RU2002111414A - Substituted pyridines and pyridazines with the ability to inhibit angiogenesis - Google Patents

Claims (16)

1. The compound having the General structural formula

where R ¹ and R ² together form a bridge containing two T ² fragments and one T ³ fragment, said bridge together with the cycle to which it is attached forms a bicyclic structure

where each T ² independently means N, CH or CG ¹ ; T ³ means S, O, CR ⁴ G ¹ , C (R ⁴ ) ₂ or NR ³ ; G ¹ is a substituent independently selected from the group consisting of —N (R ⁶ ) ₂ , —NR ³ COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino substituted alkyl; N- (lower alkyl) amino substituted alkyl; N, N-di- (lower alkyl) amino substituted alkyl; N- (lower alkanoyl) amino substituted alkyl; hydroxy substituted alkyl; cyano substituted alkyl; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; phenyl lower alkoxycarbonyl substituted alkyl; halogen-substituted alkylamino; amino substituted alkylamino; N- (lower alkyl) amino substituted alkylamino; N, N-di- (lower alkyl) amino-substituted alkylamino; N- (lower alkanoyl) amino substituted alkylamino; hydroxy substituted alkylamino; cyano-substituted alkylamino; carboxy substituted alkylamino; lower alkoxycarbonyl substituted alkylamino; phenyl lower alkoxycarbonyl substituted alkylamino group; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; halogenated lower alkoxyl; halogenated lower alkylthioyl; halogenated lower alkylsulfonyl; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CON (R ⁶ ) ₂ ; - -CH ₂ OR ³ ; -NO ₂ ; -CN; amidine; guanidine; sulfo group; -B (OH) ₂ ; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; optionally substituted saturated heterocycloalkyl; an optionally substituted partially unsaturated heterocyclic moiety; optionally substituted partially unsaturated heterocycloalkyl; -OCO ₂ R ³ ; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -CHO; -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; and —NR ³ CON (R ⁶ ) ₂ ; R ³ means H or lower alkyl; R ^{6 is} independently selected from the group consisting of H; alkyl; cycloapkyl; optionally substituted aryl; and optionally substituted aryl lower alkyl; lower alkyl-N (R ³ ) ₂ ; and lower alkyl-OH; R ⁴ means H, halogen or lower alkyl; p is 0, 1 or 2; X is selected from the group consisting of O, S, and NR ³ ; Y is selected from the group consisting of lower alkylene; -CH ₂ -O-; -CH ₂ -S-; -CH ₂ -NH-; -ABOUT-; -S-; -NH-; - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _n -S (O) _p - (5 membered heteroaryl) - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _s -; - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _n -C (G ² ) (R ⁴ ) - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _s -; n and s are independently 0 or an integer of 1-2; G ² selected from the group including —CN, —CO ₂ R ³ ; —CON (R ⁶ ) ₂ and —CH ₂ N (R ⁶ ) ₂ ; -O-CH ₂ -; -S (O) -; -S (O) ₂ -; -SCH ₂ -; -S (O) CH ₂ -; -S (O) ₂ CH ₂ -; -CH ₂ S (O) -; and —CH ₂ S (O) ₂ -; Z is N or CR ⁴ ; Q = 0.1 or 2; G ³ means a monovalent or divalent moiety selected from the group consisting of: lower alkyl; -NR ³ COR6; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CH ₂ OR ³ ; -CON (R ⁶ ) ₂ ; -S (O) ₂ N (R ⁶ ) ₂ ; -NO ₂ ; -CN; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; an optionally substituted partially unsaturated heterocyclic moiety; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; -NR ³ CON (R ⁶ ) ₂ ; and a divalent bridge of the structure T ² = T ² -T ³ , where each T ² independently means N, CH or CG ³ '; and T ³ is S, O, CR ⁴ G ³ ′, C (R ⁴ ) ₂ or NR ³ ; where G ^{3 '} means any of the above defined fragments of G ³ that are monovalent; and the terminal group T ^{2 of the} bridge is connected to L, and T ³ is connected to D, forming a 5-membered condensed cycle; A and D independently mean N or CH; B and E independently mean N or CH; L is N or CH; and under the conditions that a) the total number of N atoms in the cycle containing A, B, D, E, and L is 0, 1, 2, or 3; and b) if L is CH and any G ³ is a monovalent substituent, then at least one of A and D represents an N atom; and c) if L means CH and G ³ means a divalent bridge of the structure T ² = T ² -T ³ , then A, B, D and E also mean CH; J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl; q ′ represents the number of substituents G ⁴ in the ring J and is 0, 1, 2, 3, 4 or 5; G ⁴ means a monovalent or divalent moiety selected from the group consisting of: —N (R ⁶ ) ₂ ; -NR ³ COR ⁶ ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino substituted alkyl; N- (lower alkyl) amino substituted alkyl; N, N-di- (lower alkyl) amino substituted alkyl; N- (lower alkanoyl) amino substituted alkyl; hydroxy substituted alkyl; cyano substituted alkyl; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; phenyl lower alkoxycarbonyl substituted alkyl; halogen-substituted alkylamino; amino substituted alkylamino; N- (lower alkyl) amino substituted alkylamino; N, N-di- (lower alkyl) amino-substituted alkylamino; N- (lower alkanoyl) amino substituted alkylamino; hydroxy substituted alkylamino; cyano-substituted alkylamino; carboxy substituted alkylamino; lower alkoxycarbonyl substituted alkylamino; phenyl lower alkoxycarbonyl substituted alkylamino group; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; halogenated lower alkoxyl; halogenated lower alkylthioyl; halogenated lower alkylsulfonyl; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CON (R ⁶ ) ₂ ; -CH ₂ OR ³ ; -NO ₂ ; -CN; amidine; guanidine; sulfo group; -B (OH) ₂ ; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; an optionally substituted partially unsaturated heterocyclic moiety; -OCO ₂ R ³ ; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -CHO; -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; -NR ³ CON (R ⁶ ) ₂ ; and bivalent bridges forming a condensed cycle attached to adjacent positions of cycle J and connecting these positions, said bridges having the structure

where each T ² independently means N, CH or CG ^{4 '} ; T ³ means S, O, CR ⁴ G ^{4 '} , C (R ⁴ ) ₂ or NR ³ ; where G ⁴ 'means any of the above defined fragments of G ⁴ that are monovalent; and binding to ring J occurs at the terminal atoms of T ² and T ³ ;

where each T ² independently means N, CH or CG ⁴ '; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and provided that no more than two bridging atoms of T ² can be N; and binding to ring J occurs at the terminal atoms of T ² ; and

where all T ⁴ , T ⁵ and T ⁶ independently mean O, S, CR ⁴ G ^{4 '} , C (R ⁴ ) ₂ or NR ³ , where G ⁴ ' means any of the above defined fragments of G ⁴ that are monovalent; and binding to ring J occurs at the terminal atoms of T ⁴ or T ⁵ ; under the conditions that: i) if one T ⁴ means O, S or NR ³ , then the other T ⁴ means CR ⁴ G ⁴ or C (R ⁴ ) ₂ ; ii) a bridge comprising T ⁵ and T ⁶ atoms may contain no more than two heteroatoms O, S or N; and iii) in a bridge including T ⁵ and T ⁶ atoms, if one T ⁵ group and one T ⁶ group are O atoms, or two T ⁶ groups are O atoms, said O atoms are separated by at least one carbon atom; if G ⁴ means an alkyl group located in cycle J near the bridge - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _p -, and X means NR ³ , where R ³ means an alkyl substituent, then G ⁴ and an alkyl substituent R ³ at X can be connected to each other to form a bridge structure - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _{p '} -, where p' = 2, 3 or 4, provided that the sum of p and p '= 2, 3 or 4, which leads to the formation of a 5-, 6- or 7-membered nitrogen-containing cycle; and with the additional conditions that in G ¹ , G ² , G ³ and G ⁴ , if two groups of R ³ or R ^{6 are} alkyl and are on the same N atom, they can be connected via a bond , O, S or NR ³ with the formation of an N-containing heterocycle with 5-7 atoms in the cycle; if the aryl, heteroaryl or heterocyclic ring optionally contains substituents, then the ring may contain up to 5 substituents that are independently selected from the group consisting of amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, (lower alkanoyl) amino, halogen, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkiltioil, halogenated lower alkoxy, halogenated lower alkiltioil, lower alkanoyloxy, -CO ₂ R ^3, -CHO, -CH ₂ OR ^3, -OCO ₂ R ^3, -CON (R ⁶⁾ _2, -OCON (R ⁶⁾ _2, -NR ³ CON (R ⁶⁾ _2, itro-, amidino, guanidino, mercapto, sulfo, and cyano; and if any alkyl group is attached to O, S or N and contains a hydroxyl substituent, then said hydroxyl substituent is separated from O, S or N to which the alkyl group is attached by at least two carbon atoms. 2. The compound according to claim 1, characterized in that R ¹ and R ² together form a bridge containing two T ² fragments and one T ³ fragment, and said bridge together with the cycle to which it is attached forms a bicyclic structure

where each T ² independently means N, CH or CG ¹ ; T ³ means S, O, CH ₂ or NR ³ ; provided that if T ³ means O or S, then at least one T ² means CH or CG ¹ . 3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 4. A method of treating a mammal in which there is a condition characterized by abnormal processes of angiogenesis or the occurrence of increased permeability, comprising administering to said mammal a quantity of a compound according to claim 1, which is effective for treating said condition. 5. The method according to p. 4, characterized in that the condition is a tumor growth; retinopathy, including diabetic retinopathy, ischemic obstruction of the retinal vein, retinopathy in prematurity and age-related macular degeneration; rheumatoid arthritis; psoriasis; or bullous disease accompanied by subepidermal blistering, including bullous pemphigoid, erythema multiforme, and herpetiform dermatitis. 6. The compound having the General structural formula

where R ¹ and R ² : i) independently mean H or lower alkyl; ii) together form a building bridge

in which binding is via terminal carbon atoms; iii) together form a building bridge

in which binding is via terminal carbon atoms; iv) together form the bridge of the building

where one or two fragments of the T ¹ cycle mean N, and the rest mean CH or CG ¹ and the binding is through the terminal carbon atoms; or v) together form a bridge containing two fragments of T ² and one fragment of T ³ , and the specified bridge together with the cycle to which it is attached forms a bicyclic structure

where each T ² independently means N, CH or CG ¹ ; T ³ means S, O, CR ⁴ G ¹ , C (R ⁴ ) ₂ or NR ³ ; m is 0 or an integer of 1-4; G ¹ is a substituent independently selected from the group consisting of —N (R ⁶ ) ₂ ; -NR ³ COR ⁶ ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino substituted alkyl; N- (lower alkyl) amino substituted alkyl; N, N-di- (lower alkyl) amino substituted alkyl; N- (lower alkanoyl) amino substituted alkyl; hydroxy substituted alkyl; cyano substituted alkyl; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; phenyl lower alkoxycarbonyl substituted alkyl; halogen-substituted alkylamino; amino substituted alkylamino; N- (lower alkyl) amino substituted alkylamino; N, N-di- (lower alkyl) amino-substituted alkylamino; N- (lower alkanoyl) amino-substituted alkylamino; hydroxy substituted alkylamino; cyano-substituted alkylamino; carboxy substituted alkylamino; lower alkoxycarbonyl substituted alkylamino; phenyl lower alkoxycarbonyl substituted alkylamino group; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; halogenated lower alkoxyl; halogenated lower alkylthioyl; halogenated lower alkylsulfonyl; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CON (R ⁶ ) ₂ ; -CH ₂ OR ³ ; -NO ₂ ; -CN; amidine; guanidine; sulfo group; -B (OH) ₂ ; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; optionally substituted saturated heterocycloalkyl; an optionally substituted partially unsaturated heterocyclic moiety; optionally substituted partially unsaturated heterocycloalkyl; -OCO ₂ R ³ ; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -CHO; -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; and —NR ³ CON (R ⁶ ) ₂ ; R ³ means H or lower alkyl; R ^{6 is} independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; and optionally substituted aryl lower alkyl; lower alkyl-N (R ³ ) ₂ ; and lower alkyl-OH; R ⁴ means H, halogen or lower alkyl; P = 0, 1 or 2; X is selected from the group consisting of O, S, and NR ³ ; Y is selected from the group consisting of lower alkylene; -CH ₂ -O-; -CH ₂ -S-; -CH ₂ -NH-; -ABOUT-; -S-; -NH-; - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _n -S (O) _p - (5 membered heteroaryl) - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _s -; - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _n -C (G ² ) (R ⁴ ) - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _s -; n and s are independently 0 or an integer of 1-2; G ² selected from the group including —CN, —CO ₂ R ³ ; —CON (R ⁶ ) ₂ and —CH ₂ N (R ⁶ ) ₂ ; -O-CH ₂ -; -S (O) -; -S (O) ₂ -; -SCH ₂ -; -S (O) CH ₂ -; -S (O) ₂ CH ₂ -; -CH ₂ S (O) -; and —CH ₂ S (O) ₂ -; Z is N or CR ⁴ ; q is 1 or 2; G ³ means a monovalent or divalent moiety selected from the group consisting of: lower alkyl; -NR ³ COR ⁶ ; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CH ₂ OR ³ ; -CON (R ⁶ ) ₂ ; -S (O) ₂ N (R ⁶ ) ₂ ; -NO ₂ ; -CN; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; an optionally substituted partially unsaturated heterocyclic moiety; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy: -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; -NR ³ CON (R ⁶ ) ₂ ; and a divalent bridge with a structure of T ² = T ² -T ³ , where each T ² independently means N, CH or CG ^{3 '} ; and T ³ is S, O, CR ⁴ G ^{3 ′} , C (R ⁴ ) ₂ or NR ³ ; where G ^{3 '} means any of the above defined fragments of G ³ that are monovalent; and the end group T ² is linked to L, and T ³ is linked to D, forming a 5-membered fused ring; A and D independently mean CH; B and E independently mean CH; L is CH; and provided that in the formed phenyl ring the substituent G ³ is the indicated divalent bridge of the structure T ² = T ² -T ³ ; J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl; q ′ is the number of substituents G ⁴ in the J ring and is 0, 1, 2, 3, 4 or 5, and G ⁴ is a monovalent or divalent moiety selected from the group consisting of —N (R ⁶ ) ₂ ; -NR ³ COR ⁶ ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino substituted alkyl; N- (lower alkyl) amino substituted alkyl; N, N-di- (lower alkyl) amino substituted alkyl; N- (lower alkanoyl) amino substituted alkyl; hydroxy substituted alkyl; cyano substituted alkyl; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; phenyl lower alkoxycarbonyl substituted alkyl; halogen-substituted alkylamino; amino substituted alkylamino; N- (lower alkyl) amino substituted alkylamino; N, N-di- (lower alkyl) amino-substituted alkylamino; N- (lower alkanoyl) amino substituted alkylamino; hydroxy substituted alkylamino; cyano-substituted alkylamino; carboxy substituted alkylamino; lower alkoxycarbonyl substituted alkylamino; phenyl lower alkoxycarbonyl substituted alkylamino group; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; S (O) ₂ R ⁶ ; halogenated lower alkoxyl; halogenated lower alkylthioyl; halogenated lower alkylsulfonyl; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CON (R ⁶ ) ₂ ; -CH ₂ OR ³ ; -NO ₂ ; -CN; amidine; guanidine; sulfo group; B (OH) ₂ ; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; an optionally substituted partially unsaturated heterocyclic moiety; -OCO ₂ R ³ ; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylapcoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -CHO; -OCON (R ⁶ ) ₂ ; NR ³ CO ₂ R ⁶ ; -NR ³ CON (R ⁶ ) ₂ ; and bivalent bridges forming a condensed cycle attached to adjacent positions of cycle J and connecting these positions, said bridges having the structure

where each T ² independently means N, CH or CG ^{4 '} ; T ³ means S, O, CR ⁴ G ^{4 '} , C (R ⁴ ) ₂ or NR ³ ; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and binding to ring J occurs at the terminal atoms of T ² and T ³ ;

where each T ² independently means N, CH or CG ^{4 '} ; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and provided that no more than two bridging atoms of T ² can be N; and binding to ring J occurs at the terminal atoms of T ² ; and

where all T ⁴ , T ⁵ and T ⁶ independently mean O, S, CR ⁴ G ^{4 '} , C (R ⁴ ) ₂ or NR ³ ; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and binding to ring J occurs at the terminal atoms of T ⁴ or T ⁵ ; under the conditions that: i) if one T ⁴ means O, S or NR ³ , then the other T ⁴ means CR ⁴ G ^{4 '} or C (R ⁴ ) ₂ ; ii) a bridge comprising T ⁵ and T ⁶ atoms may contain no more than two heteroatoms O, S or N; and iii) in a bridge including T ⁵ and T ⁶ atoms, if one T ⁵ group and one T ⁶ group are O atoms, or two T ⁶ groups are O atoms, said O atoms are separated by at least one carbon atom; if G ⁴ means an alkyl group located in cycle J near the bridge - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _p -, and X means NR ³ , where R ³ means an alkyl substituent, then G ⁴ and an alkyl substituent R ³ at X can be connected to each other with the formation of a bridge structure - (CH ₂ ) _{p '} -, where p' = 2, 3 or 4, provided that the sum p and p '= 2, 3 or 4, which leads to the formation of a 5-, 6- or 7-membered nitrogen-containing cycle; and with the additional conditions that: in G ¹ , G ² , G ³ and G ⁴ , if two groups of R ³ or R ⁶ mean alkyl and are at the same atom N, they can be connected using bonds, O, S or NR ³ with the formation of an N-containing heterocycle with 5-7 atoms in the cycle; if the aryl, heteroaryl or heterocyclic ring optionally contains substituents, then the ring may contain up to 5 substituents that are independently selected from the group consisting of amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, (lower alkanoyl) amino group, halogen, lower alkyl, halogenated lower alkyl, hydroxyl, lower alkoxyl, lower apkylthioyl, halogenated lower alkoxyl, halogenated lower alkylthioyl, lower alkanoyloxyl, —CO ₂ R ³ , —CO ₂ , —CO ₂ OR ³ , —OC ₂ , OOC R ³ , -CON (R ⁶ ) ₂ , -OCON (R ⁶ ) ₂ , -NR ³ CON (R ⁶ ) ₂ , nitro, amidino, guanidino, mercapto, sulfo and cyano; and if any alkyl group is attached to O, S or N and contains a hydroxyl substituent, then said hydroxyl substituent is separated from O, S or N to which the alkyl group is attached by at least two carbon atoms. 7. The compound according to claim 6, characterized in that, in a cycle containing A, B, D, E and L and a divalent bridge of the structure T ² = T ² -T ³ , the terminal T ² means N and a fragment of T ^{3 the} specified bridge means S, O, CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ or NR ³ . 8. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier. 9. A method of treating a mammal in which there is a condition characterized by abnormal processes of angiogenesis or the occurrence of increased permeability, comprising administering to said mammal a quantity of a compound according to claim 6, which is effective for treating said condition. 10. The method according to claim 9, characterized in that said pathological condition is tumor growth; retinopathy including    diabetic retinopathy, ischemic obstruction of the retinal vein, retinopathy in prematurity and age-related macular degeneration; rheumatoid arthritis; psoriasis; or bullous disease accompanied by subepidermal blistering, including bullous pemphigoid, erythema multiforme, and herpetiform dermatitis. 11. The compound having the General structural formula

where R ¹ and R ² : i) independently mean H or lower alkyl; ii) together form a building bridge

in which binding is via terminal carbon atoms; iii) together form a building bridge

in which binding is via terminal carbon atoms; iv) together form the bridge of the building

where one or two fragments of the T ¹ cycle mean N, and the rest mean CH or CG ¹ and the binding is through the terminal carbon atoms; or v) together form a bridge containing two fragments of T ² and one fragment of T ³ , and said bridge together with the cycle to which it is attached forms a bicyclic structure

where each T ² independently means N. CH or CG ¹ ; T ³ means S, O, CR ⁴ G ¹ , C (R ⁴ ) ₂ or NR ³ ; m is 0 or an integer of 1-4; G ¹ is a substituent independently selected from the group consisting of —N (R ⁶ ) ₂ ; -NR ³ COR ⁶ ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino substituted alkyl; N- (lower alkyl) amino substituted alkyl; N, N-di- (lower alkyl) amino substituted alkyl; N- (lower alkanoyl) amino substituted alkyl; hydroxy substituted alkyl; cyano substituted alkyl; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; phenyl lower alkoxycarbonyl substituted alkyl; halogen-substituted alkylamino; amino substituted alkylamino; N- (lower alkyl) amino substituted alkylamino; N, N-di- (lower alkyl) amino-substituted alkylamino; N- (lower alkanoyl) amino substituted alkylamino; hydroxy substituted alkylamino; cyano-substituted alkylamino; carboxy substituted alkylamino; lower alkoxycarbonyl substituted alkylamino; phenyl lower alkoxycarbonyl substituted alkylamino group; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; halogenated lower alkoxyl; halogenated lower alkylthioyl; halogenated lower alkylsulfonyl; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CON (R ⁶ ) ₂ ; -CH ₂ OR ³ ; -NO ₂ ; -CN; amidine; guanidine; sulfo group; -B (OH) ₂ ; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; optionally substituted saturated heterocycloalkyl; an optionally substituted partially unsaturated heterocyclic moiety; optionally substituted partially unsaturated heterocycloalkyl; -OCO ₂ R ³ ; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -CHO; -OCON (R ⁶ ) ₂ ; -NR ₃ CO ₂ R ⁶ ; and —NR ³ CON (R ⁶ ) ₂ ; R ³ means H or lower alkyl; R ^{6 is} independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; and optionally substituted aryl lower alkyl; lower alkyl-N (R ³ ) ₂ ; and lower alkyl-OH; R ⁴ means H, halogen or lower alkyl; p is 0, 1 or 2; X is selected from the group consisting of O, S, and NR ³ ; Y is selected from the group consisting of lower alkylene; -CH ₂ -O-; -CH ₂ -S-; -CH ₂ -NH-; -ABOUT-; -S-; -NH-; - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _n -S (O) _p - (5 membered heteroaryl) - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _s -; - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _n -C (G ² ) (R ⁴ ) - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _s -; Where n and s are independently 0 or an integer 1-2; G ² selected from the group including —CN, —CO ₂ R ³ ; —CON (R ⁶ ) ₂ and —CH ₂ N (R ⁶ ) ₂ ; -O-CH ₂ -; -S (O) -; -S (O) ₂ -; -SCH ₂ -; -S (O) CH ₂ -; -S (O) ₂ CH ₂ -; -CH ₂ S (O) -; and —CH ₂ S (O) ₂ -; Z is CR ⁴ ; q is 1 or 2; G ³ means a monovalent or divalent moiety selected from the group consisting of: —NR ³ COR ⁶ ; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CH ₂ OR ³ ; -CON (R ⁶ ) ₂ ; -S (O) ₂ N (R ⁶ ) ₂ ; -NO ₂ ; -CN; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; an optionally substituted partially unsaturated heterocyclic moiety; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; -NR ³ CON (R ⁶ ) ₂ ; and a divalent bridge of the structure T ² = T ² -T ³ , where each T ² independently means N, CH or CG ^{3 '} ; and T ³ is S, O, CR ⁴ G ^{3 ′} , C (R ⁴ ) ₂ or NR ³ ; where G ^{3 '} means any of the above defined fragments of G ³ that are monovalent; and the end group T ² is linked to L, and T ³ is linked to D, forming a 5-membered fused ring; A and D independently mean N or CH; B and E independently mean N or CH; L is N or CH; and provided that a) the total number of N atoms in the cycle containing A, B, D, E, and L is 0, 1, 2, or 3; and b) if L is CH and any G ³ is a monovalent substituent, then at least one of A and D represents an N atom; and c) if L means CH and G ³ means a divalent bridge of the structure T ² = T ² -T ³ , then A, B, D and E also mean CH; J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl; q ′ is the number of substituents G ⁴ in the J ring and is 0, 1, 2, 3, 4 or 5, and G ⁴ is a monovalent or divalent moiety selected from the group consisting of —N (R ⁶ ) ₂ ; -NR ³ COR ⁶ ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino substituted alkyl; N- (lower alkyl) amino substituted alkyl; N, N-di- (lower alkyl) amino substituted alkyl; N- (lower alkanoyl) amino substituted alkyl; hydroxy substituted alkyl; cyano substituted alkyl; carboxy substituted alkyl; lower alkoxycarbonyl substituted alkyl; phenyl lower alkoxycarbonyl substituted alkyl; halogen-substituted alkylamino; amino substituted alkylamino; N- (lower alkyl) amino substituted alkylamino; N, N-di- (lower alkyl) amino-substituted alkylamino; N- (lower alkanoyl) amino substituted alkylamino; hydroxy substituted alkylamino; cyano-substituted alkylamino; carboxy substituted alkylamino; lower alkoxycarbonyl substituted alkylamino; phenyl lower alkoxycarbonyl substituted alkylamino group; -OR ⁶ ; -SR ⁶ ; -S (O) R ⁶ ; -S (O) ₂ R ⁶ ; halogenated lower alkoxyl; halogenated lower alkylthioyl; halogenated lower alkylsulfonyl; -OCOR ⁶ ; -COR ⁶ ; -CO ₂ R ⁶ ; -CON (R ⁶ ) ₂ ; -CH ₂ OR ³ ; -NO ₂ ; -CN; amidine; guanidine; sulfo group; -B (OH) ₂ ; optionally substituted aryl; optionally substituted heteroaryl; an optionally substituted saturated heterocyclic moiety; an optionally substituted partially unsaturated heterocyclic moiety; -OCO ₂ R ³ ; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S (O) _p (optionally substituted heteroaryl); optionally substituted heteroarylalkoxyl; -S (O) _p (optionally substituted heteroarylalkyl); -CHO; -OCON (R ⁶ ) ₂ ; -NR ³ CO ₂ R ⁶ ; -NR ³ CON (R ⁶ ) ₂ ; and bivalent bridges forming a condensed cycle attached to adjacent positions of cycle J and connecting these positions, said bridges having the structure:

where each T ² independently means N, CH or CG ^{4 '} ; T ³ means S, O, CR ⁴ G ^{4 '} , C (R ⁴ ) ₂ or NR ³ ; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and binding to ring J occurs at the terminal atoms of T ² and T ³ ;

where each T ² independently means N, CH or CG ⁴ '; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and provided that no more than two bridging atoms of T ² can be N; and binding to ring J occurs at the terminal atoms of T ² ; and

where all T ⁴ , T ⁵ and T ⁶ independently mean O, S, CR ⁴ G ^{4 '} , C (R ⁴ ) ₂ or NR ³ ; where G ^{4 '} means any of the above defined fragments of G ⁴ that are monovalent; and binding to ring J occurs at the terminal atoms of T ⁴ or T ⁵ ; under the conditions that: i) if one T ⁴ means O, S or NR ³ , then the other T ⁴ means CR ⁴ G ^{4 '} or C (R ⁴ ) ₂ ; ii) a bridge comprising T ⁵ and T ⁶ atoms may contain no more than two heteroatoms O, S or N; and iii) in a bridge including T ⁵ and T ⁶ atoms, if one T ⁵ group and one T ⁶ group are O atoms, or two T ⁶ groups are O atoms, said O atoms are separated by at least one carbon atom; if G ⁴ means an alkyl group located in cycle J near the bridge - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _p -, and X means NR ³ , where R ³ means an alkyl substituent, then G ⁴ and an alkyl substituent R ³ at X can be connected to each other to form a bridge structure - (CR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ ) _{p '} -, where p' = 2, 3 or 4, provided that the sum of p and p '= 2, 3 or 4, which leads to the formation of a 5-, 6- or 7-membered nitrogen-containing cycle; and with the additional conditions that: in G ¹ , G ² , G ³ and G ⁴ , if two groups of R ³ or R ⁶ mean alkyl and are at the same atom N, they can be connected using bonds, O, S or NR ³ with the formation of an N-containing heterocycle with 5-7 atoms in the cycle; if the aryl, heteroaryl or heterocyclic ring optionally contains substituents, then the ring may contain up to 5 substituents that are independently selected from the group consisting of amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, (lower alkanoyl) amino, halogen, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkiltioil, halogenated lower alkoxy, halogenated lower alkiltioil, lower alkanoyloxy, -CO ₂ R ^3, -CHO, -CH ₂ OR ^3, -OCO ₂ R ³ , -CON (R ⁶ ) ₂ , -OCON (R ⁶ ) ₂ , -NR ³ CON (R ⁶ ) ₂ , n itro, amidine, guanidine, mercapto, sulfo and cyano groups; and if any alkyl group is attached to O, S or N and contains a hydroxyl substituent, then said hydroxyl substituent is separated from O, S or N to which the alkyl group is attached by at least two carbon atoms. 12. The compound according to claim 11, characterized in that R ⁴ means N. 13. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier. 14. A method of treating a mammal in which there is a condition characterized by abnormal processes of angiogenesis or the occurrence of increased permeability, comprising administering to said mammal a quantity of a compound according to claim 11, which is effective for treating said condition. 15. The method according to 14, characterized in that the pathological condition is a tumor growth; retinopathy, including diabetic retinopathy, ischemic obstruction of the retinal vein, retinopathy in prematurity and age-related macular degeneration; rheumatoid arthritis; psoriasis; or a bullous disease accompanied by subepidermal blistering, including bullous pemphigoid, erythema multiforme, and herpetiform dermatitis. 16. A compound selected from the group comprising the compounds of examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 27, 28, 34, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 , 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 82A 82V, 82C, 82D, 85, 88, 89, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 and 112 .