JPS59500768A - 1-Carboxyalkanoylperhydroindole-2-carboxylic acid and derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 1-Carboxyalkanoylperhydroy Disclosure Summary The present invention provides novel 1-carboxy-(alkanoyl or aralkayl)-yl )7-2--))) L-bonic acid, especially the formula (wherein ph is unsubstituted 1,2-phenylene or substituted 1,2-phenylene henylene, and the substituents are lower alkyl, lower alkoxy, and lower alkylene diopter. 1 to 3 selected from oxy, hydroxy, halogeno and trifluoromethyl one or different members, Ro is hydrogen or HPh-c, R 1, R2 and R5 are each hydrogen or lower alkyl, and n is 1-1 )2, which is an integer of 0 corresponding to; its unsubstituted amides and mono- or unsubstituted lower alkyl amide; its lower alkylene amide (where the lower alkylene group is the nitrogen of the amide); together with 5, 6 or 7 to form negative apes), or hydroxy- (lower anon or lower alkanoyloxy-(lower) alkyl on i Substituted lower alkylene amide; its α-(lower)-carboalkoxy- or α-carboxy-substituted lower alkylamide; its α-(lower) carboal Coquin-ox or α-carboxy-substituted aryl(lower)alkylamide (here where aryl represents phenyl or 3-indolyl); its (amine or aryl); lower alkyl amide; lower alkyl ester thereof; Mino, mono- or di-lower alkylamino, carboxy or lower carbal coquin)-substituted lower alkyl ester; aryl-(lower) alkyl ester of (where aryl represents phenyl or pyridyl); its lower alkanoyl its (lower) alkyl ester; its phthalinolester; its (hydro) (oxy, lower alkanoyloxy, or lower alkoxy)-substituted (lower) alkoxy xymethyl ester; ester, the above ester is Bi3, Japanese Patent Publication No. 59-500768 (3) Cycloa up to 10 carbon atoms in the alkyl group; Nyloxy-(lower)alkyl ester; or a pharmaceutically acceptable salt thereof ; and the corresponding mulberry chemical composition hy9 and useful antihypertensive and cardiac agents. the preparation and application of said products, which are pharmaceutical preparations, and subjecting them to R7; With the goal.

The present invention also provides certain novel wave-rubidroindole-2-carboxylic acids and Functional derivatives thereof; corresponding pharmaceutical compositions and useful antihypertensive and cardiac agents; It concerns the production and application of said products which are viscerally active agents.

ph is unsubstituted 1,2-phenylene, or lower alkyl, lower alkoxy 1 or 2 same or different selected from oxy, hydroxy, and halogeno 1,2-7 enylene, or one lower alkyleneoxy substituted with or 1,2-phenylene substituted with a trifluoromethyl group, and Ro is water. R4, R2 and R3 are each hydrogen or lower alkyl and n is an integer from 1 to 10; and pharmaceutically acceptable alkali metals and alkaline earths of said acids; similar metal or ammonium salts, or the above aminoalkyl esters and amines. Acid addition salts of de are preferred.

pH is lower alkyl, lower alkoxy, lower alkylenezoxy, hydroxy, Halodanomata is unsubstituted or -substituted with trifluoromethyl. 1,2-phenylene, Ro is hydrogen or HPh, R4, R2 and and R3 are each hydrogen or methyl, and n is an integer from 2 to 8, the formula ■ and their ester, amide and salt derivatives are highly preferred.

1.2-phenylene group ph and/or phenyl group HPh are preferably substituted unsubstituted or -substituted, and examples of those substituents are: as follows: lower alkyl, e.g. methyl, ethyl, n-7', i -7'biru, n-butyl or i-butyl; lower alkoxy, e.g. meth xy, ethoxy, n-zolopoxy, 1-noropoquine, n-butoxy or 1-butoxy Toxy; lower alkyleneoxy, such as metelethooxy, 1,1-ethylene 2-dioxy or 1,2-ethylenedioxy; hydroxy; For example, fluoro, chloro or bromo; or trifluoromethyl.

Advantageously, the radical ph is unsubstituted or chloro, methoxy or methoxy. represents 1,2-phenylene monosubstituted by Similarly, the group HPh is advantageously is unsubstituted or monosubstituted by chloro, methoxy or methyl. O represents phenyl Each of R, R and R3 is preferably hydrogen and 2 but also lower alkyl, methyl, or others of those mentioned above. be.

"lower" and "lower" mentioned above and below in relation to organic groups or compounds respectively The term refers to up to 7, preferably up to 4, advantageously 1 or 2 carbon atoms. Define something that has .

Is the alkylene or aralkylene moiety Cn) (2n-4-R8 a straight chain? , preferably branched) and advantageously up to 8 carbon atoms in chain Contains. Thus, for example, in the case of Ro-H, ethylene, 1.2-1 or 1,3-propylene, 2-methyl-1,2- or -1,3-zo Lopylene, 1.2-, 1.3-, 2.3- or 1,4-butylene, 1.2 -, 1.3-, 1.4-, 2.4- or 1.5-pentylene, Or when R6 is enyl, ω-phenyl-(1,2-, 1,3- or Or 2,3-zolopyrene, -butylene J-L--'? thirene, 1,3-2 2.3-’l: or 2,4-butylene, -ventele:/-! Rild-1\Kin lene, or 3,5-hezotylene or -o6 butylene).

of formula I, in which one or both carboxy groups are esterified and amidated. Said mono- or bis-functional derivatives of indoline-2-carboxylic acid are preferably Examples include: unsubstituted amides; N-mono- or di-lower alkyls; Kylamides, such as mono- or di-methylamide; N-lower alkylene amide amide, e.g. N-butylene, N-benzenamide (where e.g. butylene or benzene together with the amide nitrogen atom to form pyrrolinone or pyrrolinone, respectively. hydroxyl on the pyrrolidine or piperidine ring); - (lower) alkyl, preferably hydroxymethyl; noyloxy-(lower)alkyl, preferably substituted by acetoxymethyl Substituted lower alkylene amide; α-(lower) carbalcoquine or carbo xy-substituted lower alkyl amides, such as mono N-(carboethoxymethyl)- amide, and mono N-(carboxymethyl)amide; α-(lower)carboal Koxy- or carboxy-substituted aryl(lower)alkylamides, e.g. (alboethoxy or carboxy)-substituted noenethylamides; amino(lower)-a alkylamides, such as β-aminoethylamide and β-(carbobenolylamide). xyamine) etelamide; lower alkyl esters, e.g. methyl, ethyl , n-propyl) l-noropyl, n-butyl or l-bupuruesul: substituted lower Alkyl esters, such as ω-amine, ω-mono or Il″i:N-tumethy ruamino, α-carboquine or α-carboethoxy-(ethyl, propyl or is butyl) ester; aryl (lower) alkyl ester; for example, benzyl , (methyl-, methoxy-, chloro-)substituted benzyl, and pyridyl methyl ether ster; lower alkanoyloxy-(lower) alkyl ester, e.g. pipa Loyl ox 7 methyl ester; 3-phthalidyl and (methyl-, methoxy-, chloro-)substituted 3-phthalinolester, the corresponding 3-hydroxyphthalhalide derived from (hydroxy-1 lower alkanoyloxy-1 lower alkyl oxy-) substituted lower alkoxymethyl esters, such as β-(hydroxy- , acetyloxy-, methoxy-)ethoxymethyl ester; vinyl alkyl Oxy-carbonyl-(lower)alkyl esters, e.g. bicyclic monoterpenes Noid alcohols derived from such derivatives, e.g. unsubstituted or lower alkyl substituted Conversion to bicyclo[2,2,1]butyloxycarbonyl-lower) alkyl ester or 1-(lower alkyl), advantageously bornyloxycarbonyl methyl ester; Kogicarbonyloxy)-(low M)alkyl esters, such as 1-(meth) (oxy, ethoxy, propoxy, luponyloxy)-methyl, ethyl-& 1-1f propyl ester.

Monofunctional on dicarboxylic acid of formula ■ with free indoline-2-carboxy group Most preferred are sexual derivatives.

Pharmaceutically acceptable salts are preferably metal salts or ammonium salts of said acids. , for example sodium, potassium, magnesium or calcium salts; or advantageously ammonia or organic amines, such as lower (alkyl, cycloalkyl or hydroxyalkyl)-amine, lower alkylene diamine or lower (hydroxyalkyl or aralkyl)-alkylene diamine or lower (hydroxyalkyl or aralkyl) ammonium salts, such as methylamine, diethylamine, triethylamine, Cyclohexylamine, triethanolamine, ethylenecyamine, t+)- y, -(hydroxymethyl)-aminomethane or benz#-1-! 7 methyl is an easily cyclized ammonium salt derived from ammonium hydroxide . The basic (amine, mono- or no lower alkyl-amino) Acid addition salts are preferably formed with therapeutically acceptable inorganic or organic acids. is an acid addition salt of two strong metalloids, and examples of such acids are: Hydroacids, such as hydrochloric acids, such as hydrochloric acid or hydrobromic acid: sulfuric acid , phosphoric, nitric or perchloric acids; aliphatic or aromatic carboxylic or sulfonic acids; acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, Malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydro Ximalic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-amino-benzoic acid , anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-amine salicyl Acid, pamonic acid, nicotinic acid; methanesulfonic acid, ethanesulfonic acid, hydroxy Ethanesulfonic acid, ethanesulfonic acid, halogenbenzenesulfonic acid, toluene Sulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfonic acid Fuamic acid.

In addition to the aforementioned pharmaceutically acceptable salts, the predrugs thereof Derivatives, for example, the carbonyl pharmaceutically acceptable esters of carboxylic acids of the invention which can be converted to acids; and Amide is the objective 10 of the present invention. The ester is preferably unsubstituted or suitably substituted, for example straight-chain or branched lower alkyl esters, such as pivaloyloxy Methyl, bornyloxycarbonylmethyl, bilinormethyl, α-carboxyelate methyl or appropriately esterified α-carboxyne-ethyl ester, etc. , which are manufactured by methods well known in the art and exemplified herein.

Said amides are preferably derived from e.g. amino acids and their derivatives. From simple primary and secondary niamides, e.g. alanine, phenylalanine, etc. It is a derivatized amide.

The compounds according to the invention have, inter alia, angiotensin converting enzyme inhibitory activity. , exhibiting valuable pharmacological properties, mainly hypotensive, antihypertensive and cardioactive effects . It is advantageously used as a test subject in in vivo or in vitro animal studies. Using mammals, cats, dogs or their isolated organs It is proven that Animals with normal blood pressure or hypertension, for example genetically hypertensive Rats and dogs with corticosteroids, rats, or renal hypertension, and sodium-deficient dogs. I can do it when I'm nu. The compound may be placed in a gelatin capsule, for example. It is administered enterally or parenterally to mammals in the form of a starch suspension or aqueous solution. It can advantageously be applied as a lipstick or intravenously. The application amount is approximately 00 1 to 100 mg/kg/day, preferably about 0.1 to 50 m97 for 97 days, advantageously Approximately 0.1 to 25 m97/day.

The in-vivo effects of blood pressure can be measured using catheters placed in the femoral artery of dogs, for example. f) directly to the rat's tail pulse manometer and transducer; Blood pressure was recorded indirectly and expressed in mm fig before and after administration. Implementation in this specification Representative members of the compounds of the invention illustrated by way of example include hypertensive rats and In dogs, oral doses of less than 50 mfiI/kg/day are highly effective.

As an illustration of the invention, 1-(4-carboethoxy-2R,4R-tumethylbutano yl)-indoline-28-carboxylic acid and 1-(4-carpoethoxy-2 R-methyl-4R-phenethylbutanoyl)-indoline-28-carboxylic acid is , 30 and 10+9/k17p, respectively, in spontaneously hypertensive rats. A dose of ,o, significantly lowers blood pressure and decreases stroke frequency.

The compounds of the present invention also inhibit angiotensin I pressure responses in normotensive rats. shows a blocking effect.

The enzyme renin normally consists of the circulating protein renin group 2 causes specific hydrolysis of the substance. This hydrolysis generates angiotensin I and later The body is further hydrolyzed by the action of the converting enzyme, resulting in the release of latent vasoconstrictor substances. Angiotensin ■ - One of the enzymes mentioned above is the enzyme from angiotensin I. Prevents the generation of giotensin H, therefore, after angiotensin I and dampens the pressure response of

Corresponding in-vivo studies are carried out using male normotensive rats. this rat 100-120mg/9i,p, of sodium ethyl-(l-methylpropyl) ) - Anesthetize with malonylthiourea. Direct measurement of depression in the femoral artery and saphenous vein In order to Compound D is administered intravenously. After basal blood pressure stabilizes, 0.33 μg-/9 Pressor response to three intravenous challenges of agiotensin 5 minutes apart Get it.

5, 10, 15 after intravenous or Itl, M oral (gastric tube) administration of the compound to be tested. Obtain such pressure responses at 30 and 60 minutes and compare with the initial pressure. .

The observed decrease in the vasopressor response indicates inhibition of anzeotensin 1 convertase. After intravenous administration of 9 to 10 m97 or 50 m97 kg orally After 80 minutes of oral administration, the reduction can be sustained up to 60 minutes.

As an illustration of the invention, 1-(4-carboethoxy-2R,4R-dimethylbutano il) indoline-28-carboxylic acid after angiotensin I challenge. The response of the pressure intensifier is 4 to 9 / kgp, o, or 0.3 to 9. / kg 1. v, inhibits by only about 50% at moderately low doses.

Furthermore, as an illustration of the present invention, 1-[:4-(pivaloyloxymethquine carbo Nyl)-2R,4R-dimethyl-bukunoyl]-indoline-28-carboxylic acid and 1-[4-t-formyloxylponylmethoxylponyl)-2 R,4R-dimethyl-butanoyl]-indoline-28-carboxylic acid is The vasopressor response after otensin I challenge was determined in dogs at 10 m9/ky. Inhibited by oral doses.

In vivo inhibition of angiotensin converting enzyme by the compounds of the present invention can be demonstrated by Biochi Same as m, Biophys, Acta 293 +451 (1973) You can go to work in various ways. According to this method, the compound is added to a phosphate buffer solution. at a concentration of approximately 1 mmol and externally cooled on ice. Phosphoric acid is added to these solutions. Add various μ amounts of 1 mmol histisolleucine in salt buffer and then 100 μt of 5 mmol hyperly-histinol-leucine in phosphate buffer and 50 μt of angiotensin converting enzyme. The transfer enzyme is chloride-14 In Tris buffer containing potassium and magnesium chloride and sucrose Freshly prepared from the lungs of an adult male rabbit. Incubate the solution at 37°C for 30 minutes and combined with 0.75 ml of 0.6N aqueous sodium hydroxide for further reaction. to stop. Then 100 μt of O-talaldehyde was added at room temperature, After 10 minutes, 100 μt of 6N hydrochloric acid was added.

These samples were read against water using a spectrophotometer set at 360 nm. , and estimate their optical density. Shape them during the 30 minute incubation period. The conversion coefficient represents the nanomoles of histidyl-leusone produced. Correct it accordingly. Plot the results against the drug concentration, IC5°, J') First, determine the drug concentration that halves the activity of the control sample containing no drug. again (a) of the compounds of the present invention (the human members were in charge of testing the compounds of the present invention in an in vitro test system). It is effective and reduces the engineering C5o value to 10 micromol or less.

As an illustration of the invention, 1-(4-cal J?xybutanoyl)-indoline-28 -carboxylic acid, 1-(4-carboxine-2R-methyl'tanoyl)-indoline -2S-carbaponic acid, 1-(4-car?xy-2R,4R-tumethyl-butano yl)-indoe11-28-carboxylic acid, 1-(4-carboxy-2R-mer) Tyl-4R-enethyl-ptanoyl)-indoline-28-carboxylic acid is They exhibit engineering C5o values of approximately 300°40.30 and 5 nmoles, respectively.

Therefore, the compounds of the present invention are valuable antihypertensive agents, especially antihypertensive agents. (regardless of the cause) and/or cardiac conditions, such as congestive heart attack, and/or or other edema or ascites diseases, such as liver cirrhosis. Ru. They can also be used for the preparation of other valuable products, in particular the corresponding pharmaceutical compositions. It is a useful intermediate in

Compounds of value for the present invention have the formula ■Co-CH-(Cf(2)m-CH- C0OH1 (CH2), -H(CH2,)9-R', where R is hydrogen, up to 4 carbon atoms alkyl or alkoxy, / logno or trifluoromethyl, m is an integer 0 or 1, each of p and q is an integer from 0 to 2, and R' is hydrogen or R-phenyl, where R-phenyl is unsubstituted or or alkyl or alkoxy of up to 4 carbon atoms) phenyl monosubstituted with trifluoromethyl, )6 more specifically its indoline-28-chiral evimer; mono- or bis- Amido, mono- or bis-11tM (alkyl or ω-aminoalkyl) esters mono α-(lower)carbalkoxy- or α-carboxy-substituted lower alkyl; Kylamido; mono α-(lower)carbalkoxy- or α-carboxy-substituted Aryl-(lower)alkylamide (where aryl represents phenyl); Nocarboxy- or lower carbalkoxide-substituted lower alkyl ester; mono Aryl (low i) alkyl ester (where aryl is phenyl or pyridyl) ); monovinchloralkoxycarbonyl (lower) alkyl ester (this represents where bicycloalkyl represents bornyl); mono-lower alkanoyloxy (lower class) alkyl esters; or pharmaceutically acceptable alkali metal salts of said acids. or an ammonium salt, or an acid addition salt of the aminoalkyl ester.

Side chains in the compounds of 2H and the monopotent derivatives thereof is the relative of the substituents of (CJ(,), -rr and (CH2), -R' on the side chain Depending on the orientation (none of said groups represents hydrogen), two distinct noasters Existing in the form of rheomers (referred to here as "erythro" and "threo") Can be done. The f, of the “Threo” type! I chain, preferably carrying the substituents mentioned above A compound of formula (1) in which both carbon atoms are in the (R)-configuration and its functional group sexual derivatives are preferred. 2-Indo with CC00H or its functional derivative The phosphorus carbon atom is in the (S)-configuration and (CH2), -H and (CH2 ), one or both of the carbon atoms bearing the -R' substituent are in the (R)-configuration (the group does not represent hydrogen), the compounds of formula 1a and their functional derivatives, as described below. Conductors are most preferred.

The most preferred compounds of the invention are those in which R is hydrogen, methyl, methoxy, fluoro, chloro, fluoro- or trifluoromethyl, advantageously present in the 5-position, m and p each is an integer 1, q is an integer 1 or 2, and R' is hydrogen or or the aforementioned functional acid and amine derivatives.

Additional embodiments of the invention provide that R is hydrogen, alkyl or aryl of up to 4 carbon atoms. Rukoxy, halogeno or trifluoromethyl, each of m and p is O or or 1, q is an integer from 3 to 6, and 18 and R' is R-phenyl (where R is hydrogen, an alkyl of up to 4 carbon atoms) Compounds of formula H which are methyl or alkoxy, halogen or trifluoromethyl mono- or bis-sulamido, mono- or bis-lower (alkyl or ω- (aminoalkyl) esters, pharmaceutically acceptable metal salts of said acids The present invention relates to a monium salt or an acid addition salt of the aminoalkyl ester.

R is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl , m is an integer 1, p is 0 or 1, q is an integer 3 or 4), and so on. and the above compound of 2H, wherein R' is phenyl; the mono-lower alkyl ester thereof; or its pharmaceutically acceptable alkali metal salt and ammonium salt are preferred. Delicious.

Additionally, other functional mono- and bisesters and Also included are amide derivatives, especially functional derivatives of pre-drugs. For example, Benji ester, (methyl-, methoxy-, chloro-)tk benzyl ester, Silmethyl esdel, pivaloyloxymethyl ester, β-(hydroxy-, Acetyloxy-, methoxy-)ethoxymethyl ester, and bornyloxy Cycarbonyl methyl ester is preferred.

1978 Table Sho 59-500768 (7) The compounds of the present invention can be prepared according to conventional methods. Advantageous (teha, 1) 2■ 3 or said acid or its amine derivative with the formula or 2) with a reactive functional derivative of formula ■ 3 0 (wherein, at least one of X and Y is cyanide, and the other is the free is an amidated or esterified carboxy group) Hydrolyze or alcoholize the compound, A3) 2■ or the above acid or its derivatives to convert the indole moiety into indole. and, if necessary, transfer the resulting compound to other compounds of the invention. manufactured by

The reactive functional derivatives of compound (1) are preferably ester-halides, simple anhydrides. or mixed anhydrides, such as lower alkyl half esters of said acid chlorides, cyclic anhydride, or mixed acetic anhydride or cyanacetic anhydride. compound m The condensation of or an inorganic base, such as the aforementioned salt-forming amines or alkali metal carbonates, or occurs in the presence of disubstituted carposiimide.

Said hydrolysis of the corresponding acid or amide of the nitrile V is advantageously carried out with an inorganic acid, e.g. carried out in a known manner, for example with hydrohalic acid or sulfuric acid, and Alcoholysis is also carried out between the aforementioned acids and the corresponding unsubstituted or substituted lower alkanoids. Conducted in the presence of both tools.

Finally, the hydrogenation of indole I to indoline I also According to the conventional hydrogenation of hydrocarbons, e.g. catalytically activated Presence of hydrogen at stage, e.g. platinum, radium, rhodium or di-Kel catalyst hydrogen, or electrolytically or by the action of metals on acids or alcohols. This is carried out using the generated hydrogen. Also reducing agents, e.g. simple or complex Light metal hydrides, such as borane, or advantageously alkali metal borohydrides Alternatively, cyanoborohydride can be used. Chiral catalyst, for example (R)-1 , 2-bis(θ-anisilenylphosphine)-ethaneoyohyel, 5-cyclo (R)-1,2-bis-(diphenylphosphino)-norono on octanoene Indoline-28-cal using a chiral catalyst prepared from the rhodium salt of St. Asymmetric hydrogenation to the bonic acids or said derivatives thereof is preferred.

The compounds of the invention are converted into each other according to conventional methods. can do. Thus, for example, the resulting amide or ester can be according to method 2) or aqueous alkali, e.g. alkali carbonates or hydrogenated can be further hydrolyzed or alcoholized (esterified) using Wear. The resulting free acid can be prepared in the usual manner, e.g. esterified with alkanols, alkali halides or diazoalkanes, Alternatively, it can be converted into the metal salt, ammonium salt or acid addition salt.

Thus, for example, the resulting free acid or base can be converted into an equivalent amount of the corresponding base. , by reacting with basic salts, acids or ion exchange preparations, e.g. By reacting the recording acid with an alkali or ammonium hydroxide or carbonate. or the aminoalkyl ester is added to the inorganic or organic acid, respectively. By reacting with the corresponding metal salt, ammonium salt or acid Can be converted to salt. The resulting salt is liberated with a strong acid or base. In particular, it can also be converted into the free compound. Free compounds and their salts are In view of the fact that there is a direct relationship between the compounds of the present invention or intermediates thereof, Whenever mentioned, the corresponding salt is possible or suitable under the circumstances. To the extent appropriate, such salts are also contemplated.

The starting materials of ② and ② are known or, when new, are common Manufactured according to a method, e.g., according to a method exemplified by the Examples herein. can do. Compounds of formula ■ can also be prepared according to conventional methods, e.g. and/or by condensing the corresponding nitriles of ■ according to method 1 above. can get.

When a mixture of geometric isomers or optical isomers of the compounds of formulas 1 to 2 is obtained, this by known methods, e.g. fractional distillation, crystallization and/or chromatography. can be separated into single isomers. Racemic products are e.g. , by resolution of their noastereomeric salts, e.g.

Org, Chem, 4'3.3803 (1978), e.g. is 2-(tartrate, mandelate, camphorsulfonate, or 1-naphthyl) fractional crystallization of 1-ethyl isocyanate) or d-4 & U4-(α- Methylbenzylammonium, 7-nconidine, cinchouene, quinine, quinidine , ephedrine, dehydroabiethylamine, brucine or strychnine) - By fractional crystallization of the salt it is likewise possible to resolve the optical antipodes. 2 and The preferred starting material for (2) is its 2-8-optical isomer 4. (epimer).

The reactions carried out here are carried out according to standard methods, with diluents preferably for the reaction components. Catalytic, alkaline, in the presence or absence of an inert and solvent diluent. I'i also in the presence or absence of acidic condensing agents or other agents, and/or Preferably at low temperature, room temperature or elevated temperature, in the presence or absence of an inert atmosphere. or at the boiling point of the solvent used, at atmospheric pressure or superatmospheric pressure.

Furthermore, the present invention uses intermediate products obtained at any stage of this process as starting materials. or use this method as one of the Variations of the process disclosed herein where the starting materials are interrupted under the reaction conditions. Alternative methods of forming or reacting components in their salt or optically pure enantiomer form. It includes variants for use in different situations. In the above reaction, soil was shown to be of particular value. Compounds, such as compounds of formula ■ and O, its functional derivatives and the following chiral isomers: The starting materials that produce the body should be used primarily: Certain embodiments of the invention (is 1-carboxyalkanoyl)-'! ! Ruhydro Indole-2-carboxylic acids, esters, amides, such as formula ■ (In the formula, R4 represents hydrogen or lower alkyl, and R5 represents lower alkyl. or R5 represents lower argyl substituted by aryl, where a Reel is lower alkyl, lower alkokene, trifluoromethyl or halokene represents noenyl which may be replaced by and L does not represent ot or 1. ,) compound; its unsubstituted amide and mono 26 - or no lower alkyl amide; its lower alkylene amide (where lower The kylene group forms a 5-, 6-, or 7-membered ring with the nitrogen group of the amide), or droxy-(lower)alkyl or lower alkanoyloxy-(lower)alkyl said lower alkylene amide substituted with loam; its α-(lower) carboa Lucoquine- or α-carboxy-substituted aryl-(lower)alkylamides (this where aryl represents phenyl or 3-indolyl); its (amine or acylamino)-(lower)alkylamides; lower alkyl esters thereof; Amino, mono- or di-lower alkylamino, carboxy or lower carbo (alkoxy)-substituted lower alkyl esters; their aryl-(lower) alkyl esters; (where aryl represents phenyl or pyridyl); its lower alkano yloxy-(lower) alkyl ester; its phthalinole ester; its (hydro) oxy, lower alkanoyloxy, or lower alkoxy)-substituted (lower) alkaline Koxymethyl ester; up to 10 carbon atoms in the bicycloalkyl group , its bicycloalkoxycarbonyl-(low M)alkyl ester; or its bicycloalkoxycarbonyl-(low M)alkyl ester; Lower alkoxycarbonyloxy-(lower) alkyl ester; or pharmaceuticals thereof Relates to scientifically acceptable salts.

A preferred embodiment is where R4 represents hydrogen or lower alkyl of up to 4 carbon atoms. R5 represents lower alkyl of up to 4 carbon atoms, or R5 represents a lower alkyl of up to 4 carbon atoms substituted with aryl, where ary may be monosubstituted with lower alkyl, (fa alkokene or halogen) phenyl), and t represents O or 1; preferably lower alkyl esters such as methyl, ethyl, n-propylene substituted lower alkyl ester; 1-propyl, n-butyl or l-butyl ester; esters, such as ω-amino- or ω-mono- or N-tumethylamine, α-carboxy or α-carboethoxy-(ethyl, propyl or butyl) Esters; aryl (lower) alkyl esters, such as H, Hensyl, (methyl -, methoxy-, chloro-) substituted benzyl, and ``pyridyl methyl ester; Lower alkanoyloxy-(lower)alkyl esters, e.g. Oxymethyl ester; 3-phthalidyl and (methyl-, methoxy-, chloro- ) substituted 3-7 talidyl ester (derived from the corresponding 3-hydroxyphthalide) ), (hydro8 (xy-1-lower alkanoyloxy-1-lower alkoxy-) substituted lower alkoxymethane Tyl ester, Tatoeba, β-(hydroxy-, acetyloxy-, methoxy- ) ethoxymethyl ester; bicycloalkyloxy-carbonyl-(low M) a derived from bicyclic monotylated alcohols, e.g. [2,2,1] to unsubstituted or lower alkyl substituted bicyclo[2,2,1]] methyloxycarbonyl(lower) alkyl ester, preferably bornyloxycarboxylate Bonyl methyl ester; or its 1-(, lower alkoxycarbonyloxy) -(low a)alkyl esters, such as 1-(methquine-, ethoxy/- or propoxy-carbonyloxy)-methyl, ethyl or propyl ester; and pharmaceutically acceptable salts thereof.

Said verhydroindoles in which t is 1 are preferred.

A monoester or amide derivative of a compound of formula ■ has one of the two carboxy groups is esterified or amidated. Free Wave Rubidrow 2-Indo Monoester or amide derivatives having a carboxyl group are preferred.

A preferred group is R4 represents hydrogen or lower alkyl of up to 4 carbon atoms; 5 represents lower alkyl of up to 4 carbon atoms or R5 is aryl represents a highly substituted lower alkyl of up to 4 carbon atoms, where aryl is Phrases optionally substituted with lower alkyl, lower alkoxy or halogen represents phenyl and t is 0 or 1 hydroindole-28-epimer; mono- or bis-lower alkyl esters of; and agrochemically acceptable salts thereof It is expressed by.

However, the other functional mono- and bis-ester and amide derivatives mentioned above, especially the Drug-functional derivatives are included. For example, benzyl ester, (methyl-, Toxy-, chloro-)substituted benzyl ester, pyritol methyl ester, piparo yloxymethyl ester, β-(hydroxy-, acetoxy-, methoxy-) Etquin methyl ester, and bornyloxycarbonyl methyl ester Mat, i.

Verhydroindole (octahydroindole) of formula ■ and its potency induction The body uses useful cardiovascular agents, such as antihypertensives, cardioactive agents, and antibiotics. It is useful as a giotensin convertase inhibitor.

R4 represents hydrogen or methyl, R5 represents methyl or phenethyl, and and t represents 1, front 30 The perhydroindoles listed above are most preferred. Furthermore, carbon having R4 and R5 Compounds in which the atoms are in the (R)-configuration are preferred.

As an illustration of the present invention, 1-(4-carboxy-4-tenethyl-butanoyl) 3aS, 7aS-octahydroindole-28-carboxylic acid The IC5o for inhibition of ngiotensin convertase is approximately (IXlo-8 moles).

Further, as an example of the present invention, 1-(4-carboxy-2R,4R-dimethylbutyl Noyl)-octahydro-28-carboxylic acid is an angiotensin I challenger. The response of the pressure intensifier after the injection is 10 and 0, l R9/kg i, v, respectively. and inhibited by about 77 and 40% in rats at doses of ruboethoxy-2R,4R-dimethylbutanoyl)-octahydro-28-cal Vonic acid increases the response of the pressure enhancer to 10 and 0.1 mg/kgi, v, respectively. doses of approximately 84 and 24%.

Further, in a specific embodiment of the present invention, Ph is unsubstituted 1,2-7 enylene, or Lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, noro 1 to 3 same or different members selected from trifluoromethyl and trifluoromethyl is substituted 1,2-7 enylene, Ro is hydrogen or HPh, and R4゜ each of R2 and R3 is hydrogen or lower alkyl, and n is 1 to 10; the mono- and bis-functionality of the indoline-2-carboxylic acid of formula I above, which is an integer The functional derivatives are functional derivatives in which the lower alkylene group is combined with the amide nitrogen. Lower alkylene amides, or hydroxy, forming 5-, 6-, and 7-membered monkeys -(lower)alkyl or loweralkanoyloxy-(lower)alkyl The above-substituted lower alkylene amide; α-(lower)-carboalkoxy- or α-carboxy-substituted lower alkylamide; α-(lower)carbalkoxy C- or α-carboxy-substituted aryl-(lower)-alkylamides (totote Aryl represents phenyl or 3-indolyl): (amine or acyl) (mino)-(lower)alkyl amide; aryl-(lower)alkyl ester (here and aryl represents phenyl or pyridyl); lower alkanoyloxy-( low M) alkyl ester: phthalidyl ester; (hydroxy, lower alkanoyl or lower alkoxy)-substituted (lower) alkoxy-methyl esters: Bicycloalkyl group having up to 10 carbon atoms in the bicycloalkyl group Shirikiruboyu.

-(low M) alkyl ester; and lower alkoxycarbonyloxy (fIl &) 2 from alkyl ester or a pharmaceutically acceptable salt thereof.

Indoline-2 of formula I, wherein one or both of the carboxy groups are esterified - said mono- or bis-functional derivatives of carboxylic acids, such as benzyl, ( Methyl-, methoxy-, chloro-)substituted benzyl and pyridyl methyl esters lower alkanoyloxy-(lower) alkyl esters, such as pivaloy 3-phthalidyl and (methyl-, metquin-, chloroxymethyl ester; b-) substituted 3-phthalidyl esters (derived from the corresponding 3-hydroxyphthalides) ), (Hydroxy-1-class alkanoyloxy-1-lower alkoxy- ) substituted lower alkoxymethyl esters, such as β-(hydroxy-, acetyl- (methoxy-, metquin-)ethoxy ester; bicycloalkoxy-carbonyl - (lower) alkyl esters, e.g. bicyclic monoterpenoid alcohols For example, unsubstituted or lower alkyl substituted bicycloC2,2 , 1] to] butyloxycarbonyl-lower) alkyl ester, preferably to or 1-(lower alkoxy-carbonyl oxy)-(lower)alkyl esters, such as 1-(methoxy, ethoxy) -or propoquine carbonyloxy)-methyl, ethyl or propyl ester is preferred.

Said-functionality of dicarboxylic acids of formula I with free indoline-2-carboxyne groups Derivatives are most preferred.

Furthermore, Ph is unsubstituted 1,2-phenylene, lower alkyl, or lower alkyl. one or two same or different selected from oxy, hydroxy and halogeno 1,2-phenylene or one lower alkylene dioxy substituted with or 1,2-phenylene substituted with a trifluoromethyl group, and Ro is water. or HPh, and each of R1, R2 and R3 is hydrogen or lower alkyl and n is an integer from 2 to 8; Pharmaceutically acceptable salts of are preferred.

Furthermore, Ph is lower alkyl, lower alkoxy, lower alkylene dioxy, hydride. 1. which may be monosubstituted by roxy, halogeno or trifluoromethyl; 2-phenylene, Ro is hydrogen I or HPh, Rj　R　R2 and of formula I, wherein each R3 is hydrogen or methyl, and n is an integer from 2 to 8. Said derivatives of the compounds, or pharmaceutically acceptable salts thereof, are preferred.

R is hydrogen, alkyl of up to 4 carbon atoms or 34 Alkoxy, halogeno or trifluoromethyl, m is an integer 0 or 1 , the common names of p and q are integers from O to 2, and R' is hydrogen or R-F Indoline-2-carboxylic acid mono- and and bis-functional derivatives, preferably mono-functional derivatives; Benzyl ester; (methyl-, methoxy-, chloro-) substituted benzyl ester ;Hirisyl methyl ester;Hivaloyl methyl ester;3-phthalidyl ester β-(hydroxy-, acetyloxy-, methoxy-)ethoxymethyl ester; Bornyloxycarbonyl methyl ester; and 1-(lower alkokene carbonyloxy)-lower alkyl esters; or pharmaceuticals thereof; Particular preference is given to scientifically acceptable alkali metal or ammonium salts.

Another preferred group is where R is hydrogen, m is an integer 1, and p and q are each an integer. number 1 or 2, and R' is hydrogen or phenyl, 2n and la the aforementioned mono-functional derivatives of indoline-2-carboxylic acid of Regarding salts that are acceptable to the public.

Formula 1. ] The aforementioned mono-functional derivatives of compounds I and lla are preferably free The above derivative has a free indoline-2-carboxylic acid group.

Formula ■(7) The above-mentioned hydroin] phosphorus and its functional derivatives are by reduction of the corresponding indoline derivative of in an inert solvent, e.g. ethanol, in the presence of dium or radium. Hydrogenation under atmospheric pressure or overpressure, preferably in the warm summer range of 20 to 50°C In particular, it can be manufactured.

Perhydro- or octahydro-indoles of the invention, e.g. compounds of formula and its functional derivatives advantageously have the formula ■ or a functional derivative thereof, e.g. an ester derivative, as a compound. For example, a compound of formula (■) or a functional derivative thereof and, alternatively, a CHR5COOH group Esterified or amidated, Tatoe is in the form of a lower alkyl ester. 3 to be condensed with a compound of formula ■, or a reactive functional derivative thereof, It can also be manufactured.

The reactive functional derivatives of said compounds of formula (II) and their derivatives are preferably monocarboxylic. Such as rubonic acids, such as their half ester halides and half esters or a cyclic anhydride of the dicarboxylic acid of formula (1).

A compound of formula ■ or a functional derivative thereof, such as an ester as defined above, and a compound of formula The condensation reaction of the compound of (2) with the reactive functional derivative occurs spontaneously, or or a condensing agent, e.g. an organic or inorganic base, e.g. Occurs in the presence of natural amines or alkali metal carbonates.

Preferably functional derivatives of compounds of formula ■, such as esters and free carvone Said monofunctional derivatives of compounds of formula (1) with acids, such as half-ester derivatives thereof, The condensation reaction with the conductor is carried out using a condensing agent such as 1,1-carbonyldiimidazole. carried out in the presence of a disubstituted carposiimide, e.g. dicyclohexyl carposiimide. It can also be done.

The starting material of formula ■ and its functional derivatives, preferably its cis-28-isomer, are , for reduction, as described, for example, in European Patent Application No. 37,231. For example, indoline-2-carboxylic acid (preferably the 2S-isomer) or It can be produced by hydrogenation of indole-2-carboxylic acid and its derivatives. Ru.

A glazed verhydroindole or its functional derivative with the formula ■, e.g. ■It can be produced by hydrogenation of the corresponding indole and its functional derivatives. can.

One or both of the carboxyl groups may be die-cut by, for example, the same or different groups. Indoline-2-cal, rp acid of formula I or Berch of formula Said mono- or bis-functional derivatives of droindole-2-carboxylic acid may be diacids of the formula I or 1 or their monoester derivatives; ,formula %formula%() (wherein Z represents hydroxy or preferably a reactive esterified hydroxyl group) and R6 is any of the ester groups defined above and comprising: Represents: lower alkyl, such as methyl, n-nolopyl, i-nolopyl, n- Butyl or i-butyl; substituted lower alkyl, e.g. ω-amine, ω-mono - or N-dimethylamino-1α-carboxy or α-carboethoxy-( ether, propyl or butyl); aryl (lower) alkyl 38 For example, benzyl, (methyl-, methoxy-, chloro-) substituted benzyl, or is pyridylmethyl; lower alkanoyloxy-(lower)alkyl, e.g. baloyloxymethyl; 3-phthalidyl or (methyl-, methoxy-, chloro -) substituted 3-7 talidyl, (hydroxy-1 lower alkanoyloxy-1 lower a (hydroxy-) substituted lower alkoxymethyl, e.g. thyloxy-, methoxy-)ethoxymethyl; bicycloalkyl-oxycarbo Nyl-(lower R)alkyl, such as unsubstituted or lower alkyl-substituted bicyclo[ 2.2.1) Heptyloxycarbonyl-(lower)alkyl, advantageously borni 1dl-(lower alkoxy-carbonyloxy )-(lower)alkyl, for example 1-(methyne-, ethoxy- or propoxy- (oxy-carbonyloxy)-methyl, ethyl or propyl,) It can be produced by condensation with an esterifying agent.

The reactive esterified hydroxyl group 2 in the compound of formula It is a hydroxyl group diesterified with acid. The corresponding Z group is especially halo gens, such as chlorine, bromine or preferably iodine, also sulfonyloxy groups. , e.g. lower alkyl- or arylsulfonyloxy groups, e.g. Al is a tan-, ethane-, benzene- or toluene-sulfonyloxy group.

a carboxyl group and an active ester, which can optionally be in the form of a salt. The esterification reaction with a compound of formula and, for example, in the presence of a base.

Examples of bases include organic bases, such as organic amines, such as tertiary amines, e.g. For example, tri-lower alkyl amines such as trimethylamine, triethylamine or ethyl-diisopropylamine, N,N-no-lower-alkyl-anili N, N-dimethylamine, cyclic tertiary amines, e.g. N-lower - alkylated morpholines, such as N-methyl-morpholine, salts of the pyridine type; groups, such as pyridine, inorganic bases, such as alkali metals or alkaline earths. Hydroxides, carbonates or hydrogen carbonates of similar metals, e.g. sodium, potassium Calcium hydroxide, carbonate or hydrogen carbonate, or quaternary ammonium bases, such as tetraalkylammonium hydroxides, carbonates or hydrogen carbonates (for example, where alkyl is methyl, ethyl, propyl, isopropyl, butyl, etc.), oxane or oxirane, e.g. alkylene oxide, such as ethylene oxide or propylene oxide. Ru.

The dicarboxylic acid of formula ■ or ■ or its monoester is preferably first prepared as described above. a salt of an organic or inorganic base, especially a sodium or potassium salt. conversion and then reaction with a compound of formula X.

Compounds of formula X are known or can be prepared by methods well known in the art. can be built.

Compounds of formula X where 2 is a reactive esterified hydroxyl group are prepared in situ be able to. For example, a compound of formula Z by treatment with sodium iodide in acetone or acetonitrile. can be converted to a compound of formula can be carried out in the presence of sodium iodide using a chloro compound of

The esterification reaction is carried out in a suitable inert solvent or solvent mixture, e.g. acid amides, e.g. trimethylformamide, non-loginated hydrocarbons, e.g. For example, methylene chloride, carbon tetrachloride or chlorobenzene, ketone, tatoeha, acetic acid esters, such as ethyl acetate, or nitriles, such as acetonitrile. trill or at room temperature, or if necessary at low or high temperatures, from about -40°C to about 1 00°C, advantageously between -10°C and +40°C, and/or in an inert atmosphere, For example, it is carried out in a nitrogen atmosphere.

The esterification reaction of a carboxylic acid with an alcohol of formula X in which 2 is hydroxy has been described previously. in a known manner, preferably with an acid catalyst, such as sulfuric acid or boron trifluoride ether. preferably at an elevated temperature, advantageously in the range of about 40°C to 100°C. It will be carried out later.

The pharmacologically active compounds of the present invention can be used in effective amounts and in enteral or parenteral potency. It is useful in the preparation of pharmaceutical compositions comprising suitable excipients. active ingredients and , a) Diluents such as lactose, dextrose, sucrose, mannitol sol, sorbitol, cellulose and/or glycino, b) Junso magnesi um salt or calcium salt and/￥1: or jQ l) ethylene glycol , for tablets, and C) binders, such as magnesium aluminum silicate; Starch paste, gelatin, tragacanth, methylcellulose, sodium carboxylic acid dimethylcellulose and/or polyvinylpyrrolidone, optionally d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or foaming mixture 42 and/or e) tablets and gels consisting of absorbents, colorants, flavors and sweeteners. Latin capsules are preferred. Injectable compositions are preferably aqueous isotonic solutions. or suspension, and herbal medicines are often prepared from fat emulsions or suspensions. Manufactured. The composition can be sterile and/or contain adjuvants, e.g. , preservatives, stabilizers, wetting agents or emulsifiers, solubility promoters, osmotic salts and/or or a buffering agent. Additionally, the composition has other therapeutic value. Substances, such as other antihypertensive agents and /'-! May also contain bamboo diuretics. Wear. The composition is prepared by conventional mixing, granulation or coating methods and contains about 0. , 1 to 75%, preferably about 1 to 50% active ingredient. Weight about 50-7 A unit dose for a 0 kg dairy animal contains approximately 5 to 100 #+9 active ingredients. can have

The following examples are intended to be illustrative of the invention and should not be construed as limiting the invention. No. Temperatures are 6D in degrees Celsius and all parts are by weight. Keys not mentioned All evaporation is carried out under reduced pressure, preferably at a pressure of about 15-100 mmHg. implement.

Example 1 501 indoline-28-carboxylic acid ethyl ester hydrochloride, 91 g powder To a suspension of potassium carbonate and 45 ml of methylene chloride, add 5 ml of methylene chloride. Add all of the methylglutaroyl chloride in 3611 at room temperature while stirring.

Stir the mixture overnight at room temperature, cool on ice, and add 100 ml of water. I can do it. The organic layer is separated, washed with IN hydrochloric acid and water, dried and evaporated to give 1- (/l-carbomethoxybutanoyl)-indoline-2s-carboxylic acid ethyl ethyl Stell, melting point 88-90°C, is obtained.

The starting material is prepared as follows: 12° 1-acetylindoline- 2-carboxylic acid CN1ppon Kagaku Zasshi 87, 760 (1966)] and t-cinchoninone of 1721 in a hot evaporator at 1200 mA. Dissolve it in nol. The solution is allowed to stand at room temperature overnight and then at 0° C. for 4 days. White Strain the colored crystalline salt and discard. Evaporate the p liquid, add 1ooml water, This solution is adjusted to pH-1 with concentrated hydrochloric acid.

After 15 minutes, the product was collected by filtration and diluted with 250 ml of 2N aqueous hydrochloric acid three times for 50 min. After washing twice with 0 ml of water and then twice with 100 ml of ethanol, 1- Acylindoline-2s-carboxylic acid is obtained. Melting point 214-215℃; [ α〕. --133,3° (c=4 1165, ethanol).

A suspension of 375 g of the carboxylic acid in 380 ml of 2N aqueous hydrochloric acid was purged with nitrogen. Deoxygenate by bubbling through the solution, then reflux for 2 hours.

Cool it to room temperature and put it under the door with instillation insect soil, evaporate the U solution, and remove the residue and noethyl ether. When crystallized from lysopropanol, indoline-2s-carboxylic hydrochloride is can get. Melting point 133°C (decomposition); [α], = -7071° (C = 1, ethanol ).

34. of the above hydrochloric acid base in 350 ml of ethanol.　Y solution without external cooling Dry salt (L hydrogen saturated first).

The mixture was incubated at room temperature for 2 hours at p-4 to remove the solvent until crystallization started. Ru. The knitted fabric was poured into 400 ml of noethyl ether, cooled to 0°C for 1 hour, and i 7j When boiled in a pot, indoline-28-carboxylic acid ethyl ester hydrochloride is obtained. ; melting point 1.79-181°C; [α], = -63° (C = 1.385, eta Nord).

Example 2 507 1-(4~Carbonotogypukunoyl)- in 47ml methanol In a suspension of indoline-28-carboxylic acid ethyl ester, 47 ml of IN aqueous Add IJ hydroxide and stir the mixture at room temperature for 4 hours. room it Concentrate at room temperature and reduced pressure, acidify with concentrated hydrochloric acid while cooling, and form The precipitate is collected, washed with water, and dried to give 1-(4-carboxybutanoyl)-yn. Dorin-28-carboxylic acid is obtained; melting point 175-177°C; [69075m Suspension of 115' indoline-2s-carboxylic acid fZ salt in pyridine of 1 8.259 of 4-carbomethoxy-2-methylbucnoyl chloride was added to , and let the mixture stand overnight at room temperature. Pyridine is evaporated at room temperature and reduced pressure. The residue is cooled, acidified with 3N hydrochloric acid and extracted with methylene chloride. extract liquid was evaporated, the residue was dissolved in diethyl ether, and this solution was injected with 125 mJ of Combine with a solution of 10 ml of non-chlorohexylamine in hexane. Shen p3wo When collected, washed with hot vinegar and ether, and soaked in acetone overnight, dicyclohexyl Ammonium 1-(4-carphomethoxy-2-methylbutanoyl)-India Phosphorus-2S-carboxylate, melting point 203-205°C, is obtained: the corresponding The free base melts at 97-99°C.

The wet first starting material is described as an intermediate in Example 1 and the second It can be manufactured as follows: 611 4-carboxylic acid in methylene chloride of 964 g of oxalyl chloride f 5 Q me added to a solution of rubomethoxy-2-methylbutanoic acid (U.S. Pat. No. 4,052,511). I can do it. The mixture was refluxed for 2 hours, evaporated and 4-cal H? methoxy 2 -Methylbutanoyl chloride is obtained and its it7 is obtained without further purification. 2031 indoline-2S-carboxylic acid ethyl ester in 5 ml toluene + 2.55'+7) A solution of 2-(2-phenethyl)-glutaric anhydride, Heat to 70°C under nitrogen overnight. Evaporate it and remove the residue with diethyl ether. This solution was washed with IN hydrochloric acid and extracted with saturated aqueous sodium bicarbonate. do. The extract is cooled, acidified with hydrochloric acid and re-extracted with methylene chloride. organic extraction The liquid was completely evaporated, the residue was dissolved in diethyl ether, and the solution was poured into a 25 ml tube. 1 in xane. , 2 rnl of a solution of synchhexylamine. Birth The precipitate is filtered and washed with hexane to give nocyclohexylammonium 1- [4-carboxy-4-(2-phenethyl)-butanoyl]-indoline-28 A carboxylic acid ethyl ester, melting point 132-134°C, is obtained.

It is reconverted to the free acid with IN hydrochloric acid.

The starting material is prepared as follows: 29851-indoline-28-cal Boronic acid ethyl ester hydrochloride was mixed with 300 ml of saturated aqueous sodium bicarbonate and 1 00 ml of methylene chloride. Add 200 ml of aqueous layer Extracted twice with methylene, washed the combined organic layers with saturated aqueous sodium chloride and evaporated. Upon evaporation, indoline-28-carboxylic acid ethyl ester is obtained as an oil, Is this 1730C? The IR band is shown in n.

12 g of 2-(2-phenethyl)-glutaric acid [J,C in 75 ml of acetic anhydride hem, Soc, 1950, 1683] solution f: refluxed for 4 hours and evaporated. let Crystallization of the residue from noethyl ether gives the corresponding anhydride, mp 78 -80°C is obtained.

17.6 ml methanol and 17.6 ml IN aqueous sodium hydroxide 241 of 1-[4-carboxy-4-(2-phenethyl]-butanoyl]- A solution of indoline-2S-carboxylic acid ethyl ester was stirred at room temperature for 25 hours. Zeru. It is concentrated under reduced pressure at room temperature, the aqueous solution is filtered, acidified with hydrochloric acid, Extract with tyrene. Evaporation of the extract and crystallization from petroleum ether yielded 1-[ 4-carboxy-4-(2-phenethyl)-butanoyl]-indoline-2S- Carboxylic acid, melting point 136-138°C, was obtained 8 Following the method exemplified by the previous example, ph=1.2-phenylene and R1 = The following 1-(carboxyalkanoyl or -alkanoyl) of formula I where R2=R3=H Noyl)-indoline-2s-carboxylic acid, as well as derivatives thereof, are produced: 9 Similarly, the following are produced: The starting compounds for compounds 1.2.4.6.11 and 12 are each 3-cal Bomethoxy-2-methylpropanoyl chloride, 2-methylglutaric hydrate, 4-Carbomethoxy-2-methylgulono9noyl chloride, 3-methylgluta le and erythro or threo 4-carbomethoxy-4-(2-phenethyl)-2-methane. It is tilbutanoyl chloride. The starting materials for compounds 8 and 9 are as follows: It can be prepared by: 601 men-2,4-dimethylglue in 4 ml methanol. Talic anhydride [J.

The liquid was refluxed for 1 hour and evaporated, resulting in 11.1. jChlo4-carbomethoxy-2 , 4-dimethyl 7-ptanic acid is obtained. 1 in 50 ml of methylene chloride. Reflux for 2 hours with 0 Y of oxalyl chloride and evaporate the mixture. and acid chloride is obtained.

The corresponding threo-isomers are obtained analogously from the racemic anhydrides.

Example 7 lfI in 10 ml of methanol. Noyl)-indoline-2S-carboxylic acid (Example 3) at 0°C. Saturate with ammonia and store in a pressure cooker at room temperature for 4 days. evaporate it The residue was taken up in water, the mixture was acidified with 2N hydrochloric acid at 0°C, and a few drops of of methylene chloride is added to initiate crystallization. Filter this mixture and dilute the residue. Ethyl ether? l'Crush tle. ! :, 1-(4-carbamoyl-2- methylbutanoyl)-indoline-2S-carboxylic acid, melting point 192-194°C, is obtained.

Example 8 a) 1.439 indoline-2S-carboxylic hydrochloride in 15 ml pyridine 135 g of 4-carboethoxy-2R, 4R-dimethyl Add tilbutanoyl chloride. This reaction mixture is Stir for 3 hours at room temperature and evaporate in vacuo. The residue was dissolved in 20ml of 3N hydrochloric acid. Treat, extract three times with 10 ml of methylene chloride and evaporate the extract to dryness. obtained 1-(4-carboethoxy-2R,4R-dimethylbutanoyl)indoline- The 28-carboxylic acid was dissolved in 75 ml of ether and 2.2 ml of nocyclo Treatment with hexylamine yields the crystalline dicyclohexylammonium salt. It will be done. This was mixed with 40 ml of ethyl acetate and 45 ml of 5-aqueous potassium bisulfate solution. Stir in the mixture for 1 hour. Separate the ethyl acetate layer, wash with water, and add sulfuric acid) Dry with Jum and evaporate to dryness. When crystallized from hexane, the 1-(4-carbohydrate Ethoxy-2R,4R-tumethylbutanoyl)indoline-28-carboxylic acid Obtained; melting point 125-127°C, [α], = -159° (C = 0.2 ,ethanol〕.

b) The aforementioned 4-cal? Ethoxy 2R,/IR-dimethylbutanoyl chloride 4-carboethoxy-2R-methylbutanoyl chloride is used instead of By this, 1-(4-carpoethoxy2R-methylbukunoyl)indoline -28-carboxylic acid is obtained; melting point 133-135°C, [α]9--12 0. 5° (C = 0.2, ethanol).

c) Similarly, 1-(4-carboethoxy-2R-(sopropylbutanoyl) Indoline-2S-carboxylic acid is produced.

d) Similarly, position 5 of the indoline nucleus is substituted with methoxy, chloro or methyl. 1-(4-carboethoxy-2R,4R-dimethylbutanoyl)indo Phosphorus-28-carboxylic acid is produced.

The starting material is prepared as follows: 37 g of acetyl chloride in 10 ml of acetyl chloride. 2R-methylglutaric acid [J. Am. Chem. Soc. 7 Yu, 3383 ( 1955):] is stirred at 50° C. for 2 hours. This reaction mixture is evaporated to dryness to give 2R-methylglutaric anhydride; melting point 50-52 °C, [α], = +43.8° (c = 1.o, chloroform].24,4R-dime Tylglutaric anhydride, melting point 43-45°C, [α]. -1565° (C-10, chloroform) is 2R,4R-tumethylglutaric acid [α], = -3 5. It is obtained in the same manner from 5° (C = 2.0, ethanol).

Similarly, 2R-isopropylglutaric anhydride is converted to the corresponding 2R-isopropylglutaric anhydride. Lucurucric acid [Arkiv Kemi Mineral% Geol- B 2 3, 1 (1946)].

4. 2R, 4R-di54 of 179 in 0 ml of absolute ethanol A solution of methylglutaric anhydride was heated overnight and evaporated to dryness, resulting in 4-cal Boethoxy-2R,4R-dimethyl-butanoic acid is obtained as an oil; [α]o- −494° (C=1.0, ethanol).

] A solution of 291 2R-methylglutaric anhydride in 3 ml of ethanol was Allow to flow for an hour and evaporate to dryness. 25 ml of a solution of the above oil in 25 ml of ether 5 in hexane. When treated with Oml of dicyclohexylamine, 4-cal Boethoxy-2R-methylbutanoic acid is dicyclohexylammonium salt, melting point 9 8-100°C. Convert to free acid with IN hydrochloric acid and extract with ethyl acetate. Then, 4-carboethoxy-2R-methylbutanoic acid is obtained as an oil; ], = -20,9° (C = 1.0, chloroform).

1271 of 4-carboethoxy-2R,4R-dimethyl in 15ml of methylene chloride A solution of tyl-butanoic acid was treated with 1.7 g of oxalyl chloride and heated under reflux for 3 hours. , evaporated to dryness to give 4-carboethoxy-2R.

4R-dimethyl-butanoyl chloride is obtained; NMR peak = 18.25 ．． 4.1 ppm, similarly, 4-carboethoxy-2R-methylbutanoyl Chloride (NMR 20.24.4.3 ppm) and 4-carboe Toxy-2R-isopropylbutanoyl chloride is obtained.

5-methoxyindo6-2-carboxylic acid, 5-chloro-indoline-2-carboxylic acid carboxylic acid, and 5-methylintrine-2-carboxylic acid as described in Example 1. obtained from the corresponding substituted indole-2-carboxylic acids according to the method described in .

Example 9 a) 2 in 40 ml of methylene chloride containing 4.8 g of anhydrous sodium carbonate To a solution of 63 g of ethyl indoline-2S-carboxylate, 239 g of 4 -Carboethoxy-2R,4E-dimethylbutanoyl chloride is added. this The reaction mixture is stirred at room temperature overnight and then extracted with 2ON water. 15 organic layers Washed with 1 ml of IN hydrochloric acid and 15 ml of water, dried (Na2SO4) and evaporated. ethyl 1-(4-carboethoxy-2R,4R-tumethylbutanoyl) -indoline-28-carboxylate is [α]0--130.10 (C=1 ．． 0, ethanol).

b) Similarly, 4-carboethoxy-2R-methylbutyl chloride was used as the acylating agent. Ethyl 1-(4-carboethoxy-2R-methylbutanoyl) -Indoline-28-carboxylate is an oil (NMR peak: 12.41-43 ．． 49.6.7 and 7.2 ppm).

6 Example 10 5'Q ml of [321 ethyl indoline-2S-carboxylic acid in methylene chloride] In a solution of sylate hydrochloride and 1471 triethylamine, 2.345' of 4 -carboethoxy-2R-methylbutanoic acid was added, and in the next step 297 g of 1-(3- Add trimethylaminopropyl)-3-ethylcarposiimide hydrochloride. reaction mixture The mixture is stirred at room temperature for 3 days and poured into water. Separate the organic layer and add 30 ml of IN salt. acid, 30 mL of water and 30 mL of 10% aqueous sodium bicarbonate solution. Wash. The organic layer was dried with sulfuric acid) and evaporated to dryness to give ethyl 1 -(4-carboethoxy-2R-methylbutanoyl)-indoline-28-cal boxylate (identical to the compound of Example 9b)) was obtained in 10 ml of toluene. 45 g of ethyl indoline-28-carboxylate and 2R of 0301.

The solution of 4R-dimethylglutaric anhydride is stirred at 70°C for 18 hours. this The entire reaction mixture was cooled to room temperature and washed twice with 5 ml of IN hydrochloric acid, 5% of lQml Extract twice with sodium bicarbonate. Part of the combined bicarbonate solution'f: 4.0 m Acidify with 12N hydrochloric acid and extract three times with 10ml of methylene chloride. -match The diluted methylene chloride portion was dried over Na2SO4 and evaporated to give ethyl 1-(4 -carboquine-2R,4R-tumethylbutanoyl)-indoline-28-carbo The xylate is an oil (NMR peaks: 10-1.3.415.510.72 and 8 ．． 4 ppm) is set to 1.

Example 12 a) 34f in 30ml methanol! Ethyl 1-(4-carboethquin-2) Solution of R,4R-dinotylbutanoyl)-indoline-28-carboxylate To the solution, add 28.2 ml of IN aqueous sodium hydroxide solution.

The reaction mixture was stirred at room temperature for 4 h, evaporated to remove methanol, and 3.5 m Acidify with 1 liter of concentrated hydrochloric acid.

This mixture was extracted four times with 10 ml of methylene chloride.

The combined extracts were dried over FK sodium chloride, evaporated to dryness, and the residue was dissolved in ether. - When recrystallized from petroleum ether, ■-(4-carboxy-2R,4R-dimethyl (Tylbutanoyl)-indoline-28-carboxylic acid is obtained; 132-134 °C, [α],' = -144° (C = 1.0, ethanol).

Similarly, 0.46P ethyl 1-(4-carboxy-2R, 4R-tumethylbutano )-indoline-2s-carboxylate (Example 10) was hydrolyzed and the raw Crystallization of the product from water yields 1-(4-carboxy-2R,4R-dimethylbutylene). Noyl) indoline-2S-carboxylic acid hydrate is obtained; melting point 93-95°C, [α], = -142.8° (C-1, etano no.

b) Similarly, ethyl 1-(4-carboxy-2R-methylbutanoyl)indoly Hydrolysis of 9-28-carboxylic acid produces 1-(4-carboxy-2R-methyl Butanoyl)-indoline-28-carboxylic acid is obtained, which is crystallized from ether. Crystallizes; 147-149°C, [α'], -125° (C = 0.2, ethano ). Similarly, 1-(4-carboethoxy-2R-methylbutanoyl)-yn Hydrolysis of dorine-23-carboxylic acid yields the 1-(4-carboxylic acid isolated above). diacid identical to (x-2R-methylbutanoyl)-indoline-2S-carboxylic acid is sung.

Example 13 A solution of 90 m9 of indoline-28-carboxylate desalination was prepared as detailed in Example 8. The 4-carboethoxy-2R- Treatment with methyl-4R-phenethylbutanoyl chloride results in 1-(4-carboxylic acid). ruboethoxy-2R-methyl-4R-phenethylbutanoyl)indoline-28 - Cal 7+? phosphoric acid as dicyclohexylamine salt, melting point 146-149°C. can get.

The starting material is partially molecular etrahedron Letters 1980°42 According to the general method described in 33-6, it is prepared as follows: Aqueous sodium hydroxide (IN, 25 ml)’i, 50 ml CF2Cl2 201 Noshiichi Zorolyl (U.S. Pat. No. 3,935,280) in a solution of After cooling the reaction mixture to 0°C, 401 4-phenylbutyric acid chloride was added and the reaction mixture was cooled. The reaction mixture is stirred vigorously for 4 hours at 0°C and then for 1 hour at room temperature.

Dilute the reaction mixture in equal volumes and separate the layers. Wash the organic phase with 30 ml of water, Dry with Na25O4A2CO3. When the solvent is evaporated, 441 N-(4- phenylbutanoyl)-L-prolinol is obtained; IR peak: 3280 and and 1605crn-1% [α]o--40,3° (methanol). 2051 N-methyl-N,conocyclohexylcarposimidium iodide [Ang ew, Chem, Int, Ed, 11, 229 (1972) 531 R-(-)- in 200 ml dry tetrahydrofuran under 3-benzyloxy-2-metelpronoenol [He1v, Chim, Act a 60.

925 (1977)) and the reaction mixture was stirred at room temperature for 14 hours.

The solvent is evaporated and 201R1 of ether and 5 rnl of garlic are added.

The resulting yellow solid was collected and chromatographed on 200P silica gel. When attached and eluted with 7 tane, 6,68 ff of S(t)-3-benzyloxy -2-methylpropyl iodide is obtained; Rf=0.60 (9:+11. 1° (MeOH). N-(4-phenylbutanoyl)L-prolinol f: 20 ml of dry tetrahydrofuran and 50 rul of tetrahydrofuran. of lithium diisozologylamide (15.6 mmol) at 0°C. Drip into the base. After 30 minutes at 0°C, 203 g of S-(+)-3-benzyl Oxy-2-methylpropyl iodide in 2 ml of dry tetrahydrofuran Add dropwise. The reaction mixture was stirred at 0°C for 5 hours and at -15°C for 15 hours, removing the excess. of saturated ammonium chloride solution to 0°C. Pour the reaction mixture into 30 ml of ether. Dilute with water. Separate the layers and add 15 ml of IN HCA to the organic phase f16rnl. brine, 15 ml of saturated bicarbonate), washed with IJum solution, sodium sulfate Dry with.

Evaporation of the solvent gave 36 g of oil, which was filtered through 60P silica gel. , ~2.3 when eluted with ethyl acetate! i′ N -(R,R-5-benzyloxy C-4-methyl-2-7enetelbentanoyl) L-prolinol is obtained; Rf 0.51 (EtoAc/5i02).

2.01 N-(R,R-5-benzyl A solution of L-prolinol (oxy-4-methyl-2-phenethylintanoyl) , reflux under nitrogen for 15 hours. Evaporate the solvent and remove the fluoride 'c609- Chromatographed on lica gel and eluted with panthane:ether (2:1). Then, 0.65P of ethyl R,R-5-benzyloxy-4-methyl-2-phene Netylpentanoate is obtained; Rfo, 37 (9: panthane of i: Ether/5102), [α]. +285°CEtOH).

O,, f+ in 50 Inl of absolute ethanol! ? Ether of R,R-5-bendi A solution of 0.5% Water in the presence of 5% palladium on charcoal catalyst for 3 hours at 40 psj and room temperature. Become basic. The catalyst is then removed by filtration through Celite and the solvent fN is evaporated to give 0. 415'ethyl R,R-5-hydroxy-4-methyl-2-phenethylpenta Noate is obtained; Rf = 0. ．． 36 (1:1 Pankun-Ether ).

Ethyl R, R-5-hydroxy-4-methyl-2-phenethyl ethyl entanoate) (0,35f　) under nitrogen at room temperature for 15m/! dry dimethylform Dissolves in Muamide. Add pyrinonium dichromate (251) and mix the reaction. Stir the mixture for 15 hours at room temperature and then pour into 1.50 ml of water. Aqueous solution Extract with tel (4X 40 ml). Ether extract once with 30ml of water , then 20 ml of a 1:1 solution of sodium bicarbonate:potassium carbonate (PH=10 ．． Extract 3 times in step 5). Acidify the ring-based cleaning solution to pH=2 with concentrated sulfuric acid, while keeping the temperature Maintain temperature at 5-10°C and extract with ether (4 x 20 ml). ether Wash the extract with 20 ml of brine and dry with % Na2SO4/MgSO4. do. Upon total evaporation of the solvent, 0.28p of 4-carboethoxy-2R-methyl-4 R-(phenethyl)butanoic acid is obtained; Rf=0.50 (99:1:100) Ether: AcOH: hexane), [α)D-4,91° (EtOH).

4-Carboethoxy-2R-methyl-4R-(phenethyl)butylene in methylene chloride When treated with oxalyl tannate, 4-carboethoxy-2R-methyl-4 R-Phenethyl-butanoyl chloride was prepared according to the method described in Example 10, 7 9 m9 of ethyl indoline-28-carboxylic hydrochloride was converted into 96.5 m9 of 4-carbohydrate. ruboethoxy-2R-methyl-4R-(phenethyl)butanoic acid (see Example 13) ), 005 ml of triethylamine and 66.5 m9 of 1-(3-dinothi react in the presence of (ruaminopropyl)-3-ethylcardiimide hydrochloride. and ether 1-(4-carboethoxy-2R-methyl-4R-phenethylbutano yl) indoline-28-carboxylate is obtained: Rf = 0.6 (9: I CJ (Cl3-CH30ru'j''+02).

A solution of the diester above 87mf/0 in 4 ml methanol at room temperature. ．． Add 2 ml of 2.2N aqueous potassium hydroxide and 1.5 ml of water and start the reaction. Stir the mixture on a vortex for 2 hours. The reaction mixture was prepared as above (see Example 12). When finished, 1-(4-carboethoxy-2R-methyl-4R-phenethylbutano) Noyl) indoline-28-carboxylic acid is obtained, which is dicyclohexyl-28-carboxylic acid. mp 145-148°C, and which is the compound of Example 13 It is the same as a thing.

When further subjected to basic hydrolysis as follows, 1-(4-carboxy-2R-methyl 4R-phenethylbutanoyl)indoline-2S-carboxylic acid is obtained.

0.28 in 3 ml of methanol! ? 1'-(4-carboethoxy-2R -Methyl-4R-phenethylbutanoyl)-indoline-28-carboxylic acid solution Add 2 ml of IN aqueous sodium hydroxide to the solution. The reaction mixture was incubated at 55°C for 6 Stir for a while and then evaporate.

Wash the residue in 3Q ml of water with 15 ml of diethyl ether.

The aqueous layer was acidified to PH2 with IN aqueous hydrochloric acid and Extract with 3×25 ml of methylene chloride. These combined organic parts are sulfurized. Dry with magnesium acid and evaporate. Crystallize the residue from 1'-2/tan and 1-(4-carboxy-2R-methyl-4R-phenethylbutanoyl)-y ndrine-28-carboxylic acid is obtained; melting point 137-13q°C, [α]. −1 62° (C-0,25, chloroform).

Example 15 Preparation of 10 000 tablets each containing 5 m9 of the active ingredient of Example 5: prescription 1-[4-carboxy-4-(2-phenethyl)-butanoyl]-indoline- 2S-carboxylic acid so, oog lactose] 157.00! i' Cornstarch 75.01 Polyethylene glycol 6000 75. 'OO! i’ Talc powder 75.00 g Magnesium stearate 18.005' Purified water Sufficient amount procedure Pass all powder through a sieve with an opening of 06 mm. Then the drug substance, lactose; Combine half of the gnesium and cornstarch with the talc, stearic acid in a suitable mixer. - Mix in a bowl. Suspend the other half of the cornstarch in 40ml of water and add this Add the suspension to a boiling solution of polyethylene glycol in 150 g of water. formation powder) and granulate it with additional water if necessary. . The entire granule was dried at 35°C overnight, broken through a sieve with a 1.2 mm opening, and the diameter was 6.4 mm. Compress into tablets with a concave throat punch, each top containing 1 omg of the active ingredient of Example 2. Manufacture of 10000 capsules with: prescription 1-(4-carboethoxy-2R,4R-tumethylbutanoyl)indoline-2 S.-Carboxylic acid 100.0.9 Lactose 1800. (1 Talc powder] 00. tl Pass all the powder through a 06-hole sieve.

The drug substance is then placed in a suitable mixer and mixed first with Merck and then with Lactose. Mix until homogeneous. 3 capsules delivered to 200m9 by capsule filling machine Fill again. Similarly, tablets or turnips may be prepared with the remaining compounds of the invention, e.g. Prepared from compounds exemplified by other examples in this specification.

Example 17 0781 ethylindoline-2S-carboxylene in 40ml methylene chloride 4R-carboethoxy-6-phenyl-hexane of t3in4.0.907 Into a solution of acid and 0.48 ml of triethylamine, add 0.72 g of 1-(3-di Add methylaminopropyl-3-ethylcarboimide salt. reaction mixture Stir things at room temperature for 4 days. Add 300 m, l of diethyl ether , 25m/! of this mixture! of water, 25 ml of 2N aqueous hydrochloric acid and 25 ml of saturated Wash with aqueous sodium bicarbonate solution. Dry the organic layer with magnesium sulfate and evaporate. When allowed to do so, ethyl 1-(4-carboethoxy-4R-phenethylbutanoyl)- IA 1' IJ 7-2 S-carboxylate is obtained; [α]o--6 43° (C=0.85, chloroform).

The starting material for the above procedure is prepared as follows: 59 m/! Tetrahydrof 8 during the run. N-(4-phenylbutanoyl)-L-prolinol of lOP, 71 mmol of tiumnoisoprobil in 270 ml of tetrahydrofuran Add to amide. 1 hour later, 3. Add 1 ml of allyl bromide. -20℃ After 1 hour at rest, the reaction mixture f is diluted with 250 ml of diethyl ether.

All layers were separated and the organic phase was added with 200 ml of 2N aqueous hydrochloric acid and 200 #+1 After washing with aqueous sodium chloride solution, drying with sulfuric acid, and evaporating, , N-(2R-allyl-4-phenyl-butanoyl)-L-prolinol was obtained. be; [α]. --235° (C-1, methanol).

7651 N-(2R-71J Roux 4 in 350ml 110% ethanolic sulfuric acid) -phenyl-butanoyl)-, L-prolinol solution is refluxed for 10 hours. .

The solvent was evaporated and the residue was mixed with 100 ml of water and 200 ml of diethyl ether. to be distributed between. Separate the layers and add 50 ml of saturated sodium bicarbonate solution to the organic phase. After washing with J syl--phenyl-butyrate can be obtained; Rf=o42('9:1.hexa ether/5in2).

To 22.2 ml of 1 mole borane in tetrahydrofuran at 0°C, 31 g of 2 - Add methyl-2-butene. After 2 hours at 0°C, 47g of ether 2R-allyl - Add 4-phenyl-butyrate. After 2 hours, add 7.3 ml of 3N sodium hydroxide. Triuno, aqueous solution 7. 'Add 3 ml of 30% aqueous hydrogen peroxide. 30 minutes Afterwards, the reaction mixture is diluted with 75 ml of diethyl ether. Separate all layers and remove water layer Extract with 2×25 ml of diethyl ether. combined ether extraction Solution f 25 ml of 1% aqueous sodium carbonate solution and 25+++ l of saturated sulfite Wash with aqueous sodium solution. Dry the organic phase with magnesium sulfate and evaporate. and ethyl 5-hydroxy-2R-7enethyl-internoate is obtained; N MR Beeknia 3.425.3.61, 1.55-278 and 1.27 pp m.

4.97 g of ethyl 5-hydroxy in 100 ml of dimethylformamide 2R~Phenethyl-nithanoate, 37.4p pyrinonium nochromate Add. The reaction mixture was stirred overnight and then poured into 300 ml of ice water. Pour into. Wash this mixture with 100 ml of aqueous solution of carbonic acid and IJ.

The aqueous phase was acidified to pH 2 with concentrated sulfuric acid and extracted with 3×100 ml of diethyl ether. do. These ether extracts were dried with magnesium sulfate and evaporated. Then, 4R-carpoethoxy-6-phenylhexanoic acid is obtained; [α].

-1432° (C-1, methanol).

Example 18 Ether 1-(4-carboethoxy-4R-) of 1101 in 5 ml ethanol Phenethylbutanoyl indoline-28-carboxylate, 1. ,07ml Add 221N aqueous potassium hydroxide solution. Stir the reaction mixture at room temperature for 1 hour. Stir and then evaporate. 20 ml of saturated bicarbonate (IJ) aqueous solution Residue’! : Wash with 20 ml of diethyl ether. Water layer is 2N aqueous Adjust the pH to 1 by brine and extract with 2×25 ml of methylene chloride. If The diluted methylene chloride portion is dried over magnesium sulfate and evaporated to give 1-( 4-Carboethoxy-4R-phenethylbutanoyl)-indoline-28-cal Bonic acid is obtained; melting point 100-102°C, [α], = -83.4° (c = 1, 13, chloroform).

Example 19 0.0 in 8 ml methanol. 6 7 9-1-(4-carboethoxy-7 49 ml of 1R-phenethylbutanoyl)-indoline-28-carboxylic acid Add INN lithium hydride aqueous solution. The reaction mixture was stirred at 55°C for 8 hours. , then evaporated. 3. Dissolve the residue in 0 ml of saturated aqueous sodium bicarbonate solution. , 25m+! Wash with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid, Extract with 2 x 25 ml methylene chloride.

The combined methylene chloride portions are dried over magnesium sulfate and evaporated. residue is crystallized from pentane. 1-(4-carboxy-4R-phenethyl-bu Tanoyl]-indoline-2S-carboxylic acid is obtained; melting point 132-135°C , [α], = -791° (C = 0.81, chloroform).

Example 20 5.0g ethylindoline 7O in 40ml toluene In a solution of -2S-carboxylate hydrochloride and triethylamine of 221, 3 11 (2R,4R)-dimethylglutaric ice::'Il+':1;:J Stir the dough at 80℃ for 4 hours, then leave it at room temperature. Cool and wash with 10 ml of IN hydrochloric acid and 1.0 ml of water. Sulfurize the organic layer Dry with sodium chloride and evaporate. Residue t diethyl ether-hexane When crystallized from )-ytrin-2S-carboxylate salt obtained; melting point 1.10-112 °C, [α]D-6.59-ethyl 1-(4-carboxylate) in 50 ml methanol Ethoxy-2-isopropylbutanoyl)-indoly7-28-carboquinole To the above solution, add 52 ml of INzk sodium oxide aqueous solution. This reaction mixture Stir the material at room temperature for 2 hours, then evaporate the methanol. 5 aqueous residue Acidify with rpl of concentrated hydrochloric acid and extract with 3×25 ml of cyclized methylene.

The combined organic portions are dried over sodium sulfate and evaporated. Remove the residue 1-(4-carboquine-2-isopropylbutanoyl) )-yttrin-2S-carboxylic acid is obtained; melting point 184-186°C, [α ], --81° (C=02, ethanol).

The starting material is produced as follows.

A solution of 1401 of 2-inpropylglutaric acid in 80 ml of acetyl chloride was Stirring at 0°C for 2 hours and then evaporating yields 2-1 sozolopylglutaric anhydride. NMR peak: 098.189.243 and 2.85 pp m.

Solution of 401 2-isopropylglutaric anhydride in 2Qrnl ethanol The solution was refluxed for 3 hours and then evaporated to give 4-carboethquin-2-isopropropylene. Pyrbutyric acid is obtained; NMR peaks: 476.231.184.121 and 0.95ppm.

562g ethylindoline-28-carboxylene in 8Omt methylene chloride Hydrochloric acid! , 5.0 g of 4-cargiethoxy-2-isopropylbutyric acid and 2. In a solution of 5 g of triethylamine, 5.21.9' of 1-(3-trimethylamino Add propyl)-3-ethylcarposiimide hydrochloride. Bring this reaction mixture to room temperature. So I stirred it up all night. The reaction mixture was mixed with 4 (Jml of water, 30ml of IN hydrochloric acid and and 30 ml of saturated aqueous sodium bicarbonate solution, dried and evaporated. [chill]-(4-carboethoxy-2-isozolopyl-butanoyl)-indoline -2S-carboxylate is obtained; NMR peak near 16.678, 2 511, 422, 3.31.2.31, 198, 122 and 0.95 p pm 0 Example 22 4.09-indoline-28-carboxylic hydrochloride in 40 ml of toluene and 2. 2.84 g of 3,3-methylglue was added to a solution of triethylamine in OF-. Add acid anhydride. The reaction mixture’Jh was stirred at 80°C for several hours and then evaporated. let The residue was partitioned between 25 ml of IN hydrochloric acid and 25 ml of methylene chloride. let Separate the organic layer, wash with 20 ml of water and add 2 x 20 ml of saturated sodium bicarbonate. Extract with lium aqueous solution. Acidify the bicarbonate extract with 5 ml of concentrated hydrochloric acid and 25111+1: Extract with LD methylene chloride. Dry the organic layer with sodium sulfate and evaporate. Crystallization of the residue from ether-\xane yields 1-(4-carboxylic acid). xy-3,3-nonoterubutanoyl)-yn)゛-2S-carvone The acid is obtained; melting point 132-133 °C, [α]o-10 in toluene 5-chloro4indoline-2-carboxylic hydrochloride of 0431 and triethyl of 0431 Add 0.55 g of 2R, 4R to methylglutaric anhydride to the amine solution. . The reaction mixture is stirred at 80° C. for 35 hours and then evaporated. 2 residues Partition between 0ml IN hydrochloric acid and 20ml methylene chloride. methylene chloride layer Wash with 10 liters of water, then 2×1. Oml of saturated bicarbonate) I Extract with Jum aqueous solution. Acidify the bicarbonate extract with 2.5 ml of concentrated hydrochloric acid, Extract with 3×10 ml of dichloromethane.

These organic extracts are dried over IJ sulfuric acid and evaporated. Residue sound 7 Dissolve in ml noethyl ether and 0.4 g dicyclohexylamine.

The product is filtered and recrystallized from ethyl acetate to give 1-(4-carboxine-2R ,4R-tunotylbutanoyl)-5-7/roloindoline-2-carboxylic acid bis -Non-chlorohexylammonium salt; 185-187℃, [α] 9--2650° (C=0.2, ethanol).

[Mr.]-(]4-carboquine-2R,,4R-tumethylbutanoyl- Bis-zinchlorohexylammonium 5-methyl-indoline-2-carboxylic acid It is manufactured by a manufacturer; melting point: 198-200°C, [θ] 1. -→-09° (C = 0.2, ethanol).

Similarly, 1-(4-carboquine-2R,4R-tunotylbutanoyl)- 5-nodoquinitrin-2S-carboxylic acid is produced; melting point 150-152 °C, [α1lll, = -13 (10 (C = 0.2, ethanol).

74 The starting material is prepared as follows: 20p of 5-methoxyindole-2 -carboxylic acid (J, Chem, Soc, ] ] 970, 865) and 200 The mixture with ml acetic anhydride is refluxed for 2 hours and cooled to room temperature. filter it , evaporate solution F and stir the residue in 300 ml of water. excess bicarbonate ) Add IJum and stir the mixture for 3 hours, then add 2U ml of Wash with diethyl ether. Acidify the aqueous layer with concentrated hydrochloric acid to pt (=1) and filter. and 1-anatyl-5-methoxyindole-2-carboxylic acid is obtained; melting point 173-175°C.

A solution of 1657 of the above carboxylic acid in 250 ml of ethanol was added to 1.01 of the acid. Hydrogenate in the presence of platinum chloride at 1 atm. After 2 hours, the mixture was filtered and the P solution was diluted with 10 Concentrate to 0 ml. After standing overnight at 0°C, it was filtered and colorless crystals of 1- Obtain acetyl-5-methquinindoline-2-carboxylic acid: melting point 164-]6 7℃.

The 6.051' was refluxed for 2 hours in 6 (Jml) of 2N aqueous hydrochloric acid and the mixture evaporate. Dissolve the residue in 50 ml of isozolo-gnol until the solution becomes cloudy. Add diethyl ether to the desired amount. After cooling to 0°C and filtering the precipitate, 5-meth Oxytutrin-2-carboxylic hydrochloride is obtained; melting point 90-92°C (min M) .

(substituted indoline-2-carboxylic acid of jtl, i.e. 5-chlorouttrin -2-carboxylic hydrochloride, melting point] 65-], 67°C, and 5-methyl Indoline-2-carboxylic hydrochloride, melting point 171-173°C, was prepared in the same manner as above. be done.

151 4-cyanobutyric acid, 3.0P ethyl indo in 75ml methylene chloride Dissolution of phosphorus-28-carboxylate hydrochloride salt and 135 g of triethylamine The 1-(3-trimethylaminopropyl)-3-ethyl car of 381 is added to the liquid. Add hydrochloride.

The reaction mixture was stirred at room temperature for 3 days. Reaction mixture f50 ml water, 50 ml ( Wash with 0.02N hydrochloric acid and 50 ml of saturated aqueous sodium bicarbonate solution. Organic layer is dried over magnesium sulfate and evaporated to give ethyl 1-(4-cyanobutanoyl). IR)-indoline-28-carboxylate can be obtained; IR? ff:22'4 0°]]70 and 1660Crn.

2.31 ether 1- in 30 ml tetrahydrofuran and lomt water (4-Cyanobutanoyl)-indoline-28-carboxylate, 88ml of IN lithium hydroxide solution is added. The reaction mixture is stirred at room temperature overnight.

Dilute this reaction mixture vD with 50 ml of water and wash with 50 ml of diethyl ether. 6 Ru. The aqueous layer was acidified with kJoml of 2N hydrochloric acid and extracted with 2 x 5゜ml of noethyether. put out When these extracts are dried with magnesium sulfate and evaporated, ]-(] 4-Cyanobutanoyl-indoline-28-carboxylic acid is obtained; melting power 98- 10 (J°C, [α], -] 12.fi° (C = 0.9, ethanol).

26 g of 1-(4-cyano) in 50 ml of ethanol and 50 ml of water at 0°C. A solution of (butanoyl)-yttrin-2S-carboxylic acid was saturated with hydrogen chloride gas. let The reaction mixture is then stirred for 1 hour at room temperature. Reaction mixture fc　□℃ Cool and add 50 ml of water. After 10 minutes, the reaction mixture was concentrated under reduced pressure to remove the residue. Take 2×50 ml of Eldel. The combined ether part is diluted with sulfuric acid. Dry with magnesium and evaporate. Crystallize sardium from edel-hexano and ethyl 1-(/I-carH?ethoxybutanoyl)-indoline-2S-car Luboquine rate is obtained; melting point 72-73°C, [α:], = -81. ．． 7° ( C=0.35, ittrin-28-carboxylic hydrochloride (201,44g) and Bibiritsuno (790 mJ) was added using a mechanical stirrer, dropping funnel (nitrogen inlet), and condenser ( 2 with a Drierite tube for the nitrogen outlet sump) and a nitrogen atmosphere. Pour into a round bottom flask. Cool this weakened solution in a water bath and 4-(carboetogine)-2R,4R-trimethylbutanoylchloride l゛( 189,6j7) slowly over 20 minutes. After another 10 minutes, remove the water bath and stir the stirring mixture vigorously for 3 hours while passing a stream of nitrogen over it. Pirino Most of the water was stored at room temperature in a rotary evaporator connected to a vacuum pump (0.1 mHg). The residue was then cooled in a water bath and treated with 200 ml of i6 acid to approx. acidify slowly. Extract this solution with 3 x 200 ml of methylene chloride and washed with organic extract f　　　　　　　ml of 3N hydrochloric acid and 200ml of water. and treated with magnesium sulfate and Florisil. filtered , evaporated in a rotary evaporator and then in a high vacuum pump (temperature at /IO °C neck) A crude product is obtained, which is left to stand for further crystallization; (C= 0663, ethanol). The product was stirred in anhydrous ether for 2 hours.

The product was then filtered, washed with ether, and dried under vacuum for 6 hours to yield Example 8a. ) purified compound of 1-(=1-carboetogine-2R,4R-dimethyl Butanoyl)-inotrino 28-carboxylic acid can be obtained: m, p, ]] 28 ethanol).

The starting material W is prepared as follows: condenser, nitrogen atmosphere and magnetic stirrer. Into a 10100 O round bottom-neck flask with 5° (C=1.038, chloroform)] (178,65!i’) and anhydrous ether Tanol (357.3ml) f: Supply. 1 hour in a solution stirred with nitrogen. Lather up for a while and get to know people. The mixture was then brought to reflux and kept at this temperature under nitrogen overnight. Stir. After cooling, excess ethanol is removed in a rotary evaporator (bath temperature up to 45°C). Remove and dry for 4 hours at 0.1 mmHg with occasional heating and stirring. On drying, an oil was obtained which was dissolved in ether (200 mA') and saturated heavy carbon. Extract with sodium acid solution (5X 200 ml). Basic aqueous solution in water bath Cool, then slowly acidify with concentrated hydrochloric acid to PHHg, then solid chloride. Saturate with IJum. Extract this mixture with ethyl acetate (5 x 200 ml) Ru. The ethyl acetate extract was converted with sodium sulfate, filtered, and the solvent was removed on a rotary evaporator. P, then stirred for 2 hours at 0.1 miHg and room temperature. Upon removal, N4-carboethoxy-2R,4R-tumethylbutanoic acid is obtained; α]D=-44.1° (C=1.435, ethanol).

]00 (Jmt capacity round bottom flask equipped with magnetic stirrer, dropping funnel and nitrogen atmosphere) 4-(carboethochino)-2R,4R-tunotylbutyric acid (174,7 5g). The stirred reaction was cooled in a water bath and treated with oxalyl chloride (245 m 1) slowly over 20 minutes. This mixture is cooled in a water bath for an additional 4 Stir for 0 minutes, then stir at room temperature for 2 hours in a nitrogen atmosphere. excess of oxalyl chloride is evaporated in a rotary evaporator and the residue is then evaporated under high vacuum (01 nm Hg, room temperature) for 1 hour, 4-carboethquin-2R,4R-Tumethi Loubutanoyl chloride, 5 [α], = -30.10 (C = 0.91fi, chloroform), is obtained, and this is used directly in the above condensation reaction.

3 above” IL engineering 179 of 4-(pinomaloyloxymethoxycarboxylic acid) in 25 mg of pyridine at room temperature. (bonyl)-2R,4R-tumethylbutanoyl chloride, indoline-28- Add carboxylic hydrochloride (1,2F). Stir the reaction mixture at room temperature for 3 hours. Then evaporate.

The residue was dissolved in 75 mj saturated aqueous sodium bicarbonate solution and added to 2 x 50 ml evaporators. Wash with water. Acidify the aqueous layer with 10+++ l of 2N aqueous hydrochloric acid and add 3×75 Extract with methylene chloride. Dry the combined methylene chloride layers with magnesium sulfate. Drying and evaporation yields 1-44-(pivaloyloxymethoxy-carbonyl 4R -dimethylbutanoyl]-indoline-28-caldic acid is obtained; m. p. 109-112°C, [α], = - 1 3 6.2° (C = 0.94, ethanol ), NMR (CDC), ): 1.2, 18, 2.5, 3.35, 5.1, 5 ．． 75.

7, 2, 8.3, 9.4ppm: IR (CHC7,): 350 0-3200, 2950.1740crn 0 The starting material was produced as follows. It will be done.

3. 50 g of 2R,4R-dimethylglutaric anhydride; 6 5 Ben from me3 When the mixture with dialcohol was stirred at 85°C for 3 hours, 4-(carbobenno Oxygen NMR (CDC) 3): 1.2, 1. , 8, 2.6, 5.2, 7. 4.11.2ppm0 soil acid (3.3y) was added to 5.0g me of 221N hydroxide. Treat with lium. Evaporate this solution. Add toluene (100ml) and When the mixture of is evaporated, potassium 4-(carbobenoloxy)-2R,4 R-dimethylbutanoate is obtained.

Chloromethyl pivalate (2.56y-) in 50 mg of toluene was added with sodium iodide. Add thorium (2.54F). The reaction mixture is stirred at room temperature for 3 hours.

The reaction mixture is filtered and the lachrymal fluid is evaporated. in 25 mg of trimethylformamide. The residue was treated with potassium 4-.(carbobendi 2R,4R-dimethylbutanoate (3.72) is added. this The reaction mixture is stirred at room temperature for 18 hours and then evaporated. 150m of residue ( ’ in ether, 3 x 10 ml of a 10% aqueous solution of sodium bicarbonate and Wash with 3 x 10 ml of saturated aqueous sodium chloride solution. Magnesium sulfate removes the organic layer. After drying and evaporating, pivaloyloxymethyl 4-(carbobenzyloxymethyl) C) -2R,4R-dimethylbutanoate is obtained as an oil; NMR (C DC) 3): 1, 2, 1.8, 2.5, 5.2, 5.8, 7.45 ppm 5.3 F pivaloyloxymethythin in 150 mg ethanol A solution of 4-(carbobenoloxy)-2R,4R-tumethylbutanoate , 05 carbon soil at atmospheric pressure in the presence of 10% palladium.

The reaction mixture is filtered and evaporated to give 4-(piparoyloxymethoxycarbonyl NMR (CDCA3): 12, ] 7゜2.5 5, 5.8, 1 0.3 ppm.

1.7y of 4-(piparoyloxymeth) in 30ml of methylene chloride at room temperature. (oxycarbonyl) -2R.

To the 4R-dimethylbutanoic acid, add 1.7 +++ 1L:Q oxalyl chloride. child The incubating mixture of 4-(piparo- yloxymethoxycarbonyl)-2R,4R-tumethylcitanoyl chloride is obtained: NMR (CDC43): ] 2°1.9, 2.8, 5. 85 ppm. This is used directly in the above condensation reaction.

Example 27 (7)6.5, P(7)4-(7-bornyl) in 1001nl methylene chloride oxycarbonylmethoxycarbonyl)-2R,4R-tumethylbutanoic acid, 9 ,0XIIl of oxalyl chloride is added. After stirring for 3 hours at room temperature, Evaporate the reaction mixture. The residue was dissolved in 7011Il of birinone and indoli ion-28-carboxylic hydrochloride (3,79) is added. The reaction mixture was heated at room temperature for 2 ．． Stir for 5 hours. Evaporate the reaction mixture. The residue was dissolved in 75 ml of saturated bicarbonate. Dissolve in aqueous sodium solution and wash with 3x5Q+++l ether. water layer 1 0mt! Acidified with 6N hydrochloric acid and extracted with 3x75+++l of methylene chloride.

The combined methylene chloride portions were dried over magnesium sulfate and evaporated to give 1- [4-(nobornyloxycarbonylmethoxycarbonyl)-2R.

4R-dimethylbutanoyl]-indoline-2S-carboxylic acid is obtained; m, p, 65-67°C, [α]o--139° (C-0915, ethanol), NM R (CDC13): 3.4, 4.9, 7.1-8.4 ppm, IR (C HCAρ=3500-3100.2950.1735ctn　0 Starting materials are: Produced as: 5.09 noborneol and 7.74 ml chloride When the mixture with chloroacetyl is stirred at 100°C for 3 hours and then evaporated, Nohornyl chloroacetate is obtained as an oil; NMR (CDCl2): 0.88.0.91゜1.1-2.5, 4.1, 5.0 ppm070m1 To 5.0y of no'-carnyl chloroacetate in acetone was added sodium iodide. Add lium(3,4y). The reaction mixture was stirred at room temperature for 3 hours, then After filtration and evaporation, 1-bornyl iodoacetate is obtained, which is used in the next step. used directly in the process.

! -Fornyl iodoacetate) C, 6, 79) (6,19), ]007 tl/! of dimethylformamide. This reaction mixture was heated at room temperature overnight. Stir and then evaporate. The residue was dissolved in ether at 200 mA and 2x Wash with 50 rul saturated sodium bicarbonate and 50 ml brine. organic Dry the layer with magnesium sulfate and evaporate the certo, nobornyloxycarginyl Methyl-4-(carbobenzyloxy)-2R,4R-tumethylbutanoate Obtained: NMR (CDC): 4.6,51°7, 4 ppm.

Nobornyloxycarbonylmethyl 4-(carboxylic acid) in 125 ml of ethanol bobenzyloxy)-2R.

4R-dimethylbutanoate (8,05') was mixed with 0.89 carbon loading Hydrogenate in the presence of radium at 1 atm. The reaction mixture is filtered and evaporated. 4-(1-bornyloxycarbonylmethquincarbonyl)-'2R,4R- Methyl butanoic acid is obtained; NMR (CDC): 4.6, 5.0, 8. 2 ppm0 Example 28 7m/! 4-((L-2-acetoxymethylpyrrolidium) in oxalyl chloride )-carbonyl]-2R,4R~trimethylbutanoic acid (3,6y) at room temperature. Stir for 3 hours then evaporate. Add this acid chloride to 5Qm/+ pyridine. Indoline-2S-carboxylic hydrochloride (2,767) is added.

The reaction mixture is stirred at room temperature for 2 hours and then evaporated.

The residue was dissolved in 50 ml of saturated aqueous sodium bicarbonate solution and added to 3 x 50 ml evaporators. Wash with water. The aqueous layer was acidified with 101 nl of 6N aqueous hydrochloric acid and 3x5Qml Extract with methylene chloride. Dry the combined methylene chloride portions with magnesium sulfate. When dried and evaporated, 1-(4-[L-2-acetoxymethylpyrrolituno)cal (bonyl)-2R,4R-tumethylbutanoyl)-indoline-28-carboxylic acid m, p,]0091112℃[α]ゎ=-172.4°(C=1. 03, ethanol), NIvlR (CDCi3): 1.2, 4.9, 7 ．． 1, 8.3.

9.2ppm, IR (CHCj!5): 3500-3100.

2950, ] 730Crn 0 The starting material is produced as follows: 50 m/! 4-(kat) in methylene chloride 4J to 2R,4R-dimethylbutanoic acid (3.9mJ) , ml of oxalyl chloride are added. The reaction mixture was stirred at room temperature for 3 hours and then 4-(carbobenzyloxy)-2R,4R-tumethylbut Noyl chloride is obtained, which is used directly in the next step.

in 35 ml methylene chloride and 17.7 mt IN aqueous sodium hydroxide. A mixture of L-purinol (t42y) was added with the above acid chloride (4, 31-) is added. The reaction mixture was stirred at 0°C for 4 hours and then brought to room temperature. Stir for 1 hour. Separate the layers and soak the aqueous layer with 2 x 35 mi of methylene chloride. Wash. The combined organic portions were washed with 2×40 ml of 2N aqueous hydrochloric acid and sulfurized. Drying with magnesium acid and evaporation yields benzyl 4-['L-2-hydroxy Methylpyrrolidino)-carbonyl: ]-2R,4R-dimethylbutanoate, N MR (CDC), ): ], 05, 1.2, 5.1, 7.35 pprn can get.

Soil amide (4,5F) was refluxed for 3 hours in 3 ml of acetyl chloride. Mix it up. The reaction mixture is then evaporated to give benol 4-(L-2-7-1= Toxymethylpyrrolinono)-carbonyl:]-2R,4R-dimethylbutanoate NMR (CDC) 3): 1.07, 1.15, 2.0, 5.17, 7.4 ppm0 benzyl 4-((L -2-acetoxymethylpyrrolisono)-carbonyl]-2R,4R-dimethyl Butano-r--) (4,65F) o5y No carbon supported presence of 10 tipalladium Hydrogenate at 1 atm. After filtering the reaction mixture and evaporating the P solution, 4 CL-2-acetoxymethylpyrrolituno)carbonyl)-2R,4R-tumethyl Butanoic acid is obtained: NMR (CDCi5): 1.2, 2.03 pp m0 Example 29 1 in 100ml methanol. -(4-, (L-2-acetoxymethylpyrroli) (horn) carbonyl) -2R.

4R-dimethylpukunoyl)-indoline-2S-carboxylic acid (],, 59 ) to add 122 potassium carbonate. The reaction mixture was stirred at room temperature overnight. reaction The mixture was evaporated and the residue in 1.50 mi methylene chloride was dissolved in 75 ml of 2N Acidify with aqueous hydrochloric acid. Separate the layers and wash the organic layer with 75me prine and rinse with sulfuric acid. Drying over magnesium chloride and evaporation gives 1-(4-(N-(L-2-hydroxy) (dimethylpyrrolituno)-carbonyl: ]-2R,4R-)methylbutanoyl) -indoline-2S-carboxylic acid is obtained; m, p, 95-99°C, ((1 ). =-179,3° (C=0.98, ethanol), NMR (CDCi5): 1. ], 4.2, 4.9 ppm, IR (CHCff13): 350 0-3100, 2950, 1.730 cm-10 Example 30 1,1'-Carponylneumidazole (114y) in 20ml of methylene chloride of 4-(β-methoxyethoxymethoxycarbonyl) in 20 ml of methylene chloride. )-2R,4R-trimethylbutanoic acid (1,69) is added. 1 hour later, ], Q m/! Indoline-2S-calginate hydrochloride (1,3F) in pyridine of 10 Add dropwise over a minute. The reaction mixture is stirred at room temperature overnight. reaction mixture evaporate something. 75m/! of residue! Dissolved in methylene chloride of 2×25 Wash with ml of 2N aqueous hydrochloric acid. The organic layer was dried with magnesium sulfate and evaporated. A crude product is obtained. This product was dissolved in 20 mg of ether and 2 (Add Jml of ethyl acetate and 0.46ml of norchlorhexylamine, then Add 25ml of pentane. When the product is collected by filtration, 1-[4-(β ゛-Methoxyethoxymethoxycarbonyl-2R,4R-trimethylbutanoyl -Indoline-28-carboxylic acid obtained as dicyclohexylammonium salt is: m, p, 159-161°C, [α), = -79.6° (C = 1.13, Eton).

The starting material is 49 ml of ether in 60 ml of ether at 20°C, prepared as follows. 1.8P of 4-(carbobenoloxy)-2R,4R-dimethylbutanoic acid Add potassium t-butoxide. After 30 minutes, β-methoxyethoxymethylchloride Add ride (1,82y-). The reaction mixture was allowed to warm to room temperature over 1 hour. , then stirred for a further 2 hours at room temperature.

Pour the reaction mixture into 5 Qml of saturated aqueous sodium bicarbonate solution @゛, 3 x 50 Extract with ml ether. Dry the combined ether part (magnesium sulfate) and when evaporated, β-methoxyethoxymethyl 4-(carbobenoloxy) -2R,4R-dimethylbutanoate is obtained as an oil; [α), = -32, 6° (cm119, ethanol), NMR:] 80, 3.35.

5.1.6.5.30 ppm.

25m/! A solution of Soil Nether (0,5F) in ethanol was added to 50 mg of charcoal. Hydrogenate in the presence of 10% palladium on bare metal at 1 atm and room temperature. 2 o'clock After a while, the reaction mixture is filtered. Evaporating r* gives 4-(β-methoxyethoxy (cymethoxycarbonyl)-2R,4R-dimethylbutanoic acid is obtained as an oil; [α), = -25,7° (C = 0.975, ethanol), NMR: 1.20, 1.83, 3.40, 5.40ppm0 Example 31 4-(3-phthalidoxycarbonyl)-2R,4R-2 in 45ml of pyridine Indoline-28-carboxylate to methylbutanoyl chloride (2,5F) Add acid salt. The reaction mixture is stirred at room temperature for 3 hours. evaporate the reaction mixture; Wash the residue in methylene chloride of 10(1+j) with 2 x 50 ml of water. Combine Adjust the pH of the aqueous portion to 1 with hydrochloric acid and extract with 3 x 25 m of methylene chloride. . Wash the combined methylene chloride portions with 2 x 25 ml of 2N aqueous hydrochloric acid and place in a sulfuric acid mug. Drying with nesium and evaporation gives a foam, which is removed from the ether-benzene. When crystallized, 1-(4,-(3-phthalidoxycarbonyl)-2R,4R- Methylbutanoyldi-indoline-28-carboxylic acid is obtained; 119-12 2°C; [α]o--, 104.9° (C=0.65, EtOH).

The starting material is prepared as follows: in 6 ml of 2N aqueous potassium hydroxide. Evaporating a solution of 4-(carbobenzyloxy)-2R,4R-dimethylbutanoic acid Dry. The residue is evaporated twice with 20 ml of toluene. 5QmJ trimethyl Add 3-bromophthalide (25sy) to the formamide residue. reaction mixture Stir the mixture overnight at room temperature. Evaporate the reaction mixture. 40rne in ether 2x20m/! Wash with a saturated sodium bicarbonate water bath. ether The layer was dried over magnesium sulfate and evaporated to give benol 4-(3-phthalidochloride). Cical 2=/L/)-2R,4R-tumethylbutanoate is obtained as an oil. ; NMR (CDCi3): 1.8 5, 2.60, 3.50.

5, 15 ppm, IR (film): 3035,2978.

1 1 7 7 5, ], 7 5 5, ], 7 3 0, 1 4 6 80.

45mZ! The above ester (3.5P) in ethanol of 3501n9 carbon Hydroxylation in the presence of supported 10%-' radium at 1 atm and room temperature. 3 o'clock After a period of time, the reaction mixture is filtered. When the furnace liquid is evaporated, 4-(3-phthalidoxyca Rubonyl)-2R,,4R-dimethylbutanoic acid is obtained; [α), = -21. 3° (C=078, ethanol), NMR: 1. 2, 1. 8, 　2.65.

3.70ppm.

4-(3-phthalidoxycarbonyl)-2R,4 in methylene chloride of lQmi 0.0 to R-tumethylbutanoic acid (0.30y). 2 4 ml of oxalyl chloride Add.

The reaction mixture was stirred at room temperature for 3 hours and then evaporated to give 4-(3-phthalide. (oxycarbonyl)-2R.

4R-tumethylbutanoyl chloride is obtained: [α)D=-1.6.1°( C=0.53, chloroform), NMR: 1.3, 1.9, 2.7 6, 4.3 ppm0 Example 32 Indoline-2S-carboxylic acid hydrochloride acid YA (2 ．． 2 3 5'), 4-(carbobenoloxy)-2R,4R-Tumethi Add rubutanoyl chloride (3.a'y). After stirring at room temperature for 3 hours, Evaporate the reaction mixture. The residue was dissolved in 100 ml of saturated aqueous sodium bicarbonate. Melt it, 50m/! Wash with ether. Adjust the aqueous layer to pH 1 with Hatake hydrochloric acid, Extract with 3x50me methylene chloride. 70 risi of the combined methylene chloride part After stirring in the presence of (carbobenzyloxy)-2R,4R-tumethylbutanoyldi-indoline -28-carboxylic acid is obtained; m. p. 1.　5　0　-　1　5　3℃, [ α]9 knee 139.1° (C20479, ethanol).

The starting material is prepared as follows: The above acid chloride is 3.0y of 4- (carbobenzyloxy)-2R,4R-tumethylbutanoic acid and oxa chloride Ril (],,05md) was stirred in 50 ml of methylene chloride at room temperature for 3 hours. Mixing and then evaporation of the solvent yielded 4-(carbobenzyloxy)-2R.

4R-tumethylbutanoyl chloride, which is converted from the previous reduction. Methyl 17-phenylalanine in methylene chloride used directly in the reaction Ester hydrochloride (1.39) and], - (]4-carboetquin-2R , 4R-trimethylbutanoyl)-indoly7-23-force/l/7+; 7 acid ( 2. oy) at room temperature. 8 4. m. l of triethylamine and 1 of 13g. -(3-nomethylaminophyl)-3-ethylcarbono Add imide hydrochloride. The reaction mixture is stirred at room temperature for 20 hours. reaction mixture The mixture was diluted with 3 x 25 ml of 2N aqueous hydrochloric acid and 2 x 25 ml of saturated aqueous bicarbonate. and 25 ml of prine.

The organic layer was dried over magnesium sulfate and evaporated to give N-(1.-( 4-carboethquin-2R,4R-tunotylbutanoyl)-indolinyl-2 8-Carbonyl]-L-phenylarene methyl ester obtained: m. p ．． 1. 1 0 - 1 1 3℃, [α] 0 knee 1197° (C2 35mJ e 247 N-(:1-4-carboethoxy-2R,4R-Tumethy) in tanol Loubutanoil) - Iato! J-23-carbonyl)-L-phenylaara Add 9 ml of IN sodium hydroxide and 1-oml of water to the nin methyl ester. Ru. The reaction mixture is stirred at room temperature overnight. Evaporate the ethanol and make an aqueous solution. ]Qm/! of ether and then acidified to PH1 with 2N aqueous hydrochloric acid.

This solution is extracted with 3×30 mJ of ethyl acetate. The combined ethyl acetate portion After drying with magnesium sulfate and evaporating, N-('1--(4-ka) ruboxy-2R,4R-tumethylbutanoyl)-indolinyl-28-carbony L]-L-phenylalanine is obtained: mp], ]6] -164°C , [α]. 2-1043° (C2115, ethanol).

Example 35 182 4-(α-carboethoxy-ethquine carbonyl) in 25 ml pyridine )-Acid chloride obtained from 2R,4R-tumethylbutanoic acid and India The mixture of phosphorus-28-carboxylic hydrochloride was stirred at room temperature for 3 hours and then evaporated. let The residue in 50 mg of saturated aqueous sodium bicarbonate was dissolved in 2 x 30 mJ of ether. Wash with water. The aqueous layer was acidified with solid potassium bisulfate to pH 2 Extract with 30 mi of methylene chloride. The combined methylene chloride part is 7 lalicyl. Stir in the presence of , dry with magnesium sulfate and evaporate to obtain an oil . When triturated with 10 ml of ether, 1-[α-(α-carboethoxy- (ethoxycarbonyl)-2R,4R-tumethylbutanoylcouindoline-28 -carboxylic acid is obtained: mp151-154°C, [α)D=-146,8°( c=1.06, ethanol).

The starting material is prepared as follows: 2R,4R-dimethylglutaric anhydride (0,809 mJ) , heated to 80° C. for 4 days. Crude 4-(α-carbiethoxyethoxycarbonate) Rf=o, 7(silyl)-2R,4R-dimethylbutanoic acid is used directly; Kaglu ethyl acetate), NMR (CDCi3): 5.05, 4.28゜2 ．． 58, 1.79, 1.16 ppm earth acid in methylene chloride 30ml (1,8F) was stirred with 2 ml of oxalyl chloride at room temperature for 3 hours. Zeru. Evaporation of the solvent yields 4-(α-carpoethoxyethoxyluponyl) -2R,4R-dimethylbutanoyl chloride was obtained, which was added above to 40 ml of 252 of 2R,4R-dimethylglutaric anhydride in pyrinone as described below. Indoline-2s-carboxylic hydrochloride (3,2P) was added to the acid chloride obtained from Add. The reaction mixture is stirred at room temperature for 3 hours and then evaporated. 50 Wash the residue in mJ water with 3×50 ml methylene chloride.

The aqueous layer was adjusted to pH 3.0 with 2N aqueous hydrochloric acid and extracted with 3 x 50 ml of ethyl acetate. do. The combined ethyl acetate portions are dried over magnesium sulphate and evaporated. residual The product was triturated with 5 Qml of ether to give the crude 1-[4-(3-pyridyl) methoxycarbonyl)-2R,4R-dimethylbutanoyl cloidrine-28- A carboxylic acid was obtained, which was dissolved in 30 ml of 3N aqueous hydrochloric acid and dissolved in 30 ml of vinegar. Wash with ethyl acid. The aqueous layer was evaporated and the residue was vacuum dried at 50°C. C4-C3-pyridylmethoxycarbonyl)-2R,4R-tumethylbutanoyl Couindoline-2s-carboxylic hydrochloride is obtained; mp 86-89°C, [α ), = -75,2° (c = o, s, ethanol).

The starting material is prepared as follows: 2R,4R-tumethylglutaric anhydride. A mixture of compound (2,5P) and 3-pyritulcarbinol (1,7ml) was heated at 90°C. Stir for 6 hours. When the reaction mixture was cooled, the crude 4-(3-pyridylmethoxy) Cycarbonyl-2R,4R-tumethylbutanoic acid is obtained: NMR (CDC, 1!3): 8.83, 7.86, 7.44, 519, 2.58°1.75.1. 18ppm, IR (film): 2980°2935.1735,1465,1 Add 4.5 ml of the above acid in methylene chloride to 163 tM 05QmlE. Stir with Xalyl at room temperature for 3 hours.

Evaporation of the solvent yields the acid chloride, which is used without further purification. do.

Example 37 Ethyl 1-(4-carboxy-2R,4R-tumethy) in 50 ml of methylene chloride (2,5F) and β- To carbobennoroxyaminoethylamine (t6fI), add 105 ml of Trie thylamine and 1-(3-trimethylaminopropyl)-3-ethylka – Add Boimide. The reaction mixture was stirred at room temperature for 2 days, then refluxed for 4 hours. let The reaction mixture was mixed with 2X 25 ml of 2N aqueous hydrochloric acid and 2X 25 ml of 2N aqueous hydrochloric acid. Wash with saturated aqueous sodium bicarbonate. Dry the methylene chloride layer with magnesium sulfate. Drying and evaporation yields ethyl 1-[:4-(β-carbobenoloxyamine- N-ethylcarbamoyl)-2R,4R-tumethylbutanoylcouindoline- 2S-Calphocyflate is obtained after grinding with ethyl ether; Rf -04 (Silica Glue Ethyl Acetate), N MR (CDCi3) Near, 41,5 ．． 11,4.13.1.15pprn.

Example 38 Ethyl 1-[4-(β-carbobennoroxyamino) in 25 ml of ethanol -N-ethylcarbamoyl)-2R,4R-tumethylbutanoylcouindoline -28-carboxylene) (2,4F) in 5.2 ml of I in 10 ml of water. Add N-sodium hydroxide.

The reaction mixture is stirred at room temperature for 4 hours. Evaporate the reaction mixture to remove ethanol. leave Dilute the aqueous residue to 100 mJ with water and wash with 2 x 10 m ether. acidified to pH 1 with solid potassium bisulfate and added 3X 25 ml of methylene chloride. Extract with The combined methylene chloride extracts were dried over magnesium sulfate and evaporated. let Stir the residue in 40 mi of ether,! :, 1-[4-(β -carbobennoroxyamino-N-ethylcarbamoyl)-2R,4R-Tume Tylbutanoylcouindoline-28-carboxylic acid is obtained; mp104-1 06°C, NMR (CDC7,): 8.39.

7.36, 7.2, 6.15, 5.02 ppm098 35+++/! 1-r4-(β-carbobenzyloyl) of 0827 in ethanol xyamino-N-ethylcarbamoyl)-2R,4R-dimethylbutanoylc A solution of indoline-28-carboxylic acid was mixed with 70 m9 of carbon-supported 10th palladium Hydrogenate in the presence of 1 atm and room temperature for 3 hours. Filter the reaction mixture , when P liquid is evaporated, i-[4-(β-amino-N-ethylcarbamoyl)- 2R,4R-tumethylbutanoyl] ~ indoline-2s-carboxylic acid is obtained : mp202=204℃, [α] 0 knee 995° (C2 room temperature 35m1 claw ], 99-1. - (4 = (carbobenzyloxy) -21,4-R-tumethylbutanoylseindoline-28-carboxylic acid potassium ], 15jF of iodomethyl pivalate is added to the um salt. Reaction mixture overnight Stir at room temperature. The reaction mixture was evaporated and the residue was poured into 150 ml of ether. 50m1! of saturated aqueous sodium bicarbonate and 50 ml of prine. Purify. The organic layer is dried (magnesium sulfate) and evaporated to give piparoyl oxide. Dimethyl 1-[4-(carbobenzyloxy)-2R,4R-trimethylbutanoyl Indri (CDCA3): 1.20, 3.20, 5.70, 7.25ppm , Rf208(90:9:], C1-ICj!: EtOH: HOAc, ).

Example 41 0.60 in 3QmJ of ethanol. Piparoyloxymethyl 1-[4-( Carbobenoloxy]=2R,4R-tumethylbutanoylcyindoline-2 A solution of 8-carboxylene was prepared in the presence of 50 mg of 10% palladium supported on carbon. Hydrogenate at room temperature and 1 atm. Filter the reaction mixture and evaporate the P solution. Then, piparoyloxymethyl 1-[4-carboxy-2R,4R-tumethylbutylene] Tanoyl seindoline-23-carboxylate is obtained; mp143-1 45℃, [α]. =-139,6° (C209, ethanol).

Example 42 2.4y ethyl]-(4-carboxy-2 in 1,00 ml methylene chloride) R94R-tumethylbutanoyl)-indoline-28-carboxylate, 1 ．． 0fI glycine ethyl ester hydrochloride, 1. Oml triethylamine and and 15-1-(3-methylaminozolopyl)-3-ethylcarboimide salt Add acid salt. The reaction mixture is stirred overnight at room temperature. 50ml of reaction mixture of 2N aqueous hydrochloric acid and 5 omes of saturated aqueous sodium bicarbonate. organic layer is dried over magnesium sulfate and evaporated to give ethyl 1-[400 -(carboethoxymethylcarbamoyl) -2R,4R-dimethylbutanoyl Seindoline-28-carboxylate is obtained; [α)n = -83, 6″ (C=0.78.1-ta/-B,), NMR (CD(J5): 1 ．． 30, 4-20, 5-20゜2.3 jil of ethanol in 4 Qml of ethanol Chyl l-[4-(carboethoxymethylcarbamoyl)-2R,4R-tumethyl Butanoyl seindoline-28-carboxylate, 60% 2N aqueous hydroxy acid Add potassium chloride and then 5 ml of water. The reaction mixture was kept at room temperature for 3 hours. Stir. The ethanol was removed by evaporation and the aqueous portion was poured into 2 x 10 ml of ether. Wash with water. The aqueous layer was adjusted to ptl by addition of solid potassium bisulfate, Extract with 3 x 25 ml methylene chloride.

The combined methylene chloride portions were dried over magnesium sulfate and evaporated to give 1-[ 4-carboxymethylcarbamoyl)-2R,4R-trimethylbutanoyl mp70-73℃, [α]ゎ=-86 , 5° (C=0.75, ethanol).

Example 44 1-(4-carboxy-2R,4R-tumethylbutano in 20 ml of ethanol) A solution of l)-indoline-28-cal-7jδ acid (250 mg) was added to l( l Q II + Evening Charcoal 01 Hydrogenate for 18 hours at 3 atmospheres and room temperature in the presence of unsupported pentavalent ronium.

After filtering the reaction mixture and evaporating Solution E, 1. -(,4-carboxy-2R.

4R-trimethylbutanoyl)-octahydroindole-28-carboxylic acid was obtained. mp 83-86℃, [α), = -95,5° (C=0.67, ethanol ).

Example 45 1-(4-carboethoxy-2R,4R-trimethyl in 100 ml of ethanol) butanoyl)-indoly7-28-calyt'7 acid (1,5p) o solution, 5 water for 3 days at 3 atm and room temperature in the presence of 00 m9 of carbon-supported pentadronium. Become basic. Filtering the reaction mixture and evaporating the r-liquid yields 1-(4-carboethyl xy-2R,4R-tumethylbutanoyl)-octahydroindole-28-ka Rubonic acid is obtained; mp 50-53°C, [α] 0 knees 95.00 (C21. 04, 3aS, 7aS-octahy of 047y- in etaIQml (7) pyrinone In a solution of droindole-28-carboxylic hydrochloride, 0.469- 4-carboethoxy-2R-methyl-4R-phenethylbutanoyl chloride Add. The reaction mixture is stirred at room temperature for 3 hours and evaporated in vacuo. residue treated with 3N hydrochloric acid102 10m/! of methylene chloride three times and the extracts are evaporated to dryness. residue When crystallized from ether-hexane, I-(4-carboethoxy-2R-methane) (Tyl-4R-phenethylbutanoyl)-3aS,7aS-octahydroindole 28-carboxylic acid is obtained.

The production of 3aS, 7aS-octahydroindole-28-carboxylic acid is a European specialty. Patent Application No. 37,231 and Tetrahedron Letters 23 , 1677-1680 (1982).

Example 47 4-(1-(ethoxycarbonyloxy)-eth) in 100 ml of methylene chloride (oxycarbonyl) -2R.

1,1'-carboxylic acid was added to a solution of 4R-tumethylbutanoic acid (5,65F) at 0°C. Add bonylsoimidazole (3,3F). After 1 hour, indoline-2s-ka Add the carboxylic acid hydrochloride (41p) and triethylamine (4,1y) and mix the reaction mixture. Stir the mixture overnight at room temperature.

The reaction mixture was diluted with 10(1+l) methylene chloride and cooled with 4 ml of 12N salt. Wash with 50 ml of water containing acid. The aqueous layer was diluted with 2 x 50 rnl of methylene chloride. Wash. The combined organic portions are dried (MgSO4) and evaporated. ! =, 1 -+4- [l-(ethoxycarbonyloxy)-ethoxycarbonyl)-2R , 4R-tumethyl 103 Patent B859-500768 (28) Butanoyl) -Indoline-2s-carboxylic acid is obtained.

The starting material is prepared as follows: 1-chloroethane in 75 ml of acetone. Terethyl carbonate (5,509 L) and sodium iodide (5,955 L) One solution is refluxed for 1 hour. The acetone was removed in vacuo and the residue was of ether and 100 mJ of water. 25ml of ether layer Wash with sodium metabisulfite and dry (MgSO4). vacuum the ether Remove. The remaining ethyl 1-iodoethyl carbonate was poured into 15 ml of trimethylfluorocarbonate. Potassium in 50 ml of trimethylformamide, immediately dissolved in 4-(carbobenzyloxy)-2R,4R-tumethyl-butano-ate (10 , 4F). The reaction mixture was stirred at room temperature for 18 hours, then evaporated. let The residue was dissolved in 150 ml (D x -chill, 3 x 50 ml Wash with 1×1° aqueous sodium bicarbonate. Dry the ether layer (MgSO4) L, when evaporated, ]-(]ethoxycarbonyloxy-ethyl 4-(carboxylic acid) (bobenzyloxy)-2R,4R-tumethylbutanoate is obtained.

A solution of the benzyl ester (7,97-) in ethanol of 150+++ J , 0.59 carbon affinity 10% para 04 Hydrogenate in the presence of dium at 1 atm. The reaction mixture is filtered and evaporated and '4-CI-(ethoxycarbonyloxy)-ethoxycarbonyl) -2R.

4R-dimethylbutanoic acid is obtained.

Example 48 2.0 jil of nogyl iodoacetate in 30 m1 of trimethylporumamide A solution of ethylurium salt and 23oy was stirred overnight at room temperature. Then evaporate. The residue was dissolved in 100 m/' ether and 2 x 25 l Wash with 1 l of water. The organic layer was dried over magnesium sulfate and evaporated to give ethyl 1-indoline-28-carboxylate is obtained.

Example 49 Similar to the procedure of previous examples, e.g. Example 17 and ethyl 1-[4-carbo Ethoxy-4R-(605 Monophenylhexyl)butanoyl seindoline-28-carboxylate is N-(5-phenylpentanoyl)-L-prodine-/l as the starting material, respectively. /, N-(6-phenylhexanoyl)-monorolinol, and N-(8- (phenyl octanoyl)-L-prolinol.

the corresponding monomethyl ester with free indoline-2-carboxyl group and The nocarboxylic acids were prepared as described above, for example in Example 18 and Example 1'. 9. Manufactured as in 9.

Example 50 0.57 3aS,7aS-octahydroindole in 5 ml pyrinone o53! in a solution of -28-carboxylic acid! 2-phenethylgluta/I/acid anhydride Add. The mixture was heated to 80° C. for 15 hours under a nitrogen atmosphere, concentrated, Partition between 20 ml ethyl acetate and 10 ml IN hydrochloric acid. Separate the organic layer Wash with water, dry (Na2S04), filter and concentrate to obtain a foam. child Dissolve the residue in 5 ml of diethyl ether and triturate with hexane. . The solid was collected and dried at 35°C/1 body Hg to give 1-(4-carboxylic -4-7enethylbutanoyl) -3a s+ 7a S-octahydroin Dole-28-carboxylic acid is obtained: mp60-63°C, [α)9=-28, 9°(C=],,O.

106 methanol).

The starting material is prepared as follows = 100 mL in 80 ml absolute ethanol A solution of indoline-2S-carboxylic hydrochloride of No. 1 was prepared using a carbon-supported 5-tyrhodium catalyst. Hydrogenate in the presence of 3 atm and room temperature for 24 hours. Filter the resulting mixture The catalyst is removed by evaporation to dryness. Treat the foam with hot ethyl acetate. collect solids, When dried in vacuum, 3aS,7aS-octahydroindole-28-carboxylic acid Hydrochloride is obtained: mp 136-1.39°C, [α]0--217° (C=1, ethanol).

Similarly, 1-[4-carboxy-4-(3-phenylpropyl)butanoyl : ] -3aS, 7aS -octahydroindole-28-carboxylic acid, 1- [4-Carboxy-4-(4-phenylbutyl)butanoyl octahydroyl] carboxylic acid, and 1-[4-carboxy-4-(6-phenyl) (hexyl)butanoyl)-3aS,7aS-octahydroindole-28 -carboxylic acids are each 2-(3-phenylpropyl)glutamate as starting material. glutaric anhydride, 2-(4-phenylbutyl)glutaric anhydride, and 2-(6 -phenylhexyl) glutaric anhydride.

Ethyl octahydroindole-28-carboxylic acid and 4R-carboethoxy-6 - with phenylhexanoic acid, e.g. under the conditions described in Examples 17 and ]8. , the condensation reaction is 1-(4-carboethoxy-4R-7enethylbutanoyl)-o Production of tahydroindole-28-tyrilebonic acid.

Example 51 According to the method exemplified in the previous example, of formula 1 where R4 is hydrogen and t is 1 The following 23,3aS,,',7aS-octahydroindole is produced.

b(CH2)3C6H5 ethyl ester (CH2)4C6H3- d(CH2)4C6H5 ethyl nis-thyl f(CH2)6C6H5 ethyl ester Starting material: Prepared by the procedure described in Example 7: 4R-carboethoxy-7 -phenylnotanoic acid, 4R-carboethoxy-8-phenyloctanoic acid, 4R -carboethoxy-9-phenylnonanoic acid.

Example 52 Previous implementations herein for the corresponding derivatives of indoline 2S-carboxylic acids Following the example, the following 1-08 (4-carboxy-4-phenethylbutanoyl)-3aS, 7aS-octahyde Esters and amides of loindole-28-carboxylic acid (formula ■, t-1, R4 -H5R5-phenethyl) is produced.

Pivaloyloxymethoxy 0H 1-Gylnyloxylponylmethoxy 0HL-2-acetoxymethylpyrroli Dino 0HL-2-hydroxymethylpyrrolidino OHβ-methoxyethoxyme Toxi OH β-(carbobenoloxyamine) ethylamino OC2H5β-(carbobenoloxyamine) ethyloxyamine) ethylamino OH carboethoxymethylamino 0C2 I] 5 carboxymethylamine 0H 1-(ethoxy 7)ethoxy OH09 Example 53 The following compounds can be prepared according to the procedures described in the previous examples.

a) 1-ethoxycarbonyloxyether 1-(4-carboxy-2R,4R- b) i-zluni -(4-carboxy-2R,4R-nomethylbutylene) c) pivaloyloxymethylate)-indoline-28-carboxylate, c) 1-(4-carboxy-4R-7enethylbucnoyl)-indoline-2S- carboxylate, d) 1-[4-(pivaloyloxymethoxycarbonyl)-2R-methyl-4 R-phenethylbutanoyl]-indoline-28-carboxylic acid, e) 1-(4- (ffl-bornyloxycarbonylmethoxycarbonyl)-2R-mer -4R--yenethylbutanoyl]-indole-28-carboxylic acid.

Example 54 10,000 capsules each containing 10m9 of the active ingredient of Example 26 Manufacture of agent: Prescription 1-[4-piparoyloxymethoxycarbonyl-100,0P110 Talc powder 100.1 procedure Pass all the powder through a sieve with 0.6 mm openings.

The drug substance is then placed in a suitable mixer, first with Merck and then with lactose. Mix until homogeneous. Fill 3 flat capsules with 200 m9 using a cuff 0 cell filling machine. Preparation of 10,000 tablets each containing 10 mg of the active ingredient of Example 45 : Polyethylene glycol6. O0075,00P talc powder 75.009 Magnesium stearate 18.00F Purified water Sufficient amount -Chiyu- Pass all the powder through a sieve with 06 openings.

Next, drug substances, lactose, tartar, stearin 1111 JISho 59-5007 G8 Magnesium (30) acid and half of the cornstarch in 40ml water Suspend and boil the suspension of polyethylene glycol in 150 ml of water. Add calories to the solution. Add the formed toner to the powder and add it as needed. Granulate with additional amount of water. The granules were dried overnight at 35°C, and 12 bars were opened. Destroy it on a sieve, compress it into a lock 1 with a concave punch with a diameter of 6.4W++, and Divide the section into two.

Analogously to the previous example, other octahydroindoles of formula ■ and their functionality Locks (1 and 1) containing derivatives, such as those described in the previous examples. A capsule is manufactured.

Procedural amendment (formality) %formula% 1 Display of incident PCT/US83100597 2 Name of the invention 1-Carphoki/alkanoyl〈rubidroindole-2-carboxylic acid and derivatives body 3 Person making the amendment Relationship to the incident: Patent applicant Name Civer Geigy Akchengesellschaft 4 agent Address: 8-10-5 Toranomon-chome, Minato-ku, Tokyo 105 Date of amendment order January 31, 1980 (Shipping date) 6 Target of correction (1) Translation of the description and claims (2) Certificate 7 Contents of amendment (1) Translation of the description and claims (no change in content) (2) Bettei Street 8 List of attached documents (1) Translation of specification and claims: 1 copy each (2) Certificate and translation: 1 copy each (2) international search report

Claims (1)

[Claims] 1. Formula (In the formula, R4 represents hydrogen or lower alkyl, and R5 represents lower alkyl. or R5 represents lower alkyl substituted with aryl, where aryl is lower alkyl, lower alkoxy, trifluoromethyl or halogen. represents phenyl which may be substituted, and t represents O or 1) compounds; esters; amides; or pharmaceutically acceptable salts thereof. 2 R4 represents hydrogen or lower alkyl, R5 represents lower alkyl, Alternatively, R5 represents lower alkyl di-substituted by aryl, where aryl is lower alkyl, lower alkoxy, trifluoromethyl or halogen. represents phenyl, optionally substituted, and t represents 0 or 1. the unsubstituted amide and mono- or di-lower alkyl thereof; Ami p; sono low 13 alkylene amide (where the lower alkylene group, together with the nitrogen of the amide, represents 5,6 or hydroxy-(lower) alkyl or lower said lower alkyl substituted on m by alkanoyloxy-(lower)alkyl Kyrenamide; so-(lower)-carbalcoquine- or -carboxy-substituted lower -(lower)carbalcoquine or -carboxylic alkylamide; substituted aryl-(lower)alkylamides, where aryl is phenyl or 3- (amine or acylamino)-(lower)alkyl mid; its lower alkyl ester; its (amine, seven or no lower alkyl ester; (ruamino, carboquine or lower carbalkoxy)-substituted lower alkyl ester its aryl-(lower)alkyl ester (where aryl is phenyl or represents pyridyl); its lower alkanoyloxy(lower) alkyl ester Le: its phthalinolester; its (hydroxy, lower alkanoyloxy, or lower alkoxy)-substituted (lower) alkoxymethyl ester; Alkoxyalkyloxycarbonyl-(low I)alkyl ester (where the ester has up to 10 carbon atoms in the vincloalkyl group); or Its lower alcoquine power luponyloki 114 No (lower) alkyl ester; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein L is 1. 4, R4 represents hydrogen or lower alkyl of 4 carbon atoms, and R5 represents 4 carbon atoms. represents a lower alkyl carbon atom in terms of carbon atom or R5 is substituted with aryl. represents lower alkyl of up to 4 carbon atoms, where aryl represents lower alkyl , represents phenyl which may be monosubstituted by lower alkoxy or tahhalodane. and tHo or 1; or bis-lower alkyl esters; or of said compounds having a free lubogyl group. Pharmaceutically acceptable salts. 5. The compound according to claim 4, wherein t is. 6 R4 represents hydrogen or methyl, R5 represents methyl or phenethyl , and t represents 1; the mono-lower alkyl Esters: Esters or pharmaceutically acceptable salts of said compounds. 7.1-(4-carboethoxy-2R,4R-dimethylbutanoyl)-octahy The compound according to claim 4 which is droindole-28-carboxylic acid or its A pharmaceutically acceptable salt of. 8.1-(4-cargoxy-2R,4R-dimethylbutanoyl)-octahydro The compound according to claim 4, which is indole-28-carboxylic acid, or its product Pharmaceutically acceptable salts. 9.1-(4-carboxine-4-phenethylbutanoyl)-3aS, 7a The compound according to claim 4, which is S-octahydroindole-28-carboxylic acid. compound or a pharmaceutically acceptable salt thereof. 10. A relatively effective amount of the compound according to claim 1 and one or more 1. An antihypertensive or cardioactive pharmaceutical composition comprising a pharmaceutical carrier. 11. Claiming an effective amount for mammals in need of treatment for hypertension or heart disease. Reducing hypertension in a mammal, comprising administering a composition according to scope 10. is a method of treating heart disease. 1.2. a) reduce the corresponding indoline, or b) reduce the corresponding indole, or C) formula A compound of the formula or a functional derivative thereof, wherein R4, R5 and t are within the scope of the claims. As defined in 1) or a functional derivative thereof, and optionally, d) converting the obtained compound of the invention into other compounds of the invention; A method for producing the compound according to claim 1, comprising: Jofuku, (Contents (no change)