Pharmaceutical composition for preventing, treating or inhibiting the development of a simple retinopathy and preproliferative retinopathy

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions containing 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, to prevent, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy; the method of preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy; and applying the 2-ethoxy-1-[[2'-(1 N-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]the benzimidazole-7-carboxylate. The pharmaceutical composition has a high efficiency and bioavailability. 3 N. p. F.-ly, 1 table.

The scope of the invention

The present invention relates to pharmaceutical compositions for preventing, treating or inhibiting the development of a simple retinopathy and preproliferative retinopathy, which comprises as active ingredient the compounds having antagonistic activity against angiotech a complication of diabetes, which is caused by microangiopathy associated with hyperglycemia, and duration of diabetes patients with complicated diabetic retinopathy is becoming more and more. It is reported that at least 80% of diabetic patients will suffer from retinopathy associated with diabetes, before the expiration of two decades since the development of diabetes. Diabetic retinopathy develops in simple retinopathy, preproliferative retinopathy and proliferative retinopathy. With simple retinopathy observed increase in vascular permeability, retinal edema, seal the base of the membranes, abnormalities in vascular endothelial cells, disappearance of pericytes etc. If deterioration of the potential of the retina (visual function) with subsequent blockage of blood vessels, then diagnosed preproliferative retinopathy, which eventually develops in proliferative retinopathy, in which the observed hyperplasia membranes of connective tissue and neovascularization. In some cases, proliferative retinopathy is accompanied by the rejection of the retina. Patients do not feel subjective symptoms proliferating retinopathy. Therefore, when they feel something is wrong, VI inhibit its development at an early stage. In addition, diabetic retinopathy is a major cause of blindness in adults, and it causes serious social problems in terms of comfortable social life.

The main methods of treatment of retinopathy are now laser photocoagulation when neovascularization is observed in the fundus, or vitrectomy is performed on vitreous body, when diabetes has developed, and observed hyperplasia membranes of connective tissue and rejection of the retina. However, treatment with photocoagulation or surgery of the vitreous body in some cases be impossible depending on the site affected by the disease, and in other cases, the clarity of vision is not restored even if the operation was successful. Given these circumstances, it is highly desirable creation of pharmaceutical compositions capable of treating diabetic retinopathy in the early stages.

Compounds with antagonistic activity against angiotensin II, known as agents for the treatment of circulatory diseases such as hypertension, heart disease, heart and so on), cerebral bleeding, jade and so on (see Japanese patent publication without examination, No. 4-364171/1992 and Oia angiotensin II (strong vasoconstrictor) to the receptor of angiotensin II.

Patients suffering from diabetes, are complicated by hypertension more often than patients without diabetes, and hypertension is one of the main critical factors causing the emergence and development of retinopathy. In patients with complicated diabetes retinopathy, have higher blood levels of angiotensin-transforming enzyme capable of producing angiotensin II, with a strong vasoconstrictor action than in patients without diabetes, patients with diabetes, patients with proliferating retinopathy, tend to have higher blood levels of these enzymes than patients without proliferating retinopathy.

Recently, studies were undertaken to elucidate the pathology of diabetic retinopathy, and believe that vascular endothelial growth factor (VEGF), which has a potential effect on the growth of endothelial cells, and scenicheskoe effect on vascular permeability, will induce proliferative retinopathy, which is the final symptom of diabetic retinopathy, through physiological action of VEGF, will cause increased levels of VEGF in the vitreous body of patients with proliference potential steniceski effect on the permeability of blood vessels, and believe that VEGF causes swelling of the retina are observed with simple retinopathy or preproliferative retinopathy. Report that in the retina was detected individual system the renin-angiotensin, and it becomes apparent that angiotensin II accelerates the production of VEGF in retinal tissues. These facts suggest that the system renin-angiotensin is involved in diabetic retinopathy.

Description of the invention

In the present invention proposed a pharmaceutical composition that can be used for prevention, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy.

Given the above circumstances, the present invention has made intensive studies of pharmaceutical compositions suitable for preventing, treating or inhibiting the development of retinopathy or preproliferative retinopathy, and as a result have found that the use of compounds with antagonistic activity against angiotensin II, especially compounds with antagonistic activity against angiotensin II, a specific formula is very effective not only the s), but also prevents, treats or inhibits the development of simple retinopathy or preproliferative retinopathy. They have conducted further studies based on these findings and completed the present invention. Thus, this image relates to the next.

(1) a Pharmaceutical composition for preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy, which includes the compounds having antagonistic activity against angiotensin II (the compounds having antagonistic activity against receptor angiotensin II), or Palekastro form, or its salt;

(2) the composition according to the above (1), where the compounds having antagonistic activity against angiotensin II, is ones of the connection;

(3) the composition according to the above (1), where the compounds having antagonistic activity against angiotensin II, has in the molecule the oxygen atom;

(4) the composition according to the above (1), where the compounds having antagonistic activity against angiotensin II is a compound containing ether bond or the banking activity against angiotensin II, is a compound of formula (I):

where R1represents a group capable of forming anion or a group capable of being converted into it, X indicates that fenelonov group and phenyl group are linked to each other directly or via a spacer containing in the chain of two atoms or less, n is an integer 1 or 2, ring a represents a benzene ring, optionally containing a Deputy, in addition to the group R2, R2represents a group capable of forming anion or a group capable of it developing, and R3represents an optionally substituted hydrocarbon residue, which can be reached via the heteroatom.

(6) the composition according to the above (1), where the compounds having antagonistic activity against angiotensin II is Losartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsartan, Telmisartan, Irbesartan or Tasosartan;

(7) the composition according to the above (1), where the compounds having antagonistic activity against angiotensin II is a 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid;

(8) the composition according to the above (1), where the connection with antagonistically-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate;

(9) the Composition according to the above (1), where the compounds having antagonistic activity against angiotensin II is a 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid; and

(10) the composition according to the above (1), where the compounds having antagonistic activity against angiotensin II, is a composition by (1), which is an agent for improving the capacity of the retina or reduce swelling of the retina.

In the present description antagonistic activity of angiotensin II is a complete or partial inhibition of the binding of angiotensin II to the angiotensin II receptor on the cell membranes in order to weaken the potential vasoconstrictor action or proliferative action of vascular smooth muscle induced by angiotensin II, and to reduce symptoms of hypertension.

The compounds having antagonistic activity against angiotensin II, suitable for use in the present invention may be any peptide or ones connection. To take advantage of prolonged action preferred ones connection. with antag what aktivnosti in respect of angiotensin II, preferred compounds containing in the molecule an oxygen atom, more preferable compounds containing ether bond or a carbonyl group (specified carbonyl group may form a hydroxyl group at the resonant frequency), more preferred compounds containing ether bond or a derivative of the ketone, and particularly preferred ether compounds.

For the purposes of the present invention can be used any ones the compounds having antagonistic activity against angiotensin II.

Examples of these compounds include imidazole derivatives disclosed in Japanese patent publication no examination No. 71073/1981, in Japanese patent publication no examination No. 71074/1981, in Japanese patent publication no examination No. 98270/1982, in Japanese patent publication no examination No. 157768/1983, in U.S. patent 4355040, in U.S. patent 4340598 and so on; modified imidazole derivatives disclosed in EP-253310, EP-291969, EP-324377, EP-403158, MO-9100277, in Japanese patent publication no examination No.23868/1988, in Japanese patent publication no examination No.117876/1989 etc., derivatives of pyrrole, pyrazole and triazole disclosed in U.S. patent 5183899, in EP-323841 is in U.S. patent 4880804, in EP-0392317, in EP-0399732, in EP-0400835, in EP-425921, in EP-459136, in Japanese patent publication no examination No.63264/1991 and so on; derivatives of ashenden disclosed in EP-399731, and so on; derivative pyrimidone disclosed in EP-407342, and so on; derivatives hintline disclosed in EP-411766, and so on; xanthine derivatives disclosed in EP-430300, and so on; condensed imidazole derivatives disclosed in EP-434038, etc..; derivatives of pyrimidinedione disclosed in EP-442473, and so on; derivatives of thienopyridine disclosed in EP-443568, and so on; heterocyclic compounds disclosed in EP-445811, in EP-483683, in EP-518033, in EP-520423, in EP-588299, in EP-603712, etc. in Addition, representative compounds disclosed in Journal of Medicinal Chemistry, Vol.39, No.3, pages 625-656 (1996). As ones compounds with antagonistic activity against angiotensin II, you can use any connection in addition to the compounds mentioned in the above links, if they have antagonistic activity against angiotensin II.

Along with other preferred Losartan (DuP753), Eprosartan (SK&F108566), Candesartan cilexetil (TCV-116), Valsartan (CGP-48933), Telmisartan (BIBR277), Irbesartan (SR47436), Tasosartan (ANA-756), their active metabolites (Candesartan and so on).

Preferred examples of ones connections, is desola formula (I):

where R1represents a group capable of forming anion or a group capable of it developing, X indicates that fenelonov group and phenyl group are linked to each other directly or through a spacer, the chain of which consists of 2 or less atoms, n represents an integer 1 or 2, ring a represents a benzene ring, optionally containing a substituent in addition to the group R2, R2represents a group capable of forming anion or a group capable of it developing, and R3represents an optionally substituted hydrocarbon residue which may be bound through a heteroatom (preferably optionally substituted hydrocarbon residue, which is bound via the oxygen atom), and so on, or its salt.

In the above formula (I) group capable of forming an anion (a group containing a hydrogen atom capable of chipped off in the form of a proton) as R1includes, for example, (1) carboxyl group, (2) tetrazolyl group, (3) aminogroup triftormetilfullerenov acid (-NHSO2CF3), (4) phosphonopropyl, (5) alphagroup, (6) residue optionally substituted 5 - to 7-membered (preferably 5-

Examples of the above "remainder optionally substituted 5 - to 7-membered (preferably 5 - or 6-membered) monocyclic heterocyclic ring which contains one or more of N, S and O" include

etc., a Chemical bond between the residue of the heterocyclic ring represented by R1and the phenyl group is associated with the specified residue of the heterocyclic ring may be carbon-carbon bond as shown above, or a nitrogen-carbon bond through one of several nitrogen atoms, if the symbol g is denoted by-NH-, etc., in the above formulas. For example, if R1represented by the formula

his specific choices are

Other examples of linking R1through a nitrogen atom include

and so on

in the above formulas, g is-CH2-, -NH-, -O - or S(O)m; >=Z >=Z' and >=Z ' independently represent a carbonyl group, thiocarbonyl group or an optionally oxidized sulfur atom (e.g., S, S(O), S(O)2and so on) (preferably a carbonyl group or thiocarbonyl group, more preferred is Atka heterocyclic ring, presents R1include the remainder of the heterocyclic ring, at the same time containing-NH - or-Oh group as a proton donor and a carbonyl group, thiocarbonyl group, sulfonyloxy group, etc. as a proton acceptor, such as a remainder oxadiazolones rings, oxadiazolidine rings, or thiadiazole rings, and so on

Although the remainder of the heterocyclic ring represented by R1may form a condensed ring, connecting with substituents in the heterocyclic ring, it is preferably the residue of a 5 - or 6-membered ring, more preferably a residue of a 5-membered ring.

Preferred examples of the residue of the heterocyclic ring represented by R1include a group of the formula

where i represents-O - or-S-, j represents >=O >=S or >=S(O)mand m takes values above (preferably 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-thiadiazole-3-yl; more preferably 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl).

Above the rest heterocyclic ring (R1) has the following tautomeric isomers. On the ri tautomeric isomer and', b' and', and a group of the formula

includes all the above and', b' and'.

The group capable of forming anion as R1can be protected with optionally substituted lower (C1-4) alkyl group, acyl group (e.g. lower (2-5)alkanoyl, benzoyl, and so on), and so on, its possible positions.

Examples of optionally substituted lower (C1-4) alkyl groups include (1) low (C1-4) alkyl group, optionally substituted with one to three phenyl groups, which may contain a halogen atom, nitro, lower (C1-4) alkyl, lower (C1-4)-alkoxy, and so on (for example, methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, and so on); (2) low (C1-4) alkoxy-lower (C1-4) alkyl group (for example, methoxymethyl, ethoxymethyl and so on); (3) a group of the formula-CH(R4) -OCOR5where R4represents (a) hydrogen, (b) an unbranched or branched lower (1-6) alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and so on), (C) an unbranched or branched lower WITH2-6alkenylphenol group, or (d) WITH3-8cycloalkyl grapevine lower C1-6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and so on), (b) an unbranched or branched lower WITH2-6alkenylphenol group, (C) lower1-3alkyl group, substituted C3-8cycloalkyl group (for example, cyclopentyl, cyclohexyl, cycloheptyl and so on), or optionally substituted aryl group (e.g. phenyl group, naftalina group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4)alkyl, lower (C1-4) alkoxy, and so on) such as benzyl, p-Chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, and so on, (d) lower2-3alkenylphenol group, substituted C3-8alloation, or optionally substituted aryl group (e.g. phenyl group, naftalina group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4) alkyl, lower (C1-4) alkoxy, and so on) such as cinnamyl, etc. containing alkanniny fragment, such as vinyl, propenyl, allyl, Isopropenyl, and so on, (f) optionally substituted aryl group (e.g. phenyl group, naftalina group and so on, not necessarily containing a halogen atom, nitro, lower (C1-6alkoxygroup (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, neopentylene and so on), (g) an unbranched or branched lower C2-8alkenylacyl (for example, allyloxy, isobutyryloxy and so on), (h)3-8cycloalkylation (for example, cyclopentyloxy, cyclohexyloxy, cycloheptylamine and so on), (i) lower C1-3alkoxygroup, substituted C3-8cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl and so on) or optionally substituted aryl group (e.g. phenyl group, naftalina group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4)alkyl, lower (C1-4) alkoxy, and so on), such as benzyloxy, penetrate, cyclopentyloxy, cyclohexylmethoxy etc. containing alkoxy fragment, such as methoxy, ethoxy n-propoxy, isopropoxy, and so on), (j) lower2-3alkenylacyl, substituted C3-8cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl and so on), or optionally substituted aryl group (e.g. phenyl group, naftalina group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4) al is vinyloxy, propenyloxy, allyloxy, isopropanolate, etc. or (k) optionally substituted by alloctype (for example, fenoxaprop, NATEXPO and so on, not necessarily containing a halogen atom, nitro, lower (C1-4)alkyl, lower (C1-4) alkoxy, and so on), such as phenoxy p - nitrophenoxy, naphthoxy, etc.;

The group capable of forming anion, as R1may be substituted, in addition to the above protective group, such as optionally substituted lower (1-4) alkyl group or acyl group (e.g. lower (2-5) alkanoyl, benzoyl, and so on), and so on, optional substituted lower (C1-5) alkyl group (for example, optionally substituted lower (C1-4) alkyl group, similar to the "optionally substituted lower (C1-4) alkyl group", examples of which are presented as a protective group for the above group capable of forming anion as R1), a halogen atom, nitro, cyano, lower (C1-4) alkoxy, amino, optionally substituted by 1-2 lower (C1-4)alkyl groups, and so on, its possible positions.

In the above formula the group into a group capable of forming anion (Grishaeva group, capable of forming an anion in biological or physiological conditions (for example, in vivo reactions and so on, such as oxidation, reduction, hydrolysis etc. due to in vivo enzymes, and so on) [so-called prodrugs], or group into a group capable of forming an anion represented by R1can be a group, by chemical means into a group capable of forming anion, such as cyano, N-hydroxycarbonylmethyl (-C(=N-OH)-NH2), a group selected from the class consisting of (1) carboxyl group, (2) tetrazolyl group, (3) amidopropyl triftormetilfullerenov acid (-NHSO2CF3), (4) phosphonopropyl, (5) sulfopropyl and (6) optionally substituted residue monocyclic 5 - to 7-membered (preferably 5 - or 6-membered) heterocyclic ring which contains one or more of N, S and O, each of which is protected optionally substituted lower (C1-4) alkyl group or acyl group, and so on [so-called synthetic intermediate].

As a group, R1preferred carboxyl, tetrazolyl or 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl), each of which can be protected not necessarily for what xianzhilou, p-nitrobenzyl and so on) or acyl group (e.g. lower (2-5) alkanoyl, benzoyl, and so on); or cyano, or N-hydroxycarbamoyl (preferably cyano). Among other preferably cyano.

In the above formula, X indicates that fenelonov group is associated with the adjacent phenyl group directly or via a chain consisting of 2 or less atoms (preferably directly). Examples of intermediate chain containing 2 or fewer atoms, include any divalent chain in which the number of atoms in an unbranched chain is 1 or 2, and which may have a side chain, and specifically the lower (C1-4) alkylene, in which the number of atoms in an unbranched chain is 1 or 2, -CO-, -O-, -S-, -NH-, -CO-NH-, -O-CH2-, -S-CH2-, -CH=CH-, and so on

In the above formula n represents an integer of 1 or 2 (preferably 1).

In the above formula, the ring may contain, in addition to the group R2another Deputy, for example, (1) halogen (such as F, Cl, Br and so on), (2) cyano, (3) nitro, (4) optionally substituted lower (C1-4) alkyl, (5) low (C1-4) alkoxy, (6) optionally substituted by an amino group (e.g. the example, dimethylamino, and so on), N-arylamino (for example, phenylamino and so on), anticyclically the amino group (for example, morpholino, piperidino, piperazine derivatives, N-phenylpiperazine and so on), and so on), (7) a group of the formula-CO-D' D' represents a hydroxyl group or a lower (C1-4) alkoxy, the alkyl part of which may be substituted by a hydroxyl group, lower (C1-4) alkoxy, lower (C2-6) alkanoyloxy (for example, acetoxy, pivaloyloxy and so on), low (C1-6) alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonyl and so on), or low (C1-4) cycloalkylcarbonyl (for example, cyclohexyloxycarbonyloxy and so on), or (8) tetrazolyl, amide group triftormetilfullerenov acid, phosphonopropyl or alphagroup, each of which may be protected optionally substituted lower (C1-4) alkyl (the"optionally substituted lower (C1-4) alkyl group" similar to the examples which are given as a protective group for the above groups, capable of forming an anion represented by R1and so on) or acyl (e.g. lower (2-5) alkanoyl, benzoyl, and so on), and so on

Of these substituents, one or two may simultaneously be present in any the benzene ring, presents And include optionally substituted lower (1-4)alkyl (e.g. lower (C1-4) alkyl, and so forth, optional substituted hydroxyl group, carboxyl group, halogen, and so on), halogen, etc. as a ring And is preferably a benzene ring, which has no substituents, except group R2.

In the above formula, examples of the group capable of forming an anion (a group containing a hydrogen atom capable of chipped off in the form of a proton), as R2include (1) an optionally esterified or amidinophenoxy carboxyl group (2) tetrazolyl group, (3) aminogroup triftormetilfullerenov acid (-NHS2CF3), (4) phosphonopropyl, (5) alphagroup, and so on, each of which may be protected optionally substituted lower (C1-4) alkyl group (for example, optionally substituted lower (C1-4) alkyl group, similar to the "optionally substituted lower (C1-4) alkyl group", examples of which are given as a protective group for the above group capable of forming anion, as R1) or acyl group (e.g. lower (2-5) alkanoyl, benzoyl, and so on), or any ½ and so on, such as oxidation, reduction, hydrolysis, etc. under the action of in vivo enzymes, and so on), or chemical methods.

Examples of the optionally esterified or liderando of carboxyl as R2include a group of the formula-CO-D, where D represents (1) hydroxyl group, (2) optionally substituted amino (e.g. amino, N-lower (C1-4) alkylamino, N, N-di-lower (C1-4) alkylamino and so forth) or (3) optionally substituted alkoxy [e.g., (1) low (C1-6) alkoxygroup, the alkyl part of which optionally substituted hydroxyl group, optionally substituted amino (e.g. amino, N-lower (C1-4) alkylamino, N,N-di-lower (C1-4) alkylamino, piperidino, morpholino and so on), halogen, lower (C1-6) alkoxy, lower (C1-6) alkylthio, lower (C3-8) cycloalkane or optionally substituted DIOXOLANYL (for example, 5-methyl-2-oxo-1,3-dioxolan-4-yl, and so on), or (ii) a group of the formula-O-CH(R6)-OCOR7where R6represents (a) hydrogen, (b) an unbranched or branched C1-6lower alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and so on), (C) an unbranched or R is Il, cyclohexyl, cycloheptyl and so on), and R7represents (a) an unbranched or branched C1-6lower alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and so on), (b) an unbranched or branched C2-6lower alkenylphenol group (C) low (C1-3alkyl group, substituted C3-8cycloalkyl group (for example, cyclopentyl, cyclohexyl, cycloheptyl and so on) or optionally substituted aryl group (e.g. phenyl group, naftilos group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4) alkyl, lower (C1-4) alkoxy, and so on), such as benzyl, p-Chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, and so on, (d) lower2-3alkenylphenol group, substituted C3-8cycloalkyl or optionally substituted aryl group (e.g. phenyl group, naftilos group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4)alkyl, lower (C1-4) alkoxy, and so on), such as cinnamyl, etc. containing alkanniny fragment, such as vinyl, propenyl, allyl, Isopropenyl, and so on, (f) optionally substituted aryl group (n is>-4)alkyl, lower (C1-4) alkoxy, and so on), such as phenyl, p-tolyl, naphthyl, etc., and (f), unbranched or branched lower WITH1-6alkoxygroup (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-Butylochka, n-pentyloxy, isopentylamine, neopentylene and so on), (g) an unbranched or branched lower WITH2-8alkenylacyl (for example, allyloxy, isobutyryloxy and so on), (h) C3-8cycloalkylation (for example, cyclopentyloxy, cyclohexyloxy, cycloheptylamine and so on), (h) lower C1-3group, substituted C3-8cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl and so on), or optionally substituted aryl group (e.g. phenyl group, naftilos group and so on, not necessarily containing a halogen atom, nitro, lower (C1-4)alkyl, lower (C1-4) alkoxy, and so on), such as benzyloxy, venetucci, cyclopentyloxy, cyclohexylmethoxy etc. containing alkoxy fragment, such as methoxy, ethoxy, n-propoxy, isopropoxy, and so on, and so on), (j) lower2-3alkenylacyl, substituted C3-8cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, and so on), or optionally substituted gene, nitro, lower (C1-4) alkyl, lower (C1-4) alkoxy, and so on), such as cinnamoyloxy etc. containing alkenylacyl fragment such as vinyloxy, propenyloxy, allyloxy, isopropanolate, etc. or (k) optionally substituted by alloctype (for example, fenoxaprop, NATEXPO and so on, not necessarily containing a halogen atom, nitro, lower (C1-4)alkyl, lower (C1-4) alkoxy, and so on), such as phenoxy, R nitrophenoxy, naphthoxy, and so on], and so on

As R2preferred optionally esterified carboxy, and its specific examples include-COOH and its salts-Sooma, -COOEt, -COOtBu, -COOPr, pivaloyloxymethyl, 1-(cyclohexyloxycarbonyloxy)etoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolan-4-ylmethoxycarbonyl, acetoxymethyl, propionatetestosterone, n-butyrylcholinesterase, isobutyltrimethoxysilane, 1-(ethoxycarbonyl)etoxycarbonyl, 1-(acetoxy)etoxycarbonyl, 1-(isobutyryloxy)etoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, cinnamoylcocaine, cyclopentanecarbonyl etc., R2can be any group capable of forming anion in biological or Fizeau under the action of enzymes and so on), group is able to chemically to form an anion (for example, COO-, its derivatives, and so on), or from groups that are able to transform.

The group R2may be a carboxyl group or its proletarienne form.

Preferred examples of the group R2include a group of the formula-CO-D, where D represents (1) a hydroxyl group, or (2) low (C1-4) alkoxy, the alkyl part of which optionally substituted with hydroxyl group, amino, halogen, lower (C2-6) alkanoyloxy (for example, acetoxy, pivaloyloxy and so on), low (C3-8) cycloalkanones, low (C1-6) alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonyl and so on), low (C3-8) cycloalkylcarbonyl (for example, cyclohexyloxycarbonyloxy and so on), low (C1-4) alkoxy or lower (3-8) cycloalkane.

Along with other preferred esterified carboxyl with low (C1-4) alkyl (preferably stands or ethyl).

In the above formula, examples of the "hydrocarbon residue" in the expression "optionally substituted hydrocarbon residue which may be bound through a heteroatom" represented by R3,vkluchu, (6) Uralkaliy group, etc., Along with other preferred alkyl group, Alchemilla group and cycloalkyl group.

Examples of alkyl groups in the above p.(1) include unbranched or branched lower alkyl groups containing from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl and so on

Examples alkenyl groups in the above p.(2) include unbranched or branched lower alkeneamine group containing from 2 to 8 carbon atoms, such as vinyl, propenyl, 2-butenyl, 3-butenyl, Isobutanol, 2-octenyl, etc. Examples etkinlik groups in the above p.(3) include an unbranched or branched lower alkyline group containing from 2 to 8 carbon atoms, such as ethinyl, 2-PROPYNYL, 2-butynyl, 2-pentenyl, 2-octenyl, and so on

Examples cycloalkyl groups in the above p.(4) include lower cycloalkyl group containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on

Each of the above alkyl groups, alkenyl groups, etkinlik groups and cycloalkyl groups can be C is calamine, N,N-di-lower (C1-4) alkylamino and so on), halogen, lower (C1-4) alkoxygroup, low (C1-4) alkylthiol and so on

Examples Uralkalij groups in the above p.(5) include a phenyl - lower (C1-4)alkyl, etc. such as benzyl, phenethyl and so on

Examples of aryl groups in the above p.(6) include phenyl and so on

Each of the above Uralkalij groups and aryl groups may be substituted in any possible position of the benzene ring by halogen (such as F, Cl, Br and so on), nitro, optionally substituted amino group (e.g. amino, N-lower (C1-4) alkylamino, N,N-di-lower (C1-4) alkylamino and so on), low (C1-4) alkoxy (e.g. methoxy, ethoxy and so on), low (C1-4) alkylthio (for example, methylthio, ethylthio and so on), low (C1-4) alkyl (e.g., stands, ethyl, and so on), and so on

Preferred examples of the "optionally substituted hydrocarbon residue" in the expression "optionally substituted hydrocarbon residue which may be bound through a heteroatom" represented by R3includes optionally substituted alkyl or alkenylphenol group (e.g. lower (C1-5) alkyl or lower (2-5) alkenyl the/SUB>) alkoxygroup, and so on). Among other preferred low (C1-5) alkyl (preferable ethyl).

Preferred examples of "heteroatoms" in the expression "optionally substituted hydrocarbon residue which may be bound through a heteroatom" represented by R3include-O-, -S(O)m- [m is an integer of 0-2], -NR'- [R' represents a hydrogen atom or lower (C1-4) alkyl], and so on, Among other preferably is-O-.

Among other as R3preferred lower (1-5) alkyl or lower (2-5) Alchemilla groups, each of which can be substituted by the Deputy selected from the class consisting of hydroxyl group, amino group, halogen, lower (C1-4) alkoxygroup, and which can be linked via-O-, -S(O)m- [m represents an integer of 0 to 2] or-NR'- [R' represents a hydrogen atom or lower (C1-4) alkyl], and so on, and a more preferred lower (C1-5) alkyl or lower (C1-5) alkoxy (especially ethoxy).

Among the compounds having antagonistic activity against angiotensin II and represented by the formula (I) are preferred derivatives of benzimidazole-7-carboxylic KIS the Yu group, or (3) a group of the formula

where i represents-O - or-S-, j represents >=O >=S or >=S(O)mand m takes the values indicated above; the ring a represents a benzene ring, which optionally has a Deputy selected from the class consisting of optionally substituted lower alkyl (e.g. lower (C1-4) alkyl, optionally substituted hydroxyl group, carboxyl group, halogen, etc.,) and halogen-free in addition to the group R2(preferably a benzene ring having no other deputies, except group R2); R2represents a group of formula-CO-D, where D represents (1) a hydroxyl group, or (2) low (C1-4) alkoxy, the alkyl part of which may be substituted with hydroxyl group, amino, halogen, lower (C2-6) alkanoyloxy (for example, acetoxy, pivaloyloxy and so on), low (C3-8) cycloalkanones, low (C1-6) alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonyl and so on), low (C3-8) cycloalkylcarbonyl (for example, cyclohexyloxycarbonyloxy and so on), low (C1-4) alkoxy or lower (C3-8) cycloalkane; R3is low (C1-4) alkyl or lower (2-5) alkene-[R' represents a hydrogen atom or lower (C1-4) alkyl], and which can be substituted by the Deputy selected from the class consisting of hydroxyl group, amino group, halogen atom and lower (C1-4) alkoxygroup (preferably lower (C1-4) alkyl or lower (C1-5) alkoxy; more preferably, ethoxy), etc. or their pharmaceutically acceptable salts.

Among other preferred 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]benzimida-angry-7-carboxylate, 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl] benzimidazole-7-carboxylic acid, etc. or their salts.

The above-mentioned benzimidazole derivatives can be obtained by known methods disclosed, for example, in EP-425921, EP-459136, EP-553879, EP-578125, EP-520423, EP-668272, etc., or similar methods. If the present invention using Candesartan cilexetil, then it is preferable to use a stable P-type crystal, disclosed in EP-459136.

The connection region is hinnon form or in the form of any of the possible pharmaceutically acceptable salts. Examples of these salts include salts with inorganic bases (e.g. alkali metals such as sodium, potassium, etc.; alkaline earth metals such as calcium, magnesium and so on; transition metals such as zinc, iron, copper and so on; and so on); organic bases (for example, organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenziletilendiaminom, and so on; basic amino acids, such as arginine, lysine, ornithine, and so on; and so on); and so on, if the specified compounds having antagonistic activity against angiotensin II, contains an acid group such as carboxyl group, etc.; and salts with inorganic acids or organic acids (e.g. hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluene is.; and so on, if the specified compounds having antagonistic activity against angiotensin II, contains a basic group such as amino group, and so on

The prodrug compounds with antagonistic activity against angiotensin II [hereinafter referred to as AII antagonist] means a compound that turns into an AII antagonist in physiological conditions or as a result of reactions involving enzymes, gastric acid, etc. in a living organism, i.e. a compound that turns into AII antagonist as a result of oxidation, recovery, hydrolysis, under the action of enzymes, and so on; the connection, which results in an AII antagonist under the action of gastric juice, and so on; and so on

Examples proletarienne forms AII antagonists include compounds where the amino group AII antagonist substituted acyl, alkyl, phosphoric acid and so on (for example, compounds where the amino group AII antagonist replaced by eicosanol, alnilam, intramyocardial (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidinyl, pivaloyloxymethyl, tert-bootrom, and so on); compounds in which a hydroxyl group of the AII antagonist replaced the PA AII antagonist substituted by acetyl, Palmitoyl, propanolol, pivaloyl, succinyl, fumaria, alnilam, dimethylaminomethylphenol, and so on); compounds in which a carboxyl group of the AII antagonist is a modified complex ether, amidon and so on (for example, compounds in which the carboxyl group of the AII antagonist is a modified complex ethyl ether, phenyl ether complex, carboxymethylated complex air dimethylaminomethylene complex ether, pivaloyloxymethyl complex ether, ethoxycarbonylmethylene complex ether, ptilidium complex ester(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ether complex, cyclohexyloxycarbonyloxy complex ether, methylamide and so on); and so on, These proletarienne forms are available, known in the art methods of AII antagonist.

The prodrug AII antagonist may be a compound that turns into an AII antagonist in physiological conditions, as described in "Pharmaceutical Research and Development" Vol.7 (Drug Design) pages 163-198 published in 1990 by Hirokava Publishing Co. (Tokyo, Japan).

In addition, AII antagonist may be gidratirovana.

Compounds with antagonistic activity against angiotensin II, or its prodrug, or their salts (preferably the connection is or in the form of pharmaceutical compositions with pharmaceutically acceptable carriers mammals, for example, humans, mice, rats, rabbits, dogs, cats, cows, pigs, monkeys, etc. for prevention, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy.

Examples of carriers include various organic or inorganic carriers which are usually used in this field.

For example, excipients, lubricant, binder and loosening agents is used to produce solid forms, and solvents, agents that promote solubility, suspendresume agents and agents, giving isotonicity, buffers, softeners, etc. used to prepare liquid forms. In addition, if desired, in the above compositions can be used, appropriate additives such as preservatives, antioxidants, colorants, sweetening agents, and so on

Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, starch, dextrin, crystalline cellulose, hydroxypropylcellulose with a low degree of substitution, sodium carboxymethyl cellulose, gum Arabic, pullulan, silicic acid anhydride, synthetic aluminum silicate, magnesium aluminate of metasilicate and so on

Examples of lubricating agents include STT-starch, cane sugar, gelatin, gum Arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, crystalline cellulose, saccharose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, etc.

Examples loosening agents include lactose, sucrose, starch, carboxymethylcellulose, calcixerollic, nutritionnelles, natrocarbonatite, silicic acid anhydride, hydroxypropylcellulose with a low degree of substitution, and so on

Examples of solvents include water for injection, ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.

Examples of agents that promote solubility, include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.

Examples suspendida agents include surface active agents, such as steartrimonium, nutriceuticals, lauramidopropyl acid, lecithin, benzacot, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and so on; Polysorbate modified polyoxyethylene castor oil, and so on; and so on

Examples of agents that give isotonicity include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose etc.,

Examples of buffers include buffer solution of phosphate, acetate, carbonate, citrate, etc.

Examples of the softeners include benzyl alcohol, etc.

Examples of preservatives include esters of peroxybenzoyl acid, chlorbutanol, benzyl alcohol, finitely alcohol, digitoxin acid, sorbic acid, etc.

Examples of antioxidants include sulfites, ascorbic acid and so on

Preferred examples of the dyes include water-soluble synthetic organic nutritional supplements (e.g., food dyes such as food red dye No. 2 and No. 3, food yellow dye No. 4 and 5, and blue food dyes 1 and 2), water-insoluble lake dyes (e.g., aluminum salt of the aforementioned water-soluble synthetic organic dyes, and so on), natural pigments (n is the relevant substances include sodium saharat, dicale glycyrrhizin, aspartame, Stevia, etc.

The pharmaceutical compositions are administered orally or parenteral safely, for example orally administered such compositions such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions and so on; and parenterally administered such compositions, as preparations for injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, injection inside the vitreous body, injections into the eyeball, injection into the retina, and so on), drops, medicines for external use (for example, connection for insertion through the nose or trachea, compositions for intradermal injection, ointment, and so on), suppositories (e.g. rectal suppositories, vaginal suppositories, and so on), plate (for example, records for permanent premises on the retina, and so on), drops, ophthalmic compositions for surface application (for example, eye drops, ophthalmic ointments, and so on), and the like.

The pharmaceutical compositions can be prepared by any of conventional methods used to obtain pharmaceutical compositions, for example, in accordance with the procedure described is hidden in details.

For example, pharmaceutical compositions for oral administration is prepared by adding to the active ingredient excipient (for example, lactose, sucrose, starch, D-mannitol, and so on), disintegrity agent (for example, carboxymethylcellulose, calcium and so on), a binder (e.g. starch, gum Arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and so on), lubricating agents (e.g. talc, magnesium stearate, polyethylene glycol 6000, and so on), and so on, and extruding in the form of components of the composition, and, if necessary, putting on the composition of the coating material by known methods, in order to mask the taste or to ensure the dissolution of the composition in the intestine or to give a composition strength.

Examples of the material for the coating include sugar material, the material forming the water-soluble film material forming enterohemolysin film material provides a delayed release, and so on

As sugar material used sucrose, which is applied in combination with at least one agent selected from talc, precipitated calcium carbonate, gelatin, gum Arabic, pullulan, Carnauba wax, etc.,

Examples maturegrannypornogalleries, hydroxyethylcellulose and methylhydroxyethylcellulose; synthetic polymers, such as polyvinylacetal diethylaminoacetate, copolymer E aminoalkylsilane [Eudragit S (trademark), Rhom Pharma], polyvinylpyrrolidone, etc.; polysaccharides, such as pullulan, and so on

Examples of the material forming enterohemolysin film include cellulose polymers such as phthalate of hydroxypropylmethylcellulose, acetate succinate of hydroxypropylmethylcellulose, carboxymethyl cellulose, acetate cellulose phthalate, etc.; acrylic polymers such as methacrylate copolymer LD [Eudragit L-30D55 (trademark), Rhom Pharma], methacrylic copolymer S [Eudragit S (trademark), Rhom Pharma], and natural substances such as shellac, and so on

Examples of materials that provide prolonged isolation, include cellulose polymers such as ethylcellulose; and acrylate polymers, such as aminoalkylsilanes copolymer RS [Eudragit RS (trademark), Rhom Pharma], the suspension of a copolymer of acrylate-methacrylate NE [Eudragit NE (trademark), Rhom Pharma], and so on

Each of the above materials for coating can be used in the form of a mixture of at least two of them in the right ratio. In addition, when applying the P CLASS="ptx2">Injections get by dissolving, suspending or amblyraja active ingredient in an aqueous solvent (e.g. distilled water, physiological saline, ringer's solution, and so on), in an oil solvent (for example, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, and propylene glycol, and so on), or the like in the presence of a dispersing agent (e.g., Polysorbate 80, modified with polyoxyethylene castor oil 60, and so on), polyethylene glycol, carboxymethylcellulose, sodium alginate, and so on), preservative (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol and so on), agent, providing isotonicity (for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and so on) or the like. In these drugs if necessary, it is possible to use additives, such as agents that promote solubility (e.g., sodium salicylate, sodium acetate and so on), stabilizers (for example, human serum albumin, and so on), softeners (for example, benzyl alcohol, and so on), and the like.

Preferred examples of the superficial ophthalmic agents include eye EOV or suspensions. Further, the compound may be dispersed in or adsorbed on ophthalmic ointment, gel or polymer with an extended selection for use in the compositions.

Water eye drops may contain the usual additives, such as agent, providing isotonicity, a buffer agent, regulating pH, preservative, chelating agent and the like.

Examples of agents that provide isotonicity include sodium chloride, mannitol, sorbitol, glycerol and so on; examples of buffers include phosphate, borate, acetate, citrate, and so on; examples of the agents that regulate pH, include hydrochloric acid, acetic acid, sodium hydroxide, and so on; examples of preservatives include esters of peroxybenzoyl acid, benzylaniline, chlorhexidine, benzyl alcohol, sorbic acid or their salts, thimerosal, chlorobutanol and so on; and examples of chelating agents include sodium salt of ethylenediaminetetraacetic acid, sodium citrate, condensed sodium phosphate, etc.

Water eye drops may also contain a thickener and/or suspendisse agent, examples of which include methylcellulose, carmellose or their salts, hydroxyethyl cellulose, sodium alginate, carboxy drops may contain surface-active agents (for example, polyethylene glycol, propylene glycol, modified polyoxyethylene castor oil, Polysorbate 80, and so on), and so on

If the compound is administered in the form of water suspension eye drops, the above polymeric thickener, surface-active agent, etc. can be appropriately selected for use in concrete compositions.

If the compound is administered in the form of non-aqueous eye drops, its solvent is appropriately selected from vegetable oils, such as castor oil, sesame oil, soybean oil and olive oil, and liquid paraffin, propylene glycol, octyldodecanol and the like for use in the composition.

If the compound is administered in the form of a non-aqueous suspension eye drops, the solvent for use in the composition are selected from thixotropic colloids, such as aluminum monostearate, etc.,

The pH value above eye drops set in the range of normal values for eye drops, usually from 4.0 to 9.0, preferably from 5.0 to 8.0.

If the compound is administered in the form of ophthalmic ointments, its material bases for use in the composition are selected from petrolatum, plastibase, liquid pair is s drops to choose from, for example, the carboxy vinyl polymer, methyl cellulose, sodium alginate, hydroxypropylcellulose, a polymer of maleic anhydride-modified ethylene, etc.

The compounds having antagonistic activity against angiotensin II, or its prodrug, or salt (preferably the compounds of formula (I) and their pharmaceutically acceptable salts can be used as an agent for preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy in mammals (e.g. humans, mice, rats, rabbits, dogs, cats, cows, pigs, monkeys and so on).

The compounds having antagonistic activity against angiotensin II, or its prodrug, or salt (preferably the compounds of formula (I) and their pharmaceutically acceptable salts) can be used for prevention, treatment or inhibition of the development of retinopathy, such as angiopathies retinopathy, arteriosclerotic retinopathy, hypertensive retinopathy, diabetic retinopathy, youth retinopathy, renal retinopathy, venous occlusions of the retina, age-related destruction of the cornea, and can also be used for PNA early stages, when is neovascularization, thanks to the wonderful enhance the potential of the retina (visual function) action and effect of reducing retinal edema (abnormalities in the tissues).

The dose of a compound having antagonistic activity against angiotensin II, or its prodrugs, or salts thereof (preferably compounds of formula (I) and their pharmaceutically acceptable salts) varies depending on the subject, the route of administration, subject to the treatment of the disease or the extent of disease. For example, in the case of oral administration a mammal, in particular an adult man (50 kg), usually from about 0.001 to about 500 mg, preferably from 1 to 50 mg of the above compound or its salt as an active ingredient is administered in one dose, and preferably the dose of a compound or its salt 1-3 times a day.

In that case, if the compound or its salt is administered in the form of eye drops, its concentration is usually from 0.001 to 10 wt./vol.%, preferably from 0.01 to 5 wt./vol.%, more preferably from 0.1 to 2 wt./vol.%, and preferably from 1 to a few drops, preferably 1-2 drops of eye drops (amount in one drop is about 50 µl) enter the hand, when the compound or its salt is administered in the form of ophthalmic ointment, the concentration is usually from 0.001 to 10 wt./vol.%, preferably from 0.01 to 5 wt./vol.%, more preferably from 0.1 to 2 wt./vol.%, and preferably this ointment to enter into the SAC of the conjunctiva in a dose of from about 0.1 to about 0.2 g/time, and enter this dose 1-4 times a day.

The preferred method of carrying out the invention

Further, the present invention is disclosed in more detail using the following examples and test examples, which should not be construed as limiting.

Examples

Test example 1

Inhibitory effect on the production of VEGF in the retina and actions that improve the potential of the retina from diabetic rats

Compound 1:(±)-1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carseat (Compound 1)

Method: Streptozotocin (Streptozotocin) (STZ) at a dose of 30 mg/kg administered intravenously 10-week old male rats (Stroke-Prone Spontaneously Hypertensive Rat:SHRSP). When after the injection of STZ runs 9 weeks, measure the rate of blood sugar in rats. Rats divided into 3 groups, namely the group prior to the introduction of, control group, to Aut indicator of blood sugar and measure the potentials of the retina, and then kill rats, releasing blood from the dissected aorta abdominalis under deep anesthesia with ether in order to remove the eyeballs. A suspension of compound 1 in physiological saline containing 0.5% methylcellulose, orally administered to rats once a day for 4 weeks. On the other hand, as untreated groups use 23-week-old SHRSP rats.

The rate of sugar in the blood is measured in the following way. Blood taken from the tail vein using heparin, and centrifuged to collect plasma. The amount of glucose in the plasma was measured using the auto-analyzer (Model 7070, manufacturer Hitachi Seisakusho).

The potential of the retina is measured in the following way. Experimental animal is subjected to adapt to the darkness in a dark room for 90-120 minutes, and then the anaesthetize cetomimidae (50 mg/kg, intramuscularly), and immobilized with xylazine (2 mg/kg intramuscularly). Limb and head of experimental animal fixed with wire. The left eyeball Mydriatic drops to dilate the pupil, and the cornea is placed electrode type contact lenses, using an assistive device for contact lens wearers. Xenon lamp (1/2 Joule) is placed at a distance of 10 TA (SLS-3100 manufacturer Nippon Koden K. K.). The potential of the retina generated by a light stimulus (0.5 Hz, 16-fold), increased use of neural devices (MEW-5100 manufacturer Nippon Koden K. K., lower cut-off of 0.5 Hz, and the time sweep: 200 msec). The results of the stack and average. Latency vibrational peak potential (01, 02 and 03) calculated from the received waveforms. VEGF mRNA in the retina quantitatively determined in the following way. RNA extracted from remote eyeballs, using ISOGEN (Nippon Gene). The amount of VEGF mRNA measured from extracted RNA using semiquantitative RT-PCR reaction (ABI PRISM 7700: Perkin Elmer), using two types of fluorescent probes (FAM: VEGF and VIC: -action). The amount of VEGF mRNA adjust the number of steps of mRNA and expect provided that the amount of VEGF mRNA in the retina 3D rats take over 1.

The Dunett test's used to test the statistical significance of the differences.

Rating: presented in the table.

The concentration of glucose in plasma shows a marked hyperglycemia in the group prior to the introduction, in the control group and in the group administered compound 1, and thus is not detected difference in concentrations between all 3 groups. Latency vibrational peak potential was prolonge is Oh. Latency was reduced in each of the 01, 02 and 03 for the group, which was administered compound 1, and a significant improvement was observed especially for 01 in comparison with the control group. The amount of VEGF mRNA in the tissue of the retina for the group before the introduction and for the control group were significantly increased compared with the normal value (the amount of VEGF mRNA in the retina tissue in SD rats was taken as 1). The amount of VEGF mRNA in the retina tissue in the group which was administered compound 1, was significantly reduced, and it returned to normal levels.

The value was calculated by the equation mean ± standard deviation.

The test of significance of difference from the value equivalent to each of the values for the control group: *P<0.05 ** P<0.01

Pharmaceutical composition for preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy, including the compounds having antagonistic activity against angiotensin II, or its prodrug, or salt (preferably the compound of formula (I) or its pharmaceutically acceptable salt as an active ingredient, are prepared, for example, as follows.

(4) magnesium Stearate 10

1 capsule 200

The ingredients (1), (2) and (3) and half of the ingredient (4) are mixed and this mixture granularit. The rest of the ingredient (4) is added to the granules and all the granulated mixture is placed in gelatin capsules.

Example 2

Tablets, mg:

(1) Connection 1 30

(2) Lactose 35

(3) Corn starch 150

(4) Fine crystalline cellulose 30

(5) magnesium Stearate 5

1 tablet 250

The ingredients (1), (2) and (3) and two-thirds of the ingredient (4) and half of the ingredient (5) are mixed and the mixture granularit. Remains of the ingredients (4) and (5) are added to the granules and the granulated mixture is molded under pressure to form tablets.

Example 3

Eye drops in suspension, g:

(1) Connection 1 1,0

(2) sodium Dihydrophosphate 0,2

(3) sodium Chloride 0,9

(4) Polysorbate 80 0,1

(5) Benzylaniline 0,005

(6) Sodium salt

ethylenediaminetetraacetic acid 0.01

(7) 1 N. sodium hydroxide in the right quantity

(8) Sterilized distilled water to 100 ml

Ingredients(2), (3), (4), (5) and (6) are dissolved in about 80 mulaut rest of sterilized purified water (8). The solution is filtered through a membrane filter of 0.2 μm. Pre-sterilized compound (1) is suspended in this solution to get eye drops in suspension.

Industrial applicability

The pharmaceutical composition of the present invention has an excellent improving effect on the potential of the retina (visual function and retinal edema (disorder of tissue) and can be successfully used for the prevention, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy.

1. Pharmaceutical composition for preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy, including 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

2. A method of preventing, treating or inhibiting the development of retinopathy or preproliferative retinopathy in a mammal, in which the mammal is administered an effective amount of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 1-(Ziklag the LASS="ptx2">3. The use of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate for the prevention, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy.



 

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