JP2002212101A - Gingival hypertrophy inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent gingival hypertrophy inhibitor. SOLUTION: This gingival hypertrophy inhibitor contains a compound having angiotensin II antagonism, its prodrug or its salt. The compound having the angiotensin II antagonism preferably comprises a compound expressed by formula (I) [R1 is an anion-formable group or a group which can be changed into the anion-formable group; X is a linkage which joins the phenylene and the phenyl directly or through a spacer comprising two or less atomic chains; A is a benzene ring which may be further substituted; R2 is an anion-formable group or a group which can be changed into the anion-formable group; R3 is a hydrocarbon residue which may be bonded through a hetero atom or may be substituted; and n is 1 or 2] and more preferably comprises Losartan, Eprosartan, Candesartan cilexetil, Candesartan, Valsartan, Telmisartan, Irbesartan, Olmesartan or Tasosartan.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an angiotensin
The present invention relates to a gingival hyperplasia inhibitor containing a compound having an II antagonistic action (AII antagonistic action), a prodrug thereof or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Gingival thickening refers to a condition in which gingival fibroblasts are excessively proliferated and become thickened.
Inflammation due to chronic inflammatory stimuli; (2) long-term use of various drugs (eg, diphenylhydantoin, an antiepileptic drug, nifedipine, a Ca antagonist); (3) genetic factors; Changes in hormone balance during pregnancy, etc .; The treatment of gingival thickening is
At present, it depends on surgical resection of thickened gingiva (those with advanced fibrosis and scarring), and no treatment or prevention method with drugs has been reported. On the other hand, compounds having AII antagonistic activity are known as therapeutic agents for cardiovascular diseases such as hypertension, heart disease (cardiac hypertrophy, heart failure, myocardial infarction, etc.), stroke, nephritis and the like (JP-A-4-364171, etc.). ), It is known that by inhibiting AII having a strong vasoconstrictive action on the AII receptor, a continuous hypotensive action is exhibited. However, there is no report suggesting that a compound having an AII antagonistic action exhibits an inhibitory action on gingival thickening.

[0003]

The development of a gingival hyperplasia inhibitor having excellent properties as a medicament, such as an excellent gingival hyperplasia-suppressing effect and no side effects, has been desired.

[0004]

Means for Solving the Problems In view of the above-mentioned circumstances, the present inventors have conducted intensive studies on drugs useful for suppressing gingival hyperplasia, and as a result, have found that compounds having angiotensin II antagonistic activity, particularly those having a specific structural formula, Angiotensin represented
A compound having an II (AII) antagonistic activity was found to be extremely effective in suppressing gingival hyperplasia, and as a result of further studies based on these findings, the present invention was completed.

That is, the present invention relates to (1) a compound having an angiotensin II antagonistic action (a compound having an angiotensin II receptor antagonistic action), a prodrug thereof or a gingival hyperplasia inhibitor comprising a salt thereof; The agent according to the above (1), wherein (1) the compound having an angiotensin II antagonistic action is a non-peptidic compound; and (3) the compound having an angiotensin II antagonistic action is a compound having an oxygen atom in a molecule. (4) the agent according to the above (1), wherein the compound having an angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group; (5) the compound having an angiotensin II antagonistic activity is a compound of the formula (I)

Embedded image (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. Which represents a hydrocarbon residue which may be bonded to the compound, and which may have a substituent). (6) It has an angiotensin II antagonistic action The agent according to the above (1), wherein the compound is losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan or tasosartan; Compounds having Otenshin II antagonistic activity is 2
-Ethoxy-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid according to the above (1); (8) the compound having an angiotensin II antagonistic action is 1
-(Cyclohexyloxycarbonyloxy) ethyl
2-ethoxy-1-[[2 ′-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate; (1) the agent according to (1); (9) the compound having an angiotensin II antagonistic activity is 2
-Ethoxy-1-[[2 '-(2,5-dihydro-5-
Oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7
-The agent according to the above (1), which is a carboxylic acid; (10) The agent according to the above (1), which is an agent for preventing or treating fibrous gingival proliferation.

The compounds having an angiotensin II antagonistic activity, prodrugs or salts thereof according to the present invention can be advantageously used for suppressing gingival hyperplasia.
The angiotensin II antagonism in the present invention refers to angiotensin II receptor on the cell membrane.
It refers to an action that competitively or non-competitively inhibits the binding of II, attenuates the strong vasoconstriction and vascular smooth muscle growth induced by angiotensin II, and alleviates the symptoms of hypertension. Angiotensin II used in the present invention
The compound having an antagonistic action may be peptide or non-peptide, but a compound having a non-peptide antagonistic action, which has an advantage of a long action time, is preferable. As the compound having an angiotensin II antagonistic action, a compound having an oxygen atom in the molecule is preferable, and a compound having an ether bond or a carbonyl group (the carbonyl group may form a hydroxyl group by resonance) is preferable. Preferably, a compound having an ether bond or a ketone derivative is more preferable, and an ether derivative is particularly preferable. The compound having non-peptide angiotensin II antagonistic activity is not particularly limited, but imidazole derivatives are disclosed in JP-A-56-71073 and JP-A-56-7.
No. 1074, JP-A-57-98270, JP-A-58-157768, US Pat.
And EP-253310, EP-291969, EP-32
4377, EP-403158, WO-910027
7, JP-A-63-23868 and JP-A-1-1-1
No. 17,876 discloses an improved imidazole derivative, and US Pat. No. 5,183,899, EP-
323841, EP-409332 and JP-A-1-2
JP-A-87071 discloses pyrrole, pyrazole and triazole derivatives.
0,804, EP-0392317, EP-03997
32, EP-0400835, EP-425921, E
P-59136 and JP-A-3-63264 disclose benzimidazole derivatives.
9731 and the like disclose an azaindene derivative;
No. 407342 and the like disclose pyrimidone derivatives.
411766 and the like disclose quinazoline derivatives,
P-430300 and the like disclose a xanthine derivative,
EP-434038 and the like disclose condensed imidazole derivatives, EP-442473 and the like disclose pyrimidinedione derivatives, EP-443568 and the like disclose thienopyridone derivatives, and further EP-445811.
EP-483683, EP-518033, EP-52
0423, EP-588299, EP-603712 and the like disclose heterocyclic compounds. Also, Journal of Med Chemistry
icinal Chemistry, Vol. 39, No. 3, 625-656,
(1996), representative compounds among them are described. As the compound having a non-peptide angiotensin II antagonistic action, in addition to the compounds described in the above-mentioned known documents, any non-peptide compound having an angiotensin II antagonistic action may be used, and among them, losartan (Losartan (DuP753)), Eprosartan (Eprosartan (SK & F108566)), Candesartan
Cilexetil (Candesartan cilexetil (TCV-116)),
Valsartan (CGP-48933), Telmisartan (BIBR277), Irbesartan (Irb)
esartan (SR47436)), Tasosartan (ANA
-756)), olmesartan (Olmesartan (CS-866)), and metabolically active substances thereof (such as candesartan) are preferably used.

[0007] Non-peptidic compounds having angiotensin II antagonistic activity include, for example, compounds of the formula (I)

Embedded image (Wherein, R ¹ represents a group capable of converting thereinto or a group capable of forming an anion, X is shows that the phenylene group and the phenyl group are bonded directly or via a chain of atoms of 2 or less spacers, n Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. And a hydrocarbon residue which may have a substituent (preferably, a hydrocarbon residue which may have a substituent and binds through an oxygen atom). Benzimidazole derivatives or salts thereof are preferably used. In the above formula (I), as a group capable of forming an anion as R ¹ (a group having a hydrogen atom that can be released as a proton),
For example, (1) carboxyl group, (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-
NHSO ₂ CF ₃ ), (4) phosphoric acid group, (5) sulfonic acid group, (6) 5 to 7 members (preferably 5 to 6 members) containing one or more of N, S and O )) A monocyclic optionally substituted heterocyclic residue.

The above-mentioned "5- to 7-membered (preferably 5- to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or more of N, S, and O" Is, for example,

Embedded image

Embedded image And the bond between the heterocyclic residue represented by R ¹ and the phenyl group to which the heterocyclic residue is bonded is as described above when g in the above formula represents —NH— or the like. Carbon-
The bond may be formed not only through a carbon bond but also through one of a plurality of nitrogen atoms. For example, if R ¹

Embedded image In the above formula, g is _{-CH 2 -, - NH -,} - O- or -
S (O) _m −,> = Z,> = Z ′ and> =
Z ″ is a carbonyl group, a thiocarbonyl group or a sulfur atom which may be oxidized (eg, S, S (O),
S (O) ₂ or the like (preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group);
Represents an integer of 0, 1 or 2.

R¹As a heterocyclic residue represented by
For example, oxadiazolone ring, oxadiazolothione ring or
Is a proton donor such as a thiadiazolone ring.
NH- and -OH groups and calcium as a proton acceptor
Bonyl group, thiocarbonyl group or sulfinyl group, etc.
Are preferred. Also, R¹Indicated by
Heterocyclic residues combine with cyclic substituents to form a fused ring
May be R ¹As a heterocyclic residue represented by
Is preferably a 5- to 6-membered ring, more preferably a 5-membered ring residue. R¹
As the heterocyclic residue represented by

Embedded image [Wherein, i represents -O- or -S-, j is> = O,
> = S or> = S (O) _m , wherein m is as defined above] (among which 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, especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) is preferred.

The heterocyclic residue (R ¹ ) has tautomers as shown below. For example,

Embedded image There are three tautomers of a ', b' and c 'such as

Embedded image The heterocyclic residue represented by the above includes all of the above a ′, b ′ and c ′.

The group capable of forming an anion as R ¹ is
At a substitutable position, it may be protected with an optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.). Examples of the optionally substituted lower (C _1-4 ) alkyl group include (1) a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like. A lower (C _1-4 ) alkyl group which may be substituted with 1 to 3 phenyl groups (eg, methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc.); (C _1-4 ) alkoxy-lower (C _1-4 ) alkyl group (eg,
Methoxymethyl, ethoxymethyl, etc.), (3) Formula -C
H (R ⁴ ) -OCOR ^{5 wherein} R ⁴ is (a) hydrogen,
(B) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.) ), shows the (c) linear or branched lower alkenyl group or (d) a cycloalkyl group of 3-8 carbon atoms 2-6 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), R ⁵ 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, etc.), (b) a linear or branched lower alkenyl group having 2-6 carbon atoms, (c) a cycloalkyl group having 3-8 carbon atoms (eg, cyclopentyl) , Cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, phenyl) Or a naphthyl group)
-3 lower alkyl groups (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.); (d) cycloalkyl having 3-8 carbon atoms or an optionally substituted aryl group (eg, halogen A lower alkenyl group having 2-3 carbon atoms substituted by an atom, nitro, phenyl or naphthyl group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc. (eg, , Such as those having an alkenyl moiety such as vinyl, propenyl, allyl and isopropenyl, such as cinnamyl); (e) optionally substituted aryl groups (eg, halogen atoms such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4) alkyl, lower (C _1-4) such as phenyl or naphthyl group which may have a like alkoxy), (f) the number of carbon atoms -6 linear or branched lower alkoxy groups (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, Neopentyloxy, etc.),
(G) a linear or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), (h) a cycloalkyloxy group having 3 to 8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy,
Such as cycloheptyloxy), (i) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl,
Cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ))
Lower alkoxy groups having 1 to 3 carbon atoms (eg, benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc.) substituted with alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. Methoxy, ethoxy, n-propoxy, isopropoxy and the like having an alkoxy moiety), (j) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) or optionally substituted Aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 )
A lower alkenyloxy group having 2 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (eg, having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy such as cinnamyloxy) etc.) or (k) optionally substituted aryloxy group (e.g., phenoxy, p- nitrophenoxy, halogen atom such as naphthoxy, nitro, lower (C _1-4) alkyl, lower (C _1-4) alkoxy And the like, which may have a phenoxy or naphthoxy group). Also,
The group capable of forming an anion as R ¹ is, for example, the above-mentioned optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.). In addition to the protecting group, at a substitutable position, a lower (C _1-4 ) alkyl group which may be substituted (for example, the “substituted or substituted” exemplified as the protecting group for the group capable of forming an anion as R ¹ ). And lower (C _1-4 ) alkyl groups which may be mentioned), a halogen atom,
Nitro, cyano, lower (C _1-4 ) alkoxy, 1-2
And may have a substituent such as amino which may be substituted with a plurality of lower (C _1-4 ) alkyl.

In the above formula, a group capable of forming an anion as R ¹ (a group having a hydrogen atom which can be released as a proton) is a group which can be converted under biological or physiological conditions (for example, in vivo enzyme). Or a group capable of forming an anion by a reaction such as oxidation, reduction, or hydrolysis in a living body (so-called prodrug), or a cyano or N-hydroxycarbamimidoyl group. (—C (＝ N—OH) —NH ₂ ) or (1) a carboxyl group, (2) a tetrazolyl group, each of which is protected by an optionally substituted lower (C _1-4 ) alkyl group or an acyl group. (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5)
Sulfonic acid group, (6) one or two of N, S, O
A 5 to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue containing at least one heterocyclic residue which forms an anion represented by R ¹ by a chemical reaction. It may be a group that can be converted into a group that can be converted (a so-called synthetic intermediate).

R ¹ is optionally substituted lower (C _1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl. group (e.g., lower (C _2-5) alkanoyl, benzoyl, etc.)
Optionally protected with carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl) or cyano, N-hydroxycarbamimidoyl (Preferably cyano) is preferable, and cyano is particularly preferably used.

In the above formula, X represents that an adjacent phenylene group and a phenyl group are bonded directly or preferably via a spacer having an atomic chain of 2 or less (preferably a direct bond). Any of divalent chains having 1 or 2 atoms constituting the straight chain portion may be used, and may have a side chain. Specifically, lower (C _1-4 ) alkylene having 1 or 2 atoms constituting a straight chain portion, —CO—, —O—, —S—, —NH—, —CO
_{-NH -, - O-CH 2} -, - S-CH 2 -, - CH = C
H- and the like. In the above formula, n represents an integer of 1 or 2 (preferably 1).

In the above formula, ring A represents a benzene ring which may further have a substituent other than substituent R ² , and examples of the substituent include (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 group (eg, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, etc.), N, N-di-lower (C _{1 -4} )
Alkylamino (eg, dimethylamino, etc.), N-arylamino (eg, phenylamino, etc.), alicyclic amino (eg, morpholino, piberidino, piperazino, N-phenylpiperazino, etc.), formula (7) -CO-D '
[Wherein D 'is a hydroxyl group or an alkyl moiety is a hydroxyl group, lower (C _1-4 ) alkoxy, lower (C _2-6 ) alkanoyloxy (eg, acetoxy, pivaloyloxy, etc.), lower (C _1-6 ) alkoxycarbonyl Oxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.) or lower (C _3-6 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy, etc.)
In group represented by may be substituted lower (C _1-4) an alkoxy] or (8) an optionally substituted lower (C _1-4), alkyl (anion as R ¹ described above And the same as the "optionally substituted lower (C _1-4 ) alkyl group" exemplified as the protecting group for the group capable of forming) or acyl (eg, lower (C _2-5 ) alkanoyl Benzoyl, etc.), which may be protected with tetrazolyl, a trifluoromethanesulfonic acid amide group, a phosphoric acid group or a sulfonic acid group.
These substituents are each substituted at a substitutable position on the benzene ring.
In addition to the substituent R ² , the substituent which the ring A further has may be a lower (C _1-4 ) alkyl which may be substituted (eg, a hydroxyl group, a carboxyl group, Lower (C) which may be substituted with halogen, etc.
_1-4) alkyl, etc.), are preferred, such as halogen, ring A other than the substituent R ² is more preferably has no substituent.

In the above formula, examples of the group capable of forming an anion as R ² (group having a hydrogen atom capable of being released as a proton) include (1) a carboxyl group which may be esterified or amidated , (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5) and a sulfonic acid group. these groups are optionally substituted Lower alkyl groups (the same as the “optionally substituted lower (C _1-4 ) alkyl group” exemplified as the protecting group for the group capable of forming an anion as R ¹ ). ) Or an acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.)
A group capable of forming an anion or a group capable of forming an anion under biological or physiological conditions (for example, an in vivo reaction such as oxidation, reduction, or hydrolysis by an in vivo enzyme); Either may be used.

The carboxyl that may be esterified or amidated as R ² includes, for example, a compound of the formula —CO
-D [wherein D is (1) a hydroxyl group, (2) optionally substituted amino (for example, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _{1- 4)} etc. alkylamino) or (3) an optionally substituted alkoxy {example, (i) the alkyl moiety by hydroxyl, amino which may be substituted (e.g., amino, N- lower (C _1-4) alkyl Amino, N, N-di-lower (C _1-4 ) alkylamino, piperidino, morpholino, etc., 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-
A lower (C _1-6 ) alkoxy group optionally substituted with 1,3-dioxolen-4-yl or the like, or (ii)
Formula —O—CH (R ⁶ ) —OCOR ^{7 wherein} R ⁶ is (a)
Hydrogen, (b) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, 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 (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), 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, etc.), (b) a linear or branched lower alkenyl group having 2 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl) , Cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, phenyl) Or a naphthyl group)
-3 lower alkyl groups (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (d) cycloalkyl having 3-8 carbon atoms or an optionally substituted aryl group (eg, halogen Atom, nitro, lower (C _1-4 ) alkyl, lower (C
_1-4 ) a lower alkenyl group having 2 to 3 carbon atoms substituted with a phenyl or naphthyl group optionally having an alkoxy or the like (eg, vinyl such as cinnamyl, propenyl,
(E) an aryl group which has an alkenyl moiety such as allyl and isopropenyl, and (e) an optionally substituted aryl group (eg,
Halogen atoms such as phenyl, p-tolyl and naphthyl, nitro, phenyl or naphthyl group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.), (f) carbon A linear or branched lower alkoxy group of the formula 1-6 (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec
-Butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (g) a linear or branched lower alkenyloxy group having 2-8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), (H) a cycloalkyloxy group having 3-8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.); (i) a cycloalkyl having 3-8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) Or an optionally substituted aryl group (eg, a phenyl or naphthyl group optionally having a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) Carbon number 1
-3 lower alkoxy groups (eg, those having an alkoxy moiety such as methoxy such as benzyloxy, phenethyloxy, cyclopentylmethoxy, and cyclohexylmethoxy, ethoxy, n-propoxy, and isopropoxy);
(J) C 3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) or an optionally substituted aryl group (eg, a halogen atom,
Nitro, lower (C _1-4) alkyl, lower (C _1-4) such as phenyl or naphthyl group which may have a like alkoxy) In substituted lower alkenyloxy group having a carbon number of 2-3 (e.g., Shin'namirokishi Such as those having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, and isopropenyloxy) or (k) an optionally substituted aryloxy group (eg, halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro A phenoxy or naphthoxy group which may have a lower (C _1-4 ) alkyl, a lower (C _1-4 ) alkoxy, etc.). And the like.

[0018] R ² is a good carboxyl preferably be esterified, and specific examples, -COOH and its salts, -COOMe, -COOE
t, -COOTBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, Propionyloxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutylyloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxy Carbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl and the like; Conditions (e.g., in vivo reaction such as oxidation-reduction or hydrolysis by in vivo enzymes)
Or a group capable of chemically forming an anion (eg, COO ⁻ , a derivative thereof, etc.) or a group capable of changing the same, or a carboxyl group or a prodrug thereof. Good.

The above R ² is represented by 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, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, Ethoxycarbonyloxy, etc.), lower (C _3-8 ) cycloalkoxycarbonylyloxy (eg, cyclohexyloxycarbonyloxy, etc.), lower (C _1-
4) alkoxy or lower (C _3-8) group represented by which may lower substituted with cycloalkoxy (C _1-4) an alkoxy] are preferred, lower (C _{1 -4)} alkyl (preferably Is preferably carboxyl esterified with methyl or ethyl).

In the above formula, the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ includes, for example,
(1) alkyl group, (2) alkenyl group, (3) alkynyl group, (4) cycloalkyl group, (5) aryl group,
(6) An aralkyl group and the like are mentioned, and among them, an alkyl group, an alkenyl group and a cycloalkyl group are preferable. The alkyl group of the above (1) is a lower alkyl group having about 1 to 8 carbon atoms and may be linear or branched, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and the like. As the alkenyl group of the above (2),
The lower alkenyl group having about 2 to 8 carbon atoms may be linear or branched and includes, for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl and the like. The alkynyl group of the above (3) is a lower alkynyl group having about 2 to 8 carbon atoms and may be linear or branched. For example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-pentynyl, Octynyl and the like. Examples of the cycloalkyl group (4) include lower cycloalkyl having about 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The above alkyl group, alkenyl group, alkynyl group or cycloalkyl group is a hydroxyl group, an amino group which may be substituted (eg,
Amino, N- lower (C _1-4) alkylamino, N, N- di-lower (C _1-4) alkylamino, etc.), halogen, lower (C _1-4) alkoxy group, a lower (C _1-4) It may be substituted with an alkylthio group or the like. Examples of the aralkyl group (5) include phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl, and examples of the aryl group (6) include phenyl.

Aralkyl group or aryl group described above
Can be located at any position on the benzene ring, for example, halogen
(Eg, F, Cl, Br, etc.), nitro, substituted
Amino groups (eg, amino, N-lower (C_1-4) Al
Killamino, N, N-di-lower (C _1-4A) alkylamino
Etc.), low grade (C_1-4) Alkoxy (eg, methoxy, eth
Low-grade (C_1-4) Alkylthio (eg, methyl
Thio, ethylthio, etc.), lower (C_1-4) Alkyl
(Eg, methyl, ethyl, etc.).
Among the above, R^ThreeRepresented by "through a heteroatom
A hydrocarbon residue having a substituent "
In the "hydrocarbon residue" even if substituted
Good alkyl or alkenyl groups (eg, hydroxyl, amino
Group, halogen or lower (C_1-4) Substituted with alkoxy group
Low-grade (C_1-5) Alkyl or lower
(C_2-5Alkenyl, etc.) are preferred;
Low grade (C_1-5) Alkyl (more preferably, ethyl)
preferable. R^ThreeRepresented by a “bonded through a heteroatom
May have a substituent in the hydrocarbon residue "
"Hetero atom" includes -O-, -S (O)_m− [M
Represents an integer of 0 to 2], -NR '-[R' is hydrogen
Atomic or lower (C_1-4) Represents alkyl]
In particular, -O- is preferably used. Above
Above all, R^ThreeAre -O-, -S (O)_m− [M is
Represents an integer of 0 to 2] or -NR '-[R' is water
Elementary atom or lower (C_1-4) Represents alkyl)
May be bonded to hydroxyl, amino, halogen,
And low (C_1-4) Substituted with a substituent selected from an alkoxy group
Low-grade (C_1-5) Alkyl or lower
(C_2-5) Alkenyl groups and the like are preferred,
Grade (C_1-5) Alkyl or lower (C_1-5) Alkoxy
(More preferably, ethoxy).

Among the compounds having angiotensin II antagonistic activity represented by the formula (I), the compounds represented by the formula (I ')

Embedded image (Wherein, R ¹ represents (1) a carboxyl group, (2) a tetrazolyl group, or (3)

Embedded image [Wherein, i represents -O- or -S-, j is> = O,
> = S or> = S (O) indicates a _m, m is a group represented by indicating] as defined above, Ring A may be substituted in addition to the substituent R ² a lower (C _{1 -4} ) an alkyl (eg, a hydroxyl group, a carboxyl group, a lower (C _1-4 ) alkyl which may be substituted with a halogen or the like) or a benzene ring optionally substituted with a halogen (preferably a substituent R ² And R ² is a group represented by 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, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.), lower (C _3-8 Cycloalkoxy carboxymethyl Niro alkoxy (e.g., such as cyclohexyloxycarbonyloxy), a lower (C _1-4) alkoxy or lower (C _3-8) be substituted with a cycloalkoxy optionally substituted lower (C _1-4) alkoxy R ³ represents —O—, —S (O) _m — [m represents an integer of 0 to 2] or —NR ′ — [R ′ represents a hydrogen atom or a lower (C _{1- 4)} may be bonded via an alkyl, hydroxyl, amino, halogen and lower (C _1-4) which may lower substituted with a substituent selected from alkoxy groups (C _1-5 ) Alkyl or lower ( _C2-5 ) alkenyl group (preferably lower ( _C1-5 ) alkyl or lower ( _C1-5 ) alkoxy; more preferably ethoxy). A benzimidazole-7-carboxylic acid derivative or a pharmacologically acceptable salt thereof, and particularly, 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-carboxylate, 2-
Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-
Carboxylic acids or salts thereof are preferred. The above-mentioned benzimidazole derivatives are described in, for example, EP-42592.
1, EP-559136, EP-553879, EP-
578125, EP-520423, EP-66827
The compound can be synthesized by a known method described in 2 or the like or a method analogous thereto. Also, Candesartan ci
When lexetil is used, it is preferable to use a stable C-type crystal described in EP-459136.

The compound having an angiotensin II antagonistic activity or a prodrug thereof used in the present invention may be itself or a pharmacologically acceptable salt. Examples of such salts include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, zinc, etc.) when the compound having an angiotensin II antagonistic activity has an acidic group such as a carboxyl group. , Iron, transition metals such as copper) and organic bases (eg,
Trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-
Salts with organic amines such as dibenzylethylenediamine, and basic amino acids such as arginine, lysine, and ornithine). When the compound having an angiotensin II antagonistic action has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), aspartic acid, glutamic acid and other acidic amino acids. No. A compound having an angiotensin II antagonistic action used in the present invention [hereinafter, may be referred to as an AII antagonistic compound. A prodrug is a compound which is converted into an AII antagonistic compound by a reaction with an enzyme or stomach acid or the like under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted to an AII antagonistic compound, It refers to a compound that is converted into an AII antagonistic compound by hydrolysis or the like by stomach acid or the like. Examples of the prodrug of the AII antagonistic compound include compounds in which the amino group of the AII antagonistic compound is acylated, alkylated, and phosphorylated (eg, the amino group of the AII antagonistic compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-
Dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); hydroxyl group of AII antagonistic compound is acylated, alkylated, phosphorylated , Borated compounds (eg, compounds in which the hydroxyl group of an AII antagonist compound is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); AII antagonist compounds Carboxyl group of the compound esterified, amidated (eg, AII antagonist compound) carboxyl group of ethyl esterification, phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, Ethoxycarbonyloxyethyl Sterilization, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonyloxyethyl esterification, methylamidated compound and the like); Can be These compounds can be produced from AII antagonist compounds by a method known per se. Prodrugs of AII antagonist compounds are compounds which can be converted into AII antagonist compounds under physiological conditions, as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pp. 163-198, Molecular Design. You may. Further, the AII antagonist compound may be any of a hydrate and a non-hydrate.

The compound represented by the formula (I) and a pharmaceutically acceptable salt thereof have low toxicity and can be used as such or as a mixture with a pharmaceutically acceptable carrier to form a pharmaceutical composition. Mammals (eg, humans, mice, rats,
Guinea pigs, rabbits, dogs, cats, cows, pigs, monkeys, etc.). Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , A solubilizing agent, a suspending agent, an isotonic agent, a buffer, a soothing agent and the like. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can also be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, and the like. Pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, pregelatinized starch,
Sucrose, gelatin, gum arabic, methylcellulose,
Examples include carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Preferred examples of the disintegrant include, for example, lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium,
Examples include sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like. Preferred examples of the dissolution aid include, for example, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and acetic acid. Sodium and the like. Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glyceryl monostearate; for example, polyvinyl alcohol, Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil and the like. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like.

Preferred examples of the preservative include, for example, paraoxybenzoic esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbate and the like. Preferable examples of the colorant include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blues 1 and 2, water-insoluble lake dyes) (Eg, the aluminum salt of the water-soluble edible tar dye, etc.), natural pigments (eg, β-carotene, chlorophyll, red pepper, etc.) Preferable examples of the sweetener include, for example, sodium saccharin, dipotassium glycyrrhizinate, Aspartame, stevia and the like.

The dosage form of the pharmaceutical composition includes, for example, tablets,
Oral preparations such as capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions and suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections) Intravenous injection, intravitreal injection, etc.), instillation, external preparations (eg, nasal preparations, transdermal preparations,
Ointments, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, parenterals such as drops, etc., which can be safely orally or parenterally administered, respectively. The pharmaceutical composition can be produced by a method commonly used in the field of formulation technology, for example, a method described in the Japanese Pharmacopoeia and the like.
Hereinafter, a specific production method of the preparation will be described in detail.

For example, oral preparations include, as active ingredients, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, gelatinized A starch, a gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression molded, and then, if necessary, taste masking It is produced by coating with a coating base by a method known per se for the purpose of enteric coating or sustainability.
Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base. As a sugar coating base, sucrose is used, and talc, precipitated calcium carbonate, gelatin, gum arabic,
One or two selected from pullulan, carnauba wax, etc.
More than one species may be used in combination. As the water-soluble film coating base, for example, hydroxypropyl cellulose,
Cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose and methylhydroxyethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma Co., Ltd.), polyvinylpyrrolidone; And the like.

Examples of the enteric film coating base include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L
(Trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer LD (Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]
And acrylic acid polymers; natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS
Acrylic polymers such as [Eudragit RS (trade name), Rohm Pharma Co., Ltd.] and ethyl acrylate / methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] .
The above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide, iron sesquioxide and the like may be used.

Injectable preparations contain an active ingredient as a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc., a preservative (eg, methylparaben, propylparaben, benzyl). Alcohol, chlorobutanol, phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.) and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) Alternatively, it is produced by dissolving, suspending or emulsifying in an oily solvent (eg, vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.). At this time, if necessary, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used.

The dose of the compound represented by the formula (I) and a pharmaceutically acceptable salt thereof varies depending on the administration subject, administration route, target disease, symptom and the like. When orally administered to a subject (body weight: 50 kg), the compound represented by the formula (I) as an active ingredient and a pharmaceutically acceptable salt thereof are usually administered in a dose of about 0.1 mg.
The dose is 001 to 500 mg, preferably 0.1 to 50 mg, and it is desirable to administer this amount once to three times a day.

The gingival hyperplasia inhibitor of the present invention is useful for mammals (eg, humans, mice, rats, guinea pigs, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.) and for gingival hyperplasia. It is used as a prophylactic and therapeutic agent for diseases, and particularly effectively as a prophylactic and therapeutic agent in the early stage of gingival hyperplasia (the stage in which the fibrous portion occupies most of the body and before it reaches a chronic state). The gingival thickening inhibitor of the present invention can be combined with the following various therapeutic agents. Angiotensin converting enzyme (ACE) inhibitors: captopril, enalapril, enalapril maleate, alacepril, ramipril, lisinopril, imidapril, delapril, delapril hydrochloride, etc .; endothelin (ET) antagonists (preferably ET _A receptor antagonists):
Cyclo [-D-Asp-Asp (R1) -Asp-
D-Thg (2) -Leu-D-Trp-] [In the amino acid sequence, Asp (R1) represents an aspartic acid β-4-phenylpiperazineamide residue, and Thg (2) represents a 2-thienylglycine residue. . Or disodium salt thereof,

Embedded image (Bosentan),

Embedded image (SB-217242),

Embedded image (SB-209670),

Embedded image (TBC-11251), Cyclo [-Asp-Pr
o-Val-Leu-Trp-] (BQ-123),

Embedded image (TBC-11251); anti-inflammatory drugs: aspirin, acetaminophen, non-steroidal anti-inflammatory drugs [eg, indomethacin etc.], steroid drugs [eg, dexamethasone etc.], etc .; protein C kinase inhibitor: cheerythrin
These various drugs such as e, staurosporine, etc. can be used simultaneously or at a later time. When these drugs are used in combination, each drug is separately or simultaneously mixed with a pharmacologically acceptable carrier, excipient, binder, diluent and the like to be formulated and orally as a pharmaceutical composition. Or it can be administered parenterally. When the drugs are separately formulated, they can be administered separately by mixing them with a diluent at the time of use.However, each separately formulated drug can be administered simultaneously or with a time lag. And may be separately administered to the same subject.
A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, an ampoule containing a powdered individual drug and two or more drugs mixed at the time of use and dissolved) Kits for injection containing diluents, etc.), separately formulated individual formulations,
Alternatively, kit products for administration to the same subject separately at different times (for example, tablets containing individual drugs are placed in the same or separate bags, and if necessary, a description column for the time of drug administration is provided. Further, a tablet kit for administering two or more tablets simultaneously or separately at a time interval, etc.) are also included in the medicament of the present invention. In addition, among the above-mentioned concomitant drugs, an ACE inhibitor and an ET antagonist are
It is possible to enhance the gingival thickening inhibitory effect by combining with the gingival thickening inhibitor of the present invention, but these can be used alone to increase gingival thickening (preferably fibrous gingival proliferation) or gingival fibroblasts. Can be prevented and treated.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to examples and experimental examples, but these do not limit the present invention.

[0033]

EXAMPLES The gingival hyperplasia inhibitor containing a compound having AII antagonistic activity or a salt thereof as an active ingredient in the present invention can be produced, for example, by the following formulation. Embodiment 1 FIG. Capsule (1) Candesartan cilexetil 30 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 200 mg (1), 1/2 of (2) and (3) and (4) After mixing, granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. Embodiment 2. FIG. Tablets (1) candesartan cilexetil 30 mg (2) lactose 35 mg (3) corn starch 150 mg (3) microcrystalline cellulose 30 mg (5) magnesium stearate 5 mg 1 tablet 250 mg (1), (2), (3), (4) 2/3 and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Experimental Example 1 Inhibition of gingival hyperplasia (1) Preparation and maintenance of primary gingival fibroblasts Male Hartley guinea pig (body weight 350-450 g)
After killing and phlebotomy, the gingival tissue was removed. The extracted group
Weave is ice-cold 0.05% chlorhexidine gluconate solution
The inside was washed to remove attached blood and germs in the oral cavity.
Then, ice-cold D-PBS [Dulbecco's phosphate buffe
red saline: NaCl, 137.9 mM; KCl, 2.67 mM; MgCl_Two・ 6H
_TwoO, 0.49 mM; NaHPO_Four・ 12H_TwoO, 8.06mM; CaCl_Two・ 2H_TwoO, 0.9
0 mM; KH _TwoPO_Four, 1.47 mM filter sterilized before use (0.2 μM filter)
Exclusion of connective tissue only
After that, the epithelium-like portion was removed under a stereoscopic microscope. Got
Tissue pieces were FBS (-) medium (FBS (fetal bovine serum) fr
ee medium: Dulbecco's modified Eagle medium (DMEM)
 100 units / mlpenic
illin G, 0.1 g / ml streptomycin and 0.2 mg / ml am
photericin B)
The pieces were cut into approximately 1 mm square. 24 well culture plate (culture
Area 2cm^Two), And then add collagen type I
Place the cut tissue, 37 ° C, 5% CO_TwoSet to conditions
It was left still in the incubator for 2 hours. The organization plays
10% FBS medium [the FBS (-) med
medium with FBS added to a final concentration of 10%
um] and changing the medium every 72 hours,
Culture was continued. (2) Subculture of gingival fibroblasts Approximately 80% of the bottom of the plate was exogenous from the transplanted tissue piece
Cell-covered state (subconfluent)
And passed. For cell dispersion, 0.025% bird
PBS containing Psin and 0.02% EDTA (-)
(Phosphate buffered saline-Ca²⁺, Mg²⁺ free: NaCl,
136.9 mM; KCl, 2.68 mM; NaHPO_Four・ 12H_TwoO, 8.07mM; KH_TwoPO
_Four, 1.47 mM filter sterilized before use (0.2μm filter)
Solution) (hereinafter referred to as trypsin solution)
Was. Wash the plate with 10% FBS medium with PBS (-).
After cleaning, trypsin solution heated to 37 ° C.
Incubate at 7 ° C for 10 minutes. Pipette cells
Peel off the plate by floating, collect by floating,
Centrifuge the trypsin solution from the cell suspension (1000 rpm, 5
Min, 4 ° C). Ice-cold FB of cells obtained as sediment
Resuspend in S (-) medium and centrifuge under the same conditions.
Discarded and resuspended pellet in ice-cold FBS (-) medium.
A total of three centrifugal washes were performed in the same manner. Third centrifugation
The cells obtained as sedimentation by the operation are 10% FBS medium
And seeded on a 24-well culture plate.
The cells (24 wells) obtained from the primary culture were added to four new
The cells were distributed on a plate and used as the second passage cultured cells. Similar person
And the third to fifth passage cells were used for the following experiments.
Using. (3) Effect of AII antagonist on proliferation of cultured gingival fibroblasts
Result 3 × 5 passaged cells are 1 × 10^FourCells / cm^TwoCell density
Seeded on a 96 well culture plate at a temperature and cultured for 10 days.
Further, add 1% FBS medium [FBS was added to the above FBS (-) medium.
Medium added to a concentration of 1%]
After culturing for 4 hours, it was used for the experiment. 1% FBS medium
Add angiotensin II (100 nM) and test further
Compound A [2-ethoxy-1-[[2 '-(1H-tetra
Lazol-5-yl) biphenyl-4-yl] methyl]
Of benzimidazole-7-carboxylic acid; 1 μM]
Incubated for 48 hours in the presence or absence of
Amount of medium containing angiotensin II and angiotensin
Amount of medium containing tensin II and test compound A
Is 100 μl per well and changed every 24 hours.
Changed. Add both angiotensin II and test compound A
Culture on the same schedule using medium without
Cells were used as controls. ) MTT [3- (4,5-dimethylthiazol) was added to cells after drug stimulation.
-2-yl) -2,5-diphenyltetrazolium bromide] solution (10
μl / well; 5 mM) at 37 ° C., 5% CO 2_Twoof
Incubate for 4 hours in the incubator set under the conditions
I did it. Then, SDS (sodium dodecyl sulfate)
Acid solution (100 μl), and incubate for 1 hour
And dissolve the resulting insoluble blue hormazan
Was. Measure the absorbance of each well with a microplate reader (Model 35
50; Bio-Rad Laboratories, USA) at a measurement wavelength of 57.
The measurement was performed at 0 nm and a reference wavelength of 655 nm. In addition, cells
The medium that is not included is blank and each value is
Subtracted. Table 1 shows the results.

[Table 1] The numerical values in the table indicate the mean ± standard deviation, and the significant difference is Tuk
ANO by ey-Kramer Multiple Comparatives Test
The test was performed by VA (One-way Analysis of Variance). ^* : P <0.05 vs control group ^** : p <0.01 vs AII added group As is clear from the results in Table 1, angiotensin II
Added significantly increased gingival fibroblast proliferation, and the addition of candesartan (test compound A) significantly suppressed the increase.

[0035]

Industrial Applicability The gingival thickening inhibitor of the present invention has an excellent gingival thickening inhibitory effect and is useful as a preventive or therapeutic agent for gingival thickening (preferably fibrous gingival proliferation) and gingival fibroblast proliferation. is there.

Of the front page Continued (51) Int.Cl. ⁷ identification mark FI theme Court Bu (Reference) A61K 31/522 A61K 31/522 A61P 1/02 A61P 1/02 43/00 116 43/00 116 123 123 // C07D 235 / 20 C07D 235/20 257/04 257/04 E 403/10 403/10 409/06 409/06 413/10 413/10 471/04 118 471/04 118Z F term (reference) 4C063 AA01 BB06 CC47 CC58 CC92 DD25 DD26 DD47 EE01 4C065 AA04 BB11 CC01 DD03 EE02 HH09 JJ04 KK02 LL01 PP09 4C084 AA16 BA44 DC40 NA14 ZA671 ZA672 ZC421 ZC422 4C086 AA01 AA02 BC38 BC39 BC62 BC71 CB09 GA03 GA67 MA01 NA14 ZA

Claims (10)

[Claims] A gingival hyperplasia inhibitor comprising a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. 2. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity is a non-peptidic compound. 3. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity is a compound having an oxygen atom in the molecule. 4. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group. 5. A compound having an angiotensin II antagonistic activity is represented by the formula (I): (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. Or a hydrocarbon residue which may have a substituent). 6. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity is losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, or tasosartan. 7. A compound having an angiotensin II antagonistic action is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. The agent according to claim 1. 8. The compound having an angiotensin II antagonistic action is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] 2. A benzimidazole-7-carboxylate.
Agents as described. 9. The compound having an angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl. -4-yl] methyl] benzimidazole-7-carboxylic acid. 10. The agent according to claim 1, which is an agent for preventing or treating fibrotic gingival proliferation.