Quinazoline derivatives and pharmaceutical compositions containing them
First Claim
Patent Images
1. A quinazoline derivative of the formula I:
-
wherein;
m is an integer from 1 to 2;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —
NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl);
R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;
R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X1 represents —
O—
, R4 is selected from one of the following eleven groups;
1) C1-5alkylR12 (wherein R12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or C1-5alkylR13 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
2) C2-5alkenylR14 (wherein R14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
3) C3-5alkynylR15 (wherein R15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR17CO—
, —
CONR18—
, —
SO2NR19—
, —
NR20SO2—
or —
NR21—
(wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl);
5) C1-5alkylX4COR22 (wherein X4 represents —
O—
or —
NR23—
(wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents —
NR24R25 or —
OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
6) C1-5alkylX5R27 (wherein X5 represents —
O—
, —
S—
, —
SO—
, —
SO2—
, —
OCO—
, —
NR28CO—
, —
CONR29—
, —
SO2NR30—
, —
NR31SO2—
or —
NR32—
(wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) or X5 is carbonyl, and R27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl or R27 is C1-3allyl with the proviso that when R27 is C1-3alkyl, X5 is —
S—
, —
SO—
, —
SO2—
, —
SO2NR30—
or —
NR31SO2—
;
7) C1-3alkoxyC2-4alkyl or C1-4alkyl;
8) C1-5alkylX6C1-5alkylR33 (wherein X6 represents —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR34CO—
, —
CONR35—
, —
SO2NR36—
, —
NR37SO2—
or —
NR38—
(wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substitutes selected from oxo, hydroxy, halogeno, C1-4alkyl), C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
9) R39 (wherein R39 is a group selected from pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl which group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
10) C1-5alkylR40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4hydroxyalkyl and —
CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-4alkyl); and
11) C1-5alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituent selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
with the further proviso that when R4 is selected from group
7) R1 and/or R2 is/are nitro or at least one R3 is C1-3alkanoyloxy;
or a salt thereof.
6 Assignments
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Accused Products
Abstract
The invention relates to quinazoline derivatives of formula (1)
wherein m is an integer from 1 to 2; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1 represents —O—, —CH2—, —S—, —SO—, —SO2—, —NR7CO—, —CONR8—, —SO2NR9—, —NR10SO2— or —NR11— (wherein R7, R8, R9, R10 and R11 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl); R4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
104 Citations
23 Claims
-
1. A quinazoline derivative of the formula I:
-
wherein; m is an integer from 1 to 2;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —
NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl);
R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;
R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X1 represents —
O—
,R4 is selected from one of the following eleven groups;
1) C1-5alkylR12 (wherein R12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or C1-5alkylR13 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
2) C2-5alkenylR14 (wherein R14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
3) C3-5alkynylR15 (wherein R15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR17CO—
, —
CONR18—
, —
SO2NR19—
, —
NR20SO2—
or —
NR21—
(wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl);
5) C1-5alkylX4COR22 (wherein X4 represents —
O—
or —
NR23—
(wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents —
NR24R25 or —
OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
6) C1-5alkylX5R27 (wherein X5 represents —
O—
, —
S—
, —
SO—
, —
SO2—
, —
OCO—
, —
NR28CO—
, —
CONR29—
, —
SO2NR30—
, —
NR31SO2—
or —
NR32—
(wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) or X5 is carbonyl, and R27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl or R27 is C1-3allyl with the proviso that when R27 is C1-3alkyl, X5 is —
S—
, —
SO—
, —
SO2—
, —
SO2NR30—
or —
NR31SO2—
;
7) C1-3alkoxyC2-4alkyl or C1-4alkyl;
8) C1-5alkylX6C1-5alkylR33 (wherein X6 represents —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR34CO—
, —
CONR35—
, —
SO2NR36—
, —
NR37SO2—
or —
NR38—
(wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substitutes selected from oxo, hydroxy, halogeno, C1-4alkyl), C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
9) R39 (wherein R39 is a group selected from pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl which group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
10) C1-5alkylR40 (wherein R40 is piperazin-1-yl which bears at least one substituent selected from C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4hydroxyalkyl and —
CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-4alkyl); and
11) C1-5alkylR44 (wherein R44 is morpholino which bears at least one and optionally two substituent selected from oxo, C1-4alkyl, C1-4hydroxyalkyl, carbamoyl, C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkanoyl and C1-4alkoxycarbonyl);
with the further proviso that when R4 is selected from group
7) R1 and/or R2 is/are nitro or at least one R3 is C1-3alkanoyloxy;
or a salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 22, 23)
wherein; Ra represents hydrogen, methyl, fluoro, or chloro;
Rb represents hydrogen, methyl, methoxy, bromo, fluoro or chloro;
Rc represents hydrogen or hydroxy;
Rd represents hydrogen, fluoro or chloro.
-
-
5. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R4 is selected from one of the following nine groups:
-
1) C1-4alkylR12 (wherein R12 is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or C2-4alkylR45 (wherein R45 is a group selected from imidazolidine-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl);
2) 1-R46prop-1-en-3-yl, 1-R46but-2-en-4-yl, 1-but-1-en-3-yl, 1-R46pent-2-en-4-yl or 2-R46pent-3-en-5yl (wherein R46 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a carbon atom and which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R47but-2-en-4-yl, 1-R47pent-2-en-4-yl or 2-R47pent-3-en-5-yl (wherein R47 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl);
3) 1-R48prop-1-yn-3-yl, 1-R48but-2-yn-4-yl, 1-R48but-1-yn-3-yl, 1-R48pent-2-yn-4-yl or 2-R48pent-3-yn-5-yl (wherein R48 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R49but-2-yn-4-yl, 1-R49pent-2-yn-4-yl or 2-R49pent-3-yn-5-yl (wherein R49 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkylcarbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl);
4) C2-3alkylX2C1-3alkylX3R16 (wherein X2 and X3 are as defined in claim 1 and R16 represents hydrogen or C1-3alkyl);
5) C2-3alkylX4COR22 (wherein X4 is as defined in claim 1 and R22 represents —
NR24R25 or —
OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-2alkoxyethyl));
6) C2-3alkylX5R27 (wherein X5 is as defined in claim 1 and R27 represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X5 through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl or R27 is C1-3alkyl with the proviso that when R27 is C1-3alkyl, X5 is —
S—
, —
SO—
, —
SO2—
, —
SO2N30—
or —
NR31SO2—
);
7) C2-3alkylX6C2-3alkyl33 (wherein X6 is as defined in claim 1 and R33 represents a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituent selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl, and C1-3alkoxycarbonyl);
8) C2-3alkylR40 is piperazin-1-yl which bears at least one substituent selected from acetyl, C1-2alkoxycarbonyl, C1-2hydroxyalkyl and CONR41R42 (wherein R41 and R42 each independently represents hydrogen or C1-2alky); and
9) C2-3alkylR44 is morpholino which bears at least one and optionally two substituents selected from oxo, C1-2alky, C1-2hydroxyalkyl, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acaetyl and C1-2alkoxycarbonyl).
-
-
6. A quinazoline derivative as claimed in claim 5 wherein R4 is selected from one of the following seven groups:
-
1) C1-3alkylR12 (wherein R12 is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl) or C2-3alkylR45 (wherein R45 is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylkcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl);
2) 1-R50but-2-en-4-yl (wherein R50 is a group selected from imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino and piperidino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl). 3) 1-R51but-2-yn-4-yl (wherein R51 is a group selected from imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl morpholino, thiomorpholino and piperidino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl);
4) C2-3alkylX2C1-3alkylX3R16 (wherein X2 and X3 are as defined in claim 1 and R16 represents hydrogen or C1-3alkyl);
5) 2-(3,3-dimethylureido)ethyl, 3-(3,3dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, 2-(1,3,3-trimethylureido)ethyl, 3-1,3,3-trimethylureido)propyl, 2-(isopropoxycarbonylamino)ethyl, 3-(isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl, 3-(isobutoxycarbonylamino)propyl, 2-(t-butoxycarbonylamino)ethyl or 3-(t-butoxycarbonylamino)propyl;
6) C2-3alkylX5R27 (wherein R27 is C1-2alkyl and X5 is —
S—
, —
SO—
, —
SO2—
, —
SO2NR30—
or —
NR31 SO2—
; and
7) C2-3alkyX6C2-3alkylR33 (wherein X6 is as defined in claim 1 and R33 represents a group selected from morpholino, 2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl).
-
-
8. A quinazoline derivative as claimed in claim 1 selected from:
-
4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinzoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazoline;
(E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)-quinazoline;
4-(4-chloro-2-fluoroanilino)-7-(3-(2,6-dimethylmorpholino)propoxy)-6-methoxyquinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)-propoxy)quinazoline;
7-(2-[N-tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline;
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)-propoxy)quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-2-(2-oxoimidazolidin-1-yl)ethoxy)quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline;
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline;
(S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy-6-methoxyquinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)-quinazoline;
(S)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)-quinazoline; and
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)-quinazoline;
and salts thereof.
-
-
9. A quinazoline derivative as claimed in claim 1 selected from:
-
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)-methoxyquinazoline;
4-(4-bromo-2-fluoroanilino)-7-3-(1,1-dixothiomorpholino)propoxy)-6-methoxyquinazoline;
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-2-pyrrolidin-1-ylethoxy)ethoxy)-quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)-ethoxy)quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-methoxyacetyl]amino)-ethoxy)quinazoline; and
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-2-oxopyrrolidin-1-yl)ethoxy)quinazoline;
and salts thereof.
-
-
10. A quinazoline derivative as claimed in claim 1 selected from:
-
(E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-en-1-yloxy)-quinazoline;
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline;
(S)-4-4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)-methoxyquinazoline; and
(R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)-methoxyquinazoline;
and salts thereof.
-
-
11. A quinazoline derivative as claimed in claim 1 selected from:
-
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline;
and salts thereof.
-
-
12. A quinazoline derivative as claimed in any one of claims 1 and 7-11 in the form of pharmaceutically acceptable salt.
-
13. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R1 represents methoxy.
-
14. A quinazoline derivative as claimed in claim 1 or claim 2 wherein m is 2.
-
15. A quinazoline derivative as claimed in claim 1 or claim 2 wherein the phenyl group bearing (R3)m is the 4-chloro-2-fluorophenyl group or the 4-bromo-2-fluorophenyl group.
-
16. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R4 is selected from one of the following six groups:
-
1) C1-3alkylR12 (wherein R12 is 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4- yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, piperazin-2-yl, 1-methylpiperazine-2-yl, 4-methylpiperazin-2-yl, 1,4-dimethylpiperazin-2-yl, morpholin-2-yl, morpholin-3-yl, 4-methylmorpholin-2-yl or 4-methylmorpholin-3- yl) or C2-3alkylR45 (wherein R45 is pyrrolidin-1-yl, thiomorpholino, 1,1- dioxothiomorpholino, 2-oxopyrrolidin-1-yl, 2-(N-methylcarbamoyl)pyrrolidin-1-yl, 2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl, 2-carbamoylpyrrolidin-1yl, 2- oxoimidazolidin-1-yl or 3-methyl-2-oxoimidazolidin-1-yl);
2) 1-R50but-2-en-4-yl (wherein R50 is 2-oxoimidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3- dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, 1-methylpiperidin-4- yl, pyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, piperidino or 3-methyl-2-oxoimidazolidin- 1-yl);
3) 1-R51but-2-yn-4-yl (wherein R51 is 2-oxoimidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3- dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, 1-methylpiperidin-4- yl, pyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, piperidino or 3-methyl-2-oxoimidazolidin- 1-yl);
4) C2-3alkylX2C1-3alkylX3R16 (wherein X2 and X3 are as defined in claim 17 and R16 represents hydrogen or C1-3alkyl);
5) C2-3alkylX5R27 (wherein R27 is C1-2 alkyl and X5 is -S-, -SO-, -SO2-, -SO2NR30-or- NR31SO2-(wherein R30 and R31 are as defined in claim 1)); and
6) C2-3alkylX6C2-3alkylR33 (wherein X6 is as defined in claim 1 and R33 represents a group selected from pyrrolidin-1-yl, 4-methylpiperazin-1-yl and morpholino).
-
-
21. A process for the preparation of a quinazoline derivative of formula I or salt thereof (as defined in claim 1) which comprises:
-
(a) the reaction of a compound of the formula III;
(wherein R1, R2, X1 and R4 are as defined in claim 1 and L1 is a displaceble moiety), with a compound of the formula IV;
(wherein R3 and m are as defined in claim 1) whereby to obtain compounds of the formula I and salts thereof;
(b) for the preperation of compounds of formula I and salts thereof in which the group of formula IIa;
(wherein R3 and m are as defined in claim 1) represents a phenyl group carrying one or more hydroxy groups, the deprotection of a compound of formula V;
(wherein X1, m, R1, R2, R3 and R4 are as defined in claim 1, P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that m-p1 is equal to the number of R3 substituents which are not protected hydroxy);
(c) for the preparation of those compounds of formula I and salts thereof wherein the substituent X1 is —
O—
, the reaction of a compound of the formula VI;
(wherein X1, R1, R2 and R3 are as defined in claim 1) with a compound of formula VII;
-
-
22. A pharmaceutical composition which comprises as active ingredient a compound of formula I as defined in any one of claims 1 and 7-11 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.
-
23. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 and 7-11.
-
7. A quinazoline derivative of the formula 1a:
-
wherein; R1a is hydrogen or methoxy;
R2a is hydrogen;
the phenyl group bearing (R3a)ma is the 4-chloro-2-fluorophenyl group or the 4-bromo-2-fluorophenyl group;
X1a is —
O—
;
R4a is selected from one of the following nine groups;
1) C1-4alkylR7a (wherein R7a is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or C2-4alkylR8a (wherein R8a is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl);
2) 1-R9aprop-1-en-3-yl, 1-R9abut-2-en-4-yl, 1-R9abut-1-en-3-yl, 1-R9apent-2-en-4-yl or 2-R9apent-3-en-5-yl (wherein R9a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R10abut-2-en-4-yl, 1-R10apent-2-en-4-yl or 2-R10apent-3-en-5-yl (wherein R10a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbomoyl, N,N-di(C1-3alkyl)carbamoyl, C1-3alkanoyl and C1-3alkoxycarbonyl);
3) 1-R11aprop-1-yn-3-yl, 1-R11abut-2-yn-4-yl, 1-R11abut-1-yn-3-yl, 1-R11apent-2-yn-4-yl or 2-R11apent-3-yn-5-yl (wherein R11a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R12abut-2-yn-4-yl, 1-12apent-2-yn-4-yl or 2-R12apent-3-yn-5-yl (wherein R12a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbarmoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)carbarmoyl, C1-3alkanoyl and C1-3alkoxycarbonyl);
4) C2-3alkylX2aC1-3alkylX3aR13a (wherein X2a and X3a which may be the same or different each represents, —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR14aCO—
, or —
NR15a—
(wherein R14a and R15a each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl) and R13a represents hydrogen or C1-3alkyl);
5) C2-3alkylX4aCOR16a (wherein X4a represents —
O—
or —
NR17a—
(wherein R17a represents hydrogen, C1-3alkyl or C1-2alkoxyethyl) and R16a represents —
NR18aR19a or —
OR20a (wherein R18a, R19a and R20a which may be the same or different each represents hydrogen, C1-4alkyl or C1-2alkoxyethyl));
6) C2-3alkylX5aR21a (wherein X5a represents carbonyl, —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR22aCO—
, —
NR23aSO2—
, or —
NR24a—
(wherein R22a, R23a and R23a each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl) and R21a represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X5a through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl, C1-2alkoxy, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl or R21a is C1-3alkyl with that proviso that when R21a is C1-3alkyl, X5a is —
S—
, —
SO—
, —
SO2—
or —
NR23aSO2—
);
7) C2-3alkylX6aC2-3alkylR25a (wherein X6a represents —
O—
, —
S—
, —
SO—
, —
SO2—
, —
NR26aCO—
, —
NR27aSO2—
or —
NR28a-(wherein R26a, R27a and R28a each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl) and R25a represents a 5 or 6 membered saturated heterocyclic group with one or two heteratoms selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3alkylcarbamoyl, N,N-di(C1-3alkyl)cabamoyl, C2-3alkanoyl, and C1-3allkoxycarbonyl);
8) C2-3alkylR29a (wherein R29a is piperizin-1-yl which bears at least one substituent selected from acetyl, C1-2alkoxycarbonyl, C1-2hydroxyalkyl and CONR30aR31a (wherein R30a and R31a each independently represents hydrogen or C1-2alkyl); and
9) C2-3alkylR33a (wherein R33a is morpholino which bears at least one and optionally two substituents selected from oxo, C1-2alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2alkylcarbamoyl, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl);
or a salt thereof.
-
-
17. A quinazoline derivative of the formula I:
-
wherein; m is an integer from 1 to 2;
R1 represents hydrogen, hydroxy, halogeno, nitro, trifuloromethyl, eyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or -NR5R6 (wherein R5and R6, which may be the same or different, each represents hydrogen or C1-3alkyl);
R2 represents hydrogen, hydroxy, halageno, methoxy, amino or nitro;
R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X1 represents -O-;
R4 is selected from one of the following seven groups;
1) C1-5alkylR12 (wherein R12 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy) or C1-5alkylR13 (wherein R13 is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
2) C2-5alkenylR14 (wherein R14 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroyalkyl and C1-4alkoxy);
3) C2-5alkynylR15 (wherein R15 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
4) C1-5alkylX2C1-5alkylX3R16 (wherein X2 and X3 which may be the same or different are each -O-, -S-, -SO-, -SO2-, -NR17CO-, -CONR18-, -SO2NR19-, -NR20SO- or -NR21- (wherein R17, R18, R19, R20 and R21 each independetly represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R16 represents hydrogen or C1-3alkyl);
5) C1-5alkylX4COR22 (wherein X4 represents -O- or -NR23-(wherein R23 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R22 represents -NR24R25 or -OR26 (wherein R24, R25 and R26 which may be the same or different each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
6) C1-5alkylX5R27 (wherein X5 represents -O-, -S-, -SO2-, -OCO-, -NR28CO-, -CONR29-, -SO2NR30-, -NR31SO2- or -NR32-(wherein R28, R29, R30, R31 and R32 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R27 represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy; and
7) C1-3alkoxyC2-4alkyl or C1-4alkyl;
with the proviso that when R4 is selected from group
7) R1 and/or R2 is/are nitro or at least one R3 is C1-3alkanoyloxy;
and salts thereof. - View Dependent Claims (18, 19, 20)
wherein; Ra represents hydrogen, methyl, fluoro or chloro;
Rb represents hydrogen, methyl, methoxy, bromo, fluoro or chloro;
Rc represents hydrogen or hydroxy;
Rd represents hydrogen, fluoro or chloro.
-
Specification
-
- Resources
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Current AssigneeGenzyme Corporation (Sanofi )
-
Original AssigneeZeneca Incorporated (Astrazeneca PLC), Zeneca Pharma S.A.
-
InventorsHennequin, Laurent Francois Andre, Johnstone, Craig, Thomas, Andrew Peter, Clayton, Edward, Stokes, Elaine Sophie Elizabeth, Lohmann, Jean-Jacques Marcel
-
Primary Examiner(s)MURRAY, JEFFREY H
-
Assistant Examiner(s)Patel, Sudhaker B.
-
Application NumberUS09/269,595Time in Patent Office1,195 DaysField of Search544/293, 544/283, 544/284US Class Current544/283CPC Class CodesA61F 13/02 Adhesive bandages or dressingsA61F 13/023 wound covering film layers ...A61F 2013/00221 biodegradable, non-irritatingA61F 2013/8408 with odour controlA61K 31/517 ortho- or peri-condensed wi...A61K 31/541 Non-condensed thiazines con...A61P 13/12 of the kidneysA61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 27/02 Ophthalmic agentsA61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/10 for treating ischaemic or a...C07D 239/94 Nitrogen atomsC07D 401/12 linked by a chain containin...View All
