Selective anthranilamide pyridine amides as inhibitors of vegfr-2 and vegfr-3

专利摘要:
The present invention relates to selective anthranylamide pyridine amides as inhibitors of VEGFR-2 and VEGFR-3 and their preparation and use as a medicament for the treatment of diseases caused by sustained angiogenesis. The compounds of the present invention are for example psoriasis, Kaposi's sarcoma, restenosis, for example, splint-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, for example rheumatoid arthritis, hemangioma, angiofibrosis , Ocular diseases such as diabetic retinopathy, neovascular glaucoma, kidney disease such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy, fibrotic disease, for example For example in the case of cirrhosis, hepatic vascular proliferative disease, arteriosclerosis, nerve tissue damage and after balloon catheter treatment, to prevent vascular reclosure after the use of a mechanical device for maintaining prosthetic vascular prosthesis or for the use of splints such as splints. And as immunosuppressive agents and to assist in scar healing in aging spots and contact dermatitis. In addition, the compounds of the present invention can be used as VEGFR-3 inhibitors in lymphangiogenesis in hyperplasia and dysplastic changes in the lymphatic system.
公开号:KR20030094395A
申请号:KR10-2003-7014539
申请日:2002-05-03
公开日:2003-12-11
发明作者:알렉산더 언스트；안드레아스 후쓰；마틴 크뤼거；칼-헤인즈 티어아우츠；안드레아스 멘라드；마틴 하버리
申请人:쉐링 악티엔게젤샤프트；
IPC主号:

专利说明:

SELECTION ANTHRANILAMIDE PYRIDINE AMIDES AS INHIBITORS OF VEGFR-2 AND VEGFR-3} As Inhibitors of VEGFR-2 and VEVFR-3
[2] Sustained angiogenesis can include various diseases, such as psoriasis; Arthritis such as rheumatoid arthritis, hemangioma, endometriosis, angiofibrosis; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy; Fibrogenic diseases such as cirrhosis, hepatic cell proliferative diseases and atherosclerosis can be caused or aggravated.
[3] Persistent angiogenesis is induced by the factor VEGF through its receptor. For VEGF to do this, it is necessary for VEGF to bind to the receptor, thereby inducing tyrosine phosphorylation.
[4] Direct or indirect inhibition of VEGF receptors (VEGF = Vascular Endothelial Growth Factor) can be used to treat pathological angiogenesis and vascular permeability of these diseases and other VEGF induction, such as tumor angiogenesis. For example, it is known that tumor growth can be inhibited by antibodies to soluble receptors and VEGF.
[5] psoriasis; Arthritis such as rheumatoid arthritis, hemangioma, angiofibrosis; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy; For the treatment of fibrotic diseases such as cirrhosis, hepatic cell proliferative disorders, arteriosclerosis, nerve tissue damage, and after balloon catheter treatment, for the purpose of prosthetic vascular prosthesis or to maintain vascular opening, such as the use of splints Anthranilic acid amides which are used as pharmaceutical agents for inhibiting vascular reclosure are known from WO 00/27819.
[6] In the case of endometriosis, strong angiogenesis is essential for the proliferation of the endometrium. Thus, angiogenesis inhibition can also be used for the treatment of this type of disease that causes pain conditions and often can lead to infertility.
[7] In general, known compounds are effective for the indications mentioned, but in general, their effectiveness entails toxicity and inferior dosage compatibility.
[8] Therefore, there is a need for compounds that are more effective on one side and more toxicly harmless on the other side, and yet also more compatible.
[1] The present invention relates to selective anthraninilamide pyridineamides as VEGFR-2 and VEGFR-3 inhibitors, their preparation and use as pharmaceutical agents for the treatment of diseases caused by sustained angiogenesis.
[9] We have now found that the compounds of the formula (I) as well as their isomers, enantiomers and salts overcome this drawback.
[10]
[11] In the above formula,
[12] A, B and D represent nitrogen or carbon atoms independently of one another such that at least one nitrogen atom is included in the ring,
[13] E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently ⁴ , -SOR ⁴ or aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN, -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
[14] G represents a nitrogen atom or a group -C-X,
[15] L represents a nitrogen atom or a group -C-X,
[16] M represents a nitrogen atom or a group -C-X,
[17] Q represents a nitrogen atom or the group -C-X, where at most one nitrogen atom is present in the ring,
[18] X represents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyloxy or C ₁ -C ₆ -carboxyalkyl, which is hydrogen, halogen or unsubstituted or optionally substituted with one or more positions halogen;
[19] R ¹ is optionally at least one position in the same way or differently with halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl and / or groups -NR ² R ³ Branched or unbranched C ₁ -C ₁₂ -alkyl or C ₂ -C ₁₂ -alkenyl substituted with; Or C ₃ -optionally substituted at least one position in the same way or differently with halogen, hydroxy, C ₁ -C ₆ -alkyloxy, C ₁ -C ₆ -alkyl and / or the group -NR ² R ³ C ₁₀ -cycloalkyl or C ₃ -C ₁₀ -cycloalkenyl; Or halogen, cyano, hydroxy, C ₁ -C ₆ -alkyloxy, C ₂ -C ₆ -alkenyl, aryl-C ₁ -C ₆ -alkyloxy, aralkyl in one or more positions in the same manner or differently Optionally with oxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or groups ═O, —SO ₂ R ⁴ , OR ⁵ , —R ⁵ or —PO (OR ¹² ) (OR ¹³ ) Substituted aryl or hetaryl,
[20] R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ -alkyl, or C optionally substituted with the group -NR ⁶ R ⁷ , -OR ⁵ , C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
[21] R ² and R ³ , together with the nitrogen atom, may optionally include another nitrogen, sulfur or oxygen atom in the ring or may contain the group —N (R ¹⁰ ) and one or more positions are the same or different. ^May be optionally substituted with halogen, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or a group -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ Form a C ₃ -C ₈ -ring,
[22] R ⁴ represents hydroxy, C ₁ -C ₆ -alkyl, aryl, heteroaryl or the group -NR ² R ³ ,
[23] R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl or
[24] Halo-C ₃ -C ₆ -cycloalkyl, or C ₁ -C ₁₂ -alkyl wherein one or more positions are interrupted by oxygen, or a group-(CH ₂ ) ₂ NR ² R ³ , -CH ₂ CN or- CH ₂ CF ₃ is represented,
[25] R ⁶ and R ⁷ independently of each other represent hydrogen or C ₁ -C ₆ -alkyl, or
[26] R ⁶ and R ⁷ together form a 5 to 7 membered ring which may include an oxygen or sulfur atom or a group -N (R ¹⁰ )-,
[27] R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl or hetaryl optionally substituted at least one position by halogen,
[28] R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, tri-C _1-6 -alkylsilyl, aryl, hetaryl or group —COR ¹¹ ,
[29] R ¹⁰ represents hydrogen, C ₁ -C ₆ -alkyl or aryl,
[30] R ¹¹ represents hydrogen, C ₁ -C ₆ -alkyl or the group —NR ² R ³ , and
[31] R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl.
[32] It is prominent that the compounds according to the invention prevent tyrosine phosphorylation or stop persistent angiogenesis and thus stop tumor growth and proliferation, and in particular inhibit the isoforms (2C9 and 2C19) of cytochrome P 450 more slightly. .
[33] Many pharmaceutical agents are degraded through these isoforms. Inhibiting these isoforms increases the plasma levels of these pharmaceutical agents, which can cause undesirable side effects.
[34] Alkyl in each case is a straight chain such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl or It is defined as a branched alkyl radical.
[35] Alkoxy is in each case, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy And straight or branched alkoxy radicals such as nonyloxy, decyloxy, undecyloxy or dodecyloxy.
[36] Cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or monocyclic alkyl rings such as cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and also bicyclic rings such as, for example, adamantanyl Or a tricyclic ring.
[37] Cycloalkenyl is in each case defined as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, and can be linked to both double bonds and single bonds.
[38] Halogen is defined in each case as fluorine, chlorine, bromine or iodine.
[39] Alkenyl is in each case defined as a straight or branched alkenyl radical comprising 2-6, preferably 2-4 C atoms. For example, the following radicals may be mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, boot- 2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, boot- 1-en-3-yl, but-3-en-1-yl and allyl.
[40] In each case the aryl radical has 6-12 carbon atoms, for example naphthyl, biphenyl and especially phenyl.
[41] In each case, the heteroaryl radical contains 3-16 ring atoms and may contain one or more heteroatoms, such as oxygen, nitrogen or sulfur, instead of carbon in the ring, monocyclic, bicyclic, Or tricyclic, and in each case may also be benzocondensed.
[42] For example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl and the like and benzo derivatives thereof For example, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindoleyl and the like; Or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, isoquinolyl and the like; Or azosinyl, indolinyl, furinyl and the like and benzo derivatives thereof; Or cinnaolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pterridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xentenyl, oxepinyl And the like can be mentioned.
[43] An aryl radical and a heteroaryl radical in each case 1, 2 or 3 where the same way or differently with hydroxy, halogen, C ₁ -C ₄ in-a is alkoxy, substituted one or more positions by halogen, C ₁ -C ₄ - Alkyl or C ₁ -C ₄ -alkyl.
[44] When containing acid groups, physiologically compatible salts of organic and inorganic bases, such as readily available alkali and alkaline earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine , Lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, cerinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and 1-amino-2,3 , 4-butanetriol is suitable as a salt.
[45] When containing a basic group, physiologically compatible salts of organic and inorganic acids are suitable, for example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid and the like.
[46] In addition, the compounds of the formula (I) according to the invention comprise possible tautomeric forms and comprise E- or Z-isomers, or racemic and enantiomers, if chiral centers are present.
[47] A, B, and D represent nitrogen or carbon atoms independently of one another such that one or more nitrogen atoms are included in the ring,
[48] E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently ⁴ , -SOR ⁴ or aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN, -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
[49] G represents a nitrogen atom or a group -C-X,
[50] L represents a nitrogen atom or a group -C-X,
[51] M represents a nitrogen atom or a group -C-X,
[52] Q represents a nitrogen atom or the group -C-X, where at most one nitrogen atom is present in the ring,
[53] X represents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyloxy or C ₁ -C ₆ -carboxyalkyl which is hydrogen, halogen or unsubstituted or optionally substituted at least one position by halogen,
[54] R ¹ is at least one position in the same way or differently halogen, cyano, hydroxy, C ₁ -C ₆ -alkyloxy, C ₂ -C ₆ -alkenyl, aryl-C ₁ -C ₆ -alkyloxy, Aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or group ═O, —SO ₂ R ⁴ , —OR ⁵ , —R ⁵ or —PO (OR ¹² ) (OR ¹³ ) Aryl or hetaryl optionally substituted by
[55] R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ - alkyl or a group ^{-NR 6 R 7, -OR 5,} C 1 -C 6 - alkyl, -OR ^5, -SR ^4, -SOR ⁴ or -SO ₂ R ^4, optionally substituted C ₁ to -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
[56] R ² and R ³ , together with the nitrogen atom, may optionally include another nitrogen, sulfur or oxygen atom in the ring or may contain the group —N (R ¹⁰ ) and one or more positions are the same or different. ^May be optionally substituted with halogen, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or a group -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ Form a C ₃ -C ₈ ring,
[57] R ⁴ represents hydroxy, C ₁ -C ₆ -alkyl, aryl, heteroaryl or the group -NR ² R ³ ,
[58] R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl or
[59] Halo-C ₃ -C ₆ -cycloalkyl, or C ₁ -C ₁₂ -alkyl wherein one or more positions are interrupted by oxygen, or a group-(CH ₂ ) ₂ NR ² R ³ , -CH ₂ CN or- CH ₂ CF ₃ is represented,
[60] R ⁶ and R ⁷ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,
[61] or
[62] R ⁶ and R ⁷ together form a 5 to 7 membered ring which may include an oxygen or sulfur atom or a group -N (R ¹⁰ )-,
[63] R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl, hetaryl optionally substituted at least one position by halogen,
[64] R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, tri-C ₁ -C ₆ -alkylsilyl, aryl, hetaryl or group —COR ¹¹ ,
[65] R ¹⁰ represents hydrogen, C ₁ -C ₆ -alkyl or aryl,
[66] R ¹¹ represents hydrogen, C ₁ -C ₆ -alkyl or the group —NR ² R ³ , and
[67] R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
[68] The compounds of formula (I), as well as their isomers, enantiomers and salts, have proved to be particularly effective.
[69] A, B and D represent nitrogen or carbon atoms independently of one another such that at least one nitrogen atom is included in the ring,
[70] E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or group -OR ⁵ ,-in one or more positions in the same way or differently Aryl or hetaryl optionally substituted with SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN, -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
[71] G represents a nitrogen atom or a group -C-X,
[72] L represents a nitrogen atom or a group -C-X,
[73] M represents a nitrogen atom or a group -C-X,
[74] Q represents a nitrogen atom or the group -C-X, where at most one nitrogen atom is present in the ring,
[75] X represents hydrogen or halogen,
[76] R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or a group in one or more positions in the same way or differently Aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , -OR ⁵ , -R ⁵ or -PO (OR ¹² ) (OR ¹³ ),
[77] R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ -alkyl, or C optionally substituted with the group -NR ⁶ R ⁷ , -OR ⁵ , C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
[78] R²And R³May optionally contain another nitrogen, sulfur or oxygen atom in the ring together with the nitrogen atom or the group —N (R¹⁰) And one or more positions in the same way or differently halogen, cyano, C_One-C₆-Alkyl, halo-C_One-C₆-Alkyl, aryl or group -OR⁵, -SR⁴, -SOR⁴Or -SO₂R⁴in C may be optionally substituted₃-C₈Forming a ring,
[79] R ⁴ represents a hydroxy or a group -NR ² R ³ ,
[80] R ⁵ is hydrogen, C ₁ -C ₁₂ - alkyl, with a one or more positions with oxygen interrupted C ₁ -C ₁₂ - represents an alkyl group or ^{_{- (CH 2) 2 NR 2}} R 3, -CH 2 CN or - CH ₂ CF ₃ is represented,
[81] R ⁶ and R ⁷ independently of each other represent hydrogen or C ₁ -C ₆ -alkyl, or
[82] R ⁶ and R ⁷ together form a 5 to 7 membered ring which may include an oxygen or sulfur atom or a group -N (R ¹⁰ )-,
[83] R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl or hetaryl optionally substituted at least one position by halogen,
[84] R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, tri-C _1-6 -alkylsilyl, aryl, hetaryl or group —COR ¹¹ ,
[85] R ¹⁰ represents hydrogen, C ₁ -C ₆ -alkyl or aryl,
[86] R ¹¹ represents hydrogen, C ₁ -C ₆ -alkyl or the group —NR ² R ³ , and
[87] R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
[88] Particularly effective are the compounds of formula (I), as well as their isomers, enantiomers and salts.
[89] A, B and D represent nitrogen or carbon atoms such that at least one nitrogen atom is included in the ring,
[90] E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently ⁴ , -SOR ⁴ or -SO ₂ R ⁴ optionally substituted hetaryl or -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN , -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ,
[91] G represents the group -C-X,
[92] L represents a group -C-X,
[93] M represents the group -C-X,
[94] Q represents a nitrogen atom or a group -C-X,
[95] X represents hydrogen or halogen,
[96] R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or a group in one or more positions in the same way or differently Optionally substituted with -SO ₂ R ⁴ , -OR ⁵ , -R ⁵ or -PO (OR ¹² ) (OR ¹³ )
[97]
[98] (Wherein T represents hydrogen, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy) substituted phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyri Represents midines, triazines, quinolines, isoquinolines,
[99] R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ -alkyl, or C optionally substituted with the group -NR ⁶ R ⁷ , -OR ⁵ , C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
[100] R ² and R ³ , together with the nitrogen atom, may optionally include another nitrogen, sulfur or oxygen atom in the ring or may contain the group —N (R ¹⁰ ) and one or more positions are the same or different. ^May be optionally substituted with halogen, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or a group -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ Form a C ₃ -C ₈ -ring,
[101] R ⁴ represents a hydroxy or a group -NR ² R ³ ,
[102] R ⁵ is hydrogen, C ₁ -C ₁₂ - alkyl, with a one or more positions with oxygen interrupted C ₁ -C ₁₂ - represents an alkyl group or ^{_{- (CH 2) 2 NR 2}} R 3, -CH 2 CN or - CH ₂ CF ₃ is represented,
[103] R ⁶ and R ⁷ independently of each other represent hydrogen or C ₁ -C ₆ -alkyl, or
[104] R ⁶ and R ⁷ together form a 5 to 7 membered ring which may comprise oxygen or sulfur atoms,
[105] R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl or hetaryl optionally substituted at least one position by halogen, and
[106] R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, or tri-C ₁ -C ₆ -alkylsilyl, and
[107] R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
[108] The compounds of formula (I) as well as their isomers, enantiomers and salts have excellent properties.
[109] A, B and D represent nitrogen or carbon atoms independently of one another such that at least one nitrogen atom is included in the ring,
[110] E represents thienyl, pyridyl or the group -COOR ⁸ , -CONR ² R ³ , or -C≡CR ⁹ ,
[111] G represents the group -C-X,
[112] L represents a group -C-X,
[113] M represents the group -C-X,
[114] Q represents a nitrogen atom or a group -C-X,
[115] X represents hydrogen or halogen,
[116] R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or a group in one or more positions in the same way or differently Optionally substituted with -SO ₂ R ⁴ , -OR ⁵ , -R ⁵ or -PO (OR ¹² ) (OR ¹³ )
[117]
[118] (Wherein T represents hydrogen, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy) substituted on phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyra Sol, pyridine, pyrimidine, triazine, quinoline, or isoquinoline,
[119] R ² and R ³ independently of one another are hydrogen, or halogen, C ₁ -C ₆ -alkyl, phenyl or group —NR ⁶ R ⁷ , —OR ⁵ or C ₁ -C ₆ in the same way or differently at one or more positions; Or C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, phenyl or pyridyl optionally substituted with -alkyl-OR ⁵ , or
[120] R ² and R ³ , together with a nitrogen atom, may optionally include another nitrogen or oxygen atom in the ring and one or more positions may be optionally substituted in the same way or differently with C ₁ -C ₆ -alkyl Form a C ₃ -C ₈ -ring,
[121] R ⁴ represents a hydroxy or a group -NR ² R ³ ,
[122] R ⁵ , R ⁶ and R ⁷ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl, or
[123] R ⁶ and R ⁷ together form a 5 to 7 membered ring which may comprise oxygen or sulfur atoms,
[124] R ⁸ represents hydrogen, C ₁ -C ₆ -alkyl or benzyl, and
[125] R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl or tri-C ₁ -C ₆ -alkylsilyl, and
[126] R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
[127] The compounds of formula (I) as well as their isomers, enantiomers and salts have remarkable properties.
[128] The compounds according to the invention, as well as their physiologically compatible salts, prevent tyrosine phosphorylation or arrest persistent angiogenesis and thus stop tumor growth and proliferation, in particular the isoforms of cytochrome P 450 (2C9 and It is noticeable that it slightly suppresses 2C19). Thus, although pharmaceutical agents are administered simultaneously and degraded through these isoforms, dosing with the compounds according to the invention can be carried out without risk.
[129] Compounds of formula (I), as well as their physiologically compatible salts, can be used as pharmaceutical agents based on their inhibitory activity with respect to phosphorylation of VEGF receptors. The compounds according to the invention are suitable for treating diseases caused or promoted by sustained angiogenesis, based on their action profile.
[130] Since compounds of formula (I) have been identified as inhibitors of the tyrosine kinases VEGFR-1 and VEGFR-2, they may be used to treat diseases caused or promoted by sustained angiogenesis induced through VEGF receptors or due to increased vascular permeability. Particularly suitable for
[131] Also an object of the present invention is the use of the compounds according to the invention as inhibitors of the tyrosine kinases VEGFR-1 and VEGFR-2, or KDR and FLT.
[132] Accordingly, it is also an object of the present invention for a pharmaceutical medicament or use thereof for treating a tumor.
[133] The compounds according to the invention, alone or in preparation, can be used for psoriasis, Kaposi's sarcoma, restenosis, for example splint-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; Arthritis such as rheumatoid arthritis, hemangioma, angiofibrosis; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy; For the treatment of fibrotic diseases such as cirrhosis, hepatic cell proliferative disorders, arteriosclerosis, nerve tissue damage, and after balloon catheter treatment, for the purpose of prosthetic vascular prosthesis or to maintain vascular opening, such as the use of splints As an immunosuppressive agent for inhibiting postvascular reclosure, it can be used as a pharmaceutical agent for scar healing aid in aging spots and contact dermatitis.
[134] In treating nerve tissue damage, the compounds according to the invention can prevent rapid scar formation at the site of injury, ie the occurrence of scar formation before axon reconnection. Thus, the reconstruction of the nerve compound is facilitated.
[135] In addition, the formation of a plurality of patients can also be inhibited with the compounds according to the invention. In addition, VEGF induced edema can also be inhibited.
[136] Lymphoangiogenesis plays an important role in lymphoid metastasis (Karpanen, t. Et al., Cancere Res. 2001 Mar 1, 61 (5): 1786-90, Veikkola, T., et al., EMBO J 2001, Mar 15; 20 (6): 1223-31).
[137] In addition, the compounds according to the invention presently show significant action as VEGFR kinase 3 inhibitors and are also suitable as effective inhibitors of lymphangiogenesis.
[138] Treatment with the compounds according to the invention not only reduces the size of the metastasis but also reduces the number of metastases.
[139] In addition, the compound according to the present invention is effective in the case of diseases related to excessive lymphangiogenesis is expected to be effective in the case of lymphovascular hyperplasia and dysplastic syndromes.
[140] Such pharmaceutical agents, their formulations and uses are also an object of the present invention.
[141] Thus, the present invention also relates to psoriasis, Kaposi's sarcoma, restenosis, for example, splint-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; Arthritis such as rheumatoid arthritis, hemangioma, angiofibrosis; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy; Mechanisms for the treatment of fibrotic diseases such as cirrhosis, hepatic liver proliferative disease, arteriosclerosis, nerve tissue damage, and after balloon catheter treatment, for maintaining vascular prosthesis or opening of blood vessels such as splints To the inhibition of vascular reclosure after use, it relates to the use of a compound of formula (I) for the preparation of a pharmaceutical medicament used as an immunosuppressive agent in assisting scar-free healing in aging spots and contact dermatitis.
[142] In addition, the formation of a plurality of patients can also be inhibited with the compounds according to the invention. In addition, VEGF induced edema can also be inhibited.
[143] In order to use the compound of formula (I) as a pharmaceutical agent, the pharmaceutical agent must be in the form of a pharmaceutical preparation, which, in addition to the active ingredient, is suitable for enteral transdermal or parenteral administration, for example, water, gelatin, Organic or inorganic inert carrier materials such as gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. Pharmaceutical formulations may be present in solid form, such as tablets, coated tablets, suppositories, capsules or liquid forms, such as solutions, suspensions or emulsions. They also include adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts or buffers for changing the osmotic pressure.
[144] For parenteral administration, in particular injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated perm oils are suitable.
[145] As the carrier system, not only surface-active aids such as bile salts or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or components thereof, can be used.
[146] For oral administration, in particular tablets, coated tablets or capsules with talc and / or hydrocarbon excipients or binders such as lactose, corn starch or potato starch are suitable. In addition, administration can be carried out in liquid form, for example as juice, to which is optionally added a sweetening agent or, if necessary, one or more flavoring substances.
[147] The dosage of the active ingredient may vary depending on the method of administration, the age and weight of the patient, the type and depth of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose may be provided in a single dose administered once or divided into two or more daily doses.
[148] Such formulations and dosage forms are also an object of the present invention.
[149] The preparation of the compounds according to the invention is carried out according to methods known in the art. For example, a compound of formula (I) is obtained by reacting a compound of formula (II) with an amine of formula (III) in an appropriate solvent and in an appropriate organic base, according to methods known in the literature (when E denotes a nitrile group, the nitrile is saponified To form an amide, or a compound of formula IV is converted to the corresponding amide).
[150]
[151] (Wherein A, B, D, G, L, M, Q, W and R ¹ have the meanings described in formula (I), and E represents carboxylic acid-COOH.)
[152] H-NR ⁸ R ⁹
[153] (Wherein, R ⁸ and R ⁹ have the meaning described in the formula (I).)
[154]
[155] (Wherein A, B, D, G, L, M, Q, W, R ⁸ and R ⁹ have the meanings described in formula (I), and R ^x means an ester or an acid group).
[156] Amide formation is carried out according to methods known in the literature.
[157] For amide formation, it is possible to start from the corresponding ester. J. ORg. Chem. 1995, 8414, esters and aluminum trimethyl and the corresponding amines are reacted in a solvent such as toluene at a temperature between 0 ° C. and the boiling point of the solvent. If the molecule contains two ester groups, both are converted to the same amide. Instead of aluminum trimethyl, sodium hexamethyldisilazide can also be used.
[158] However, for amide formation, any method known from peptide chemistry is also available. For example, the corresponding acid is used, for example, in an aprotic polar solvent such as dimethylformamide, for example hydroxybenzotriazole and carbodiimide, for example diisopropylcarbodiimide The boiling point of the solvent, preferably 0 ° C. to the solvent, via an active acid derivative obtainable, otherwise using a previously prepared reagent, for example HATU (see Chem. Comm. 1994, 201) or BTU. Can be reacted with an amine at a temperature of 80 ° C. In addition, for the amide formation, this method can be used with mixed acid anhydrides, imidazolides or azides.
[159] In addition, according to methods known in the literature, nitriles can be saponified to form amides. According to Synthesis, 1989, 949, the reaction with potassium carbonate and hydrogen peroxide is very effective at room temperature, preferably in aprotic polar solvents such as dimethyl sulfoxide.
[160] In addition, the compounds of formula (I) according to the invention can be prepared as follows.
[161] a. Heck reaction of an appropriately substituted terminal alkene with a compound of formula IIa (see “Palladium Reagents in Organic Syntheses,” Academic Press 1985, New York, pp. 179 ff.) Or vinyl perboric acid or Suzuki reaction with vinyl perborate ester (see Tetrahedron Lett. 1983, 39, 3271 ff.) Or Stille reaction with vinyl stannan (Pure & Appl. Chem. 1985, 57). , 1771), or
[162] b. Coupling a compound of formula (IIa) with any substituted terminal alkyne according to, for example, the method of Stephens-Castro (see J. ORg. Chem. 1963, 28, 3313 ff.) Or according to the method of Sonogashira (see “Comprehensive Organic Synthesis: Carbon-Carbon σ-Bond Formation,” Pergamon Press 1991, Oxford UK, Volume 3, pp. 551ff.). Or
[163] c. Suzuki reaction of aryl and hetaryl perboric acid or their esters with a compound of formula IIa (Acc. Chem. Res. 1991, 63, 419 ff. Or J. Am. Chem. Soc. 2000, 122, 4020 ff. Or a still reaction with aryl and hetaryl stannane (see Angew. Chem. 1986, 98, 504 ff. Or Angew. Chem. Int. Ed. 1999, 38, 2411 ff.). Or Negishi reaction with aryl and hetaryl Grignard compounds or similar zinc-organic derivatives ("Metal-Catalyzed Cross-Coupling Reaction," Eds. Diederich / Stang, Wiley-VCH). 1998, New York, Chapter 1 or else J. Am. Chem. Soc. 2001, 123, 2719 ff.
[164] d. The compounds of formula (IIa) are converted to the corresponding carboxylic acid esters via palladium-catalyzed carbonylation in the presence of the corresponding alcohols in dimethylformamide, under a carbon monoxide atmosphere of 1 to 20 bar ("Palladium Reagents in Organic Syntheses, "Academic Press 1985, New York, pp. 352 ff. Or Synth. Comm. 1997, 27, 515 ff.), Or
[165] e. The compound of formula IIa is converted to the corresponding carboxylic acid by palladium-catalyzed carbonylation in a dimethylformamide-water mixture under a carbon monoxide atmosphere of 1 to 20 bar (J. ORg. Chem. 1981, 46 , 4614 ff.]. Carboxylic acids can also be obtained by saponification of carboxylic acid esters; or
[166] f. The corresponding carboxylic acid amides are obtained by palladium-catalyzed carbonylation, in the presence of amines, in a dimethylformamide, under a carbon monoxide atmosphere of 1 to 20 bar ("Palladium Reagents in Organic Syntheses," Academic Press 1985, New York, pp. 352 ff., Tetrahedron Lett. 1982, 23, 3383 ff.]. In addition, the synthesis of carboxylic acid amides can be carried out from carboxylic esters; The method according to Weinreb has proved particularly useful (see Tetrahedron Lett. 1977, 17, 4171 ff., J. ORg. Chem. 1995, 60, 8414 ff.). In addition, carboxylic acid amides can be synthesized from carboxylic acids prepared under e); For this purpose, basically all methods known from peptide chemistry can be used (see Synthesis 1972, 453-63 or “Comprehensive Organic Transformations,” Wiley-VCH 1989, New York, 972-6). For example, the corresponding carboxylic acid in an aprotic polar solvent, such as dimethylformamide, is prepared at an temperature of 0-120 ° C., preferably at room temperature, with an amine such as HATU (Chem. Comm. 1994, 201). Together with, for example, activated carbonic acid derivatives prepared by adding carbonyldiimidazole, or
[167] g. The corresponding sulfide is for example in the presence of a base or transition metal such as, for example, potassium hydride or potassium tert-butanolate, for example copper flakes, copper chloride or copper bromide, or palladium dichloride, for example dimethylform In an aprotic solvent such as amide, N-methylpyrrolinone, dimethyl sulfoxide or xylene, direct conversion is made with thioalkylene, thioarylene and thiohethylene at a temperature of 20-200 ° C. In this case, it may prove advantageous to carry out the reaction in microwave devices (see Tetrahedron 1983, 39, 4153 ff.). The preparation of 2-thio-substituted pyridyl derivatives is also described in Phosphorous Penta sulfide from 2-pyridone derivatives (Bull. Soc. Chim. Fr .; 1953; 1001ff.). Or Labeson (Lawesson's) Thionylation and alkyl halides using reagents (see Tetrahedron 1984, 40, 2047 ff.), Preferably alkyl iodides (J. ORg. Chem. 1999; 64, 7935-9) Or an alkyl sulfonate, preferably after subsequent alkylation with alkyltrifluoromethylsulfonate.
[168] h. Corresponding sulfoxides are, for example, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide, N-methylpyrrolididone, dimethyl sulfoxide, dimethoxyethane, diglyme, tetraglyme or In a solvent such as water, at a temperature of 20 ° C. to the boiling point of the solvent, for example, hydrogen peroxide, sodium periodate, tert-butoxy hypochloride, sodium chlorite, metachloroperbenzoic acid, trifluoroperoxyacetic acid, dimethyl It can be obtained by oxidation of the sulfide using standard oxidants such as deoxyram, cerium ammonium nitrate or nitric acid (see "Oxidations in Organic Chemistry," ACS Washington 1990, pp. 252-63). Thus, the sulfoxide obtained can be further oxidized to the corresponding sulfone; This is, for example, by means of oxidizing agents such as hydrogen peroxide, potassium permanganate, sodium perborate or potassium persulfate (see Tetrahedron Lett. 1981, 22, 1287 ff.), For example, dichloromethane, dichloroethane, In a solvent such as chloroform, tetrahydrofuran, acetonitrile, dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide or water, it is achieved at a temperature between 20 ° C. and the boiling point of the solvent. Sulphide is treated with an excess of the above-cited oxidants to obtain the corresponding sulfones directly (see "The Chemistry of Sulphones and Sulfoxdes" in Patai, Wiley 1988, New York, pp. 165-231).
[169] i. By oxidation of the thiol obtained in g), chlorosulfonates can be prepared; Oxidizing with chlorine or sulfuric acid in aqueous hydrochloric acid solution (see J. ORg. Chem. 1999; 64, 5896-903) or carbon tetrachloride (see J. Med. Chem. 2000, 43, 843-58). (See Tetrahedron Asymm. 1997; 8; 3559-62) It has proved particularly useful in this case to oxidize with sodium hypochlorite.
[170] j. For example, cupdan and rhodanone in polar aprotic solvents such as acetonitrile, dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diglyme, tetraglyme, N-methylpyrrolidone By reaction with a mixture of calcium, the corresponding thiocyanate can be obtained (J. Chem. Soc. Chem. Comm. 1989, 81ff). Again from the latter, the corresponding sulfonic acid chlorides can be obtained by oxidation with hypochlorous acid.
[171] k. From 0 ° C. to the boiling point of the solvent, for example, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide, N-methyl-pyrrolidone, N, N-dimethylacet In solvents such as amides, dimethoxyethane or water, the corresponding sulfonamides can be obtained by reaction of the chlorosulfonates mentioned in i) with amines (see Tetrahedron 2000, 56, 8253-62).
[172] l. At temperatures of 5 ° C. and 100 ° C., the corresponding sulfonic acid is obtained by hydrolysis of chlorosulfonate obtained under i) in water or aqueous alkali solution.
[173] m. At a boiling point of 0 ° C. to a solvent, preferably at 80 ° C., for example, aprotic such as dimethylformamide, N-methyl-pyrrolidinone, N, N-dimethylacetamide, dimethyl sulfoxide or toluene In magnetic solvents, the corresponding phosphonates can be obtained by palladium-catalyzed reaction with O, O-dialkylphosphite, for example in the presence of a base such as triethylamine or diisopropylethylamine. (See Bull. Chem. Soc. Jpn. 1982, 55, 909 ff.).
[174] n. For example, in an aprotic solvent such as diethyl ether, tetrahydrofuran or dioxane, at a temperature of -100 ° C to 0 ° C, in tetrahydrofuran, at -78 ° C, for example n-butyllithium, Corresponding carboxylic acid amides can be obtained by metallization with sec-butyllithium, tert-butyllithium, methyllithium, lithium diisopropylamide or ethyl magnesium bromide, and by reaction with isocyanates.
[175] o. The corresponding carboxylic ester can be obtained by carrying out the reaction similarly as described in n) and recovering the intermediate step metallized with chloroformate.
[176] p. The corresponding aldehyde can be obtained by carrying out the reaction similarly as described in n) and recovering the intermediate step metalized with dimethylformamide, ethyl formate or N-formylmorpholine.
[177] q. The reaction is carried out similarly as described in n) and the corresponding pyri is recovered by recovering the intermediate step metalized with an alkyl halide or alkyl sulfonate, preferably alkyl iodide or alkyltrifluoromethanesulfonate. Dialkyl derivatives may be prepared.
[178] r. In the presence of a catalytic amount of palladium, nickel or rhodium metal or salts of these metals, for example palladium on activated carbon, in a polar-protic solvent or solvent mixture, for example methanol-glacial acetic acid, under a) The pyridylalkenes prepared and the pyridylalkynes prepared under b) are converted to the corresponding pyridylalkanes.
[179]
[180] Wherein A, B, D, G, L, M, Q, W and R ¹ have the meanings described in formula (I), and E is halogen or O-sulfonate, for example chlorine, bromine or iodine Atom, O-trifluoromethanesulfonate or O-methylsulfonate.
[181] In all cases, the order of the process steps can be interchanged.
[182] Preparation of the compounds according to the invention
[183] The following examples illustrate the preparation of compounds according to the invention without limiting the scope of the claimed compounds to these examples.
[184] Example 1
[185] Preparation of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid propylamide
[186]
[187] 50 mg (0.13 mmol) of 5-{[2- (isoquinolin-3-ylcarbamoyl) phenylamino] -methyl} -pyridine-2-carboxylic acid and 42 mg (0.26 mmol) of carbonyldiiimi Dozol was introduced into 2.5 ml of dimethylformamide under argon and in a humid environment, and stirred for 30 minutes at room temperature. Then 15 mg (0.26 mmol) of n-propylamine were added to the batch and stirring continued for 12 hours at room temperature. Then diluted with water to about 30 ml and shaken three times with 20 ml of ethyl acetate each. The collected organic phases were dried, filtered and concentrated by evaporation and the residue was flash column (5 g; Isolute flash silica, using a gradient of 100% hexanes to 50% hexanes and 50% ethyl acetate). Chromatography on Separtis Company. 45 mg (79% of theory) of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid propylamide were obtained (mole peak MS m / e = 439).
[188] In addition, the following compounds were similarly prepared:
[189]
[190]
[191]
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199]
[200]
[201]
[202]
[203]
[204]
[205]
[206]
[207]
[208]
[209] Example 2.0
[210] Preparation of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid pyridin-3-ylamide
[211]
[212] Under argon, 120 mg (0.3 mmol) of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid in 5 ml of anhydrous dimethylformamide Dissolved in, 56 mg (0.6 mmol) 3-aminopyridine, 76 mg (0.75 mmol) N-methylmorpholine and 136 mg (0.36 mmol) O- (7-azabenzotriazol-1-yl) Mixed with -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 48 hours at room temperature. Then it was concentrated by evaporation in vacuo and the residue was subjected to a flash column (5 g of Isorut flash silica, Celestis Company) using a gradient of methylene chloride: ethanol = 100: 0 to 95: 5 as eluent. Sepostis Company). Mg of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid pyridin-3-ylamide was obtained.
[213] MS (m / e 474)
[214] Similarly the following compounds were prepared:
[215]
[216]
[217] Example 3.0
[218] Preparation of 5-{[2- (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[219]
[220] 36 mg (0.09 mmol) of 2-[(6-cyano-pyridin-3-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H -indol-5-yl) -Benzamide was mixed with 30 mg (0.22 mmol) potassium carbonate and 0.05 ml (0.42 mmol) hydroxy peroxide (30%) in 1 ml dimethyl sulfoxide and stirred at room temperature for 3.5 hours. Then it was diluted with water and extracted with ethyl acetate. The organic phase was washed, dried, filtered and concentrated by evaporation. The residue was absorbed precipitated with warm methanol. 5 mg (11% of theory) of 5-{[2- (2-oxo-2,3-dihydro-1 H -indol-5-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2 -Carboxylic acid amide was obtained.
[221] Similarly the following compounds were prepared:
[222] Example 3.1
[223] 4-{[2- (7-methoxy-3-methyl-quinolin-2-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[224]
[225] Example 3.2
[226] 4-{[2- (7-methoxy-2-oxo-2H-chromen-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[227]
[228] Example 3.3
[229] 5-{[2- (7-methoxy-2-oxo-2H-chromen-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[230]
[231] Example 3.4
[232] 5-{[2- (7-methoxy-3-methyl-quinolin-2-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[233]
[234] Example 3.5
[235] 4-{[2- (isoquinolin-3-ylcarbamoyl) -6-azaphenylamino] -methyl} -pyridine-2-carboxylic acid amide
[236]
[237] Example 3.6
[238] 5-{[2- (2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[239]
[240] Example 3.7
[241] 4-{[2- (2-Methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[242]
[243] Example 3.8
[244] 4-{[2- (1H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[245]
[246] Example 3.9
[247] 4-{[2- (1-Methyl-1H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[248]
[249] Example 3.10
[250] 5-{[2- (isoquinolin-3-ylcarbamoyl) -6-azaphenylamino] -methyl} -pyridine-2-carboxylic acid amide
[251]
[252] Example 3.11
[253] 4-{[2- (2-Oxo-2,3-dihydro-1 H-indol-5-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid amide
[254]
[255] Example 4.0
[256] Preparation of N-tert-butyl- (4-{[2- (isoquinolin-3-ylcarbamoyl) -6-azaphenylamino] -methyl} -pyridine-2-carboxylic acid amide)
[257]
[258] In 5 ml of toluene, under protective gas and in a humid environment, 72 mg (0.5 mmol) of 3-aminoisoquinoline are mixed with 0.25 ml of trimethylaluminum (0.5 mmol; 2 mol in toluene) and at room temperature for 30 minutes. Stirred. Then 120 mg (0.45 mmol) of 2-[(2- tert -butylcarbamoyl-pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester were added and heated to 120 ° C. for 2 hours. After cooling, it was mixed with 30 ml of dilute sodium bicarbonate solution and extracted three times with 30 ml of ethyl acetate each. The collected ethyl acetate phases were washed with water, dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using methylene chloride: ethanol = 95: 5 as eluent. Second chromatography on silica gel using hexane: ethyl acetate = 1: 1 as eluent, followed by 70 mg (30% of theory) of N- tert -butyl- (4-{[2- (isoquinoline-3- Ylcarbamoyl) -6-azaphenylamino] -methyl} -pyridine-2-carboxylic acid amide) was obtained (melting point 201 ° C.).
[259] Example 5.0
[260] Preparation of 4-{[2- (isoquinolin-3-ylcarbamoyl) -6-azaphenylamino] -methyl} -pyridine-2-carboxylic acid (2-hydroxy-propyl) -amide
[261]
[262] 283 mg (1 mmol) of 2-chloro- N -isoquinolin-3-yl-nicotinamide was dissolved in 5 ml of pyridine at about 1.66 mmol of 4-aminomethyl-pyridine-2-carboxylic acid (2-hydroxy- Propyl) -amide and heated to 100 ° C. for 2 hours. After concentration by evaporation, it was taken up in water and shaken three times with 30 ml of ethyl acetate each. The collected organic phases were washed with water, dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using methylene chloride: acetone = 1: 1 as eluent. 40 mg (9% of theory) of 4-{[2- (isoquinolin-3-ylcarbamoyl) -6-azaphenylamino] -methyl} -pyridine-2-carboxylic acid (2-hydroxy- Propyl) -amide was obtained as a resin.
[263] Example 6.0
[264] Preparation of N- (isoquinolin-3-yl) -2- [3- (pyridin-3-yl) -pyridin-4-ylmethylamino] -benzoic acid amide
[265]
[266] 94 mg (0.22 mmol) of N- (isoquinolin-3-yl) -2- [3-bromopyridin-4-yl-methylamino] -benzoic acid amide in 3.7 ml of toluene 0.73 ml of ethanol, 0.36 ml Was continuously mixed with 2 mol of sodium carbonate solution, 6 mg of palladium (o) tetrakistriphenylphosphine and 32 mg of pyridine-3-perboric acid and heated to a bath temperature of 120 ° C. for 6.5 hours. It was then diluted with water to 25 ml and extracted three times with 25 ml of ethyl acetate each. The collected ethyl acetate phases were dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using methylene chloride: ethanol = 10: 1 as eluent. 45 mg (47% of theory) of N- (isoquinolin-3-yl) -2- [3- (pyridin-3-yl) -pyridin-4-yl-methylamino] -benzoic acid amide were obtained as resin.
[267]
[268] Example 6.1
[269] Preparation of N- (isoquinolin-3-yl) -2- [3- (thien-3-yl) -pyridin-4-ylmethylamino] -benzoic acid amide
[270] In addition, N- (isoquinolin-3-yl) -2- [3- (thien-3-yl) -pyridin-4-yl-methylamino] -benzoic acid amide was similarly prepared:
[271]
[272] Example 6.2
[273] Preparation of N- (isoquinolin-3-yl) -2- [2-aminocarbonylpyridin-4-yl-methylamino] -benzoic acid amide
[274]
[275] 130 mg (0.34 mmol) of N- (isoquinolin-3-yl) -2- [2-cyanopyridin-4-yl-methylamino] -benzoic acid amide in 2.5 ml of dimethyl sulfoxide 126 mg of potassium carbonate And 0.25 ml of hydrogen peroxide (30%) and stirred for 1 hour at room temperature. Then it was mixed with water and the precipitated product was aspirated. The residue was absorbed precipitated in a mixture of methylene chloride / ethanol and aspirated. 96 mg (71% of theory) of N- (isoquinolin-3-yl) -2-[(2-aminocarbonylpyridin-4-yl) -methylamino] -benzoic acid amide were obtained (melting point 200 ° C.).
[276]
[277] Example 6.3
[278] Preparation of N- (isoquinolin-3-yl) -2-[(2-aminocarbonylpyridin-5-yl) -methylamino] -benzoic acid amide
[279] In addition, N- (isoquinolin-3-yl) -2-[(2-aminocarbonylpyridin-5-yl) -methylamino] -benzoic acid amide was similarly prepared.
[280]
[281] MS (ESI): 398 (78%, [M + H] ⁺ )
[282] Example 6.4
[283] Preparation of N- (isoquinolin-3-yl) -2-[(2-methoxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide
[284]
[285] 20 mg N- (isoquinolin-3-yl) -2- [2-bromopyridin-4-yl-methylamino] -benzoic acid amide (0.05 mmol), 1.6 mg (0.003 mmol) bis- (diphenyl Phosphine) ferrocene (DPPF), 0.35 mg (0.0015 mmol) palladium (II) acetate and 14 μl (0.1 mmol) triethylamine are suspended in a mixture consisting of 1 ml methanol and 1 ml dimethylformamide, It was stirred for 5 hours in an autoclave at 50 ° C. under a CO atmosphere (3 bar). The reaction mixture was filtered using a membrane filter, concentrated by evaporation and chromatographed on silica gel using hexanes: EtOAc = 3: 7 as eluent. 12 mg (58% of theory) of N- (isoquinolin-3-yl) -2-[(2-methoxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide were obtained.
[286]
[287] Example 6.5
[288] Preparation of N- (isoquinolin-3-yl) -2-[(2-benzyloxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide
[289] In addition, N- (isoquinolin-3-yl) -2-[(2-benzyloxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide was similarly prepared.
[290]
[291] Example 6.6
[292] Preparation of N- (isoquinolin-3-yl) -2-[(2-hydroxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide
[293]
[294] a. 20 mg of N- (isoquinolin-3-yl) -2-[(2-methoxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide (0.05 mmol) in 1 ml of tetrahydrofuran and 1 In a mixture of ml of methanol was mixed with 10.2 mg (0.25 mmol) of lithium hydroxide in water and stirred at 22 ° C. for 4 hours. The reaction mixture was filtered using a membrane filter, concentrated by evaporation and chromatographed on silica gel using toluene: acetic acid: water = 10: 10: 1 as eluent. 14 mg (69% of theory) of N- (isoquinolin-3-yl) -2-[(2-hydroxy-carbonylpyridin-4-yl) -methylamino] -benzoic acid amide were obtained.
[295] b. 433 mg N- (isoquinolin-3-yl) -2- [2-bromopyridin-4-yl) -methylamino] -benzoic acid amide (1 mmol), 50 mg (0.09 mmol) bis (diphenyl Phosphine) ferrocene (DPPF), 10 mg (0.045 mmol) palladium (II) acetate, and 280 μl (2 mmol) triethylamine were suspended in a mixture consisting of 5 ml of water and 10 ml of dimethylformamide and , Was stirred for 5 hours in an autoclave at 50 ° C. under a CO atmosphere (3 bar). The reaction mixture was filtered using a membrane filter, concentrated by evaporation, dissolved in dichloromethane, mixed with activated carbon, heated, filtered and concentrated by evaporation. The obtained solid was recrystallized from dichloromethane. 283 mg (71% of theory) of N- (isoquinolin-3-yl) -2-[(2-hydroxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide were obtained.
[296]
[297] Both are not observed or masked.
[298] MS (CI-NH3): 399 (75%, [M + H] ⁺ )
[299] Melting Point: 185 ℃
[300] Example 6.7
[301] Preparation of N- (isoquinolin-3-yl) -2-[(2-morpholinocarbonylpyridin-4-yl) -methylamino] -benzoic acid amide
[302]
[303] 40 mg N- (isoquinolin-3-yl) -2-[(2-hydroxycarbonylpyridin-4-yl) -methylamino] -benzoic acid amide (0.1 mmol) and 9 in 1 ml of dimethylformamide. A mixture of μl (0.1 mmol) of morpholine was mixed in portions with 34 mg (0.2 mmol) of carbonyldiimidazole. After stirring for 4 h at 22 ° C., it is concentrated by evaporation, the residue is dissolved in 5 ml of dichloromethane, washed with 1 mol of aqueous potassium carbonate solution (2 ml), dried (MgSO ₄ ), Filtered and concentrated by evaporation. Colorless resin (38 mg, 81% of theory).
[304]
[305] Example 6.8
[306] Preparation of N- (isoquinolin-3-yl) -2- [3-trimethylsilylethynylpyridin-4-yl) -methylamino] -benzoic acid amide
[307]
[308] 108 mg (0.25 mmol) of N- (isoquinolin-3-yl) -2- [3-bromopyridin-4-yl) -methylamino] -benzoic acid amide in 1 ml of dimethylformamide Mix with ethylamine, 5 mg (0.026 mmol) copper-1-iodide, 9 mg (0.008 mmol) palladium tetrakis triphenylphosphine and 0.07 ml trimethylsilylacetylene, 3.5 hours under argon and in a humid environment Heated to a bath temperature of 70 ° C. It was then mixed with 40 ml of water and extracted three times with 25 ml of ethyl acetate each. The ethyl acetate phase was washed with water, dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using ethyl acetate: hexane = 1: 1 as eluent. 38 mg (33.6% of theory) of N- (isoquinolin-3-yl) -2- [3-trimethylsilyl-ethynylpyridin-4-yl) -methylamino] -benzoic acid amide were obtained as an amorphous solid.
[309]
[310] Example 6.9
[311] Preparation of N- (isoquinolin-3-yl) -2- [2-trimethylsilylethynylpyridin-4-yl) -methylamino] -benzoic acid amide
[312]
[313] In addition, N- (isoquinolin-3-yl) -2- [2-trimethylsilylethynylpyridin-4-yl) -methylamino] -benzoic acid amide was prepared in a similar manner as in Example 9.
[314] Preparation of Starting and Intermediate Compounds
[315] If the preparation of the intermediate compound is not described, it can be prepared similarly to known compounds or methods known or described herein.
[316] Example A
[317] Process step 1
[318] A-1) Preparation of 2-bromopyridine-5-carbaldehyde
[319]
[320] 2-bromopyridine-5-carbaldehyde is described in F. J. Romero-Salguerra et al. THL 40, 859 (1999).
[321] A-2) Preparation of 2-bromo-isonicotinic acid
[322]
[323] 160 g (0.93 mol) of 2-bromo-4-methyl-pyridine was added dropwise to 152 g (0.96 mol) of potassium permanganate in 4 l of water. Then, before adding 152 g (0.96 mol) of potassium permanganate once more, it was stirred under reflux for 1 hour. After stirring for 2 h under reflux, it was aspirated with Celite at high temperature and washed with water. The aqueous phase was shaken three times with dichloromethane. The aqueous phase was concentrated by evaporation to half the original volume and the pH was fixed at 2 with concentrated hydrochloric acid. The precipitated solid was aspirated and dried in vacuo at 70 ° C. 56.5 g (28% of theory) of 2-bromo-isonicotinic acid accumulate as a white solid product.
[324] A-3) Preparation of 2-bromo-4-hydroxymethyl-pyridine
[325]
[326] 30.2 ml (295 mmol) triethylamine were added to 56.5 g (280 mmol) 2-bromo-isonicotinic acid in 1.2 l tetrahydrofuran (THF). It was then cooled to −10 ° C. and mixed dropwise with 38.2 ml (295 mmol) isobutyl formate. After 1 hour at −10 ° C., stirring was continued and it was cooled to −70 ° C. and mixed dropwise with 590 ml (590 mmol) of lithium aluminum hydride (LiAlH ₄ ) solution (1 M in THF). Stirring was continued at 70 ° C. for 1 hour before reaching −40 ° C. 600 ml of 50% acetic acid was added. It was stirred overnight at room temperature. Insoluble components were aspirated and the filtrate was concentrated by evaporation. The residue was purified on silica gel using hexane and hexane / ethyl acetate 1: 1. 28.0 g (55% of theory) of 2-bromo-4-hydroxymethyl-pyridine accumulate as a white solid oil.
[327] A-4) Preparation of 2-bromo-4-formyl-pyridine
[328]
[329] Within 6 hours, 149 g (1714 mmol) of manganese dioxide were added in measurable amounts to 28.0 g (148.9 mmol) 2-bromo-4-hydroxymethyl-pyridine in 500 ml of dichloromethane. Then it was stirred for at least 48 hours at room temperature. It was aspirated over Celite and concentrated by evaporation. 16.4 g (60% of theory) of 2-bromo-4-formyl-pyridine accumulate as a solidified white oil.
[330] Process step 2
[331] A-5) Preparation of 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide
[332]
[333] 3.46 g (13.17 mmol) of 2-amino- N -isoquinolin-3-yl-benzamide were introduced into 50 ml of methanol, 1.5 ml of glacial acetic acid and 2.45 g (13.17 mmol) of 2-bromopyridine-5 Mix with carbaldehyde and stir for 24 hours at room temperature under argon and in a humid environment. It was then mixed with 828 mg (13.17 mmol) sodium cyanoborohydride and stirred for a further 24 hours at room temperature. After concentration by evaporation under vacuum, the residue was taken up in dilute sodium bicarbonate solution and aspirated. The residue obtained was absorbed precipitated in some ethyl acetate and aspirated again. In this case, the obtained residue was chromatographed on silica gel using hexane: ethyl acetate = 1: 1 as eluent. 3.27 g (57% of theory) of 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N -isoquinolin-3-yl-benzamide were obtained.
[334] A-6) Preparation of N- (isoquinolin-3-yl) -2- [3-bromopyridin-4-yl-methylamino] -benzoic acid amide
[335]
[336] 263 mg (1 mmol) of N- (isoquinolin-3-yl) -2-aminobenzoic acid amide were added in 6 ml of MeOH in 0.06 ml of glacial acetic acid, 298 mg (1.6 mmol) of 3-bromo-pyridine-4- It was continuously mixed with carbaldehyde (prepared according to Tetrahedron 2000, 347) and stirred at room temperature for 24 hours. Then 100 mg (1.6 mmol) of sodium cyanoborohydride were added and stirred for a further 24 hours. It was then mixed with 50 ml of dilute sodium bicarbonate solution and the precipitated product was aspirated. The residue was chromatographed on silica gel using methylene chloride: ethanol = 95: 5 as eluent. N- (isoquinolin-3-yl) -2- [3-bromopyridin-4-yl-methylamino] -benzoic acid amide was obtained as a resin. The 3-bromo-pyridine-4-carbaldehyde used is described in Chem. Pharm. Bull. 1970, 38 , 2446.
[337] Similarly the following compounds were prepared:
[338] A-7) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide
[339]
[340]
[341] A-8) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H-indol-6-yl) -benzamide
[342]
[343] A-9) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H-indol-5-yl) -benzamide
[344]
[345] A-10) 2-[(6-Bromo-pyridin-3-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H-indol-6-yl) -benzamide
[346]
[347] A-11) 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H-indol 5-yl) -benzamide
[348]
[349] A-12) 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide
[350]
[351] A-13) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide
[352]
[353] A-14a) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide
[354]
[355] A-14b) 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N- (7-methoxy-3-methylquinolin-2-yl) -benzamide
[356]
[357] Process step 3
[358] A-15) Preparation of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[359]
[360] In 75 ml of dimethylformamide, 2.2 ml of 3.27 g (7.55 mmol) of 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N -isoquinolin-3-yl-benzamide Triethylamine, 36 ml of water, 362 mg (0.65 mmol) of bisdiphenylphosphinoferrocene and 75 mg (0.33 mmol) of palladium (II) acetate, mixed under carbon monoxide, at a pressure of 3 bar and at 50 ° C. At the temperature of, it was shaken in the autoclave for 3 hours. After cooling, it was aspirated over diatomaceous earth and concentrated by evaporation. The residue was taken up in water, the pH was fixed at 5-6 with glacial acetic acid, aspirated and the filter cake was washed again with hexane. 3.35 g of 5-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid were obtained, which were reacted further without further purification.
[361] Similarly the following compounds were prepared:
[362] A-16) 4-{[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[363]
[364] A-17) 4-{[2- (2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[365]
[366] A-18) 5-{[2- (2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -phenylamino]
[367] -Methyl} -pyridine-2-carboxylic acid
[368]
[369] A-19) 4-{[2- (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[370]
[371] A-20) 5-{[2- (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[372]
[373] A-21) 5-{[2- (7-methoxy-2-oxo-2H-chromen-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[374]
[375] A-22) 4-{[2- (7-methoxy-2-oxo-2H-chromen-3-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[376]
[377] A-23) 4-{[2- (7-methoxy-3-methyl-quinolin-2--2-ylcarbamoyl) phenylamino] -methyl} -pyridine-2-carboxylic acid
[378]
[379] A-24) 5-{[2- (7-methoxy-3-methyl-quinolin-2-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[380]
[381] A-25) 5-{[2- (1-methyl-1H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[382]
[383] A-26) 4-{[2- (1-methyl-1H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[384]
[385] A-27) 4-{[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[386]
[387] A-28) 5-{[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[388]
[389] A-29) 4-{[2- (3-trifluoromethyl-phenylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[390]
[391] Melting point 151 ℃
[392] A-30) 4-{[2- (1H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[393]
[394] A-31) 4-{[2- (1H-indazol-5-ylcarbamoyl) -phenylamino] -methyl} -pyridine-2-carboxylic acid
[395]
[396] Example B
[397] Process step 1
[398] B-1) Preparation of 5-nitro-1,3-dihydro-indol-2-one
[399]
[400] 5-nitro-1,3-dihydro-indol-2-one is described in R. t. Courts, J. ORg. Chem. 48, 3747, (1970).
[401] B-2) Preparation of dinitrophenylacetic acid methyl ester
[402]
[403] 22.6 g (100 mmol) of 2,4-dinitrophenylacetic acid are dissolved in a mixture of 200 ml of methanol and 830 ml of toluene and 83 ml of trimethylsilyldiazomethane (2 mol in toluene; 166 mmol) at room temperature Mixed with and stirred at room temperature for 3 hours. After evaporating to dryness and drying in vacuo at 70 ° C., 24 g (100% of theory) of 2,4-dinitrophenylacetic acid methyl ester were obtained.
[404] B-3) Preparation of 6-nitro-1,3-dihydro-indol-2-one
[405]
[406] At room temperature for 1.5 hours under 20 bar of hydrogen, 20 g (83 mmol) of 2,4-dinitrophenylacetic acid methyl ester was hydrogenated to 2.1 g of palladium / carbon (10%) in 400 ml of glacial acetic acid. The catalyst was filtered off, then concentrated by evaporation and dried very rapidly over solid potassium hydroxide in vacuo. The residue was chromatographed on silica gel using a gradient consisting of methylene chloride: ethanol = 97.5: 2.5 to 90:10 as eluent. After recrystallization from ethyl acetate, 4 g (30% of theory) of 6-nitro-1,3-dihydro-indol-2-one were obtained (melting point 206 ° C.).
[407] Process step 2
[408] B-4) Preparation of 5-amino-1,3-dihydro-indol-2-one
[409]
[410] At room temperature and atmospheric pressure, for 1 hour, 356 mg of 5-nitro-1,3-dihydro-indol-2-one are converted to 400 mg of palladium on carbon in 30 ml of tetrahydrofuran: ethanol = 1: 1 ( 10%). The catalyst was aspirated on diatomaceous earth and concentrated by evaporation to yield 320 mg (100% of theory) of 5-amino-1,3-dihydro-indol-2-one.
[411] B-5) Preparation of 6-amino-1,3-dihydro-indol-2-one
[412]
[413] 6-amino-1,3-dihydro-indol-2-one was similarly prepared from the corresponding nitro compound.
[414] Process step 3
[415] B-6) 2-nitro-N- (2-oxo-2,3-dihydro-1 H-indol-5-yl) -benzamide
[416]
[417] 320 mg of 5-amino-1,3-dihydro-indol-2-one were dissolved in 1 ml of dimethylacetamide and mixed dropwise with 371 mg (2 mmol) of 2-nitrobenzoyl chloride, where Some heating occurred. After stirring at room temperature overnight, it was concentrated by evaporation in vacuo and the residue was taken up in ethyl acetate and water. The insoluble solids were aspirated to give 130 mg (21.9% of theory) of 2-nitro- N- (2-oxo-2,3-dihydro-1 H -indol-5-yl) -benzamide. After shaking, the organic phase is washed, filtered, concentrated by evaporation and 400 mg (67% of theory) of 2-nitro- N- (2-oxo-2,3-dihydro-1 H -indole-5 -Yl) -benzamide was obtained again (melting point 265 ° C.).
[418] B-7) Preparation of 2-nitro-N- (2-oxo-2,3-dihydro-1 H-indol-6-yl) -benzamide
[419]
[420] 2-nitro- N- (2-oxo-2,3-dihydro-1 H -indol-6-yl) -benzamide was prepared analogously to I) (melting point> 300 ° C.).
[421] Process step 4
[422] B-8) Preparation of 2-Amino-N- (indol-2-one-5-yl) -benzoic acidamide
[423]
[424] In addition, 2-amino-N- (indol-2-one-5-yl) benzoic acid amide was prepared in a similar manner to process step 2 (melting point 219 ° C.).
[425] B-9) Preparation of 2-amino-N- (indol-2-one-6-yl) benzoic acid amide
[426]
[427] In addition, 2-amino-N- (indol-2-one-6-yl) benzoic acid amide was prepared in a similar manner to step 2 (melting point 230 ° C.).
[428] Example C
[429] C-1) Preparation of 2-Amino-N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide
[430]
[431] Process step 1
[432] C-2) Preparation of 3-nitro-7-methoxy-chromen-2-one
[433]
[434] 13 g (85.4 mmol) of 2-hydroxy-4-methoxybenzaldehyde together with 9.8 g (102.5 mmol) of n-propylamine hydrochloride and 11.5 ml (102.5 mmol) of nitroacetic acid ethyl ester in 300 ml of toluene Heated in water separator for 15 hours. Then 3 ml of nitroacetic acid ethyl ester were added again and boiled for an additional 5 hours in a water separator. After cooling, it was diluted with ethyl acetate and shaken with water. The ethyl acetate phase was dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using methylene chloride as eluent. 6.14 g (33% of theory) of 3-nitro-7-methoxy-chromen-2-one were obtained.
[435] Process step 2
[436] C-3) Preparation of 3-amino-7-methoxy-chromen-2-one
[437]
[438] In a similar manner to process step 2 of Example B, 3-amino-7-methoxy-chromen-2-one was prepared from 3-nitro-7-methoxy-chromen-2-one in ethanol.
[439] Process step 3
[440] C-4) Preparation of 2-nitro-N- (7-methoxybenzopyran-2-one-3-yl) benzoic acid amide
[441]
[442] In a similar manner to Process Step 3 from Example B, 2-nitro-N- (7-methoxybenzopyran-2-one-3-yl) benzoic acid amide was converted to 2-nitrobenzoyl chloride and 3-amino-7- Prepared from methoxy-chromen-2-one and 2-nitro- N- (7-methoxy-2-oxo-2 H -chromen-3-yl) -benzamide.
[443] Process step 4
[444] C-5) Preparation of 2-amino-N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide
[445]
[446] In a similar manner to Process Step 2 from Example B, 2-amino- N- (7-methoxy-2-oxo- 2H -chromen-3-yl) -benzamide was added to ethanol: tetrahydrofuran = 5 Prepared from 2-nitro- N- (7-methoxy-2-oxo- 2H -chromen-3-yl) -benzamide in: 2.
[447] Example D
[448] D-1) of 2-[(6-cyano-pyridin-3-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H-indol-5-yl) -benzamide Produce
[449]
[450] 59 mg (0.5 mmol) zinc (II) cyanide, 12 mg (0.013 mmol) tris (dibenzylidene acetone) -dipalladium, 10 mg (0.018 mmol) bis (diphenylphosphino) ferrocene and 4 mg with zinc powder (0.06 mmol), 219 mg (0.5 mmol) of 2 - [(6-bromo-pyridin-3-ylmethyl) amino] - N - (2- oxo-2,3-dihydro -1 H -indol-5-yl) -benzamide was added to 7 ml of dimethyl acetamide and stirred at a bath temperature of 150 ° C. for 7.5 hours under argon and in a humid environment. After cooling, it was diluted with water, shaken with ethyl acetate, the organic phase was dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using a gradient of methylene chloride: ethanol = 97.5: 2.5 to 90:10 as eluent. 65 mg of 2 (30% of theory) of [(6-cyano-pyridin-3-ylmethyl) -amino] - N - (2- oxo-2,3-dihydro -1 H-indol-5- I) -benzamide was obtained.
[451] Similarly the following compounds were prepared:
[452] D-2) 2-[(6-cyano-pyridin-3-ylmethyl) -amino] -N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide
[453]
[454] Example E
[455] Process step 1
[456] E-1) Preparation of 2-chloro-nicotinic acid methyl ester
[457]
[458] 5.6 g of 2-chloro-nicotinic acid is dissolved in 280 ml of toluene and 80 ml of methanol, mixed with 37.4 ml (74.8 mmol) trimethylsilyldiazomethane (2 mol in hexane) and stirred at room temperature for 3 hours. It was. After the batch was concentrated by evaporation, 7 g (100% of theory) of 2-chloro-nicotinic acid methyl ester were obtained.
[459] Process step 2
[460] E-2) Preparation of 2-[(pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester
[461]
[462] 4.0 g (23.3 mmol) of 2-chloro-nicotinic acid methyl ester were heated with a bath temperature of 100 ° C. for 1.5 h with 2.52 g (23.3 mmol) of 4-aminomethylpyridine. After cooling, it was diluted with 100 ml of dilute sodium bicarbonate solution and shaken three times with 50 ml of ethyl acetate each. The combined organic phases were washed, dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using methylene chloride: ethanol = 10: 1 as eluent. 1.36 g (24% of theory) of 2-[(pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester were obtained.
[463] Similarly the following compounds were prepared:
[464] E-3) 2-[(pyridin-3-ylmethyl) -amino] -nicotinic acid methyl ester
[465]
[466] Process step 3
[467] E-4) Preparation of 2-[(1-oxy-pyridin-4-ylmethyl) -amino] -nicotinic acid-methyl ester
[468]
[469] 2.09 g (8.59 mmol) of 2-[(pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester was mixed with 2.21 g (9.88 mmol) of m-chloroperbenzoic acid in 150 ml of methylene chloride and 24 hours Stirred at room temperature. It was mixed with 50 ml of dilute sodium bicarbonate solution, shaken, the organic phase was separated and extracted three times with 50 ml of methylene chloride each. The combined organic phases were washed, dried, filtered and concentrated by evaporation. 2.7 g (100% of theory) of 2-[(1-oxy-pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester were obtained as oil.
[470] Similarly the following compounds were prepared:
[471] E-5) 2-[(1-oxy-pyridin-3-ylmethyl) -amino] -nicotinic acid methyl ester
[472]
[473] Process step 4
[474] E-6) Preparation of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester
[475]
[476] 2.7 g (10.4 mmol) 2-[(1-oxy-pyridin-4-ylmethyl) -amino]-with 3.15 g (31.2 mmol) triethylamine and 9.19 g (62.4 mmol) trimethylsilyl cyanide Nicotinic acid methyl ester was heated in a pressurized vessel in 52 ml of dimethylformamide to a bath temperature of 110 ° C. for 8 hours. After concentration in vacuo, the residue was taken up in 100 ml of dilute sodium bicarbonate solution and extracted three times with 100 ml of ethyl acetate each. The combined organic phases were washed, dried, filtered and concentrated by evaporation. The residue was chromatographed on a flash column (50 g; isolute flash silica; Separtis Company) with a gradient of methylene chloride: ethanol = 100: 0 to 95: 5 as eluent. 1.31 g (47% of theory) of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester were obtained.
[477] Similarly the following compounds were prepared:
[478] E-7) Preparation of 2-[(6-cyano-pyridin-3-ylmethyl) -amino] -nicotinic acid methyl ester
[479]
[480] In preparation, a small amount of 2-[(2-cyano-pyridin-3-ylmethyl) -amino] -nicotinic acid methyl ester accumulates simultaneously.
[481]
[482] Process step 5
[483] E-8) Preparation of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -N-isoquinolin-3-yl-nicotinamide
[484]
[485] In 10 ml of toluene, 277 mg (1.92 mmol) of 3-aminoisoquinoline and 0.86 ml of trimethylaluminum (2 mol solution in toluene) were stirred at 4 ° C. for 30 minutes under argon and in a humid environment. 468 mg (1.74 mmol) of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -nicotinic acid methyl ester were then added and refluxed for 2 hours. It was mixed with 30 ml of dilute sodium bicarbonate solution and shaken three times with 30 ml of ethyl acetate each. The combined organic phases were washed, dried, filtered and concentrated by evaporation. The residue was chromatographed on a flash column (20 g; isolute flash silica; Separtis Company) using a gradient of methylene chloride: ethanol = 100: 0 to 95: 5 as eluent. 400 mg (60% of theory) of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -N -isoquinolin-3-yl-nicotinamide were obtained.
[486] E-9) N- (isoquinolin-3-yl) -2- [2-cyanopyridin-4-yl-methylamino] -benzoic acid amide
[487]
[488] 920 mg (2.5 mmol) N- (isoquinolin-3-yl) -2- (4-pyridylmethyl) -aminobenzoic acid amide-N-oxide in 20 ml of dimethylformamide, 760 mg in a glass pressurized container (7.5 mmol) triethylamine and 1.24 g (12.5 mmol) trimethylsilylcyanide were mixed successively and then heated to a bath temperature of 110 ° C. for 10 hours. It was then diluted with water to about 200 ml and shaken three times with 50 ml of ethyl acetate each. The collected organic phases were washed with 50 ml of water, dried, filtered and concentrated by evaporation. The residue was first chromatographed on silica gel using ethyl acetate: hexane = 1: 1 and then chromatographed on silica gel again using dichloromethane: ethanol = 100: 2 as eluent. 132 mg (14% of theory) of N- (isoquinolin-3-yl) -2- (4-2-cyanopyridylmethyl) amino-benzoic acid amide were obtained as resin.
[489] If the preparation of the intermediate compound is not described, it can be prepared similarly to known compounds or methods known or described herein.
[490] Similarly the following compounds were prepared:
[491] E-10) 2-[(2-cyano-pyridin-3-ylmethyl) -amino] -N-isoquinolin-3-yl-nicotinamide
[492]
[493] E-11) 2-[(6-cyano-pyridin-3-ylmethyl) -amino] -N-isoquinolin-3-yl-nicotinamide
[494]
[495] Example F
[496] 1. Process Steps
[497] F-1) Preparation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid-methyl ester
[498]
[499] 6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml of methanol was mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of 2-bromopyridine-4-carbaldehyde and stirred at 40 ° C. overnight. . 3.8 g (60 mmol) of sodium cyanoborohydride were added thereto and stirred at 40 ° C. overnight. 3.8 g (60 mmol) of sodium cyanoborohydride were added again and stirred at 40 ° C. over the weekend. It was mixed with water and usually concentrated by evaporation. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel using a gradient consisting of hexane and hexane / ethyl acetate 1: 3 and hexane / ethyl acetate 1: 1 as eluent. 10.0 g (78% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester were obtained as a colorless oil.
[500] 2. Process Steps
[501] F-2) Preparation of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester
[502]
[503] 0.532 g (4.56 mmol) zinc cyanide (II) in 1.28 g (4.0 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester in 140 ml of dimethylacetamide , 0.072 g (0.08 mmol) tris- (dibenzylideneacetone) -dipalladium, 0.088 g (0.16 mmol) bis- (diphenylphosphino) -ferrocene and 0.029 g (0.46 mmol) zinc powder . It was stirred at 150 ° C. for 6 hours. After cooling, the reaction mixture was poured into water. It was extracted three times with ethyl acetate; The combined organic phases were dried over sodium sulphate and concentrated by evaporation. The reaction product was chromatographed on silica gel using a gradient consisting of hexane: ethyl acetate = 100: 0 to 50:50 as eluent. 0.887 g (83% of theory) of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester were obtained in the form of a yellow solid.
[504] 3. process steps
[505] F-3) 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -N- (7-methoxy-3-methyl-quinolin-2-yl) -benzamide
[506]
[507] At 0 ° C., 0.25 ml trimethylaluminum (2M in toluene) was added dropwise to 0.094 g (0.5 mmol) of 7-methoxy-3-methyl-quinolin-2-ylamine in 4 ml of toluene. After 10 min of continuous stirring at 0 ° C., 0.133 g (0.5 mmol) of 2-[(2-cyano-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester in 2 ml of toluene was added dropwise. . Then it was refluxed for 2 hours and stirred overnight at room temperature. The precipitate was aspirated and suspended in saturated sodium bicarbonate solution. Then ethylenediaminetetraacetic acid was added. It was shaken with ethyl acetate, dried over sodium sulfate and concentrated by evaporation. Purified by column chromatography on silica gel using a hexane: acetone = 100: 0 to 50:50 gradient as eluent to yield 0.113 g (54% of theory) of 2-[(2-cyano-pyridin-4-ylmethyl ) - amino] - N - (7- methoxy-3-methyl-quinolin-2-yl) benzamide was obtained as a yellow foam.
[508] Example G
[509] 1. Process Steps
[510] G-1) Preparation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid
[511]
[512] 10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester was dissolved in 290 ml of ethanol and mixed with 31.2 ml of 2 M sodium hydroxide solution. . After stirring at room temperature overnight, ethanol was removed and the aqueous phase was shaken with ethyl acetate. The aqueous phase was acidified with concentrated hydrochloric acid. The precipitate formed was aspirated and dried. 5.93 g (62%) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid accumulates in the form of a white solid.
[513] 2. Process Steps
[514] G-2) Preparation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide
[515]
[516] 0.500 g (1.6 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid in 25 ml of dimethylformamide, 0.471 g (3.2 mmol) of 2-methyl-2 H- Indazol-6-ylamine, 0.4 ml (3.68 mmol) N-methylmorpholine and 0.729 g (1.92 mmol) O- (7-azabenzotriazol-1-yl) -1,1,3,3 Tetramethyluronium hexafluorophosphate (HATU) was stirred for 16 hours at room temperature. Dimethylformamide was removed in an oil pump vacuum. The remaining residue was taken up in saturated sodium bicarbonate solution. It was extracted three times with ethyl acetate and the combined organic phases were dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using a gradient consisting of hexane: acetone = 100: 0 to 50:50 as eluent. Benzamide - 0.669 g of 2 (96% of theory) of [(2-bromo-pyridin-4-ylmethyl) -amino] - N- (2-methyl -2 H-indazol-6-yl) Obtained in the form of a beige foam.
[517] Similarly the following compounds were prepared:
[518] G-3) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-1 H-indazol-6-yl) -benzamide
[519]
[520] G-4) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1H-indazol-6-yl) -benzamide
[521]
[522] G-5) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1H-indazol-5-yl) -benzamide
[523]
[524] G-6) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H indol-6-yl) -benzamide
[525]
[526] G-7) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-oxo-2,3-dihydro-1 H indol-5-yl) -benzamide
[527]
[528] H-1) 4- (tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid
[529] Chem. Eur. J. 2, 2000 , 216, 4- ( tert -butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid is selected from (2-cyano-pyridin-4-ylmethyl) -carbamic acid- Prepared from tert -butyl ester.
[530] H-2) [2- (2-hydroxy-propylcarbamoyl) -pyridin-4-ylmethyl] -carbamic acid-tert-butyl ester of optical activity
[531] According to the method provided in Example 2.0, an optically active [2- (2-hydroxy-propylcarbamoyl) -pyridin-4-ylmethyl] -carbamic acid- tert -butyl ester was obtained from 4- ( tert -butoxy Prepared from carbonylamino-methyl) -pyridine-2-carboxylic acid and S-(+)-1-amino-2-propanol to yield 91% yield.
[532] H-3) 4-Aminomethyl-pyridine-2-carboxylic acid (2-hydroxy-propyl) -amide of optical activity
[533]
[534] 480 mg (1.7 mmol) of [2- (2-hydroxy-propylcarbamoyl) -pyridin-4-ylmethyl] -carbamic acid- tert -butyl ester are mixed with 17 ml of 1N hydrochloric acid in 30 ml of ethanol And heated to a bath temperature of 110 ° C. for 3 hours with nitrogen passing through it. The batch was concentrated by evaporation in vacuo, dried and used in Example 5.0 without further purification.
[535] H-4) 2-Chloro-N-isoquinolin-3-yl-nicotinamide
[536]
[537] 2.9 g (20 mmol) of 3-aminoisoquinoline are suspended in 45 ml of tetrahydrofuran, and one drop with a solution of 3.5 g (20 mmol) of 2-chloro-nicotinoyl chloride in 45 ml of tetrahydrofuran. Mix gently. After stirring overnight at room temperature, the batch was aspirated and the residue was rewashed with tetrahydrofuran. The residue was suspended, aspirated again and dried. 3.14 g (55% of theory) of 2-chloro- N -isoquinolin-3-yl-nicotinamide were obtained.
[538] The following sample application illustrates the biological action and use of the compounds according to the invention without limiting these examples.
[539] Required solution for the test
[540] Storage solution
[541] Stock solution A: 3 mmol of ATP in water, pH 7.0 (-70 ° C.)
[542] Stock solution B: g-33 P-ATP 1 mCi / 100 μl
[543] Stock Solution C: Poly- (Glu4 Tyr) in 10 mg / ml water
[544] Diluted solution
[545] Substrate solvent: 10 mmol of DTT, 10 mmol of manganese chloride, 100 mmol
[546] Magnesium chloride
[547] Enzyme solution: 120 mmol Tris / HCl, pH 7.5, 10 μM sodium vanadium oxide
[548] Sample application 1
[549] Inhibition of KDR- and FLT-1 kinase activity in the presence of a compound according to the invention
[550] In a pointed microtiter plate (no protein binding), 10 μl of substrate mixture (10 μl volume of ATP stock solution A + 25 μCi g-33P-ATP (about 2.5 μl stock solution B) + 30 μl of poly- (Glu4Tyr) stock solution C + 1.21 ml of substrate solvent), 10 μl of inhibitor solution (material corresponding to diluent, 3% DMSO in substrate solvent as control) and 10 ml of enzyme solution (11.25 μg Enzyme storage solution (KDR or FLT-1 kinase) was added in 1.25 ml of enzyme solution (dilution) at 4 ° C. It was thoroughly mixed and incubated for 10 minutes at room temperature, then 10 μl of stop ) Solution (250 mmol EDTA, pH 7.0) was added, mixed and 10 μl of the solution was transferred to a P 81 phosphocellulose filter, which was then washed several times in 0.1 M phosphoric acid. , Meltilex coated, microbeta counter (microb) eta counter).
[551] IC50 values needed to inhibit phosphate incorporation up to 50% of uninhibited incorporation after removal of the blank read (EDTA-stopped response) were determined from inhibitor concentrations.
[552] The results of kinase inhibition IC50 in nM units are shown in the table below:
[553] Example numberVEGFR II (KDR) [nM]1.3240
[554] Sample application 2
[555] Cytochrome P450 Inhibition
[556] Publications: Crespi et al. (Anal. Biochem., 248, 188-190 (1997)), cytochrome P450 inhibition was induced by baculovirus / insect cell-expression, human cytochrome P 450 isoenzyme (1A2, 2C9, 2C19, 3A4). Was carried out.
[557] The results are shown in the table below.
[558] Inhibition of cytochrome P450 isozyme (IC50, μM)
[559] Cytochrome P450 Homozyme1A22C92C193A4 Example 2.54 of WO 00/278195.20.20.053.6 Example 1.32302.94.925
[560] It is clear from the above results that the excellent action of the compounds according to the invention over the known compounds is clear, i.e., the compounds according to the invention significantly inhibit the detoxification of the P450 system in comparison to the known compounds, which means that other active ingredients Significantly less interaction with.

权利要求:
Claims (12)
[1" claim-type="Currently amended] Compounds of formula (I), and isomers, enantiomers and salts thereof.
<Formula I>

In the above formula,
A, B and D represent nitrogen or carbon atoms independently of one another such that at least one nitrogen atom is included in the ring,
E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently ⁴ , -SOR ⁴ or aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN, -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
G represents a nitrogen atom or a group -C-X,
L represents a nitrogen atom or a group -C-X,
M represents a nitrogen atom or a group -C-X,
Q represents a nitrogen atom or the group -C-X, where at most one nitrogen atom is present in the ring,
X represents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyloxy or C ₁ -C ₆ -carboxyalkyl which is hydrogen, halogen or unsubstituted or optionally substituted at least one position by halogen,
R ¹ is optionally at least one position in the same way or differently with halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl and / or groups -NR ² R ³ Branched or unbranched C ₁ -C ₁₂ -alkyl or C ₂ -C ₁₂ -alkenyl substituted with; Or C ₃ -optionally substituted at least one position in the same way or differently with halogen, hydroxy, C ₁ -C ₆ -alkyloxy, C ₁ -C ₆ -alkyl and / or the group -NR ² R ³ C ₁₀ -cycloalkyl or C ₃ -C ₁₀ -cycloalkenyl; Or halogen, cyano, hydroxy, C ₁ -C ₆ -alkyloxy, C ₂ -C ₆ -alkenyl, aryl-C ₁ -C ₆ -alkyloxy, aralkyl in one or more positions in the same manner or differently Optionally with oxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or groups ═O, —SO ₂ R ⁴ , —OR ⁵ , —R ⁵ or —PO (OR ¹² ) (OR ¹³ ) Aryl or hetaryl substituted by
R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ -alkyl, or C optionally substituted with the group -NR ⁶ R ⁷ , -OR ⁵ , C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
R ² and R ³ , together with the nitrogen atom, may optionally include another nitrogen, sulfur or oxygen atom in the ring or may contain the group —N (R ¹⁰ ) and one or more positions are the same or different. ^May be optionally substituted with halogen, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or a group -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ Form a C ₃ -C ₈ -ring,
R ⁴ represents hydroxy, C ₁ -C ₆ -alkyl, aryl, heteroaryl or the group -NR ² R ³ ,
R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl or
Halo-C ₃ -C ₆ -cycloalkyl, or C ₁ -C ₁₂ -alkyl wherein one or more positions are interrupted by oxygen, or a group-(CH ₂ ) ₂ NR ² R ³ , -CH ₂ CN or- CH ₂ CF ₃ is represented,
R ⁶ and R ⁷ independently of each other represent hydrogen or C ₁ -C ₆ -alkyl, or
R ⁶ and R ⁷ together form a 5 to 7 membered ring which may include an oxygen or sulfur atom or a group -N (R ¹⁰ )-,
R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl or hetaryl optionally substituted at least one position by halogen,
R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, tri-C _1-6 -alkylsilyl, aryl, hetaryl or group —COR ¹¹ ,
R ¹⁰ represents hydrogen, C ₁ -C ₆ -alkyl or aryl,
R ¹¹ represents hydrogen, C ₁ -C ₆ -alkyl or the group —NR ² R ³ , and
R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl.
[2" claim-type="Currently amended] The method of claim 1,
A, B, and D represent nitrogen or carbon atoms independently of one another where one or more nitrogen atoms are included in the ring,
E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently ⁴ , -SOR ⁴ or aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN, -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
G represents a nitrogen atom or a group -C-X,
L represents a nitrogen atom or a group -C-X,
M represents a nitrogen atom or a group -C-X,
Q represents a nitrogen atom or the group -C-X, where at most one nitrogen atom is present in the ring,
X represents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyloxy or C ₁ -C ₆ -carboxyalkyl which is hydrogen, halogen or unsubstituted or optionally substituted at least one position by halogen,
R ¹ is at least one position in the same way or differently halogen, cyano, hydroxy, C ₁ -C ₆ -alkyloxy, C ₂ -C ₆ -alkenyl, aryl-C ₁ -C ₆ -alkyloxy, Aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or group ═O, —SO ₂ R ⁴ , —OR ⁵ , —R ⁵ or —PO (OR ¹² ) (OR ¹³ ) Aryl or hetaryl optionally substituted by
R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ - alkyl or a group ^{-NR 6 R 7, -OR 5,} C 1 -C 6 - alkyl, -OR ^5, -SR ^4, -SOR ⁴ or -SO ₂ R ^4, optionally substituted C ₁ to -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
R ² and R ³ , together with the nitrogen atom, may optionally include another nitrogen, sulfur or oxygen atom in the ring or may contain the group —N (R ¹⁰ ) and one or more positions are the same or different. ^May be optionally substituted with halogen, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or a group -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ Form a C ₃ -C ₈ ring,
R ⁴ represents hydroxy, C ₁ -C ₆ -alkyl, aryl, heteroaryl or the group -NR ² R ³ ,
R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl or
Halo-C ₃ -C ₆ -cycloalkyl, or C ₁ -C ₁₂ -alkyl wherein one or more positions are interrupted by oxygen, or a group-(CH ₂ ) ₂ NR ² R ³ , -CH ₂ CN or- CH ₂ CF ₃ is represented,
R ⁶ and R ⁷ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,
or
R ⁶ and R ⁷ together form a 5 to 7 membered ring which may include an oxygen or sulfur atom or a group -N (R ¹⁰ )-,
R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl, hetaryl optionally substituted at least one position by halogen,
R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, tri-C ₁ -C ₆ -alkylsilyl, aryl, hetaryl or group —COR ¹¹ ,
R ¹⁰ represents hydrogen, C ₁ -C ₆ -alkyl or aryl,
R ¹¹ represents hydrogen, C ₁ -C ₆ -alkyl or the group —NR ² R ³ , and
R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
Compounds of formula (I), and isomers, enantiomers and salts thereof
[3" claim-type="Currently amended] The method according to claim 1 or 2,
A, B and D represent nitrogen or carbon atoms independently of one another such that at least one nitrogen atom is included in the ring,
E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently ⁴ , -SOR ⁴ or aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN, -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
G represents a nitrogen atom or a group -C-X,
L represents a nitrogen atom or a group -C-X,
M represents a nitrogen atom or a group -C-X,
Q represents a nitrogen atom or the group -C-X, where at most one nitrogen atom is present in the ring,
X represents hydrogen or halogen,
R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or a group in one or more positions in the same way or differently Aryl or hetaryl optionally substituted with -SO ₂ R ⁴ , -OR ⁵ , -R ⁵ or -PO (OR ¹² ) (OR ¹³ ),
R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ -alkyl, or C optionally substituted with the group -NR ⁶ R ⁷ , -OR ⁵ , C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
R²And R³May optionally contain another nitrogen, sulfur or oxygen atom in the ring together with the nitrogen atom or the group —N (R¹⁰) And one or more positions in the same way or differently halogen, cyano, C_One-C₆-Alkyl, halo-C_One-C₆-Alkyl, aryl or group -OR⁵, -SR⁴, -SOR⁴Or -SO₂R⁴in C may be optionally substituted₃-C₈Forming a ring,
R ⁴ represents a hydroxy or a group -NR ² R ³ ,
R ⁵ is hydrogen, C ₁ -C ₁₂ - alkyl, with a one or more positions with oxygen interrupted C ₁ -C ₁₂ - represents an alkyl group or ^{_{- (CH 2) 2 NR 2}} R 3, -CH 2 CN or - CH ₂ CF ₃ is represented,
R ⁶ and R ⁷ independently of each other represent hydrogen or C ₁ -C ₆ -alkyl, or
R ⁶ and R ⁷ together form a 5 to 7 membered ring which may include an oxygen or sulfur atom or a group -N (R ¹⁰ )-,
R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl or hetaryl optionally substituted at least one position by halogen,
R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, tri-C _1-6 -alkylsilyl, aryl, hetaryl or group —COR ¹¹ ,
R ¹⁰ represents hydrogen, C ₁ -C ₆ -alkyl or aryl,
R ¹¹ represents hydrogen, C ₁ -C ₆ -alkyl or the group —NR ² R ³ , and
R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
Compounds of formula (I), and isomers, enantiomers and salts thereof.
[4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
A, B and D represent nitrogen or carbon atoms such that at least one nitrogen atom is included in the ring,
E is halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl or the group -OR ⁵ , -SR in one or more positions in the same way or differently Hetaryl optionally substituted with ⁴ , -SOR ⁴ or -SO ₂ R ⁴ , or a group -COOR ⁸ , -CONR ² R ³ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , -SCN , -PO (OR ¹² ) (OR ¹³ ), -CH = CH-COR ⁹ or -C≡CR ⁹ ;
G represents the group -C-X,
L represents a group -C-X,
M represents the group -C-X,
Q represents a nitrogen atom or a group -C-X,
X represents hydrogen or halogen,
R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or a group in one or more positions in the same way or differently Optionally substituted with -SO ₂ R ⁴ , -OR ⁵ , -R ⁵ or -PO (OR ¹² ) (OR ¹³ )

(Wherein T represents hydrogen, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy) substituted phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyri Midine, triazine, quinoline, or isoquinoline,
R ² and R ³ independently of one another are hydrogen, or halogen, cyano, C ₁ -C ₆ -alkyl, phenyl, hydroxy-C ₁ -C ₆ -alkyl, halo- in one or more positions in the same way or differently; C ₁ -C ₆ -alkyl, or C optionally substituted with the group -NR ⁶ R ⁷ , -OR ⁵ , C ₁ -C ₆ -alkyl-OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ ₁ -C ₆ - alkyl, C ₃ -C ₆ - cycloalkyl, C ₃ -C ₆ - cycloalkenyl, or represent aryl or H. taril, or
R ² and R ³ , together with the nitrogen atom, may optionally include another nitrogen, sulfur or oxygen atom in the ring or may contain the group —N (R ¹⁰ ) and one or more positions are the same or different. ^May be optionally substituted with halogen, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or a group -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁴ Form a C ₃ -C ₈ -ring,
R ⁴ represents a hydroxy or a group -NR ² R ³ ,
R ⁵ is hydrogen, C ₁ -C ₁₂ - alkyl, with a one or more positions with oxygen interrupted C ₁ -C ₁₂ - represents an alkyl group or ^{_{- (CH 2) 2 NR 2}} R 3, -CH 2 CN or - CH ₂ CF ₃ is represented,
R ⁶ and R ⁷ independently of each other represent hydrogen or C ₁ -C ₆ -alkyl, or
R ⁶ and R ⁷ together form a 5 to 7 membered ring which may comprise oxygen or sulfur atoms,
R ⁸ represents hydrogen or C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, benzyl, aryl or hetaryl optionally substituted at least one position by halogen, and
R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl, or tri-C ₁ -C ₆ -alkylsilyl, and
R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
Compounds of formula (I), and isomers, enantiomers and salts thereof.
[5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
A, B and D represent nitrogen or carbon atoms independently of one another such that at least one nitrogen atom is included in the ring,
E represents thienyl, pyridyl or the group -COOR ⁸ , -CONR ² R ³ , or -C≡CR ⁹ ,
G represents the group -C-X,
L represents a group -C-X,
M represents the group -C-X,
Q represents a nitrogen atom or a group -C-X,
X represents hydrogen or halogen,
R ¹ is halogen, hydroxy, C ₁ -C ₆ -alkyloxy, aralkyloxy, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl or a group in one or more positions in the same way or differently Optionally substituted with -SO ₂ R ⁴ , -OR ⁵ , -R ⁵ or -PO (OR ¹² ) (OR ¹³ )

(Wherein T represents hydrogen, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy) substituted on phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyra Sol, pyridine, pyrimidine, triazine, quinoline, or isoquinoline,
R ² and R ³ independently of one another are hydrogen, or halogen, C ₁ -C ₆ -alkyl, phenyl or group —NR ⁶ R ⁷ , —OR ⁵ or C ₁ -C ₆ in the same way or differently at one or more positions; Or C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, phenyl or pyridyl optionally substituted with -alkyl-OR ⁵ , or
R ² and R ³ , together with a nitrogen atom, may optionally include another nitrogen or oxygen atom in the ring and one or more positions may be optionally substituted in the same way or differently with C ₁ -C ₆ -alkyl Form a C ₃ -C ₈ -ring,
R ⁴ represents a hydroxy or a group -NR ² R ³ ,
R ⁵ , R ⁶ and R ⁷ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl, or
R ⁶ and R ⁷ together form a 5 to 7 membered ring which may comprise oxygen or sulfur atoms,
R ⁸ represents hydrogen, C ₁ -C ₆ -alkyl or benzyl, and
R ⁹ represents hydrogen, C ₁ -C ₆ -alkyl or tri-C ₁ -C ₆ -alkylsilyl, and
R ¹² and R ¹³ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl
Compounds of formula (I), and isomers, enantiomers and salts thereof.
[6" claim-type="Currently amended] A pharmaceutical agent comprising at least one compound of any one of claims 1 to 5.
[7" claim-type="Currently amended] The method of claim 6, further comprising psoriasis, Kaposi's sarcoma, restenosis, eg, splint-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; Arthritis such as rheumatoid arthritis, hemangioma, angiofibrosis; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy; In the case of fibrotic diseases such as liver cirrhosis, hepatic cell proliferative disease, arteriosclerosis, nerve tissue damage, after balloon catheter treatment, the use of mechanical devices for maintaining vascular prosthesis or for vascular opening, such as the use of splints A pharmaceutical agent for inhibiting postvascular reclosure and as an immunosuppressive agent, and for assisting scar healing in aging spots and contact dermatitis.
[8" claim-type="Currently amended] The pharmaceutical agent according to claim 6 for use as a VEGFR kinase 3-inhibitor for lymphangiogenesis and hyperplasia and dysplasia of the lymphatic system.
[9" claim-type="Currently amended] Contains a suitable agent and excipient A compound according to any one of claims 1 to 5 and a pharmaceutical agent according to any one of claims 6 to 8.
[10" claim-type="Currently amended] Use of a compound of formula (I) according to any one of claims 1 to 5 as an inhibitor of tyrosine kinase KDR and FLT.
[11" claim-type="Currently amended] Intestinal transdermal, parenteral and oral administration of a compound of formula (I) according to any one of claims 1 to 5 in the form of a pharmaceutical formulation.
[12" claim-type="Currently amended] Psoriasis, Kaposi's sarcoma, restenosis, for example splint-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia of the compound of formula (I) according to any one of claims 1 to 5; Arthritis such as rheumatoid arthritis, hemangioma, angiofibrosis; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephropathy, thrombotic microvascular syndrome, transplant rejection and glomerulopathy; In the case of fibrotic diseases, such as cirrhosis, hepatic cell proliferative disease, arteriosclerosis, nerve tissue damage, and after balloon catheter treatment, a mechanism for maintaining vascular prosthesis or opening of blood vessels such as splints Use for inhibiting vascular reclosure and as an immunosuppressive agent, and for assisting scar-free healing in aging spots and contact dermatitis.

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同族专利:

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公开号 | 公开日

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IL158783D0|2004-05-12|

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JP2004528379A|2004-09-16|

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EP1392680B1|2009-07-22|

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BR0209485A|2004-07-06|

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CN1518546A|2004-08-04|

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CA2453223A1|2002-11-14|

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PE20021092A1|2003-01-11|

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US20040254185A1|2004-12-16|

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WO2002090352A3|2003-05-01|

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WO2002090352A2|2002-11-14|

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DE50213703D1|2009-09-03|

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MXPA03010099A|2004-03-10|

---

NO20034957D0|2003-11-07|

---

EP1392680A2|2004-03-03|

---

PL364478A1|2004-12-13|

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:
2001-05-08|Priority to DE10123574.7

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2001-05-08|Priority to DE2001123574

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2001-05-15|Priority to DE2001125294

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2001-05-15|Priority to DE10125294.3

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2001-12-21|Priority to DE2001164590

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2001-12-21|Priority to DE10164590.2

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2002-05-03|Application filed by 쉐링 악티엔게젤샤프트

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2002-05-03|Priority to PCT/EP2002/004924

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2003-12-11|Publication of KR20030094395A

优先权:

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申请号 | 申请日 | 专利标题

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DE10123574.7|2001-05-08|

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DE2001123574|DE10123574A1|2001-05-08|2001-05-08|New heterocyclylmethyl-substituted anthranilamide derivatives and analogs as KDR/FLT tyrosine kinase inhibitors, used for treating e.g. psoriasis, restenosis, leukemia, arthritis, eye or kidney disease or arteriosclerosis|

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DE2001125294|DE10125294A1|2001-05-15|2001-05-15|New heterocyclylmethyl-substituted anthranilamide derivatives and analogs as KDR/FLT tyrosine kinase inhibitors, used for treating e.g. psoriasis, restenosis, leukemia, arthritis, eye or kidney disease or arteriosclerosis|

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DE10125294.3|2001-05-15|

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DE10164590.2|2001-12-21|

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DE2001164590|DE10164590A1|2001-12-21|2001-12-21|New heterocyclylmethyl-substituted anthranilamide derivatives and analogs as KDR/FLT tyrosine kinase inhibitors, used for treating e.g. psoriasis, restenosis, leukemia, arthritis, eye or kidney disease or arteriosclerosis|

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PCT/EP2002/004924|WO2002090352A2|2001-05-08|2002-05-03|Selective anthranilamide pyridine amides as inhibitors of vegfr-2 and vegfr-3|