¹⁶ .
[209] NR ¹⁷ R ¹⁸ in R ¹⁷ and R ¹⁸ is hydrogen, C _l-4 alkyl, hydroxy C _1-4 alkyl, cyano C _1-4 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C Preferably selected from _1-4 alkoxyC _1-3 alkyl and hydroxyC _1-3 alkoxyC _1-3 alkyl.
[210] NR ¹⁷ R ¹⁸ in R ¹⁷ and R ¹⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, cyanomethyl, 2-cyanoethyl, 2-hydroxyethyl, vinyl, allyl, 2- ( More preferred are ethoxy) ethyl and 2- (2-hydroxyethoxy) ethyl. It is preferred that one of R ¹⁷ and R ¹⁸ is hydrogen or methyl.
[211] R ¹⁷ and R ¹⁸ are each selected from hydrogen, methyl, ethyl, propyl, isopropyl, 2-methylpropyl and allyl.
[212] Particular groups of compounds are the above formula (I) or chemically acceptable salts or prodrugs thereof.
[213] In the above formula,
[214] Ring A is phenyl or pyridyl, in particular phenyl,
[215] m is 1, 2 or 3,
[216] Z, R ¹ , R ² and R ³ are as described above, X ¹ is —O—, —S—, —NR ⁷ CO—, —NR ⁷ SO ₂ — or —NR ⁷ — (where R ⁷ is Hydrogen, methyl, ethyl, methoxyethyl or ethoxyethyl), R ⁴ is selected from the groups 1a) to 8a) as described above,
[217] m is an integer from 1 to 3, R ¹ is methoxy, R ² is hydrogen, Z is -NH-, R ³ is halogeno or Cl _-3 alkyl, X ¹ is -O- and R ⁴ is Not selected from one of three aircraft,
[218] a) -C _2-5 alkylR ¹⁹ , wherein R ¹⁹ represents one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy It can be piperidin-4-yl),
[219] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[220] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above,
[221] Wherein any alkyl, alkenyl or alkynyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, halogeno and amino.
[222] Another specific group of compounds of Formula (I) or pharmaceutically acceptable salts or prodrugs thereof is as follows.
[223] Ring A is phenyl,
[224] m is 1, 2 or 3,
[225] Z is -NH-,
[226] R ¹ , R ² and R ³ are as described above, X ¹ is —O—, —S—, —NR ⁷ CO—, —NR ⁷ SO ₂ — or —NR ⁷ —, where R ⁷ is hydrogen , Methyl, ethyl or methoxyethyl), R ⁴ is selected from lb) to 4b) as described above,
[227] when m is 1 to 3, R ¹ is methoxy, R ² is hydrogen, Z is -NH-, R ³ is halogeno or Cl _-3 alkyl, and X ¹ is -0-, then R ⁴ is Not selected from one of three groups,
[228] a) -C _2-5 alkylR ¹⁹ , wherein R ¹⁹ represents one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy It can be piperidin-4-yl),
[229] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[230] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above,
[231] Wherein any alkyl, alkenyl or alkynyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, halogeno and amino.
[232] Another specific group of compounds of Formula (I) or pharmaceutically acceptable salts or prodrugs thereof is as follows.
[233] Ring A is phenyl,
[234] m is 1, 2 or 3,
[235] Z is -NH-,
[236] R ¹ , R ² and R ³ are as described above,
[237] X ^l is -O- or -S-,
[238] R ⁴ is of the formula —Y ¹ R ² 0 or Y ¹ NR ¹⁷ R ¹⁸ as described above,
[239] when m is 1 to 3, R ¹ is methoxy, R ² is hydrogen, Z is -NH-, R ³ is halogeno or Cl _-3 alkyl, and X ¹ is -0-, R ⁴ is Is not selected from one of
[240] a) -C _2-5 alkylR ¹⁹ , wherein R ¹⁹ represents one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy It can be piperidin-4-yl),
[241] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[242] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above.
[243] Another specific group of compounds of Formula (I) or pharmaceutically acceptable salts or prodrugs thereof is as follows.
[244] Ring A is phenyl,
[245] Z is -NH-,
[246] m is 1, 2 or 3,
[247] R ^l is hydrogen or methoxy,
[248] R ² is hydrogen,
[249] R ³ is fluoro, chloro, bromo, methyl or methoxy,
[250] X ^l is -O- or -S-,
[251] R ⁴ is of the formula -Y ¹ -R ²⁰ or -Y ¹ -NR ¹⁷ R ¹⁸ , wherein Y ¹ , R ¹⁷ , R ¹⁸ and R ²⁰ are as described above,
[252] when m is 1 to 3, R ¹ is methoxy, R ² is hydrogen, Z is -NH-, R ³ is halogeno or Cl _-3 alkyl, and X ¹ is -0-, then R ⁴ is Not selected from one of three groups,
[253] a) -C _2-5 alkylR ¹⁹ , wherein R ¹⁹ represents one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy It can be piperidin-4-yl),
[254] b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
[255] c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above,
[256] Wherein any alkyl, alkenyl or alkynyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, halogeno and amino.
[257] Specific compounds of the present invention include the following and pharmaceutically acceptable salts thereof,
[258] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6methoxy) quinazoline
[259] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxy) quinazoline
[260] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy) quinazoline
[261] 4- (4-chloro-2-fluorophenylamino) -7- (2-hydroxy-3- (morpholino) propoxy) -6-methoxy) quinazoline
[262] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (thiazolidin-3-yl) propoxy] -6-methoxy) quinazoline
[263] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline
[264] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-morpholinoethyl) piperazin-1-yl) propoxy] -6- Methoxyquinazoline
[265] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (3-hydroxypropyl) piperazin-1-yl) propoxy] -6-meth Oxyquinazoline
[266] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-hydroxyethyl) piperazin-1-yl) propoxy] -6-meth Oxyquinazoline
[267] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (1,2,3,6-tetrahydropyridin-1-yl) propoxy] 6-methoxy Quinazoline
[268] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-tbutyl-N-methylamino) propoxy] -6-methoxyquinazoline
[269] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride
[270] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline
[271] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy] -6-methoxy Quinazoline
[272] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (morpholino) propoxy] -6-methoxyquinazoline
[273] 4- (4-bromo-2-fluorophenylamino) -7- (2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline
[274] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-l-yl) propoxy] -6-methoxyquinazoline
[275] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[276] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-1-yl) propoxy] -6-methoxyquinazoline
[277] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (homopiperidin-1-yl) propoxy] -6-methoxyquinazoline
[278] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy] -6-methoxyquina Sleepy
[279] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (thiazolidin-3-yl) propoxy] -6-methoxyquinazoline
[280] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline
[281] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (thiomorpholin-4-yl) propoxy] -6-methoxyquinazoline
[282] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-hydroxypyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[283] 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-morpholinoethyl) piperazin-1-yl] propoxy} -6-meth Oxyquinazoline
[284] 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (3-hydroxypropyl) piperazin-1-yl] propoxy} -6-methoxy Quinazoline
[285] 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-hydroxyethyl)] piperazin-1-yl) propoxy} -6-meth Oxyquinazoline
[286] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (azetidin-1-yl) propoxy] -6-methoxyquinazoline
[287] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2,5-dimethyl-3-pyrrolin-1-yl) propoxy] -6-methoxyquina Sleepy
[288] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperidin-1-yl) propoxy] -6-methoxyquinazoline
[289] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (prop-2-yn-1-yl) -N-methylamino) propoxy]- 6-methoxyquinazoline
[290] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2-methylpyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[291] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-cyanoethyl) -N-methylamino) propoxy] -6-methoxyquina Sleepy
[292] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline
[293] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline
[294] 4- (4-Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (n-propyl) -N-ethylamino) propoxy] -6-methoxyquinazoline
[295] Further specific compounds of the present invention include the following and pharmaceutically acceptable salts thereof.
[296] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4-pyridylsulfanyl) propoxy] -6-methoxyquinazoline
[297] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (1-methylimidazol-2-ylsulfanyl) propoxy] -6-methoxyquinazoline
[298] 4-chloro-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[299] 4-chloro-2-fluoro-5-hydroxyphenylamino-7- (2-acetoxy-3-piperidinopropoxy) -6-methoxyquinazoline
[300] 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-acetoxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[301] 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[302] Preferred compounds of the present invention include the following compounds.
[303] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6methoxy) quinazoline
[304] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxy) quinazoline
[305] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy) quinazoline
[306] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (thiazolidin-3-yl) propoxy] -6-methoxy) quinazoline
[307] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline
[308] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-morpholinoethyl) piperazin-1-yl) propoxy] -6- Methoxyquinazoline
[309] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (3-hydroxypropyl) piperazin-1-yl) propoxy] -6-meth Oxyquinazoline
[310] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-hydroxyethyl) piperazin-1-yl) propoxy] -6-meth Oxyquinazoline
[311] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (1,2,3,6-tetrahydropyridin-1-yl) propoxy] -6-meth Oxyquinazoline
[312] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-tbutyl-N-methylamino) propoxy] -6-methoxyquinazoline
[313] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride
[314] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline
[315] 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy] -6-methoxy Quinazoline
[316] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (morpholino) propoxy] -6-methoxyquinazoline
[317] 4- (4-bromo-2-fluorophenylamino) -7- (2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline
[318] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-1-yl) propoxy] -6-methoxyquinazoline
[319] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[320] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline
[321] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (homopiperidin-1-yl) propoxy] -6-methoxyquinazoline
[322] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy] -6-methoxyquina Sleepy
[323] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline
[324] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (thiomorpholin-4-yl) propoxy] -6-methoxyquinazoline
[325] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-hydroxypyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[326] 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-morpholinoethyl) piperazin-1yl] propoxy} -6-methoxy Quinazoline
[327] 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-hydroxyethyl)] piperazin-1-yl) propoxy} -6-meth Oxyquinazoline
[328] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2,5-dimethyl-3-pyrrolin-1-yl) propoxy] -6-methoxyquina Sleepy
[329] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperidin-1-yl) propoxy] -6-methoxyquinazoline
[330] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2-methylpyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[331] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-cyanoethyl) -N-methylamino) propoxy] -6-methoxyquina Sleepy
[332] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline
[333] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline
[334] 4-chloro-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[335] 4-chloro-2-fluoro-5-hydroxyphenylamino-7- (2-acetoxy-3-piperidinopropoxy) -6-methoxyquinazoline
[336] 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[337] The present invention relates to the compounds of formula (I) as described above as well as to their salts. Salts for pharmaceutical compositions may be pharmaceutically acceptable salts, but other salts may be useful for the production of compounds of formula I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention include, for example, acid addition salts of compounds of formula I as described above which are sufficiently basic to form salts. These acid addition salts include, for example, hydrogen halides (especially hydrochloric acid or hydrobromic acid). And double hydrochloric acid is preferred) or sulfuric acid or phosphoric acid, or salts with inorganic or organic acids which provide pharmaceutically acceptable anions such as trifluoroacetic acid, citric acid or maleic acid. In addition to being sufficiently acidic, the pharmaceutically acceptable salts may be formed with inorganic bases or organic bases that provide pharmaceutically acceptable cations. These salts with inorganic bases or organic bases are for example alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts or for example methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Salts with tris- (2-hydroxyethyl) amine.
[338] Various forms of prodrugs are well known in the art. Examples of these prodrug derivatives are described in the following documents.
[339] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985),
[340] b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991),
[341] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992),
[342] d) H. Bundgaard, et al ., Journal of Pharmaceutical Sciences, 77, 285 (1988), and
[343] e) N. Kakeya, et al ., Chem Pharm Bull, 32, 692 (1984).
[344] One example of a prodrug is an in vivo hydrolyzable ester formed from a hydroxy group. In vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups produce molar alcohols in animals. The term includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds that are destroyed as a result of in vivo hydrolysis of the esters to provide the parent hydroxyl group. α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Examples of hydrolyzable ester forming groups in vivo with respect to hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (which provides alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (which provides carbamate), dialkylaminoacetyl and carboxyacetyl.
[345] The compounds of formula (I) or salts thereof and other compounds of the present invention (compounds as defined below) may be prepared by any known process that can be applied to the preparation of chemically related compounds. These processes are described, for example, in European Patent Applications, Publication Nos. 0520722, 0566226, 0606051, 0635498, 0873319, 0880508 and 0929530. These processes are provided as further features of the present invention and are described below. Essential starting materials can be obtained by the standard public of organic chemistry. The preparation of these starting materials is described in the non-limiting examples described later. In addition, essential starting materials can be obtained by processes similar to those exemplified as belonging to the ordinary techniques of organic chemists.
[346] Therefore, the following steps (a) to (f) and (iii) to (iii) constitute further features of the present invention.
[347] a) Compounds of formula (I) and salts thereof can be prepared by the reaction of compounds of formula (III) with compounds of formula (IV).
[348]
[349] Wherein R ¹ , R ² , X ¹ and R ⁴ are as described above and L 1 is a substitutable moiety.
[350]
[351] In the above formula, the rings A, Z, R ³ and m are as described above.
[352] Convenient substitutable portions L ¹ are for example halogeno, alkoxy (preferably C _1-4 alkoxy), aryloxy, alkylsulfanyl, arylsulfanyl, alkoxyalkylsulfanyl or sulfonyloxy groups, for example dechloro, bromo, meso Methoxy, phenoxy, methylsulfanyl, 2-methoxyethylsulfanyl, methanesulfonyloxy or toluene-4-sulfonyloxy group.
[353] The reaction is advantageously affected in the presence of either acid or base. These acids are, for example, anhydrous inorganic acids such as hydrogen chloride. These bases are for example organic amine bases, for example pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, tetramethylguanidine, morpholine, N-methylmorpholine or diazabicyclo [5.4. 0] undeck-7-ene, or an alkali or alkaline earth metal carbonate or hydroxide, such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Furthermore, these bases are for example alkali metal hydrides, for example sodium hydrides, or alkali metal or alkaline earth metal amides, for example sodium amide, sodium bis (trimethylsilyl) amide, potassium amide or potassium bis (trimethylsilyl) amide. The reaction is carried out with an inert solvent or diluent such as an alkanol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, tetrahydrofuran or 1,4-dioxane Ethers, aromatic hydrocarbon solvents such as toluene, or dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulfoxide In the presence of the desired influence. If the ring is heterocyclic it is preferred to use a base. The reaction is suitably effected at temperatures in the range from 10 to 150 ° C., preferably in the range from 20 to 80 ° C.
[354] The compounds of the present invention can be obtained from this process in the form of free bases or alternatively in the form of salts with acids of the formula HL ¹ , wherein L ¹ has the meaning defined above. If a free base is to be obtained from the salt, this salt can be treated with the base as defined above using conventional processes.
[355] b) When the group of formula (IIa) is a ring carrying one or two hydroxy groups, the compounds of formula (I) and salts thereof can be prepared by deprotection of compounds of formula (V).
[356]
[357] In the above formula, the rings A, R ³ and m are as described above.
[358]
[359] In the above formula, the rings A, X ¹ , m, R ¹ , R ² , R ³ , R ⁴ and Z are as described above, P is a hydroxy protecting group and p ¹ is the same number as the number of protected hydroxy groups. Is an integer from 5 to mp ¹ is equal to the number of R ³ substituents that are not protected hydroxy. Selections of the hydroxy protecting group P are within the standard knowledge of the organic chemist, for example ethers (eg methyl, methoxymethyl, allyl and benzyl), silyl ethers (eg t-butyldiphenylsilyl and t-butyldimethylsilyl) , "Protective Groups in Organic Synthesis" TW Greene and RGM Wuts, 2nd Ed, including esters (eg acetate and benzoate) and carbonates (eg methyl and benzyl). Wiley 1991] is included in standard textbooks. Removal of this hydroxy protecting group can be effected by any known process for modification, or by related processes, including these reaction conditions described in the above standard textbooks. The reaction conditions are preferably such that the hydroxy derivative is produced without unwanted reaction at the starting compound or at other positions in the resulting compound. For example, when the protecting group P is acetate, the modification is preferably a quinazoline derivative having the aforementioned bases, including ammonia, in the presence of a protic solvent or cosolvent such as water or an alcohol such as methanol or ethanol, and Can be suitably carried out by treatment of mono and di-alkylated derivatives thereof. This reaction can be carried out at temperatures ranging from 0 to 50 ° C., suitably about 20 ° C., in the presence of additional inert solvents or diluents as described above.
[360] c) The production of these compounds of formula (I) and salts thereof, wherein substituent X ¹ is —O—, —S— or —NR ^7, is suitably in the presence of the aforementioned bases It can be achieved by the reaction of the compound of VII.
[361]
[362] In the above formula, the rings A, m, X ¹ , R ¹ , R ² , R ³ and Z are as described above.
[363] R ⁴ -L ¹
[364] In the above formula, R ⁴ and L ¹ are as described above. L ¹ is a substitutable moiety, such as a halogeno or sulfonyloxy group, such as a bromo or methanesulfonyloxy group. The reaction is preferably in the presence of a base (as described above in step (a)) and preferably an inert solvent or diluent (as described above in step (a)), preferably in the range from 10 to 150 ° C., suitably It is preferably carried out at a temperature of about 50 ° C.
[365] d) Compounds of formula (I) and salts thereof can be prepared by the reaction of compounds of formula (VIII) with compounds of formula (IX).
[366]
[367] R ⁴ -X ¹ -H
[368] In the above formula, the rings A, m, X ¹ , R ¹ , R ² , R ³ and Z are as described above. The reaction is carried out in the presence of a base (as described above in step (a)) and preferably an inert solvent or diluent (as described above in step (a)), preferably in the range of 10 to 150 ° C., suitably Is preferably performed in the range of about 100 ° C.
[369] e) compounds of formula (I) and salts thereof, wherein R ⁴ contains a 2-hydroxypropyl chain or a ring nitrogen atom substituted by —NR ¹⁷ R ¹⁸ (R ¹⁷ and R ¹⁸ are as described above); And a saturated or partially saturated heterocyclic ring which is linked through it and contains no more than two additional ring heteroatoms selected from O, S and N] can be prepared by reaction of a compound of formula have.
[370]
[371] In the above formula, the rings A, R ¹ , R ² , R ³ , Z, m and X 1 are as described above. The reaction can be suitably carried out at temperatures ranging from 0 ° C. to 100 ° C. in an inert organic solvent such as ethanol or chloroform. Similar reactions can be used to prepare compounds of formula (I), wherein R ⁴ comprises a longer hydroxy substituted alkylene, alkenylene or alkynylene chain.
[372] f) The compounds of formula (I) and salts thereof, wherein the groups in R ⁴ connected to -Y ¹ -or -Y ² -are linked via an N, O or S atom, the compounds of formula (XI) and HN, It can be prepared by the reaction of a suitable compound containing a HO or HS group.
[373]
[374] In the above formula, the rings A, L ¹ , X ¹ , R ¹ , R ² , R ³ , Z and m are as described above and Q is -Y ¹ -or -Y ^2- . The reaction is suitably carried out at temperatures in the range of 0 to 150 ° C. in the presence of a base (as described above in step (a)) and an inert organic solvent (as described above in step (a)).
[375] Synthesis of Intermediate
[376] (i) Compounds of formula III and salts thereof constitute a further feature of the invention. These compounds, wherein L ¹ is halogeno, can be prepared by halogenating a compound of formula XII, for example.
[377]
[378] In the above formula, R ¹ , R ² , R ⁴ and X ¹ are as described above.
[379] Convenient halogenating agents include inorganic acid halides such as thionyl chloride, phosphorus (III) chloride, phosphorus (V) oxychloride and phosphorus (V) chloride. The halogenation reaction is suitably carried out in the presence of an inert solvent or diluent, for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is suitably carried out at temperatures in the range of 10 to 150 ° C., preferably 40 to 100 ° C.
[380] Compounds of formula (XII) and salts thereof which constitute a further feature of the present invention can be prepared, for example, by reacting a compound of formula (XIII) with a compound mur of IX described above.
[381]
[382] In the above formula, R ¹ , R ² and L ¹ are as described above. The reaction is in the presence of a base (as described above in step (a)) and preferably in the presence of an inert solvent or diluent (as described above in step (a)), preferably in the range of 10 to 150 ° C, for example. , Suitably, at a temperature of about 100 ° C.
[383] In addition, compounds of formula (XII) and salts thereof may be prepared by cyclizing compounds of formula (XIV).
[384]
[385] In the above formula, R ¹ , R ² , R ⁴ and X ¹ are as described above, and A ¹ is a hydroxy, alkoxy (preferably C _1-4 alkoxy) or amino group. Said cyclization is carried out by reacting the formula XIV, wherein A ¹ is a hydroxy or alkoxy group, with the formamide or the equivalent thereof to give cyclization [3- (dimethylamino) -2-azaprop-2 A compound of formula (XII) or a salt thereof, such as -enylidene] dimethylammonium chloride. The cyclization is suitably carried out in the presence of formamide as solvent or in the presence of an inert solvent or diluent such as ether, for example 1,4-dioxane. The cyclization is suitably carried out at elevated temperatures, preferably in the range from 80 to 200 ° C. Compounds of formula (XII) can also be prepared by cyclizing a compound of formula (XIV) with formic acid or an equivalent thereof effective to cause cyclization when A 1 is an amino group. Equivalents of formic acid effective for causing cyclization include, for example, Tri-C _1-4 alkoxymethane, for example triethoxymethane and trimethoxymethane. The cyclization is carried out in the presence of a catalytic amount of anhydrous acid such as sulfonic acid such as p-toluenesulfonic acid and for example an inert solvent or diluent such as methylene chloride, trichloromethane or halogenated carbon tetrachloride, diethyl ether or tetra Suitably in the presence of ethers such as hydrofuran, or aromatic hydrocarbon solvents such as toluene. The cyclization is suitably carried out at temperatures in the range of 10 to 100 ° C., preferably 20 to 50 ° C., for example.
[386] Compounds of formula (XIV) and salts thereof which constitute a further feature of the present invention can be prepared, for example, by reduction of nitro groups in compounds of formula (XV), thereby obtaining compounds of formula (XIV) as described above.
[387]
[388] In the above formula, R ¹ , R ² , R ⁴ , X ¹ and A ¹ are as described above. Reduction of the nitro group can be suitably carried out by any known process for modification. The reduction can be carried out, for example, by hydrogenation of the nitro compound solution in the presence of the aforementioned inert solvent or diluent and in the presence of a metal effective to catalyze the hydrogenation reaction such as palladium or platinum. Further reducing agents are activated metals such as activated iron, for example prepared by washing iron powder with a dilute solution of an acid such as hydrochloric acid. Thus, for example, the reduction may be carried out by heating the nitro compound and the activating metal in the presence of a solvent or diluent such as a mixture of water and alcohol such as methanol or ethanol, for example in the range of 50 to 150 ° C., suitably about 70 ° C. have.
[389] Compounds of formula (XV) and salts thereof which constitute further features of the present invention may be prepared by reaction of a compound of formula (XVI) with a compound of formula (IX) above.
[390]
[391] In the above formula, R ¹ , R ² , L ¹ and A ¹ are as described above. The reaction of the compounds of the formulas XVI and IX is suitably carried out under the conditions described for process (d) above.
[392] Compounds of formula (XV) and salts thereof may also be prepared by reaction of the compounds of formula (XVII) with the compounds of formula (VII) described above.
[393]
[394] In the above formula, R ¹ , R ² , X ¹ and A ¹ are as described above and X ¹ is not -CH _2- . The reaction of the compounds of formulas XVII and VII is suitably carried out under the conditions described for process (c) above.
[395] Compounds of formula III and salts thereof are prepared by reacting a compound of formula XVIII with a compound of formula VII described above, whereby a compound of formula III in which L ¹ is represented by L ² can be obtained.
[396]
[397] In the above formula, R ¹ , R ² and X ¹ are the same as described above, provided that X ¹ is not —CH ² — and L ² is a replaceable protecting moiety.
[398] Compounds of formula (XVIII) are suitably used when L ² is a phenoxy group which can carry up to 5 substituents, preferably up to 2 substituents selected from halogeno, nitro and cyano, if necessary. The reaction can be suitably carried out under the conditions described for step (c) above.
[399] The aforementioned compounds of formula (XVIII) and salts thereof can be prepared, for example, by deprotecting the compounds of formula (XIX).
[400]
[401] In the above formula, R ¹ , R ² , P, X ¹ and L ² are as described above, provided that X ¹ is not —CH ₂ —. Deprotection can be carried out by techniques well known in the literature, for example when P is a benzyl group, deprotection can be carried out by hydrogenolysis or by treatment of trifluoroacetic acid.
[402] One compound of formula III can be converted to another compound of formula III, wherein the L ¹ addition is different if necessary. Thus, for example L ¹ additional halogeno furnace, not for example, form a phenoxy admitted compound of formula (III) substituted in the formula III the compound singer cattle by decomposition L ¹ is halogeno elderly formula (III) (L ¹ is halogeno than will a) The compound of formula (III) wherein L ¹ is halogen may be obtained by converting to a compound to obtain a compound of formula (XII) as described above and then introducing a halide into the compound of formula (XII).
[403] (Ii) Compounds of formula (V) and salts thereof constitute further features of the present invention and may be prepared, for example, by reaction of a compound of formula (III) with a compound of formula (XX).
[404]
[405] In the above formula, the rings A, R ³ , m, p ¹ , P and Z are as described above. The reaction can be carried out, for example, as described for process (a) above.
[406] Compounds of formula V and salts thereof may also be prepared by reacting a compound of formula XXI with a compound of formula IX described above.
[407]
[408] In the above formula, A, R ¹ , R ² , L ¹ , Z, R ³ , m, p ¹ and P are as described above. The reaction can be carried out, for example, as described for process (d) above.
[409] Compounds of formula (V) and salts thereof may also be prepared by reacting a compound of formula (XXII) with a compound of formula (VII) above.
[410]
[411] In the above formula, the rings A, R ¹ , R ² , R ³ , X ¹ , Z, P, p ¹ and m are as described above provided that X ¹ is not —CH ₂ —. The reaction can be carried out as described for process (c) above.
[412] Compounds of formula XXI and salts thereof can be prepared, for example, by reaction of compounds of formula XXIII with compounds of formula XX described above.
[413]
[414] In the formula, R ^1, R ² and L ¹ may be equal to L ¹ are the same as above, 4-and 7-positions or different. The reaction can be carried out, for example, by the process described in (a) above.
[415] Compounds of formula (XXII) and salts thereof can be prepared by reacting compounds of formulas (XIX) and (XX) described above under the conditions described in (a) above, to provide compounds of formula (XXIV).
[416]
[417] In the above formula, the rings A, R ¹ , R ² , R ³ , P, Z, X ¹ , p ¹ and m are as described above, provided that X ¹ is not —CH ₂ —. The compound of formula (XXIV) is then deprotected, for example as described in (iii) above.
[418] (Iii) The compounds of formula (VI) and salts thereof can be prepared by deprotecting the compounds of formula (XXV) by, for example, a process as described in (iii) above.
[419]
[420] In the above formula, the rings A, R ¹ , R ² , R ³ , P, Z, X ¹ and m are as described above.
[421] The compound of formula XXV and salts thereof may be prepared by reacting the compounds of formulas XIX and IV described above under the conditions described in (a) above.
[422] (Iii) The aforementioned compound of formula (VIII) and salts thereof may be prepared by reacting the compounds of formulas (XXIII) and (IV) described above, and this reaction may be carried out by, for example, the process described in (a) above.
[423] (Iii) the compound of formula (X) is a suitable epoxy compound substituted with a leaving group such as halo (e.g., Y ¹ or Y ² is 2,3-epoxyprop-1-yl, 1-bromo-2,3-epoxypre Can be used in the case of a plate) to prepare a compound of formula XXV (eg 7-hydroxyquinazolin derivatives). This reaction may suitably be carried out in the presence of a mild base such as metal carbonate (eg potassium carbonate).
[424] (Iii) The compounds of formula (XI) and salts thereof can be prepared by reaction of the compounds of formula (VI) with the compounds of formula (XXVI).
[425] L ¹ -QL ¹
[426] In the above formula, L ¹ and Q are as described above. The reaction can be carried out by the process described in (c) above.
[427] Compounds of formula (XI) and salts thereof can be prepared by deprotecting compounds of formula (XXVII), for example by the process described in (b) above.
[428]
[429] In the above formula, the rings A, L ¹ , Q, X ¹ , R ¹ , R ² , R ³ , Z, P, m and p ¹ are as described above.
[430] The compounds of formula (XXVII) and salts thereof can be prepared, for example, by reacting the compounds of formulas (XXII) and XXVI described above under the conditions described in (c) above.
[431] If a pharmaceutically acceptable salt of a compound of formula (I) is required, it can be obtained by reacting the compound with an acid having a pharmaceutically acceptable anion, using conventional methods.
[432] Some of the intermediates described herein, such as the intermediates of Formulas V and X, are novel and they serve as additional features of the present invention.
[433] Any substituent may be converted to any other substituent. For example, alkylthio groups can be oxidized to alkylsulfinyl or alkylsulfonyl groups, nitro groups can be reduced to amino groups, hydroxy groups can be alkylated with methoxy groups, or bromo groups can be converted to alkylthio groups.
[434] Various substituents may be introduced into the compounds of formula (I) and intermediates when appropriate in the preparation of compounds of formula (I) and formula (I) using standard methods known in the art. For example, nitro groups can be introduced to the activated benzene ring by nitrification with concentrated nitric acid and concentrated sulfuric acid and bromination with bromine or tetra (n-butyl) ammonium tribromide.
[435] It will be appreciated that at certain stages of the sequence of reactions for compounds of formula I, it is necessary to protect certain functional groups of the intermediate to prevent side reactions. If protection is no longer needed, deprotection can be carried out at a convenient stage of the reaction sequence.
[436] The protecting group can generally be selected from any group described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and can be introduced by conventional methods. The protecting group can be removed by any conventional method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, and these methods remove the protecting group with minimal disturbance to other groups of the molecule. Is chosen to be.
[437] Specific examples of protecting groups are given below for convenience, where "lower" as in lower alkyl, for example, is a group adapted to have from 1 to 4 carbon atoms. It will be understood that these examples are not exclusive.
[438] Specific examples of methods for protecting group removal are described below, which are similarly not exclusive. Of course, the use of protecting groups and deprotection methods not specifically mentioned is also within the scope of the present invention.
[439] The carboxy protecting group may be a residue of an ester forming aliphatic or arylaliphatic alcohol or a residue of an ester forming silanol (the alcohol or silanol preferably contains 1 to 20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (1-12C) alkyl groups (eg isopropyl and t-butyl), lower alkoxy-lower alkyl groups (eg methoxymethyl, ethoxymethyl and isobutoxymethyl), lower acyloxy-lower Alkyl groups (e.g. acetoxymethyl, propynyloxymethyl, butyryloxymethyl and pivaloyloxymethyl), lower alkoxycarbonyloxy-lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl and 1-ethoxycar Carbonyloxyethyl), aryl-lower alkyl groups (e.g. benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl), tri (lower alkyl) silyl groups (e.g. trimethyl Silyl and t -butyldimethylsilyl), tri (lower alkyl) silyl-lower alkyl groups (eg trimethylsilylethyl), and (2-6C) alkenyl groups (eg allyl). Particularly suitable methods for the removal of carboxyl protecting groups are acid-, base-, metal- or enzymatically catalyzed cleavage.
[440] Examples of hydroxy protecting groups include lower alkyl groups (eg t -butyl), lower alkenyl groups (eg allyl), lower alkanoyl groups (eg acetyl), lower alkoxycarbonyl groups (eg t -butoxycarbonyl), lower al Kenyloxycarbonyl groups (eg allyloxycarbonyl), aryl-lower alkoxycarbonyl groups (eg benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl) , Tri (lower alkyl) silyl (eg trimethylsilyl and t -butyldimethylsilyl) and aryl-lower alkyl (eg benzyl) groups.
[441] Examples of amino protecting groups include formyl, aryl-lower alkyl groups (eg benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl and triphenylmethyl), di-4-anisyl Methyl and furylmethyl groups, lower alkoxycarbonyls (e.g. t -butoxycarbonyl), lower alkenyloxycarbonyls (e.g. allyloxycarbonyl), aryl-lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl, 4- Methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl), trialkylsilyl (e.g. trimethylsilyl and t -butyldimethylsilyl), alkylidene (e.g. methylidene) and benzylidene And substituted benzylidene groups.
[442] Suitable methods for the removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymatically catalyzed hydrolysis to groups such as 2-nitrobenzyloxycarbonyl, hydrogenation to groups such as benzyl, and 2 -Photolytically to groups such as nitrobenzyloxycarbonyl.
[443] For general guidance on reaction conditions and reagents, see 'Advanced Organic Chemistry', 4th Edition, by J. March, published by John Wiley & Sons 1992, and for general guidance on protecting groups see 'Protective Groups in Organic'. Synthesis', 2nd Edition, by T. Greene and RGM Wuts].
[444] It is desirable to identify compounds that strongly inhibit tyrosine kinase activity associated with VEGF receptors such as Flt and / or KDR and inhibit angiogenesis and / or increase in vascular permeability, which is a subject of the present invention. These properties can be assessed using, for example, one or more processes described below.
[445] (a) In vitro receptor tyrosine kinase inhibition test
[446] This assay measures the ability of test compounds to inhibit tyrosine kinase activity. DNA encoding the cytoplasmic domain of VEGF, FGF or EGF receptors can be obtained by synthesis of whole genes (Edwards M, International Biotechnology Lab 5 (3), 19-25, 1987) or by cloning. They can then be expressed in an appropriate expression system to obtain polypeptides having tyrosine kinase activity. For example, the cytoplasmic domains of VEGF, FGF or EGF receptors obtained by expression of recombinant proteins in insect cells have been shown to exhibit native tyrosine kinase activity. In the case of the VEGF receptor Flt (Ginbank Accession No. X51602), a 7 kb DNA fragment encoding most cytoplasmic domains, starting with methionine 783 and comprising a stop codon, is described in Shibuya et al., Oncogene, 1990, 5 : 519-524, isolated from cDNA and cloned into a baculovirus transplacement vector {see, eg, pAcYM1 (The Baculovirus Expression System: A Laboratory Guide, LA King and RD Possee, Chapman and Hall). , 1992) or pAc360 or pBlueBacHis (available from Invitrogen Corporation). This recombinant construct was co-infected with viral DNA (eg, Pharmingen BaculoGold) with insect cells (eg, Spodoptera frugiperda21 (Sf21)) to produce recombinant baculovirus. (Details of the combination of recombinant DNA molecules and methods for the preparation and use of recombinant baculovirus are described, for example, in Sambrook et al , 1989, Molecular cloning-A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory Press and O'Reilly et. al , 1992, Baculovirus Expression Vectors-A Laboratory Manual, WH Freeman and Co, New York. For other tyrosine kinases for use in the assay, from methionine 806 (KDR Genbank Accession No. L04947), methionine 668 (EGF Receptor, Genbank Accession No. X00588) and methionine 399 (FGF R1 Receptor, Genbank Accession No. X51803) Starting cytoplasmic fragments can be cloned and expressed in a similar manner.
[447] For expression of cFlt tyrosine kinase activity, Sf21 cells were infected with plaque-pure cFlt recombinant virus at three times of infection and harvested after 48 hours. The harvested cells were washed with iced phosphate buffered saline solution (PBS) (10 mM sodium phosphate pH7.4, 138 mM sodium chloride, 2.7 mM potassium chloride), followed by ice cold HNTG / PMSF (20 mM Hepes pH7.5, 150 mM sodium chloride, 10% v / v glycerol, 1% v / v Triton X100, 1.5 mM magnesium chloride, 1 mM ethylene glycerol bis (β aminoethyl ether) N, N, N ', N'-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulfonyl Fluoride; this PMSF was added immediately before use from a 100 mM solution in freshly prepared methanol) and suspended using 1 ml HNTG / PMSF per 10 million cells. The suspension was centrifuged at 13,000 rpm for 10 minutes at 4 ° C, the supernatant (enzyme stock) was removed, and an aliquot was stored at -70 ° C. Each new batch of enzyme stock was titrated in the assay by dilution with enzyme dilution (100 mM Hepes pH 7.4, 0.2 mM sodium orthovannadate, 0.1% v / v Triton X100, 0.2 mM dithiothritol). For representative batches, the stock enzyme is diluted to 1 in 2000 with enzyme dilution and 50 μl of diluted enzyme is used for each assay well.
[448] The stock solution of the substrate solution was prepared from any copolymer containing tyrosine, such as Poly (Glu, Ala, Tyr) 6: 3: 1 (Sigma P3899), stored at −20 ° C. as 1 mg / ml in PBS and plate Dilute to 1 in 500 with PBS for coating.
[449] 100 μl of diluted substrate solution was distributed to all wells of sealed assay plates (Nunc maxisorp 96-well immunoplates) the day before analysis and left overnight at 4 ° C.
[450] The substrate solution was discarded on the day of analysis and the assay plate wells were washed once with PBST (PBS containing 0.05% v / v Tween 20) and once with 50 mM Hepes pH7.4.
[451] Test compounds were diluted with 10% dimethylsulfoxide (DMSO) and 25 μl of diluted compound was transferred to wells in a washed assay plate. "Whole" control wells contained 10% DMSO in place of the compound. 25 milliliters of 40 mM manganese chloride containing 8 μM of adenosine-5'-triphosphate (ATP) was added to all test wells except for the "blank" control wells containing manganese chloride without ATP. To start the reaction, 50 μl of freshly diluted enzyme was added to each well and the plate was incubated for 20 minutes at room temperature. The liquid was then discarded and the wells washed twice with PBST. Add 100 microliter mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology Inc. product 05-321) diluted to 1 in 6000 with PBST containing 0.5% w / v bovine serum albumin (BSA) and plate After incubating for 1 hour at room temperature, the liquid was discarded and the wells were washed twice with PBST. 10 microliters of 2,2'-azine-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) solution freshly prepared 50 mM phosphate citrate buffer pH5.0 + 0.03% sodium perborate (distilled Freshly prepared using one 50 mg ABTS tablet (Boehringer 1204 521) in 50 ml of phosphate citrate buffer capsule (made with one Sigma P4922) with sodium perborate per 100 ml of water and added to each well. The plates were then incubated for 20-60 minutes at room temperature until the optical density of the "whole" control wells was about 1.0 as measured at 405 nm using a plate read spectrophotometer. The values of the "blank" (ATP free) and "total" (compound free) controls were used to determine the dilution range of the test compound conferring 50% inhibition of enzyme activity.
[452] (b) In vitro HUVEC proliferation assay
[453] This assay measures the ability of test compounds to inhibit growth factor stimulated proliferation of human maternal venous epithelial cells (HUVEC).
[454] HUVEC cells were isolated in MCDB 131 (Bibco BRL) + 7.5% v / v fetal serum (FCS) and 96 cells in MCDB 131 + 2% v / v FCS + 3 μg / ml heparin + 1 μg / ml hydrocortisone Plate out (2-8 passes) at a concentration of 1000 cells / well in the well plate. After a minimum of 4 hours they were dosed with appropriate growth factors (ie VEGF 3 ng / ml, EGF 3 ng / ml or b-FGF 0.3 ng / ml) and compounds. This culture was then incubated with 7.5% CO ₂ at 37 ° C. for 4 days. On day 4 the cultures were vibrated with 1 μCi / well of titrated thymidine (Amersham product TRA 61) and incubated for 4 hours. The cells were harvested using a 96-well plate harvester (Tomtek) and then analyzed for incorporation of tritium with a beta plate counter. Incorporation of radioactivity into cells, represented by cpm, was used to determine the inhibition of growth factor stimulated cell proliferation by compounds.
[455] (c) in vivo solid tumor disease models
[456] This test tests the ability of a compound to inhibit solid tumor growth.
[457] Thymus-free female Schux nu / nu mice were cultured by CaLu-6 tumor xenografts by subcutaneous injection of 1 × 10 ⁶ CaLu-6 cells / mouse in 100 μl of 50% (v / v) Matrigel solution in serum free culture medium. Settled on the side of the. Ten days after cell transplantation, mice were allocated to groups 8-10 to achieve an average volume of comparable groups. Tumors were measured using vernier calipers and volume calculated as (l × w) × √ (l × w) × (Π / 6), where l is the longest diameter and w is now perpendicular to the longest. Test compounds were administered orally once a day for a minimum of 21 days and control animals received diluted compounds. Tumors were measured twice a week. Growth inhibition levels were calculated by comparison of the mean tumor volume of control versus test using the Student T test and / or the Mann-Whitney Rank Sum Test. The inhibitory effect of compound treatment was considered significant when p <0.05.
[458] Although the pharmacological properties of the compounds of formula (I) usually vary with structural changes, the activity possessed by the compounds of formula (I) may be represented by the following concentrations or dosages in one or more of the tests (a) and (b) above. .
[459] Test (a):-IC ₅₀ in the range of <10 μM, for example
[460] Test (b):-IC ₅₀ in the range of <10 μM, for example
[461] In the example of test (a), Example 1 used the KDR receptor and IC50 was 0.015-0.05 micrometers.
[462] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient or carrier.
[463] The composition may be administered orally, e.g., as a tablet or capsule, parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion) such as sterile solutions, suspensions or emulsions, topical such as ointments or creams. Administration, or a form suitable for rectal administration such as suppositories. Typically the composition can be prepared by conventional methods using conventional excipients.
[464] The compositions of the present invention are advantageously present in unit dosage form. The composition is a unit dose within the normal body size range 1m 5 ~ 5000 mg per ^second of the animal that is to be administered to a warm-blooded animal of approximately 0.1 ~ 100mg / kg. For example, unit dosages in the range of 1-100 mg / kg, preferably 1-50 mg / kg, are observed, which usually provides a therapeutically effective dosage. Unit dosage forms such as tablets or capsules contain for example 1-250 mg of active ingredient.
[465] According to a further aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a human or animal by treatment.
[466] We have found that the compounds of the present invention are related to their ability to inhibit VEGF receptor tyrosine kinase activity and thus cause their antiangiogenic effects and / or decrease their vascular permeability.
[467] A further feature of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, suitably for use as a medicament for causing anti-angiogenic and / or vascular permeability reducing effects in warm blooded animals such as humans. Compound of formula (I) or a pharmaceutically acceptable salt thereof.
[468] Therefore, according to a further aspect of the present invention, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in causing anti-angiogenic and / or vascular permeability-reducing effects in warm-blooded animals such as humans Is provided.
[469] According to a further feature of the invention, said animal in need of antiangiogenesis and / or vascular permeability reduction treatment comprising administering to said warm blooded animal such as a human said compound of formula (I) or a pharmaceutically acceptable salt thereof A method of causing antiangiogenic and / or vascular permeability reducing effects is provided.
[470] As mentioned above, the size of dosage required for the therapeutic or prophylactic treatment of a particular disease state will of course depend on the host being treated, the route of administration and the severity of the disease to be treated. It is preferred to use a dosage in the range of 1-50 mg / kg per day. However, the daily dose will depend on the host being treated with water, the particular route of administration and the severity of the disease to be treated. Thus, the optimal dosage can be determined by the physician treating any particular patient.
[471] The antiangiogenic and / or vascular permeation inhibitory treatments described above may be applied as a single treatment or may include one or more other substances and / or treatments in addition to the compounds of the present invention. These co-treatments can be in the manner of simultaneous, continuous or separate administration of the individual therapeutic compounds. It is common practice in the medical oncology field to use different types of treatment combinations to treat each patient with cancer. In medical oncology, in addition to the antiangiogenic and / or vascular permeability reduction treatments described above, the other component (s) of these joint therapies may be surgery, radiation therapy or chemotherapy. This chemotherapy may comprise three main categories of therapeutic agents: (iii) to (iii).
[472] (Iii) other antiangiogenic agents acting by mechanisms different from those described above (e.g., linomide, inhibitors of integrin αvβ3 function, angiostatin, lagoxin, thalidomide) and the entire specification herein by reference Vascular targeting agents (eg, combretastatin phosphate) and vascular damaging agents (eg, N-acetylcolchinol-O-phosphate) described in International Patent Application Publication No. WO 99/02166,
[473] (Ii) cell proliferation inhibitors such as antiodesterogens (eg tamoxifen, toremifene, raloxyphene, droloxyphene, iodoxifen), progestogens (eg megestrol acetate), aromatase inhibitors (Eg, anastrozole, retrazole, borazol, dexemstan), antiprogestogen, antiandrogen (eg, flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists And antagonists (e.g. goserelin acetate, lutrolide), testosterone 5α-dihydroreducing agents (e.g. finasteride), antiinvasive agents (e.g. metalloproteinase inhibitor-like marimastat and urokinase plasminogen activator receptor activity Inhibitors of growth factor and growth factor function inhibitors (these growth factors include, for example, platelet derived growth factors and hepatocyte growth factors, these inhibitors include growth factor antibodies, growth factors Includes antibodies, tyrosine kinase inhibitors and serine / threonine kinase inhibitor of the receptor),
[474] (Iv) antiproliferative / antitumor agents and combinations thereof used in medicinal oncology, eg metabolic agents (e.g., antihydrochloric acid-like methotrexate, fluoropyrimidine-like 5-fluorouracil, purine and adenosine analogues, cytosine ara Binoside); Anti-tumor antibiotics (eg, anthracycline like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin); Platinum derivatives (eg, cisplatin, carboplatin); Alkylating agents (eg, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); Cell division inhibitors (eg, vinca alkaloid-like vincristine and taxoid-like taxol, taxotere); Topoisomerase inhibitors (for example epipodophyllotoxin-like etoposide and teniposide, amsacrine, topotecan and irinotecan); Also enzymes (eg, asparaginase); And thymidylate synthase inhibitors (eg, raltiltrexed).
[475] Further types of chemotherapeutic agents include the following (i) and (iii).
[476] (Iii) biological response modifiers (eg interferon),
[477] (Iii) an antibody (eg, edrecolomab).
[478] For example, this co-treatment may be simultaneous, continuous or separate of the vascular targeting agent described in WO 99/02166 (Example 1 of WO 99/02166), such as the compound of formula I and N-acetylcolchinol-O-phosphate as described above. Can be achieved by way of administration.
[479] As mentioned above, the compounds defined in the present invention are important for their antiangiogenic and / or vascular permeability inhibitory effects. These compounds of the invention include cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atherosclerosis, arterial restenosis, autoimmune disease, acute inflammation, excessive It is expected to be useful for a wide range of disease states, including scar formation and cementation, endometriosis, uterine bleeding of dysfunction, and ocular diseases with retinal vessel surges. Specifically, these compounds of the present invention are advantageously expected to slow the growth of early and recurring solid tumors of the colon, breast, prostate, lung and skin, for example. More specifically these compounds of the present invention rely heavily on VEGF for early and recurrent solid tumors associated with VEGF, especially for growth and reproduction, including certain tumors of the colon, breast, prostate, lung, vulva and skin. It is expected to inhibit the growth of these tumors.
[480] In addition to their use as therapeutic medicaments, the compounds of formula (I) and their pharmaceutically acceptable salts are VEGF receptor tyrosine kinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice as part of the search for new therapeutic agents. It is useful as a pharmacological tool in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors.
[481] The term "ether" as used herein is to be understood as referring to diethyl ether.
[482] The invention will now be described in the following non-limiting examples unless otherwise specified.
[483] (Iii) the operation was performed under an atmosphere of an inert gas such as argon at ambient temperature, i.
[484] (Ii) evaporation was carried out by vacuum rotary evaporation and the inspection process was carried out after the removal of residual solids by filtration;
[485] (Iii) reverse phase silica Merck Lichroprep RP-18 (Art. 9303) or Merck Kieselgel purchased from E. Merck, Darmstadt, Germany, for column chromatography (by flash process) and medium pressure liquid chromatography (MPLC) either on silica (Art. 9385) or high pressure liquid chromatography (HPLC), for example on C18 reversed phase silica, such as a Dynamax C-18 60Å preparative reversed phase column,
[486] (Iii) where the product is present, this is given for illustrative purposes only and is not necessarily the maximum that can be obtained;
[487] (Iii) Usually, the final product of formula (I) is subjected to sufficient microanalysis and these structures are confirmed by nuclear magnetic resonance (NMR) and / or mass spectral techniques; Fast-atom bombardment (FAB) mass spectral data is obtained using a platform spectrometer and, where appropriate, collects either cation data or anion data; Chemical shift values of NMR were measured on a delta scale (proton magnetic resonance spectra were measured using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz or a Bruker AM300 spectrometer operating at a field strength of 300 MHz); s stands for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, b for broadness,
[488] (Iii) the intermediate product is usually not fully characterized and purity is determined by thin layer chromatography (HPLC) infrared (IR) and / or NMR analysis,
[489] (Iii) Melting points were not calibrated and were measured using a Mettler SP62 automatic melting point apparatus or an oil bath apparatus, and the melting point for the final product of formula (I), alone or in admixture, was determined by conventional ethanol, methanol, acetone, ether or hexane. Measured after crystallization from organic solvent,
[490] (Iii) The following abbreviations were used.
[491] DMF N, N-dimethylformamide
[492] DMSO dimethyl sulfoxide
[493] TFA trifluoroacetic acid
[494] Gold reagent {dimethylaminomethyleneaminomethylene) dimethylammonium chloride, [3- (dimethylamino) -2-azaprop-2-ene-1-ylidene] dimethylammonium chloride}
[495] Example 1
[496] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy-6-methoxy) quinazoline
[497]
[498] 7- [2-acetoxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy-4-chloroquinazolin (103 mg, 0.25 mmol) and 2 in isopropanol (3 ml) -Fluoro-4-bromoaniline (52.7 mg, 0.28 mmol) was heated at 80 ° C. for 2 hours. After cooling, ether (1 ml) was added and the precipitate was filtered off and washed with isopropanol / ether (2/1) followed by ether (2 ml). The solid was suspended in a methanol solution saturated with ammonia (5 ml) and the mixture was stirred at ambient temperature for 20 hours. Volatile material was removed under vacuum. The solid was titrated with ether, filtered and dried in vacuo at 50 ° C. overnight. The solid was dissolved in methanol / methylene chloride (5/95) and eluted through isolute® trademark SPE Column (NH ₂ , 10 g) using methanol / methylene chloride (5/95). Fractions containing the expected product were mixed and evaporated to give the title product (36 mg, 27%).
[499] MS-ESI: 520 [MH ⁺ ]
[500] ^' H NMR Spectrum (DMSOd ₆ ): 2.1 (s, 3H); 2.15-2.5 (m, 10 H); 3.9 (s, 3H); 3.9-4.0 (m, 2 H); 4.1 (m, 1 H); 4.85 (br s, 1 H); 7.15 (s, 1 H); 7.4 (d, 1 H); 7.45 (dd, 1 H); 7.6 (d, 1 H); 7.75 (s, IH); 8.3 (s, 1 H); 9.5 (s, 1H)
[501] Starting material was prepared as follows.
[502] Reagent of gold in 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol) (J. Med. Chem. 1977, vol 20, 146-149), and dioxane (100 ml) (7.4 g, 0.05 mol) was stirred and heated to reflux for 24 h. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for another 3 hours. The volatiles were removed by evaporation, water was added to the residue, and the solids were collected by filtration, washed with water and dried. Recrystallization from acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
[503] Sodium hydride (1.44 g of 60% suspension in mineral oil, 36 mmol) was added 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol) in DMF (70 ml). To the solution was added in portions over 20 minutes and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate (100 ml) and poured into ice / water (400 ml) and 2 M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate, the combined extracts were washed with brine and dried (MgSO ₄ ), and the solvent was removed by evaporation. The residue is titrated with a mixture of ether and petroleum ether and the solid is collected by filtration and dried under vacuum to afford 7-benzyloxy-6-methoxy-3-((pivaloyloxy) methyl) -3,4di Hydroquinazolin-4-one was obtained (lO g, 84%).
[504] ^' H NMR Spectrum: (DMSOd ₆ ) 1.ll (s, 9H); 3.89 (s, 3 H); 5.3 (s, 2H); 5.9 (s, 2 H); 7.27 (s, 1 H); 7.35 (m, 1 H); 7.47 (t, 2 H); 7.49 (d, 2 H); 7.51 (s, 1 H); 8.34 (s, 11)
[505] 7-benzyloxy-6-methoxy-3- (pivaloyloxymethyl) -3,4dihydroquinazolin- in ethyl acetate (250 ml), DMF (50 ml), methanol (50 ml) and acetic acid (0.7 ml) A mixture of 4-one (7 g, 17.7 mmol) and palladium catalyst (700 mg) on 10% charcoal was stirred under hydrogen for 40 minutes at atmospheric pressure. The catalyst was removed by filtration and the solvent was removed from the filtrate by evaporation. The residue was titrated with ether, collected by filtration and dried under vacuum to afford 7-hydroxy-6-methoxy-3- (pivaloyloxymethyl) -3,4-dihydroquinazolin-4-one Was obtained (4.36 g, 80%).
[506] ^' H NMR Spectrum: (DMSOd ₆ ) 1.l (s, 9H); 3.89 (s, 3 H); 5.89 (s, 2 H); 7.0 (s, 1 H); 7.48 (s, 1 H); 8.5 (s, 1H)
[507] 7-hydroxy-6-methoxy-3-((pivaloyloxymethyl) -3,4-dihydroquinazolin-4-one (15 g, 49 mmol) in DMF (150 ml), 1-bro A solution of mother-2,3-epoxypropane (6.3 ml, 73.5 mmol) and potassium carbonate (13.5 g, 98 mmol) was stirred at 60 ° C. for 1 hour and then at 80 ° C. After cooling, the mixture was iced. Poured into water (600 ml) The precipitate was filtered off and washed with water followed by ether The replacement was dried under vacuum overnight to give 7- (2,3-epoxypropoxy) -6-methoxy-3- (Pivaloyloxymethyl) -3,4-dihydroquinazolin-4-one was obtained (17.3 g, 98%).
[508] MS-ESI: 385 [MNa ⁺ ]
[509] ^' H NMR Spectrum (DMSOd ₆ ): 1.15 (s, 9H); 2.75 (m, 1 H); 2.9 (t, 1 H); 3.4 (m, 1 H); 3.9 (s, 3H); 3.97 (dd, 1 H); 4.52 (dd, 1 H); 5.9 (s, 2 H); 7.2 (s, 1 H); 7.52 (s, 1 H); 8.35 (s, 1H)
[510] 7- (2,3-epoxypropoxy) -6-methoxy-3- (pivaloyloxymethyl) -3,4-dihydroquinazolin-4-one (5 g, 13.8 in chloroform (70 ml) mmol) and N-methylpiperazine (1.7 ml) solution were refluxed for 21 hours. After cooling, the mixture was poured onto a silica column and methanol / methylene chloride / ethylacetate (5/45/50), then (8/42/50), then methanol (saturated with ammonia) / methylene chloride / methanol (5 / 45/50), followed by (8/42/50). Fractions containing the expected product were mixed and volatiles were removed in vacuo. The solid was titrated with ether, filtered, washed with ether and dried under vacuum to afford 7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy- 3- (pivaloyloxymethyl) -3,4-dihydroquinazolin-4-one was obtained (4.8 g, 75%).
[511] ^' H NMR Spectrum (DMSOd ₆ ): 1.1 (s, 9H); 2.15 (s, 3 H); 2.2-2.55 (m, 10 H); 3.9 (s, 3H); 3.95-4.02 (m, 2 H); 4.15 (d, 1 H); 4.95 (br s, 1 H); 5.9 (s, 2 H); 7.2 (s, 1 H); 7.45 (s, 1 H); 8.32 (s, 1H)
[512] 7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy-3- (pivaloyloxymethyl)-in methanol (100 ml) saturated with ammonia A 3,4-dihydroquinazolin-4-one (4.3 g, 9.3 mmol) solution was stirred at ambient temperature for 2 days. The volatiles were removed in vacuo and the residue was titrated with ether, filtered, washed with ether and then evaporated to dryness 7- (2-hydroxy-3- (4-methylpiperazin-1-yl) Propoxy) -6-methoxyquinazolin-4-one (3.4 g, calculated as amount)
[513] ^' H NMR Spectrum (DMSOd ₆ ): 2.15 (s, 3H); 2.2-2.6 (m, 10 H); 3.9 (s, 3H); 4.05 (d, 2 H); 4.15 (m, 1 H); 4.9 (br s, 1 H); 7.15 (s, 1 H); 7.45 (s, 1 H); 8.0 (s, 1H)
[514] 7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxyquinazolin-4-one (1.2 g, 3.3 mmol) and ace in ether (2 ml) Tic anhydride (670 μl) solution was stirred at ambient temperature for 10 minutes. Further ether (2 ml) was added followed by acetic anhydride (670 μl). After 1 h of stirring at ambient temperature, water (305 μl) was added and stirring continued for 1.5 h. The mixture was partitioned between methylene chloride and tartium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with methylene chloride. The organic layers were mixed, dried (MgSO ₄ ) and evaporated. The solid was titrated with ether, filtered and washed with ether and dried under vacuum to afford 7- [2-acetoxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxyquinazolin- 4-one was obtained (0.93 g, 72%).
[515] MS-ESI: 391 [MH] &lt; + &gt;
[516] ^' H NMR Spectrum (DMSOd ₆ ): 2.0 (s, 3H); 2.12 (s, 3 H); 2.3 (br s, 4H); 2.4-2.7 (m, 6 H); 3.9 (s, 3H); 4.3 (m, 2 H); 5.3 (m, 1 H); 7.2 (s, 1 H); 7.45 (s, 1 H); 8.0 (s, 1 H); 12.07 (br s, lH)
[517] 7- [2-acetoxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxyquinazolin-4- in thionyl chloride (10 ml) containing DMF (150 μl) The warm (930 mg, 2.4 mmol) solution was heated at 80 ° C. for 5 hours. The volatiles were removed under vacuum and the residue was azeotrope mixed with toluene. The solid was partitioned between methylene chlorandide and water and the pH of the aqueous layer was adjusted by solid sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography eluting with methanol (95/5) saturated with methylene chloride / ammonia. Fractions containing the expected product were mixed and the volatiles removed in vacuo to afford 7- [2-acetoxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy-4-chloro Quinazolin was obtained (859 mg, 88%).
[518] MS-ESI: 409 [MH ⁺ ]
[519] ^' H NMR Spectrum (DMSOd ₆ ): 2.02 (s, 3H); 2.13 (s, 3); 2.2-2.35 (m, 4 H); 2.35-2.6 (m, 4 H); 2.6 (m, 2 H); 4.0 (s, 3H); 4.2 (m, 2 H); 5.35 (m, 1 H); 7.41 (s, 1 H); 7.53 (s, 1 H); 8.51 (s, 1H)
[520] Example 2
[521] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-l-yl) propoxy] -6-methoxy) quinazolin
[522]
[523] 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline (56 mg) in a mixture of chloroform (500 μl) and ethanol (500 μl) , 0.15 mmol) and pyrrolidine (26 mg, 0.37 mmol) were stirred at 40 ° C. for 5 hours. Methylene chloride (10 ml) is added and the mixture is poured onto silica, followed by methylene chloride, followed by methylene chloride / methanol (98/2), followed by methanol (97/3) and (95/5) saturated with methylene chloride / ammonia Eluted. Fractions containing the expected product were mixed and volatiles were removed in vacuo. The residue was titrated with 6.2 N etheric hydrogen chloride (25 μl). The precipitate was filtered off and dried in vacuo to afford the title compound as hydrogen chloride (31.5 mg, 41%).
[524] MS-ESI: 447 [MH] &lt; + &gt;
[525] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.85-2.1 (m, 4H); 3.1-3.2 (m, 2H); 3.38 (d, 2 H); 3.6-3.7 (m, 2 H); 4.05 (s, 3 H); 4.25 (d, 2 H); 4.4 (t, 1 H); 7.43 (s, 1 H); 7.45 (d, 1 H); 7.6-7.7 (m, 2 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[526] Starting material was prepared as follows.
[527] 7-benzyloxy-4-chloro-6-methoxyquinazolin (1.2 g, 4 mmol) (e.g., prepared as described in WO 00/47212 Example 1) and 4-chloro in 2-propanol (40 ml) A solution of -2-fluoroaniline (444 μl, 4 mmol) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration and washed with 2-propanol, then ether and dried under vacuum to afford 7-benzyloxy-4- (4-chloro-2-fluorophenylamino) -6-methoxyquinazoline Hydrochloride was obtained (1.13 g, 64%).
[528] m.p. 239-242 ℃
[529] ^' H NMR Spectrum: (DMSOd ₆ ) 4.0 (s, 3H); 5.36 (s, 2 H); 7.39-7.52 (m, 9H); 8.1 (s, 1 H); 8.75 (s, 1H)
[530] MS-ESI: 410 [MH] ⁺
[531] Component Analysis: Discovery C 59.2 H 4.3 N 9.4
[532] C ₂₂ H _l7 N ₃ O ₂ CIF 1HC1 Required C 59.2 H 4.1 N 9.41%
[533] A solution of 7-benzyloxy-4- (4-chloro-2-fluorophenylamino) -6-methoxyquinazoline hydrochloride (892 mg, 2 mmol) in TFA (10 ml) was refluxed for 50 minutes. After cooling, the mixture was poured on ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and basified to pH 11 with aqueous ammonia solution. After concentration by evaporation, the solid product is collected by filtration, washed with water then ether and then dried under vacuum to afford 4- (4-chloro-2-fluorophenylamino) -7-hydroxy-6-methoxy Quinazolin was obtained as a yellow solid (460 mg, 72%).
[534] m.p. 141-143 ℃
[535] ^' H NMR Spectrum: (DMSOd ₆ ) 3.95 (s, 3H); 7.05 (s, 1 H); 7.35 (d, 1 H); 7.54-7.59 (m, 2H); 7.78 (s, 1 H); 8.29 (s, 1H)
[536] MS-ESI: 320-322 [MH] ⁺
[537] 7-hydroxy-6-methoxy-4- (2-fluoro-4-chlorophenylamino) quinazoline (5.56 g, 17.4 mmol in DMF (100 ml) containing potassium carbonate (4.8 g, 34.8 mmol) To the solution was added 1-bromo-2,3-epoxypropane (1.49 ml, 17.4 mmol). The mixture was stirred at 60 ° C. for 3 hours. After cooling, water (400 ml) was added. The precipitate was filtered off and dried in vacuo at 60 ° C. for 2 h under P ₂ O ₅ . The product was purified by column chromatography eluting with methylene chloride followed by methanol 98/2 saturated with methylene chloride / ammonia. Fractions containing the expected product were mixed and evaporated to afford 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline (2.82 g , 43%).
[538] MS-ESI: 376-378 [MH] ⁺
[539] ^l H NMR spectrum _{(DMSO-d 6): 2.8} (m, 1H); 2.92 (m, 1 H); 3.45 (m, 1 H); 3.98 (s, 3 H); 4.02 (m, 1 H); 4.55 (dd, lH); 7.25 (s, 1 H); 7.35 (d, 1 H); 7.5-7.65 (m, 2 H); 7.85 (s, 1 H); 8.4 (s, 1 H); 9.6 (br s, 1 H)
[540] Example 3
[541] 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy) quinazoline
[542]
[543] 4- (4-Chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin (56 mg, 0.15 mmol) using a process similar to that described in Example 2 ) And methyl piperazine (37 mg, 0.37 mmol) were reacted. After column chromatography and evaporation of the volatiles the title compound was isolated with free base (45 mg, 63%).
[544] MS-ESI: 476 [M−H] ⁺
[545] ^' H NMR Spectrum (DMSOd ₆ ): 2.15 (s, 3H); 2.2-2.6 (m, 10 H); 3.45 (m, 2 H); 3.98 (s, 3 H); 4.05 (m, 2 H); 4.2 (m, 1 H); 4.92 (d, 1 H); 7.22 (s, 1 H); 7.35 (d, 1 H); 7.5-7.65 (m, 2 H); 7.8 (s, 1 H); 8.35 (s, 1 H); 9.55 (s, 1H)
[546] Example 4
[547] 4- (4-chloro-2-fluorophenylamino) -7- (2-hydroxy-3- (morpholino) propoxy) -6-methoxy) quinazoline
[548]
[549] 4- (4-Chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline (56 mg, 0.15 mmol) using a process similar to that in Example 2 And morpholine (32 mg, 0.37 mmol) and the title compound was obtained with hydrogen chloride after salt formation (17.5 mg, 22%),
[550] MS-ESI: 463 [M−H] ⁺
[551] ^' H NMR Spectrum (DMSOd ₆ ): 3.12 (m, 4H); 3.4 (m, 2 H); 3.8 (m, 4 H); 4.0 (s, 3H); 4.2 (m, 2 H); 4.3-4.4 (br s, 1 H); 7.28 (s, 1 H); 7.38 (d, 1 H); 7.5-7.65 (m, 2 H); 7.9 (s, 1 H); 8.4 (s, 1 H); 8.9-9.1 (br s, 1 H); 9.7 (br s, 1 H)
[552] Example 5
[553] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (thiazolidin-3-yl) propoxy] -6-methoxy) quinazoline
[554]
[555] Thiazolidine (53 mg, 0.6 mmol) was added to 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxy in a mixture of ethanol (1 ml) and chloroform (1 ml). Propoxy) -6-methoxyquinazoline (100 mg, 0.24 mmol) solution. The mixture was stirred at 40 ° C. for 24 hours. Methylene chloride (20 ml) is added and the mixture is poured onto a silica column of Isolute® trademark followed by methylene chloride (15 ml) followed by methylene chloride / ethylacetate / methanol (48/50/2) (60 ml) Eluted with methanol (46/50/4), then (42/50/8) (90 ml) saturated with methylene chloride / ethylacetate / ammonia. Fractions containing the expected product were mixed and volatiles were removed in vacuo. The residue was diluted with isopropanol (2 ml) and 6 N hydrogen chloride in isopropanol (25 μl) was added. The precipitate was filtered off, washed with ether and dried in vacuo to afford the title compound as hydrogen chloride (65 mg, 48%).
[556] MS-ESI: 509-511 [MH] ⁺
[557] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.25 (m, 2H); 3.4-3.6 (m, 2 H); 3.6-3.9 (br m, 2H); 4.05 (s, 3 H); 4.25 (s, 2 H); 4.4-4.5 (m, 1 H); 4.5-4.6 (m, 2 H); 7.42 (s, 1 H); 7.5-7.62 (m, 2 H); 7.8 (d, 1 H); 8.12 (s, 1 H); 8.9 (s, 1H)
[558] Starting material was prepared as follows.
[559] A solution of 4-bromo-2-fluoroaniline (5.65 g, 29.7 mmol) in 7-benzyloxy-4-chloro-6-methoxyquinazolin (8.35 g, 27.8 mmol) and 2-propanol (200 ml) was added to 4 Heated to reflux for time. The resulting precipitate was collected by filtration, washed with 2-propanol, then ether and dried in vacuo to give 7-benzyloxy-4- (4-bromo-2-fluorophenylamino) -6-methoxyquinazoline Hydrogen chloride was obtained (9.46 g, 78%).
[560] ^' H NMR Spectrum: (DMSOd ₆ , CD ₃ COOD) 4.0 (s, 3H); 5.37 (s, 2 H); 7.35-7.5 (m, 4 H); 7.52-7.62 (m, 4 H); 7.8 (d, 1 H); 8.14 (9s, 1 H); 8.79 (s, 1H)
[561] MS-ESI: 456 [MH] ⁺
[562] Component Analysis: Found in C 54.0 H 3.7 N 8.7
[563] C ₂₂ H ₁₇ N ₃ O ₂ BrF 0.9 HCl Required C 54.2 H 3.7 N 8.6%
[564] A solution of 7-benzyloxy-4- (4-bromo-2-fluorophenylamino) -6-methoxyquinazoline hydrochloride (9.4 g, 19.1 mmol) in TFA (90 ml) was heated to reflux for 50 minutes. The mixture was cooled and poured on ice. The resulting precipitate was collected by filtration and dissolved in methanol (70 ml). The solution was adjusted to pH 9-10 with concentrated aqueous ammonia solution. The mixture was concentrated by evaporation to one half of the initial volume. The resulting precipitate was collected by filtration, washed with water then ether and dried in vacuo to afford 4- (4-bromo-2-fluorophenylamino) -7-hydroxy-6-methoxyquinazolin ( 5.66 g, 82%).
[565] ^' H NMR Spectrum: (DMSOd ₆ , CD ₃ COOD) 3.95 (s, 3H); 7.09 (s, 1 H); 7.48 (s, 1 H); 7.54 (t, 1 H); 7.64 (d, 1 H); 7.79 (s, 1 H); 8.31 (s, 1H)
[566] MS-ESI: 366 [MH] ⁺
[567] Component Analysis: Found C 49.5 H 3.1 N 11.3
[568] C ₁₅ H ₁₁ N ₃ O ₂ BrF Required C 49.5 H 3.0 N 11.5%
[569] To prepare 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline using a process similar to that described in Example 2, carbonic acid 7-hydroxy-6methoxy-4- (2-fluoro-4-bromophenylamino) quinazolin (6 g, 16.5 mmol) and DMF (50 ml) in the presence of potassium (4.55 g, 3.3 mmol) 1-bromo-2,3-epoxypropane (1.7 ml, 19.8 mmol) in reaction was purified as described above and 4- (4-bromo-2-fluorophenylamino) -7- (2, 3-epoxypropoxy) -6-methoxyquinazoline was obtained (1.8 g, 26%).
[570] MS-ESI: 420-422 [M−H] ⁺
[571] ^' H NMR Spectrum (DMSOd ₆ ): 2.75 (m, 1H); 2.9 (m, 1 H); 3.42 (m, 1 H); 3.97 (s, 3 H); 4.02 (m, 1 H); 4.55 (dd, 1 H); 7.22 (s, 1 H); 7.48 (d, 1 H); 7.52 (dd, 1 H); 7.65 (d, 1 H); 7.82 (s, lH); 8.37 (s, 1 H); 9.58 (s, lH)
[572] HPLC duration (minutes): 3.20
[573] HPLC duration was measured as follows.
[574] TSK gel Super registered ODS 2 μm 4.6 mm × 5 cm − elute with a straight slope of 0 to 100% CH ₃ CN in water containing 0.1% TFA over 7 minutes. Flow rate: 1.4 ml / min detection UV (254 nm) and LDD. Samples are dissolved in 1 drop of DMSO and diluted with water.
[575] Example 6
[576] 4- (4-Bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin (from Example 5) using a process similar to that described in Example 5 (100 mg, 0.24 mmol) was reacted with the appropriate amine to afford the following compound shown in Table I.
[577] TABLE I
[578]
[579]
[580] a) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 3-pyrroline (41 mg) to react 4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazolin hydrochloride was obtained.
[581] ^' H NMR Spectrum (DMSO, CF ₃ COOD): 3.45-3.55 (m, 2H); 4.01 (s, 3 H); 4.05-4.2 (m, 2 H); 4.2-4.5 (m, 5 H); 6.0 (s, 2H); 7.4 (s, 1 H); 7.5-7.65 (m, 2 H); 7.85 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[582] b) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1- (2-morpholinoethyl) piperazine ( 120 mg) was reacted to 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-morpholinoethyl) piperazin-1-yl) Propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[583] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.2-3.8 (m, 18H); 3.9 (br s, 4 H); 4.08 (s, 3 H); 4.3 (d, 2H); 4.55 (br s, 1 H); 7.5 (s, 1 H); 7.52-7.65 (m, 2H); 7.8 (d, 1 H); 8.22 (s, 1 H); 8.9 (s, 1H)
[584] c) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1- (3-hydroxypropyl) piperazine (87 mg) (Chem. Pharm. Bull. 1994, 42 (4), 963-71) to react 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- ( 4- (3-hydroxypropyl) piperazin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[585] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.75-1.95 (m, 2H); 3.2-3.9 (m, 14 H); 4.1 (s, 3 H); 4.3 (s, 2 H); 4.5-4.6 (m, 1 H); 7.5 (s, 1 H); 7.55-7.65 (m, 2H); 7.75 (d, 1 H); 8.25 (s, 1 H); 8.85 (s, 1 H)
[586] d) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1- (2-hydroxyethyl) piperazine (78 mg) to react 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-hydroxyethyl) piperazin-1-yl) propoxy ] -6-methoxyquinazoline hydrochloride was obtained.
[587] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.3 (br s, 2H); 3.3-3.9 (m, 12H); 4.1 (s, 3 H); 4.25 (d, 2 H); 4.55 (m, 1 H); 7.5 (s, 1 H); 7.55-7.65 (m, 2H); 7.8 (d, 1 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[588] e) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1,2,3,6-tetrahydropyridine (50 mg) to react 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (1,2,3,6-tetrahydropyridin-1-yl) propoxy ] -6-methoxyquinazoline hydrochloride was obtained.
[589] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.25-3.5 (m, 5H); 3.5-3.65 (m, 1 H); 3.75 (d, 1 H); 3.95 (m, 1 H); 4.02 (s, 3 H); 4.25 (d, 2 H); 4.5 (m, 1 H); 5.8 (d, 1 H); 5.95 (br s, 1 H); 7.45 (s, 1 H); 7.55-7.65 (m, 2H); 7.8 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[590] f) Reaction of 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline with Ntbutyl-N-methylamine (52 mg) To give 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (Ntbutyl-N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride .
[591] g) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N-isopropyl-N-methylamine (44 mg) To 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline Hydrochloride was obtained.
[592] h) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N- (iso-butyl) -N-methylamine ( 52 mg) to react 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-meth Oxyquinazoline hydrochloride was obtained.
[593] i) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N- (2-hydroxyethyl) -N-methyl Amine (45 mg) was reacted to 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) Propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[594] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 2.90 (s, 3H); 3.2-3.35 (m, 2 H); 3.35-3.45 (m, 2 H); 3.82 (br s, 2 H); 4.02 (s, 3 H); 4.25 (s, 2 H); 4.45 (br s, 1 H); 7.45 (s, 1 H); 7.5-7.65 (m, 2 H); 7.82 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[595] j) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and morpholine (52 mg) to react 4- (4 -Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (morpholino) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[596] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.1-3.45 (m, 4H); 3.5 (t, 2H); 3.7-3.9 (m, 2 H); 3.95 (d, 2 H); 4.02 (s, 3 H); 4.3 (d, 2H); 4.5 (m, 1 H); 7.45 (s, 1 H); 7.5-7.62 (m, 2 H); 7.8 (d, 1 H); 8.2 (s, lH); 8.9 (s, 1H)
[597] k) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and dimethylamine (27 mg) were reacted to give 4- (4 -Bromo-2-fluorophenylamino) -7- (2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[598] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 2.9 (s, 3H); 2.95 (s, 3 H); 3.3 (m, 2 H); 4.05 (s, 3 H); 4.25 (d, 2 H); 4.45 (m, 1 H); 7.42 (s, 1 H); 7.5-7.65 (m, 2 H); 7.8 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[599] l) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and piperidine (51 mg) were reacted to give 4- (4- 4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[600] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.4-1.5 (m, lH); 1.7-1.9 (m, 5H); 2.9-3.2 (m, 2 H); 3.3-3.4 (m, 2 H); 3.55 (t, 2 H); 4.02 (s, 3 H); 4.25 (d, 2 H); 4.5 (m, 1 H); 7.45 (s, 1 H); 7.5-7.6 (m, 2 H); 7.8 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[601] m) 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and pyrrolidine (45 mg) are reacted to give 4- (4- 4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazolin hydrochloride was obtained.
[602] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.9-2.15 (m, 4H); 3.2 (m, 2 H); 3.4 (d, 2H); 3.7 (m, 2 H); 4.05 (s, 3 H); 4.3 (d, 2H) 4.4 (m, 1H); 7.42 (s, 1 H); 7.5-7.65 (m, 2 H); 7.8 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[603] Example 7
[604] 4- (4-Chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline (100 mg, 0.26 mmol) using a process similar to that described in Example 4 ) (Obtained from Example 4) with the appropriate amine (0.65 mmol) to give the compounds shown in Table II.
[605] TABLE II
[606]
[607]
[608]
[609] a) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and dimethylamine (29 mg) are reacted to give 4- (4- Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[610] ¹ H NMR (DMSO-d ₆ , CF ₃ COOD): 2.87 (s, 3H); 2.92 (s, 3 H); 3.3 (m, 2 H); 4.05 (s, 2 H); 4.22 (d, 2 H); 4.42 (m, 1 H); 7.45 (s, 1 H); 7.5 (d, 1 H); 7.62 (dd, 1 H); 7.7 (dd, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[611] b) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and piperidine (55 mg) to react 4- (4 -Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[612] ^' H NMR Spectrum (DMSOd ₆ ): 1.4-1.5 (m, 1H); 1.6-1.95 (m, 5 H); 2.45-3.05 (m, 2 H); 3.1-3.25 (m, 2 H); 3.55 (br s, 2 H); 4.02 (s, 3 H); 4.2 (d, 2H); 4.5 (m, 1 H); 6.1 (br s, 1 H); 7.45 (s, 1 H); 7.47 (d, 1 H); 7.6 (dd, 1 H); 7.65 (d, 1 H); 8.25 (s, 1 H); 8.8 (s, 1 H); 9.75 (br s, 1 H)
[613] c) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and homopiperidine (64 mg) are reacted to give 4- (4- 4-Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (homopiperidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[614] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.6-1.8 (m, 4H); 1.8-2.0 (m, 4 H); 3.20-3.35 (m, 3 H); 3.4-3.55 (m, 3 H); 4.02 (s, 3 H); 4.25 (d, 2 H); 4.45 (m, lH); 7.45 (s, 1 H); 7.5 (d, 1 H); 7.62 (dd, 1 H); 7.7 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[615] d) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N-methyl-N- (2-hydroxyethyl) amine (49 mg) to react 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy ] -6-methoxyquinazoline hydrochloride was obtained.
[616] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 2.95 (d, 3H); 3.2-3.55 (m, 4 H); 3.8 (t, 2H); 4.02 (s, 3 H); 4.25 (s, 2 H); 4.5 (m, 1 H); 7.45 (s, 1 H); 7.5 (d, 1H); 7.85 (dd, 1H); 7.75 (dd, 1 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[617] e) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and thiazolidine (58 mg) were reacted to give 4- (4 -Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (thiazolidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[618] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.25 (t, 2H); 3.45-3. 62 (m, 2H); 3.7-3.9 (m, 2 H); 4.05 (s, 3 H); 4.28 (d, 2 H); 4.5 (m, 1 H); 4.6 (m, 2 H); 7.48 (s, 1 H); 7.5 (d, 1 H); 7.65 (dd, 1 H); 7.7 (dd, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[619] f) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 3-pyrroline (45 mg) are reacted to give 4- (4- 4-Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[620] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.4-3.6 (m, 2H); 4.02 (s, 3 H); 4.15 (d, 2 H); 4.25 (d, 2 H); 4.35 (dd, 2 H); 4.40 (m, 1 H); 6.0 (s, 2H); 7.45 (s, 1 H); 7.5 (d, 1 H); 7.67 (dd, 1 H); 7.7 (d, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[621] g) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and thiomorpholine (67 mg) to react 4- (4 -Chloro-2-fluorophenylamino) -7- [2hydroxy-3- (thiomorpholin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[622] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 2.8-3.0 (m, 2H); 3.1 (t, 2 H); 3.15-3.45 (m, 4 H); 3.5 (d, 1H); 3.9 (t, 2H); 4.05 (s, 3 H); 4.3 (d, 1 H); 4.55 (m, 1 H); 7.45 (s, lH); 7.5 (d, 1 H); 7.7-7.8 (m, 2 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[623] h) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 3-hydroxypyrrolidine (57 mg) were reacted 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-hydroxypyrrolidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride Got.
[624] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.85-2.15 (m, 2H); 3.1-3.5 (m, 4H); 3.55-3.8 (m, 2 H); 4.02 (s, 3 H); 4.25 (t, 2 H); 4.4-4.55 (m, 2 H); 7.45 (s, 1 H); 7.5 (d, 1 H); 7.7 (dd, 1 H); 7.75 (dd, 1 H); 8.15 (s, 1 H); 8.9 (s, 1H)
[625] i) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1- (2-morpholinoethyl) -piperazine ( 130 mg) is reacted to 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-morpholinoethyl) piperazin-1-yl] prop Foxy} -6-methoxyquinazoline hydrochloride was obtained.
[626] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.25-3,75 (m, 18H); 3.95 (br s, 4 H); 4.05 (s, 3 H); 4.3 (d, 2H); 4.55 (m, 1 H); 7.48 (s, 1 H); 7.5 (d, 1 H); 7.62 (dd, 1 H); 7.68 (dd, 1 H); 8.2 (s, 1 H); 8.9 (s, 1H)
[627] j) 4- (4-Chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1- (3-hydroxypropyl) -piperazine (94 mg) is reacted to 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (3-hydroxypropyl) piperazin-1-yl] propoxy} -6-methoxyquinazoline hydrochloride was obtained.
[628] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.8-1.9 (m, 2H); 3.2-3.95 (m, 14 H); 4.02 (s, 3 H); 4.3 (s, 2 H); 4.55 (m, 1 H); 7.5 (m, 2 H); 7.65 (dd, 1 H); 7.7 (dd, 1 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[629] k) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 1- (2-hydroxyethyl) -piperazine (85 mg) to react 4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-hydroxyethyl)] piperazin-1-yl) propoxy } -6-methoxyquinazoline hydrochloride can be obtained.
[630] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 3.25-3.95 (m, 14H); 4.05 (s, 3 H); 4.3 (d, 2H); 4.55 (m, 1 H); 7.45 (d, 1 H); 7.5 (s, 1 H); 7.6-7.7 (m, 2 H); 8.3 (s, 1 H); 8.9 (s, 1H)
[631] l) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline with azetidine (37 mg) to react 4- (4- Chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (azetidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[632] m) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and 2,5-dimethyl-3-pyrroline (63 mg) To 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2,5-dimethyl-3-pyrrolin-1-yl) propoxy] -6- Methoxyquinazoline hydrochloride was obtained.
[633] n) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and 4-methylpiperidine (64 mg) to react 4 -(4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained .
[634] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.1 (d, 3H); 1.35-1.75 (m, 3 H); 1.75-1.9 (m, 2H); 3.1 (td, 2 H); 3.35 (m, 2 H); 3.5-3.65 (m, 2 H); 4.1 (s, 3 H); 4.3 (d, 2H); 4.5 (m, 1 H); 7.45 (s, 1 H); 7.5 (d, 1 H); 7.65 (dd, 1 H); 7.7 (d, 1 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[635] o) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N- (prop-2-yn-1-yl) 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (prop-2-yn-1-) by reacting -N-methylamine (45 mg) Il) -N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride was obtained.
[636] ^' H NMR Spectrum (DMSOd ₆ ): 2.9 (s, 3H); 3.3-3.4 (m, 2 H); 3.9 (s, 1 H); 4.0 (s, 3H); 4.19 (s, 2 H); 4.25 (d, 2 H); 4.42 (m, 1 H); 6.15 (br s, 1 H); 7.4 (s, 1 H); 7.42 (d, 1 H); 7.6 (dd, 1 H); 7.65 (d, 1 H); 8.25 (br s, 1 H); 8.7 (br s, 1 H)
[637] p) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and 2-methylpyrrolidine (55 mg) to react 4 -(4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2-methylpyrrolidin-1-yl) propoxy] -6-methoxyquinazoline hydrochloride was obtained .
[638] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.4 (2d, 3H); 1.6-1.8 (m, 1 H); 1.9-2.1 (m, 2 H); 2.15-2.3 (m, 1 H); 3.15-3.35 (m, 2 H); 3.4-3.5 (m, 1 H); 3.5-3.7 (m, 1 H); 3.7-3.8 (m, 1 H); 4.05 (s, 3 H); 4.25 (br s, 2 H); 4.3-4.5 (m, 1 H); 7.45 (d, 1 H); 7.5 (d, 1 H); 7.62 (dd, 1 H); 7.7 (d, 1 H); 8.12 (s, 1 H); 8.95 (s, 1H)
[639] q) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and N-isopropyl-N-ethylamine (57 mg) To react 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-ethylamino) propoxy] -6-methoxyquinazoline hydrochloride Got.
[640] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.25-1.37 (m, 9H); 3.1-3.45 (m, 4 H); 3.75 (m, 1 H); 4.05 (s, 3 H); 4.3 (m, 2 H); 4.4 (m, 1 H); 7.45 (s, 1 H); 7.47 (d, 1 H); 7.62 (dd, 1 H); 7.68 (d, 1 H); 8.22 (s, 1 H); 8.9 (s, 1H)
[641] r) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline and N-methyl-beta-alaninenitrile (55 mg) 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-cyanoethyl) -N-methylamino) propoxy] -6-methoxy Quinazolin hydrochloride was obtained.
[642] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 2.95 (br s, 3H); 3.15 (br s, 2 H); 3.4 (br s, 2 H); 3.6 (br s, 2 H); 4.05 (s, 3 H); 4.25 (d, 2 H); 4.5 (br s, 1 H); 7.45 (s, 1 H); 7.47 (d, 1 H); 7.6-7.72 (m, 2 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[643] s) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N-isopropyl-N-methylamine (48 mg) To react 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride Got.
[644] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.3 (m, 6H); 2.8 (s, 3 H); 3.05-3.5 (m, 2H); 3.5-3.75 (m, 1 H); 4.05 (s, 3 H); 4.25 (d, 2 H); 4.45 (br s, 1 H); 7.4-7.55 (m, 2 H); 7.65 (dd, 1 H); 7.7 (dd, 1 H); 8.22 (s, 1 H); 8.95 (s, 1H)
[645] t) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N-isobutyl-N-methylamine (57 mg) To react 4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride Got it.
[646] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.0 (m, 6H); 2.15 (m, 1 H); 2.95 (s, 3 H); 3.0 (m, 1 H); 3.05-3.35 (m, 2H); 3.35-3.5 (m, 1 H); 4.02 (s, 3 H); 4.25 (br s, 2 H); 4.5 (m, 1 H); 7.45 (d, 1 H); 7.5 (s, 1 H); 7.70 (dd, 1 H); 7.85 (d, 1 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[647] u) 4- (4-chloro-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin and N- (n-propyl) -N-ethyl (57 mg ) To react 4- (4-chloro-2-fluorophenylamino) -7- [2hydroxy-3- (N- (n-propyl) -N-ethylamino) propoxy] -6-methoxy Quinazolin hydrochloride was obtained.
[648] ^' H NMR Spectrum (DMSOd ₆ , CF ₃ COOD): 1.0 (m, 3H); 1.25 (t, 3 H); 1.75 (m, 2 H); 3.05-3.2 (m, 2H); 3.2-3.4 (m, 4 H); 4.02 (s, 3 H); 4.25 (s, 2 H); 4.5 (br s, 1 H); 7.4 (s, 1 H); 7.45 (d, 1 H); 7.6-7.75 (m, 2 H); 8.25 (s, 1 H); 8.9 (s, 1H)
[649] Example 8
[650] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4-pyridylsulfanyl) propoxy] -6-methoxyquinazoline
[651]
[652] 4-mercaptopyridine (93 mg) was added to a suspension of 60% (12 mg) of sodium hydride in DMF (2 ml). After stirring for 15 minutes 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazolin (100 mg) (obtained from Example 5) Was added and the mixture was stirred at ambient temperature for 3 hours. The volatiles were removed under vacuum. The residue was partitioned between methylene chloride and water and adjusted to pH 7 of the aqueous layer with 1N HCl. The organic layer was separated, washed with water, then chlorine, dried (MgSO ₄ ) and evaporated to 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- Pyridylsulfanyl) propoxy] -6-methoxyquinazoline was obtained (20 mg).
[653] ¹ H NMR Spectrum: (DMSOd ₆ ) 3.2 (dd, 2H), 4.0 (s, 3H), 4.15 (m, 1H), 4.22 (d, 2H), 5.7 (d, 1H), 7.22 (s, 1H) , 7.32 (d, 2H), 7.5 (d, 1H), 7.55 (dd, 1H), 7.68 (dd, 1H), 7.85 (s, 1H), 8.4 (d, 2H), 8.4 (s, 1H), 9.6 (s, 1H)
[654] Mass Spectrum: M ^- H ^- 529 and 531
[655] Example 9
[656] 4-4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3-1-methylimidazol-2-ylsulfanyl) propoxy] -6-methoxyquinazoline
[657]
[658] Using a process similar to that described for the preparation of Example 8, 4- (4-bromo-2-fluorophenylamino) -7- (2,3-epoxypropoxy) -6-methoxyquinazoline ( 100 mg) (obtained from Example 5) and 2-mercapto-1-methylimidazole (32.6 mg) were reacted to 4- (4-bromo-2- fluorophenylamino) -7- [2- Hydroxy-3- (1-methylimidazol-2-ylsulfanyl) propoxy] -6-methoxyquinazoline was obtained (65 mg).
[659] ¹ H NMR Spectrum: (DMSOd ₆ ) 3.15-3.35 (m, 2H), 3.6 (s, 3H), 3.95 (s, 3H), 4.1-4.25 (m, 3H), 5.8 (d, 1H), 6.95 ( s, 1H), 7.2 (s, 1H), 7.25 (s, lH), 7.5 (d, 1H), 7.55 (dd, 1H), 7.7 (d, 1H), 7.82 (s, 1H), 8.38 (s , 1H), 9.6 (br s, 1H)
[660] Mass spectrum: M ⁺ H ⁺ 534.4 and 536.4
[661] Example 10
[662] 4-chloro-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[663]
[664] 4-Chloro-2-fluoro-5-hydroxyphenylamino-7- [2-acetoxy-3 (pyrrolidin-l-yl) propoxy] -6- in methanol (6 ml) saturated with ammonia. The methoxyquinazoline (170 mg) suspension was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water. The pH of the aqueous layer was adjusted to 6.5. The organic layer was separated, washed with water, dried (MgSO ₄ ) and evaporated. The residue is triturated under diethyl ether, filtered, washed with ether and dried under vacuum to afford 4-chloro-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- ( Pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline was obtained (20 mg).
[665] ¹ H NMR Spectrum: (DMSOd ₆ , CF ₃ COOD) 1.9-2.0 (m, 2H), 2.0-2.1 (m, 2H), 3.1-3.2 (m, 2H), 3.4 (m, 2H), 3.6-3.7 (m, 2H), 4.03 (s, 3H), 4.25 (d, 2H), 4.4 (m, 1H), 7.15 (d, 1H), 7.42 (s, 1H), 7.55 (d, 1H), 8.1 ( s, 1H), 8.9 (s, 1H)
[666] Mass spectrum: M ⁺ H ⁺ 463.55
[667] Starting material was prepared as follows.
[668] 7-hydroxy-6-methoxy-3-((pivaloyloxy) methyl) -3,4-dihydroquinazolin-4-one (40 g) in DMF (400 ml) (obtained from Example 1) ) And potassium carbonate (36 g) were stirred at ambient temperature for 10 minutes before epibromohydrin (16.8 ml) was added and the reaction mixture was heated at 70 ° C. for 1.5 hours. The mixture was poured into ice / water (1.5 l) with stirring. The precipitate was collected by filtration, washed with water (1.6 l) and ether (500 ml) and then vacuum dried under phosphorus pentoxide to give the desired epoxide (46.7 g).
[669] A portion (8 g) of the epoxide was dissolved in chloroform (120 ml) and pyrrolidine (1.98 ml) was added. The reaction mixture was heated to reflux overnight, the spirit medium was evaporated, and the crude product was purified by flash chromatography using dichloromethane / methanol (95: 5 to 40:60) as eluent. 7- (2-hydroxy-3- (pyrrolidin-1-yl) propoxy) -6-methoxy-3-(() by evaporation of solvent and titration in ether / petroleum ether (1: 1). Pivaloyloxy) methyl) -3,4-dihydroquinazolin-4-one (7.8 g) was obtained as a white foam.
[670] 7- (2-hydroxy-3- (pyrrolidin-1-yl) propoxy) -6-methoxy-3-((pivaloyloxy) methyl) -3,4-dihydroquinazolin-4 -On (7.8 g) was stirred for 48 h in methanol solution (200 ml) saturated with ammonia. The solvent was evaporated and the solid obtained was washed with ether (2 ×) and ether / dichloromethane (95: 5, 2 × 100 ml) to give 7- (2-hydroxy-3 (pyrrolidin-l-yl) propoxy ) -6-methoxy-3,4-dihydroquinazolin-4-one (5.5 g) was obtained.
[671] 7- (2-hydroxy-3- (pyrrolidin-1-yl) propoxy) -6-methoxy-3,4-dihydroquinazolin-4-one (5 g) was added to acetic anhydride (7.4 in ml). The reaction mixture was stirred at ambient temperature for 90 minutes, after which additional water (2.8 ml) was added to hydrolyze diacetate byproduct and the reaction mixture was stirred for another 2 hours. The mixture was cooled in an ice bath, more water (100 ml) was added, and sodium hydroxide (2 N) was added slowly to pH 9.5. The product was extracted with dichloromethane (3 times), the organic layers were mixed, washed with water, chlorine, dried under magnesium sulfate, filtered and the solvent was evaporated to 7- (2-acetoxy-3- (Pyrrolidin-1-yl) propoxy) -6-methoxy-3,4-dihydroquinazolin-4-one (4.2 g) was obtained as a white solid.
[672] 7- (2-acetoxy-3- (pyrrolidin-1-yl) propoxy) -6-methoxy-3,4-dihydroquinazolin-4-one (4.7 g) was dissolved in thionyl chloride (55 ml), and the mixture was heated to reflux for 1 hour after the addition of DMF (0.5 ml). The thionyl chloride was dried in vacuo and the solvent was evaporated after the addition of toluene. This process was repeated twice. The residue was taken up in ice / water, the pH was adjusted to 7.5 with a saturated solution of sodium bicarbonate, then brought to pH 9 with 2N sodium hydroxide, and the aqueous solution was extracted twice with dichloromethane. The combined extracts were washed with water and brine, dried under magnesium sulfonate and filtered. The filtrate was evaporated in vacuo and the residue triturated with ether to afford 4-chloro-7- [2-acetoxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazolin (4.1 g) was obtained as a white foam.
[673] ¹ H NMR Spectrum: (CDCl ₃ +4 drops of CD ₃ COOD) 2.05 (s, 4H), 2.15 (s, 3H), 3.45 (br s, 4H), 3.65 (m, 2H), 4.05 (s, 3H ), 4.4 (d, 2H), 5.65 (m, 1H), 7.4 (s, 1H), 7.55 (s, 1H), 8.9 (s, 1H).
[674] 4-chloro-7- [2-acetoxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline in isopropanol (6 ml) containing 6N hydrogen chloride in isopropanol (58 μl) (120 mg) and 4-chloro-2-fluoro-5-hydroxyaniline (56 mg) suspension (as described in European Patent 61741 A2) were stirred at 80 ° C. for 1.5 hours. After cooling, ether (1 ml) is added, the precipitate is filtered off, washed with ether and dried in vacuo to 4-chloro-2-fluoro-5-hydroxyphenylamino-7- [2-acetoxy-3 -(Pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline (170 mg) was obtained.
[675] ¹ H NMR Spectrum: (DMSOd ₆ ) 1.9-2.0 (m, 2H), 2.0-2.1 (m, 2H), 2.18 (s, 3H), 3.1-3.25 (m, 2H), 3.5-3.7 (m, 4H ), 4.05 (s, 3H), 4.4-4.55 (m, 2H), 5.6 (m, 1H), 7.2 (d, 1H), 7.42 (s, 1H), 7.55 (d, 1H), 8.3 (s, 1H), 8.8 (s, 1H)
[676] Example 11
[677] 4-chloro-2-fluoro-5-hydroxyphenylamino-7- (2-acetoxy-3-piperidinopropoxy-6-methoxyquinazoline
[678]
[679] Using a process similar to that described in Example 10, 4-chloro-7- (2-acetoxy-3-piperidinopropoxy) -6-methoxyquinazolin (120 mg) and 2-fluoro- 4-chloro-5-hydroxyaniline (54 mg) was reacted (as described in European Patent 61741 A2) to 4-chloro-2-fluoro-5-hydroxyphenylamino-7- (2-acetoxy 3-piperidinopropoxy) -6-methoxyquinazoline (160 mg) was obtained.
[680] ¹ H NMR Spectrum: (DMSOd ₆ ) 1.3-1.5 (m, 1H), 1.6-1.9 (m, 5H), 2.15 (s, 3H), 2.9-3.1 (m, 2H), 3.4-3.6 (m, 4H ), 4.05 (s, 3H), 4.4-4.5 (m, 2H), 5.65 (m, 1H), 7.2 (d, 1H), 7.42 (s, 1H), 7.55 (d, 1H), 8.32 (s, 1H), 8.8 (s, 1H)
[681] Mass spectrum: M ⁺ H ⁺ 519.6 and 521.6
[682] Starting material was prepared as follows.
[683] Using a process similar to that described in Example 10, 4-chloro-7- (2-acetoxy-3-piperidinopropoxy) -6-methoxyquinazoline was prepared.
[684] ¹ H NMR Spectrum: (CDCl ₃ +4 drops of CD ₃ COOD) 1.6 (m, 2H), 1.9 (m, 4H), 2.1 (s, 3H), 3.2 (br s, 4H), 3.5 (m, 2H ), 4.05 (s, 3H), 4.35 (m, 2H), 5.7 (m, 1H), 7.4 (s, 1H), 7.5 (s, 1H), 8.9 (s, 1H)
[685] Examples 12 and 13
[686] 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-acetoxy-3- (pyrrolidin-l-yl) propoxy] -6-methoxyquinazoline
[687] 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
[688]
[689] Using a process similar to that described in Example 11, 4-chloro-7- [2-acetoxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazolin (120 mg) (Example Obtained from Example 10) and 2-fluoro-4-bromo-5-hydroxyaniline (71 mg) (as described in European Patent No. 61741 A2) to 4-bromo-2-fluoro- 5-hydroxyphenylamino-7- [2-acetoxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazolin (135 mg) was obtained.
[690] ¹ H NMR Spectrum: (DMSOd ₆ , CF ₃ COOD) 1.9-2.0 (m, 2H), 2.05-2.15 (m, 2H), 2.15 (s, 3H), 3.15-3.25 (m, 2H), 3.6-3.8 (m, 4H), 4.05 (s, 3H), 4.4-4.6 (m, 2H), 5.65 (m, 1H), 7.2 (d, 1H), 7.42 (s, 1H), 7.62 (d, 1H), 8.2 (s, 1H), 8.9 (s, 1H)
[691] Mass spectrum: M ⁺ H ⁺ 549.49 and 551.5
[692] 4-Bromo-2-fluoro-5-hydroxyphenylamino-7- [2-acetoxy-3- (pyrrolidin-1-yl) using a process similar to that described in Example 10 Propoxy] -6-methoxyquinazolin (106 mg) was treated with methanol saturated with ammonia to treat 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (Pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline (68 mg) was obtained.
[693] ¹ H NMR Spectrum: (DMSOd ₆ , CF ₃ COOD) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.1-3.25 (m, 2H), 3.4 (d, 2H), 3.6-3.7 (m, 2H), 4.05 (s, 3H), 4.25 (d, 1H), 4.4 (m, 1H), 7.2 (d, 1H), 7.45 (s, 1H), 7.65 (d, 1H), 8.2 ( s, 1H), 8.9 (s, 1H)
[694] Mass spectrum: M ⁺ H ⁺ 507.47 and 509.47
[695] Example 14
[696] The following describes representative pharmaceutical dosage forms containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (hereinafter referred to as compound X) for therapeutic or prophylactic use in humans.
[697] (a) Tablet I mg / tablet
[698] Compound X ...
[699] Lactose Ph. Eur .............................. 182.75
[700] Croscarmellose Sodium ......... 12. 0
[701] Corn starch dough (5% w / v dough).
[702] Magnesium Stearate ......... 3. 0
[703] (b) tablet II mg / tablet
[704] Compound X ...
[705] Lactose Ph. Eur ......... 223. 75
[706] Croscarmellose Sodium ............... 6 0
[707] Corn Starch ........................... 15.0
[708] Polyvinylpyrrolidone (5% w / v dough) .. 25
[709] Magnesium Stearate ............... 3.0
[710] (c) tablets IIImg / tablet
[711] Compound X ...
[712] Lactose Ph. Eur .................................. 93. 25
[713] Croscarmellose Sodium ......... 4. 0
[714] Corn Starch Dough (5% w / v Dough) ........ 75
[715] Magnesium Stearate ........................... 1. 0
[716] (d) Capsule mg / Capsule
[717] Compound X ...
[718] Lactose Ph. Eur ........... 488. 5
[719] Magnesium Stearate ........................... 1.5
[720] (e) Injection I (50 mg / ml)
[721] Compound X ........................ 5.0% w / v
[722] 1N Sodium Hydroxide Solution ............... 15.0% v / v
[723] 0.1N hydrochloric acid
[724] (adjust pH to 7.6)
[725] Polyethylene Glycol 400 .................. 4.5% w / v
[726] Injectable water up to 100%
[727] (f) 10 mglml of Injection II)
[728] Compound X ........................................ 1.0% w / v
[729] Sodium Phosphate BP ............ 3.6% w / v
[730] 0.1N Sodium Hydroxide Solution ..................... 15.0% v / v
[731] Injectable water up to 100%
[732] (g) Injection III (1 mg / ml, buffered to pH6)
[733] Compound X ........................... 0.1% w / v
[734] Sodium Phosphate BP ............................ 2.26% w / v
[735] Citric acid ........................ 0.38% w / v
[736] Polyethylene Glycol 400 ............... 3.5% w / v
[737] Injectable water up to 100%
[738] State
[739] The formulations can be obtained by conventional processes well known in the pharmaceutical art. The tablets (a)-(c) may be enteric skin by conventional means, for example providing a coating of cellulose acetate phthalate.

权利要求:
Claims (16)
[1" claim-type="Currently amended] A compound of formula (I) or salt thereof.
[Formula I]
In the above formula,
Ring A may be saturated, partially saturated, unsaturated, aromatic or non-aromatic and a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 ring heteroatoms selected from O, N and S Or a phenyl ring,
Z is -0-,-NH- or -S-,
m is an integer from 0 to 5,
R ¹ is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio or —NR ⁵ R ⁶ (where R ⁵ And R ⁶ may be the same or different and is hydrogen or C _1-3 alkyl,
R ² is hydrogen, hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, trifluoromethyl, amino or nitro,
R ³ is hydroxy, halogeno, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro, ring A is 5- or 6- At least one R ³ when it is a heterocyclic ring is one of hydroxy or halogeno,
X ¹ is -O-, -CH _2- , -S-, -SO-, -SO _2- , -NR ^7- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ⁷ -or -NR ⁷ SO _2- , wherein R ⁷ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl,
R ⁴ is selected from one of the following groups:
1) -Y ¹ X ² COR ⁸ wherein -Y ¹ -is a C _2-5 alkylene chain, wherein each methylene group (excluding the methylene group of α-carbon) is hydroxy, halogeno, amino and C _1- Optionally substituted with 1 substituent each selected from ₄ alkanoyloxy, provided that at least one substituent is no more than 3 on the C _2-5 alkylene chain, X ² is -O- or -NR ⁹ -Wherein R ⁹ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl, and R ⁸ is C _1-3 alkyl, -NR ¹⁰ R ¹¹ or -OR ¹² , wherein R ¹⁰ , R ¹¹ and R ¹² may be the same or different and are hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl],
2) -Y ² -X ³ R ¹³ wherein -Y ² -is C _2-5 alkylene, C _3-5 alkenylene or C _3-5 alkynylene, wherein each methylene group (methylene of α-carbon Groups are optionally substituted with 1 substituent independently selected from hydroxy, halogeno, amino and C _1-4 alkanoyloxy, provided that at least one or more than three or less on the alkylene, alkenylene or alkynylene chain Provided that there is a substituent; X ³ is -O-, -S-, -SO-, -SO _2- , -OCO-, -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or- NR ⁷ - (wherein, R ⁷ is as described above), and R ¹³ is hydrogen or C _1-3 alkyl, wherein C _l-3 alkyl group is selected from oxo, hydroxy, halogeno and C _l-4 alkoxy 1 May have two or two substituents;
3) -Y ¹ -X ⁶ C _1-5 alkyl R ¹⁴ wherein Y ¹ is as described above and X ⁶ is —O—, —S—, —SO—, —SO ₂ —, —NR ⁷ CO— , -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- (where R ⁷ is as described above) and R ¹⁴ is 3 or less selected from O, S and N, respectively C _3-7 cycloalkyl or a _3-7 membered saturated or partially saturated heterocyclic group containing a ring heteroatom of wherein the carbocyclic group or heterocyclic group is optionally oxo, hydroxy, halogeno, C _1-4 alkyl, wherein the C _1-4 alkyl group is optionally hydroxy, cyano, halogeno, amino, nitro, morpholino, C _3-5 cycloalkyl, piperidin-1-yl and piperazine- Substituted with one or two substituents selected from 1-yl), C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, carbamoyl, C _1-3 alkylcarbamoyl, N, N -di (C _1-3 alkyl) carbamoyl, C _2-4 alkanoyl, C _{1- 4} alkoxycarbonyl, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N- C _1-3 alkyl-C _2-4 alkanoyl Amino, N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino and N- C _1-3 alkyl-C _1-3 alkanes Substituted by one or two substituents selected from sulfonylamino,
Or R ¹⁴ is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms each selected from O, N and S, wherein the pyridone group, phenyl group or heterocyclic group optionally halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _l-4 hydroxyalkyl, C _1-4 aminoalkyl, C _1-4 alkylamino, C _1-4 hydroxy alkoxy, carboxy, Cyano, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfa Moyl, C _1-3 alkanesulfonylamino, N- C _1-3 alkyl-C _1-3 alkanesulfonylamino, -CONR ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ , wherein R ¹⁰ and R ¹¹ are as described above. Substituted with up to 5 substituents selected from
4) -Y ¹ -X ⁴ C _1-5 alkylX ⁵ R ¹⁵ wherein Y ¹ is as described above and X ⁴ and X ⁵ may be the same or different and each is -O-, -S-, -SO -, -SO _2- , -NR ⁷ CO-, -CONR ^7- , -SO ₂ NR ^7- , -NR ⁷ SO ₂ -or -NR ^7- (wherein R ⁷ is as described above and R ¹⁵ is hydrogen Or C _1-3 alkyl),
5) -Y ¹ -OC _1-3 alkyl, wherein X ¹ is as described above when X ¹ is -O-, -S-, -SO- or -SO _2- ;
6) -Y ² -R ¹⁶ {wherein -Y ² -is as described above and R ¹⁶ is saturated or partially saturated and contains 3-7 members containing up to 3 hetero atoms selected from O, S and N; Heterocyclic ring, wherein the heterocyclic ring is optionally oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl, wherein , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl are optionally hydroxy, halogeno, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, substituted by up to three substituents selected from methyl, amino, nitro and the foregoing R ¹⁴ trifluoromethyl), C _l-4 alkoxy, carbamoyl, C _1-4 alkyl Carbamoyl, NN -di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C _1-4 alkoxycarbonyl, C _3-7 cycloalkyl, C _1-4 alkylthio, C _{1- 4} alkylsulfinyl, C _1-4 alkylsulfonyl, C _2-4 alkanoylamino, N − C _1-3 alkyl, -C _2-4 alkanoylamino, N -C _1-3 alkyl sulfamoyl, N, N - di - [C _1-3 alkyl] sulfamoyl, C _{l-3-amino-alkane-sulfonyl} and N -C _1-3 substituted by up to 3 substituents selected from alkyl-C _1-3 alkanesulfonylamino or R ¹⁶ is a pyridone group, a phenyl group or 1 to 3 ring heteroatoms selected from O, N and S A 5 or 6-membered aromatic heterocyclic group containing a pyridone group, a phenyl group or a heterocyclic group, optionally a halogeno, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl , C _l-4 alkyl, amino, C _1-4 alkylamino, C _1-4 hydroxy alkoxy, carboxy, cyano, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, , N- C _1-3 alkylsulfamoyl, N, N -di- [C _1-3 alkyl] sulfamoyl, C _1-3 alkanesulfonylamino, N- C _1-3 alkyl-C _1-3 alkanesul Ponylamino, -CONR ¹⁰ R ¹¹ and -NR ¹⁰ COR ¹¹ , wherein R ¹⁰ and R ^ll are as described above Substituted with up to 5 substituents selected from
7) -Y ² -X ⁶ -R ¹⁴ , wherein Y ² , X ⁶ and R ¹⁴ are as described above,
8) -Y ² -NR ¹⁷ R ¹⁸ wherein Y ² is as described above and R ¹⁷ and R ¹⁸ are each hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-3 alkoxycarbonyl C _1-6 alkyl (wherein, R ¹⁷ or R ¹⁸ is any alkyl group of hydroxy, halogeno, C _l-3 alkyl, C _l-3 alkoxy, C _l-3 alkanoyloxy, trifluoromethyl Is optionally substituted with up to two substituents selected from rommethyl, cyano, amino or nitro).
9) -Y ³ -R ^a , wherein Y ³ is C _1-5 alkylene, C _2-5 alkenylene or C _2-5 alkynylene, wherein each methylene group (excluding the methylene group of α-carbon) is Optionally substituted by one substituent each selected from hydroxy, halogeno, amino and C _1-4 alkanoyloxy provided that there are no more than three substituents on the alkylene, alkenylene or alkynylene chain R ^a is substituted by one substituent selected from hydroxy, amino and halogeno on the ring carbon linked to Y ³ and optionally substituted with oxo, hydroxy, halogeno, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, carbamoyl, C _1-4 alkylcarbamoyl, NN -di (C _1-4 alkyl) carbamoyl, C _2-4 alkanoyl, C _{1- 4} alkoxycarbonyl and C _3-7 cycloalkyl, wherein C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _3-7 cycloalkyl are optionally hydroxy, halogeno, cyano , C _1-3 eggs Up to 3 substituents selected from K, C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and up to 3 substituents selected from R ¹⁴ described above) C _3-7 cycloalkyl further substituted by substituent;
m is an integer of 1 to 3,
R ¹ is methoxy, R ² is hydrogen, Z is -NH-,
R ³ is halogeno or Ci _-3 alkyl, and
If X ^l is -O-,
R ⁴ is not selected from one of the following three groups:
a) -C _2-5 alkylR ¹⁹ , wherein R ¹⁹ represents one or two substituents selected from hydroxy, halogeno, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy It can be piperidin-4-yl),
b) -C _2-5 ^{alkenylR 19} , wherein R ¹⁹ is as described above,
c) -C _2-5 alkynylR ¹⁹ , wherein R ¹⁹ is as described above,
Wherein any alkylene, alkenylene or alkynylene chain in the groups a) to c) is optionally substituted by one or more substituents selected from hydroxy, halogeno and amino.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ² is hydrogen.
[3" claim-type="Currently amended] The compound of claim 1 or 2, wherein R ¹ is hydrogen or methoxy.
[4" claim-type="Currently amended] 4. The compound of claim 1, wherein ring A is phenyl or pyridyl.
[5" claim-type="Currently amended] 5. The compound of claim 1 wherein R ³ is hydroxy, halogeno, C _1-2 alkyl, C _1-2 alkoxy, trifluoromethyl, cyano, amino or nitro. compound.
[6" claim-type="Currently amended] 6. The compound of claim 1, wherein m is 2 or 3. 7.
[7" claim-type="Currently amended] The ring A according to any one of claims 1 to 6, wherein R carries (R ³ ) _m is 2-fluoro-4-chloro-5-hydroxyphenyl, 2-fluoro-4-bromo -5-hydroxyphenyl, 2-fluoro-4-chlorophenyl or 2-fluoro-4-bromophenyl.
[8" claim-type="Currently amended] 8. The compound of claim 1, wherein X ¹ is —O—, —S—, —NR ⁷ CO— or —NR ⁷ SO ₂ —, wherein R ⁷ is hydrogen, methyl, or ethyl. ) Compound.
[9" claim-type="Currently amended] 9. The compound of claim 1, wherein R ⁴ is of the formula —Y ² —R ¹⁶ —, —Y ² —NR ¹⁷ R ¹⁸ or —Y ³ —R ^a , wherein Y ² , Y ³ , R ^a , R ¹⁶ , R ¹⁷ and R ¹⁸ are as defined in claim 1.
[10" claim-type="Currently amended] 10. The alkylene, alkenylene or alkynylene chain of any one of claims 1 to 9 wherein Y ¹ or Y ² in R ⁴ is substituted with hydroxy or acetoxy, wherein Y ¹ , Y ² and Y ⁴ is as defined in claim 1.
[11" claim-type="Currently amended] 4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy) quinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxy) quinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperazin-1-yl) propoxy] -6-methoxy) quinazoline
4- (4-chloro-2-fluorophenylamino) -7- (2-hydroxy-3- (morpholino) propoxy) -6-methoxy) quinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (thiazolidin-3-yl) propoxy] -6-methoxy) quinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-morpholinoethyl) piperazin-1 yl) propoxy] -6-meth Oxyquinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (3-hydroxypropyl) piperazin-1yl) propoxy] -6-methoxy Quinazoline
4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (4- (2-hydroxyethyl) piperazin-1yl) propoxy] -6-methoxy Quinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (1,2,3,6-tetrahydropyridin-1-yl) propoxy] -6-meth Oxyquinazoline
4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-tbutyl-N-methylamino) propoxy] -6-methoxyquinazoline
4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline hydrochloride
4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline
4- (4-Bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy] -6-methoxy Quinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (morpholino) propoxy] -6-methoxyquinazoline
4- (4-bromo-2-fluorophenylamino) -7- (2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-bromo-2-fluorophenylamino) -7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N, N-dimethylamino) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (piperidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (homopiperidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-hydroxyethyl) -N-methylamino) propoxy] -6-methoxyquina Sleepy
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-pyrrolin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (thiomorpholin-4-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (3-hydroxypyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-morpholinoethyl) piperazin-1-yl] propoxy} -6-meth Oxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- {2-hydroxy-3- [4- (2-hydroxyethyl)] piperazin-1-yl) propoxy} -6-meth Oxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2,5-dimethyl-3-pyrrolin-1-yl) propoxy] -6-methoxyquina Sleepy
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (4-methylpiperidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (2-methylpyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N- (2-cyanoethyl) -N-methylamino) propoxy] -6-methoxyquina Sleepy
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isopropyl-N-methylamino) propoxy] -6-methoxyquinazoline
4- (4-chloro-2-fluorophenylamino) -7- [2-hydroxy-3- (N-isobutyl-N-methylamino) propoxy] -6-methoxyquinazoline
4-chloro-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
4-chloro-2-fluoro-5-hydroxyphenylamino-7- (2-acetoxy-3-piperidinopropoxy) -6-methoxyquinazoline
4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-acetoxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazoline
Compound selected from 4-bromo-2-fluoro-5-hydroxyphenylamino-7- [2-hydroxy-3- (pyrrolidin-1-yl) propoxy] -6-methoxyquinazolin Or salts thereof.
[12" claim-type="Currently amended] The compound of any one of claims 1-11, wherein the compound is in the form of a pharmaceutically acceptable salt.
[13" claim-type="Currently amended] A process for preparing a compound of formula (I) or a salt thereof as defined in claim 1,
(a) reaction of a compound of formula III with a compound of formula IV:
[Formula III]
(Wherein R ¹ , R ² , X ¹ and R ⁴ are as defined in claim ¹ and L ¹ is a substitutable moiety)
[Formula IV]
(In the above formula, the rings A, Z, R ³ and m are as defined in claim 1).
(b) when the group of formula (IIa) is a ring carrying one or more hydroxy groups, deprotection reaction of a compound of formula (V);
[Formula IIa]
(Wherein ring A, R ³ and m are as defined in claim 1)
[Formula V]
(Wherein ring A, X ¹ , m, R ¹ , R ² , R ³ , R ⁴ and Z are as defined in claim ¹ , P is a hydroxy protecting group, p ¹ is a hydroxy group of An integer from 1 to 5 equivalent to the number, mp ¹ is equivalent to the number of R ³ substituents that are not protected hydroxy);
(c) a compound of formula (I) and salts thereof, wherein substituent X ¹ is —O—, —S— or —NR ⁷ —, wherein R ⁷ is as defined in claim 1; It can be prepared by the reaction of a compound of formula
[Formula VI]
(Wherein A, m, X ¹ , R ¹ , R ² , R ³ and Z are as defined in claim 1)
[Formula VII] R ⁴ -L ¹
(Wherein R ⁴ is as defined in claim 1 and L ¹ is as defined in this section);
(d) Reaction of a compound of Formula VIII with a compound of Formula IX:
[Formula VIII]
[Formula IX] R ⁴ -X ¹ -H
(Wherein rings A, R ¹ , R ² , R ³ , R ⁴ , Z, m and X ¹ are all as defined in claim ¹ and L ¹ is defined in this section);
(e) a compound of formula I and salts thereof, wherein R ⁴ is a 2-hydroxypropyl chain substituted by -NR ¹⁷ R ¹⁸ , wherein R ¹⁷ and R ¹⁸ are as defined in claim 1 or a ring nitrogen; To a saturated or partially saturated heterocyclic ring comprising at least two additional ring heteroatoms selected from O, S, and N, wherein said compound is of formula May be reacted with a suitable amine, and similar reactions may be used to prepare compounds of formula (I) wherein R ⁴ comprises a longer hydroxy substituted alkylene, alkenylene or alkynylene chain:
[Formula X]
(In the above formula, the rings A, R ¹ , R ² , R ³ , Z, m and X ¹ are all as defined in claim 1);
(f) to prepare a compound of formula (I) and salts thereof (groups in R ⁴ linked to -Y ¹ -or -Y ² -are linked via an N, O or S atom), a compound of formula (XI) and HN, Appropriate compounds containing HO or HS groups can be reacted:
Formula XI

In the above formula, the rings A, X ¹ , R ¹ , R ² , R ³ , Z and m are as defined in claim ¹ , L ¹ is as defined in this paragraph, and Q is -Y ^1. -Or -Y ² -wherein -Y ¹ -and -Y ² -are as defined in claim ¹ );
If a pharmaceutically acceptable salt of the compound of formula (I) is desired, the method comprises reacting the obtained compound with an acid or a base to obtain the desired pharmaceutically acceptable salt.
[14" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 together with a pharmaceutically acceptable excipient or carrier.
[15" claim-type="Currently amended] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for use in causing antiangiogenic and / or vascular permeability reducing effects in warm blooded animals such as humans.
[16" claim-type="Currently amended] A method of causing anti-angiogenic and / or vascular permeability-reducing effects in warm-blooded animals requiring anti-angiogenic and / or decreased vascular permeability, the method comprising the effective amount of a compound of formula (I) or a pharmaceutically acceptable salt as defined in claim 1 A method comprising administering to an animal.

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同族专利:

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公开号 | 公开日

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KR100858069B1|2008-09-22|

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WO2001077085A1|2001-10-18|

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AU779695B2|2005-02-10|

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DK1274692T3|2006-10-30|

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CN1433405A|2003-07-30|

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EP1274692B1|2006-08-02|

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PT1274692E|2006-11-30|

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NO20024763D0|2002-10-03|

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DE60121931T2|2007-03-01|

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-04-07|Priority to EP00400968

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2000-04-07|Priority to EP00400967.6

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2000-04-07|Priority to EP00400968.4

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2000-04-07|Priority to EP00400967

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2000-04-13|Priority to EP00401034

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2000-04-13|Priority to EP00401033.6

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2000-04-13|Priority to EP00401034.4

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2000-04-13|Priority to EP00401033

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2001-04-03|Application filed by 아스트라제네카 아베

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2002-11-04|Publication of KR20020084295A

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2008-09-22|Application granted

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2008-09-22|Publication of KR100858069B1

优先权:

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申请号 | 申请日 | 专利标题

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EP00400968|2000-04-07|

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EP00400967.6|2000-04-07|

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EP00400968.4|2000-04-07|

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EP00400967|2000-04-07|

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EP00401034|2000-04-13|

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EP00401033.6|2000-04-13|

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EP00401034.4|2000-04-13|

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EP00401033|2000-04-13|