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    • 专利摘要:
    A TNF-α inhibitor containing a heterocyclic compound having angiotensin II antagonistic activity, useful as a prophylactic / treatment agent for inflammatory diseases and the like.
    公开号:KR20030016229A
    申请号:KR1020027010709
    申请日:2001-02-15
    公开日:2003-02-26
    发明作者:이께야가즈아끼；기따요시다까히또
    申请人:다케다 야쿠힌 고교 가부시키가이샤；
    IPC主号:
    专利说明:

    TNP-α inhibitor {TNF-αINHIBITORS}
    [2] TNF (Tumor Necrosis Factor) -α is believed to play an important role in various diseases. For example, chronic rheumatoid arthritis, an inflammatory disease, increases TNF-α production, which can lead to destruction of joint tissue.
    [3] There is a need for the development of TNF-α inhibitors with sufficiently good pharmaceutical characteristics such as good prophylactic or therapeutic effects on inflammatory diseases and no side effects.
    [1] The present invention relates to a TNF-α inhibitor containing a heterocyclic compound having angiotensin II antagonism, a prodrug or salt thereof, and useful as a prophylactic or therapeutic agent for inflammatory diseases and the like.
    [4] In view of this situation described above, the inventors have endeavored to develop a medicament useful for inhibiting TNF- [alpha], thereby providing heterocyclic compounds with angiotensin II antagonism, in particular angiotensin II (AII) antagonism represented by certain structural formulas. Unexpectedly found that the compound having is very effective in inhibiting TNF-α, and further study from this knowledge, to complete the present invention.
    [5] That is, the present invention relates to the following (1) to (17) and the like:
    [6] (1) the following formula:
    [7]
    [8] [Wherein, ring B is an optionally substituted nitrogen-containing heterocyclic group, R 1 is a group capable of forming an anion or can be converted to such a group, and X is a phenylene group and a phenyl group directly or in an atomic chain 2 Heterocyclic compounds (compounds having angiotensin II receptor antagonism) having angiotensin II antagonism represented by the following spacers, n being an integer of 1 or 2;
    [9]
    [10] Compound represented by [5,7-dimethyl-1-{[2 '-(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl] methyl} -3,4-dihydro -1,6-naphthyridin-2 (1H) -one], a TNF-α inhibitor containing a prodrug thereof or a salt thereof;
    [11] (2) the inhibitor according to the above (1), wherein the heterocyclic compound is a compound having an oxygen atom in the molecule;
    [12] (3) the inhibitor according to the above (1), wherein the heterocyclic compound is a compound having an ether bond or a carbonyl group;
    [13] (4) the inhibitor according to (1) above, wherein ring B is an optionally substituted nitrogen-containing aromatic heterocyclic ring;
    [14] (5) the inhibitor according to (1) above, wherein ring B is an optionally substituted 5- to 6-membered nitrogen-containing heterocyclic ring;
    [15] (6) the inhibitor according to the above (1), wherein ring B is an optionally substituted imidazole ring;
    [16] (7) The inhibitor according to the above (1), wherein the heterocyclic compound is a compound represented by the following formula (I):
    [17]
    [18] [Wherein R 1 is a group capable of forming an anion or a group which can be converted to such a group, X represents a phenylene group and a phenyl group bonded directly or through a spacer having up to 2 atomic atoms, n is 1 or Is an integer of 2, ring A is further an optionally substituted benzene ring, R 2 is a group capable of forming anions or a group that can be converted to such groups, and R 3 can be bonded via a heteroatom Substituted hydrocarbon residues;
    [19] (8) The above-mentioned (1), wherein the heterocyclic compound is losartan, eprosartan, candesartan cilexetil, candesartan, telmisartan, irbesartan, olmesartan or tasosartan Phosphorus inhibitors;
    [20] (9) The above-mentioned (1), wherein the heterocyclic compound is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole Inhibitors which are -7-carboxylic acids;
    [21] (10) The above-mentioned (1), wherein the heterocyclic compound is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) Inhibitors which are biphenyl-4-yl] methyl] benzimidazole-7-carboxylates;
    [22] (11) The above-mentioned (1), wherein the heterocyclic compound is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole- Inhibitors which are 3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid;
    [23] (12) the inhibitor according to (1), which is a prophylactic or therapeutic agent for a disease involving TNF-α (eg, a disease that develops or worsens in the presence of TNF-α);
    [24] (13) the inhibitor according to the above (1), which is an anti-inflammatory agent;
    [25] (14) use for the inhibition of TNF-α of a heterocyclic compound having angiotensin II antagonism, a prodrug thereof, or a salt thereof;
    [26] (15) use for the preparation of a medicament for inhibiting TNF-α of a heterocyclic compound having angiotensin II antagonism, a prodrug thereof, or a salt thereof;
    [27] (16) the following formula:
    [28]
    [29] [Wherein, ring B is an optionally substituted nitrogen-containing heterocyclic group, R 1 is a group capable of forming an anion or can be converted to such a group, and X is a phenylene group and a phenyl group directly or in an atomic chain 2 Heterocyclic compounds (5,7-dimethyl-1-{[2 '-(1H-tetrazole) having angiotensin II antagonism represented by the following spacers, n being an integer of 1 or 2; -5-yl) -1,1'-biphenyl-4-yl] methyl} -3,4-dihydro-1,6-naphthyridin-2 (1H) -one), a prodrug thereof A method of inhibiting TNF-α in a mammal comprising administering an salt thereof to the mammal in an effective amount;
    [30] (17) the following formula:
    [31]
    [32] [Wherein, ring B is an optionally substituted nitrogen-containing heterocyclic group, R 1 is a group capable of forming an anion or can be converted to such a group, and X is a phenylene group and a phenyl group directly or in an atomic chain 2 Heterocyclic compounds (5,7-dimethyl-1-{[2 '-(1H-tetrazole) having angiotensin II antagonism represented by the following spacers, n being an integer of 1 or 2; -5-yl) -1,1'-biphenyl-4-yl] methyl} -3,4-dihydro-1,6-naphthyridin-2 (1H) -one), a prodrug thereof Use for the preparation of TNF-α inhibitors thereof.
    [33] Heterocyclic compounds having angiotensin II antagonism, prodrugs or salts thereof, according to the present invention may inhibit TNF-α (eg, inhibit TNF-α production or inhibit TNF-α by TNF-α receptor inhibition). Can be used to advantage.
    [34] Angiotensin II antagonism according to the present invention means a competitive or noncompetitive inhibitory effect on the binding of angiotensin II to angiotensin II receptor on the cell membrane, which reduces the strong vasoconstriction or vascular smooth muscle proliferation induced by angiotensin .
    [35] Heterocyclic compounds having angiotensin II antagonism used in the present invention are preferably non-peptidic heterocyclic compounds having antagonistic action, which show a long advantage. Such heterocyclic compounds having angiotensin II antagonism are particularly preferably compounds having oxygen atoms in the molecule, preferably compounds having ether bonds or carbonyl groups (wherein the carbonyl groups can be conjugated to form hydroxyl groups) More preferably a compound or ketone derivative having an ether bond, most preferably an ether derivative.
    [36] In the above formula, the “optionally substituted nitrogen-containing heterocyclic ring” represented by ring B is preferably an optionally substituted nitrogen-containing aromatic heterocyclic ring. Such “optionally substituted nitrogen containing heterocyclic rings” represented by ring B are preferably optionally substituted 5- to 6-membered nitrogen containing heterocyclic rings, especially optionally substituted 5- to 6-membered nitrogen-containing aromatic hetero Rings, optionally substituted imidazole rings, which may be condensed into cyclic rings (eg, aromatic rings, such as optionally substituted benzene rings, which may have substituents similar to those exemplified as substituents on ring A described below), typically Optionally substituted imidazole ring, optionally substituted benzimidazole ring). The substituents that the "nitrogen-containing heterocyclic ring" in the "optionally substituted nitrogen-containing heterocyclic ring" represented by ring B may have may be a substituent similar to that exemplified by the substituent on ring A described below.
    [37] Non-peptide heterocyclic compounds having angiotensin II antagonism are not particularly limited, but JP-A-56-71073, JP-A-56-71074, JP-A-57-98270, JP-A-58-157768 , Modifications disclosed in the imidazole derivatives disclosed in USP 4,355,040 and USP 4,340,598, etc., EP-253310, EP-291969, EP-324377, EP-403158, WO-9100277, JP-A-63-23868 and JP-A-1-117876 and the like. Pyrrole, pyrazole and triazole derivatives disclosed in imidazole derivatives, USP 5,183,899, EP-323841, EP-409332 and JP-A-1-287071, etc., USP 4,880,804, EP-0392317, EP-0399732, EP-0400835, EP- Benzimidazole derivatives disclosed in 425921, EP-459136 and JP-A-3-63264, etc., azaindene derivatives disclosed in EP-399731, pyrimidone derivatives disclosed in EP-407342, etc., quinazoline derivatives disclosed in EP-411766, etc. Xanthine derivative disclosed in 430300, condensed imidazole derivative disclosed in EP-434038, etc., pyrimidinedione derivative disclosed in EP-442473, and thienopyridone disclosed in EP-443568, etc. The conductor, as well as the heterocyclic compounds disclosed in EP-445811, EP-483683, EP-518033, EP-520423, EP-588299, EP-603712 can be mentioned. Among those listed above, representative compounds are also described in Journal of Medicinal Chemistry, Vol. 39, No. 3, p. 625-656, 1996. The non-peptide heterocyclic compound having angiotensin II antagonism may also be any other non-peptidic heterocyclic compound other than the compounds described in the publications described above, and may include losartan (DuP753), eprosartan (SK & F108566). , Candesartan cilexetil (TCV-116), telmisartan (BIBR277), irbesartan (SR47436), tasosartan (ANA-756), olmesartan and their metabolic active agents (eg candesartan) ) Is preferably used.
    [38] As a heterocyclic compound having angiotensin II antagonism, benzimidazole derivatives represented by the following formula (I) or salts thereof are preferably used:
    [39] [Formula I]
    [40]
    [41] [Wherein R 1 is a group capable of forming an anion or a group which can be converted to such a group, X represents that the phenylene group and the phenyl group are bonded directly or through a spacer having up to 2 atomic atoms, and n is 1 or Is an integer of 2, ring A is further an optionally substituted benzene ring, R 2 is a group capable of forming anions or a group that can be converted to such a group, and R 3 can be bonded via a heteroatom Substituted hydrocarbon residues (preferably optionally substituted hydrocarbon residues bonded via an oxygen atom).
    [42] In the above formula, the group represented by R 1 capable of forming an anion (a group having a hydrogen atom that can be liberated by protons) is, for example, (1) carboxyl group, (2) tetrazolyl group, (3) Optionally substituted 5-containing one or more heteroatoms selected from trifluoromethanesulfonamide groups (-NHSO 2 CF 3 ), (4) phosphoric acid groups, (5) sulfonic acid groups, (6) N, S and O To 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic moieties.
    [43] The above-described "optionally substituted 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic moieties containing at least one heteroatom selected from N, S and O" is for example Can be:
    [44]
    [45]
    [46] The bond between the heterocyclic moiety represented by R 1 and the phenyl group to which the heterocyclic moiety is bonded is not only the carbon-carbon bond shown above but also one of several nitrogen atoms when g in the formula represents -NH-. Can be. For example, R 1 is represented by the formula:
    [47]
    [48] Where indicated, the following types of combinations are specifically listed:
    [49]
    [50] Other nitrogen atom-mediated bonds include those represented by the formula:
    [51]
    [52] In the above formula, g is -CH 2- , -NH-, -O- or -S (O) m -and each> = Z,> = Z 'and> = Z "is a carbonyl group, thiocar A carbonyl group or optionally oxidized sulfur atom (eg, S, S (O), S (O) 2, etc.) (preferably carbonyl or thiocarbonyl groups, more preferably carbonyl groups), m Is an integer of 0, 1 or 2.
    [53] Preferably, the heterocyclic moiety represented by R 1 is a group having, for example, a -NH- or -OH group as a proton donor and a carbonyl group, thiocarbonyl group or sulfinyl group as a proton acceptor, such as an oxadiazolone ring , An oxydiazolothione ring or a thiadiazolone ring. In addition, the heterocyclic moiety represented by R 1 may form a condensed ring together with the cyclic substituent, in which case the heterocyclic moiety represented by R 1 is preferably a 5- to 6-membered ring moiety, more preferably Preferably a 5-membered ring residue.
    [54] The heterocyclic moiety represented by R 1 is preferably a group represented by the following formula:
    [55]
    [56] Wherein i is -O- or -S-, j is> = O,> = S or> = S (O) m and m is as defined above (2,5-dihydro-5) Oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro- 5-oxo-1,2,4-thiadiazol-3-yl, in particular 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl).
    [57] The heterocyclic moieties (R 1 ) described above exist in tautomeric forms as shown below. For example, when Z = O and g = O in the formula:
    [58]
    [59] There are three tautomeric forms a ', b' and c 'represented by the formula:
    [60]
    [61] It is understood that the heterocyclic moiety represented by the following formula includes all of a ', b' and c 'shown above:
    [62]
    [63] Groups represented by R 1 capable of forming anions are protected at positions substitutable with optionally substituted lower (C 1-4 ) alkyl groups or acyl groups (eg lower (C 2-5 ) alkanoyl, benzoyl) and the like Can be.
    [64] The optionally substituted lower (C 1-4 ) alkyl group includes, for example, (1) 1 to 1 which may have a halogen atom, nitro, lower (C 1-4 ) alkyl, lower (C 1-4 ) alkoxy, and the like. Lower (C 1-4 ) alkyl groups which may be substituted with three phenyl groups (eg methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl), (2) lower (C 1-4 ) Alkoxy-lower (C 1-4 ) alkyl groups (eg, methoxymethyl, ethoxymethyl), and (3) the formula -CH (R 4 ) -OCOR 5, wherein R 4 is (a) hydrogen, ( b) linear or branched lower alkyl groups of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl ), (c) a linear or branched lower alkenyl group having 2 to 6 carbon atoms or (d) a cycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl), and R 5 is ( a) linear or branched lower alkyl groups of 1 to 6 carbon atoms (e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl), (b) linear or minute carbon atoms Topographic lower alkenyl groups, (c) cycloalkyl groups having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl) or optionally substituted aryl groups (eg, halogen atoms, nitro, lower (C) 1-4 ) lower alkyl groups having 1 to 3 carbon atoms (eg, benzyl, p-chlorobenzyl, phenethyl, substituted with alkyl, phenyl or naphthyl groups which may have lower (C 1-4 ) alkoxy), Cyclopentyl, methyl, cyclohexylmethyl), (d) cycloalkyl or optionally substituted aryl groups having 3 to 8 carbon atoms (e.g., halogen atoms, nitro, lower (C 1-4 ) alkyl, lower (C 1-) 4) a lower alkenyl group (e.g., having 2 to 3 substituted with a phenyl or naphthyl group) which may have an alkoxy example, plastic that contains a cinnamyl, Groups having alkenyl moieties such as rophenyl, allyl, isopropenyl), (e) optionally substituted aryl groups (e.g. halogen atoms, nitro, lower, including phenyl, p-tolyl, naphthyl) C 1-4 ) alkyl, phenyl or naphthyl group which may have lower (C 1-4 ) alkoxy), (f) linear or branched lower alkoxy groups having 1 to 6 carbon atoms (eg methoxy, Oxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy), (g) 2 to 8 carbon atoms Linear or branched lower alkenyloxy groups (eg allyloxy, isobutenyloxy), (h) cycloalkyloxy groups having 3 to 8 carbon atoms (eg cyclopentyloxy, cyclohexyloxy, cyclo Heptyloxy), (i) cycloalkyl having 3 to 8 carbon atoms (eg cyclopentyl, cyclohexyl, cyclobutyl) or optionally substituted aryl groups (eg Lower alkoxy groups having 1 to 3 carbon atoms (eg, benzyl) substituted with halogen atoms, nitro, lower (C 1-4 ) alkyl, phenyl or naphthyl groups which may have lower (C 1-4 ) alkoxy) Groups having alkoxy moieties such as methoxy, ethoxy, n-propoxy and isopropoxy, including oxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy), (j) having from 3 to 8 carbon atoms Cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl) or optionally substituted aryl groups (eg, halogen atoms, nitro, lower (C 1-4 ) alkyl, lower (C 1-4 ) alkoxy Lower alkenyloxy groups (e.g., vinyloxy, propenyloxy, allyloxy and isopropenyloxy, including cinnamiloxy) substituted with phenyl or naphthyl groups which may have Groups having alkenyloxy moieties) or (k) optionally substituted aryloxy groups (eg, When, p- you neoplasm Peroxy, which contains a naphthoxy a halogen atom, nitro, lower (C 1-4) alkyl, lower (C 1-4) alkoxy or phenoxy which may have a naphthoxy group); Included groups include.
    [65] The group represented by R 1 capable of forming an anion is a protecting group as described above such as an optionally substituted lower (C 1-4 ) alkyl group or an acyl group (eg lower (C 2-5 ) alkanoyl, benzoyl) in addition to, an additional substituent, for example an optionally substituted lower (C 1-4) alkyl (for example, the above-exemplified as the protective group for groups represented by R 1 to form a negative ion "optionally substituted lower (C 1-4 ) Alkyl group "), a halogen atom, nitro, cyano, lower (C 1-4 ) alkoxy, and amino, which may be substituted with one or two lower (C 1-4 ) alkyls.
    [66] In the above formula, the group represented by R 1 capable of forming anions (groups having oxygen atoms which may liberate protons) is subjected to biological, ie physiological, conditions (eg, in vivo reactions such as oxidation by enzymes in vivo). Can be converted into a group capable of forming anions (ie, as a result of reduction or hydrolysis) (ie, a prodrug), or converted into a group capable of forming anions represented by R 1 as a result of a chemical reaction. Groups which may be (ie synthetic intermediates) such as cyano, N-hydroxycarbamimidoyl groups (-C (= N = OH) -NH 2 ), and optionally substituted lower (C 1-4 ) alkyls Groups (1)-(6) protected by groups or acyl groups: (1) carboxyl groups, (2) tetrazolyl groups, (3) trifluoromethanesulfonamide groups (-NHSO 2 CF 3 ), (4) phosphoric acid groups, (5) sulfonic acid groups and (6) one or more heteroatoms selected from N, S and O Optionally substituted 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic moieties.
    [67] R 1 is preferably an optionally substituted lower (C 1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl) or acyl group Carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazole-3 that may be protected (eg, lower (C 2-5 ) alkanoyl, benzoyl) -Yl (preferably tetrazolyl), or cyano, N-hydroxycarbamimidoyl (preferably cyano), particularly preferably tetrazolyl is used.
    [68] In the above formula, X represents that adjacent phenylene groups and phenyl groups are bonded (preferably direct bonds) directly or through spacers of atomic chain 2 or less, and such spacers of atomic chain 2 or less represent atoms that constitute a straight chain portion. It can be any divalent chain that can be 1 or 2 and have side chains. Lower (C 1-4 ) alkylene having 1 or 2 atoms constituting the straight-chain moiety, -CO-, -O-, -S-, -NH-, -CO-NH-, -O-CH 2- , -S-CH 2- , -CH = CH- and the like are typically exemplified.
    [69] In the above formula, n is an integer of 1 or 2 (preferably 1).
    [70] In the above formula, ring A is a benzene ring which may have additional substituents in addition to substituent R 2 , and such substituents include, for example, (1) halogen (eg, F, Cl, Br), (2) Cyano, (3) nitro, (4) optionally substituted lower (C 1-4 ) alkyl, (5) lower (C 1-4 ) alkoxy, (6) optionally substituted amino groups (eg, amino, N-lower (C 1-4 ) alkylamino (eg, methylamino), N, N-di lower (C 1-4 ) alkylamino (eg, dimethylamino), N-arylamino (eg Phenylamino), cycloaliphatic amino (eg, morpholino, piperidino, piperazino, N-phenylpiperadino), (7) Formula -CO-D 'wherein D' The hydroxyl group, or alkyl moiety, is a hydroxyl group, lower (C 1-4 ) alkoxy, lower (C 2-6 ) alkanoyloxy (eg, acetoxy, pivaloyloxy), lower (C 1-6 Alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycar Or lower (C 1-4 ) alkoxy which may be substituted by lower carbonyloxy) or lower (C 3-6 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy); or (8) an optionally substituted lower (C 1-4) alkyl (for example, the above-exemplified as the protective group of groups R 1 as capable of forming an anion "optionally substituted lower (C 1-4) alkyl group" Similar) or tetrazolyl, trifluoromethanesulfonamide groups, phosphoric acid groups or sulfonic acid groups, which may be protected with acyl (eg, lower (C 2-5 ) alkanoyl, benzoyl).
    [71] While one or two substituents listed above may occur simultaneously in a substitutable position on a benzene ring, further substituents other than the substituents R 2 that Ring A may have are preferably optionally substituted lower (C 1-4 ) alkyl ( For example, hydroxyl groups, carboxyl groups, lower (C 1-4 ) alkyl groups optionally substituted with halogen) and halogen, more preferably, ring A has no substituents other than substituent R 2 .
    [72] In the above formula, the group represented by R 2 capable of forming an anion (a group having a hydrogen atom which may liberate protons) is, for example, (1) an optionally esterified or amidated carboxyl group, (2 ) Tetrazolyl groups, (3) trifluoromethanesulfonamide groups (-NHSO 2 CF 3 ), (4) phosphoric acid groups, (5) sulfonic acid groups, and any such groups may be optionally substituted lower alkyl groups ( For example, as a protecting group for a group represented by R 1 capable of forming an anion, similar to the “optionally substituted lower (C 1-4 ) alkyl group” exemplified above) or an acyl group (eg, lower ( C 2-5 ) alkanoyl, benzoyl), and under biological or physiological conditions (eg, as a result of oxidation, reduction or hydrolysis by in vivo reactions such as enzymes in vivo) or by chemical reactions. As a result, anions may be formed or transferred to such groups. It may be any of the date which may be. Optionally esterified or amidated carboxyl represented by R 2 is, for example, a formula -CO-D- wherein D is (1) a hydroxyl group, (2) an optionally substituted amino (eg, Amino, N-lower (C 1-4 ) alkylamino, N, N-di-lower (C 1-4 ) alkylamino) or (3) optionally substituted alkoxy {eg, (i) alkyl moiety Hydroxyl groups, optionally substituted amino (eg, amino, N-lower (C 1-4 ) alkylamino, N, N-di-lower (C 1-4 ) alkylamino, piperidino, morpholino) , Halogen, lower (C 1-6 ) alkoxy, lower (C 1-6 ) alkylthio, lower (C 3-8 ) cycloalkoxy or optionally substituted dioxorenyl (eg, 5-methyl-2-oxo Lower (C 1-6 ) alkoxy groups which may be substituted with -1,3-dioxoren-4-yl), or (ii) -O-CH (R 6 ) -OCOR 7 -wherein R 6 is ( a) hydrogen, (b) linear or branched lower alkyl groups of 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl), (c) linear or branched lower alkenyl groups of 2 to 6 carbon atoms or (d) cycloalkyl groups of 3 to 8 carbon atoms (example For example, cyclopentyl, cyclohexyl, cycloheptyl), R 7 is (a) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl), (b) linear or branched lower alkenyl groups having 2 to 6 carbon atoms, (c) cyclo having 3 to 8 carbon atoms An alkyl group (e.g. cyclopentyl, cyclohexyl, cycloheptyl) or an optionally substituted aryl group (e.g. halogen atom, nitro, lower (C 1-4 ) alkyl, lower (C 1-4 ) alkoxy Lower alkyl groups of 1 to 3 carbon atoms substituted with phenyl or naphthyl groups which may have (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, Have a close-cyclohexylmethyl), (d) cycloalkyl or optionally substituted aryl group (e.g., halogen atom, nitro, lower (C 1-4 with 3 to 8 carbon atoms) alkyl, lower (C 1-4) alkoxy Lower alkenyl groups of 2 to 3 carbon atoms substituted with phenyl or naphthyl groups (e.g., groups having alkenyl moieties such as vinyl, propenyl, allyl, isopropenyl, including cinnamic) (e) have an optionally substituted aryl group (e.g., a halogen atom, including phenyl, p-tolyl, naphthyl, nitro, lower (C 1-4 ) alkyl, lower (C 1-4 ) alkoxy Phenyl or naphthyl groups), (f) linear or branched lower alkoxy groups having 1 to 6 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobu Methoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy), (g) linear or branched lower alkenyloxy of 2 to 8 carbon atoms Groups (eg allyloxy, isobutenyloxy), (h) cycloalkyloxy groups having 3 to 8 carbon atoms (eg cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), (i) 3 carbon atoms Cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl) to 8 to 8 or optionally substituted aryl groups (eg, halogen atoms, nitro, lower (C 1-4 ) alkyl, lower (C 1-4) Lower alkyl alkoxy groups (eg, benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy) substituted with a phenyl or naphthyl group which may have alkoxy) , Groups having alkoxy moieties such as ethoxy, n-propoxy and isopropoxy), (j) cycloalkyl having 3 to 8 carbon atoms (eg cyclopentyl, cyclohexyl, cycloheptyl) or optionally substituted aryl group (e.g., halogen atom, nitro, lower (C 1-4) alkyl, lower (C 1-4) al Lower alkenyloxy groups (e.g., vinyloxy, propenyloxy, allyloxy and isopropenyloxy, including cinnamiloxy) substituted with a phenyl or naphthyl group which may have a c. Groups having an alkenyloxy moiety such as) or (k) an optionally substituted aryloxy group (e.g., phenoxy, p-nitrophenoxy, naphthoxy, halogen atom, nitro, lower (C 1- 4 ) phenoxy or naphthoxy group which may have alkyl and lower (C 1-4 ) alkoxy).
    [73] As R 2 , optionally esterified carboxyl is preferred, typical examples of which are -COOH and its salts, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohex) Siloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxoren-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n -Butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutyryloxy ) Ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamiloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, and the like, under biological or physiological conditions (e.g., For example, in vivo reactions as a result of oxidation, reduction or hydrolysis by enzymes in vivo) or chemical reactions. It can be any group that can form anions (eg, COO - or derivatives thereof) as a result of the reaction or can be converted to such groups, and can also be a carboxyl group or a prodrug thereof.
    [74] As R 2 described above, the formula -CO-D (wherein D is either (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group, amino, halogen, lower (C 2-6 ) alkanoyloxy (e.g. For example, acetoxy, pivaloyloxy), lower (C 3-8 ) cycloalkanoyloxy, lower (C 1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy ), Lower (C 3-8 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy), lower (C 1-4 ) alkoxy or lower (C 3-8 ) cycloalkoxy Group is a lower (C 1-4 ) alkoxy group], and particularly preferred is a carboxyl esterified with lower (C 1-4 ) alkyl (preferably methyl or ethyl).
    [75] In the above formula, as the "hydrocarbon moiety" in the "optionally substituted hydrocarbon moiety which may be bonded via a heteroatom" represented by R 3 , for example, (1) an alkyl group, (2) an alkenyl group, ( 3) alkynyl groups, (4) cycloalkyl groups, (5) aryl groups, (6) aralkyl groups and the like may be included, among which alkyl groups, alkenyl groups and cycloalkyl groups are preferred.
    [76] The alkyl groups of (1) described above are linear or branched lower alkyl groups of about 1 to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl , i-pentyl, hexyl, heptyl, octyl and the like.
    [77] The alkenyl groups of (2) described above are linear or branched lower alkenyl groups having about 2 to 8 carbon atoms, for example vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-jade Tenyl and the like.
    [78] The alkynyl groups of (3) described above are linear or branched lower alkynyl groups having about 2 to 8 carbon atoms, for example ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-jade Tinyl and the like.
    [79] The cycloalkyl group of (4) described above may be lower cycloalkyl having about 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
    [80] Any of the alkyl groups, alkenyl groups, alkynyl groups or cycloalkyl groups described above are hydroxyl groups, optionally substituted amino groups (eg, amino, N-lower (C 1-4 ) alkylamino, N, N -Di-lower (C 1-4 ) alkylamino), halogen, lower (C 1-4 ) alkoxy groups, lower (C 1-4 ) alkylthio groups and the like.
    [81] The aralkyl group of (5) described above can be for example phenyl-lower (C 1-4 ) alkyl such as benzyl and phenethyl, and the aryl group of (6) described above can be for example phenyl.
    [82] The aralkyl group or aryl group described above may be, at any position on its benzene ring, for example, halogen (eg F, Cl, Br), nitro, optionally substituted amino group (eg amino, N-lower (C 1-4 ) alkylamino, N, N-di-lower (C 1-4 ) alkylamino), lower (C 1-4 ) alkoxy (eg, methoxy, ethoxy), lower (C 1-4 ) alkylthio (eg methylthio, ethylthio), lower (C 1-4 ) alkyl (eg methyl, ethyl).
    [83] Among those listed above, the "hydrocarbon moiety" in the "optionally substituted hydrocarbon moiety which may be bonded via a heteroatom" represented by R 3 is preferably an optionally substituted alkyl or alkenyl group (e.g. Preference is given to lower (C 1-5 ) alkyl or lower (C 2-5 ) alkenyl groups) which may be substituted with a hydroxyl group, amino group, halogen or lower (C 1-4 ) alkoxy group, among which lower (C 1-5 ) Alkyl (more preferably ethyl) is particularly preferred.
    [84] Examples of the "heteroatom" in the "optionally substituted hydrocarbon moiety which may be bonded via a heteroatom" represented by R 3 include, for example, -O-, -S (O) m [m is an integer of 0 to 2; ], -NR'- [R 'is a hydrogen atom or lower (C 1-4 ) alkyl], of which -O- is particularly preferred.
    [85] Among those listed above, R 3 is preferably -O-, -S (O) M- [m is an integer from 0 to 2] or -NR '-[R' is a hydrogen atom or a lower (C 1- 4 ) alkyl; lower (C 1-5 ) alkyl or lower (C) which may be bonded via a substituent selected from a hydroxyl group, an amino group, a halogen and a lower (C 1-4 ) alkoxy group 2-5 ) alkenyl groups, more preferably lower (C 1-5 ) alkyl or lower (C 2-5 ) alkoxy (especially ethoxy).
    [86] Among the heterocyclic compounds represented by formula (I) having angiotensin II antagonism, benzimidazole-7-carboxylic acid derivatives represented by formula (I '), or physiologically acceptable salts thereof, are preferred:
    [87]
    [88] [Wherein R 1 is a group represented by the following formula (1) carboxyl group, (2) tetrazolyl group or (3):
    [89]
    [90] (Wherein i is -O- or -S-, j is> = O,> = S or> = S (O) m and m is as defined above), ring A is in addition to substituent R 2 an optionally substituted lower (C 1-4) alkyl (for example, a hydroxyl group, a carboxyl group or may be substituted by halogen, lower (C 1-4) alkyl), or a benzene ring (preferably optionally substituted by halogen Benzene ring having no substituent other than substituent R 2 ), and R 2 is of the formula -CO-D, wherein D is (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group, amino, halogen, lower (C 2-6 ) alkanoyloxy (eg, acetoxy, pivaloyloxy), lower (C 3-8 ) cycloalkanoyloxy, lower (C 1-6 ) alkoxycarbonyloxy (eg , Methoxycarbonyloxy, ethoxycarbonyloxy), lower (C 3-8 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy), lower (C 1-4 ) alkoxy or lower (C 3-8) when A lower alkoxy (C 1-4) alkoxy group] which may be substituted with, R 3 is -O-, -S (O) m - [m is an integer from 0 to 2] or -NR'- [ R 'is a hydrogen atom or lower (C 1-4 ) alkyl] and may be substituted with substituents selected from hydroxyl groups, amino groups, halogens and lower (C 1-4 ) alkoxy groups (C 1-5 ) alkyl or lower (C 2-5 ) alkenyl group (preferably lower (C 1-5 ) alkyl or lower (C 2-5 ) alkoxy; more preferably ethoxy)], Double 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid [candesartan], 1- ( Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate [ Candesartan cilexetil], pivaloyloxymethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-car Carboxylate, 2- Methoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- Particular preference is given to carboxylic acids or salts thereof.
    [91] Any of the above described benzimidazole derivatives are prepared by known or similar methods, for example as described in EP-425921, EP-459136, EP-553879, EP-578125, EP-520423, EP-668272. can do. When using candesartan cilexetil, it is preferable to use the stable C-form crystals described in EP-459136.
    [92] Heterocyclic compounds having angiotensin II antagonism or prodrugs thereof used in the present invention may be themselves or in the form of pharmaceutically acceptable salts thereof. When the heterocyclic compound having angiotensin II antagonism has an acidic group such as a carboxyl group, such salts include, for example, inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, transition metals such as Zinc, iron and copper) or organic bases (eg, organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N-dibenzyl Salts with ethylenediamine, basic amino acids such as arginine, lysine and ornithine).
    [93] When the heterocyclic compound having angiotensin II antagonism has a basic group such as an amino group, an inorganic acid or an organic acid (e.g. hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid) Salts with oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid) or acidic amino acids such as aspartic acid and glutamic acid.
    [94] Prodrugs of heterocyclic compounds having angiotensin II antagonistic action (hereinafter referred to as AII-antagonist compounds) used in the present invention are compounds which are converted into AII-antagonist compounds by reaction with enzymes or gastric acids under in vivo conditions, ie, enzyme oxidation , A compound which is converted into an AII-antagonist compound by reduction or hydrolysis, a compound which is hydrolyzed by gastric acid and converted into an AII-antagonist compound. Prodrugs of AII-antagonist compounds include, for example, compounds formed by acylation, alkylation or phosphorylation of the amino groups of the AII-antagonist compounds (e.g., eicosanoylation of the amino groups of the AII-antagonist compounds, Allah Nylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxoren-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation , tert-butylated compounds); Compounds formed by acylation, alkylation, phosphorylation or boration of the hydroxyl groups of the AII-antagonist compounds (e.g., acetylation, palmitoylation, propanoylation, pivaloyl lakes, succinates of the hydroxyl groups of the AII-antagonist compounds) Compounds formed by nilation, fumarylation, alanylation, dimethylaminomethylcarbonylation); And compounds formed by esterification or amidation of carboxyl groups of AII-antagonist compounds (eg, ethyl-esterification, phenyl-esterification, carboxymethyl-esterification, dimethylaminomethyl of carboxyl groups of AII-antagonist compounds). Esterification, pivaloyloxymethyl-esterification, ethoxycarbonyloxyethyl-esterification, phthalidyl-esterification, (5-methyl-2-oxo-1,3-dioxoren-4-yl Methyl-esterified, cyclohexyloxycarbonyloxyethyl-esterified and methylamidated compounds). Any such compounds can be prepared from AII-antagonist compounds by known methods.
    [95] Prodrugs of AII-antagonists are compounds that can be converted to AII-antagonists under physiological conditions as described in "IYAKUHINNOKAIHATSU (Pharmaceutical development), Vol. 7, Molecular designing, p163-198, HIROKAWASHOTEN, 1990". Can be.
    [96] AII-antagonist compounds may be hydrates or anhydrides.
    [97] Heterocyclic compounds having angiotensin II antagonism or pharmaceutically acceptable salts thereof used in the present invention are low-toxic and can be used in mammals (eg, in the form of pharmaceutical compositions as such or as a mixture with a pharmaceutically acceptable carrier). For example, humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys, etc.) as a TNF-α inhibitor.
    [98] Pharmaceutically acceptable carriers as used herein include any of a variety of organic and inorganic carriers commonly used as pharmaceutical materials, such as excipients, lubricants, binders and disintegrants for solid formulations; Solvents, solubilizers, suspending agents, isotonic agents, buffers and analgesics for liquid formulations. Pharmaceutical additives such as preservatives, antioxidants, colorants and sweeteners may also be used if desired.
    [99] Preferred examples of excipients include, for example, lactose, sugars, D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, gum arabic, dextrin , Pullulan, hard silicic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.
    [100] Preferred examples of lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
    [101] Preferred examples of binders include, for example, α-starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, sugars, D-mannitol, trehalose, dextrin, pullulan, Hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
    [102] Preferred examples of disintegrants include, for example, lactose, sugars, starch, carboxymethyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, hard silicic anhydride, low substituted hydroxypropylcellulose, and the like. do.
    [103] Preferred examples of the solvent include water for injection, saline solution, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
    [104] Preferred examples of solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like. This includes.
    [105] Preferred examples of suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; Hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like; Polysorbate and polyoxyethylene cured castor oil and the like.
    [106] Preferred examples of isotonic agents include, for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
    [107] Preferred examples of buffers include, for example, buffered solutions of phosphate, acetate, carbonate, citrate and the like.
    [108] Preferred examples of analgesic agents include, for example, benzyl alcohol and the like.
    [109] Preferred examples of preservatives include, for example, p-oxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
    [110] Preferred examples of antioxidants include, for example, sulfites, ascorbates and the like.
    [111] Preferred examples of the colorant include, for example, water-soluble food tar pigments (food dyes such as food red 2 and 3, food yellow 4 and 5, food blue 1 and 2), and water insolubles. Lake pigments (eg, aluminum salts of the water-soluble edible tar pigments described above), naturally occurring pigments (eg β-carotene, chlorophyll, iron withdrawal) and the like.
    [112] Preferred examples of sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhetinate, aspartame, stevioside and the like.
    [113] Formulations of pharmaceutical compositions include, for example, oral formulations such as tablets, capsules (including soft capsules, microcapsules), granules, powders, syrups, emulsions, suspensions, and the like; And injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, intravitreal injections), infusion formulations, external preparations (eg nasal formulations, transdermal formulations, ointments), suppositories ( Parenteral formulations such as, for example, rectal suppositories, vaginal suppositories), pellets, drop formulations, and the like, which can be safely administered via the oral or parenteral route.
    [114] The pharmaceutical composition may be prepared by methods commonly used in the pharmaceutical manufacturing field, for example, by the methods described in Japanese Pharmacopoeia. Typical methods of preparing pharmaceutical formulations are described below.
    [115] For example, oral formulations may include excipients (eg, lactose, sugars, starches, D-mannitol), disintegrants (eg, carboxymethylcellulose calcium), binders (eg, α-starch, gum arabic) , Carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone) and lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000) are added to the active ingredient, compression molded and, if necessary, It is prepared by coating with a coating substrate by methods known per se for the purpose of shielding, enteric function or sustained release.
    [116] The coating base material includes, for example, a sugar coating base material, a water-soluble film coating base material, an enteric film coating base material, a sustained release film coating base material, and the like.
    [117] As the sugar coating substrate, sugar is used, and may also be used in combination with one or more kinds of substrates selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like.
    [118] As the water-soluble film coating substrate, for example, cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and the like; Synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E ™, Rohm Pharma], polyvinylpyrrolidone; Polysaccharides such as pullulan and the like.
    [119] Enteric film coating substrates include, for example, cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like; Acrylic acid-based polymers such as methacrylic acid polymer L [Eudragit L ™, Rohm Pharma], methacrylic acid copolymer LD [Eudragit L-30D55 ™, Rohm Pharma], methacrylic acid copolymer S [Eudragit S ( Trade name), Rohm Pharma] and the like; And naturally occurring substances such as shellac.
    [120] Sustained release film coating substrates, for example, cellulose-based polymers such as ethylcellulose; And acrylic acid-based polymers such as aminoalkylmethacrylate copolymer RS [Eudragit RS ™, Rohm Pharma], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE ™, Rohm Pharma], and the like. .
    [121] Two or more of the above described coating substrates may be used as appropriate proportions of admixture. The coating may be supplemented with an opacity-imparting agent such as titanium oxide and Fe 3 O 2 .
    [122] Injectables can be prepared by dispersing the active ingredient in an aqueous solvent (e.g., distilled water, saline, Ringer's solution) or an oily solvent (e.g., vegetable oils such as olive oil, sesame oil, cottonseed oil and corn oil, propylene glycol). Bait 80, polyoxyethylene cured castor oil 60), polyethylene glycol, carboxymethylcellulose, sodium alginate, preservatives (eg methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol), isotonic agents (eg, It can be prepared by dissolving, suspending or emulsifying with sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose). In such cases, if desired, additives such as solubilizers (eg sodium salicylate, sodium acetate), stabilizers (eg human serum albumin), analgesic agents (eg benzyl alcohol) and the like can be added. .
    [123] The daily dosage of the heterocyclic compound having angiotensin II antagonistic action or a pharmaceutically acceptable salt thereof used in the present invention depends on the subject to be treated, the route of administration, the disease and the condition to be treated, for example, for oral administration, Heterocyclic compound having angiotensin II antagonism or a pharmaceutically acceptable salt thereof in an amount of about 0.001 to 1000 mg, preferably about 0.1 to 50 mg active ingredient once daily to mammals, especially humans (50 kg body weight) It is common to administer three to three times.
    [124] The TNF-α inhibitors of the present invention are directed to mammals (eg, humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys) as a prophylactic or therapeutic agent for diseases involving TNF-α. Can be used. Diseases involving TNF-α are diseases that develop or worsen in the presence of TNF-α and can be treated through an inhibitory effect on TNF-α. Such diseases include, for example, inflammatory diseases [eg, diabetic complications such as retinopathy, nephropathy, neuropathy and macrovascular disorders, diabetic nephropathy; Arthritis such as chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis and periostitis; Postoperative / post-traumatic inflammation; Relief of swelling; pharyngitis; cystitis; Pneumonia; myocarditis; Cardiomyopathy; Atopic dermatitis; Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; meningitis; Inflammatory eye disease; Inflammatory lung disease, such as pneumonia, tuberculosis tuberculosis, pulmonary sarcoma and pulmonary tuberculosis], circulatory diseases (eg, arrhythmia, including atherosclerosis, chronic heart failure, such as arrhythmia, angina, myocardial infarction, heart failure and congestive heart failure) Hypertension, deep vein thrombosis, obstructive peripheral circulatory disorder, ischemic cerebral circulation disorder, disseminated intravascular coagulation syndrome, Raynaud's disease, Burger's disease), portal hypertension, pulmonary hypertension, asthma, allergic rhinitis, conjunctivitis, digestive tract allergy, hay fever and hypersensitivity Allergic diseases such as, chronic obstructive pulmonary disease, collagen (eg, lupus erythematosus, scleroderma, polyarteritis), Crohn's disease, autoimmune hemolytic anemia, psoriasis, hepatitis and chronic liver disease, including chronic diseases Diseases, pancreatic diseases such as pancreatitis, neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy), central nervous system disorders (e.g. For example, cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, and sequelae thereof, head trauma, spinal cord injury, cerebral edema, dementia, memory disorders, conscious disorders, multiple symptomatosis), ischemia (e.g. Shock, Gram-negative sepsis, toxin shock syndrome), menopausal disorders, pregnancy addiction, obesity, hyperlipidemia, hypercholesterolemia, impaired glucose tolerance, solid tumors, tumors (e.g. malignant melanoma, malignant lymphoma, digestive organs (e.g. stomach) Cancer), cancer and accompanying cachexia, endocrine diseases (Addison's disease, Cushing's syndrome, melanoma, primary aldosteroneism), Creutzfeldt-Jakob disease, viral infections (e.g., cytomegalovirus, influenza virus, herpes virus) Back infection), vascular thickening or occlusion after percutaneous coronary angioplasty, vascular reclosure / restriction after PTCA / stent placement / bypass surgery, inter Vascular thickening or blockage after shedding, inhibition of vascular disorders and rejection at the time of transplantation, dialysis hypotension, glaucoma, ocular hypertension, myasthenia gravis, chronic fatigue syndrome, bone disease (e.g., fractures, osteoporosis, osteomalacia, bone behette disease, Spastic spondylitis, chronic rheumatoid arthritis, degenerative knee osteoarthritis as well as destruction of joint tissue in related diseases).
    [125] The TNF-α inhibitors of the present invention may be used alone in treatment, or as a hypolipidemic or cholesterol lowering agent, a HMG-Co A reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitor, a myocardial protective agent, Coronary artery disease, Other hypertension, Chronic heart failure, Diabetes, Other insulin sensitivity, Hypothyroidism, Nephrotic syndrome, Anti-inflammatory (NSAIDS), Bone disease (such as osteoporosis) or Chronic renal failure It can be used in combination with other pharmaceutically active ingredients, in which case any such ingredients are preferably administered as oral formulation or, if necessary, as rectal formulation in the form of suppositories. Possible combination components described above include, for example, fibrate [e.g. clofibrate, benzafibrate, GEMFIBRODIL], nicotinic acid, derivatives and analogues thereof [e.g. ACIPIMOX and probucol], bile acid binding resins [Eg, cholestyramine, cholestipol], cholesterol absorption inhibitors [eg, cytosterol, neomycin], squalene epoxidase inhibitors [eg, NB-598 and analogs], and the like.
    [126] Other components that can be combined are oxidesqualene-lanosterol cyclases such as decalin derivatives, azadecalin derivatives and indan derivatives.
    [127] Treatment of hypertension: diuretics (eg, furosemide (Lassix), bumetanide, azosemide (Diart)), hypertensives [eg, ACE inhibitors (enalapril maleate) And Ca antagonists (manidipine, amlodipine), α or β receptor blockers];
    [128] Treatments for chronic heart failure: cardiac agents (e.g., cardiac glucosides (digoxin, etc.), β receptor stimulants (caterramine formulations such as denofamin and dobutamine) and PDE inhibitors), diuretics [e.g. furosemide ( Lasix), spironolactone], ACE inhibitors (eg, enalapril maleate, Renavice), Ca antagonists [eg, amlodipine], and β receptor blockers;
    [129] Antiarrhythmic agents: Disopyramide, lidocaine, quinidine sulfate, flcainide acetate, mexyltine hydrochloride, amiodarone hydrochloride and β blockers, Ca antagonists and the like;
    [130] Diabetes Therapeutics: Actos, Rosiglidazone, Kinedak, Benpil, Benum, Humulin, Euglucon, Glimicron, Daonil ), Nobolin, Monotard, Insulin, Glucobay, Dimelin, Laston, BASILCON, Diamelin S, Deamelin S, Ise Iszilin;
    [131] Therapeutic agents for hypothyroidism: dry thyreoid, sodium levothyroxine (Thyradin S), lyotyronidine sodium (Thyronin, Thyronamin);
    [132] Nephrotic Syndrome Therapeutics: As a first option, steroid therapy includes prednisolone, sodium prednisolone succinate, sodium methylprednisolone succinate, betamethasone, Rinderon and the like. Anticoagulants include anticoagulants such as dipyridamole (BELSANTIN), dilazef hydrochloride (Comelian), pyropidine, clopidogrel, FXa inhibitors;
    [133] HMG-Co A reductase inhibitors: cerivastatin, atorvastatin, pravastatin, simvastatin, itavastatin, lovastatin, fluvastatin, (+)-3R, 5S-7- [4- (4-fluorophenyl) -6 Isopropyl-2- (N-methyl-N-methanesulfonylamino) pyridin-5-yl] -3,5-hydroxy-6 (E) -heptenic acid and the like;
    [134] Bone Disease Therapeutics: Calcium Formulation (e.g. Calcium Carbonate), Calcitonin Formulation, Active Vitamin D 3 Formulation (e.g. Alphacalcidol (Alfarol, etc.), Calcitriol), Sex Hormone (e.g. For example, estrogens, estrandiol), hormonal formulations (eg, bound estrogens (Premarin)], IPRIFLAVON formulations (Osten, etc.), vitamin K 2 , vitamin K 2 formulations [eg , Menaterenone (Glakay, et al.), Bisphosphonic acid based formulations (ethidronate, etc.), prostaglandin A1, fluorine compounds (eg sodium fluoride), bone morphogenic proteins (BMP), fibroblast growth factor ( FGF), platelet-derived growth factor (PDGF), converting growth factor (TGF-β), insulin-like growth factor-1 and 2 (IGF-1, -2), parathyroid hormone (PTH), EP-A1-376197 , EP-A1-460488 and the compounds described in EP-A1-719782 (eg, (2R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2, 4,5-tetra Draw-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothienyl-pin-2-carboxamide), and the like;
    [135] Chronic Renal Failure Therapeutics: Diuretics (e.g., furosemide, bumetanide, azosemide, Diart), hypertensives (e.g., ACE inhibitors (enalapril maleate) ) And Ca antagonists (manidipine), α receptor blockers and the like;
    [136] Is preferably administered via the oral route.
    [137] In addition, the TNF-α inhibitors of the present invention are useful for the prevention and treatment of thrombosis. In this case, it may be provided alone or in combination with known pharmaceuticals listed below, preferably via the oral route.
    [138] Thrombosis prevention and treatment: anticoagulants [e.g., heparin sodium, heparin calcium, warfarin calcium, anticoagulant factor Xa inhibitors and coagulation-fibrinolytic balance modifiers], thrombolytics [e.g. , tPA, urokinase], antiplatelet agents [eg, aspirin, sulfinpyrazone (ANTULAN), dipyridamole (Persantin), ticlopidine (Pnalal), cilostazol (Pletal), GPIIb / IIIa antagonist (ReoPro)], etc. .
    [139] Vascular dilators: Nifedipine, diltiazem, nicoradil, nitrile formulations and the like.
    [140] Myocardial Protectors: Heart ATP-K openers, Na-H exchange inhibitors, endothelin antagonists, urotensin antagonists, and the like.
    [141] Anti-inflammatory agents: Aspirin, acetaminophen, non-steroidal anti-inflammatory agents [eg indomethacin], steroids [eg dexamethasone] and the like.
    [142] Anti-allergic agents: antihistamines [eg chlorphenylamine maleate], stimulation therapy [eg busilamine], as well as azelastine, ceratlast, tranilas, oxatomid, potent neo Neo-Minophagen C, tranexamic acid, ketotifen fumarate and the like.
    [143] Antitumor agents: alkylating agents, metabolic antagonists, antitumor antibiotic formulations, antitumor plant component formulations and other antitumor agents.
    [144] CNS agonists: anti-anxiety, hypnotic sedatives, anesthetics, antispasmodics, autonomic neo-economics, anti-Parkinson's and other psychoneuroplastic
    [145] In addition, anti-obesity agents, anti-rheumatic agents and the like.
    [146] In addition, therapies using various biological factors or representative gene introduction (eg, treating angiogenic promoters such as HGF and VEGF or ischemic disease treatment using representative gene introduction), and the like.
    [147] The TNF-α inhibitors of the invention can be used simultaneously with any of the above listed or at regular time intervals.
    [148] When used in combination with any of these pharmaceuticals, the formulations can be prepared individually or simultaneously with pharmaceutically acceptable carriers, excipients, binders, diluents and the like, which can be prepared orally or parenterally as pharmaceutical compositions. May be administered. If the active ingredients are formulated individually, the resulting individual formulations may be mixed just prior to use, for example using diluents, or the individual formulations may be administered to the same subject simultaneously or at regular time intervals. Kit products for mixing and administering individual formulations immediately prior to use with diluents (e.g., for injection containing ampoules containing individual powders and diluents for mixing and dissolving two or more agents immediately before use). The kit product (eg, containing separate formulations in the same or separate bags, provided with a label describing the time of administration, if necessary, for the same subject), at the same time or at regular time intervals, for the individual formulations prepared separately. A tablet kit for administering two or more tablets simultaneously or separately at regular time intervals, on which the tablets are placed) is also embodied in the pharmaceutical according to the invention.
    [149] Heterocyclic compounds having angiotensin II antagonism used in the present invention may be used orally or parenterally, by injection, drop, aspiration, rectal administration or topical administration, and may be used as is or in formulations of pharmaceutical compositions (eg, Powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions). That is, the heterocyclic compound having angiotensin II antagonistic action according to the present invention may be used alone or in a mixture with a pharmaceutically acceptable carrier (adjuvant, excipient, adjuvant and / or diluent).
    [150] Pharmaceutical compositions can be formulated by known methods. Such formulations can generally be prepared by mixing / kneading the active ingredient with additives such as excipients, diluents, carriers and the like. The term "parenteral" administration, as used herein, is meant to include subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and drip. Injectable formulations, such as suspensions or oily suspensions in sterile water for injection, can be prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable formulations can be injectable sterile solutions or suspensions such as aqueous solutions in diluents or solvents which can be provided non-toxically and parenterally. Vehicles and solvents that may be used are water, Ringer's solution, isotonic saline and the like. In addition, sterile, nonvolatile oils can generally be employed as a solvent or suspending medium. For this purpose, any non-volatile oil or fatty acid can be used, including naturally occurring or synthetic or semisynthetic fatty oils or fatty acids, as well as naturally occurring or synthetic or semisynthetic mono-, di- and triglycerides.
    [151] Suppositories for rectal administration can be prepared by mixing the active ingredient with suitable non-irritating aids such as cocoa butter and polyethylene glycol that are solid at ambient temperature but liquid at intestinal temperature and melt in the rectum to release the active ingredient.
    [152] Solid dosage forms for oral administration can be, for example, powders, granules, tablets, pills, capsules and the like as mentioned above. Formulations of such formulations contain the active ingredient in one or more additives such as sucrose, lactose, cellulose sugar, mannitol (D-mannitol), maltitol, dextran, starch (eg corn starch), microcrystalline cellulose, agar, know It can be prepared by mixing and / or kneading with nates, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymers or glycerides. Such formulations generally include additional additives such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, α-tocopherol and cysteine, disintegrants (e.g. sodium cross) Carmellose), a binder (eg hydroxypropyl cellulose), a thickener, a buffer, a sweetener, a copper, a fragrance, and the like. Tablets or pills may further be enteric coated. Oral liquid formulations include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, which may contain inert diluents such as water commonly used in the art and may, if necessary, also contain additives. have. Such oral liquid formulations may be prepared by conventional methods, for example by mixing the active ingredient with an inert diluent and, if desired, other additives. Depending on the formulation, oral formulations generally contain from 0.01 to 99% by weight, preferably from 0.1 to 90% by weight and generally from 0.5 to 50% by weight of the active compounds of the invention. .
    [153] Dosage in certain patients depends on age, weight, general health condition, sex, meal, time of administration, mode of administration, rate of administration, combination of drugs, severity of the condition to be treated, as well as other factors.
    [154] The daily dosage of a TNF-α inhibitor containing a heterocyclic compound having angiotensin II antagonism used in the present invention may vary depending on the condition and weight of the patient, the type of compound used, the route of administration, etc. Oral daily dosage of 0.01 to 1000 mg, preferably about 0.1 to 50 mg, and parenteral daily administration of about 0.001 to 100 mg, preferably about 0.01 to 50 mg, generally about 0.1 to 20 mg as active ingredient The dose may be administered to an adult (about 60 kg body weight) as a prophylactic / treatment for an inflammatory disease.
    [155] Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
    [156] Example
    [157] TNF-α inhibitors containing heterocyclic compounds or salts thereof having angiotensin II antagonism in the present invention can be prepared, for example, by the following formulation.
    [158] Example 1 Capsule
    [159] (1) candesartan cilexetil 30 mg
    [160] (2) lactose 90 mg
    [161] (3) 70 mg of microcrystalline cellulose
    [162] (4) magnesium stearate 19 mg
    [163] 1 capsule 200 mg
    [164] After mixing components (1), (2), (3) and half (4), the mixture is granulated. The remaining ingredient (4) is then added and the whole is filled into gelatin capsules.
    [165] Example 2. Purification
    [166] (1) candesartan cilexetil 30 mg
    [167] (2) Lactose 35 mg
    [168] (3) 150 mg corn starch
    [169] (4) microcrystalline cellulose 30 mg
    [170] (5) magnesium stearate 5 mg
    [171] 1 tablet 250 mg
    [172] After mixing components (1), (2), (3), (2) (4) and 1/2 (5), the mixture is granulated. The remaining granules (4) and (5) are added to the resulting granules and compressed into tablets.
    [173] Experimental Example 1
    [174] TNF-α Inhibitory Effect
    [175] [K. According to the method described in Murase et al., Diabetologia 41: 257-264, 1988, the test drug is administered to a model animal in obese and diabetic conditions, and the change in TNF-α level in the blood or tissue is measured. The TNF-α inhibitory effect of the compound is confirmed.
    [176] The TNF-α inhibitor of the present invention has excellent TNF-α inhibitory effect and is useful as a prophylactic / treatment agent for inflammatory diseases.
    权利要求:
    Claims (15)
    [1" claim-type="Currently amended] Formula:

    [Wherein, ring B is an optionally substituted nitrogen-containing heterocyclic group, R 1 is a group capable of forming an anion or can be converted to such a group, and X is a phenylene group and a phenyl group directly or in an atomic chain 2 Heterocyclic compounds (5,7-dimethyl-1-{[2 '-(1H-tetrazole) having angiotensin II antagonism represented by the following spacers, n being an integer of 1 or 2; -5-yl) -1,1'-biphenyl-4-yl] methyl} -3,4-dihydro-1,6-naphthyridin-2 (1H) -one), or a prodrug thereof Or a TNF-α inhibitor containing a salt thereof.
    [2" claim-type="Currently amended] The inhibitor of claim 1, wherein the heterocyclic compound is a compound having an oxygen atom in the molecule.
    [3" claim-type="Currently amended] The inhibitor according to claim 1, wherein the heterocyclic compound is a compound having an ether bond or a carbonyl group.
    [4" claim-type="Currently amended] 2. The inhibitor of claim 1, wherein ring B is an optionally substituted nitrogen-containing aromatic heterocyclic ring.
    [5" claim-type="Currently amended] 2. The inhibitor of claim 1, wherein ring B is an optionally substituted 5- to 6-membered nitrogen-containing heterocyclic ring.
    [6" claim-type="Currently amended] 2. The inhibitor of claim 1, wherein ring B is an optionally substituted imidazole ring.
    [7" claim-type="Currently amended] The inhibitor of claim 1 wherein the heterocyclic compound is a compound represented by Formula I:
    [Formula I]
    [Wherein R 1 is a group capable of forming an anion or a group which can be converted to such a group, X represents that the phenylene group and the phenyl group are bonded directly or through a spacer having up to 2 atomic atoms, and n is 1 or Is an integer of 2, ring A is further an optionally substituted benzene ring, R 2 is a group capable of forming anions or a group that can be converted to such a group, and R 3 can be bonded via a heteroatom Substituted hydrocarbon residues].
    [8" claim-type="Currently amended] The inhibitor according to claim 1, wherein the heterocyclic compound is losartan, eprosartan, candesartan cilexetil, candesartan, telmisartan, irbesartan, olmesartan or tasosartan.
    [9" claim-type="Currently amended] The heterocyclic compound according to claim 1, wherein the heterocyclic compound is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid Inhibitors.
    [10" claim-type="Currently amended] The heterocyclic compound of claim 1, wherein the heterocyclic compound is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl ] Methyl] benzimidazole-7-carboxylate.
    [11" claim-type="Currently amended] The compound according to claim 1, wherein the heterocyclic compound is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl -4-yl] methyl] benzimidazole-7-carboxylic acid.
    [12" claim-type="Currently amended] The inhibitor according to claim 1, which is a prophylactic or therapeutic agent for a disease involving TNF-α.
    [13" claim-type="Currently amended] The inhibitor of claim 1, which is an anti-inflammatory agent.
    [14" claim-type="Currently amended] Formula:

    [Wherein, ring B is an optionally substituted nitrogen-containing heterocyclic group, R 1 is a group capable of forming an anion or can be converted to such a group, and X is a phenylene group and a phenyl group directly or in an atomic chain 2 Heterocyclic compounds (5,7-dimethyl-1-{[2 '-(1H-tetrazole) having angiotensin II antagonism represented by the following spacers, n being an integer of 1 or 2; -5-yl) -1,1'-biphenyl-4-yl] methyl} -3,4-dihydro-1,6-naphthyridin-2 (1H) -one), a prodrug thereof A method of inhibiting TNF-α in a mammal comprising administering an salt thereof to the mammal in an effective amount.
    [15" claim-type="Currently amended] Formula:

    [Wherein, ring B is an optionally substituted nitrogen-containing heterocyclic group, R 1 is a group capable of forming an anion or can be converted to such a group, and X is a phenylene group and a phenyl group directly or in an atomic chain 2 Heterocyclic compounds (5,7-dimethyl-1-{[2 '-(1H-tetrazole) having angiotensin II antagonism represented by the following spacers, n being an integer of 1 or 2; -5-yl) -1,1'-biphenyl-4-yl] methyl} -3,4-dihydro-1,6-naphthyridin-2 (1H) -one), a prodrug thereof Use for the preparation of TNF-α inhibitors thereof.
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    同族专利:
    公开号 | 公开日
    EP1262180A4|2005-06-01|
    PL356422A1|2004-06-28|
    NO20023913D0|2002-08-16|
    US6833381B2|2004-12-21|
    US20030055039A1|2003-03-20|
    AU2001234088B2|2005-12-01|
    CA2400124C|2010-12-14|
    CN1404390A|2003-03-19|
    HU0301057A3|2004-01-28|
    EP1262180A1|2002-12-04|
    HU0301057A2|2003-12-29|
    AU3408801A|2001-08-27|
    WO2001060362A1|2001-08-23|
    CA2400124A1|2001-08-23|
    NO20023913L|2002-09-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-02-18|Priority to JP2000046828
    2000-02-18|Priority to JPJP-P-2000-00046828
    2001-02-15|Application filed by 다케다 야쿠힌 고교 가부시키가이샤
    2003-02-26|Publication of KR20030016229A
    优先权:
    申请号 | 申请日 | 专利标题
    JP2000046828|2000-02-18|
    JPJP-P-2000-00046828|2000-02-18|
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