CZ2001153A3 - Thiobenzimidazole derivatives - Google Patents

Abstract

The present invention relates to thiobenzimidazole derivatives represented by the general formula (1) or their pharmaceutically acceptable salts having strong activity inhibition of human chymase. Therefore, they are strong preventive and / or therapeutic agents that are clinically applied various diseases involving human chymase.

Description

Technical field

The present invention relates to thiobenzimidazole derivatives represented by the general formula 1, in particular thiobenzimidazole derivatives useful as inhibitors of human chymase activity.

BACKGROUND OF THE INVENTION

Chymase is one of the neutral proteases found in mast cell granules and has been implicated in a number of biological processes involving mast cells. A number of effects are reported, including, for example, promoting mast cell degranulation, activation of interleukin-β (IL-1β), matrix protease activation, decomposition of fibrionectin and type IV collagen, promoting release of transforming growth factor-β (TGF-β), activation of substance P and vasoactive intestinal polypeptides (VIP), conversion of angiotensin I (Ang I) to Ang II, endothelin conversion and the like.

The foregoing indicates that inhibitors of said chymase activity may be promising as preventive and / or therapeutic agents for respiratory diseases such as bronchial asthma, inflammation / allergic diseases such as rhinitis, atopic dermatitis and urticaria; circulatory organ diseases such as sclerosing vascular lesions, intravascular stenosis, peripheral circulation disorder, renal failure and heart failure; bone and cartilage metabolism diseases such as rheumatoid arthritis and osteoarthritis, and the like.

Triazine derivatives are known as inhibitors of chymase activity (Japanese Unexplored Japanese Patent Application (Kokai) No. 8-208654); hydantoin derivatives (Japanese Unexplored Japanese Patent Application (Kokai) No. 9-31061); imidazolidine derivatives (PCT Application WO 96/04248); quinazoline derivatives (PCT Application WO 97/11941); heterocyclic amide derivatives (PCT Application WO 96/33974); etc.

However, the structures of these compounds differ substantially from those of the present invention.

* · · ···· · · · · · · ···

On the other hand, compounds known in the art close to those of the present invention are described in U.S. Pat. No. 5,124,336. This document discloses thiobenzimidazole derivatives having thromboxane receptor antagonizing activity. However, no inhibition of human chymase is disclosed.

It is an object of the present invention to provide novel compounds that are potent and clinically applicable inhibitors of human chymase.

SUMMARY OF THE INVENTION

After intensive research to achieve the above subject, the present inventors have come to the following 1 to 15 conclusions and thus complete the present invention.

A thiobenzimidazole derivative represented by the following general formula 1;

wherein R ¹ and R ² , simultaneously or independently, represent a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or R ¹ and R ² together form -O CH ₂ -O-, -O-CH ₂ -CH ₂ -O- or -CH 2 -CH 2 -CH 2 -, wherein the carbon atoms may be substituted with one or more C 1 -C 4 alkyl groups;

A represents a single bond, a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms,

a substituted or unsubstituted arylene group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms, which may contain one or more oxygen, sulfur or nitrogen ring atoms, wherein the substituents are halogen, OH, NO2, CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents can be linked to each other at adjacent sites through an acetyl bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, linear or a branched alkylsulfonyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms, a linear or branched acylamino group having 1 to 6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, o a xeno group, a phenoxy group which may be substituted by one or more halogen atoms, and wherein the substituents may be independently substituted at any position on the ring by an alkylene group;

E represents COOR ³ , SO ₃ R ³ , CONHR ³ , SO ² NH ³ , a tetrazole group, a 5-oxo-1,2,4-oxadiazole group or a 5-oxo-1,2,4-thiadiazole group wherein R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms;

G represents a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, which may be interrupted by one or more of O, SO, SO 2 and NR ³ , where R ³ is as defined above and the substituent is halogen, OH, NO2, CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents can be linked to each other at adjacent sites via an acetyl bond), trihalomethyl, trihalomethoxy, phenyl or oxo;

m is an integer from 0 to 2;

when m is 0 and A is a substituted or unsubstituted alkylene group having 1 to 6 carbon atoms, then J is substituted or unsubstituted,

C 1 -C 6 linear, cyclic or branched alkyl substituted or unsubstituted C 7 -C 9 aryl, C 10 -C 11 substituted aryl, C 4 -C 10 substituted or unsubstituted heteroaryl which may contain one or more oxygen, nitrogen or sulfur ring atoms;

when m is 0 and A is a substituted or unsubstituted arylene group having 6 to 11 carbon atoms or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms which may contain one or more oxygen, nitrogen or sulfur ring atoms, then J is substituted or an unsubstituted, linear, cyclic or branched alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 11 carbon atoms, a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen atoms , nitrogen and sulfur in the ring;

or when m is 0 and A is a single bond, or when m is 1 or 2, then J represents a substituted or unsubstituted, cyclic or branched alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, sulfur or nitrogen ring atoms, wherein the substituents are a halogen atom, OH, NO ₂ , CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents may be linked to each other at adjacent sites through an acetyl bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, linear or ro C 1 -C 6 extended acyl, linear or branched C 1 -C 6 acylamino, substituted or unsubstituted anilide, trihalomethyl, trihalomethoxy, phenyl, oxo, COOR ³ or phenoxy, which may be substituted with one or more halogen atoms, and

wherein the substituents may be independently substituted at any ring position or by an alkylene group;

X is CH or N;

or a pharmaceutically acceptable salt (defined above as a "thiobenzimidazole derivative of the invention").

2. A thiobenzimidazole derivative characterized in that in the above formula (1):

A is a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted arylene group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms, which may contain one or more oxygen atoms , nitrogen and sulfur in the ring, or a pharmaceutically acceptable salt thereof.

3. A thiobenzimidazole derivative characterized in that in formula 1, A is a substituted or unsubstituted heteroaryl group containing 4 to 10 carbon atoms, which may contain one or more oxygen, nitrogen and sulfur ring atoms, or a pharmaceutically acceptable salt thereof.

A thiobenzimidazole derivative characterized in that in the above formula 1, m is 1 or a pharmaceutically acceptable salt thereof.

5. A thiobenzimidazole derivative characterized in that in the above formula 1, m is 2 or a pharmaceutically acceptable salt thereof.

A thiobenzimidazole derivative characterized in that in the above formula 1 m is 0, A is a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, J is a substituted or unsubstituted aryl group having 7 to 9 carbon atoms, a (C 10 -C 11) substituted aryl group or a (C 4 -C 10) substituted or unsubstituted heteroaryl group

carbon atoms, which may contain one or more oxygen, nitrogen and sulfur atoms in the ring, or a pharmaceutically acceptable salt thereof.

A thiobenzimidazole derivative characterized in that in the above formula 1, m is 0, A is a substituted or unsubstituted arylene group having 6 to 11 carbon atoms or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms, which may contain one or a plurality of oxygen, nitrogen, and sulfur atoms in the ring, and J is a substituted or unsubstituted (C až-C a a) substituted or unsubstituted aryl group, which may contain one or more oxygen, nitrogen, and sulfur atoms in the ring; or a pharmaceutically acceptable salt thereof.

A thiobenzimidazole derivative characterized in that in the above general formula 1 G is -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ CO-, -CH ₂ CH ₂ O-, -CH ₂ CONH-, -CO-, -SO ₂ -, -CH ₂ SO ₂ -, -CH ₂ S- or -CH ₂ CH ₂ S- or a pharmaceutically acceptable salt thereof.

A thiobenzimidazole derivative characterized in that in the above general formula 1, R ¹ and R ^{2 are} simultaneously hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy or R ¹ and R ² independently represent a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a trihalomethyl group, a cyano group or a hydroxy group, or a pharmaceutically acceptable salt thereof.

A thiobenzamidazole derivative characterized in that in the above general formula (1), E represents COOH or a tetrazole group or a pharmaceutically acceptable salt thereof.

11. A thiobenzimidazole derivative characterized in that in the above general formula (1), X is CH or a pharmaceutically acceptable salt thereof.

12. A thiobenzimidazole derivative having human chymase inhibiting activity or a pharmaceutically acceptable salt thereof.

• · · · · · · ·

A pharmaceutical composition comprising at least one thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

A pharmaceutical composition which is a preventive and / or therapeutic agent for a disease.

A preventive and / or therapeutic agent, wherein said disease is an inflammatory disease, allergic disease, respiratory organ disease, circulatory novel disease, or bone or cartilage metabolism disease.

The present invention will now be explained in more detail.

The above definitions relating to the substituents of the compound of formula I according to the invention are as follows:

R ¹ and R ² , simultaneously or independently, represent a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or R ¹ and R ² together form -OCH ² - O-, -O-CH 2 -CH 2 -O- or -CH 2 -CH 2 -CH 2 -, wherein the carbon atoms may be substituted with one or more C 1 -C 4 alkyl groups. C 1 -C 4 alkyl includes methyl, ethyl and (n, iso-) propyl and (n, iso, sec, and tert) butyl, preferably methyl. R @ ¹ and R @ ^{2 are} preferably simultaneously hydrogen, halogen, C1 -C4 alkyl, C1 -C4 alkoxy or R @ ¹ and R @ ² independently represent hydrogen, halogen, trihalomethyl, cyano, hydroxy , (C 1 -C 4) -alkyl or (C 1 -C 4) -alkoxy. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom and the like can be mentioned, preferably a chlorine atom and a fluorine atom. C 1 -C 4 alkyl includes methyl, ethyl, and (n, iso-) propyl, and (n, iso, and tert.) Butyl, preferably methyl. As alkoxy group containing from 1 to 4

the carbon atoms are methoxy, ethoxy and (n, iso-) propyloxy and (n, iso, sec, and tert.) butyloxy, preferably methoxy.

A represents a single bond, a substituted or unsubstituted linear or branched alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted arylene group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms, which may contain one or more oxygen, sulfur or nitrogen atoms in the ring. Preferably, a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted arylene group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms, which may contain one or more atoms oxygen, nitrogen and sulfur in the ring. As substituted or unsubstituted, linear or branched alkylene having 1 to 6 carbon atoms, methylene, ethylene (n, iso-) propylene and (n, iso, tert.) Butylene are mentioned and preferably ethylene is mentioned. As substituted or unsubstituted arylene group having 6 to 11 carbon atoms, mention may be made of phenylene, indenylene and naphthylene, etc., and preferably phenylene. A substituted or unsubstituted C 4 -C 10 heteroarylene group which may contain one or more oxygen, nitrogen and sulfur ring atoms is pyridilene, furanyl, thiophenylene, imidazolone, thiazolone, pyrimidilene, oxazolone, an isoxazolone group, a benzphenylene group, a benzimidazolone group, a quinoline group, an indolene group, a benzthiazolone group and the like and preferably a pyridilene group, a furanylene group and a thiophenylene group.

Further, substituents which may be used herein are halogen, OH,

NO ₂ , CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, the substituents can be linked to each other at adjacent sites through an acetyl bond, a linear or branched alkylthio group having 1 to 6 carbon atoms a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms, a linear or branched acylamino group having 1 to 6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, a phenoxy group which may be substituted with one or more halogen atoms. They may be independently substituted at any position of the ring or alkylene group. Specifically, OH, chlorine, bromine, nitro, methoxy, cyano, methylenedioxy, trifluoromethyl, methyl, ethyl, (n, iso-) propyl, (n, iso-, tert.) Butyl and the like are mentioned. .

E is COOR ³ , SO ³ R ³ , CONHR ³ , SO ² NH ³ , tetrazole, 5-oxo-1,2,4-oxadiazole or 5-oxo-1,2,4-thiadiazole, and preferably COOR ³ or tetrazole group. R ⁵ is hydrogen or a linear or branched alkyl group having 1 to 6 carbon atoms, preferably methyl, ethyl or tert-butyl, most preferably hydrogen.

G represents a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms which may be interrupted by one or more of O, SO, SO ₂ and NR ³ , where R ³ is as defined above and the substituent is halogen, OH , NO ₂ , CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents may be linked to each other at adjacent sites through an acetyl bond), trihalomethyl, trihalomethoxy, phenyl or oxo. Specifically, -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ CO-, -CH ₂ CH ₂ O-, -CH ₂ CONH-, -CO-, -SO ₂ -, -CH ₂ SO ₂ -CH ₂ CH ₂ S- and the like are mentioned. preferably -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ CO- or CH ₂ CH ₂ O-.

m is an integer from 0 to 2, preferably 0 or 2.

When m is 0 and A is a substituted or unsubstituted alkylene group having 1 to 6 carbon atoms, then J is a substituted or unsubstituted, linear, cyclic or branched alkyl group having 1 to 6 carbon atoms a substituted or unsubstituted aryl group having 7 to 9 carbon atoms is a substituted aryl group having 10 to 11 carbon atoms, a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, nitrogen or sulfur ring atoms. Preferably, a substituted aryl group having 10 to 11 carbon atoms and a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, nitrogen and sulfur ring atoms, are preferably mentioned. A substituted or unsubstituted, linear, cyclic or branched group having 1 to 6 carbon atoms includes (n, iso-) propyl and (n, iso-, sec. And tertiary) butyl and (n, iso-, n-). , tert.) pentyl and cyclohexyl. A substituted or unsubstituted C7-C9 aryl group is an indenyl group and a substituted C10-C11 aryl group is a naphthyl group. A substituted or unsubstituted C 4 -C 10 heteroaryl group which may contain one or more oxygen, nitrogen and sulfur ring atoms is pyridyl, furanyl, thiophenyl, imidazole, thiazole, pyrimidine, oxazole, isoxazole, benzofuran, benzimidazole, quinoline, isoquinoline, quinoxaline, benzoxadiazole, benzothiadiazole, indole, N-methylindole, benzothiazole, benzothiophenyl, benzisoxazole, and the like, preferably benzothiophenyl, preferably benzothiophenyl group.

When m is 0 and A is a substituted or unsubstituted arylene group having 6 to 11 carbon atoms or a substituted or unsubstituted 4 to 10 carbon heteroarylene group that may contain one or more oxygen, nitrogen or sulfur ring atoms, then J is substituted or an unsubstituted, linear, cyclic or branched alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 11 carbon atoms, a substituted or substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, nitrogen and sulfur ring atoms, preferably a substituted or unsubstituted aryl group containing 6 to 11 carbon atoms, a substituted or unsubstituted heteroaryl group containing 4 to 10 carbon atoms, which may contain one or more; and of oxygen, nitrogen and sulfur in the ring. As a substituted or unsubstituted aryl group having 6 to 11 atoms, phenyl is phenyl, naphthyl and the like, preferably phenyl or naphthyl. As a substituted or unsubstituted, linear or branched alkyl group having 1 to 6 carbon atoms and as a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, sulfur or nitrogen atoms in the ring, the groups described above are mentioned. The substituents used herein are halogen, OH, NO ₂ , CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents may be attached to each other at adjacent sites) via an acyl bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms, a linear or branched acylamino group having 1 to 6 carbon atoms, substituted or unsubstituted anilide, trihalomethyl, trihalomethoxy, phenyl or phenoxy, which may be substituted by one or more halogen atoms. Independently, one or more ring or alkyl sites may be substituted. Specifically mentioned are OH, chlorine, bromine, nitro, methoxy, cyano, methylenedioxy, trifluoromethyl, trifluoromethoxy, methyl, ethyl and (n, iso-) propyl and (n, iso-, sec and tert. butyl group, anilide group and the like.

X is CH or N, preferably a CH group.

Specific compounds of formula 1 described in Tables 1 to 40 are preferred. Of these, the compounds listed under 37, 50, 63, 64, 65, 84, 115, 117, 119, 121, 123, 130, 143, 147, 168, 174, 256, 264, 272, 311, 319, 320, 321, 324, 349, 352, 354, 355, 358, 364, 380, 392, 395, 398, 401, 402, 444, 455, 459, 460, 506, 863, 866, and 869.

A1 to A21 and J1 to J85 described in Tables 1 to 40 are the groups below, wherein E and G are as described above.

σ ° xf φ ° and ^G _F ° 0 ° F and: HER J2 J3 J4 J5 J6 J7 c, O ^G Q ^G Cl and: Pr ^G Br-Cl 0 ^G Br Q ^G J8 J9 J10 JU J12. JI3 _FjC o ^g 0 ° CF ₃ O ^G MeO 2 0 ^G OMe and ^G ^ OMe J14 J15 J16 J17 J18 J19 , coO ^G 0 ^G OCF ₃ αλ Pr ^G 0 ^G CN Q ^G J20 J21 J22 J23 J24 J25 _Ero n ^G 0 ^G OEt cC _N 0 ^G 0 ^G no ₂ ος • J26 J27 J28 J29 J30 J31 • 0 ° HO '^ Q ^G OH C ^G C ^ OH pe xx ^G TX ^G J32 J33 J34 J35 J36 J37 á ^G 0 :, Cl Ci ^ CAci o _c , Cl (V < 0- _C ) No. J38 J39 J40 J41 J42 J43 Pr ^G OMεΟ'ν OMe q ^g Y OMe OMe MeO 5, G IN About me MeO. ,G ^ • Άον MeO ^ x ^ G MeOV ^le OMe G ^G γ'ΌΜε 0 ° About me J44 J45 J46 J47 J43 J49 J50

Ul 152 153 J54 J55

162 163 164 J65 J66 J67 J68

169 170 J71 J72 J73 J74 J75

íY N YY ^G nY go Y ^G 176 J77 J78 J79 J80 Y Y o ^G 7 Y ^G 1S1 182 183 184 JS5

Table 1

Compound number R ¹ R ² AND E G J m X l H 11 Al COOH CH ₂ ^CH 2 HER 0 CH 2 H H Al COOH ch ₂ J2 0 CH 3 H H Al COOH ch ₂ J3 0 CH 4 H H Al COOH ch ₂ J4 0 CH 5 H H Al COOH ch ₂ J5 0 CH 6 H H Al COOH ch ₂ J6 0 CH 7 H H Al COOH ch ₂ J7 0 CH 8 H H Al COOH ch ₂ J8 0 CH 9 H 11 Al COOH ch ₂ J9 0 CH 10 H H Al COOH ch ₂ J10 0 CH 11 H H Al COOH ch ₂ Clay 0 CH 12 H H Al COOH ch ₂ J12 0 CH 13 H H Al COOH ch ₂ J13 0 CH 14 · H H Al COOH ch ₂ J14 0 CH 15 Dec H H Al COOH ch ₂ J15 0 CH 16 H H Al COOH ch ₂ J16 0 CH 17 H H Al COOH ch ₂ J17 0 CH 18 H H Al COOH ch ₂ J18 0 CH 19 Dec H H Al COOH ch ₂ J19 0 CH 20 May H H Al COOH ch ₂ J20 0 CH 21 H H Al COOH ch ₂ J21 0 CH 22nd H H Al COOH Cll ₂ J22 0 CH 23 H H Al COOH ch ₂ J23 0 CH 24 H H Al COOH ch ₂ J24 0 CH 25 H H Al COOH ch ₂ J25 0 CH

TABLE 2

Compound number R ¹ R ² AND E G J m X 26 H H Al COOH ch ₂ 126 0 CH 27 Mar: H H AI COOH ch ₂ J27 0 CH 28 H H Al COOH ch ₂ J28 0 CH 29 H H Al COOH ch ₂ 129 0 CH 30 H H Al COOH ch ₂ 130 0 CH 31 H H Al COOH ch ₂ 131 0 CH 32 H H Al COOH ch ₂ 132 0 CH 33 H H Al COOH ch ₂ 133 0 CH 34 H H Al COOH ch ₂ 134 0 CH 35 H H Al COOH ch ₂ 135 0 CH 36 H H Al COOH ch ₂ 136 0 CH 37 H H Al COOH ch ₂ 137 0 CH 38. H H Al COOH ch ₂ 138 0 CH 39 H H Al COOH ch ₂ 139 0 CH 40 H H Al COOH ch ₂ 140 0 CH 41 H H Al COOH ch ₂ 141 0 CH 42 H H Al COOH ch ₂ J42 0 CH 43 H H Al COOH ch ₂ 143 0 CH 44 H H Al COOH ch ₂ 144 0 CH 45 H 11 Al COOH ch ₂ J45 0 CH 46 H H Al COOH ch ₂ 146 0 CH 47 H H Al COOH ch ₂ J47 0 CH 48 H H Al COOH ch ₂ J48 0 CH 49 H H Al COOH ch ₂ 149 0 CH 50 H H Al COOH ch ₂ J50 0 CH

• In «00«

0

0 0 0

Table 3 r · r • 0 00 • · * 0 * * * 0 0

Compound number R ^l R ² AND E G } m X 51 H H Al COOH ch ₂ J51 0 CH 52 H H Al COOH ch ₂ J52 0 CH 53 H H Al COOH ch ₂ J53 0 CH 54 H H Al COOH ch ₂ J54 0 CH 55 H H Al COOH ch ₂ J55 0 CH 56 H H Al COOH ch ₂ J56 0 CH 57 H H Al COOH ch ₂ J57 0 CH 58 H H Al COOH ch ₂ J58 0 CH 59 H H Al COOH ch ₂ J59 0 CH 60 H H Al COOH ch ₂ J6O 0 CH 61 H H Al COOH ch ₂ J61 0 CH 62 H H Al COOH ch ₂ J62 0 CH 63 H H Al COOH ch ₂ J63 0 CH 64 H H Al COOH ch ₂ J64 0 CH 65 H H Al COOH ch ₂ J65 0 CH 66 H H Al COOH ch ₂ J66 0 CH 67 H H Al COOH ch ₂ J67 0 CH 68 H H Al COOH ch ₂ 168 0 CH 69 H H • Al COOH ch ₂ J69 0 CH 70 H H Al COOH ch ₂ 170 0 CH 71 H H Al COOH ch ₂ J71 0 CH 72 H H Al COOH ch ₂ J72 0 CH 73 H H Al COOH ch ₂ J73 0 CH 74 H H Al COOH ch ₂ J74 0 CH 75 H H Al COOH ch ₂ J75 0 CH

Table 4 · · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

Compound number R ¹ R ² AND E G J m X 76 H H Al COOH ch ₂ J76 0 CH 77 H H Al COOH ch ₂ J77 0 CH 78 H H Al COOH ch ₂ J78 0 CH 79 H H Al COOH ch ₂ J79 0 CH 80 H H Al COOH ch ₂ J80 0 CH 81 Me Me Al COOH ch ₂ HER 0 CH 82 Me Me Al COOH ch ₂ J2 0 CH 83 Me Me Al COOH ch ₂ J3 0 CH 84 Me Me Al COOH ch ₂ J4 0 CH 85 Me Me Al COOH ch ₂ J5 0 CH 86 Me Me Al COOH ch ₂ J6 0 CH 87 Me Me Al COOH ch ₂ J7 0 CH 88 Me Me Al COOH ch ₂ J8 0 CH 89 Me Me Al COOH ch ₂ J9 0 CH 90 Me Me Al 'COOH ch ₂ J10 0 CH 91 Me Me Al COOH ch ₂ J11 0 CH 92 Me Me Al COOH ch ₂ J12 0 CH 93 Me Me Al COOH ch ₂ J13 0 CH 94 Me Me Al COOH ch ₂ J14 0 CH 95 Me Me Al COOH ch ₂ J15 0 CH 96 Me Me Al COOH ch ₂ J16 0 CH 97 Me Me Al COOH ch ₂ J17 0 CH 98 Me Me Al COOH ch ₂ J18 0 CH 99 Me Me Al COOH ch ₂ J19 0 CH 100 ALIGN! Me Me Al COOH ch ₂ J20 0 CH

Table 5

Compound number R ¹ R ² AND E G J m X 101 Me Me Al COOH ch ₂ J21 0 CH 102 Me Me Al COOH ch ₂ J22 0 CH 103 Me Me Al COOH ch ₂ J23 0 CH 104 Me Me Al COOH ch ₂ J24 0 CH 105 Me Me Al COOH ch ₂ J25 0 CH 106 Me Me Al COOH ch ₂ 126 0 CH 107 Me Me Al COOH ch ₂ J27 0 CH 108 Me Me Al COOH ch ₂ J28 0 CH 109 Me Me Al COOH ch ₂ J29 0 CH 110 Me Me Al COOH ch ₂ J30 0 CH 111 Me Me Al COOH ch ₂ J31 0 CH 112 Me Me Al COOH ch ₂ J32 0 CH 113. Me Me Al COOH ch ₂ J33 0 CH 114 Me Me Al COOH ch ₂ J34 0 CH 115 Me Me Al COOH ch ₂ J35 0 CH 116 Me Me Al COOH ch ₂ J36 0 CH 117 Me Me Al COOH ch ₂ J37 0 CH 118 Me Me Al COOH ch ₂ J38 0 CH 119 Me Me Al COOH ch ₂ J39 0 CH 120 Me Me Al COOH ch ₂ J40 0 CH 121 Me Me Al COOH ch ₂ J4I 0 CH 122 Me Me Al COOH ch ₂ J42 0 CH 123 Me Me Al COOH ch ₂ J43 0 CH 124 Me Me Al COOH ch ₂ 144 0 CH 125 Me Me Al COOH ch ₂ J45 0 CH

Table 6

Compound number R * R ^Z AND E G J m X 126 Me Me Al COOH ch ₂ J46 0 CH 127 Me Me Al COOH ch ₂ J47 0 CH 128 Me Me Al COOH ch ₂ J48 0 CH 129 Me Me Al COOH ch ₂ J49 0 CH 130 Me Me Al COOH ch ₂ J50 0 CH 131 Me Me Al COOH ch ₂ J51 0 CH 132 Me Me Al COOH ch ₂ J52 0 CH 133 Me Me Al COOH ch ₂ J53 0 CH 134 Me Me Al COOH ch ₂ J54 0 CH 135 Me Me Al COOH ch ₂ J55 0 CH 136 Me Me Al COOH ch ₂ J56 0 CH 137 Me Me Al COOH ch ₂ J57 0 CH 138 Me Me Al COOH ch ₂ J58 0 CH 139 Me Me Al COOH ch ₂ J59 0 CH 140 Me Me Al COOH ch ₂ J60 0 CH 141 Me Me Al COOH ch ₂ ¹⁶¹ 0 CH 142 Me Me Al COOH ch ₂ J62 0 CH 143 Me Me Al COOH ch ₂ J63 0 CH 144 Me Me Al COOH ch ₂ J64 0 CH 145 Me Me Al COOH ch ₂ J65 0 CH 146 Me Me Al COOH ch ₂ J66 0 CH 147 Me Me Al COOH ch ₂ J67 0 CH 148 Me Me Al COOH ch ₂ J68 0 CH 149 Me Me Al COOH ch ₂ J69 0 CH 150 Me Me Al COOH ch ₂ J70 0 CH

Table 7

Compound number R ¹ R ² AND E G J m X 151 Me Me Al COOH ch ₂ J71 0 CH 152 Me Me Á1 COOH ch ₂ J72 0 CH 153 Me Me Al COOH ch ₂ J73 0 CH 154 Me Me Al COOH ch ₂ J74 0 CH 155 Me Me Al COOH ch ₂ J75 0 CH 156 Me Me Al COOH ch ₂ J76 0 CH 157 Me Me Al COOH ch ₂ J77 0 CH 158 Me Me Al COOH ch ₂ J78 0 CH 159 Me Me Al COOH ch ₂ J79 0 CH 160 Me Me Al COOH ch ₂ J80 0 CH 161 Cl Cl Al COOH ch ₂ ch ₂ HER 0 CH 162 Cl Cl Al COOH ch ₂ J4 0 CH 163. Cl Cl Al COOH ch ₂ J10 0 CH 164 Cl Cl Al COOH ch ₂ J18 0 CH 165 Cl Cl Al COOH ch ₂ J21 0 CH 166 Cl Cl Al COOH ch ₂ J28 0 CH 167 Cl Cl Al COOH ch ₂ J35 0 CH 168 Cl Cl Al COOH ch ₂ J37 0 CH 169 Cl Cl Al COOH ch ₂ J39 0 CH 170 Cl Cl Al COOH ch ₂ J43 0 CH 171 Cl Cl Al COOH ch ₂ J46 0 CH 172 Cl Cl Al COOH ch ₂ J50 0 CH 173 Cl Cl Al COOH ch ₂ J54 0 CH 174 Cl Cl Al COOH ch ₂ J63 0 CH 175 Cl Cl Al COOH ch ₂ J64 0 CH

Table 8

Compound number R * R ² AND E G J m X 176 Cl Cl Al COOH ch ₂ J65 0 CH 177 Cl Cl Al COOH ch ₂ J66 0 CH 178 Cl Cl Al COOH ch ₂ J67 0 CH 179 Cl Cl Al COOH ch ₂ J71 0 CH 180 -ch ₂ ch ₂ ch ₂ - Al COOH ^CH 2 ^CH 2 HER 0 CH 181 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J4 0 CH 182 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J10 0 CH 183 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J18 0 CH 184 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J21 0 CH 185 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ .128 0 CH 186 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J35 0 CH 187 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J37 0 CH 188 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J39 0 CH 189 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J43 0 CH 190 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J46 0 CH 191 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J50 0 CH 192 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J54 0 CH 193 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J63 0 CH 194 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J64 0 CH 195 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J65 0 CH 196 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J66 0 CH 197 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J67 0 CH 198 -ch ₂ ch ₂ ch ₂ - Al COOH ch ₂ J71 0 CH 199 -och ₂ o- Al COOH ^CH 2 ^CH 2 HER 0 CH 200 -och ₂ o- Al COOH ch ₂ J4 0 CH

Table 9

Compound number R * R ^Z AND E C J m X 201 -och ₂ o- Al COOH ch ₂ J10 0 CH 202 -och ₂ o- Al COOH ch ₂ J18 0 CH 203 -och ₂ o- Al COOH ch ₂ J21 0 CH 204 -och ₂ o- Al COOH ch ₂ J28 0 CH 205 -och ₂ o- Al COOH ch ₂ J35 0 CH 206 -och ₂ o- Al COOH ch ₂ J37 0 CH 207 -och ₂ o- Al COOH ch ₂ J39 0 CH 208 -och ₂ o- Al COOH ch ₂ J43 0 CH 209 -och ₂ o- Al COOH ch ₂ J46 0 CH 210 -och ₂ o- Al COOH ch ₂ J50 0 CH 211 -och ₂ o- Al COOH ch ₂ J54 0 CH 212 -och ₂ o- Al COOH ch ₂ J63 0 CH 213. -och ₂ o- Al COOH ch ₂ J64 0 CH 214 -och ₂ o- Al COOH ch ₂ J65 0 CH 215 -och ₂ o- Al COOH ch ₂ J66 0 CH 216 -och ₂ o- Al COOH ch ₂ J67 0 CH 217 -och ₂ o- Al COOH ch ₂ J71 0 CH 218 -och ₂ ch ₂ o- Al COOH ^CH 2 ^CH 2 HER 0 CH 219 -och ₂ ch ₂ o- Al COOH ch ₂ J4 0 CH 220 -och ₂ ch ₂ o- Al COOH ch ₂ J10 0 CH 221 -och ₂ ch ₂ o- Al COOH ch ₂ J18 0 CH 222 -och ₂ ch ₂ o- Al COOH ch ₂ J35 0 CH 223 -och ₂ ch ₂ o- Al COOH ch ₂ J37 0 CH 224 -och ₂ ch ₂ o- Al COOH ch ₂ J39 0 CH 225 -och ₂ ch ₂ o- Al COOH ch ₂ J50 0 CH

• ·

Table 10

Compound number R * R ² AND E G J m X 226 -och ₂ ch ₂ o- Al COOH ch ₂ J63 0 CH 227 -och ₂ ch ₂ o- Al COOH ch ₂ J64 0 CH 228 -och ₂ ch ₂ o- Al COOH ch ₂ J65 0 CH 229 -och ₂ ch ₂ o- Al COOH ch ₂ J67 0 CH 230 -och ₂ ch ₂ o- Al COOH ch ₂ J7l 0 CH 231 About me About me Al COOH ch ₂ ch ₂ HER 0 CH 232 About me About me Al COOH ch ₂ J4 0 CH 233 About me About me Al COOH ch ₂ J10 0 CH 234 About me About me Al COOH ch ₂ J18 0 CH 235 About me About me Al COOH ch ₂ J35 0 CH 236 About me About me Al COOH ch ₂ J37 0 CH 237 About me About me Al COOH ch ₂ J39 0 CH 238. About me About me Al COOH ch ₂ . J50 0 CH 239 About me About me Al COOH ch ₂ J63 0 CH 240 About me About me Al COOH ch ₂ J64 0 CH 241 About me About me Al COOH ch ₂ J65 0 CH 242 About me About me Al COOH ch ₂ J67 0 CH 243 About me About me Al COOH ch ₂ J71 0 CH 244 F F Al COOH ch ₂ J35 0 CH 245 F F Al COOH ch ₂ J37 0 CH 246 F F Al COOH ch ₂ J39 0 CH 247 F F Al COOH ch ₂ J50 0 CH 248 F F Al COOH ch ₂ J63 0 CH 249 F F Al COOH ch ₂ J64 0 CH 250 F F Al COOH ch ₂ J65 0 CH

Table 11

Compound number R ¹ R ² AND E G J m X 251 F F Al COOH ch ₂ J67 0 CH 252 H H Al COOH ch ₂ J35 0 N 253 H H Al COOH ch ₂ J37 0 N 254 H H Al COOH ch ₂ J39 0 N 255 H H Al COOH ch ₂ J50 0 r 256 H H Al COOH ch ₂ J63 0 r 257 H H Al COOH ch ₂ J64 0 r 258 H H Al COOH ch ₂ J65 0 r 259 H H Al COOH ch ₂ J67 0 r 260 Me H Al COOH ch ₂ J35 0 CH 261 Me H Al COOH ch ₂ J37 0 CH 262 Me H Al COOH ch ₂ J39 0 CH 263 Me H Al COOH ch ₂ J50 0 CH 264 Me H Al COOH ch ₂ J63 0 CH 265 Me H Al COOH ch ₂ J64 0 CH 266 Me H Al COOH ch ₂ J65 0 CH 267 Me H Al COOH ch ₂ J67 0 CH 268 About me H Al COOH ch ₂ J35 0 CH 269 About me H Al COOH ch ₂ J37 0 CH 270 About me H Al COOH ch ₂ J39 0 CH 271 About me H Al COOH ch ₂ J50 0 CH 272 About me H Al COOH ch ₂ J63 0 CH 273 About me H Al COOH ch ₂ J64 0 CH 274 About me H Al COOH ch ₂ J65 0 CH 275 About me H Al COOH ch ₂ J67 0 CH

• · ··········

Table 12

Compound number R ¹ R ^Z AND E G J m X 276 OE t H Al COOH ch ₂ -J63 0 CH 277 OEt H Al COOH ch ₂ J64 0 CH 278 OEt H Al COOH ch ₂ J65 0 CH 279 CF3 H Al COOH ch ₂ J63 0 CH 280 CF3 H Al COOH ch ₂ J64 0 CH 281 CF3 H Al COOH ch ₂ J65 0 CH 282 CN H Al COOH ch ₂ J63 0 CH 283 CN H Al COOH ch ₂ J64 0 CH 284 CN H Al COOH ch ₂ J65 0 CH 285 Cl H Al COOH ch ₂ J63 0 N 286 Cl H Al COOH ch ₂ J64 0 N 287 Cl H Al COOH ch ₂ J65 0 N 288 Me Me A2 COOH ch ₂ J35 0 CH 289 Me Me A2 COOH ch ₂ J37 0 CH 290 Me Me A2 COOH ch ₂ J39 0 CH 291 Me Me A2 COOH ch ₂ J63 0 CH 292 Me Me A2 COOH ch ₂ J64 0 CH 293 Me Me A2 COOH ch ₂ J65 0 CH 294 Me Me A2 COOH ^CH 2 ^CH 2 HER 0 CH 295 Me Me A3 COOH ch ₂ HER 0 CH 296 Me Me A3 COOH ch ₂ J35 0 CH 297 Me Me A3 COOH ch ₂ J37 0 CH 298 Me Me A3 COOH ch ₂ J39 0 CH 299 Me Me A3 COOH ch ₂ J5O 0 CH 300 Me Me A3 COOH ch ₂ J63 0 CH

Table 13 ·

Compound number R ¹ R ² AND E G J m X 301 Me Me A3 COOH ch ₂ J64 0 CH 302 Me Me A3 COOH ch ₂ J65 0 CH 303 Me Me A3 COOH ch ₂ J67 0 CH 304 Me Me A3 COOH ^CH 2 ^CH 2 HER 0 CH 305 Me Me A3 COOH ^CH 2 ^CH 2 J63 0 CH 306 Me Me· A4 COOH ch ₂ HER 0 CH 307 Me Me A4 COOH ch ₂ J35 0 CH 308 Me Me A4 COOH ch ₂ J37 0 CH 309 Me Me A4 COOH ch ₂ J39 0 CH 310 Me Me A4 COOH ch ₂ J50 0 CH 311 Me Me A4 COOH ch ₂ J63 0 CH 312 Me Me A4 COOH ch ₂ J64 0 CH 313 Me Me A4 COOH ch ₂ J65 0 CH 314 Me Me A4 COOH ch ₂ J67 0 CH 315 Me Me A4 COOH ^CH 2 ^CH 2 HER 0 CH 316 Me Me A4 COOH ch ₂ ch ₂ J63 0 CH 317 H H A4 COOH ch ₂ J37 0 CH 318 H H A4 COOH ch ₂ J39 0 CH 319 H H A4 COOH ch ₂ J63 0 CH 320 H H A4 COOH ch ₂ J64 0 CH 321 H H A4 COOH ch ₂ J65 0 CH 322 Cl Cl A4 COOH ch ₂ J37 0 CH 323 Cl Cl A4 COOH ch ₂ J39 0 CH 324 Cl Cl A4 COOH ch ₂ J63 0 CH 325 Cl Cl A4 COOH ch ₂ J64 0 CH

Table 14 · · 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14

Compound number R ¹ R ² AND E G J m X 326 Cl Cl A4 COOH ch ₂ J65 0 CH 327 H H A4 COOH ch ₂ J37 0 N 328 H H A4 COOH ch ₂ J39 0 N 329 H H A4 COOH ch ₂ J63 0 N 330 H H A4 COOH ch ₂ J 64 0 N 331 H H A4 COOH ch ₂ J65 0 N 332 Me Me A5 COOH ch ₂ HER 0 CH 333 Me Me A5 COOH ch ₂ ch ₂ HER 0 CH 334 Me Me A6 COOH ch ₂ HER 0 CH 335 Me Me A6 COOH ^CH 2 ^CH 2 HER 0 CH 336 Me Me A7 COOH ch ₂ HER 0 CH 337 Me Me A7 COOH ^CH 2 ^CH 2 HER 0 CH 338. Me Me A8 COOH ch ₂ HER 0 CH 339 Me Me A8 COOH ch ₂ ch ₂ HER 0 CH 340 Me Me A9 COOH ch ₂ HER 0 CH 341 Me Me A9 COOH ^CH 2 ^CH 2 HER 0 CH 342 Me Me A10 COOH ch ₂ HER 0 CH 343 Me Me A10 COOH ch ₂ ch ₂ HER 0 CH 344 Me Me Al 1 COOH ch ₂ J37 0 CH 345 Me Me All COOH ch ₂ J39 0 CH 346 Me Me All COOH ch ₂ J50 0 CH 347 Me Me Al 1 COOH ch ₂ J63 0 CH 348 Me Me All COOH ch ₂ J64 0 CH 349 H H All COOH ch ₂ J37 0 CH 350 H H All COOH ch ₂ J39 0 CH

Table 15

Compound number R ¹ R ² AND E G J m X 351 H H All COOH ch ₂ 150 0 CH 352 H H All COOH ch ₂ 163 0 CH 353 H H All COOH ch ₂ 164 0 CH 354 H H All COOH ch ₂ 165 0 CH 355 Cl Cl All COOH ch ₂ 137 0 CH 356 Cl Cl All COOH ch ₂ J39 0 CH 357 Cl Cl All COOH ch ₂ J50 0 CH 358 Cl Cl All COOH ch ₂ 163 0 CH 359 Cl Cl All COOH ch ₂ 164 0 CH 360 Cl Cl All COOH ch ₂ J65 0 CH 361 H H All COOH ch ₂ 137 0 N 362 H H All COOH ch ₂ 139 0 N 363. H H All COOH ch ₂ J50 0 N 364 H H All COOH ch ₂ 163 0 N 365 H H All COOH ch ₂ 164 0 N 366 H H All COOH . ^CH 2 J65 0 N 367 Me Me Al 2 COOH ch ₂ 11 0 CH 368 Me Me Al 2 COOH ^CH 2 ^CH 2 11 0 CH 369 Me Me AI 3 COOH ch ₂ HER 0 CH 370 Me Me Al 3 COOH ch ₂ ch ₂ 11 0 CH 371 Me Me A14 COOH ch ₂ 11 0 CH 372 Me Me AI4 COOH ^CH 2 ^CH 2 11 0 CH 373 Me Me Al 5 COOH ch ₂ 11 0 CH 374 Me Me A15 COOH ^CH 2 ^CH 2 HER 0 CH 375 Me Me Al 6 COOH ch ₂ HER 0 CH

Table 16

Compound number R * R ² AND E G J m X 376 Me Me A16 COOH CH ₂ ^CH 2 HER 0 CH 377 Me Me AI 6 COOH . ch ₂ J37 0 CH 378 Me Me A16 COOH ch ₂ J39 0 CH 379 Me Me Al 6 COOH ch ₂ J50 0 CH 380 Me Me A16 COOH ch ₂ J63 0 CH 381 Me Me A16 COOH ch ₂ J64 0 CH 382 Me Me Al 6 COOH ch ₂ J65 0 CH 383 H H Al 6 COOH ch ₂ J37 0 CH 384 H H AI 6 COOH ch ₂ J39 0 CH 386 H H A16 COOH ch ₂ J50 0 CH 386 H H A16 COOH ch ₂ J63 0 CH 387 H H A16 COOH ch ₂ J64 0 CH 388 H H A16 COOH ch ₂ J65 0 CH 389 Me Me A17 COOH ch ₂ HER 0 CH 390 Me Me Al 7 COOH ^CH 2 ^CH 2 HER 0 CH 391 Me Me A18 COOH ^CH 2 ^CH 2 HER 0 CH 392 Me Me A18 COOH ch ₂ J37 0 CH 393 Me Me A18 COOH ch ₂ J39 0 CH 394 Me Me A18 COOH ch ₂ J50 0 CH 395 Me Me A18 COOH ch ₂ J63 0 CH 396 Me Me A18 COOH ch ₂ J64 0 CH 397 Me Me A18 COOH ch ₂ J65 0 CH 398 H H A18 COOH ch ₂ J37 0 CH 399 H H AI 8 COOH ch ₂ J39 0 CH 400 H H A18 COOH ch ₂ J50 0 CH

Table 17

9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 10 11 12 »» ···

Compound number R ¹ R ² AND E G 1 m X 401 H H A18 COOH ch ₂ 163 0 CH 402 H H AIS COOH ch ₂ 164 0 CH 403 H H A18 COOH ch ₂ J65 0 CH 404 Cl Cl A18 COOH ch ₂ 137 0 CH 405 Cl Cl A18 COOH ch ₂ 163 0 CH 406 Cl Cl A18 COOH ch ₂ 164 0 CH 407 Cl Cl A18 COOH ch ₂ 165 0 CH 408 H H A18 COOH ch ₂ 137 0 N 409 H H A18 COOH ch ₂ 139 0 N 410 H H A18 COOH ch ₂ 163 0 N 411 H H A18 COOH ch ₂ J64 0 N 412 H H A18 COOH ch ₂ J65 0 N 413 Me H A18 COOH ch ₂ 137 0 CH 414 Me H A18 COOH ch ₂ 139 0 CH 415 Me H A18 COOH ch ₂ 163 0 CH 416 Me H A18 COOH ch ₂ 164 0 CH 417 Me H A18 COOH ch ₂ J65 0 CH 418 About me H A18 COOH ch ₂ 137 0 CH 419 About me H A18 COOH ch ₂ J39 0 CH 420 About me H Al 8 COOH ch ₂ 163 0 CH 421 About me H Al 8 COOH ch ₂ 164 0 CH 422 About me H A18 COOH ch ₂ J65 0 CH 423 OEt H A18 COOH ch ₂ 163 0 CH 424 OEt H A18 COOH ch ₂ 164 0 CH 425 0E1 H Al 8 COOH t ch ₂ 165 0 CH

Table 18 • «» 9 · 9999 99

9 <t »· ·

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Compound number R ¹ R ² AND E C J m X 426 CF3 H AI8 COOH ch ₂ J63 0 CH 427 CF3 H AIS COOH ch ₂ J64 0 CH 428 CF3 H AIS COOH ch ₂ J65 0 CH 429 CN H A18 COOH ch ₂ J63 0 CH 430 CN H AIS COOH ch ₂ J64 0 CH 431 CN H AIS COOH ch ₂ J65 0 CH 432 F H AIS COOH ch ₂ 163 0 CH 433 F H AIS COOH ch ₂ J64 0 CH 434 F H AIS COOH ch ₂ J65 0 CH 435 Cl H AIS COOH ch ₂ J63 0 N 436 Cl H AIS COOH ch ₂ J64 0 N 437 Cl H AIS COOH ch ₂ J65 0 N 438 H H AIS COOH ch ₂ J37 0 N 439 Me Me A19 COOH ch ₂ HER 0 CH 440 Me Me A19 COOH ch ₂ ch ₂ HER 0 CH 441 Me Me A19 COOH ch ₂ J37 0 CH 442 Me Me A19 COOH ch ₂ J39 0 CH 443 Me Me A19 COOH ch ₂ J50 0 CH 444 Me Me A19 COOH ch ₂ J63 0 CH 445 Me Me Al 9 COOH ch ₂ J64 0 CH 446 Me Me A19 COOH ch ₂ J65 0 CH 447 H H AI9 COOH ch ₂ HER 0 CH 448 H H AI9 COOH ^ch 2 ^ch 2 HER 0 CH 449 H H Al 9 COOH ch ₂ J37 0 CH 450 H H A19 COOH ch ₂ J39 0 CH

• ································

33 Table 19 • · · · · • · · · • · · Compound number R ¹ R ^z AND E G J m X 451 H H A19 COOH ch ₂ J50 0 CH 452 H H A.19 COOH ch ₂ J63 0 CH 453 H H A19 COOH ch ₂ J64 0 CH 454 H H AI 9 COOH ch ₂ J65 0 CH 455 Me Me A20 COOH ch ₂ J64 0 CH 456 Me Me A20 COOH ch ₂ 165 0 CH 457 Me Me A20 COOH ch ₂ 167 0 CH 458 Me Me A20 COOH ch ₂ J71 0 CH 459 H H A20 COOH ch ₂ J64 0 CH 460 H Ή A20 COOH ch ₂ J65 0 CH 461 H H A20 COOH ch ₂ J67 0 CH 462 H H A20 COOH ch ₂ J71 0 CH 463 Cl Cl A20 COOH ch ₂ J64 0 CH 464 Cl Cl A20 COOH ch ₂ J65 0 CH 465 Cl Cl A20 COOH ch ₂ J67 0 CH 466 Cl Cl A20 COOH ch ₂ J71 0 CH 467 H H A20 COOH ch ₂ J64 0 N 468 H H A20 COOH ch ₂ J65 0 N 469 H H A20 COOH ch ₂ 167 0 N 470 11 H A20 COOH cii ₂ J71 0 N 471 Me H A20 COOH ch ₂ J64 0 CH 472 Me H A20 COOH ch ₂ J65 0 CH 473 Me H A20 COOH ch ₂ J67 0 CH 474 Me H A20 COOH ch ₂ J71 0 CH 475 About me 11 A20 COOH ch ₂ J64 0 CH

• «« »» »» »» »» »» »» »» »»

34 Table 20 May • · · · · • · • «· · Compound number R ¹ R ^z AND E G J m X 476 About me H A20 COOH ch ₂ J65 0 CH 477 About me H A20 COOH ch ₂ J67 0 CH 478 About me H A20 COOH ch ₂ J71 0 CH 479 OEt H A20 COOH ch ₂ J64 0 CH 480 OEt H A20 COOH ch ₂ J65 0 CH 481 OEt H A20 COOH ch ₂ J67 0 CH 482 OEt H A20 COOH ch ₂ 171 0 CH 483 F H A20 COOH ch ₂ J64 0 CH 484 F H A20 COOH ch ₂ J65 0 CH 485 F H A20 COOH ch ₂ 167 0 CH 486 F H A20 COOH ch ₂ J71 0 CH 487 CF3 H A20 COOH ch ₂ 164 0 CH 488 CF3 H A20 COOH ch ₂ J65 0 CH 489 CF3 H A20 COOH ch ₂ J67 0 CH 490 CF3 H A20 COOH ch ₂ J71 0 CH 491 CN H A20 COOH ch ₂ J64 0 CH 492 CN H A20 COOH ch ₂ J65 0 CH 493 CN H A20 COOH ch ₂ J67 0 CH 494 CN H A20 COOH ch ₂ J71 0 CH 495 Cl H A20 COOH ch ₂ J64 0 N 496 Cl H A20 COOH ch ₂ J65 0 N 497 Cl H A20 COOH ch ₂ J67 0 N 498 Cl H A20 COOH ch ₂ J71 0 N 499 H H A21 COOH ch ₂ J63 0 CH 500 H H A21 COOH ch ₂ J65 0 CH

Table 21 • · · · · ·

Compound number R ¹ _r 2 AND E G J m X 501 Me Me AI COOH ^CH 2 ^CH 2 HER 0 CH 502 Me Me Al COOH ^CH 2 ^CH 2 J37 0 CH 503 Me Me Al COOH ^CH 2 ^CH 2 J39 0 CH 504 Me Me Al COOH ^CH 2 ^CH 2 J50 0 CH 505 Me Me Al COOH ^CH 2 ^CH 2 J62 0 CH 506 Me Me Al COOH ^CH 2 ^CH 2 J63 0 CH 507 Me Me Al COOH ^CH 2 ^CH 2 J64 0 CH 508 Me Me Al COOH ^CH 2 ^CH 2 J65 0 CH 509 H H Al COOH ^CH 2 ^CH 2 HER 0 CH 510 H H Al COOH ch ₂ ch ₂ J37 0 CH 511 H H Al COOH ^CH 2 ^CH 2 J39 0 CH 512 H H Al COOH ^CH 2 ^CH 2 J50 0 CH 513 H H Al COOH ^CH 2 ^CH 2 J62 0 CH 514 H H Al COOH ^CH 2 ^CH 2 J63 0 CH 515 H H Al COOH CH ₂ ^CH 2 J64 0 CH 516 H H Al COOH ^CH 2 ^CH 2 J65 0 CH 517 Me Me A4 COOH ^CH 2 ^CH 2 J37 0 CH 518 Me Me A4 COOH CH ₂ ^CH 2 J39 0 CH 519 Me Me A4 COOH ^CH 2 ^CH 2 J67 0 CH 520 Me Me A4 COOH ^CH 2 ^CH 2 J64 0 CH 521 Me Me A4 COOH ch ₂ ch ₂ J65 0 CH 522 H H A4 COOH CH ₂ ^CH 2 J37 0 CH 523 H H A4 COOH CH ₂ CH 2 J39 0 CH 524 H H A4 COOH CH ₂ ^CH 2 J63 0 CH 525 H H A4 COOH ^CH 2 ^CH 2 J64 0 CH

Table 22

Compound number R ¹ R ² AND E G J m X 526 H H A4 COOH ^CH 2 ^CH 2 J65 0 CH 527 H H All COOH ^CH 2 ^CH 2 J37 0 CH 528 H H All COOH ^CH 2 ^CH 2 J39 0 CH 529 H H All COOH ^CH 2 ^CH 2 J63 0 CH 530 H H All COOH ^CH 2 ^CH 2 J64 0 CH 531 H H All COOH ^CH 2 ^CH 2 J65 0 CH 532 H H A18 COOH ^CH 2 ^CH 2 J37 0 CH 533 H H A18 COOH ^CH 2 ^CH 2 J39 0 CH 534 H H A18 COOH ^CH 2 ^CH 2 J63 0 CH 535 H H 418 COOH ^CH 2 ^CH 2 J64 0 CH 536 H H A18 COOH CH ₂ ^CH 2 J65 0 CH 537 Me Me A20 COOH ^CH 2 ^CH 2 J37 0 CH 538 Me Me A20 COOH ^CH 2 ^CH 2 J39 0 CH 539 Me Me A20 COOH ch ₂ ch ₂ J63 0 CH 540 Me Me A20 COOH ch ₂ ch ₂ J64 0 CH 541 Me Me A20 COOH ^CH 2 ^CH 2 J65 0 CH 542 H H A20 COOH ^CH 2 ^CH 2 J37 0 CH 543 H H A20 COOH ^CH 2 ^CH 2 J 39 0 CH 544 H H A20 COOH ^CH 2 ^CH 2 J63 0 CH 545 H H A20 COOH ^CH 2 ^CH 2 J64 0 CH 546 H H A20 COOH ^CH 2 ^CH 2 J65 0 CH 547 Me Me Al COOH WHAT HER 0 CH 548 Me Me Al COOH WHAT J63 0 CH 549 H H . Al COOH WHAT HER 0 CH 550 H H Al COOH WHAT J63 0 CH

Table 23

Compound' number R ¹ R ² AND E G J m X 551 Me Me A4 COOH WHAT HER 0 CH 552 Me Me A4 COOH WHAT J63 0 CH 553 H H A4 COOH WHAT HER 0 CH 554 H H A4 COOH WHAT J63 0 CH 555 H H All COOH WHAT HER 0 CH 556 H H All COOH WHAT J63 0 CH 557 H H A18 COOH WHAT HER 0 CH 558 H H A18 COOH WHAT J63 0 CH 559 H H A20 COOH WHAT HER 0 CH 560 H H A20 COOH WHAT J63 0 CH 561 Me Me Al COOH Sat ₂ HER 0 CH 562 Me Me Al COOH Sat ₂ J63 0 CH 563 H H Al COOH Sat ₂ HER 0 CH 564 H H Al COOH Sat ₂ J63 0 CH 565 H H A4 COOH Sat ₂ HER 0 CH  566 H H A4 COOH Sat ₂ J63 0 CH 567 H H All COOH Sat ₂ HER 0 CH 568 H H All COOH Sat ₂ J63 0 CH 569 H H A18 COOH Sat ₂ HER 0 CH 570 H H AIS COOH Sat ₂ J63 0 CH 571 H H A20 COOH Sat ₂ HER 0 CH 572 H H A20 COOH Sat ₂ J63 0 CH 573 H H Al COOH ch ₂ co HER 0 CH 574 H H Al COOH ch ₂ co J2 0 CH 575 H H Al COOH ch ₂ co J3 0 CH

Table 24

Compound number R ^l R ² 'A E G J m X ~ 576 H H Al COOH ch ₂ co J4 0 CH 577 H H Al COOH ch ₂ co J5 0 CH 578 H H Al COOH ch ₂ co J6 0 CH 579 H H Al COOH ch ₂ co J7 0 CH 580 H H Al COOH ch ₂ co J8 0 CH 581 H H Al COOH ch ₂ co J9 0 CH 582 H H Al COOH ch ₂ co J10 0 CH 583. H H Al COOH ch ₂ co JI l 0 CH 584 H H Al COOH ch ₂ co J12 0 CH 585 H H Al COOH ch ₂ co 113 0 CH 586 H H Al COOH ch ₂ co J17 0 CH 587 H H Al COOH ch ₂ co J18 0 CH 588 H H Al COOH ch ₂ co J19 0 CH 589 H H AT COOH ch ₂ co J23 0 CH 590 H H Al COOH ch ₂ co J24 0 CH 591 H H Al COOH ch ₂ co J25 0 CH 592 H H Al COOH ch ₂ co J36 0 CH 593 H H Al COOH ch ₂ co J47 0 CH 594 H H Al COOH ch ₂ co J57 0 CH 595 H H Al COOH ch ₂ co J62 0 CH 596 Me Me Al COOH ch ₂ co HER 0 CH 597 Me Me Al COOH ch ₂ co J2 0 CH 598 Me Me Al COOH ch ₂ co J3 0 CH 599 Me Me Al COOH ch ₂ co J4 0 CH 600 Me Me Al COOH ch ₂ co J5 0 CH

Table 25

Compound number R ¹ R ² AND E G J m X 601 Me Me Al COOH ch ₂ co Í6 0 CH 602 Me Me Al COOH ch ₂ co J7 0 CH 603 Me Me Al COOH ch ₂ co J8 0 CH 604 Me Me Al COOH ch ₂ co J9 0 CH 605 Me Me Al COOH ch ₂ co J10 0 CH 606 Me Me Al COOH ch ₂ co Jll 0 CH 607 Me Me Al COOH ch ₂ co J12 0 CH 608 Me Me Al COOH ch ₂ co J13 0 CH 609 Me Me Al COOH ch ₂ co J17 0 CH 610 Me Me Al COOH ch ₂ co J18 0 CH 611 Me Me Al COOH ch ₂ co J19 0 CH 612 Me Me Al COOH ch ₂ co J23 0 CH 613 Me Me Al COOH ch ₂ co J24 0 CH 614 Me Me Al COOH ch ₂ co J25 0 CH 615 Me Me Al COOH ch ₂ co J36 0 CH 616 Me Me Al COOH ch ₂ co J47 0 CH 617 Me Me Al COOH ch ₂ co J57 0 CH 618 Me Me Al COOH ch ₂ co J62 0 CH 619 H H Al COOH ch ₂ conh HER 0 CH 620 H H Al COOH ch ₂ conh J2 0 · CH 621 H H Al COOH ch ₂ conh J3 0 CH 622 H H Al COOH ch ₂ conh J4 0 CH 623 H H Al COOH ch ₂ conh J5 0 CH 624 H H Al . COOH ch ₂ conh J6 0 CH 625 H H Al COOH ch ₂ conh J7 0 CH

Table 26 ··· · · · · ·······

Compound number R ¹ R ² AND E G J m X 626 H H Al COOH ch ₂ conh J8 0 CH 627 H H Al COOH ch ₂ conh J9 0 CH 628 H H Al COOH ch ₂ conh J10 0 CH . 629 H H Al COOH ch ₂ conh Jll 0 CH 630 H H Al COOH ch ₂ conh J12 0 CH 631 H H Al COOH ch ₂ conh J13 0 CH 632 H H Al COOH ch ₂ conh J14 0 CH 633 H H Al COOH ch ₂ conh J15 0 CH 634 H H Al COOH ch ₂ conh JI6 0 CH 635 H H Al COOH ch ₂ conh J17 0 CH 636 H H Al COOH ch ₂ conh J18 0 CH 637 H H Al COOH ch ₂ conh J19 0 CH 638 H H Al COOH ch ₂ conh J20 0 CH 639 H H Al COOH ch ₂ conh J21 0 CH 640 H H Al COOH ch ₂ conh J22 0 CH 641 H H Al COOH ch ₂ conh J23 0 CH 642 H H Al COOH ch ₂ conh J24 0 CH 643 H H Al COOH ch ₂ conh J25 0 CH 644 H H Al COOH ch ₂ conh J26 0 CH 645 H H Al COOH ch ₂ conh J27 0 CH 646 H H Al COOH ch ₂ conh J28 0 CH 647 H H Al COOH ch ₂ conh J29 0 CH 648 H H Al COOH ch ₂ conh J30 0 CH 649 H H Al COOH ch ₂ conh J31 0 CH 650 H H Al COOH ch ₂ conh J32 0 CH

• • •

41 »· • • • • · · • • · · • · · • · «· · • · · • · · • · · · • · · · • · · • · · · • «· · · Table 27 Compound number R * R ² AND E G J m X 651 H H Al COOH ch ₂ conh J33 0 CH 652 H H Al COOH CH _Z CONH J34 0 CH 653 H H Al COOH ch ₂ conh J35 0 CH 654 H H Al COOH ch ₂ conh J37 0 CH 655 H H Al COOH ch ₂ conh J39 0 CH 656 H H Al COOH ch ₂ conh J62 0 CH 657 H H Al COOH ch ₂ conh J63 0 CH 658 Me Me Al COOH ch ₂ conh HER 0 CH 659 Me Me Al COOH ch ₂ conh J2 0 CH 660 Me Me Al COOH ch ₂ conh J3 0 CH 661 Me Me Al COOH ch ₂ conh J4 0 CH 662 Me Me Al COOH ch ₂ conh J5 0 CH 663 Me Me Al COOH ch ₂ conh J6 0 .CH 664 Me Me Al COOH ch ₂ conh J7 0 CH 665 Me Me Al COOH ch ₂ conh J8 0 CH 666 Me Me Al COOH ch ₂ conh J9 0 CH 667 Me Me Al COOH ch ₂ conh J10 0 CH 668 Me Me Al COOH ch ₂ conh J11 0 CH 669 Me Me Al COOH ch ₂ conh J12 0 CH 670 Me Me Al COOH ch ₂ c.ohh J13 0 CH 671 Me Me Al COOH ch ₂ conh J14 0 CH 672 Me Me Al COOH ch ₂ conh J15 0 CH 673 Me Me Al COOH ch ₂ conh J16 0 CH 674 Me Me Al COOH ch ₂ conh J17 0 CH 675 Me Me Al COOH ch ₂ conh J18 0 CH

Table 28

Compound number R ¹ R ² AND E C J m X 676 Me Me Al COOH ch ₂ conh J19 0 CH 677 Me Me Al COOH ch ₂ conh J20 0 CH 678 Me Me Al COOH ch ₂ conh J21 0 CH 679 Me Me Al COOH ch ₂ conh J22 0 CH 680 Me Me Al COOH ch ₂ conh J23 0 CH 681 Me Me Al COOH ch ₂ conh J24 0 CH 682 Me Me Al COOH ch ₂ conh J25 0 CH 683 Me Me Al COOH ch ₂ conh J26 0 CH 684 Me Me Al COOH ch ₂ conh J27 0 CH 685 Me Me Al COOH ch ₂ conh J28 0 CH 686 Me Me Al COOH ch ₂ conh J29 0 CH 687 Me Me Al COOH ch ₂ conh J30 0 CH 688 Me Me Al COOH ch ₂ conh J31 0 CH 689 Me Me Al COOH ch ₂ conh J32 0 CH 690 Me Me Al COOH ch ₂ conh J33 0 CH 691 Me Me Al COOH ch ₂ conh J34 0 CH 692 Me Me Al COOH ch ₂ conh J35 0 CH 693 Me Me Al COOH ch ₂ conh J37 0 CH 694 Me Me Al COOH ch ₂ conh J39 0 CH 695 Me Me Al COOH ch ₂ conh J62 0 CH 696 Me Me Al COOH ' ch ₂ conh J63 0 CH 697 H H Al COOH ch ₂ ch ₂ o HER 0 CH 698 H H Al COOH ch ₂ ch ₂ o J2 0 CH 699 H H Al COOH ch ₂ ch ₂ o J3 0 CH 700 H H Al COOH ch ₂ ch ₂ o J4 0 CH

Table 29

Compound number R ¹ R ² AND E C J m X 701 H H Al COOH ch ₂ ch ₂ o J5 0 CH 702 H H Al COOH ch ₂ ch ₂ o J6 0 CH 703 H H Al COOH ch ₂ ch ₂ o J7 0 CH 704 H H Al COOH ch ₂ ch ₂ o J8 0 CH 705 H H Al COOH ch ₂ ch ₂ o J9 0 CH 706 H H Al COOH ch ₂ ch ₂ o J10 0 CH 707 H H Al COOH ch ₂ ch ₂ o J11 0 CH 708 H H Al COOH ch ₂ ch ₂ o J12 0 CH 709 H H Al COOH ch ₂ ch ₂ o J13 0 CH 710 H H Al COOH ch ₂ ch ₂ o J14 0 CH 711 H H Al COOH ch ₂ ch ₂ o J15 0 CH 712 H H Al COOH ch ₂ ch ₂ o J16 0 CH 713 H H Al COOH ch ₂ ch ₂ o J17 0 CH 714 H H Al COOH ch ₂ ch ₂ o J18 0 CH 715 H H Al COOH ch ₂ ch ₂ o J19 0 CH 716 H H Al COOH ch ₂ ch ₂ o J20 0 CH 717 H H Al COOH ch ₂ ch ₂ o J21 0 CH 718 H H Al COOH ch ₂ ch ₂ o J22 0 CH 719 H H Al COOH ch ₂ ch ₂ o J23 0 CH 720 H H Al COOH ch ₂ ch ₂ o J24 0 CH 721 H H Al COOH ch ₂ ch ₂ o J25 0 CH 722 H H Al COOH ch ₂ ch ₂ o J26 0 CH 723 H H Al COOH ch ₂ ch ₂ o J 27 0 CH 724 H H Al COOH ch ₂ ch ₂ o J28 0 CH 725 H H Al COOH ch ₂ ch ₂ o J29 0 CH

Table 30

Compound number R ¹ R ² AND E G J m X 726 H H Al COOH ch ₂ ch ₂ o J30 0 CH 727 H H Al COOH ch ₂ ch ₂ o J31 0 CH 728 H H Al COOH ch ₂ ch ₂ o J32 0 CH 729 H H Al COOH ch ₂ ch ₂ o J33 0 CH 730 H H Al COOH ch ₂ ch ₂ o J34 0 CH 731 H H Al COOH ch ₂ ch ₂ o J35 0 CH 732 H H Al COOH ch ₂ ch ₂ o J37 0 CH 733 H H Al COOH ch ₂ ch ₂ o J39 0 CH 734 H H Al COOH ch ₂ ch ₂ o J62 0 CH 735 H H Al COOH ch ₂ ch ₂ o J63 0 CH 736 Me Me Al COOH ch ₂ ch ₂ o HER 0 CH 737 Me Me Al COOH ch ₂ ch ₂ o J2 0 CH 738 Me Me Al COOH ch ₂ ch ₂ o J3 0 CH 739 Me Me Al COOH ch ₂ ch ₂ o J4 0 CH 740 Me Me Al COOH ch ₂ ch ₂ o J5 0 CH 741 Me Me Al COOH ch ₂ ch ₂ o J6 0 CH 742 Me Me Al COOH ch ₂ ch ₂ o J7 0 CH 743 Me Me Al COOH ch ₂ ch ₂ o J8 0 CH 744 Me Me Al COOH ch ₂ ch ₂ o J9 0 CH 745 Me Me Al COOH ch ₂ ch ₂ o J10 0 CH 746 Me Me Al COOH ch ₂ ch ₂ o Jll 0 CH 747 Me Me Al COOH ch ₂ ch ₂ o J12 0 CH 748 Me Me Al COOH ch ₂ ch ₂ o J13 0 CH 749 Me Me AI COOH ch ₂ ch ₂ o J14 0 CH 750 Me Me Al COOH ch ₂ ch ₂ o J15 0 CH

Table 31

Compound number R ¹ R ² AND E G J m X 751 Me Me Al COOH ch ₂ ch ₂ o J15 0 CH 752 Me Me Al COOH ch ₂ ch ₂ o J16 0 CH 753 Me Me Al COOH ch ₂ ch ₂ o J17 0 CH 754 Me Me Al COOH ch ₂ ch ₂ o J18 0 CH 755 Me Me Al COOH ch ₂ ch ₂ o J19 0 CH 756 Me Me Al COOH ch ₂ ch ₂ o J2O 0 CH 757 Me Me Al COOH ch ₂ ch ₂ o J21 0 CH 758 Me Me Al COOH ch ₂ ch ₂ o J22 0 CH 759 Me Me Al COOH ch ₂ ch ₂ o J23 0 CH 760 Me Me Al COOH ch ₂ ch ₂ o J24 0 CH 761 Me Me Al COOH ch ₂ ch ₂ o J25 0 CH 762 Me Me Al COOH ch ₂ ch ₂ o J26 0 CH 763 Me Me Al COOH ch ₂ ch ₂ o J27 0 CH 764 Me Me Al COOH ch ₂ ch ₂ o J28 0 CH 765 Me Me Al COOH ch ₂ ch ₂ o J29 0 CH 766 Me Me Al COOH ch ₂ ch ₂ o J30 0 CH 767 Me Me Al COOH ch ₂ ch ₂ o J31 0 CH 768 Me Me Al COOH ch ₂ ch ₂ o 132 0 CH 769 Me Me Al COOH ch ₂ ch ₂ o J33 0 CH 770 Me Me Al COOH ch ₂ ch ₂ o J34 0 CH 771 Me Me Al COOH ch ₂ ch ₂ o J35 0 CH 772 Me Me Al COOH ch ₂ ch ₂ o J37 0 CH 773 Me Me Al COOH ch ₂ ch ₂ o J39 0 CH 774 Me Me Al COOH ch ₂ ch ₂ o 162 0 CH 775 Me Me Al COOH ch ₂ ch ₂ o J63 0 CH

Table 32 • 9 · 9 · 9 99

9 9 9 9 9

999 99 99 99 • 9999 99 99 99 9

Compound number R ¹ R ² AND E G J m X 776 H H Al COOH ch ₂ s HER 0 CH 777 H H Al COOH ch ₂ s J2 0 CH 778 H H Al COOH ch ₂ s J3 0 CH 779 H H Al COOH ch ₂ s J4 0 CH 780 H H Al COOH ch ₂ s J8 0 CH 781 H H Al COOH ch ₂ s J9 0 CH 782 H H Al COOH ch ₂ s J10 0 CH 783 Me Me Al COOH ch ₂ s HER 0 CH 784 Me Me Al COOH ch ₂ s J2 0 CH 785 Me Me Al COOH ch ₂ s J3 0 CH 786 Me Me Al COOH ch ₂ s J4 0 CH 787 Me Me Al COOH ch ₂ s J8 0 CH 788 Me Me Al COOH ch ₂ s J9 0 CH 789 Me Me Al COOH ch ₂ s J10 0 CH 790 H H Al COOH CH ₂ ^with ° ₂ HER 0 CH 791 H H Al COOH ^ch 2 ^SO 2 J2 0 CH 792 H H Al COOH CH ₂ ^with ° ₂ J3 0 CH 793 H H Al COOH CH ₂ ^with ° 2 J4 0 CH 794 H H Al COOH ^CH 2 ^SO 2 J8 0 CH 795 H H Al COOH ch ₂ so ₂ J9 0 CH 796 H H Al COOH ^CH 2 ^SO 2 J10 0 CH 797 Me Me Al COOH ^CH 2 ^SO 2 HER 0 CH 798 Me Me Al COOH ^CH 2 ^SO 2 J2 0 CH 799 Me Me Al COOH ch ₂ so ₂ J3 0 CH 800 Me Me Al COOH ^CH 2 ^SO 2 J4 0 CH

· • ♦

Table 33 · · • 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33

Compound number R ¹ R ² AND E C J m X 801 Me Me Al COOH CH ₂ ^with ° 2 J3 0 CH 802 Me Me Al COOH ch ₂ so ₂ J9 0 CH 803 Me Me Al COOH ch ₂ s ° ₂ J10 0 CH 804 Me Me Al COOH ch ₂ J81 0 CH 805 Me Me Al COOH ch ₂ J82 0 CH 806 Me Me Al COOH ch ₂ J83 0 CH 807 Me Me Al COOH ch ₂ J84 0 CH 808 Me Me Al COOH ch ₂ J85 0 CH 809 H H Al COOH ch ₂ J81 0 CH 810 H H Al COOH ch ₂ J82 0 CH 811 H H Al COOH ch ₂ J83 0 CH 812 H H Al COOH ch ₂ J84 0 CH 813 H H Al COOH ch ₂ J85 0 CH 814 Me Me Al COOH ^CH 2 ^CH 2 HER 1 CH 815 Me Me Al COOH ch ₂ HER 1 CH 816 Me Me Al COOH ch ₂ J37 1 CH 817 Me Me Al COOH ch ₂ J39 1 CH 818 Me Me Al COOH ch ₂ J50 1 CH 819 Me Me Al COOH ch ₂ J63 1 CH 820 Me Me Al COOH ch ₂ J64 1 CH 821 Me Me Al COOH ch ₂ J65 1 CH 822 H H Al COOH ch ₂ J37 1 CH 823 H H Al COOH ch ₂ J39 1 CH 824 H H Al COOH ch ₂ J5O 1 CH 825 H H Al COOH ch ₂ J63 1 CH

Table 34

Compound number R ¹ R ² AND E G J m X 826 H H Al COOH ch ₂ J64 1 CH 827 H H Al COOH ch ₂ J65 1 CH 828 Cl Cl Al COOH ch ₂ J37 1 CH 829 Cl Cl Al COOH ch ₂ J39 1 CH 830 Cl Cl Al COOH ch ₂ J50 1 CH 831 Cl Cl Al COOH ch ₂ J63 1 CH 832 Cl Cl Al COOH ch ₂ J64 1 CH 833 Cl Cl Al COOH ch ₂ J65 1 CH 834 H H A4 COOH ch ₂ J37 1 CH 835 H H A4 COOH ch ₂ J39 1 CH 836 H H A4 COOH ch ₂ J50 1 CH 837 H H A4 COOH ch ₂ J63 1 CH 838 H H A4 COOH ch ₂ J64 1 CH 839 H H A4 COOH ch ₂ J65 1 CH 840 H H All COOH ch ₂ J 37 1 CH '841 H H All COOH ch ₂ J39 1 CH 842 H H All COOH ch ₂ J50 1 CH 843 H H All COOH ch ₂ J63 1 CH 844 H H All COOH ch ₂ J64 1 CH 845 H H All COOH ch ₂ J65 1 CH 846 H H Al 8 COOH ch ₂ J37 1 CH 847 H H Al 8 COOH ch ₂ J39 1 CH 848 H H Al 8 COOH ch ₂ J50 1 CH 849 H H Al 8 COOH čh ₂ J63 1 CH 850 H H Al 8 COOH ch ₂ J64 l CH

Table 35 • 4 • 4 • 4 • 4 • 4 • 4 • 4 • 4 • 4 • 4 • 4 44 44 · «

Compound number R ^l R ² AND E G J m X 851 H H A18 COOH ch ₂ J65 1 CH 852 H H A20 COOH ch ₂ J37 1 CH 853 H H A20 COOH ch ₂ J39 1 CH 854 H H A20 COOH ch ₂ J50 1 CH 855 H H A20 COOH ch ₂ J63 1 CH 856 H H A20 COOH ch ₂ J64 1 CH 857 H H A20 COOH ch ₂ J65 1 CH 858 Me Me Al COOH ^CH 2 ^CH 2 HER 2 CH 859 Me Me Al COOH ch ₂ HER 2 CH 860 Me Me Al COOH ^CH 2 J37 2 CH 861 Me Me Al COOH ch ₂ J39 2 CH 862 Me Me Al COOH ch ₂ J50 2 CH 863 Me Me Al COOH ch ₂ J63 2 CH 864 Me Me Al COOH ch ₂ J64 2 CH 865 Me Me Al COOH ch ₂ J65 2 CH 866 H H Al COOH ch ₂ J37 2 CH 867 H H Al COOH ch ₂ J39 2 CH 868 H H Al COOH ch ₂ J50 2 CH 869 H H Al COOH ch ₂ J63 2 CH 870 H H Al COOH ch ₂ J64 2 CH 871 H H Al COOH ch ₂ J65 2 CH 872 Cl Cl Al COOH ch ₂ J37 2 CH 873 Cl Cl Al COOH ch ₂ J39 2 CH 874 Cl Cl Al COOH ch ₂ J5O 2 CH 875 Cl Cl Al COOH ch ₂ J63 2 CH

Table 36 * 9 9 9

Compound number R ¹ R ² AND E G J m X 876 Cl Cl Al COOH ch ₂ J64 2 CH 877 Cl Cl Al COOH ch ₂ J65 2 CH 878 H H Al COOH ch ₂ J37 2 r 879 H H Al COOH ch ₂ J39 2 r 880 H H Al COOH ch ₂ J50 2 r 881 H H Al COOH ch ₂ J63 2 r 882 H H Al COOH ^CH 2 164 2 r 883 H H Al COOH ch ₂ J65 2 r 884 Me H Al COOH ch ₂ J37 2 CH 885 Me H Al COOH ch ₂ J63 2 CH 886 Me H Al COOH ch ₂ J64 2 CH 887 Me H Al COOH ch ₂ J65 2 CH 888 H H A4 COOH ch ₂ J37 2 CH 889 H H A4 COOH ch ₂ 163 2 CH · 890 H H A4 COOH ch ₂ J64 2 CH 891 H H A4 COOH ch ₂ 165 2 CH 892 Me Me A4 COOH ch ₂ J37 2 CH 893 Me Me A4 COOH ch ₂ 163 2 CH 894 Me Me 'A4 COOH ch ₂ 164 2 CH 895 Me Me A4 COOH ch ₂ 165 2 CH 896 Cl Cl A4 COOH ch ₂ J37 2 CH 897 Cl Cl A4 COOH ch ₂ J63 2 CH 898 Cl Cl A4 COOH ch ₂ 164 2 CH 899 Cl Cl A4 COOH ch ₂ 165 2 CH 900 H H A4 COOH ch ₂ J37 2 N

• ·· ·· · · · · · · · · · · · · · · · · · · · · · · ·

Table 37

Compound number 'R ¹ R ² AND E G J m X 901 H H A4 COOH ch ₂ J63 2 N 902 H H A4 COOH ch ₂ J64 2 N 903 H H A4 COOH ch ₂ J65 2 N 904 H H All COOH ch ₂ J37 2 CH 905 H H All COOH ch ₂ J63 2 CH 906 H H All COOH ch ₂ J64 2 CH 907 H H All COOH ch ₂ J65 2 CH 908 Me Me All COOH ch ₂ J37 2 CH 909 ' Me Me All COOH ch ₂ J63 2 CH 910 Me Me All COOH ch ₂ J64 2 CH 911 Me Me All COOH ch ₂ J65 2 CH 912 Cl Cl All COOH ch ₂ J37 2 CH 913 Cl Cl All COOH ch ₂ J63 2 CH 914 Cl Cl All COOH ch ₂ J64 2 CH 915 Cl Cl All COOH ch ₂ J65 2 CH 916 H H All COOH ch ₂ J37 2 N 917 H • H All COOH ch ₂ J63 2 N 918 H H All COOH ch ₂ J64 2 N 919 H H All COOH ch ₂ J65 2 N 920 Me Me Al 8 COOH ch ₂ J37 2 CH 921 Me Me AI 8 COOH ch ₂ J63 2 CH 922 Me Me Al 8 COOH ch ₂ J64 2 CH 923 Me Me A18 COOH ch ₂ J65 ' 2 CH 924 H H Al 8 COOH ch ₂ J37 2 CH 925 H H A18 COOH ch ₂ J63 2 CH

·· ·· ····

Table 38

Compound number R ¹ AND E C J m X 926 H H A18 COOH ch ₂ J64 2 CH 927 H H A18 COOH ch ₂ J65 2 CH 928 Cl Cl A18 COOH ch ₂ J37 2 CH 929 Cl Cl A18 COOH ch ₂ J63 2 CH 930 Cl Cl A18 COOH ch ₂ J64 2 CH 931 Cl Cl A18 COOH ch ₂ J65 2 CH 932 H H A18 COOH ch ₂ J37 2 N 933 H H A18 COOH ch ₂ J63 2 N 934 H H A18 COOH ch ₂ J64 2 N 935 H H A18 COOH ch ₂ J65 2 N 936 Me Me A20 COOH ch ₂ J37 2 CH 937 Me Me A20 COOH ch ₂ J63 2 CH 938 Me Me A20 COOH ch ₂ J64 2 CH 939 Me Me A20 COOH ch ₂ J65 2 CH 940 H H A20 COOH ch ₂ J37 2 CH 941 H H A20 COOH ch ₂ J63 2 CH 942 H H A20 COOH ch ₂ J64 2 CH 943 H H A20 COOH ch ₂ J65 2 CH 944 Cl Cl A20 COOH ch ₂ J37 2 CH 945 Cl Cl A20 COOH ch ₂ J63 2 CH 946 Cl Cl A20 COOH ch ₂ J64 2 CH 947 Cl Cl A20 COOH ch ₂ J65 2 CH 948 H H A20 COOH ch ₂ J37 2 N 949 H H A20 COOH ch ₂ J63 2 N 950 H H A20 COOH ch ₂ J64 2 N

Table 39

Compound number R ^l R ² AND E G and m X 951 H H A20 COOH ch ₂ J65 2 N 952 Me Me Al tetrazole ch ₂ J37 0 CH 953 Me Me Al telrazole ch ₂ J63 0 CH 954 Me Me Al tetrazole ch ₂ J64 0 CH 955 Me Me Al tetrazole. ch ₂ J65 0 CH 956 H H AI tetrazole ch ₂ J37 0 CH 957 H H Al tetrazole ch ₂ J63 0 CH 958 H H Al tetrazole ch ₂ J64 0 CH 959 H H Al tetrazole ch ₂ J65 0 CH 960 Cl Cl Al tetrazole ch ₂ J37 0 CH 961 Cl Cl Al tetrazole ch ₂ J63 0 CH 962 Cl Cl Al tetrazole ch ₂ J64 0 CH 963 Cl Cl Al tetrazole ch ₂ J65 0 CH 964 H H Al tetrazole ch ₂ J37 0 r 965 H H Al tetrazole ch ₂ J63 0 r 966 H H Al tetrazole ch ₂ J64 0 N 967 H H Al tetrazole ch ₂ J65 0 N 968 H H A4 tetrazole ch ₂ J37 0 CH 969 H H A4 tetrazole ch ₂ J63 0 CH 970 H H A4 telrazole ch ₂ J64 0 CH 971 H H A4 tetrazole ch ₂ J65 0 CH 972 H H Al 8 tetrazole ch ₂ J37 0 CH 973 H H Al 8 tetrazole ch ₂ J63 0 CH 974 H H A18 telrazole ch ₂ J64 0 CH 975 H H Al 8 tetrazole ch ₂ J65 0 CH

Table 40

Compound number R ¹ R ² AND E G J m X 976 Me Me A19 tetrazole ch ₂ J37 0 CH 977 Me Me A19 letrazole ch ₂ J63 0 CH 978 Me Me A19 telrazole ch ₂ J64 0 CH 979 Me Me A19 tetrazole ch ₂ J65 0 CH 980 H H A19 telrazole ch ₂ J37 0 CH 981 H H A19 tetrazole ch ₂ J63 0 CH 982 H H A19 tetrazole ch ₂ J64 0 CH 983 H H A19 tetrazole ch ₂ J65 0 CH 984 Me Me A20 tetrazole ch ₂ J37 0 CH 985 Me Me A20 tetrazole ch ₂ 163 0 CH 986 Me Me A20 tetrazole ch ₂ J64 0 CH 987 Me Me A20 tetrazole ch ₂ J65 0 CH 988 H H A20 tetrazole ch ₂ J37 0 CH 989 H H A20 tetrazole ch ₂ J63 0 CH .990 H H A20 tetrazole ch ₂ J64 0 CH 991 H H A20 tetrazole ch ₂ J65 0 CH

The thiobenzimidazole derivative of the general formula 1 according to the present invention wherein E is COOH and m is 0 can be prepared by synthetic method A or B below:

Synthetic method

(a5)

R ¹

R ²

XX ^rsH (a3)

Λ (a6)

Ft

R2 / ^COOR3

R ¹

R ²

-COOH (a7) (a8) wherein Z represents a halogen atom, R ¹ , R ² , R ³ , A, G, J and X are as defined above.

Thus, the nitro group of the 2-nitroaniline derivative a1 is reduced to give orthophenylenediamine a2. CS ₂ reacts with a diamine to form compound a3, with which a halogenated ester derivative a4 is reacted to form a5. Thereafter, this compound is reacted with a halogen derivative a6 to obtain a7 which is hydrolyzed to form the benzimidazole derivative a8 of the invention.

Reduction of the nitro group can be carried out under standard catalytic reduction conditions. For example, the reaction is carried out with hydrogen gas in the presence of a catalyst such as Pd-C at room temperature to 100 ° C. Alternatively, a process using zinc or tin under acidic conditions or a zinc powder under neutral or alkaline conditions may be used.

The reaction of the orthophenylene diamine derivative α2 with CS ₂ can be carried out using, for example, the method described in J. Org. Chem. 19: 631-637, 1954, or J. Med. Chem. 36: 1175-1187, 1993 (EtOH solution).

The reaction of thiobenzimidazole a3 and halogen ester a4 can be carried out according to conventional S-alkylation conditions, for example in the presence of a base such as NaH, Et ₃ N, NaOH or K ₂ CO ₃ , at a temperature of 0 ° C to 200 ° C with stirring .

The reaction of the thiobenzimidazole a5 and the halogen derivative a6 can be carried out according to conventional N-alkylation or N-acylation conditions, for example in the presence of a base such as NaH, Et ₃ N, NaOH or K ₂ CO ₃ at 0 to 200 ° C with stirring .

The elimination reaction of the carboxyl protecting group R ³ is preferably carried out by hydrolysis using an alkali such as lithium hydroxide or an acid such as trifluoroacetic acid.

Synthetic method

The amino group of the 2-nitroaniline derivative a1 can be protected by L to give b1. The halogen derivative a6 is reacted with this compound to form b2, from which the protecting group is cleaved to give b3. The nitro group in b3 is reduced to give the orthophenylenediamine derivative b4. CS2 reacts with this compound to obtain compound b5, with which a halogen ester derivative a4 is reacted to give a7, which can be hydrolyzed to form the benzimidazole derivative of the invention. Alternatively, compound b3 can also be obtained directly by reacting the 2-nitroaniline derivative a1 in unprotected form with a halogen derivative a6 or an aldehyde derivative b6.

As the protecting group L, acetyl group derived from trifluoroacetic acid, acetyl group, tert-butoxycarbonyl group, benzyl group and the like can be mentioned. Reaction of 2-nitroaniline derivative of a1 and aldehyde derivative B6 can be performed under the conditions of the conventional reductive amination using a reducing agent such as L1AIH4, nabb, NaB ₃ CN, NaBH (OAc) _3, or diborane, in a solvent such as ethanol, methanol and dichloromethane at 0 ° C to 200 ° C. Other reactions can be carried out as in the case of Synthetic Method A.

The benzimidazole derivative 1 of the present invention wherein E is COOH, m is 0 and G is an amide bond may be prepared by the synthetic method set out below:

Synthetic method

COOR ³

From COOtBu (c1)

R ¹

R ²

(c2)

COOR ³

X 'N

HOOC

N ^ _ _and ^ COOR ³ _jn ^ (C4)

(c5) (c3) wherein Q represents a methylene group, a phenylene group, etc., and Z represents a halogen atom. R ¹ , R ² , R ³ , A, J and X are as defined above, provided that R ³ is a protecting group such as ethyl, methyl, etc., which is inactive in acid.

Thus, the tert-butyl ester halogen derivative c1 is reacted with thiobenzimidazole compound a5 to give compound c2, which is subjected to hydrolysis under acidic conditions to obtain c3. The amine derivative α4 is reacted with this compound to obtain c5 which is subjected to hydrolysis to obtain the benzimidazole derivative of the present invention.

The condensation amidation can be carried out in a conventional manner using a condensation agent. As condensing agent, DCC, DIPC, EDC = WSCI, WSCI.HCI, BOP, DPPA, etc. may be used, which may be used alone or

in combination with HONSu, HOBt, HOOBt, etc. The reaction may be carried out in a suitable solvent such as THF, chloroform, tert-butanol, etc., at a temperature of from 0 ° C to 200 ° C. Other reactions can be performed according to Method A.

The thiobenzimidazole derivative 1 of the present invention wherein E is COOH, m is 0 and G is an ether bond can be prepared according to Synthetic Method D below:

Synthetic method

COOR ³

COOR ³

wherein Z is halogen, R ¹ , R ² , R ³ , A, J and X are as defined above.

Thus, the thiobenzoimidazole compound a5 is reacted with, for example, the halogen alcohol derivative d1 to form compound d2. The phenol derivative d3 is reacted with this compound to obtain an ether d4 which is subjected to hydrolysis to obtain the benzimidazole derivative a8 of the present invention.

Etherification may be accomplished using a phosphine compound such as triphenylphosphine and tributylphosphine and an azo compound such as DEAD and TMAD in a suitable solvent such as N-methylmorpholine and THF at a temperature of 0 ° C to 200 ° C by a Mitsunobu reaction or a related reaction. Further reactions can be carried out as in Synthetic Method A.

The thiobenzimidazole derivative 1 of the present invention wherein E is tetrazole and m is 0 can be prepared by the synthetic method E described below:

Synthetic method

wherein R ¹ , R ² , A, G, J and X are as defined above.

Nitrile e1 reacts with various azo compounds to convert to tetrazole e2.

As the azo compound, a trialkyltinazide compound such as trimethyltinazide and hydrazoic acid or an ammonium salt thereof is mentioned. When an organic tin azide is used, it is used in 1 to 4 times the amount with respect to compound e1. When hydrazoic acid or a salt thereof is used, 1 to 5 times the molar amount of sodium azide or tertiary amine such as ammonium chloride or triethylamine can be used relative to compound e1. Each reaction can be carried out at a temperature of from 0 ° C to 200 ° C in a solvent such as toluene, benzene and DMF.

The thiobenzimidazole derivative of general formula 1 of the present invention wherein m is 1 or 2 can be prepared by the synthetic method F below:

Synthetic method F

COOR ³ κ

from COOR ³

COOR ³ wherein R ¹ , R ² , R ³ , A, G, J and X are as defined above.

Thus, the thiobenzimidazole compound a7 can be reacted with the peroxide compound in a suitable medium to give the sulfoxide derivative f1 and / or the sulfone derivative f2. As the peroxide compound, perbenzoic acid, lorperbenzoic acid, peracetic acid, hydrogen peroxide and the like can be used, and chloroform, dichloromethane and the like can be used as the solvent. The ratio of compound a7 to peroxide compound to be used is selected over a wide range, usually 1.2 to 5 times the molar amount. Each reaction is generally carried out at a temperature of about 0 to 50 ° C, preferably at a temperature of from 0 ° C to room temperature, and is generally completed within 4 to 20 hours.

The benzimidazole derivatives of the invention can be converted, if desired, to their medically acceptable, non-toxic cationic salts. Such salts include alkali metal ions such as Na ⁺ K ⁺ ; alkaline earth metal ions such as Mg ²⁺ and Ca ²⁺ ; metal ions such as Al ³⁺ and Zn ²⁺ ; or an organic base such as ammonia, triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, Ν, Ν-diethylethanolamine, 4-hydroxypiperidine, glucosamine and N-methylglucamine. Among these, Na ⁺ , Ca ²⁺ , lysine, choline, N, N-dimethylethanolamine and N-methylglucamine are preferred.

• · ·

The benzimidazole derivatives of the present invention inhibit human chymase activity. In particular, the IC 50 is not greater than 1000, preferably not less than 0.01 and less than 1000 and more preferably not less than 0.05 and less than 500. The benzimidazole derivatives of the invention having such excellent inhibitory action on human chymase may be used as clinically useful preventive and / or therapeutic agents for various diseases.

The benzimidazole derivatives of the present invention can be administered as pharmaceutical compositions together with pharmaceutically acceptable carriers by the oral route, after they have been formed into various dosage forms. Parenteral administration may include intravenous, subcutaneous, intramuscular, percutaneous, rectal, nasal and eye drops administration.

Dosage forms for said pharmaceutical compositions include the following. For example, in the case of oral administration, dosage forms such as tablets, pills, granules, powders, solutions, suspensions, syrups and capsules are mentioned.

Capsules are shaped by conventional techniques using a pharmaceutically acceptable carrier such as an excipient, a binder, and a disintegrant. Pills, granules and powders can be shaped using conventional methods using excipient etc. Solutions, suspensions and syrups can be formed using conventional methods using glycerin esters, alcohols, water, vegetable oils and the like. Capsules may be formed by filling granules, powders and solutions into capsules made of gelatin, etc.

Among the parenteral formulations, those administered intravenously, subcutaneously and intramuscularly are administered by injection. For injection, the benzoic acid derivative is dissolved in a water-soluble liquid such as saline or a water-insoluble liquid comprising an organic ester such as propylene glycol, polyethylene glycol and vegetable oil.

For percutaneous administration, dosage forms such as ointments and creams are used. Ointments may be prepared by mixing the benzoic acid derivative with fat or lipid, petrolatum, etc., and creams may be prepared by mixing the benzoic acid derivative with an emulsifier.

In the case of rectal administration, gelatin soft capsules for suppositories may be used.

For nasal administration, formulations comprising a liquid or powder composition may be used. As the base for the liquid formulation, water, saline, phosphate buffer, acetate buffer, etc. may be used, and may further include surfactants, antioxidants, stabilizers, preservatives and thickeners. Powder formulation bases include polyacrylic acid salts which are readily soluble in water, lower alkyl cellulose ethers, polyethylene glycol, polyvinylpyrrolidone, amylose, pullulan, etc., which are capable of absorbing water or celluloses, starches, proteins, gums, cross-linked vinyl polymers, etc. which are difficult to dissolve in water, and preferably which are capable of absorbing water. Alternatively, they may be combined. Further, in the case of powder formulations, antioxidants, colorants, preservatives, disinfectants, corrigents, etc. may be added. Such liquid formulations and powders may be administered using, for example, a spray device.

In the case of eye drops, they can be used as aqueous or non-aqueous eye drops. For aqueous eye drops, sterile purified water, saline, etc. is used as the solvent. If sterile purified water is used as the solvent, a suspending agent as a surfactant and a polymeric thickener may be added to prepare the eye drops in the form of suspensions. Alternatively, a solubilizing agent such as a nonionic surfactant may be used in the preparation of eye drops in the form of a solution. Non-aqueous eye drops may use a non-aqueous solvent for injection as a solvent and may be used as a non-aqueous solution.

Where the administration to the eye is by a method other than the use of eye drops, eye ointments, application solutions, pastes and inserts are used.

In the case of nasal or oral inhalation, they may be inhaled as a solution or suspension of the benzimidazole derivative of the invention together with the usual

used excipients using, for example, an aerosol spray for inhalation, etc. Alternatively, the benzimidazole derivatives of the present invention may be administered in the form of a lyophilized powder to the lungs using an inhalation device that allows direct contact with the lungs.

To such various formulations, pharmaceutically acceptable carriers such as an isotonicity agent, preservative, disinfectant, wetting agent, buffer, emulsifier, dispersant, stabilizer, etc. may be added as desired.

Such pharmaceutical compositions may be sterilized by the addition of antimicrobial agents, filtration through a bacteria-retaining filter, heating, irradiation, etc. Alternatively, sterile formulations may be prepared which can be used by dissolving or suspending them in a suitable sterile solution immediately prior to use.

Dosages of the benzimidazole derivatives of the present invention may vary depending on the type of disease, route of administration, condition, age, sex, body weight, etc. of the patient, may generally be in the range of 1-500 mg / day / patient for oral administration, and preferably 1. up to 300 mg / day / patient. For parenteral administration such as intravenous, subcutaneous, intramuscular, percutaneous, rectal, nasal, eye drops and inhalation, doses are in the range of 0.1 to 100 mg / day / patient, preferably 0.3 to 30 mg / day / patient .

When used as a preventive agent, the benzimidazole derivatives of the present invention are administered according to known methods, depending on the particular condition.

As regards diseases in which the compounds of the invention can be used as preventive and / or therapeutic agents, for example, respiratory diseases such as bronchial asthma, inflammatory and allergic diseases such as allergic rhinitis, atopic dermatitis, and urticaria circulatory organs such as sclerosing vascular lesions, intravascular stenosis, peripheral circulation disorders, renal failure and heart failure; bone and cartilage metabolism diseases such as rheumatoid arthritis and osteoarthritis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be explained in more detail with reference to Preparative Examples, Working Examples and Test Examples. It is to be understood that these examples in no way limit the scope of the invention.

Reference Example 1

Preparation of 5,6-dimethylbenzimidazole-2-thiol

To 5,6-dimethylorthophenylenediamine (4.5 g, 33 mmol) in pyridine (40 mL) was added carbon disulfide (40 mL, 0.66 mol). The resulting solution was heated to reflux with stirring for 18 hours, then water was added thereto, followed by extraction with ethyl acetate. After drying the ethyl acetate layer with anhydrous magnesium sulfate, the mixture was concentrated and dried under reduced pressure at 80 ° C for 6 hours to give the title compound (4.1 g, 70% yield).

Reference Example 2

Preparation of 2- (5,6-dimethylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester

To the resulting 5,6-dimethylbenzimidazole-2-thiol (89 mg, 0.50 mmol) in dimethylformamide (2 mL) was added triethylamine (84 μΙ, 0.6 mmol) and 2-bromomethylbenzoic acid methyl ester (137 mg, 0.6 mmol). ). The resulting solution was stirred at 80 ° C for 1.5 hours, water was added followed by extraction with ethyl acetate. After drying the ethyl acetate layer with anhydrous magnesium sulfate, the mixture was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (146 mg, yield 90%). The compound was confirmed by molecular weight identification. Calcd. 326.11, found (M + H) = 327.2

In · · · · · · · ·

9 98 9 9 9

In a similar manner to Reference Example 2, the following compounds were prepared. The compounds were confirmed by molecular weight identification using LC-MS.

3 - ((5,6-Dimethylbenzimidazol-2-ylthio) methyl) pyridine-2-carboxylic acid ethyl ester

Calcd. M = 341.12, found (M + H) ⁺ = 342.2

3 - ((5,6-Dimethylbenzimidazol-2-ylthio) methyl) furan-3-carboxylic acid methyl ester

Calcd. M = 316.09, found (M + H) ⁺ = 317.2

3 - ((5,6-Dimethylbenzimidazol-2-ylthio) methyl) thiophene-2-carboxylic acid methyl ester

Calcd. M = 332.07 found (M + H) ⁺ = 333.2

2- (Benzimidazol-2-ylthiomethyl) benzoic acid methyl ester

Calcd. 298.08, found (M + H) ⁺ = 299.2

3- (Benzimidazol-2-ylthiomethyl) pyridine-2-carboxylic acid ethyl ester Calculated 313.9, found (M + H) ⁺ = 314.2

3- (Benzimidazol-2-ylthiomethyl) thiophene-2-carboxylic acid methyl ester Calculated 304.3 found (M + H) ⁺ = 305.2

2- (Benzimidazol-2-ylthiomethyl) furan-3-carboxylic acid methyl ester Calculated 288.06 found (M + H) ⁺ = 289.2

4-Benzimidazol-2-yl-thiobutanoic acid methyl ester

Calcd. 264.09, found (M + H) ⁺ = 265.2

2 - ((5,6-dichlorobenzimidazol-2-ylthiomethyl) -5-chlorobenzoic acid methyl ester) Calculated 399.96 found (M + H) ⁺ = 401.2 • · · ·

2- (Benzimidazol-2-ylthiomethyl) -5-chlorobenzoic acid methyl ester

Calcd. M = 332.04, found (M + H) ⁺ = 333.2

4- (5,6-Dimethylbenzimidazol-2-ylthio) butanoic acid ethyl ester

Calcd. M = 292.12, found (M + H) ⁺ = 293.40

2 - ((5,6-Dimethylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester Calculated M = 366.00, found (M + H) ⁺ = 367.0

2 - ((5,6-dichlorobenzimidazol-2-ylthio) methyl) pyridine-3-carboxylic acid methyl ester

Calcd. 366.99 found (M + H) ⁺ = 368.0

Example 1

Preparation of Compound 143

Sodium hydride (11 mg, 0.306 mmol) and 2 mL of tetrahydrofuran were added to the previously dried reaction vessel. 2 - ((5,6-Dimethylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester (50 mg, 0.153 mmol) and 1-chloromethylnaphthalene were added and the mixture was stirred at 60 ° C for 45 min. Water was added to the mixture and then the mixture was extracted with ethyl acetate. After drying the ethyl acetate layer with anhydrous sodium sulfate, the mixture was concentrated and purified on silica gel by column chromatography (hexane: ethyl acetate = 4: 1) to give methyl ester 2 ((5,6-dimethyl-1- (1-naphthylmethyl) benzimidazole-2-). (thio) methyl) benzoic acid (32% yield).

To a 2 - ((5,6-dimethyl-1- (1-naphthylmethyl) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (23 ng) in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added a 4N aqueous solution sodium hydroxide (0.25 mL). The mixture was stirred at room temperature for 5 hours, 6N hydrochloric acid was added to quench the reaction, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo

vacuum to give the title compound (24 mg, quantitative yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 452.16, found (M + H) ⁺ = 453.2

Example 2

In a similar manner to Working Example 1, the compounds listed in Tables 41 to 45 were prepared using Reference Examples 2 or 4 and various halogen derivatives. Compounds were confirmed by molecular weight identification using LC-MS.

• · · · · ···

Table 41

Compound No. Calcd Found (M + H) * Yield (%) (total) 390 406, 14 407, 2 29 391 422, 1 1 423, 2 16 315 417, 15 418, 2 32 376 406, 14 407, 2 25 333 417, 15 418, 2 6 82 416, 16 417, 2 12 83 416, 16 417, 2 9 84 416, 16 417, 2 33 97 432, 15 433, 2 18 98 432, 15 433, 2 26 99 432, 15 433, 2 8 94 470, 13 471, 2 14 95 470, 13 471, 2 10 96 470, 13 471, 2 13 100 ALIGN! 486, 12 487, 2 26 101 486, 12 487, 2 8 85 420, 13 421.2 9 86 420, 13 421, 0 12 87 420, 13 421, 2 44 88 436, 10 437, 2 42 89 436, 10 437, 2 40 90 436, 10 .437, 2 28 91 480, 07 481, 0 12 103 427, 14 428, 2 12 104 427, 14 428, 2 6 105 427, 14 428, 2 11 784 434, 11 435, 2 36

• · · ·

Table 42

Compound No. Calcd Found (M + H) * Yield (%) (total) 787 468, 07 469, 2 31 112 418, 14 419, 2 40 141 480, 12 481, 0 72 138 494, 17 495, 2 34 135 446, 13 447, 2 19 Dec 137 478, 17 479, 2 6 143 452, 16 453, 2 35 142 452, 16 453, 0 30 139 428, 16 429.4 22nd 140 458, 20 459, 2 5 63 424, 12 425, 2 25 311 453, 1 5 454, 5 21 115 430, 17 431, 5 68 116 430, 17 431, 5 52 117 430, 17 431, 5 41 118 430, 17 431, 5 56 125 462, 16 463.0 59 126 462, 16 463, 0 25 128 492, 17 493, 0 27 Mar: 134 446, 13 447, 0 34 108 446, 1 7 447, 0 75 107 446, 17 447, 0 57 119 470, 06 471, 0 36 120 470, 06 471, 0 57 121 470, 06 471.0 60 122 470, 06 471, 0 37 123 430, 17 431.3 57

Table 43

Compound No. Calcd Found (M + H) * Yield (%) (total) 124 462, 16 463, 3 67 127 462, 16 463, 3 62 129 446, 17 447. 3 47 130 446, 17 447, 3 40 319 425, 12 426, 3 30 506 466, 17 467.2 16 505 466, 17 467, 0 14 93 480, 07 481.0 45 136 478, 17 479, 2 60 37 402, 14 403, 4 25 39 442, 03 443, 0 51 317 403, 14 404, 0 56 318 443, 03 444, 0 46 380 442, 14 443, 2 51 377 420, 15 421, 2 34 378 460, 04 461.0 30 386 414, 10 415, 2 37 383 392, 12 393, 2 30 384 432, 01 433, 0 29 395 458, 1 1 459.2 23 392 436, 13 437, 2 15 Dec 393 476, 02 477, 0 15 Dec 401 430, 08 431, 2 50 398 408, 10 409, 2 20 May 399 447.99 449, 0 7

Table 44 • »

Compound No. Calcd Found (M + H) * Yield (%) (total) 544 476, 18 377, 2 62 50 418, 14 419, 2 42 459 382, 08 383, 2 65 402 436. 04 437, 2 50 1 388, 12 389, 0 38 161 456, 05 457, 0 54 81 402, 14 403, 3 57 154 444, 13 445, 0 32 160 408, 10 409, 0 72 159 421, 15 422, 2 84 148 482, 17 483, 5 64 149 453.1 5 · 454, 5 71 155 459, 1 1 460, 0 64 150 453, 1 5 454, 2 36 151 487, 1 1 488, 1 62 153 460, 10 461, 0 69 152 454, 1 5 455, 0 62 64 430, 08 431, 2 85 455 410, 11 411, 2 17 596 430, 14 431, 2 56 539 418, 17 419, 2 20 May 349 436, 10 437, 1 50 352 458, 09 459, 2 74 168 470.06 471, 1 57 355 504, 02 505, 0 26 174 492, 05 493, 0 89 358 526, 01 527, 1 38

Table 45

Compound No. Calcd Found (M + H) * Yield (%) (total) 324 493, 04 494, 2 32 320 431, 08 432, 1 15 Dec 147 466, 17 467, 2 72 616 490, 16 491, 2 22nd 805 382, 1 7 383, 2 52 804 368, 16 369, 2 56 66 438, 14 440, 2 54 592 430, 14 432, 3 5 811 380, 16 382, 2 72 582 436, 06 437, 1 59 580 436, 06 437, 1 59 584 480, 03 483, 1 37 583. 480, 03 483, 0 52 578 420, 09 421, 2 30 574 416, 12 417, 2 39 595 452, 1 2 453, 2 22nd 594 478, 14 479, l 23 588 432, 1 1 433, 1 65 587 432, 1 1 433, 2 48 586 432, 11 433, 1 50 590 427, 10 428.2 24 589 427, 10 428, 3 17

Example 3

Preparation of Compound No. 547

Triethylamine (276 μΙ, 1.98 mmol) and tert-butyl 2- (bromoethyl) benzoate (538 mg, 1.99 mmol) were added to 5,6-dimethylbenzimidazole-2-thiol (236 mg, 1.32 mmol) ) in 2 ml of dimethylformamide and stirred at 80 ° C for 3 hours. After completion of the reaction, water is added followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, the solution was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 2 - ((5,6-dimethylbenzimidazol-2-ylthio) methyl) benzoic acid tert-butyl ester (288 mg, 59% yield).

2 - ((5,6-Dimethylbenzimidazol-2-ylthio) methyl) benzoic acid tert -butyl ester (30 mg, 0.082 mmol) was dissolved in 3 mL of chloroform and triethylamine (17 μΙ, 0.123 mmol) and benzoyl chloride were added sequentially. (14 μΙ, 0.123 mmol) was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water is added followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, the solution was concentrated to give 2 - ((5,6-dimethyl-1- (phenylcarbonyl) benzimidazol-2-ylthio) methyl) benzoic acid tert-butyl ester (38 mg, quantitative yield).

2 - ((5,6-Dimethyl-1- (phenylcarbonyl) benzimidazol-2-ylthio) methyl) benzoic acid tert -butyl ester was dissolved in 1 mL dichloromethane, trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 6 hours . After completion of the reaction, the solvent was evaporated under reduced pressure and dried overnight to give the title compound (33 mg, quantitative yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 416.12, found (M + H) ⁺ = 417.0

Example 4

Preparation of Compound 561

The title compound was obtained in a similar manner to Working Example 3. The compound was confirmed by molecular weight identification using LCMS. Calcd. M = 452.09, found (M + H) ⁺ = 453.2

Reference Example 4

Preparation of 3- (naphthylmethyl) imidazolo (5,4-b) pyridine-2-thiol

To 2-amino-3-nitropyridine (1680 mg, 12 mmol) in dimethylformamide (20 mL) was added sodium hydride (75 mg, 0.55 mmol) and 1-chloromethylnaphthalene (74 μΙ, 0.55 mmol). The resulting solution was stirred at 80 ° C for 17 hours, water was added followed by extraction with ethyl ether. After drying the ethyl acetate phase with anhydrous magnesium sulfate, the mixture was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give naphthylmethyl (3-nitro (2-pyridyl)) amine (903 mg, 27% yield). .

To naphthylmethyl (3-nitro (2-pyridyl)) amine (900 mg, 3.2 mmol) in ethanol (40 mL) was added 90.0 mg of 10% Pd-C. The resulting solution was stirred under a hydrogen atmosphere at 50 ° C for 8 hours and then filtered through celite to remove Pd-C. The resulting solution was concentrated to give (3-amino (2-pyridyl)) naphthylmethylamine (860 mg, yield 99%). To the resulting (3-amino (2-pyridyl)) naphthylmethylamine (860 mg, 3.2 mmol) in ethanol (20 mL) was added carbon disulfide (6.1 mL, 102 mmol). The solution was heated to reflux with stirring for 12 hours and then allowed to stand at room temperature for 5 hours. The precipitate was filtered and washed three times with ethanol (5 mL). It was then dried at 80 ° C under reduced pressure for 5 hours to give the title compound (555 mg, 56% yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 291.08, found (M + H) ⁺ = 292.3

Reference Example 5

Preparation of 3 - ((2,5-dimethylphenyl) methyl) imidazolo (5,4-b) pyridine-2-thiol

The title compound was prepared in a similar manner to Reference Example 4. The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 269.01, found (M + H) ⁺ = 270.2

Example 5

Preparation of Compound No. 256

Using 3- (naphthylmethyl) imidazolo (5,4-b) pyridine-2-thiol (30 mg, 0.1 mmol) obtained in Reference Example 4, in a similar manner to Reference Example 2, gave the methyl ester 2 - ((3)). (naphthylmethyl) imidazolo (5,4-b) pyridin-2-ylthio) methyl) benzoic acid (30 mg, 70% yield).

2 - ((3- (Naphthylmethyl) imidazolo (5,4-b) pyridin-2-ylthio) methyl) benzoic acid methyl ester (30 mg, 0.068 mmol) thus obtained was subjected to hydrolysis in a similar manner to Example 1 to give the compound title compound (18.3 mg, 66% yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 425.12, found (M + H) ⁺ = 426.1.

Example 6

Compounds listed in Table 46 were prepared using the compounds obtained in Reference Examples 4 and 5 and various halogenated ester derivatives, in a similar manner to Example 5. The compounds were confirmed by molecular weight identification using LC-MS.

Table 46

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 253 403.14 407.2 67 327 404.13 423.2 46 329 426.12 418.2 58 361 437.10 438.0 52 364 459.08 460.0 66

Table 47

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 321 428.13 429.2 27 Mar: 354 461.10 462.2 20 May 460 379.14 380.2 19 Dec

Table 48

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 52 493.15 494.2 12 53 493.15 494.2 11

Example 7

Preparation of Compound 264

4-Methyl-2-nitroaniline (913 mg, 6 mmol) was dissolved in acetonitrile (18 mL), anhydrous trifluoroacetic acid (1.0 mL, 7.2 mmol) was added and the mixture was heated under reflux for 1.5 h . After cooling to room temperature, the mixture was concentrated under reduced pressure and dried to give 4-methyl-2-nitro trifluoroacetanilide (1.396 g, yield 94%).

4-Methyl-2-nitro trifluoroacetanilide (1.366 g, 5.63 mmol) was dissolved in dimethylformamide (14 mL) and potassium carbonate (940 mg, 6.80) was gradually added at room temperature. mmol) and 1-chloromethylnaphthalene (1.15 g, 6.51 mmol) and the mixture was then heated to 100 ° C. After 1 hour and 40 minutes, a 5N aqueous sodium hydroxide solution (7.5 ml) was added and the mixture was heated under reflux for 15 minutes. After 15 minutes, the mixture was cooled to room temperature, water (180 mL) was added and the mixture was stored at 4 ° C overnight. The separated crystals were filtered and dried to give ((1-naphthyl) methyl) (4-methyl-2-nitrophenyl) amine (1.587 g, yield 96%).

To ((1-naphthyl) methyl) (4-methyl-2-nitrophenyl) amine (1.0021 g, 3.43 mmol) was added ethanol (5 mL) and 1,4-dioxane (5 mL), followed by 2.058 M aqueous sodium hydroxide solution (1 mL) was added and the mixture was heated to reflux in an oil bath. After 15 minutes the oil bath was removed and zinc powder (897 mg, 13.72 mmol) was added portionwise. Then the mixture was refluxed again in an oil bath for 2 hours. After 2 h, the mixture was concentrated under reduced pressure, dissolved in ethyl acetate (50 mL), and washed twice with saturated saline (25 mL). After drying with magnesium sulfate, the mixture was concentrated under reduced pressure to give a brown oil of ((1-naphthyl) methyl) (2-amino-4-methylphenyl) amine (943.1 mg).

((1-Naphthyl) methyl) (2-amino-4-methylphenyl) amine (943.1 mg, 3.59 mmol) was gradually dissolved in ethanol (6.4 mL), to which carbon disulfide (7 mL) was added. (116 mmol) and the mixture was heated to reflux. After 10 hours, the temperature was returned to room temperature and the mixture was concentrated under reduced pressure. Ethanol (2 mL) was added to the residue and the mixture was stirred at room temperature for 30 minutes and further stirred on ice for 30 minutes. The resulting crystals were filtered and dried to give 1 - ((1-naphthyl) methyl) -6-methylbenzimidazole-2-thiol (459.1 mg, yield 44%, 2 steps).

1 - ((1-Naphthyl) methyl) -6-methylbenzimidazole-2-thiol (431.1 mg, 1.42 mmol) was dissolved in dimethylformamide (12 mL) and triethylamine (0.296 mL, 2.12 mmol) was added. and 2-bromomethyl-benzoic acid methyl ester (390.1 mg, 1.70 mmol) and the mixture was heated to 80 ° C. After 5 hours and 50 minutes, triethylamine (0.296 mL, 2.12 mmol) and 2-bromomethylbenzoic acid methyl ester (325 mg, 1.42 mmol) were added and heating was continued for 1 hour and 10 minutes. Then, the mixture was concentrated under reduced pressure, dissolved in ethyl acetate (80 mL), washed twice with water (30 mL), and dried over magnesium sulfate. Concentrate the solvent under reduced pressure. The residue was crystallized in ethyl acetate-hexane to give 410 mg of the product and the mother liquor was purified by column chromatography (hexane: ethyl acetate = 6: 1) to give 87 mg of the same fraction as the crystals to give a total of 497 mg of methyl 2- ( (1 - ((1-naphthyl) methyl) -6-methylbenzimidazol-2-ylthio) methyl) benzoic acid (78% yield) ·

2 - ((1 - ((1-Naphthyl) methyl) -6-methylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester (497 mg, 1.098 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (6.86 mL) was added. The mixture was stirred at room temperature for 2 hours and 30 minutes, and to quench the reaction, a saturated aqueous citric acid solution (10 mL) was added, and the mixture was concentrated under reduced pressure to reduce the solvent volume to 1/3, then redissolved in ethyl acetate (80 mL). ml) and washed five times with water (20 ml). After concentrating the organic layer under reduced pressure, acetonitrile (10 mL) was added to the residue, and the mixture was concentrated again under reduced pressure, and the resulting crystals were filtered off and dried to give the title compound (439.1 mg, yield 91%).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 438.14, found (M + H) ⁺ = 439.3

Example 8

Preparation of Compound No. 272

In a similar manner to the working example, the title compound was prepared. The compound was confirmed by molecular weight identification using LC-MS. calculated M = 454.14, found (M + H) ⁺ = 455.3

Example 9

Preparation of Compound No. 65

Dissolve 2-nitroaniline (829 mg, 6 mmol) and 1-methylindole carboxaldehyde (1242 mg, 7.8 mmol) in 20 mL tetrahydrofuran, gradually add acetic acid (200 μΙ) and

NaBH (OAc) ₃ (5087 mg, 24 mmol) and the mixture was stirred at room temperature overnight. Aqueous sodium bicarbonate solution was added and then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated. Purification by silica gel column chromatography (hexane: ethyl acetate = 95: 5) gave ((1-methylindol-3-yl) methyl) (2-nitrophenyl) amine (264 mg, 18% yield).

((1-Methylindol-3-yl) methyl) (2-nitrophenyl) amine (264 mg, 0.939 mmol) was dissolved in ethanol (10 mL) and Pd-C (50 mg, 10% Pd, 0.047 mmol) was added. and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. After completion of the reaction, Pd-C was filtered off and the solvate was evaporated to give ((1-methylindol-3-yl) methyl) (2-aminophenyl) amine (212 mg, 90% yield).

((1-Methylindol-3-yl) methyl) (2-aminophenyl) amine (212 mg, 0.845 mmol) was dissolved in pyridine (1 mL) and carbon disulfide (1 mL, 16.9 mmol) was added. The mixture was refluxed under nitrogen for 1 hour. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain ((1-methylindol-3-yl) methyl) benzimidazole-2-thiol (96 mg, yield 39%).

Sodium hydride (12 mg, 0.342 mmol) and dimethylformamide (2 mL) were added to the previously dried reaction vessel. ((1-Methylindol-3-yl) methyl) benzimidazole-2-thiol (50 mg, 0.171 mmol) and 2-bromomethylbenzoic acid methyl ester (59 mg, 0.257 mmol) were added and the mixture was stirred at 60 ° C for 1 hour. Add water and extract with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 2 - ((1 - ((- (methyl-indol-3-yl) methyl) benzimidazole) methyl ester). 2-ylthio) methyl) benzoic acid (54 mg, 74% yield).

To 2 - ((1 - ((- (methylmethyl-indol-3-yl) methyl) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (54 mg, 0.122 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 4N aq. lithium hydroxide solution (0.5 mL). The mixture was stirred at room temperature overnight and 6N hydrochloric acid was added to stop the reaction and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Solvent • · ·

evaporate under reduced pressure to give the title compound (48 mg, 92% yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 427.14, found (M + H) ⁺ = 428.2

Example 10

The compounds in Table 47 above were prepared using various halogenated ester derivatives in a similar manner to Working Example 9. The compounds were confirmed by molecular weight identification using LC-MS.

Example 11

Preparation of Compound No. 51

Sodium hydride (104 mg, 2.86 mmol) and tetrahydrofuran (16 mL) were added to the previously dried reaction vessel. 2- (Benzimidazol-2-ylthiomethyl) benzoic acid methyl ester (428 mg, 1.43 mmol) and tert-butyl 2 (bromomethyl) benzoate (466 mg, 3.46 mmol) were added and the mixture was stirred at 60 ° C for 50 minutes. Water was added followed by extraction with ethyl acetate. The ethyl acetate phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2 - ((1 - ((2 - ((tert-butyl) oxycarbonyl) phenyl) methyl ester) (methyl) benzimidazol-2-ylthio) methylbenzoic acid (495 mg, 71% yield).

To 2 - ((1 - ((2 - ((tert-butyl) oxycarbonyl) phenyl) methyl) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (248 mg, 0.51 mmol) was added 4N hydrochloric acid in dioxane (1). (28 mL, 5.1 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated, the mixture was dried under reduced pressure to give 2 - ((2 ((2- (methoxycarbonyl) phenyl) methylthio) benzimidazolyl) methyl) benzoic acid (220 mg, quantitative yield).

2 - ((2 - ((2- (Methoxycarbonyl) phenyl) methylthio) benzimidazolyl) methyl) benzoic acid (180 mg, 0.42 mmol) was dissolved in chloroform (6 mL) and HOBT (68 mg, 0.504) was added gradually mmol), aniline (46 μΙ, 0.504 mmol), tert-butanol (1.2 mL) and EDCI (97 mg, 0.504 mmol) and stirring was continued at room temperature overnight. Water was added, followed by extraction with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (hexane: ethyl acetate = 3: 2) to give 2 - ((1 - ((2- (N-phenylcarbamoyl) phenyl) methylthio) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (86 mg, yield). 40%).

To the thus obtained 2 - ((1 - ((2- (N-phenylcarbamoyl) phenyl) methylthio) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (86 mg, 0.169 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) 4N aqueous lithium hydroxide solution (0.5 mL) was added and the mixture was stirred at 60 ° C for 2 hours.

A 6N aqueous hydrochloric acid solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After washing the ethyl acetate phase with saturated saline, the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (83 mg, quantitative yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. 493.15, found (M + H) ⁺ = 494.2

Example 12

In a similar manner to Working Example 11, the compounds listed in Table 48 were obtained using various benzoic ester derivatives. Compounds were confirmed by molecular weight identification using LC-MS.

Example 13

Preparation of Compound No. 619 9 9 9 9

Sodium hydride (400 mg, 10.0 mmol) and dimethylformamide (30 mL) were charged to a pre-dried reaction vessel. 2- (Benzimidazol-2-ylthiomethyl) benzoic acid methyl ester (1500 mg, 5.0 mmol) and tert-butyl bromoacetate (1463 mg, 7.5 mmol) were added and the mixture was stirred at 80 ° C for 2 hours . Water was added followed by extraction with ether. The ether phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 2- (2 - ((2 (methoxycarbonyl) phenyl) methylthio) benzimidazolyl) tert-butyl ester acetic acid (1298 mg, 63% yield).

To 2- (2 - ((2- (methoxycarbonyl) phenyl) methylthio) benzimidazolyl) acetic acid tert-butyl ester (1290 mg, 3.13 mmol) was added trifluoroacetic acid (15 mL) and the mixture was stirred at room temperature overnight . The solvent was evaporated and dried under reduced pressure to give 2- (2 - ((2- (methoxycarbonyl) phenyl) methylthio) benzimidazolyl) acetic acid (715 mg, 64% yield).

2- (2 - ((2- (methoxycarbonyl) phenyl) methylthio) benzimidazolyl) acetic acid (35 mg, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL) and aniline (11.2 mg, 0.12) was added mmol) and EDCI (23 mg, 0.12 mmol) and the mixture was stirred at room temperature overnight. Water was added followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give 2 - ((1 ((N-phenylcarbamoyl) methyl) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (27.5 mg, yield) 64%).

2 - ((1 - ((N-phenylcarbamoyl) methyl) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (20 mg, 0.046 mmol) so obtained was hydrolyzed as in Example 1 to give the title compound (6). 9 mg, 36% yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 417.11, found (M + H) ⁺ = 418.0

Example 14 «·· 949999 9 9

9 9 9 9 9 9 9 9 9 9 9 9

9 99 9 9 49 9 9

In a similar manner to Example 13, the compounds listed in Table 49 were obtained using various aniline derivatives. Compounds were confirmed by molecular weight identification using LC-MS.

Table 49

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 622 431.13 432.3 5 621 431.13 432.3 5 620 431.13 432.3 21 637 447.13 448.2 13 636 117.13 448.1 23 635 447.13 448.3 44 642 442.11 443.2 27 Mar: 657 467.13 488.1 19 Dec

Table 50

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 765 457.15 458.2 5 767 457.15 458.2 32

Table 51

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 866 434.13 435.2 76 869 456.11 457.3 83 904 468.09 469.1 52 937 436.15 437.2 61

·· ·· ····· • • «t · tr *« * ··· · »·« * • * _M · »· · · ··· *

Table 52

Compound No. Calcd Found (M + H) ⁺ Yield (total)% 953 476.18 477.2 36 985 428.18 429.2 67 977 400.15 401.4 2

Reference Example 6

Preparation of 2 - ((1- (2-hydroxyethyl) -5,6-dimethylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester

To the 2 - ((5,6-dimethylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester (326 mg, 1 mmol) obtained in Reference Example 2 in dimethylformamide was added potassium carbonate (207 mg, 1.5 mmol) and 2- bromoethanol (150 mg, 1.2 mmol) and the resulting solution was stirred at 80 ° C for 12 h. After completion of the reaction, the mixture was extracted with ether and the solvent was evaporated. The residue was purified by flash chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (248 mg, yield 67%).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 370.14, found (M + H) ⁺ = 371.2

Example 15

Preparation of Compound No. 736

To 2 - ((1- (2-hydroxyethyl) -5,6-dimethylbenzimidazol-2-ylthio) methyl) benzoic acid methyl ester (45 mg, 0.23 mmol) in N-methylmorpholine (3 mL) was added Pph 3 (62 mg, 0.24 mmol) and DEAD (10.6 mL, 40% in toluene, 0.24 mmol) and the mixture was stirred at room temperature. After 10 minutes, phenol (11.3 mg, 0.12 mmol) was added and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was purified by thin layer chromatography (hexane: ethyl acetate = 1: 1) to give 2 - ((5,6-dimethyl-1- (2-phenoxyethyl) benzimidazol-2-ylthio) methyl) benzoate methyl ester acid (44 mg, 81% yield).

Using 2 - ((5,6-dimethyl-1- (2-phenoxyethyl) benzimidazol-2-ylthio) methyl) benzoic acid methyl ester (35 mg, 0.078 mmol) was carried out in a manner similar to Example 1 to give the title compound. (31 mg, 94% yield). The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 432.15, found (M + H) ⁺ = 433.2

Example 16

In a similar manner as described in Example 15, the compounds listed in Table 50 were obtained using various phenol derivatives. The compound was confirmed by molecular weight identification using LC-MS.

Example 17

Preparation of Compound No. 825

To the ester (33 mg, 0.075 mmol) of compound No. 68 obtained in Example 2 in dichloromethane was added 50-60% m-chloroperbenzoic acid (26 mg, 0.083 mmol) under ice-cooling. The resulting solution was stirred on ice for 2 hours, saturated sodium bicarbonate solution was added, and the solution was extracted with chloroform. The chloroform phase was washed with water, concentrated, and the residue was purified by thin layer chromatography (hexane: ethyl acetate = 1: 1) to give methyl ester 2 (((5,6-dimethyl-1- (1-naphthylmethyl) benzimidazole-2-)). yl) sulfinyl) methyl) benzoic acid (7.1 mg, 21% yield).

The mixture was subjected to hydrolysis in a similar manner to Example 1 to give the title compound (5.2 g, yield 76%).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 440.12, found (M + H) ⁺ = 441.3

Example 18

• · · ·

Preparation of Compound No. 869

To the ester (39 mg, 0.094 mmol) of Compound No. 37 obtained in Example 2 in dichloromethane (5 mL) was added 50-60% m-chloroperbenzoic acid (64 mg, 0.374 mmol) under ice-cooling. The resulting solution was stirred at room temperature for 4 hours, saturated sodium bicarbonate solutions were added and the solution was extracted with chloroform. The chloroform phase is washed with water and concentrated to dryness, and the residue is purified by flash chromatography (hexane: ethyl acetate = 5: 1) to give 2 - ((((- ((2,5-dimethylphenyl) methyl) methyl) benzimidazol-2yl) methyl ester) (sulfonyl) methyl) benzoic acid (37 mg, 87% yield).

In a similar manner to Example 1, 2 - ((((1 - ((2,5-dimethylphenyl) methyl) benzimidazol-2-yl) sulfonyl) methyl) benzoic acid methyl ester (64 mg, 0.14 mmol) was subjected to hydrolysis to give the title compound (53 mg, 87% yield).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 434.13, found (M + H) ⁺ = 435.2

Example 19

In a similar manner to Example 18, the compounds listed in Table 51 above were prepared using esters of the compounds obtained in Working Example 2. The compounds were confirmed by molecular weight identification using LC-MS.

Example Compound No. 952

To 5,6-dimethylbenzimidazole-2-thiol (713 mg, 4 mmol) in dimethylformamide (10 mL) was added triethylamine (836 μΙ, 6 mmol) and 2-bromomethylbenzonitrile (1176 mg, 6 mmol). The mixture was stirred at 80 ° C overnight, water was added, followed by extraction with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give 2 - ((5,6-dimethylbenzimidazol-2-ylthio) methyl) benzenecarbonitrile (1159 mg). yield 99%).

Sodium hydride (178 mg, 4.90 mmol) and tetrahydrofuran (30 mL) were charged to a pre-dried reaction vessel. To the mixture was added 2 - ((5,6-dimethylbenzimidazol-2-ylthio) methyl) benzenecarbonitrile (719 mg, 2.45 mmol) and 2,5-dichlorobenzyl chloride (543 μ mmol, 4.90 mmol) and the mixture was stirred at 60 ° C. 33 ° C. Water was added and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2 - ((1 - ((2,5-dimethylphenyl) methyl) -5,6-dimethylbenzimidazole) (2-ylthio) methyl) benzenecarbonitrile (370 mg, 37% yield).

2 - ((1 - ((2,5-dimethylphenyl) methyl) -5,6-dimethylbenzimidazol-2-ylthio) methyl) benzenecarbonitrile (165 mg, 0.401 mmol) was dissolved in toluene (3 mL) and Me ₃ SnN _{3 was added.} (124 mg, 0.602 mmol) and the mixture was heated to reflux under nitrogen overnight. After completion of the reaction, the solvent was evaporated and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 19: 1) to give the title compound (75 mg, yield 41%).

The compound was confirmed by molecular weight identification using LC-MS. Calcd. M = 454.19, found (M + H) ⁺ = 455.2

Example 21

In a similar manner to Example 20, the compounds listed in Table 52 above were prepared. Compounds were confirmed by molecular weight identification using LC-MS.

Example 22 • · ··· '·· * ·· ·· ··

Preparation of recombinant chymase of human mast cell

Recombinant pro-type chymase human mast cells were prepared according to the method of Urada et al. (Journal of Biological Chemistry 266: 17173,1991). Insect cell (Tn5) culture supernatant infected with recombinant baculovirus containing cDNA encoding chymase of human mast cell is purified by heparin sepharose (Pharmacia). It is then activated by the method described by Murakami et al. (Journal of Biological Chemistry 270: 2218, 1995) and purified by heparin safarose to obtain activated mast cell chymase.

Example 23

Determination of chymase inhibition activity of recombinant human mast cell

A DMSO solution (2 μΙ) containing a compound of the present invention is added to 50 μΙ of Buffer A (0.5 - 3.0 NaCl, 50 mM Tris-HCl, pH 8.0) containing 1 to 5 ng of activated human mast cell chymase obtained in Example 22, and then 0.5 mM succinyl-alanyl-histidyl-prolyl-phenylalanylparanitroanilide (Bacchem) is added and the mixture is allowed to react at room temperature for 5 minutes. To assess inhibitory activity, changes in absorbance at 405 nm are measured as a function of time.

As a result, IC 50 = greater than 1 nM and less than 10 nM was observed for compounds no.

63, 64, 65, 143, 174, 256, 264, 272, 311, 354, 319, 349, 358, 395, 401, and 402 and IC 50 = greater than 10 nM and less than 100 nm was observed for compounds No. 37 50, 84, 115, 117, 119, 121, 123, 130, 147, 168, 256, 320, 321, 324, 352, 355, 364, 380, 392, 398, 444, 455, 459, 460, 506 863, 866 and 869.

As described above, the benzimidazole derivatives of the present invention exhibit potent chymase inhibitory activity. Thus, the benzimidazole derivatives of the present invention have been shown to be clinically useful inhibitors of human chymase activity and can be used for the prevention and / or therapy of various diseases in which human chymase is involved.

Example 24 • · · · «·

Preparation of tablets Tablets containing the following ingredients per tablet are prepared: Compound (No 37) 50 mg Lactose 230 mg Potato starch 80 mg Polyvinylpyrrolidone 11 mg Magnesium stearate 5 mg

The compound of the present invention (compound of Working Example 2), lactose and potato starch are mixed and the mixture allowed to soak in 20% polyvinylpyrrolidone in ethanol. The mixture was filtered through a 20 nm screen, dried at 45 ° C and again filtered through a 15 nm screen. The granules so obtained are mixed with magnesium stearate and compressed into tablets.

Industrial applicability

The thiobenzimidazole derivatives of the present invention and their pharmaceutically acceptable salts exhibit potent human chymase inhibiting activity. Thus, the thiobenzimidazole derivatives and their pharmaceutically acceptable salts can be used as a human chymase inhibitor, which is clinically useful for prevention and / or as a therapeutic agent for inflammatory diseases, allergic diseases, respiratory diseases, circulatory organ diseases or bone and cartilage metabolism diseases.

Claims (15)

PATENT CLAIMS 1. A thiobenzimidazole derivative of the general formula 1: wherein R ¹ and R ² , simultaneously or independently, represent a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or R ¹ and R ² together form -0CH ₂ -O-, -O-CH 2 -CH 2 -O- or -CH 2 -CH 2 -CH 2 -, wherein the carbon atoms may be substituted with one or more C 1 -C 4 alkyl groups; A represents a single bond, a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted arylene group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms, which may contain one or more oxygen, sulfur or nitrogen ring atoms, wherein the substituents are halogen, OH, NO ₂ , CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (substituents may be linked to each other at adjacent sites through an acetyl bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms a linear or branched acylamino group having 1 to 6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group, a phenoxy group which may be substituted by one or more halogen atoms, and wherein the substituents may independently be substituted at each position by alkylene; E represents COOR ³ , SO ³ R ³ , CONHR ³ , SO ² NHHR ³ , a tetrazole group, a 5-oxo-1,2,4-oxadiazole group or a 5-oxo-1,2,4-thiadiazole group wherein R ³ represents a hydrogen atom or a linear or a branched alkyl group having 1 to 6 carbon atoms; G represents a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, which may be interrupted by one or more of O, SO, SO 2 and NR ³ , where R ³ is as defined above and the substituent is halogen, OH, NO2, CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents can be linked to each other at adjacent sites via an acetyl bond), trihalomethyl, trihalomethoxy, phenyl or oxo; m is an integer from 0 to 2; when m is 0 and A is a substituted or unsubstituted alkylene group having 1 to 6 carbon atoms, then J represents a substituted or unsubstituted, linear, cyclic or branched alkyl group having 1 to 6 carbon atoms a substituted or unsubstituted aryl group having 7 to 9 carbon atoms, substituted C 10 -C 11 aryl, substituted or unsubstituted C 4 -C 10 heteroaryl which may contain one or more oxygen, nitrogen or sulfur ring atoms; when m is 0 and A is a substituted or unsubstituted arylene group having 6 to 11 carbon atoms or a substituted or unsubstituted 4 to 10 carbon heteroarylene group which may contain one or more oxygen, nitrogen or sulfur ring atoms, then J is substituted or an unsubstituted, linear, cyclic or branched alkyl group containing C 1 -C 6 substituted or unsubstituted C 6 -C 11 aryl, C 4 -C 10 substituted or unsubstituted heteroaryl that may contain one or more oxygen, nitrogen and sulfur ring atoms; or when m is 0 and A is a single bond, or when m is 1 or 2, then J represents a substituted or unsubstituted, cyclic or branched alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 11 carbon atoms, or a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, sulfur or nitrogen ring atoms, wherein the substituents are a halogen atom, OH, NO ₂ , CN, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms (the substituents may be linked to each other at adjacent sites through an acetyl bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, linear or ro C 1 -C 6 extended acyl, linear or branched C 1 -C 6 acylamino, substituted or unsubstituted anilide, trihalomethyl, trihalomethoxy, phenyl, oxo, COOR ³ or phenoxy, which may be substituted with one or more halogen atoms, and wherein the substituents may be independently substituted at any position of the ring or by an alkylene group; X is CH or N; or a pharmaceutically acceptable salt (defined above as a "thiobenzimidazole derivative of the invention"). A compound according to claim 1, wherein A is a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted arylene group having 6 to 6 carbon atoms. QA · · · ····· * Up to 11 carbon atoms or a substituted or unsubstituted 4-10 carbon heteroarylene group which may contain one or more oxygen, nitrogen and sulfur ring atoms or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the general formula 1 according to claim 1 or 2, wherein A represents a substituted or unsubstituted heteroaryl group having 4 to 10 carbon atoms, which may contain one or more oxygen, nitrogen and sulfur ring atoms or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the general formula 1 according to any one of claims 1, 2 and 3, wherein m represents 1 or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the general formula 1 according to any one of claims 1, 2 and 3, wherein m represents 2 or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the general formula 1 according to any one of claims 1, 2 and 3, wherein m represents 0, A represents a substituted or unsubstituted, linear or branched alkylene group having 1 to 6 carbon atoms, J represents a substituted or unsubstituted aryl group containing 7 or a substituted or unsubstituted heteroaryl group containing 4 to 10 carbon atoms, which may contain one or more oxygen, nitrogen and sulfur ring atoms, or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1, wherein m is 0, A is a substituted or unsubstituted arylene group having 6 to 11 carbon atoms or a substituted or unsubstituted heteroarylene group having 4 to 10 carbon atoms which: it may contain one or more oxygen, nitrogen and sulfur ring atoms, and J represents a substituted or unsubstituted aryl group containing 6 to 11 carbon atoms, a substituted or unsubstituted heteroaryl group containing 4 to 10 carbon atoms, which may contain one or more oxygen atoms, nitrogen and sulfur in the ring, or a pharmaceutically acceptable salt thereof. • · · · · · · · · · · · · · · · · · · · · · · · · · A thiobenzimidazole derivative of the general formula 1 according to any one of claims 1 to 7, wherein G represents -CH ₂ -, -CH ₂ -CH ₂ - -CH ₂ CO-, -CH ₂ CH ₂ O- -CH ₂ CONH- - CO-, -SO ₂ -, -CH ₂ SO ₂ -, -CH ₂ S- or -CH ₂ CH ₂ S-, or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the general formula 1 according to any one of claims 1 to 8, wherein R ¹ and R ^{2 are} simultaneously hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy or R ¹ and R ² independently represents hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trihalomethyl, cyano or hydroxy, or a pharmaceutically acceptable salt thereof. A thiobenzamidazole derivative of the Formula 1 according to any one of claims 1 to 9, wherein E is COOH or a tetrazole group, or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the Formula 1 according to any one of claims 1 to 10, wherein X is CH or a pharmaceutically acceptable salt thereof. A thiobenzimidazole derivative of the general formula I according to any one of claims 1 to 11, characterized in that it has human chymase inhibiting activity or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising at least one thiobenzimidazole derivative of the general formula I according to claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 13, which is a preventive and / or therapeutic agent of the disease. 15. The preventive and / or therapeutic agent of claim 14, wherein said disease is an inflammatory disease, allergic disease, respiratory organ disease, circulatory belt disease, or bone or cartilage metabolism disease.