MXPA98002729A - Heterociclic novedous derivatives and pharmaceutical use of mis - Google Patents

Abstract

A heterocyclic derivative of the formula I (See Formula), characterized in that each symbol is as defined in the specification and pharmaceutically acceptable salts thereof, the compound I of the present invention, and the pharmaceutically acceptable salts thereof, exhibit superior inhibitory activity. of ACAT and lipoperoxidation in mammals, and are useful as inhibitors of ACAT and lipoperoxidation, specifically, are useful for the prophylaxis and treatment of arteriosclerosis, hyperlipemia, arteriosclerosis in diabetes, and cerebrovascular and cardiovascular ischemic diseases

Description

HETEROCICLIC NOVEDOUS DERIVATIVES AND PHARMACEUTICAL USE OF THEMSELVES TECHNICAL FIELD The present invention relates to novel heterocyclic derivatives and to the pharmaceutical use thereof. More particularly, the present invention relates to novel heterocyclic derivatives having an indolino ring, indole ring or tetrahydroquinoline ring, the derivatives of which have inhibitory activity on acyl-CoA: cholesterol acyltransferase (hereinafter referred to as ACAT) and inhibitory activity of lipoperoxidation, and the pharmaceutical use thereof.

TECHNICAL BACKGROUND It is a well-known fact that atherosclerosis is an extremely important factor causing several circulatory diseases, and active studies have been carried out in an attempt to achieve the suppression of the evolution of arterial sclerosis or the regression of it. In particular, although the utility of a pharmaceutical agent that reduces cholesterol in blood and arterial walls has been recognized, an ideal pharmaceutical agent exhibiting positive clinical effects while causing fewer side effects has not been obtained. It has been desired to obtain a pharmaceutical agent that directly inhibits the deposition of cholesterol in arterial walls, as a pharmaceutical agent that prevents or effectively treats arterial sclerosis, and studies in this field are prosperous. However, an ideal pharmaceutical agent has not yet been developed. In recent years, it has become clear that blood cholesterol accumulates in the arterial walls in the ester form thereof, and that it significantly evolves into arteriosclerosis. A decrease in the level of cholesterol in blood leads to the reduction of cholesterol ester accumulation in the arterial walls, and is effective for the suppression of the evolution of arteriosclerosis and the regression of it. Cholesterol from food is esterified in the mucous membrane of the small intestine, and is absorbed into the blood as chylous icron. It is known that ACAT plays an important role in the generation of cholesterol ester in the mucous membrane of the small intestine. Thus, if the esterification of cholesterol can be suppressed by inhibiting ACAT in the mucous membrane of the small intestine, the absorption of cholesterol by the mucous membrane and in the blood can perhaps be prevented to finally result in a lower level of blood cholesterol. In arterial walls, ACAT esterifies cholesterol and causes the accumulation of cholesterol ester. It is expected that the inhibition of ACAT in arterial walls effectively suppresses cholesterol ester accumulation. Based on the above, it is concluded that an ACAT inhibitor will become an effective pharmaceutical agent for hyperlipidemia and arteriosclerosis, as a result of the suppression of cholesterol absorption in the small intestine and the accumulation of cholesterol in the arterial walls. Formally, for example, as inhibitors of said ACAT, amide and urea derivatives have been reported [J. lied. Chem., 29: 1131 (1986), Unexamined Publication of Japanese Patent Nos. 117651/1990, 7259/1990, 234839/1992, 327564/1992 and 32666/1993], However, pharmacological studies and studies of these compounds have been far from sufficient. At the same time, the hyperoxidation of low density lipoprotein (LDL) is also highly responsible for the intracellular incorporation of accumulated cholesterol as an ester of cholesterol in arterial blood vessels. Furthermore, it is known that the hyperoxidation of lipids in a living body is profoundly related to the onset of atherosclerosis and ischemic cerebrovascular and cardiovascular diseases. Therefore, a compound having an ACAT inhibitory activity and a lipoperoxidation inhibitory activity is quite useful as a pharmaceutical product, since it effectively reduces the accumulation of cholesterol ester in arterial walls, and inhibits lipoperoxidation in living organisms. , thus preventing and treating various vascular diseases caused by them. It is therefore an object of the present invention to provide a compound having ACAT inhibitory activity and lipoperoxidation inhibitory activity, as well as the pharmaceutical use thereof, particularly inhibitor of ACAT and inhibitor of lipoperoxidation.

DESCRIPTION OF THE INVENTION The present inventors have carried out intensive studies to achieve the aforementioned objectives, and found that a certain heterocyclic derivative having an indolino ring, indole ring or tetrahydroquinoline ring, is superior in water solubility, in comparison with the conventional inhibitors of ACAT, and which has lipoperoxidation inhibitory activity as well as strong inhibitory activity of ACAT, and that said compound allows superior oral absorption, strong anti-hyperlipidemia and anti-arteriosclerosis effects, which resulted in the completion of the present invention. Thus, the present invention relates to heterocyclic derivatives of the formula (I) wherein one of R1, R2 and R5 is hydroxy, carboxy, alkoxycarbonyl, a group of the formula -NR9R * or, wherein R9 and Rio are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, acid group, alkoxycarbonyl or a group of the formula -NR9R * °, wherein R9 and R10 are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy; any R 3 or RA is a group of the formula -NHCOR 7, wherein R 7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR 8, wherein Rβ is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; R6 is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl; and Z is a linking group which forms a 5- or 6-membered ring together with a nitrogen atom substituted by R6, a benzene ring carbon atom to which said nitrogen atom is attached, and a carbon atom adjacent to said nitrogen atom. carbon, and pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical compositions, ACAT inhibitors and lipoperoxidation inhibitors containing the aforementioned heterocyclic derivative or a pharmaceutically acceptable salt thereof. In the present specification, each symbol denotes the following. Lower alkyl in R *, R **, R, R * e, R2, R c, R3 t R3a, R3 »», R3c t R «t R C > RS p 5cf% R c f RIO and RIOC can be linear or branched, and has from 1 to 6 carbon atoms.

Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentylhexyl, and the like. Lower alkoxy, Rlb, Rie, R2, R < -, R3, R3 * », R3c, R *, R-4"1, R5 and R5c can be linear or branched, and has from 1 to 6 carbon atoms Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like Alkyl in R *, Rβ », R6b,« «=, R7, R7», R7- », R7« =, Rß _ R b and R bc can be linear or branched, and preferably has from 1 to 20 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, icosyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylhexyl, 1,1-dimethylheptyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl, and the like. In alkoxyalkyl in R6, R6b, R6c, R7, R7b and R7c, the alkoxy portion thereof preferably has 1 to 6 carbon atoms, and the alkyl portion thereof preferably has 1 to 6 carbon atoms. Examples of alkoxyalkyl include ethoxybutyl, ethoxyhexyl, butoxybutyl, butoxyhexyl, hexyloxybutyl, hexyloxyhexyl, and the like. In alkylthioalkyl in R ", R6 °, R6 < =, R7, R7b, and R? C. both alkyl portions preferably have 1 to 6 carbon atoms. Examples of alkylthioalkyl include ethylthioethyl, ethylthiohexyl, butylthiobutyl, butylthiohexyl, hexylthiobutyl, hexylthiohexyl, and the like. The cycloalkyl in R *, R * «, R6b, Rfic, R7, R7«, R7, R7c, R8, R8b and R8c preferably have from 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In cycloalkylalkyl in R6, R6 », R6b, R6 *, R, R7 *, R7b, R *, Rβ, R8 and R8 < -, its cycloalkyl portion preferably has from 3 to 8 carbon atoms, and the alkyl portion preferably has from 1 to 3 carbon atoms.

Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentyl ethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cycloheptylmethyl, cyclooctylmethyl, and the like. Examples of aryl in R7, R7b, R7 *, R8, R8b and Rc include phenyl, naphthyl, and the like. The arylalkyl in R *, R «, R * < -, R7, R b, R7 «-, R8, R8b and Rcc has the aforementioned aryl portion, and their alkyl portion preferably has from 1 to 4 carbon atoms. Examples of arylalkyl include benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, and the like. The alkenyl in R6, R6b and R6c may be linear or branched, and preferably has from 3 to 12 carbon atoms. Examples thereof include propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl, and the like. The acid group in R1, R2 and Re is exemplified by carboxy, sulfonic acid group, phosphonic acid group, and the like. Examples of alkoxycarbonyl in R1, Rlc, R2, R, R2 «-, R5 and RSc include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and the like. The alkyl to be substituted in R 1, R 2, R ", R 2b and RS can be linear or branched, and preferably has 1 to 8 carbon atoms. Examples thereof include methyl, ethyl, propyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, 2,2-dimethylpropyl, and the like. Examples of substituted alkyl include hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, carboxypropyl, ethoxycarbonylmethyl, dimethylaminomethyl, dimethylaminoethyl, sulfomethyl, phosphonomethyl, and eimilar. The alkenyl to be substituted in, R2 and R * can be linear or branched, and preferably has from 2 to 8 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl, and eimilar. Examples of substituted alkenyl include carboxyvinyl, carboxypropenyl, hydroxypropenyl, and the like. Z is preferably In the compounds of the present invention, 1 when one of R *, R2 and RS is alkyl or alkenyl substituted by hydroxy, acid group, alkoxycarbonyl or a group of the formula -NR9RIO} wherein R9 and R10 are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, the compound can be (a) indole or indole derivative, or (b) ) tetrahydroquinoline derivative. (a) When the compound of the present invention is indolino or indole derivative, the preferable compound is that of the aforementioned formula (I), wherein one of R1, R2 and RS is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R10, wherein R9 and Rio are each independently lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy; any R3 or R * is a group of the formula -NHCOR7, wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8 is alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and R * is as defined above. A more preferable compound is that of the formula (I) mentioned above, wherein R and R3 are each independently hydrogen atom, lower alkyl or lower alkoxy; any R2 or Re is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR Rio, wherein R9 and R ° are each independently lower alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; * is a group of the formula -NHCOR7, wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8 is alkyl; and R6 is as defined above. An even more preferable compound is that of the aforementioned formula (I), wherein R 1 and R 3 are each independently hydrogen atom, lower alkyl or lower alkoxy; any R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R10, wherein R9 and R10 are each independently lower alkyl, and the other is hydrogen atom; R * is a group of the formula -NHCOR7, wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8 is alkyl; and R6 is as defined above. An even more preferable compound is that of the above-mentioned formula (I), wherein R and R3 are each independently hydrogen atom or lower alkyl, any R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R °, wherein R9 and R are each independently lower alkyl, and the other is hydrogen atom; R * is a group of the formula -NHCOR7, wherein R7 is alkyl, cycloalkyl or cycloalkylalkyl; and R * ee alkyl, cycloalkyl or cycloalkylalkyl.

An even more preferred composition is that of the above-mentioned formula (I), wherein R and R3 are each independently hydrogen atom or lower alkyl; R2 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9Ri °, wherein R9 and R ° are each independently lower alkyl, and R5 is hydrogen atom; R * is a group of the formula -NHCOR7, wherein R7 is alkyl, cycloalkyl or cycloalkylalkyl; and R6 is alkyl, cycloalkyl or cycloalkylalkyl. An even more preferable compound is that of the following formula (lia): wherein R * »is hydrogen atom or lower alkyl; R3"is lower alkyl; R2 * is alkyl substituted by hydroxy or carboxy; R * "is a group of the formula -NHCOR7, wherein R7" is alkyl, cycloalkyl or cycloalkylalkyl; and R6"is alkyl, cycloalkyl or cycloalkylalkyl. An even more preferable compound is that of the formula (lia) above, where Ri "is hydrogen atom or lower alkyl; R3"is lower alkyl, R2" is alkyl substituted by hydroxy or carboxy, "RA" is a group of the formula -NHCOR7", wherein R7 * is alkyl, and R6 is alkyl Examples of the most preferable compound include N- (l -hexyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-di-ethylpropanamide, N- (l-heptyl-5-carboxymethyl-4,6-dime-ilindolin-7-yl) -2, 2-dimethylpropanamide, N- (1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-nonyl-5-carboxymethyl-4,6-dimethylindolin-7) -yl) -2,2-dimethylpropanamide, N- (1-decyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-undecyl-5-carboxymethyl-4) , 6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, N- (l-dodecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-hexyl -5-hi roxime til -6-met ili ndol in-7-yl) -2,2-dimethylpropanamide, N- (l-hexyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl) -2.2 -dimethylpropanamide, N- (l-heptyl-5-hydroxymethyl-6-methylindolin-7-yl) -2,2-dimethylpropanamide, N- (l-heptyl-5-hydroxymethyl-4,6-dime) tilindolin-7-yl) -2,2-di-ethylpropanamide, N- (1-octyl-5-hydroxymethyl-6-methylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-octyl-5- hydroxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, and the like, and pharmaceutically acceptable salts thereof. (b) When the compound of the present invention is a tetrahydroquinoline derivative, a compound of the following formula (Hb) is preferred. wherein R1b and R3b are each independently hydrogen atom, lower alkyl or lower alkoxy, R2b is alkyl substituted by hydroxy, carboxy or alkoxycarbonyl, R * b is a group of the formula -NHC0R7b, wherein R7b is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8b is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and R6b is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl. An even more preferable compound is that of the formula (Hb), wherein R 1b and R 3b are each independently lower alkyl or lower alkoxy; R2b is alkyl substituted by hydroxy, carboxy or alkoxycarbonyl; R * b is a group of the formula -NHC0R7b, wherein R7b is alkyl, cycloalkylalkyl, arylalkyl or a group of the formula -NHR8b, wherein R8b is alkyl; and R6b is alkyl, alkoxyalkyl, alkylthioalkyl or cycloalkylalkyl. An even more preferable compound is that of the formula (Ilb), wherein R b and R 3b each independently being lower alkyl; R2b is alkyl substituted by hydroxy or carboxy; R * b is a group of the formula -NHCOR7 °, wherein R7b is alkyl; and R6b is alkyl. Examples of the most preferable compound include N- (l-hexyl-6-carboxymethyl-5,7-dimethyl-l, 2,3,4-tetrahydroquinolin-8-yl) -2,2-dimethyldimethylpropanamide, N- (l-heptyl) -6-carboxymethyl-5,7-dimethyl-l, 2,3,4-tetrahydroquinolin-8-yl) -2,2-di-ethylpropanamide, N- (l-octyl-6-carboxymethyl-5,7-dimethyl- l, 2,3,4-tetrahydroquinolin-8-yl) -2,2-dimethyl-dimethylpropanamide, N- (l-nonyl-6-carboxymethyl-5,7-dimethyl-l, 2,3,4-tetrahydroquinolin-8-yl) -2,2-dimethyl-dimethylpropanamide, N- (l-decyl-6-) carboxymethyl-5,7-dimethyl-l, 2,3,4-te rahi-roquinolin-8-yl) -2,2-dimethyl-dimethylpropanamide, N- (l-hexyl-6-hydroxymethyl-5,7-dimethyl) -l, 2,3,4-tetrahydroquinolin-8-yl) -2,2-dime-il-di-ethylpropanamide, N- (l-heptyl-6-hydroxymethyl-5,7-dimethyl-l, 2,3,4 -te rahydroquinolin-8-yl) -2,2-dimethyl-di-ethylpropanamide, N- (1-octyl-6-hydroxymethyl-5,7-dimethyl-1,, 3, -tetrahydroquinolin-8-yl) -2, 2-dimethyl ildimet i lpropanamide, N- (l-nonyl-6-hydroxymethyl-5,7-dimethyl-l, 2,3,4-tetrahydroquinolin-8-yl) -2,2-dimethyl-dimethylp opanamide, N - (1-decyl-6-hydroxymethyl-5,7-dimethyl-1,2,3-tet rahydroquinol-n-8-i 1) -2, 2-dimet i lp -fashionamide and the like, and pharmaceutically salts acceptable of the same. 2 When the compound of the present invention is one in which one of R1, R2 and R5 is hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R °, wherein R9 and RIO are each independently hydrogen atom or lower alkyl , and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, the compound of the following formula (He) is preferred. wherein one of R c, R2c and RSc is hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9cRi ° c, wherein 9c and RIOC are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy; any R3c or R * c is a group of the formula -NHCOR7 c, wherein R7c is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8c, wherein R8c is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; and R6c is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl. The most preferable compound is a compound of the formula (He) above, wherein R c and R 3c are each independently hydrogen atom, lower alkyl or lower alkoxy; R2"= is carboxy; R * c is a group of the formula -NHC0R7c, wherein R7c is alkyl, cycloalkyl or cycloalkylalkyl; RS < = is hydrogen atom; and R-Se is alkyl, cycloalkyl or cycloalkylalkyl. An even more preferable compound is a compound of formula (He) above, wherein R c is hydrogen atom or lower alkyl; R3e is lower alkyl; R2c is carboxy; R * c is a group of the formula -NHC0R7c, wherein R7c is alkyl; RSC is a hydrogen atom; and R6c is alkyl. Examples of the most preferable compound include N- (1-hexyl-5-carboxy-6-methyl-1-indol-n-7-yl) -2,2-dimethyl-propane-amide, N- (1-octyl-5-carboxy-6) methylindolin-7-yl) -2,2-dimethylpropanamide, N- (l-decyl-5-carboxy-6-methylindolin-7-yl) -2,2-dimethylpropanamide, N- (l-hexyl-5-carboxy- 4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-octyl-5-carboxy-4,6-di ethyli ndol i n-7-yl) -2,2-dimethylpropanamide, N- (l-decyl-5-carboxy-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide and the like, and pharmaceutically acceptable salt of loe miemoe. The compound (I) can form pharmaceutically acceptable eleates. When the compound (I) has a basic group, it can form addition acidic saltse. The acid which forms said addition acids is not subject to any particular limitation, as long as it can form a salt with a basic portion, and is a pharmaceutically acceptable acid. Examples of such acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, toluene sulfonic acid, and similaree. When the compound (I) has an acid group such as carboxy, it can form, for example, alkali metal salts such as sodium salt, potassium salt, and eilamylate; alkaline earth metal salts, such as calcium salt, magnesium salt, and the like; and basic organic salts such as triethylamine salt, dicyclohexylamine salt, pyridine salt, and the like. The composition (I) of the present invention and the pharmaceutically acceptable salts thereof can be produced by any of the following 1 to 7 methods.

Production method 1 Production method 2 ) in the group nitro ác group nitro) pr acid or baby (XI) R13 Elimination of the protective group in R1S + - Production method 3 R < • X (XI) (XX) (le) Production method 4 (xxvi D Production method 5 (le) Production method 6 (XXXI I I) (XXXIV) (XXX V) removal of the protective group in R * ' (If) Production method 7 (XXXVI I) (I) In each of the above formulas, R6, R7, R8, R and RIO are each as defined above; R11 and Ri2 are each independently hydrogen atom, lower alkyl or lower alkoxy; R 3 is amino protecting group; Ri * is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R * 5 is alkyl or alkenyl sub-substituted by halogen atom; i * is alkyl or alkenyl substituted by hydroxy, protected hydroxy, acid group, protected acid group, alkoxycarbonyl or -NRβR 9, wherein R18 and 9 are each independently hydrogen atom, lower alkyl or amino protecting group; Ri7 is alkyl or alkenyl substituted by hydroxy, acid group, alkoxycarbonyl or -NR9R °; R20 is protected carboxy; R2 is protected hydroxy and R22 is -NR ßR 9, wherein R e and RI 9 are as defined above. The amino protecting group in R 3, Rie and RI 9 is, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, 2,2,2-trieloroethoxycarbonyl, tri ethylsilyl, 2-methylenesulfonylethyloxycarbonyl, tert-butoxycarbonyl or trityl. The hydroxy protecting group in R * 6 and R2 is, for example, formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoyl, trityl, tetrahydropyranyl, trimethylsilyl, or eimilaree. . The protecting group of acid group in R 16 and R 20 ee, when the carboxy protective group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, tert-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, diphenylmethoxybenzene-sulfonylmethyl, dimethylaminoethyl, and the like. The aforementioned protective groups can be removed by a method known per se. and the method for removing them can be determined in accordance with the type of protective group. Exemplified are a decomposition by an acid (for example, that by an acid such as hydrochloric acid, trifluoroacetic acid and the like, for formyl, tert-butoxycarbonyl, trityl, tetrahydropyranyl, and the like); a decomposition by a base (for example, that by a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like, for acetyl, dichloroacetyl, trifluoroacetyl, and the like); and catalytic reduction (for example, decomposition by palladium carbon and similar for benzyl, benzyloxycarbonyl, and eimilaree). The production method of the objective object of the present invention, and the starting material compound, are described in detail below.

Production method 1 The compound (IV) can be produced by reducing the compound (III) CJ. Eric Nordlander et al., J. Org. Chem., 46, 778-782 (1981), Robin D. Clark et al., Heterocycle, 22, 195-221 (1984), Vernon H. Brown et al., J. Heterocycle. Chem., 6 (4), 539-543 (1969)] to introduce an indoline skeleton, protecting the amino group, introducing a nitro group into the benzene ring by a method known per se. and reducing the nitro group using a catalyst such as palladium carbon. The compound (VII) can be produced by reacting the compound (IV) with the compound (V) or a reactive derivative thereof in the carboxy group, or the compound (VI). Said reaction is generally carried out in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, water and mixed solvents thereof. In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, and the like can be used. The reaction temperature is generally -10-160 ° C, preferably 0-60 ° C, and the reaction time is generally 30 minutes to 10 hours. The compound (V) can be subjected in the present reaction as a free carboxylic acid or a reactive derivative thereof, and both modes are encompassed by the present invention. That is, it is used in this reaction as free acid or a salt such as sodium, potassium, calcium, triethylamine, pyridine and the like, or as a reactive derivative such as its acid halide (for example, acid chloride, acid bromide , and similaree), acid anhydride, mixed acid anhydride [e.g., substituted phosphoric acid (dialkyl phosphate and similaree), alkyl carbonate (monoethyl carbonate and eimilar), and the like], reactive amide (amide with imidazole and similar), ester (cyanomethyl ester, 4-nitrophenyl ester, etc.), and the like. When the compound (V) is used as the free acid or salt in this reaction, a condensation agent is preferably used. Examples of the condensing agent include dehydration agents such as N, N'-disubstituted carbodiimides (eg, N, N'-dichlohexylcarbodiimide); composed of carbodiimide (e.g., l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N'-morpholinoethyl carbodiimide and N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide); azolide compounds (for example, N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole); and similar. When these condensation agents are used, it is considered that the reaction proceeds by a reactive carboxylic acid derivative. The compound (VIII) can be produced by haloalkylation of the compound (VII) [R.C. Fuson et al., Org. React. , 1, 63 (1969), G.A. O ah et al, "Friedel Crafts and Related Reactions" Vol. 2, 659 (1964)]. The compound (TX) can be produced by converting the halogenoalkyl of the compound (VTTT) to hydroxy, an acid group such as carboxy or a group of the formula -NR R. by a conversion reaction of the known substi tutant per se, and if necessary, by injecting a corresponding protecting group. The compound (XII) can be produced by removing the amino protecting group on R 3 of the compound (IX) by a method known per se to give the compound (X), and by N-alkylation using the compound (XI). Said N-alkylation can be carried out generally in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, water and mixed solvents thereof. In addition, a base such as triethylamine, pyridine, 4-dimethylaminopi ridine, potassium carbonate, and the like can be used. The reaction temperature is generally -10-100 ° C, preferably 0-60 ° C, and the reaction time is generally 30 minutes to 10 hours. The compound (Ta) can be produced by removing the protective group in Ri * of the compound (XTT) by a method known per se.

Production method 2 Compound (XIII) can be produced by hydroxyalkylation of compound (III) [Adolf H. Philipp. and others, J. Med. Chem. 19 (3), 391-395 (1976)], reduction, introduction of an indoline skeleton, protection of the amino group and halogenation of the hydroxy. The compound (XIV) can be produced from the compound (XIII) according to the method to obtain the compound (IX) from the compound (VIII), as described in the production method 1. The composition (XV) can be produce from the compound (XIV) by introducing a nitro group and reducing the member by a known method per ee. The component (XVI) can be produced from the compoteto (XV) in accordance with the method to obtain the compoteto (VII) from the compoteto (IV), as it is written in the production method 1. The compoteto (Ib) can to be produced from the compound (XVI) by the compound (XVII) and the compound (XIII) according to the method to obtain the compound (la) from compound (IX), as described in production method 1.

Production method 3 Compound (XIX) can be produced by oxidation of compound (X) by a method known per se (for example, oxidation using chloranil, palladium, and the like). The compound (le) can be produced from the compound (XIX) by the compound (XX) according to the method for obtaining the compound (a) from the compound (X), as described in production method 1.

Production method 4 Compound (XXI) can be produced by reducing the 2,3-dihydroquinolin-4-one derivative [J.R. Merchant and other, J. Chem. Soc. Perkin I, 932-935 (1972)] using a reducing agent r such as lithium aluminum hydride, aluminum chloride, and the like. The compound (XXIII) can be produced from the compound (XXII) by protecting the amino group of the compound (XXI) by a known method per ee to give the compound (XXII), and in accordance with the method to obtain the compound (VIII ) from the compoteto (VII), as described in the production method 1. The compoteto (XXV) can be produced from the compoteto (XXIII) by the compound (XXIV) in accordance with the method to obtain the compound (XII ) from the compound (VIII) by the compound (IX) and the compound (X), as described in the production method 1. The compound (XXVI) can be produced from the compound (XXV) by introducing a nitro group and reducing the limb by a known method per ee. The composition (XXVII) can be produced from the composition (XXVI) according to the method for obtaining the compound (VII) from the compound (IV), as described in the production method 1. The compound (Id) can to be produced from the compound (XXVII) according to the method for obtaining the compound (la) from the compound (XII), as described in the production method 1.

Production method 5 The compound (XXIX) can be produced from the compound (XXVIII) [W.G. Gall et al., J. Org. Chem. 20, 1538 (1955)] according to the method for obtaining the compound (XII) from the compound (X), as described in the production method 1. The compound (XXX) can be produced by converting the halogen of the compound (XXIX) to cyano group by a method known per se. hydrolysis of the cyano group, and introducing a protective group into the carboxy obtained. The compoteto (XXXI) can be produced from the compoteto (XXX) by reducing the nitro group of the compoteto (XXX) by a known method per ee. and in accordance with the method for obtaining the compound (VII) from the compound (IV), as described in the production method 1. The compound (le) can be produced by removing the protecting group in R20 of the compound (XXXI) by a method known per se.

Production method 6 The compound (XXXII) can be produced by converting the amino group of the compound (IV) to hydroxy by a method known per se. and introducing a protective group in the hydroxy. The compound (XXXIII) can be produced from the compound (XXXII) by introducing a nitro group and reducing it by a method known per se. The compound (XXXIV) can be produced from the compound (XXXIII) according to the method to obtain the compound (VII) from the compound (IV), as described in the production method 1. The compound (XXXV) can be produced from the compound (XXXIV) according to the method to obtain the compound (XII) from the compound (IX) by the compound (X) , as described in the production method 1. The compound (If) can be produced by removing the protective group in R2? of the compound (XXXV) by a method known per se.

Production method 7 The compound (XXXVI) can be produced by alkylation of the amino group or by introducing an amino protecting group of the compound (IV) by a method known per se. The compound (XXXVII) can be produced from the compound (XXXVI) by introducing a nitro group and reducing it by a method known per se. The compound (XXXVIII) can be produced from the compound (XXXVII) according to the method for obtaining the compound (VII) from the compound (IV), as described in the production method 1. The compound (XXXIX) can to be produced from the compound (XXXVIII) according to the method for obtaining the compound (XII) from the compound (IX) by the compound (X), as described in the production method 1. The compound (Ig) can be produced by removing the protecting group in R22 of the compound (XXXIX), by a method known per se. The compound (I) of the present invention obtained by the above methods can be purified by a conventionally known method, such as chromatography and recrystallization. Said compound (I) can be converted to pharmaceutically acceptable salts by a method known per se. A pharmaceutical composition containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may further contain additives. Examples of additives include excipients (e.g., starch, lactose, sugar, calcium carbonate and calcium phosphate), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose and crystalline cellulose), lubricants (e.g., magnesium stearate) and talc) and disintegrant (e.g., carboxymethylcellulose calcium and talc), and the like. The aforementioned ingredients are mixed, and the mixture is prepared in oral preparations such as capsules, tablets, fine granules, granules and dried syrups, or parenteral preparations as injections and suppositories by a method known per se. Although the doeie of the compound (I) of the present invention and the pharmaceutically acceptable elements thereof vary depending on the purpose of administration, the symptoms and others, when, for example, they are administered orally to adult patients suffering from hypercholesterolemia, It is usually 0.1 mg to 50 mg / kg of body weight per dose, which is given approximately one to three times a day. The compound (I) of the present invention and the pharmaceutically acceptable saltse of the mieme exhibit euperior inhibitory activity of ACAT and of lipoperoxidation in mammals (eg, human, cow, horse, dog, cat, rabbit, rat, mouse, hameter , etc.), and are useful as inhibitors of ACAT and inhibitors of lipoperoxidation. In other words, they are useful for the prophylaxis and treatment of arteriosclerosis, hyperlipaemia, teriosclerosis in diabetic, cerebrovascular ischemic and cardiovascular disease, and the like. The present invention is described in more detail by examples, to which the present invention is not limited.

EXAMPLE 1 N- (1-octyl-5-hydroxyethyl-4,6-imetilin-olin-7-yl) -2.2.- dimethylpropanamide (1) N- (1-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (7.0 g) was dissolved in a mixed solvent (50 ml) of CH 3 CN / DMF = 1 /1. Potassium acetate (12.0 g) was added, and the mixture was stirred at 60 ° C for one hour. CH3CN was evaporated under reduced pressure and AcOEt (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 / MeOH = l / 0-10/1) to give 7.5 g of N- (l-acetyl-5-acetoxymethyl-4,6-dimethylindolin-7). -il) -2, 2-dimethyl pylori. 1 H-NMR (CDCl 3) d: 1.27 (9H, s, -C (CH 3) 3), 2.04 (3H, s, OCOCH 3), 2.23, 2.26, 2.30 (9H, s X 3, -CH3 X 2, > NC0CH3), 3.00 (2H, br, Indolino C3-H), 4. 05 (2H, br, Indolino C2-H), 5.20 (2H, s.-CH2O-), 9.10 (HH, br, > NH). (2) N- (1-Acety-5-acetoxymethyl 1-4,6-dimethylindolin-7-yl) -? ,? - dimethyl propanamide (7.5 g) in FtOH (70 ml), and a solution of NaOH (8.3 g) in water (20 ml) was added, which was followed by reflux for 10 hours. The FtOH was evaporated under reduced pressure, and CHCl3 (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and ßl CHC 3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 / MeOH = l / 0-10 / 1) to give 3.0 g of N- (5-hydroxyethyl -4,6-dimethyl indolin-7-i) - ?, 2-di eti Ip ropanami d. H-NMR (CDCl 3) d: 1.35 (9H, s, -C (CH 3) 3), 2.23, 2.26 (6H, s X 2, -CH 3 X 2), 2.99 (2H, t, J = 8.5Hz, Indolino C3-H), 3.58 (? H, t, J = 8.5Hz, Tndolino C2-H), 4.65 (2H, s, -CH2OH), 7.10 (2H, br, OH, > NH). (3) N- (5-hydroxymethyl-4,6-dimethylindolin-7-yl) - ?, 2-dimethylpipropanamide (1.5g) was dissolved in DMF (15ml), and 1-iodooctane? 6g was added. ) and K2CO3 (1.5 g), which was followed by stirring under a nitrogen atmosphere at 50 ° C for 2 hours. AcOFt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOFt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: -10/1) to give 1.0 g of the title compound.

TR (Nujol) cm-l: 165 ?, 1600, 1508.

H-NMR (CDCl 3) d: 0.70 ~ 1.10 (3H, br, - (Cta CHs), 1.10 ~ 1.70 (12H, m, -CH2 (CH2_) 6CH3), 1.37 (9H, s, -C (CH3) 3 ), 2.14, 2.22 (6H, e X 2, -CH3 X 2), 2.87 (2H, t, J = 8.5Hz, Indolino C3-H), 3.14 (2H, t, J = 7.5Hz, > NCH2- ), 3.42 (2H, t, J = 8.5Hz, Indolino C2-H), 4.62 (2H, s, -CH2.OH), 6.86 (2H, br, OH, > NH).

EXAMPLE 2 N- (1-octyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl) -2.2- dimethylpropanamide (1) N- (1-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl) -2,2-dimethyl-propanamide (2.0 g) was dissolved in CHCl3 (40 ml), and (CH3) added. ) 2NH ^ HC1 (3.5 g) and K2CO3 (11.8 g), which was followed by stirring at room temperature for 4 hours. CHCl 3 (300 ml) was added, and the mixture was washed successively with 2N-hydrochloric acid, 2N aqueous NaOH and saturated brine, and dried over anhydrous sodium eulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 / MeOH = 10/1 - 1/1) to give 700 mg of N- (1-acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7). -il) -2,2-di et i lp ropana ida. H-NMR (CDCl 3) d: 1.26 (9H, s, -C (CH 3) 3), 2.12, 2.15 (6H, SX 2, -CH 3 X 2), 2.24 (6H, s, -N (CH 3) 2) , 2.31 (3H, s,> NC0CH3), 3.00 (2H, br, Indolino C3-H), 3.35 (2H, e, > NCH2-), 4.15 (2H, br, Indolino C2-H), 9.23 ( ÍH, br, > NH). (2) N- (l-Acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl) -2,2-dimethyl-ropanamide (1.0 g) was dissolved in MeOH (10 mL), and a solution was added NaOH (580 mg) in water (3 ml), which was followed by stirring at 60 * C for 2 hours. MeOH was evaporated under reduced pressure and CHCl3 (100 mL) was added.

The mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure to give 700 mg of N- (5-dimethylaminomethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide. 1 H-NMR (CDCl 3) d: 1.30 (9H, s, -C (CH 3) 3), 2.19 (12H, e, -CH 3 X 2, -N (CH 3) 2), 3.00 (2H, t, J = 8.5Hz, Indolino C3-H), 3.28 (2H, e, > NCH2-), 3.55 (2H, t, J = 8.5Hz, Indolino C2-H), 4.40 (HH, br, > NH), 7.20 (HH, br, > NH). (3) N- (5-Dimethylaminomethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (700 mg) was dissolved in DMF (7 ml), and NaH was added (P = 60%, 160 mg) under a nitrogen atmosphere at 5 * C. After stirring at the same temperature for 30 minutes, 1-iodooctane (240 mg) was added, which was followed by stirring at 30 ° C for 3 hours. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. The AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 / Me0H = 10 / l - 3/1) to give 500 mg of the title compound. TR (Nujol) cm-: 1654, 1600. 1 H-NMR (CDCl 3) d: 0.70 ~ 1.10 (3H, br, - (CH 2) 7CH 3), 1.10 * 1.70 (12H,, - CH (CH 2) 6CH 3), 1-33 (9H, s, -C (CH3) 3), 2.00, 2.09 (6H, s X?, -CH3 X 2), 2.23 (6H, s, -N (CH3) 2), 2.85 (2H, t, J = 8.5Hz, Tndolino C3-H), 3.18 (2H, br-t, >; NCH2-), 3.31 (2H, s, -CH2N <), 3.38 (2H, t, J = 8.5Hz, Indolino C2-H), 6.84 (ÍH, br, > NH).

EXAMPLE 3 N- (1-octy1-5-ethoxycarbonylmethyl-6-dimethy1indolin-7-i1) -2_2-dimethylpropanamide (1) 1-Acetyl-5-bromo-4,6-riimeti-7-nor troindolin (30 g) was dissolved in a mixture (600 ml) of / l and 5% Pd-C (5.0 g) was added, which was followed by catalytic hydrogenation at 35ßC. The precipitate was collected by filtration together with Pd-C, and dissolved in CHC 3 (300 ml). The mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure from the filtrate and CHCl3 (300 mL) was added. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and combined with the aforementioned CHCI3 layer. The combined layer of CHCl3 was washed with saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure, and the residue was dissolved in CHCl3 (150 ml). Pivaloyl chloride (11.7 g) and Et3N (10.8 g) were successively added at 10 ° C. The mixture was stirred at room temperature for 1 hour and CHCl3 (200 ml) was added. The mixture was washed successively with 5% aqueous citric acid and water, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure, and the crude residue obtained was washed with cold Et ?O (100 ml) to give 21 g of N- (1-acetyl-4,6-dimethylindolin-7-yl) -2.2 -dimethylpropanamide. IR (Nujol) cm-i: 1676, 1639, 1581. H-NMR (CDCl 3) d: 1.24 (9H, S, -C (CH 3) 3), 2.17 (6H, s, -CH 3 X 2), 2.30 ( 3H, s, > NC0CH3), 2.99 (2H, t, J = 8.5Hz, Indolino C3-H), 4.10 (2H, t, J = 8.5Hz, Indolino C2-H), 6.87 (1H, s, Indolino Cs-H), 9.10 (ÍH, br, > NH). (2) N- (l-acetyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (20.0 g) was dissolved in concentrated hydrochloric acid (100 ml), and 35% formalin was added (8.5 g) and zinc chloride (1.8 g). The mixture was stirred at 40 to 50 ° C for 2 hours, while blowing in the same hydrogen chloride. The reaction mixture was poured into ice water and extracted with CHCl3 (400 ml). The CHCl3 layer was washed twice with saturated brine, and dried over anhydrous sodium sulfate. The CHCl3 was evaporated under reduced pressure to give 21 g of N- (1-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl) -2,2-dimethyl lp-aphenamide. IR (Nujol) cm-i: 1679, 1645, 1587. H-NMR (CDCl 3) d: 1.27 (9H, 8, -C (CH 3) 3), 2.25 (3H, s, -CH 3), 2.30 (6H, S, -CH3, > NC0CH3), 3.00 (2H, br, Indolino C3-H), 4.05 (2H, br, Indolino C2-H), 4.68 (2H, s, -CH2Cl), 9.16 (1H, br, > NH). (3) N- (L-acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (21 g) was suspended in CH 3 CN (150 ml), and NaCN (8.1 g) was added. ) and lS-crown-6 (870 mg), which was followed by reflux for 15 hours. The CH3CN under reduced pressure and CHCl3 (300 mL) was added. The mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The obtained residue was washed with boiling MeOH to give 15.5 g of N- (1-acetyl-5-cyanome i 1-4,6-dimethyl indole in-7-yl) -2,2-dimethylp-aphenamide. IR (Nujol) cm -: 2232, 1678, 1639. 1 H-NMR (CDCl 3) d: 1.27 (9H, e, -C (CH 3) 3), 2.26, 2.30, 2.40 (9H, 8X3, -CH3X2, > NC0CH3), 3.00 (2H, br, Indolino C3-H), 3.66 (2H, e, -CH2CN), 4. 05 (2H, br, Indolino C2-H), 9.21 (HH, br, > NH. (4) N- (l-acetyl-5-cyanomethyl-4,6-dimethylindolin-7-lyl) -2 was emitted. , 2-dimethylpropanamide (5.0 g) in n-PrOH (25 ml), and a solution of NaOH (9.6 g) in water (10 ml) was added, which was followed by stirring at 90 ° C for 8 hours in a Autoclave under a nitrogen atmosphere The aqueous layer was separated, and the organic layer was neutralized with 2N-hydrochloric acid The solvent was evaporated under reduced pressure The residue was suspended in EtOH (200 ml), and HCl-EtOH was added. to ION (7.2 ml), which was followed by reflux for 1 hour.The EtOH was evaporated under reduced pressure, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with AcOEt (200 ml). The AcOEt layer was washed with water, dried over anhydrous sodium sulfate, AcOEt was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: - 20/1). to give 3.0 g of N- (5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropropanamide. IR (Nujol) cm -i: 1732, 1654. l H-NMR (CDC13) d: 1.34 (9H, s, -C (CH3) 3), 2.14, 2.18 (6H, sX2, -CH3X2), 2.99 (2H , t, J = 8.5Hz, Indolino C3-H), 3.56 (2H, t, J = 8.5Hz, Indolino C2-H), 3.60 (2H, s, -CH2CO2-), 4.11 (2H, q, J = 7.8Hz, -CH2CH3), 4.20 (ÍH, br, >NH), 7.00 (ÍH, br, &NH). (5) N- (5-Ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (3.5g) was dissolved in DMF (15ml), and 1-iodooctane (5.0g) was added and K2CO3 (2.9 g), which was followed by stirring under a nitrogen atmosphere at 50 ° C for 2 hours. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. The AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: - 50/1) to give 3.5 g of the title compound. IR (pure) cm "i: 1732, 1654, 1600. H-NMR (CDCl 3) d: 0.70 ~ 1.10 (3H, br, - (CH 2)? CHs.), 1.10 * 1.70 (15H, m, -CH 2 CH 3. , - CH2 (CH2 = .CH3), 1.33 (9H, s, -C (CH3) 3), 2.04, 2.13 (6H, eX2, -CH3X2), 2.87 (2H, t, J = 8.5Hz, Indolino C3- H), 3.12 (2H, t, J = 7.5Hz, > NCH2-), 3.39 (2H, t, J = 8.5Hz, Indolino C2-H), 3.58 (2H, s, -CH2CO2-), 4.12 ( 2H, q, J = 7.5Hz, -CH2.CH3), 6.79 (ÍH, br, &NH).

EXAMPLE 4 N - (l-octyl-5-carboxymethyl-4,6-dimethylinctolin-7-yl) -2.2- dimeti lp ropanamida N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH (1.6 g) was added. ) in water (20 ml), which was followed by stirring at 60 ° C for 1 hour. The EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml), and the mixture was washed with AcOEt (20 ml). The aqueous layer was neutralized with 2N-hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.4 g of the title compound.

IR (Nujol) cm - *: 1732, 1651, 1600. 1 H-NMR (CDCI3) d: 0.70 * 1.10 (3H, br, -Ota)? CHa.), 1.10 * 1.70 (12H, m, - CH2 (CH2) &CH3). 1.33 (9H, s, -C (CH3) 3), 2.01, 2.15 (6H, eX2, - CH3X2), 2.70 * 3.20 (4H, m, Indolino C3-H,> NCH2 ~), 3.41 (2H, t , J = 8.5Hz, Indolino C2-H), 3.56 (2H, e, -CH2.CO2H), 7.60 (1 H, br, > NH), 7.90 (1H, br, -CO2H).

EXAMPLE 5 N- (l-octyl-5-carboxymethyl-4,6-dimethylindolin * -7-yl) -2.2-dimethyl-lpropanamide hydrochloride N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a NaOH solution (1.6 g) was added. ) in water (20 ml), which was followed by stirring at 60 ° C for 1 hour. The EtOH was evaporated under reduced pressure. The reflux was dissolved in water (20 ml), and the mixture was washed with AcOEt (20 ml). The aqueous layer was adjusted to pH 1-2 with hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. The AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound. IR (Nujol) cm -1: 1722, 1654. 1 H-NMR (CDCl 3) d: 0.70 * 1.10 (3H, br, - (CH 2 7? ± a.), 1-10 * 1.70 (12H, m, - CH2 (CH2 ßCH3) 1.39 (9H, e, -C (CH3) 3), 2.06, 2.26 (6H, eX2, -CH3X2), 2.90 * 3.30 (4H, m, Indolino C3-H,> NCH2 ~) , 3.50 * 3.90 (2H, br-t, Indolino C2-H), 3.72 (2H, e, -CH2.CO2H), 6.00 * 7.00 (OH, br, HCl), 9.05 (2H, br, > NH, -CO2H).

EXAMPLE 6 N- (l-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylp-clothing N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (4.0 g) was dissolved in EtOH (57 ml), and a solution of NaOH (1.8 g) was added. ) in water (23 ml), which was followed by stirring at 60 ° C. for 1 hour. The EtOH was evaporated under reduced pressure. The residue was dissolved in water (30 ml), and the mixture was washed with AcOEt (30 ml). The aqueous layer was adjusted to pH 1-2 with sulfuric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. The AcOEt was evaporated under reduced pressure to give 2.5 g of the title compound. IR (Nujol) cm -1: 1718, 1654, 1637. 1 H-NMR (CDCl 3) d: 0.70 * 1.10 (3H, br, - (CH 2) 7CH 3), 1.10 * 1.70 (12H, m, -CH 2 (CH 2 16 CH 3 ), 1.33 (9H, s, -C (CH3) 3), 2.02, 2.16 (6H, 8X2, - CH3X2), 2.80 * 3.30 (4H, m, Indolino C3-H, > NCH2-), 3.30 * 3.70 (2H, br-t, Indolino C2-H), 3.59 (2H, s, -CH2CO2H), 6.00 * 7.00 (2H, br, H2SO4), 7.20 (ÍH, br, -CO2H), 8.30 (1H, br, > NH).

EXAMPLE 7 N- (l-octyl-5-carboxymethyl-4,6-dip? Ethylindolin-7-yl) -2,2-dimethylpropanamide Nitrate N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (3.0 g) was dissolved in EtOH (42 ml), and an NaOH solution (1.4 g) was added. ) in water (17 ml), which was followed by stirring at 60 ° C for 1 hour. The EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml), and the mixture was washed with AcOEt (20 ml). The aqueous layer was adjusted to pH 1-2 with nitric acid, and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. The AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound. IR (Nujol) cm -: 1724, 1654 H-NMR (CDCI3) d: 0.70 * 1.10 (3H, br, - (CH2) 7CHj.), 1.10 * 1.70 (12H, m, -CH2 (C £ taj £ CH -3), 1.33 (9H, s, -C (CH3) 3), 2.02, 2.21 (6H, SX2, -CH3X2), 2.80 * 3.30 (4H,, Indolino C3-H, > NCH2 ~), 3.50 * 3.80 (2H, br-t, Indoline C2-H), 3.64 (2H, e, -CH2.CO2H), 6.00 * 7.00 (H, br, HNO3), 9.03 (2H, br, > NH, -CO2H) .

EXAMPLE 8 Sodium salt of N- (l-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH (1.6 g) was added. ) in water (20 ml), which was followed by stirring at 60 ° C for 1 hour. The EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was absorbed on DAY I0NR HP-21 (70 ml). After washing with water, the mixture was eluted with 50% aqueous methanol. The objective fraction was concentrated under reduced pressure. The residue was freeze-dried to give 1.0 g of the title compound. IR (Nujol) cm "; 1630, 1605. 1RMN (CDCl-3) d: 0.70 * 1.10 (3H, br, - (CH2) 7CH3, 1.10 * 1.70 (12H, m, -CH2 (CH2_1 = _CH3), 1.38 (9H, S, -C (CH3) 3), 1-93, 2.08 (6H, sx2, -CH3x2), 2.70 * 3.20 (4H,, Indoline C3-H, > NCH2-), 3.30 * 3.40 ( 2H, br ~ t, Indoline C2-H), 3.15 (2H, s, -CH2_C02Na), 8.54 (ÍH, br, > NH).

EXAMPLE 9 N- [l-Octyl-3- (2-hydroxyethyl) -4-6-dimethylindolin-7-yl]] - 2,2- di-tilpropanamide (1) 4,6-dimethylindole (130 g) was dissolved in Ft2? (130 ml) and oxalyl chloride (23.0 g) was added dropwise in 0 * C. The mixture was stirred at room temperature for 5 hours and the Et 2 was evaporated under reduced pressure. EtOH (200 ml) was added to the residue and the mixture was stirred at room temperature for 15 hours. The FtOH was evaporated under reduced pressure. The residue was dissolved in CHCl3 in (200 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue obtained was added to a suspension of LiAlH /, (17.0 g) in Et2? (200 ml), which was followed by flow during? hours. The reaction mixture was poured into ice water and extracted with AcOEt (200 ml). The AcOFt layer was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by column chromatography on eluent silica gel: - 10/1) to give 13.0 g of 3- (2-hydroxyethyl) -4,6-dimethylindole. TR (Nuj? L) cm -1; 1656, 1377 1RMN (CDCl-3) d: 3.39, 2.63 (6H, sx2, -CH3X?), 3.13 (? H, t, J = 7.0Hz, CHiCH ^ OH), 3. I know (? H, t, J = 7.nHz, CH ^ CH ^ OH, < < ... (1H_?, Indo! C5-H), e..91 (ÍH, m, Tndo C2-H , C7-H), 6.9 (H, br, -OH), 7.90 (H, br, <NH). (2) 3- (2-hydroxyethyl) -4,6-rhymethyl indole (13.0 g) was dissolved. ) in AcOH (100 ml) and NaBH 3 CN (8.7 g), proportions in ice-cooling were added.After stirring at the same temperature for 1 hour, the reaction mixture was poured into ice water and neutralized with aqueous NaOH. The mixture was extracted with CHCl3 (200 ml), the CHCl3 layer was washed with water and dried over anhydrous sulfate, CHCI3 was evaporated under reduced pressure, the residue was dissolved in benzene. (100 ml) and AC2O (15 g) and Ft3N (8.3 g) were added, which was followed by stirring at room temperature for 1 hour. AcOFt (? 00 ml) was added and the mixture was washed substantially with saturated aqueous sodium hydrogen carbonate solution, 5% aqueous citric acid and saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Purified < = »! residue by column chromatography on silica gel (eluent: CHCl3 / Me H = 50 / l - 10/1) to give 13.0 g of l-acetyl-3- (2-acetoxyPti) -4,6-dimethyl indol . IR (Nuj? L) cm "i; 165 ?, 1460. 1RMN (CDCI-3) d: 1.60 * 2.20 (2H, m, -CH2.CH2O-), 2.04 (3H, s, -OCOCH3), 2.24 ( 3H, s, > NC0CH3), 2.24, (6H, sx2, -CH3x?), 3.34 (IH, m, Tndoline C3 -H), 3.94 (1H, m, Indoline C2-H), 4.12 (2H, t , J = 7.1Hz, -CH2CH2.O-), 6.67 (1H, s, Indole C5-H), 7.90 (1H, < s, Indole C7-H). (3) l-Acetyl-3- (2-acetoxyethyl) -4,6-dimethylindoline (2.0 g) was dissolved in AcOH (40 ml) and Bp_ (1.9 g) was added, which was followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice water and collected by precipitate filtration. The precipitate was dissolved in CHCl3, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: CHCl3 / MeOH = 50 / l - 10/1) to give 2.7 g of crude creitals of l-acetyl-3- (2-acetoxyethyl) -5-bromo -4,6-dimethylindoline. The crude crystals were added in proportions to a mixture of nitric acid (0.47 g), AcOH (10 ml) and concentrated hydrochloric acid (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into ice water and collected by precipitate filtration. The precipitate was dissolved in CHCl 3 - After washing with water, the mixture was dried over anhydrous sodium sulfate and the CHCl 3 was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl 3 / MeOH = 50 / l - 10/1) to give 1.4 g of l-acetyl-3- (2-acetoxyethyl) -5-bromo-4,6-dimethyl indole in-7-nitroindole. 1 NMR (CDCl-3) d: 1.60 * 2.20 (2H, m, -CHb_CH20-), 1.99 (3H, s, -OCOCH3), 2.21 (3H, e, > NC0CH3), 2.38, (6H, ex2, - CH3X2), 3.40 (ÍH, m, Indoline C3-H), 4.11 (2H, t, J = 7.1HZ, -CH2CH2_0-), 4.14 (2H, d, J = 8.5Hz, Indolin C2-H). (4) l-Acetyl-3- (2-acetoxyethyl) -5-bromo-4,6-dimethyl-nitroindoline (1.4 g) was dissolved in benzene (20 ml) and Pd-C (500 mg) was added. which was followed by catalytic hydrogenation at room temperature and at atmospheric pressure. Pd-C was filtered off and evaporated to benzene under reduced pressure. The residue was dissolved in CHCl3 (50 ml) and the mixture was washed successively with acidic aqueous sodium carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. Pivaloyl chloride (440 mg) and Et3N (448 mg) were added to the obtained solution and the mixture was stirred at room temperature for 30 minutes. The mixture was washed successively with 5% aqueous citric acid and saturated saline, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50 / l - 10/1) to give 1.0 g of N- [1-acetyl-3- (2-acetoxyethy1) -4.6 -dimethylindolin-7-yl] -2,2-dimethylpropanamide. IR (Nujol) cm -i; 1730, 1649. 1 NMR (CDCl-3) d: 1.27 (9H, s, -C (CH3) 3), 1.60 * 2.20 (2H, m, -CH2.CH2O-), 2.06 (3H, S, -OCOCH3) , 2.17 (6H, 8, -CH3X2), 2.30 (3H, s,> NC0CH3), 3.10, (ÍH, m, Indoline C3-H), 4.03 (2H, d, J = 8.5Hz, Indolin C2-H ), 4.14 (2H, t, J = 7.0Hz, -CH2CH2.O-). 6.88 (ÍH, e, Indolin Cs-H), 9.00 (ÍH, br, &NH). (5) N- [l-Acetyl-3- (2-acetoxyethyl) -4,6-dimethylindolin-7-yl] -2,2-dimethylpropanamide (4.0 g) was dissolved in EtOH (40 ml) and a NaOH solution (2.2 g) in water (10 ml), which was followed by stirring at 60 ° C for 10 hours. EtOH was evaporated under reduced pressure and CHCl3 (100 mL) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate and the CHCl3 was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: -10/1) to give 1.6 g of N- [l-acetyl-3- (2-hydroxyethyl) -4,6-dimethyl-indol in-7 -il] -2,2-dimethylphenamide. NMR (CDCl-3) d: 1.34 (9H, s, -C (CH3) 3), 1.60 * 2.20 (2H, m, -CH2.CH2OH), 2.17, 2. 19 (6H, ex2, -CH3X2), 3.20 * 3.80 (7H, m, Indoline C2-H, C3-H, > NH, -CH2CH OH). 6.45 (ÍH, s, Indoline Cs-H), 7.20 (ÍH, br, -CONH-). (6) N- [3- (2-Hydroxyethyl) -4,6-dimethylindolin-7-yl] -2,2-dimethylpropanamide (1.6 g) was dissolved in DMF (16 ml) and 1-iodooctane (3.9 g) and K-2CO3 (2.3 g), which was followed by stirring at 70 ° C for 10 hours. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: benzene / AcOEt = 5 / l-1/2) to give 300 mg of the title compound. IR (Nujol) cm "i; 1645, 1600. 1RMN (CDCl-3) d: 0.70 * 1.00 (3H, brt, - (CH2) eCH3_), 1.33 (9H, s, -C (CH3) 3), 1.00 * 2.00 (14H,, - (CH2) ßCH3. -CH2.CH2OH), 2.07, 2.16 (6H, 8X2, -CH3X2), 2.60 * 3.60 (8H, m, Indolin C2-H, C3-H, > NCH2 -, -CH2.OH), 6.44 (H, s, Indolin Cs-H), 6.78 (H, br, -CONH-).

EXAMPLE 10 N - [(l-Octyl-3- (2-me oxy-ributylethyl) -4,6-dimethyl-indolin-7-yl]] - 2,2-dimethylpropanamide (1) l-Acetyl-3- (2-acetoxyethyl) -4,6-dimethylindoline (2.0 g) was dissolved in a mixture of (25 ml), and a NaOH solution (1.5 g) in water (5 g) was added. ml), which was followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure. CHCl3 (100 mL) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50 / l - 10/1) to give 1.2 g of l-acetyl-3- (2-hydroxyethyl) -4,6-di ethylindoline . 1 NMR (CDCl-3) d: 1.60 * 2.00 (3H, m, -CH2.CH2OH), 2.26, 2.30, 2.39 (9H, sx3, -CH3X2, > NC0CH3), 3.50 (H, m, Indoline C3-H ), 3.77 (2H, t, J = 7.0Hz, -CH2CH2.OH), 3.97 (2H, m, Indolin C2-H), 6.67 (H, s, Indoline Cs-H), 7.89 (H, s, Indoline) C7-H). (2) l-Acetyl-3- (2-hydroxyethyl) -4,6-dimethylindoline (7.0 g) and CBm (9.9 g) were dissolved in CH3CN (70 ml), and Ph3P (9.4 g) was added, which was followed by stirring at room temperature for 30 minutes. CH3CN was evaporated under reduced pressure. AcOEt (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: benzene / AcOEt = 5 / l - 10/1) to give 5.4 g of l-acetyl-3- (2-bro-oeti1) -4, -dimethyl-indoline. IR (Nujol) cm -i 1650, 1460. 1RMN (CDCI-3) d: 1.80 * 2.20 (2H, m, -CH2.CH2.Br), 2.23, 2.26, 2.30 (9H, SX3, -CH3X2, > NC0CH3), 3.42 (2H, t, J = 7.0Hz, -CH2.CH2.Br), 3.20 * 3.60 (HH,, Indoline C3-H), 4.00 (2H, m, Indoline C2-H), 6.68 (HH) , s, Indoline Cs-H), 7.89 (OH, s, Indoline C7-H). (3) L-Acetyl-3- (2-bromoethyl) -4,6-dimethylindoline (5.4 g) and NaCN (3.7 g) were eospeneiated and 18-crown-6 (480 mg) in CH3CN (50 ml) was added. , and the suspension was refluxed for 15 hours. CH3CN was evaporated under reduced pressure. CHCl3 (100 mL) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50/1 - 10/1) to give 4.5 g of l-acetyl-3- (2-cyanoethyl) -4,6-dimethylindoline. NMR (CDCl-3) d: 1.70 * 2.00 (2H, m, -CH2.CH2CN), 2.26, 2.31, (9H, sx3, -CH3x2, > NC0CH3), 2.20 * 2.40 (2H,, -CH2CH2.CN ), 3.44 (Indoline C3-H), 3.70 * 4.20 (2H, m, Indolin C2-H), 6.69 (H, s, Indoline Cs-H), 7.70 (H, s, Indoline C7-H). (4) l-Acetyl-3- (2-cyanoethyl) -4,6-dimethylindoline (4.5 g) was dissolved in EtOH (150 ml), and a solution of KOH (10.4 g) in water (50 ml) was added. , which was followed by reflux for 15 hours. EtOH was evaporated under reduced pressure, and the aqueous acid layer was adjusted and with 6N hydrochloric acid and extracted with CHCl3 (100 ml). The CHCl3 layer was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated at reduced pressure. The residue was dissolved in CHCl3 (20 ml) and AC2O (1.9 g) was added, which was followed by stirring at room temperature for 1 hour. CHCl3 (100 mL) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: - 10/1) to give 3.4 g of l-acetyl-3- (2-carboxyethyl) -4,6-di-ethylindoline. NMR (CDCl-3) d: 1.60 * 2.20 (2H, m, -CH2.CH2.CO2 H), 2.26, 2.29 (9H, sx3, -CH3x2,> NC0CH3), 2.20 * 2.40 (2H, m, - CH2.CH2.CO2H), 3.37 (ÍH, m, Indoline C3-H), 3.80 * 4.10 (2H, m, Indoline C2-H), 6.68 (1H, s, Indoline Cs-H), 7.50 (1H, br , -CO2H), 7.88 (OH, s, Indoline C7-H). (5) l-Acetyl-3- (2-carboxyethyl) -4,6-dimethylindoline (3.4 g) was dissolved in EtOH (50 ml), and ION HC1-EtOH (3.9 ml) was added, which was followed by reflux for 30 minutes. EtOH was evaporated under reduced pressure and AcOEt (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50 / l - 10/1) to give 3.3 g of 1-acetyl-3- (2-ethoxycarbonylethyl) -4,6-dimethylindoline. i H-NMR (CDCl 3) d: 1.24 (3H, t, J = 7.1Hz, -CH 2 CH 3), 1.60 * 2.20 (2H, m, -CH 2 .CH 2 CO 2 -), 2.22, 2.27, 2.30 (9H, sx3, - CH3x2, > NC0CH3), 2.00 * 2.20 (2H, m, -CH2CH2.CO2-), 3.10 * 3.30 (H,,, Indoline C3-H), 3.90 (2H,, Indoline C2-H), 4.10 (2H, q, J = 7.Hz, -CH2.CH3), 6.76 (HH, e, Indoline Cs-H, 7.90 (HH, e, Indoline C7-H. (6) l-Acetyl-3- (2-) was dissolved ethoxycarbonylethyl) -4,6-di-ethylindoline (3.3 g) in AcOH (30 ml) and Bp_ (0.93 ml) was added, which was followed by stirring for 30 min.The reaction mixture was poured into ice water and the reaction mixture was poured into ice water. the crystals were collected by filtration and the precipitated crystals were dissolved, the crystals obtained were dissolved CHCI3 (100 ml) After washing with water, the mixture was dried anhydrous sodium sulfate, CHCl3 was evaporated under reduced pressure, the residue was purified by chromatography over column of gel of gel (eluent: CHCl3 / MeOH = 50 / l - 10/1) to give 3.0 g of l-acetyl-5-bromo-3- (2-ethoxycarbonylethyl) -4,6-dimethylindoline. IR (Nujol cm - 1: 1729, 1641. 1 H-NMR (CDCl 3) d: 1.24 (3H, t, J = 7.1Hz, -CH2CH3), 1.60 * 2.30 (2H, m, -CH2.CH2CO2-), 2.00 * 2.20 (2H, m, -CH2Cn) - 2.21 (3H, e,> NC0CH3), 2.36, 2.39 (6H, ex2, -CH3X2), 3.10 * 3.60 (ÍH, m, Indoline C3-H), 2.36, 2.39 (6H, ex2, -CH3X2) , 3.10 * 3.60 (ÍH, m, Indoline C3-H), 3.90 (2H, m, Indoline C2-H), 4.10 (2H, q, J = 7.1 Hz, -CH2.CH3), 8.08 (ÍH, e, Indoline C7-H). (7) To a mixture of AcOH (10 ml), concentrated etulfuric acid (10 ml) and nitric acid (0.55 ml) was added l-acetyl-5-bromo-3- (2-ethoxy-carbonylethyl) -4, 6-dimethylindoline (3.0 g) at 0 ° C, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was poured into ice water and extracted with CHCl3 (100 mL). After washing with water, the mixture was washed with anhydrous eodium sulfate. CHCl3 was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50 / l - 10/1) to give 2.7 l-acetyl-5-bromo-3- (2-ethoxycarbonylethyl) -4.6 -dimethyl-7-nitroindoline. l H-NMR (CDCl 3) d: 1.26 (3H, t, J = 7.1Hz, -CH2CH3.), 1.60 * 2.20 (2H, m, -CH2.CH2CO2-), 2.00 * 2.20 (2H, m, -CH2CH2 .CO2 -), 2.23 (3H, s,> NC0CH3), 2.44, 2.47 (6H, 8X2, -CH3X2), 3.10 * 3.60 (ÍH, m, Indoline C3-H), 4.00 (2H, m, Indoline C2 -H), 4.10 (2H, q, J = 7.1Hz, -CH2.CH3). (8) l-Acetyl-5-bromo-3- (2-ethoxycarbonylethyl) -4,6-dimethyl-7-nitro-indoline (2.7 g) was dissolved in benzene (100 ml), and 5% Pd- C (500 mg), which was followed by catalytic hydrogenation at room temperature and at atmospheric pressure. The Pd-C was filtered off and the benzene was evaporated under reduced pressure. The CHCl3 residue (100 ml) was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was dissolved in CHCl3 (20 ml) and pivaloyl chloride (790 mg) and Et3N (80 mg) was added, which was followed by stirring at room temperature for 30 minutes. CHCl3 (100 ml) was added, and the mixture was washed successively with 5% aqueous citric acid and saturated saline and dried over anhydrous sodium sulfate. CHCl3 was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50/1 - 10/1) to give 2.6 g of N- [1-acetyl-3- (2-ethoxycarbonyl) -4) , 6-dimethyindol-7-yl] -2,2-dimethylpropanamide. 1 H-NMR (CDCl 3) d: 1.25 (9H, s, -C (CH 3) 3), 1.26 (3H, t J = 7.1Hz, -CH 2 CH 3, 1.60 * 2.20 (2.H, m, -C 1, 2. CH2CO2 -), 2.00 * 2.20 (2H, m, -CH2CH2.CO2-), 2.17, 2.20, 2.27 (9H, sx3, -CH3x2, > NC0CH3), 3.00 * 3.20 (ΔH,, Indoline C3-H), 3.90 (2H, m Indoline C2-H), 4.10 (2H, q.J = 7.1Hz, -CH2.CH3), 6.88 (ÍH, s, Indoline Cs-H) .9.00 (ÍH, br, -CONH-) (9) N- [l-Acetyl-3- (2-ethoxycarbonylethyl) -4,6-dimethylindoline-7-yl] -2,2-dimethylpropanamide (2.6 g) was dissolved in EtOH (40 ml), and added a solution of KOH (1.3 g) in water, (10 ml), which was followed by refluxing for 20 hours EtOH was evaporated under reduced pressure, and the mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with CHCl 3 (100 ml) The CHCl 3 layer was washed with water and dried over anhydrous sodium sulfate CHCl 3 was evaporated under reduced pressure to give 1.5 g of N- [3-2-carboxyethyl) -4,6-dimethylindoline -7-yl] -2,2-dimethylpropanamide. 1 H-NMR (CDCl 3) d: 1.33 (9H, s, -C (CH 3) 3), 1.60 * 2.20 (2.20 (2H, m, -CH2.CH2CO2H), 2.14, 2.26 (6H, sx3, -CH3X2 ), 2.20 * 2.40 (2H, m, -CH2CH2.CO2H), 3.10 * 3.80 (3H,, Indoline C2-H, C3-H), 6.44 (ÍH, s, Indoline Cs-H), 6.74 (2H, br , -CO2H, > NH). (10) N- [3- (2-carboxyethyl) -4,6-dimethylindolin-7-yl] -2,2-dimethyl-propanamide (1.5 g) was dissolved in AcOEt ( 10 ml) and a solution of CH2N2 in ether was added AcOEt (100 ml) was added, and after washing with water, the anhydrous sodium sulfate-sulfate mixture was dried AcOEt was evaporated under reduced pressure. chromatography on a column of silica gel (eluent: CHCl3 / MeOH = 50 / l - 10/1 to give 1.0 g of N- [3- (2-methoxycarbonylethyl) -4,6-dimethylindoline-7-yl] -2, 2-dimet ilp ropanamide H-NMR (CDCI3) d: 1.34 (9H, s, -C (CH3) 3), 1.60 * 2.20 (2H, m, -CH-2CO2-) 2.15, 2.23 (6H, sx2 , -CH3x2), 2.20 * 2.40 (2H, m, -CH2CH2.CO2CH3), 3. 10 * 3.80 (3H, m, IndOlina C2-H, C3-H), 3.64 (2H, s, -CO2CH3), 6.40 (1H, s, Tndoline C5-H), 7.05 (1H, br, > NH) . (11) N- [3 - (? - methoxycarbonylethyl) -, 6-dimeti-1-indol-7-yl] -?,? - dimethyl-1-propanamide (1.0 g) was dissolved and added in DMF (10 ml) - iodoctane (1.44 g) and K2CO3 (830 mg), which was followed by stirring at 40 ° C for 10 hours. AcOFt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: benzene / Ac.0Ft =? 0 / l -5 / 1) to give 1.1 g of the title compound. IR (Nujol) cm-1: 1730, 16? 0. 1 H-NMR (CDCl 3) d: 0.70 * 1.00 (3H, br-t, - (CH 2) s - (H2J, 1.32 (9H, s, -C (CH 3) 3), 1.00 * 1.60 (12H, m, - (CH?) É_CH3), 1.60 * 7.20 (2H, m, -CH2.CH2CO2 -), 2.05, 2.18 (6H, sx2, -CH3x2), 2.20 * 2.40 (2H, m, -CH2CH2.CO2CH3), 3.10 * 3.80 (5H, m, Tndoline C2-H, C3-H, > NCH2-), 3.64 (3H, s, -CO2CH3), 6.38 (H, s, Tndoline C5-H), 6.70 (H, br, -CONH-).

EXAMPLE 11 N - [(l-Octyl-3- (2-carboxyethyl) ~ 4-6-dimethylindoIina-7-iI)] - 2.2- dimethyl-p opanamide N - [(1-Octyl-3 - (β-methoxycarbonylethyl) -4,6-dimethylindolin-7-yl)] - ?, 2-dimethylpropanamide (1.1 g) was dissolved in FtOH (10 ml) and a solution of NaoH (494 mg) in water (3 ml) was added, which was followed by stirring at room temperature for 30 minutes. EtOH was evaporated under reduced pressure and CHCl3 (50 ml) was added. After washing successively with 5% aqueous citric acid and saturated saline, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated at reduced pressure. The residue was purified by chromatography on eluent silica gel column: CHCl3 / MeOH = 59 / L-10/1) to give 800 mg of the title compound. IR (Nujol) cm-: 1700, 1680 l H-NMR (CDCI3) d: 0.70 * 1.00 (3H, br-t, - (CH2) 7CH3_), 1.38 (9H, s, -C (CH3) 3), 1.00 * 1.60 (12H, m, -C | ±.) FeCH3), 1.60 * 2.20 (2H, m, -CH2.CH2CH2H), 2.07, 2.16 (6H, sx2, -CH3X2), 2.20 * 2.40 (2H, m , -CH2CH2CO2H), 3.10 * 380 (3H, m, Indoline C-2-H, C2-H, C3-H), 3.27 (2H, br-t, > NCH2-), 6.45 (H, s, Indoline Cs-H), 7.20 (HH, br, -CONH-), 7.60 (HH, br, -CO2H).

EXAMPLE 12 N- (l-Octyl-5-carboxymethyl-4,6-dimethylindol-7-yl) -2,2-dimethyl-propanamide (1) N- (5-Ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl) -2,2-dimethyl-propanamide (1.0 g) was dissolved in exylene (75 ml), and 10% Pd-C ( 250 mg), which was followed by reflux for 1 hour. Pd-c was filtered off and the exylene was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: benzene-CHCl3) to give 0.9 g N- (5-ethoxy-rbonylmethi-4, 6-dimet-lindol-7-yl) -2,2-dimethylpropanamide . IR (Nujol) cm-: 1732, 1629. H-NMR (CDC1) 3) d: 1.2 (3H, t, J = 7.0Hz, -CH2CH3), 1.40 (9H, s, -C (043) 3), 2.32 (3H, S, -CH3), 2.52 (3H, 8, (3H, s, -CH3), 3.80 (2H, m, -CH2CO2-), 4.13 (2H, q, J = 7.00Hz, -CÜ2.CH3 ), 6.50 (ÍH, t, J = 2. 0Hz, Indola C3-H), 7.11 (ÍH, t, J = 2.0Hz, Indole C2-H), 7.35 (IH, br, -C0NH-), 8.88 (IH, br, > NH). (2) N- (5-Ethoxycarbonylmethyl-4,6-dimethylindole-7-yl) -2,2-dimethylpropanamide (1.45 g) was dissolved in DMF (10 ml) and NaH P = 60%, 132 mg was added) under a nitrogen atmosphere, which was followed by stirring at room temperature for 1 hour. Then, 1-iodoctane (1.06 g) was added and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice water. The mixture was extracted with AcOEt (100 ml), washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: benzene / AcOEt = 1 / 0-1 / 1 to give 1.02 g of N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylolindole). 7-yl) -2, 2-dimethylpropanamide, IR (Nujol) cm-1: 1735, 1651.

H-NMR (CDCl 3) d: 0.70 * 1.10 (3H, br-t, - (CH 2)? CH-3). 1.10 * 1.70 (15H,, -CH2CtL3_, - (CH2.) Fe.CH3), 1.38 (9H, s, -C (CH3) -3), 2.21 (3H, s, -CH3), 2.47 (3H, s , -CH3), 3.79 (2H, m, -CH2CO2-), 3.90 * 4.30 (4H, m, -CH2.CH3. >; NCH2-), 6.42 (1H, t, J = 3.5Hz, Indole C3-H), 6.91 (IH, t, J = 3.5Hz, Indole C2-H), 7.12 (IH, br, -CONH-). (3) N- (1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl) -2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH was added. (1.6 g) in water (20 ml), which was followed by stirring at 60 ° C for 1 hour. The EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (10 ml =.) The aqueous layer was neutralized with 2N HCl and extracted with AcOEt (50 ml). washed the AcOEt layer successively with saturated saline and dried over anhydrous sodium sulfate, The AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound, IR (Nujol) cm-1: 1705, 1647. 1 H- NMR (CDCl3) d: 0.70 * 1.10 (3H, br, - (CH2) 7CH3_), 1.10 * 1.70 (12H, m, -CH2 (Ota sCHs), 1.33 (9H, s, -C (CH3) 3), 2.10 (3H, s, -CH3), 2.39 (3H, s, -CH3), 3.65 (ÍH, br, -CO2H), 4.07 (2H, br-t,> NCH2 ~), 4.15 (2H, s, -CH2CO2-), 6.38 (ÍH, t, J = 3.5Hz, Indole C3-H), 6.89 (IH, t, J = 3.5 Hz, Indole C2-H), 7.25 (IH, br, -CONH-).

EXAMPLES 13-119 According to the method as described in any of the above-mentioned examples 1-12, compounds of tables 1-9 were obtained.

BOX 1 BOX 2 COI-DRO 3 CD? BOD 5 NHCOR7 CD-UXO 6 NHCONHR7 C? ADRO 7 NHCOR7 CUAERO 8 4_ NHCOR7 CDMSO 9 75 NHCOR7 The values of ^ H-BNN of the category of the above Examples 13-119 are shown below. Bjagio 13: 0.7 -1.1 (3H, br-t), 1.1 -1.7 (6H, m), 1.33 (9H, s), 2. 01 (3H, s), 2.15 (3H, s), 2.70-3.10 (4H, m), 3.41 (2Hf t), 3.56 (2H, s), 7.6 -8.1 (2H, br). Axis-peep 14: 0.70 - 1.70 (8H, ra), 1.1 - 1.7 (6H, ra), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (3H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 15: 0.87 (6H, d), 1.1 - 1.8 (3H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, tn), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ejago 16: 1.65 (6H, s), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2. 70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 5.20 (1H, br-t), 7.6 - 8.1 (2H, br). example 17: 1.59 (3H, t), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2. 70 - 3.10 (4H, m), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 18: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (8H, m), 1.33 (9H, s), 2.01 (3H; s), 2.15 (3H, s), 2.70 - 3.10 (HE, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ejapio 19: 0.7 - 1.70 (10H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (3H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 20: 0.7 - 1.70 (9H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ejape 21: 0.87 (6H, d), 1.1 - 1.8 (5H, m), 1.33 (9H, s), 2.01 (3H, s), 2. 15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 22: 0.7 - 1.0 (6H, br-t), 1.0 - 1.7 (5H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, ra), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Bjapio 23: 1.59 (3H, br-t), 1.0 - 1.7 (2H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m) , 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 24: 0.7 - 1.10 (3H, br-t), 1.1 - 1.7 (10H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 25: 0.7 - 1.70 (11H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ejapio 26: 0.87 (6H, d), 1.1 - 1.8 (TH, m), 1.33 (9H, s), 2.01 (3H, s), 2. 15 (3H, s), 2.T0 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), T.6 - 8.1 (2H, br). Ejapio 2T: 1.59 (6H, br-t), 1.1 - 1.7 (7H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Figure 28: 1.59 (3H, br-t), 1.0 - 1.7 (4H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ejapio 29: 0.7 - 1.70 (13H, m), 1.33 (9H, s), 2.01. (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, ra), 3.41 (2H, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ax-pplo 30 0.87 (6H, d), 1.1 - 1.8 (9H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (ZH, t), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Example 31 1.59 (6H, br-t), 1.0-1.7 (9H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Ejaplo 32 1.59 (3H, br-t), 1.0 - 1.7 (6H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) 2.70 - 3.10 (4H, DI), 3.3 - 3.6 (6H, m), 3.56 (2H, s), 7.6 - 8.1 (2H, br). Ejenplo 33 0.7 - 1.10 (3H, br-t), 1.1 - 1.7 (14H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) Z.70 - 3.10 (4H, tn), 3.41 (2H, t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Ejenplo 34 0.87 (6H, d), 1.1 - 1.8 (1 H, ra), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) Z.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Example 35 1.59 (6H, br-t), 1.0-1.7 (11H, ra), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) 2.70 - 3.10 (4H, rp), 3.41 (2H, t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Example 36 0.7 - 1.10 (3H, br-t), 1.1 - 1.7 (16H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) 2.70 - 3.10 (4H, m) , 3.41 (ZH, t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Ejen_plo 37 0.87 (6H, d), 1.1 - 1.8 (13H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) 2.70 - 3.10 (4H, m), 3.41 (2H , t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Ejenplo 38 0.7 - 1.10 (3H, bi-t), 1.1 - 1.7 (18H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) Z.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s) 7.6 - 8.1 (ZH, br). Example 39 0.87 (6H, d), 1.1 - 1.8 (15H, m), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s) Z.70 - 3.10 (4H, ra), 3.41 (ZH, t), 3.56 (ZH, s) 7.6 - 8.1 (ZH, br). Ejenplo 40 0.7 - 1.10 (3H, br-t), 1.1 - 1.7 (Z0H, ra), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, rn ), 3.41 (SH, t), 3.56 (ZH, s), 7.6 - 8.1 (ZH, br). Bjeaplo 41: 0.87 (6H, d), 1.1 - 1.8 (17H, m), 1.33 (9H, s), 2.01 (3H, s), S.15 (3H, s), Z.70 - 3.10 (4H, m), 3.41 (SH, t), 3.56 (ZH, s), 7.6 - 8.1 (ZH, br). Axis-po 42: 0.7 - 1.10 (6H, br-t), 1.1 - SO (SOH, m), 2.01 (3H, s), 2.15 (3H, s), S.70 - 3.10 (4H, m), 3.41 (ZH, t), 3.56 (SH, s), 7.6 - 8.1 (ZH, br). Axis-plo 3: 0.7 - 1.10 (6H, br-t), 1.0 - ZO (ZZH, m), 2.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H, m ), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Eje__plo 44: 0.7 - 1.10 (6H, br-t), 1.0 - SO (Z4H, m), S.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H, s) ), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Example 5: 0.7 - 1.10 (6H, br-t), 1.0 - SO (S4H, m), S.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H, m ), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Bjenplo 46: 0.7 - 1.10 (6H, br-t), 1.0 - SO (S6H, m), S.01 (3H, s), 2.15 (3H, s), S.70 - 3.10 (4H, m), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Ejeaplo 47: 0.7 - 1.10 (6H, br-t), 1.0 - SO (S8H, rp), S.01 (3H, s), 2.15 (3H, s), S.70 - 3.10 (4H, ra), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Axle 48: 0.7 - 1.10 (6H, br-t), 1.0 - SO (Z8H, m), S.01 (3H, s), S.15 (3H, s), Z.70 - 3.10 (4H, m ), 3.41 (ZH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Axle 49: 0.7 - 1.10 (6H, br-t), 1.0 - ZO (30H, m), S.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H, s) ), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Example 50: 0.7-1.10 (6H, br-t), 1.0 - SO (3SH, rp), S.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H, m ), 3.41 (SH, t), 3.56 (SH, s), 7.6 - 8.1 (SH, br). Ejeaplo 51 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (14H, m), 1.33 (9H, s), 2.42 (2H, q), 2.46 (2H, q), 2.7 - 3.1 (4H, rp ), 3.41 (ZH, t), 3.56 (ZH, t), 7.6 - 8.1 (SH, br). Eg «celery5 ?: 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (16H, m), 1.33 (9H, s), S.4S (ZH, q), S.46 (ZH, q), S.7 - 3.1 (4H, m), 3.41 (ZH, t), 3.56 (ZH, t), 7.6 - 8.1 (ZH, br). Ejepío 53: 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (18H, m), 1.33 (9H, s), S.4S (ZH, q), Z.46 (ZH, q), S. 7 - 3.1 (4H, m), 3.41 (ZH, t), 3.56 (ZH, t), 7.6 - 8.1 (ZH, br). Bjengio 54 • 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (SOH, m), 1.33 (9H, s), S.4S (ZH, q), S.46 (ZH, q), S. 7 - 3.1 (4H, m), 3.41 (ZH, t), 3.56 (ZH, t), 7.6 - 8.1 (ZH, br). Bjeaplo 55: 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (S? H, ra), 1.33 (9H, s), S.4S (ZH, q), S.46 (ZH, q), S.7 - 3.1 (4H, ra), 3.41 (ZH, t), 3.56 (ZH, t), 7.6 - 8.1 (ZH, br). gjenpio 56: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (8H, m), 1.33 (9H, s), S.50 - 3.10 (4H, ra), 3.3S (ZH, t), 3.45 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (ZH, br). Éjeapio 57: 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (10H, rp), 1.33 (9H, s), S.50 - 3.10 (4H, ra), 3.3S (ZH, t), 3.45 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (ZH, br). Example 58: 0.7-1.1 (3H, br-t), 1.0-1.7 (1ZH, m), 1.33 (9H, s), S.50-3.10 (4H, ra), 3.3S (ZH, t), 3.45 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (ZH, br). Bjeaplo 59: 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (14H, ra), 1.33 (9H, s), Z.50 - 3.10 (4H, ra), 3.3S (ZH, t), 3.45 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (ZH, br). Eje-c io 60: 0.7 - 1.1 (3H, br-t), 1.0 - 1.7 (16H, m), 1.33 (9H, s), S.50 - 3.10 (4H, m), 3.3S (SH, t ), 3.45 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.6 - 8.1 (ZH, br). Example 61: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (8H, m), 1.33 (9H, s), S.14 (3H, s), S.22 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (ZH, t), 4.6Z (ZH, s), 6.86 (ZH, br). Example 62; 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (10H, m), 1.33 (9H, s), S.14 (3H, s), 2.22 (3H, s), 2.70 - 3.10 (4H, m ), 3.41 (ZH, t), 4.6Z (ZH, s), 6.86 (ZH, br). Ejajpio63: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (14H, ra), 1.33 (9H, s), S.14 (3H, s), S.SS (3H, s), 2.70 - 3.10 (4H, m), 3.41 (ZH, t), 4.6S (ZH, s), 6.86 (ZH, br). Ejeaplo 64: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (16H, m), 1.33 (9H, s), 2.14 (3H, s), 2.SS (3H, s), 2.70 - 3.10 ( 4H, m), 3.41 (ZH, t), 4.6S (ZH, s), 6.86 (ZH, br). Ejeaplo 65: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (8H, m), 1.33 (9H, s), S.00 (6H, s), S.09 (3H, s), S. S3 (3H, s), S.70 - 3.S0 (4H, rn), 3.31 (ZH, s), 3.38 (SH, t), 6.84 (1H, br). Ejeapio 66: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (10H, m), 1.33 (9H, s), S.00 (6H, s), S.09 (3H, s), S. S3 (3H, s), S.70 - 3.S0 (4H, rp), 3.31 (ZH, s), 3.38 (ZH, t), 6.84 (1H, br). Ejapio 67: 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (14H, rn), 1.33 (9H, s), Z.00 (6H, s), S.09 (3H, s), S. S3 (3H, s), S.70 - 3.20 (4H, na), 3.31 (ZH, s), 3.38 (ZH, t), 6.84 (ÍH, br). Example 68; 0.7 - 1.1 (3H, br-t), 1.1 - 1.7 (16H, m), 1.33 (9H, s), S.00 (6H, s), 2.09 (3H, s), 2.S3 (3H, s) ), S.70 - 3.S0 (4H, rn), 3.31 (ZH, s), 3.38 (ZH, t), 6.84 (ÍH, br). Bjcapio 69: 0.7 - 1.0 (3H, br), 1.0 - 1.7 (8H, m), 1.33 (9H, s), 1.97 (3H, s), S.7 - 3.1 (4H, m), 3.35 (ZH, t), 3.47 (ZH, s), 6.90 (1H, s), 7.6 - 8.1 (ZH, br). Ejapio 70: 0.7 - 1.0 (3H, br), 1.0 - 1.7 (10H, ra), 1.33 (9H, s), 1.97 (3H, s), S.7 - 3.1 (4H, m), 3.35 (SH, t), 3.47 (ZH, s), 6.90 (1H, s), 7.6 - 8.1 (ZH, br). Ejapio 71: 0.7 - 1.0 (3H, br), 1.0 - 1.7 (1ZH, m), 1.33 (9H, s), 1.97 (3H, s), S.7 - 3.1 (4H, m), 3.35 (ZH, t), 3.47 (ZH, s), 6.90 (1H, s), 7.6 - 8.1 (ZH, br). Ejapio 72: 0.7 - 1.0 (3H, br), 1.0 - 1.7 (14H, m), 1.33 (9H, s), 1.97 (3H, s), S.7 - 3.1 (4H, ra), 3.35 (ZH, t), 3.47 (ZH, s), 6.90 (1H, s), 7.6 - 8.1 (ZH, br). Ax-gao 73: 0.7 - 1.0 (3H, br), 1.0 - 1.7 (16H, m), 1.33 (9H, s), 1.97 (3H, s), S.7 - 3.1 (4H, m), 3.35 ( ZH, t), 3.47 (ZH, s), 6.90 (1H, s), 7.6 - 8.1 (ZH, br). Ejeaplo 74: 0.7 - 1.0 (3H, br), 1.0 - 1.7 (8H, ra), 1.33 (9H, s), Z.07 (3H, s), S.89 (ZH, t), 3.09 (ZH, t), 3.40 (ZH, t), 4.51 (ZH, s), 6.90 (1H, s), 7.0 - 7.4 (ZH, br). Ejaplo 75 0.7 - 1.0 (3H, br), 1.0 - 1.7 (10H, tu), 1.33 (9H, s)., Z.07 (3H, s), S.89 (ZH, t), 3.09 (ZH, t), 3.40 (? H, t), 4.51 (ZH, s), 6.90 OH, s), 7.0 - 7.4 (ZH, br). Ejeaplo 76 0.7 - 1.0 (3H, br), 1.0 - 1.7 O? H, m), 1.33 (9H, s), S.07 (3H, s), S.89 (ZH, t), 3.09 (ZH, t), 3.40 (ZH, t), 4.51 (ZH, s), 6.90 (1H, s), 7.0 - 7.4 (ZH, br). Ejaplo 77 0.7 - 1.0 (3H, br), 1.0 - 1.7 (14H, m), 1.33 (9H, s), S.07 (3H, s), S.89 (ZH, t), 3.09 (ZH, t ), 3.40 (ZH, t), 4.51 (ZH, s), 6.90 OH, s), 7.0 - 7.4 (ZH, br). Ejeaplo 78 0.7 - 1.0 (3H, br), 1.0 - 1.7 (16H, m), 1.33 (9H, s), S.07 (3H, s), S.89 (ZH, t), 3.09 (ZH, t ), 3.40 (SH, t), 4.51 (ZH, s), 6.90 OH, s), 7.0 - 7.4 (ZH, br). Ejeaplo 79 0.7 - 1.0 (3H, br), 1.0 - 1.7 (8H, m), 1.33 (9H, s), S.08 (3H, s), S.S3 (6H, s), S.89 (ZH , t), 3.14 (ZH, t), 3.30 (ZH, s), 3.38 (ZH, t), 6.84 (1H, s), 6.90 (1H, br).

.Example 80 0.7 - 1.0 (3H, br), 1.0 - 1.7 OOH, ra), 1.33 (9H, s), Z.08 (3H, s), Z.S3 (6H, s), S.89 (ZH , t), 3.14 (ZH, t), 3.30 (ZH, s), 3.38 (ZH, t), 6.84 (1H, s), 6.90 (1H, br).

Example 81 0.7 - 1.0 (3H, br), 1.0 - 1.7 (1ZH, m), 1.33 (9H, s), S.08 (3H, s), S.S3 (6H, s), S.89 (ZH , t), 3.14 (ZH, t), 3.30 (ZH, s), 3.38 (ZH, t), 6.84 (1H, s), 6.90 (1H, br).

Axle 8Z 0.7 - 1.0 (3H, br), 1.0 - 1.7 (14H, m), 1.33 (9H, s), S.08 (3H, s), Z.Z3 (6H, s), Z.89 (ZH , t), 3.14 (ZH, t), 3.30 (ZH, s), 3.38 (ZH, t), 6.84 (1H, s), 6.90 (1H, br).

Ejeaplo 83 0.7 - 1.0 (3H, br), 1.0 - 1.7 06H, rn), 1.33 (9H, s), 2.08 (3H, s), 2.S3 (6H, s), 2.89 (ZH, t), 3.14 (ZH, t), 3.30 (2H, s), 3.38 (ZH, t), 6.84 (1H, s), 6.90 (1H, br).

Ejeapio 84: 0.7 - 1.0 (3H, br-t), 1.00 - 1.60 (8H, m), 1.38 (9H, s), 1.60 - S.SO (ZH, m), S.07 (3H, s), 2.16 (3H, s), S.SO - S.40 (ZH, m), 3.10 - 3.80 (3H, ra), 3.S7 (ZH, br-t), 6.45 (1H, s), 7.Z0 - 7.60 (ZH, br). Ejeaplo 85: 0.7 - 1.0 (3H, br-t), 1.00 - 1.60 (10H, m), 1.38 (9H, s), 1.60 - S.S0 (ZH, m), S.07 (3H, s), S.16 (3H, s), S.SO - S.40 (ZH, m), 3.10 - 3.80 (3H, rn), 3.S7 (ZH, br-t), 6.45 (1H, s), 7 .S0 - 7.60 (ZH, br). Example 86.0.7 - 1.0 (3H, br-t), 1.0 - ZO (10H, rn), 1.33 (9H, s), Z.07 (3H, s), S.16 (3H, s), 2.60 - 3.60 (TH, ra), 6.44 (1H, s), 6.78 (ZH, br). Example 87: 0.7-1.0 (3H, br-t), 1.0-SO (1ZH, m), 1.33 (9H, s), S.07 (3H, s), S.16 (3H, s), Z. 60-3.60 (TH, m), 6.44 (1H, s), 6.78 (ZH, br). Ejeapio 88: 0.7 - 1.0 (3H, br-t), 1.0 - ZO (10H, m), 1.35 (9H, s), S.07 (3H, s), S.16 (3H, s), 2.19 ( 6H, s), 2.21 (ZH, t), S.6 - 3.6 (5H, m), 6.45 OH, s), 7.Z (1H, br). Example 89: 0.7 - 1.0 (3H, br-t), 1.0 - SO (1SH, rn), 1.35 (9H, s), S.07 (3H, s), 2.16 (3H, s), 2.19 (6H, s), 2.21 (ZH, t), S.6 - 3.6 (5H, m), 6.45 OH, s), 7.S (1H, br). Ejapium 90: 0.7 - 1.0 (3H, br-t), 1.0 - SO (14H, ra), 1.35 (9H, s), S.07 (3H, s), S.16 (3H, s), S. 19 (6H, s), S.S1 (ZH, t), S.6-6.6 (5H, m), 6.45 OH, s), 7.S (1H, br). Example 91: 0.70 - 1.10 (6H, m), 1.10 - 1.90 (16H, m), 2.10 (6H, s), 1.80 - 2.00 (ZH, br-t), S.00 - 4.00 (6H, rn), 3.55 (ZH, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Example 9Z: 0.70 - 1.10 (6H, ra), 1.10 - 1.90 (18H, m), 2.10 (6H, s), 1.80 - 2.00 (2H, br-t), S.00 - 4.00 (6H, m), 3.55 (ZH, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Example 93: 0.70 - 1.10 (6H, ra), 1.10 - 1.90 (SOH, m), S.10 (6H, s), 1.80 - 2.00 (2H, br-t), 2.00-4.00 (6H, m), 3.55 (2H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Ejeaplo 94: 0.70 - 1.10 (6H, m), 1.10 - 1.90 (2SH, m), S.09 (4H, br-t), 1.80 - S.00 (SH, br-t), S.00 - 4.00 (6H, m), 3.55 (SH, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Bjapio 95: 0.70 - 1.10 (6H, m), 1.10 - 1.90 (S4H, ra), 2.09 (4H, br-t), 1.80 - 2.00 (SH, br-t), 2.00 - 4.00 (6H, m), 3.55 (SH, s), 4.80 (1H, br), 5.50 OH, br), 6.40 (1H, br). Example 96; 0.70 - 1.10 (6H, m), 1.10 - 1.90 (26H, ra), 2.09 (4H, br-t), 1.80 - S.00 (SH, br-t), S.00 - 4.00 (6H, m) , 3.55 (SH, s), 4.80 (1H, br), 5.50 OH, br), 6.40 (1H, br). Ejeaplo 97: 0.70 - 1.10 (6H, ra), 1.10 - 1.90 (16H, m), 1.80 - S.00 (SH, br-t), S.00 - 4.00 (6H, rp), 3.35 (SH, s ), 3.74 (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Example 98: 0.70 - 1.10 (6H, ra), 1.10 - 1.90 (18H, ra), 1.80 - S.OO (SH, br-t), S.00 - 4.00 (6H, ra), 3.35 (SH, s ), 3.74 (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Ejeaplo 99: 0.70 - 1.10 (6H, m), 1.10 - 1.90 (SOH, m), 1.80 - S.00 (SH, br-t), S.00 - 4.00 (6H, ra), 3.35 (SH, s ), 3.74 (3H, s), 3.78 (3H, s), 4.80 (1H, br), 5.50 (1H, br), 6.40 (1H, br). Example 100: 0.70-1.10 (3H, br-t), 1.10-1.70 (14H, m), 1.33 (9H, s), S.10 (3H, s), S.39 (3H, s), 3.71 ( SH, br), 3.99 (SH, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 (1H, d). Example] Q.0.70 - uo (3H, br-t), 1.10 - 1.70 (10H, m), 1.33 (9H, s), 2.10 (3H, s), 2.39 (3H, s), 3.71 (SH, br ), 3.99 (ZH, br-t), 4.15 (SH, s), 6.38 (1H, d), 6.89 OH, d). Bjeaplo 102: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (18H, m), 1.33 (9H, s), 2.08 (SH, q), S.46 (? H, q), 3.71 (2H , br), 3.99 (? H, br-t), 4.15 (SH, s), 6.38 (1H, d), 6.89 (1H, d).

Bjeapo 103: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (20H, m), 1.33 (9H, s), S.08 (SH, q),? .46 (2H, q), 3.71 ( 2H, br), 3.99 (SH, br-t), 4.15 (? H, s), 6.38 (1H, d), 6.89 OH, d).

Example 104: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (SSH, m), 1.33 (9H, s), S.4S (SH, q), S.46 (SH, q), 3.71 ( SH, br), 3.99 (SH, br-t), 4.15 (2H, s), 6.38 (1H, d), 6.89 OH, d).

Ejeapio 105: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (12H, m), 1.33 (9H, s), 3.60 (3H, s), 3.65 (3H, s), 3.71 (SH, br) , 3.99 (SH, br-t), 4.15 (? H, s), 6.15 OH, d), 6.70 (1H, d).

Ejecta 1Q6: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (14H, m), 1.33 (9H, s), 3.60 (3H, s), 3.65 (3H, s), 3.71 (SH, br) , 3.99 (2H, br-t), 4.15 (? H, s), 6.15 OH, d), 6.70 (1H, d).

Axis celery 1Q7: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (16H, m) r 1.33 (9H, s), 3.60 (3H, s), 3.65 (3H, s), 3.71 (2H, br), 3.99 (SH, br-t), 4.15 (? H, s), 6.15 OH, d), 6.70 (1H, d).

Bjeapio 1Q8: 0.70 - 1.10 (3H, br-t), 1.10 - S.00 (15H, rn), S.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H , m), 3.37 (3H, s), 3.40 (SH, t), 3.41 (SH, t), 3.56 (SH, s), 7.60 - 8.10 (2H, br). Example 109: 0.70 - 1.10 (3H, br-t), 1.10 - 2.00 (15H, m), 2.01 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.45 (SH, s) , S.70 - 3.10 (4H, rn), 3.41 (2H, t), 3.56 (SH, s), 7.60 - 8.10 (SH, br). Bjeapio 110: 0.70 - 1.10 (3H, br-t), 1.10 - S.OO (S3H, ra), 2.01 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (? H, t), 3.56 (SH, s), 7.60 - 8.10 (SH, br). Bjeapio n .0.70 - 1.10 (3H, br-t), 1.10 - S.00 (S5H, m), S.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, m), 3.41 (SH, t), 3.56 (SH, s), 7.60 - 8.10 (SH, br). Axis 112; 0.70 - 1.10 (3H, br ~ t), 1.10 - 1.70 (1SH, m), S.01 (3H, s), S.15 (3H, s), S.70 - 3.10 (4H, m), 3.41 (SH, t), 3.56 (SH, s), 7.30 - 7.80 (3H, m), 7.60 - 8.10 (2H, br), 8.12 (SH, d).

Eieapio H3: 0.70 - 1.10 (3H, br-t), 1.10 - 1.70 (12H, m), 2.01 (3H, s), 2.15 (3H, s), 2.70 - 3.10 (4H, ra), 3.41 (2H, t), 3.53 (2H, s), 3.56 (2H, s), 7.30 (5H, s), 7.60 - 8.10 (2H, br). Ejeaplo 114: 1.59 (3H, br-t), 1.10 - 1.70 (4H, ra), 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 2.10 - 2.50 (4H, rp) , 2.70 - 3.10 (4H, m), 3.41 (2H, t), 3.56 (2H, s), 7.60 - 8.10 (ZH, br). Example 115: 1.33 (9H, s), 2.01 (3H, s), 2.15 (3H, s), 3.02 (2H, t), 3.41 (2H, t), 3.56 (ZH, s), 4.30 (ZH, s) ), 7.30 (5H, s) 7.60 - 8.10 (ZH, br). Example 116: 0.70 - 1.10 (3H, br-t), 1.10 - 1.60 (15H, ra), 1.34 (9H, s), 2.02 (3H, s), 2.90 (ZH, t), 3.13 (ZH, t) , 3.38 (ZH, t), 3.50 (ZH, s), 4.1S (SH, q), 6.80 (1H, br), 6.85 (1H, s). Axis 117: 0.70 - 1.10 (3H, br-t), 1.10 - S.00 (8H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70 - 3.10 ( 4H, m), 3.39 (2H, t), 3.35 (ZH, s), 6.60-7.50 (ZH, br). Bjeaplo 118; 0.70 - 1.10 (3H, br-t), 1.10 - 2.00 (12H, ra), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70 - 3.10 (4H, m), 3.39 (2H, t), 3.35 (2H, s), 6.60-7.50 (ZH, br). Example 119: 0.70 - 1.10 (3H, br-t), 1.10 - 2.00 (16H, m), 1.23 (9H, s), 2.07 (3H, s), 2.24 (3H, s), 2.70 - 3.10 (4H, ra), 3.39 (ZH, t), 3.35 (ZH, s), 6.60 - 7.50 (ZH, br).

EXAMPLE 120 N- (l-Octyl-5-cartyl> oxyethyl-4,6-dimethylindolin-7-yl) -2. 2- dimethyl propanamide (1) N- (1-octyl-5-chloroethyl-4,6-dimethylindolin-7-yl) -2,2-dimethyl-propanamide (3.0 g) was dissolved in CH 3 CN (30 ml), and NaCH ( 3.7 g) and 18-crown-6 (0.1 g), which was followed by reflux for 17 hours under nitrogen atmosphere. The CH3CN was evaporated under reduced pressure and water (100 ml) was added to the obtained residue. The mixture was extracted twice with AcOEt (100 ml). The AcOEt layer was washed with sterile saline (100 ml) and dried over anhydrous sodium sulfate and the AcOEt was evaporated under reduced pressure. The residue obtained was purified by chromatography on a column of silica gel (eluent: AcOEt / benzene = 1 / 10-15) to give 1.14 g of N- (1-octyl-5-cyanoethyl-4,6-dimethylindolin-7) il) -2, 2-dimethyl lpropanamide. IR (Nujol) cm-i: 2243, 1647, 1601. H-NMR (CDCI3) d: 0.88 (3H, br-t, J = 6.0Hz. - (CH2) 7CH2L), 1.10 * 1.90 (12H, m, -CH2 (J2_l £ CH3), 1.33 (9H, s, -C (CH3) 3), 2.05, 2.15 (3HX2, sX2, indoline C4.6 -CH3), 2.38 (2H, t, J = 7Hz, -CH2CN ), 2.70 * 3.30 (6H, m, indoline C3-H2 >; NCH2-, -CH2CH2CH). 3.41 (2H, t, J = 9Hz, indoline C2-H2), 6.81 (ÍH, br, -CONH-). (2) N- (l-octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl) -2,2-dimethyl-propanamide (1.14 g) was dissolved in EtOH (26 ml), and added a solution of NaOH (1.1 g) in water (7.5 ml), which was followed by reflux for 14 hours under a nitrogen atmosphere. The EtOH was evaporated at reduced pressure. The residue obtained was dissolved in moderately hot water (30 ml) and washed with AcOEt (30 ml). The aqueous layer was neutralized with 2 H HCl and extracted with CHCl 3 (50 mL). The CHCl3 layer was evaporated under reduced pressure to give 830 mg of the title compound. IR (Nujol) cm-i: 1724, 1655, 1618. H-NMR (CDCI3) d: 0.86 (3H, br-t, J = 5.0Hz, - (CH2) 7CHs_), 1.10 * 2.10 (12H, m, - CH2 H2JJ6.CH3), 1-42 (9H, s, -C (CH3) 3), 2.12, 2.26 (3HX2, sX2, indoline, e -CH3), 2.30 * 2.60 (2H, m, -CH2CO2-) , 2.90 * 3.40 (6H, m, indoline C3-H2, > NCH2-, -CH2CH2CO2-), 3.78 (H, br, indoline C2-H 2), 7.70 (H, br -C02H), 9.91 (H, br , -C0NH-).

EXAMPLES 121-123 The compounds of Table 10 were obtained according to the method of Example 120 above.

TABLE 10 -NHCOR7 The H-NMR values of compounds of Examples 121-123 above are shown below.

EXAMPLE 121 (3H, br-t), 1.00 * 1.80 (12H, m), 1.37 (9H, s), (3H, s), 2.06 (3H, s), 2.47 (4H, br-t), (4H, s) ), 3.30 * 3.90 (4H, m), 8.60 * 9.90 (2H, br).

EXAMPLE 122 0. 90 (3H, br-t), 1.00 * 1.80 (6H, m), 2.08 (3H, s), 2.21 (3H, s), 2.48 (4H, br-t), 2.90 * 3.40 (4H, m), 3.40 * 3.80 (2H, m), 3.61 (2H, s), 7.34 (HH, br), 8.48 (HH, br).

EXAMPLE 123 0. 86 (3H, br-t), 1.00 * 1.50 (12H, m), 1.42 (9H, s), 2.00 * 2.90 (6H, m), 2.11 (3H, s), 2.23 (3H, s), 2.90 * 3.30 (4H, m), 3.70 (2H, br), 6.10 (1H, br), 9.21 (1H, br).

EXAMPLE 124 H- (1-Octyl-6-ethoxycarbonylmethyl-5,7-dimethyl 1-1.2.3-4-tetrahydroquinolin-8-yl) -2. 2-dimethyl lpropanamide (1) 3,5-xylidine (5.0 g) was dissolved and ac rilonit ri lo (2.3 g) in acetic acid (2 ml) and the mixture was stirred at 60 ° C for 20 hours. Ethyl acetate (220 ml) was added to the reaction mixture and it was neutralized with saturated aqueous sodium hydrogen carbonate solution. The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate / benzene = 1/10-l / 3) to give 4.5 g of ß- (3,5-dimethyl-anilino) propionitrile oily. IR (Nujol) cm-l; 2248, 1602. i H-NMR (CDCI3) d: 2.24 (6H, S, C3.5 -CH3), 2.60 (2H, t, J = 7.5Hz, -CH2CH2CN), 3.48 (2H, t, J = 7.5 Hz, -CH2CH2CN), 3.90 (HH, br, > NH, 6.24 (2H, e, C2.6-H), 6.43 (HH, 8, C4-H). (2) It was dissolved &-( 3 , 5-dimethylanilino) propionitrile (4.5 g) in ethanol (50 ml), and a solution of NaOH was added (5.1 g) in water (25 ml), which was followed by reflux for 4 hours. The solvent was evaporated under reduced pressure. Hydrochloric acid was added at 2 H to adjust the residue to acid and the mixture was washed with chloroform (100 ml). The aqueous layer was concentrated to approximately 20 ml and allowed to stand. The precipitated crystals were collected by filtration and dried to give 4.0 g of acid (J- (3,5-dimethylanilino) propionic) IR (Nujol) cm-1560. H-NMR (DMSO-de) d: 2.29 (6H, s, C3.5-CH3), 2.7 ml and allowed to stand, the precipitated crystals were collected by filtration and dried to give 4.0 g of β- (3,5-dimethylanilino) propionic acid. Nujol) cm-l; 1500. 2.29 (6H, s, C3.5 -CH3), 2.73 (2H, t, J = 7.5HZ, -CH2CH2CO-), 3. 44 (2h, T, j = 7.5hZ, -CH2CH2CO-), 7.0 (3H, s, C2.4.6-H), 9.80 (2H, br, -CO2H, > NH). (3) β- (3,5-dimethylanilino) propionic acid (1.2 g) was added portionwise to sulfuric acid (60 β C, 12 ml) and the mixture was stirred at the same temperature for 0.5 hour. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate / benzene = 1/5-l / l) to give 750 mg of ,7-dimethylquinolone as crystals. IR (Nujol) cm-l; 1645, 1614. 1 H-NMR (CDCl 3) d; 2.19 (3H, s, C5-CH3), 2.57 (3H, s, C -CH3), 2.63 (2H, t, J = 7.5Hz, C3-H2), 3.49 (2H, t, J = 7.5Hz, C2 -H2), 4.39 (ÍH, br, > NH), 6.32 (2H, S, Cß.β-H). (4) Lithium aluminum hydride hydride (687 mg) was suspended in ether (16 ml), and aluminum chloride (4.2 g) was added. A solution of 5,7-dimethylquinolone (1.6 g) in ether (16 ml) was added dropwise and the mixture was refluxed for 0.5 hour. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The 5,7-dimethyl-l, 2,3,4-tetrahydroquinoline was dissolved in chloroform (30 ml) and acetic anhydride (929 mg) was added, which was followed by stirring at room temperature for 1 hour. Chloroform (100 ml) was added to the reaction mixture and the mixture was washed successively with saturated aqueous solution of acid carbonate in eodium and water and anhydrous sodium sulfate was added. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate / benzene = 1/5 - 1/1) to give 1.5 g of l-acetyl-5, 7-dimethyl-l, 2,3,4-tetrahydroquinoline oily. IR (Nujol) cm-l; ? 625, 1614. H-NMR (CDCI3) d; 1.70-2.10 (2H, m, C3-H-2), 2.21 (6H, sX2, -COCH3, Ar-CH3), 2.29 (3H, s, Ar-CH3), 2.54 (2H, t, J = 7.1Hz , C -H2), 3.77 (2H, t, J = 7.1Hz, C2-H2), 6.83 (2H, S, C6.8 ~ H). (5) l-Acetyl-5,7-dimethyl-1,2,3-tetrahydroquinoline (3.0 g) was dissolved in concentrated hydrochloric acid (6 ml), and 35% formaldehyde solution (2.5 g) and chloride were added. of zinc (400 ml). The mixture was stirred at 40-50 ° C for 2 hours while blowing hydrogen chloride. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained l-acetyl-6-chloromethyl-5,7-dimethyl-1,2,3-tetrahydroquinoline was dissolved in acetonitrile (30 ml), and sodium cyanide (3.6 g) was added and 18-crown-6 (780 mg), which was followed by reflux for 5 hours. The solvent was evaporated under reduced pressure and the residue extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform-chloroform / methanol = 10/1) to give 2.4 g of l-acetyl-6-cyanomethyl-1-5, 7-dimethyl-l, 2,3,4-tetrahydroquinoline oily. IR (Nujol) cm-l; 2248, 1650. 1 H-NMR (CDCl 3) d; 1.80-2.20 (2H, m, C3-H2), 2.21, 2.29 (3H X2, sX2, CS.7-CH3), 2.37 (3H, s, -COCH3), 2.68 (2H, t, J = 7.5Hz , C4-H2), 3.66 (2H, S, -CH2CN), 3.76 (2H, t, J = 7.5Hz, C2H2), 7.00 (IH, s, Cs-H). (6) l-Acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline (2.7 g) was dissolved in ethanol (30 ml), and a solution of NaOH (4.4 g) was added. in water (10 ml), which was followed by reflux for 10 hours under nitrogen. The solvent was evaporated under reduced pressure and the residue extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The 6-carbamoylmethyl-5,7-dimethyl-l, 2,3,4-tetrahydroquinoline obtained in N, N-dimethylformamide (10 ml) was dissolved, and octyl bromide (1.6 g), potassium carbonate (1.2 g) was added. g) and potassium iodide (166 mg), which was followed by stirring at 49 ° C for 10 hours under nitrogen. The reaction mixture was extracted with ethyl acetate (100 ml). After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (31: roformo / methanol = 50 / 1-10 / 1) to give 600 mg of l-octyl-16-carbamoylmethyl-5,7-dimethyl-1,2. , 3,4-tetrahydroquinoline as crystals. IR (Nujol) cm-l; 1654, 1624. l H-NMR (CDCl 3) d; 0.60-1.10 (3H, br-t, - (CH2) 7CH3), 1.10-1.80 (12H, m, - (CH2) 6CH3), 1.80-2.10 (2H, m, C3-H2), 2.16, 2.24 (3HX2 , sX2, C5.7-CH3), 2. 63 (2H, t, J = 7.5Hz, C4-H2), 3.00-3.50 (4H, m, C2H2, > NCH2), 3.57 (2h; s, -CH2CO-), 3.44 (2H, br, -CONH2 ), 6.35 (ÍH, s, Cß- H). (7) l-Octyl-6-carbamoylmethyl-5,7-dimethyl-l, 2,3,4-tetrahydroquinoline (2.5 g) was dissolved in n-propanol (50 ml) and a solution of NaOH (3.0 g) was added. ) in water (30 ml), which was followed by stirring at 130 ° C for 20 hours under nitrogen. The organic layer was separated from the reaction mixture and the solvent was evaporated under reduced pressure. The residue was dissolved in water (300 ml) and washed with ethyl acetate (100 ml). The aqueous layer was adjusted to pH 1-2 with 6N hydrochloric acid and extracted with chloroform (200 ml). The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 1-octyl-6-carboxymethyl-1, 5, 7-dimethyl-1,2,4-tetrahydroquinoline was dissolved in ethanol (50 ml) and concentrated hydrochloric acid (4 ml) was added, which was followed by stirring at 70 ° C for 1 hour. The solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: benzene) to give 1.0 g of oily-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,3, -ethohydrous rahydroquinoline. IR (Nujol) cm-l; 1732, 1599. 1 H-NMR (CDCl 3) d; 0.70-1.00 (3H, br-t, - (CH2) 7CH3), 1.10-1.80 (15H, m, -CH2) ßCH3, -COCH2CH3), 1.80-2.10 (2H, m, C3-H2), 2.12, 2.26 (3HX2, SX2, CS.7-CH3), 2.62 (2H, t, J = 7.5Hz, -H2), 3.00-3.30 (4H, m, C2-H2, > NCH2 ~), 3.59 (2H, s , -CH2CO-), 4.13 (2H- q- J = 7.0Hz, -COCH2-), 6.33 (ÍH, s, C * - «). (8) l-Octyl-6-ethoxycalbonylmethyl-5,7,7-dimethyl-1,2,3,4-tetrahydroquinoline (1.0 g) was dissolved in acetic anhydride (5 ml) and a solution was added dropwise. of 70% anhydrous acid (517 mg) in acetic anhydrous (3 ml), which was followed by stirring at the same temperature for 0.5 hour.

The reaction mixture was poured into ice water (50 ml), neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform (50 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane-ethyl acetate / n-hexane = 1/5) to give 700 mg of l-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl- 8-nitro-l, 2,3,4-tetahydroquinoline oily. IR (Nujol) cm-l; 1732, 1527. H-NMR (CDCl 3) d; 0.70-1.00 (3H, br-t, - (CH2 H3), 1.10-1.70 (15H, m, - (CH2) ECH3, -COCH2CH3), 1.80-2.10 (2H, m, C3-H2), 2.16 (6H , s, Cs. -CH3), 2.64 (2H, t, J = 7.5 Hz, C4-H2), 2.70-3.20 84H, m, C2-H2, > NCH2-), 3.65 (2H, s, -CH2CO -), 4.13 (2H, q, J = 7.0 Hz, -COCH2-). (9) l-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-nitro-l, 2,3,4-tetrahydroquinoline (700 mg) was dissolved in ethanol (500 ml) and palladium-carbon was added. to 10% (200 mg). The mixture was subjected to hydrogenation at room temperature and at atmospheric pressure. The 10% palladium-carbon was filtered off and the solvent was evaporated under reduced pressure. The 1-octylated 1-6-ethoxycarbonylmethyl 1-5,7-dimethyl-8-ami no-1, 2,3,4-tet rahydroquinoline obtained in chloroform (50 ml) was dissolved. Pivaloyl chloride (207 mg) and triethylamine (192 mg) were added under cooling with ice and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed successively with 5% aqueous citric acid and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform-chloroform / methanol = 10/1) to give 230 mg of the title compound. IR (Nujol) cm-l; 1732, 1483. H-NMR (CDCl 3) d; 0.70-1.00 (3H, br-t, - (CH) 7CH3), 1.10-1.70 (15H, m, -. (CH2) 6CH3 -COCH2CH3), 1.35 (9H, s, -C (CH3), 1.80-2.10 (2H, m, C3-H2), 2.05, 2.11 (3Hx2, ex2, C5.7 -CH3), 2.40.2.70 (4H, m, C4-H2, > NCH2 ~), 2.80-2.90 (2H, m , C2-H2), 3.68 (2H, s, -CH2CO-), 4.14 (2H, q, J = 7.0 Hz, -COCH2-), 7.35 (H, br, -COCH-).

EXAMPLE 125 N- (l-Octyl-6-carboxymethyl-5,7-dimethyl-l.2.3. -tetrahydroquinolin-8-i1) -2,2-dimethylpropanamide N- (l-octyl-6-ethoxycarbonylmethyl-5,7-dimeti1-1, 2, 3, 4-tetrahydroquinolin-8-yl) -2,2-dimethylpropanamide (230 mg) was dissolved and a solution of NaOH was added (100 mg) in water (2 ml), which was followed by stirring at 50 ° C for one hour. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (50 ml) and washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 1-2 with 2N sulfuric acid and extracted with chloroform. The chloroform layer was dried over anhydrous chloro sulfate. The solvent was evaporated under reduced pressure to give 130 mg of the title compound powder. TLC; Silica gel 60F254 Art. 5714 (Merck), CHCl3-Me0H (10: 1), Rf value 0.5 IR (Nujol) cm-i; 1732, 1722. 1 H-NMR (CDCl 3) d; 0.70-1.00 (3H, br-t, - (CH2) 7CH3), 1.10-1.70 (12H, m, - CH2I £ CH3), 1.35 (9H, S, -C (CH3) 3), 1.80-2.10 (2H , m, C3-H2), 2.10, (6H, s, C5.7 -CH3), 2.40.2.70 (4H, m, O. -H, > NCH2-), 2. 80-2.90 (2H, m, C2 -H2), 3.68 (2H, s, -CH2CO-), 7.35 (H, br, -CONH-), 9.50 (2H, br, I / 2H2SO4, -CO2H-).

EXAMPLES 126-154 The compounds of tables 11 and 12 were obtained according to the method of example 124 above.

I cause 11 R4 = -NHCOR7 CDAERO 12 -NHCOR7 The values of 1H-BMN of the coapuesto of the previous 126-154 Axis are shown below. Example 126: 0.70-1.00 (3H, br-t), 1.10-1.70 (8H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 OH, br), 9.50 (2H, br). Example 127: 0.70-1.00 (6H, br-t), 1.10-1.70 (5H, ra), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (2H, ra), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br). Example 128: 0.70-1.00 (3H, br-t), 1.10-1.70 (10H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (2H, m), 3.68 (ZH, s), 7.35 (1H, br), 9.50 (SH, br). Example 129: 0.80-1.70 (11H, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (2H, ra), 3.68 (2H, s), 7. 35 OH, br), 9.50 (2H, br). Ejenplo 130. 0.70-1.00 (6H, br-t), 1.10-1.70 (TH, m), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.T0 (4H , ra), 2.80-2.90 (2H, m), 3.68 (2H, s), 7.35 (1H, br), 9.50 (2H, br).

Ejaplo 131: 0.70-1.10 (3H, br-t), 1.10-1.70 (4H, ra), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (2H, ra), 3.30-3.60 (4H, ra), 3.68 (2H, s), 7.35 OH, br), 9.50 (2H, br). Example 132: 0.70-1.10 (3H, br-t), 1.10-1.70 (4H, ra), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (2H, ra), 3.20-3.50 (4H, m), 3.68 (2H, s), 7.35 OH, br), 9.50 (2H, br). Ejaplo 133: 0.80-1.70 (13H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), 2.10 (6H, s), 2.40-2.70 (4H, ra), 2.80-2.90 (2H, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br). Ejeaplo 134: 0.70-1.00 (6H, br-t), 1.10-1.70 (9H, ra), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br). Example 135 0.70-1.10 (3H, br-t), 1.10-1.70 (6H, ra), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.70 (4H, m) ), 2.80-2.90 (ZH, m), 3.30-3.60 (4H, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br). Ejeaplo 136: 0.70-1.10 (3H, br-t), 1.10-1.70 (6H, ra), 1.35 (9H, s), 1.80-2.10 (2H, ra), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (ZH, m), 3.20-3.50 (4H, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br). Ejeaplo 137: 0.70-1.10 (3H, br-t), 1.10-1.70 (14H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), 2.10 (6H, s), 2.40-2.70 ( UH, m), 2.80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br).

Example 138: 0.70-1.10 (3H, br-t), 1.10-1.70 (16H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 (1H, br), 9.50 (ZH, br).

Example 139: 0.70-1.10 (3H, br-t), 1.10-1.70 (14H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), 2.40 (2H, q), 2.43 (2H, q), 2.40-2.70 (4H, m), 2. 80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br). Example] lQ. 0.70-1.10 (3H, br-t), 1.10-1.70 (18H, m), 1.35 (9H, s), 1.80-2.10 (SH, m), Z.40 (ZH, q), S.43 (ZH) , q), S.40-S.70 (4H, ra), S.80-S.90 (ZH, m), 3.68 (ZH, s), 7.35 OH, br), 9.50 (ZH, br).

Example 1 1. 0.70-1.10 (3H, br-t), 1.10-1.70 (22H, ra), 1.35 (9H, s), 1.80-2.10 (ZH, m), 2.40 (ZH, q), 2.43 (ZH, q), 2.40-2.70 (4H, m), 2. 80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 (1H, br), 9.50 (ZH, br).

Ejeaplo 142: 0.70-1.10 (3H, br-t), 1.10-1.70 (8H, o), 1.35 (9H, s), 1.80-2.10 (2H, m), 2.40-2.70 (4H, m), 2.80- 2.90 (ZH, ra), 3.52 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.35 OH, br), 9.50 (ZH, br). Ejeaplo 1 3: 0.70-1.10 (3H, br-t), 1.10-1.70 (1SH, ra), 1.35 (9H, s), 1.80-2.10 (ZH, ra), 2.40-2.70 (4H, m), 2.80 -2.90 (ZH, ra), 3.52 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.35 OH, br), 9.50 (ZH, br). Example 144; 0.70-1.10 (3H, br-t), 1.10-1.70 (16H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), S.40-S.70 (4H, m), Z .80-2.90 (ZH, ra), 3.52 (ZH, s), 3.73 (3H, s), 3.77 (3H, s), 7.35 OH, br), 9.50 (SH, br). Example 1 5: 0.70-1.10 (3H, br-t), 1.10-1.70 (8H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), S.17 (3H, s), 2.23 (3H, s), 2.40-2.70 (4H, m), 2. 80-2.90 (ZH, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (ZH, br). Example 146: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.35 (9H, s), 1.80-2.10 (ZH, m), 2.17 (3H, s), 2.23 (3H, s), 2.40-2.70 (4H, m), 2. 80-2.90 (2H, ra), 4.65 (2H, s), 7.35 OH, br), 9.50 (2H, br). Example 1 7: 0.70-1.10 (3H, br-t), 1.10-1.70 (16H, m), 1.35 (9H, s), 1.80-2.10 (2H, ra), 2.17 (3H, s), 2.23 (3H , s), 2.40-2.70 (4H, m), 2. 80-2.90 (ZH, m), 4.65 (2H, s), 7.35 (1H, br), 9.50 (2H, br). Example 148: 0.70-1.00 (6H, br-t), 1.10-1.70 (18H, ra), 1.35 (6H, s), 1.80-2.10 (ZH, ra), 2.10 (6H, s), 2.40-2.70 ( 4H, m), 2.80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 (1H, br), 9.50 (ZH, br).

Example 149: 0.70-1.00 (6H, br-t), 1.10-1.70 (22H, m), 1.35 (6H, s), 1.80-2.10 (ZH, m), 2.10 (6H, s), 2.40-2.70 ( 4H, ra), 2.80-2.90 (ZH, m), 3.68 (ZH, s), 7.35 (1H, br), 9.50 (ZH, br).

Ejenpio 150: 0.70-1.10 (3H, br-t), 1.10-2.00 (27H, ra), 2.10 (6H, s), 2.40-2.70 (4H, m), 2.80-2.90 (ZH, m), 3.68 ( 2H, s), 7.35 (1H, br), 9. 50 (ZH, br). Example 151: 0.70-1.10 (3H, br-t), 1.10-1.70 (12H, m), 1.80-2.10 (ZH, m), 2.10 (6H, s), 2.40-2.70 (4H, ra), 2.80- 2.90 (ZH, m), 3.53 (ZH, s), 3.68 (2H, s), 7.30 (5H, s), 7.35 (1H, br), 9.50 (ZH, br). Ejenplo 152: 0.70-1.10 (6H, br-t), 1.10-1.70 (1ZH, m), 1.80-2.10 (2H, m), 2.10 (6H, s), 2.40-2.90 (8H, m), 3.68 ( 2H, s), 7.35 (1H, br), 9.50 (2H, br). Ejeaplo 153: 0.70-1.10 (6H, br-t), 1.10-1.70 (16H, m), 1.80-2.10 (ZH, ra), 2.10 (6H, s), 2.40-2.90 (8H, m), 3.68 ( ZH, s), 7.35 OH, br), 9.50 (2H, br). Axis-celery 154: 0.70-1.10 (6H, br-t), 1.10-1.70 (20H, m), 1.80-2.10 (ZH, m), 2.10 (6H, s), 2.40-2.90 (8H, m), 3.68 (ZH, s), 7.35 (1H, br), 9.50 (2H, br).

EXAMPLE 155 N- (l-Octyl-5-carboxy-6-methylindolin-7-yl) -2.2.- dimethylpropanamide (1) 5-bromo-7-methyl-7-nitroindoline 83.6 g) in N, N-dimethylformamide 836 ml) and sodium hydride (677 mg) was added, which was followed by stirring at room temperature for 0.5 hour. 1-iodoctane (3.4 g) was added to the reaction mixture and the mixture was stirred at the same temperature for 24 hours. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure. The residue was purified by chromatography on a column of gel (eluent: ethyl acetate / n-hexane = 1/100 - 1/50 to give 4.0 g l-octyl-5-bromo-6-methyl-7-nitroindoline oily. (Nujol) cm-1; 1610, 1568. i H-NMR (CDCl 3) d; 0.88 (3H, br-t, J = 7 Hz, - (CH 2) 7CH 3_), 1.00 * 1.70 (12H, m, -CH 2 .

(CH2) fi-). 2.25 (3H, s, indoline Ce (CH3), 2.93 (2H, t, indoline C3-H2), 2.94, (2H, t, J = 7 Hz,> NCH2-), 3.57 (2H, t, indoline C2-H2), 7.19 (H, s, indoline C4-H). (2) l-Octyl-5-bromo-6-methyl-7-nitroindoline (4.0 g) was dissolved in N-methylpyrrolidone (40 ml) and copper cyanide (1.9 g) was added, which was followed by stirring at 1906C for 1 hour. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture. Insoluble matter was filtered off. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate / n-hexane = 1/2 -1/3) to give 2.4 g l-octyl-5-cyano-6-methyl-7-nitroindoline aceitoea. IR (Nujol) cm-i; 2214, 1620. i H-NMR (CDCl 3) d; 0.88 (3H, br-t, J = 7 Hz, - (CH2) 7CHa_), 1.00 * 1.70 (12H, m, -CH2.

(CH2) ..-). 2.38 (3H, s, indoline C6 (CH3), 3.03 (2H, t, indoline C3-H2), 3.04, (2H, t, J = 7 Hz, > NCH2 ~), 3.73 (2H, t, J = 8 Hz, indoline C2-H2), 7.15 (H, 8, indoline G4-H). (3) l-Octyl-5-cyano-6-methyl-7-nitroindoline (2.4 g) was dissolved in N-propanol and a solution of NaOH (3.0 g) in water 810 ml) was added, or which was followed by reflux for 20 hours. The n-Propanol was evaporated under reduced pressure and ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate / benzene = 1/5 - 1/1) to give 1.4 g of l-octyl-5-carboxy-6-methyl-7-nitroindoline as crystals. IR (Nujol) cm-l; 1679, 1620. 1 H NMR (CDCl 3) d; 0. 88 (3H, br-t, J = 7 Hz, - (Ota CHi), 1.00 * 1.70 (12H, m, -CHjj. (CH2) ß-) 2.47 (3H, s, indoline Ce (CH3), 3.02 (2H, t, J = 8 Hz, indoline C3-H2), 3.03, (2H, t, J = 7 Hz, > NCH2-), 3.69 (2H, t, J = 8 Hz, indoline C2-H2) , 5.00 (1H, br, indoline G? -H). (4) l-Octyl-5-carboxy-6-methyl-7-nitroindoline (1.4 g) was dissolved in methanol (30 ml) and concentrated sulfuric acid was added. (4.1 g), which was followed by reflux for 4 hours The methanol was evaporated under reduced pressure Ethyl acetate (100 mg) was added to the residue The mixture was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure The residue was purified by chromatography on a column of silica gel (eluent: chloroform / methanol = 1 / 0-10/1) to give 750 mg of l-octyl-5-methoxycarbonyl- 6-methyl-7-nitroindoline as crystals IR (Nujol) cm-l; 1679, 1620. H NMR (CDCl 3) d; 0.88 (3H, br-t, J = 7 Hz, - (CH2) 7? J3_), 1.00 * 1.70 (12H, m, -CH2. (CH2) 6 ~). 2.43 (3H, s, indoline C6 (CH3), 3.00 (2H, t, J = 8 Hz, indoline C3-H2), 3.02, (2H, t, J = 7 Hz, > NCH2-), 3.66 (2H , t, J = 8 Hz, indoline C2-H2), 3.82 (3H, s, -CO2CH3), 7.62 (OH, s, indoline G4-H). (5) l-octyl-5-methoxycarbonyl-6 was dissolved -methyl-7-nit roindoline (750 mg) in ethanol (50 ml) and 10% palladium-carbon (150 mg), which was followed by hydrogenation at 40 * c for 15 hours. The 10% palladium-carbon solution was evaporated and the ethanol evaporated under reduced pressure, chloroform (100 ml) was added to the residue, the mixture was washed with water and dried over anhydrous sodium sulfate. The l-octyl-7-amino-5-methoxycarbonyl-6-methylindoline obtained in chloroform (10 ml) was dissolved in. Pivaloyl chloride (310 mg) and triethylamine (286 mg 9 in ice-cooling were added, which was After stirring at room temperature for 1 hour, chloroform (50 ml) was added to the reaction mixture. successively with 5% aqueous citric acid and water, and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform / methanol = l / 0 - 20/1) to give 580 mg of N- (1-octyl-5-methoxycarbonyl-6-methylindoline-7-yl). ) -2, 2-Dimethyl Oily Clothesamid IR (Nujol) cm-1: 1708, 1651; 1 H NMR (CDCl 3) d; 0.87 (3H, br-t, J = 7 Hz, - (CH2) 7CHj_), 1.00 * 1.70 (12H, m, -OJ2. (CH2) 6-). 1.34 (9H, S, -C (CH3) 3), 2.39 (3H, s, indoline C6 -CH3), 2.93, (2H, t, J = 8 Hz, indoline C3 -H2), 3.25 (2H, t, J = 7 Hz, > NHC2-), 3.51 (2H, t, J = 8 Hz indoline C2-H2), 3.79 (3H, s, -CO2CH3), 6.76 (OH, br, -CONH-), 7.55 (OH, s, indoline C4-H). (6) N- (1-octyl-5-methoxycarbonyl-6-methylindol-na-7-yl) -2,2-dimethylpropanamide (580 mg) in methanol (10 ml) and a solution of NaOH (290 ml) was added. mg) in water (5 ml), which was followed by stirring at 60 ° C for 4 hours. The methanol was evaporated under reduced pressure. Water (50 ml) was added to the residue and the mixture was washed with ethyl acetate (20 ml). The aqueous layer was adjusted to pH 6-7 with 2N sulfuric acid and extracted with chloroform (100 ml). The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to give 380 mg of the title compound. IR (Nujol) cm-l; 1668, 1645, 1615. 1 H NMR (CDCl 3) d; 0.79 (3H, br, - (CH2)? CH3_), 0.80 * 1.80 (12H, m, -CH¿ (CH2) &-). 1.34 (9H, s, -C (CH3) 3), 2.38 (3H, e, indoline Ce -CH3), 2.94, (2H, t, J = 8 Hz, indoline C3 -H2), 3.27 (2H, t, J = 7 Hz, > NHC2-), 3.54 (2H, t, J = 8 Hz indoline C2-H2), 6.80 (2H, br, -CONH-, CO2H), 7.67 (OH, s, indoline O.- H).

EXAMPLES 156 - 160 The compounds of Table 13 were obtained according to the method of Example 155 above.

TABLE 13 R * = -NHCOR? The values of 1 H-NMR of the compounds of the preceding examples 156-160 are shown below.

EXAMPLE 156 0. 79 (3H, br-t), 0.80 * 1.80 (8H, m), 1.34 (9H, s), 2.38 (3H, e), 2.94 (2H, t), 3.27 (2H, t), 3.54 (2H, t), 6.80 (2H, br), 7.67 (ÍH, e).

EXAMPLE 157 0. 79 (3H, br-t), 0.80 * 1.80 (16H, m), 1.34 (9H, e), 2.38 (3H, e), 2.94 (2H, t), 3.27 (2H, t), 3.54 (2H, t), 6.80 (2H, br), 7.67 (ÍH, s).

EXAMPLE 158 0. 79 (3H, br-t,), 0.80 * 1.80 (8H, m), 1.33 (9H, s), 2.40 (3H, s), 2.45 (3H, s), 2.95 (2H, t), 3.26 (2H , t), 3.54 (2H, t), 6.80 (2H, br).

EXAMPLE 159 0. 79 (3H, br-t), 0.80 * 1.80 (12H, m), 1.33 (9H, s), 2.40 (3H, S), 2.45 (3H, s), 2.95 (2H, t), 3.26 ( 2H, t), 3.54 (2H, t), 6.80 (2H, br).

EXAMPLE 160 0. 79 (3H, br-t), 0.80 * 1.80 (16H, m), 1.33 (9H, e), 2. 40 (3H, s), 2.45 (3H, s), 2.95 (2H, t), 3.26 (2H, t), 3.54 (2H, t), 6.80 (2H, br).

In order to show the superior properties of the compound of the present invention, the inhibitory activity of ACAT, the reducing effect of total cholesterol in the serum, the inhibitory activity of plasma lipoperoxidation in vitro were determined. the inhibitory activity of ex vivo plasma lipoperoxidation, the solubility of water at pH 6.8 and the concentration of plaema in oral administration.

EXPERIMENTAL EXAMPLE 1 ACAT inhibitory activity A supply of high cholesterol was provided [added supply with cholesterol (1%), Clea Japan, Inc.] to male Japanese white rabbits weighing 2-2.5 kg, at a rate of 100 g per day and rabbits were reared for 4 weeks. He killed the rabbits by bleeding under anesthesia and removed the large intestine. The mucous membrane of the large intestine was operated, collected and homogenized. The homogenate was centrifuged at 4 * C and 10,000 rpm for 15 minutes. The supernatant obtained was further centrifuged at 4ßC and 41,000 rpm for 30 minutes to give microsomal fractions. Microsomal suspension was added as an enzyme sample, dimethyl sulfoxide (DMSO, 5 μl) or a test compound dissolved in DMSO (5 μl test compound solution) and reaction substrate [l ~? * C] -oleoyl CoA to the phosphate pH regulator at 0.15 M up to an amount of 500 μl. After incubation at 37 ° C for 7 minutes, the coroform-methanol mixture was added to stop the reaction. Water was added thereto and mixed, and the chloroform layer was separated. The solvent was evaporated to dryness and the residue redissolved in n-hexane. The mixture was subjected to thin layer chromatography, using a layer of silica gel. The cholesteryl oleate stains were scraped onto a silica gel plate and analyzed quantitatively on a liquid scenting counter. The ACAT inhibitory activity of the test compound was expressed as a ratio (%) of the inhibition of coleeteryl oleate, namely, the inhibition ratio of the production of cholesteryl oleate compared to the control, the result of which is shown in Table 14 TABLE 14 YM-750: l-cycloheptyl-1 - [(2-fluorenyl) methyl] -3- (2,4,6-trimethyl-phenyl) urea EXPERIMENTAL EXAMPLE 2 Reducing effect of total coléeterol in the serum He raised male Wister rats that weighed 180-200 grams with free access to the supply of high cholesterol [added cholesterol (1%), cholic acid (0.5%) and coconut oil (10%), Clea Japan, Inc.] for 3 days, period during which A test compound (3 mg / kg and 10 mg / kg) suspended in 5% gum arabic solution was orally administered once daily for three days. Only 5% gum arabic solution was administered to the control animals. After the final administration, the test animals were fasted and their blood was drawn 5 hours later. The level of total cholesterol in the serum was determined using a commercially available analysis kit (CBI-Wako-WBC, Wako Pure Chemical Industries, Ltd.). The activity of the test compound was expressed as a ratio (%) of the reduction of the total cholesterol level in the serum, namely, the ratio of the reduction of total cholesterol in the serum as compared to the control, the result of which is shown in Table 15.

TABLE 15 YM-750: l-cycloheptyl-1 - [(2-fluorenyl) methyl] -3- (2,4,6-trimethyl-phenyl) urea EXPERIMENTAL EXAMPLE 3 Inhibitory activity of plasma liperoperoxidation in vitro Under anesthesia with ether, blood was drawn from male Wister rats weighing 160-190 grams and subjected to fasting for 16 hours, and the heparanized plasma was separated by a conventional method. DMSO (10 μl) was added to a test compound (final concentration 10-5 M) dissolved in DMSO (10 μl test compound solution) to plasma (1.0 ml), and the mixture was incubated at 37 ° C for 5 minutes. Distilled water (10 μl) was added to aqueous solution (10 μl) of copper sulfate (final concentration 1 M), followed by incubation at 37 ° C for 4 minutes. After the equation, the concentration of lipid peroxide in the mueetra was determined, using commercially available analysis equipment (Lipoperoxide Test Wako, Wako Pure Chemical Industries, Ltd.). Specifically, the lipid peroxide in the sample was allowed to develop color by the thiobarbiturate method and was analyzed as malondialdehyde. The activity of the test compound was expressed as a proportion (%) of the inhibition of malondialdehyde production, namely, the inhibition rate of malondialdehyde production compared to the control, the results of which are shown in Table 16.

TABLE 16 Test Compound Inhibition (%) of lipoperoxidation of plaema Example 1 5 1. 7 Example 3 4 9. 2 Example 4 5 1. 2 Example 11 4 4. 5 Example 18 4 4. 0 Example 25 6 3. 5 Example 36 4 1. 5 Example 71 4 8. 1 Example 76 5 1. 7 Example 81 4 7. 1 Example 116 4 5. 5 Example 121 4 1. 6 Example 125 4 8. 0 Example 155 4 7. 7 Example 159 4. 8. 3 EXPERIMENTAL EXAMPLE 4 Inhibitory activity of plasma lipoperoxidation ex vivo A test kit euspended in 5% gum arabic solution was orally administered orally to male Wister rats weighing 160-190 grams and having been fasted for 16 hours. Only 5% gum arabic solution was administered to the control animals. At one hour after the administration, blood was extracted under anesthesia with ether and the heparanized plasma was separated by the conventional method. Plasma (1.0 ml) was treated in the same manner as in Experimental Example 3 and the amount of malondialdehyde produced was determined. The activity of the test compound was expressed as a proportion (%) of the inhibition of malondialdehyde production, namely the composition of the inhibition of malondialdehyde production compared to the control, the result of which is shown in Table 17.

TABLE 17 Probucol: 4,4-isopropylidenedithiobis (2,6-di-t-butylphenol) EXPERIMENTAL EXAMPLE 5 Solubility A powdered test compound (10 mg) was added to regulate the pH (ml, pH 6.8) and the mixture was stirred for 1 hour at 25 ° C. The mixture was passed through a membrane filter and the concentration of the test compound in the filtrate was determined by high performance liquid chromatography, the result of which is shown in Table 18.

TABLE 18 YM-750: l-cycloheptyl-1 - [(2-fluorenyl) methyl] -3- (2,4,6-trimethyl-phenyl) urea EXPERIMENTAL EXAMPLE 6 Oral administration A test compound (30 mg / kg) was durably administered in oral 5% gum arabic solution to male Wister rats weighing 200-250 grams, which had been fasted for 16 hours. At 0.5, 1, 2, 4 and 6 hours after the administration, blood was drawn and the heparanized plasma was separated by the conventional method. The concentration of the test compound in the plasma was determined by high performance liquid chromatography, the result of which is shown in Table 19.

TABLE 19 Test Compound Maximum concentration in plaema C (μg / ml) Example 4 1. 4 Example 36 2. 2 EXPERIMENTAL EXAMPLE 7 Oral administration A test compound (30 mg / kg) was durably administered in a solution of 5% gum arabic gum orally to male SD lae ratae weighing 200-250 grams and fasting for 16 hours. At 0.5, 1, 2, 4 and 6 hours after the administration, blood was drawn and the heparanized plasma was separated by the conventional method. The concentration of the test compound in the plasma was determined by high performance liquid chromatography, the result of which is shown in Table 20.

TABLE 20

Claims (24)

1. NOVELTY OF THE INVENTION CLAIMS A heterocyclic derivative of the formula (I) characterized in that one of Ri, R2 and R5 is hydroxy, carboxy, alkoxycarbonyl, a group of the formula -NR9Ri °, wherein R9 and R or are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, acid group, alkoxycarbonyl or a group of the formula -NR9Ri °, wherein R9 and Ri ° are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy; any R3 or R * is a group of the formula -NHCOR7, where R? is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy; R6 is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl; and Z is a linking group which forms a 5- or 6-membered ring together with a nitrogen atom substituted by R6, a benzene ring carbon atom to which said nitrogen atom is attached, and a carbon atom adjacent to said nitrogen atom. carbon, or a pharmaceutically acceptable salt thereof.
2. 2. The heterocyclic derivative of claim 1, characterized in that in the formula (I) one of R, R2 and R- »is alkyl or alkenyl substituted by hydroxy, acid group, alkoxycarbonyl or a group of the formula -NR9R °, wherein R9 and Rio are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof.
3. 3. The heterocyclic derivative of claim 2, characterized in that in the formula (I) Z is or a pharmaceutically acceptable salt thereof.
4. 4. The heterocyclic derivative of claim 3, characterized in that in the formula (I) one of R1, R2 and R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9Ri °, wherein R9 and R ° are each independently lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, and any R3 or R * is a group of the formula -NHCOR7, wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8 is alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof.
5. 5. The heterocyclic derivative of claim 4, characterized in that in the formula (I) R and R3 are each independently hydrogen atom, lower alkyl or lower alkoxy, any R2 or R * 5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R °, wherein R9 and Ri ° are each independently lower alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy, and R * is a group of the formula -NHCOR7, wherein R7 is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8, wherein R8 is alkyl, or a pharmaceutically acceptable salt thereof.
6. 6. The heterocyclic derivative of claim 5, characterized in that in the formula (I) any R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9Rio, wherein R9 and R or are each independently lower alkyl, and the other is hydrogen atom, or a pharmaceutically acceptable salt thereof.
7. 7. The heterocyclic derivative of claim 6, characterized in that in formula (I) R1 and R3 are each independently hydrogen atom or lower alkyl, any R2 or R5 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9Ri °, wherein R9 and Rio are each independently lower alkyl, and the other is hydrogen atom, R4 is a group of the formula -NHCOR7, wherein R7 is alkyl, cycloalkyl or cycloalkylalkyl, and R6 is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
8. 8. The heterocyclic derivative of claim 7, characterized in that in the formula (I) R2 is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9R °, wherein R9 and Ri ° are each independently alkyl lower, and R * "- is hydrogen atom, or a pharmaceutically acceptable salt thereof
9. 9. The heterocyclic derivative of claim 8, which is represented by the formula (lia) wherein R1"is hydrogen atom or lower alkyl, R3" is lower alkyl, R2 * is alkyl substituted by hydroxy or carboxy, R * a is a group of the formula -NHCOR7, wherein R7"is alkyl, cycloalkyl or cycloalkylalkyl , and R6 »is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt thereof.
10. 10. The heterocyclic derivative of claim 9, characterized in that in formula (lia), R * is hydrogen atom or lower alkyl, R3"is lower alkyl, R2 * is alkyl substituted by hydroxy or carboxy, R ** is a group of the formula -NHC0R7", wherein R7" is alkyl, and Rβ is alkyl, or a pharmaceutically acceptable salt thereof.
11. 11. The heterocyclic derivative of the claim 10, characterized in that the compound of the formula (lia) is selected from the group that you were connected to: (1) N- (l-hexyl-5-carboxymethyl -4,6-dimethylindolin-7-yl) -2,2-dimethyl lp ropanamide, (2) N- (l-heptyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylp-ropanamide, (3) N- (l-octyl-5-carboxymethyl-4) , 6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, (4) N- (1-nonyl-5-caboximeti 1 -4, 6-dimethylindol i n-7-yl) -2, 2- dimethyl lpropanamide, (5) N- (1-decyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, (6) N- (1-undecyl-5-carboxymethyl-4, 6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, (7) N- (1-dodecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2, 2-dimethyl-ilp-clothing, (8 ) N- (l-hexy-1 -5-hydroxymethyl-6-methyl-indole-n-7-yl) -2,2-dimethyl-aphenamide, (9) N- (l-hexyl-5-hydroxymethyl-4, 6-dimethyl-indolin-7-yl) -2,2-dimethylpropanamide, (10) N- (1-heptyl-5-hydroxymethyl-6-methyl-indole-7-yl) -2, 2-dimethyl-Ip-clothing, ( 11) N- (l-heptyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropropane amide, (12) N- (l-octyl-5-hydroxymethyl-6-methylindolin-7-yl) -2,2-dimethylpropanamide and (13) N- (l-octyl-5-hydroxymethyl-4,6-dimethylindolin -7-yl) -2, 2-dimethyl lp, or a pharmaceutically acceptable salt thereof.
12. 12. The heterocyclic derivative of the claim 2, characterized in that in formula (1), Z is or a pharmaceutically acceptable salt thereof.
13. 13. The heterocyclic derivative of claim 12, which is represented by the formula (Ilb) wherein Rib and R3b are each independently hydrogen atom, lower alkyl or lower alkoxy, R2 is alkyl substituted by hydroxy, carboxy or alkoxycarbonyl, R * is a group of the formula -NHCOR7 b, wherein R7b is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8h, wherein R8b is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and R6b is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, or a pharmaceutically acceptable salt thereof.
14. 14. The heterocyclic derivative of claim 13, characterized in that in the formula (Ilb), R * and R e each independently lower alkyl or lower alkoxy, R * be alkyl substituted by hydroxy, carboxy or alkoxycarbonyl, R * b is a group of the formula -NHCOR7 b, wherein R7b is alkyl, cycloalkylalkyl, arylalkyl or a group of the formula -NHR8b, wherein R8b is alkyl, and R * b is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkylalkyl, or a pharmaceutically salt acceptable of them.
15. 15. The heterocyclic derivative of the claim 14, characterized in that in formula (Ilb), Rib and R3 are each independently lower alkyl, R2b is alkyl substituted by hydroxy or carboxy, R * b is a group of the formula -NHC0R7b, wherein R7b is alkyl, and Rβ is alkyl, or a pharmaceutically acceptable salt thereof.
16. 16. The heterocyclic derivative of the claim 15, characterized in that the compound of the formula (Ilb) is selected from the group consisting of: (1) N- (1-hexyl-6-carboxymethyl-1-5, 7-dimethyl-1,2,3-tetrahydroquinoline-8) -yl) -2,2-dimethyldimethylpropanamide, (2) N- (l-heptyl-6-carboxymethyl-5,7-dimethyl-l, 2,3, 4-tetrahydroquinolin-8-yl) -2,2-dimethylpropanamide, (3) N- (1-octyl-6-carboxymethyl-5,7-dimethyl-1, 2, 3, 4- tet rahid roquinol in-8 -yl) -2, 2-dimet i 1-dimethyl-propapropanamide, (4) N- (1-nonyl-6-carboxymethyl-5,7-dimethyl-1, 2,3,4-tetrahydroquinolin-8-yl) - 2,2-dimethyl-dimethylpropanamide, (5) N- (1-decyl-6-carboxymethyl-5,7-dimethyl-1, 2,3,4-tetrahydroquinolin-8-yl) -2,2-dimethyl-dimethylpropanamide , (6) N- (l-hexyl-6-hydroxymethyl-5,7-dimethyl- 1, 2, 3, 4- tet rahid roqui noli n-8-yl) -2, 2-dimeti 1-dimethylp-clothing, (7) N- (1-heptyl-6-hydroxymethyl-5,7-dimethyl-1, 2.3, 4- tet rahid roquinol i n-8-yl) -2, 2-dimeti 1-dimethylp ropanamide, (8) N- (1-octyl-6-hydroxymethyl-5,7-dimethyl-1, 2,3,4-tetrahydroquinol in-8-yl) -2,2-dimethyl-dimethylpropanamide, (9) N- ( l-nonyl-6-hydroxymethyl-5,7-dimethyl-1,2,3- 4 -ethehydroquinoline i n-8-yl) -2, 2-dimethyl-dimethylp-aphenamide and (10) N- (l- decyl-6-hydroxymethyl-5,7-dimethyl-1,2,4,4-tetrahydroquinolin-8-yl) -2,2-dimethylpropanamide or a pharmaceutical salt You are acceptable of them.
17. 17. - The heterocyclic derivative of claim 1, characterized in that in the formula (I) one of R, R2 and RS is hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9Ri °, wherein R9 and Rt 0 are each one independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof.
18. 18. - Heterocyclic rivate of claim 17, characterized in that it is represented by the formula (lie) wherein one of R "=, R * c and R bc is hydroxy, carboxy, alkoxycarbonyl or a group of the formula -NR9 < -Ri? Cf wherein R9c and RIOC are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, any R3c or R * c is a group of the formula -NHCOR7c, wherein R7c is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula -NHR8c, wherein R c is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is an hydrogen, lower alkyl or lower alkoxy, and R6c is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, or a pharmaceutically acceptable salt thereof.
19. 19. The heterocyclic derivative of the claim 18, characterized in that in the formula (lie), Ric and R3c are each independently hydrogen atom, lower alkyl or lower alkoxy, R2c is carboxy, R * c is a group of the formula -NHCOR7 c, wherein R7c is alkyl , cycloalkyl or cycloalkylalkyl, R5 is hydrogen atom, and R < -e is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt of the mimes.
20. 20. The heterocyclic derivative of the claim 19, characterized in that in the formula (lie), Rie is hydrogen atom or lower alkyl, R3c is lower alkyl, R2 = is carboxyl, R * c is a group of the formula -NHC0R7c, wherein R7c is alkyl, RSe is hydrogen atom, and R6c is alkyl, or a pharmaceutically acceptable salt thereof.
21. 21. The heterocyclic derivative of claim 20, characterized in that the composition of the formula (lie) is selected from the group consisting of: (1) N- (l-hexyl-5-carboxy-6-methylindolin-7-yl) ) -2,2-dimethylpropanamide, (2) N- (1-octyl-5-carboxy-6-methylindolin-7-yl) -2,2-dimethylpropanamide, (3) N- (1-decyl-5-carboxy) -6 -methyl indole-7-yl) -2, 2-dimet ilp-clothing, (4) N- (l-hexyl-5-carboxy-4,6-dimethylindolin-7-yl) -2,2-dimethylp-aphenamide, (5) N- (l-octyl-5-carboxy-4,6- dimethyl indolin-7-yl) -2,2-dimethylpropanamide, and (6) N- (l-decyl-5-ca rboxi -4,6-dimethyl indole i n-7-yl) -2, 2-dimet ilp clothing, or a pharmaceutically acceptable eal thereof.
22. 22. A pharmaceutical composition comprising a heterocyclic derivative of any of claims 1 to 21, or a pharmaceutically acceptable salt thereof.
23. 23. The pharmaceutical composition of claim 22, characterized in that it is an inhibitor of acyl -CoA: cholesterol acyl transferase.
24. 24. The pharmaceutical composition of claim 22, characterized in that it is a lipoperoxidation inhibitor.