KR900001195B1 - Preparation process for 3-amino-(1)benzazepin-2-one-1-alkanoic acid - Google Patents

Abstract

3-Amino-[1 -benzazepin-2-one-1-alkanoic acid of formula (I), its stereoisomer or its salt is prepd. by the cyclization of a compd. of formula (II) or its ester. In the formulas, RA is -CH-R(R0), RB is - CH-R2(R0), R0 is COR6 or COR7; R6 and R7 are each hydroxy, lower alkoxy, 3-phthalidoxy, amino, lower alkyl, aminoalkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; R2 is H or lower alkyl; R3 and R4 are each H, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, hydrogen or trifluoro methyl; R5 is H or lower alkyl; X is oxo, phenyl or phridil. (I) is useful as an angiotensin conversion enzyne inhibitor.

Description

Method for preparing 3-amino- [1] benzazin-2-one-1-alkanoic acid

The present invention provides a method for preparing novel 3-amino- [1] benzazin-2-one-1 alkanoic acid and derivatives thereof useful as an angiotensin converting enzyme inhibitor. A method of preparing a pharmaceutical composition composed of these compounds and a method for treating a disease that can be cured by angiotensin converting enzyme inhibition by administering the compound and the composition to a mammal.

The present invention is based on the discovery that certain substituted 2-amino- [1] benzazin-2-one-1-alkanoic acids and derivatives thereof are novel potent angiotensin converting enzyme (ACE) inhibitors.

3-amino- [1] benzazine which may be prepared according to the present invention for the prevention of diseases healed by inhibition of angiotensin converting enzymes, such as cardiovascular diseases such as hypertension and heart conditions such as congestive heart failure, from the above findings It has been found to be particularly useful to administer -2- warms to mammals alone or in combination.

Compounds which can be prepared according to the invention relate to the following general formula (I) compounds and their salts and stereoisomers:

및

의 라디칼[여기서, R₀는 카복시 또는 기능적으로 개질된 카복시이며, R₁은 수소, 저급알킬, 아미노(저급)알킬, 아릴, 아릴(저급)알킬, 사이클로알킬 또는 사이클로알킬(저급)알킬이고, R₂는 수소 또는 저급알킬이다]이고, R₃및 R₄는 각각 독립적으로 수소, 저급알킬, 저급알콕시, 저급알카노일옥시, 하이드록시, 할로겐, 트리플루오로메틸이거나, R₃및 R₄가 함께는 저급알킬렌 디옥시이며, R₅는 수소 또는 저급알킬이고, X는 옥소, 2개의 수소, 또는 하나의 수소와 하나의 하이드록시이며, 카보사이클릭 환은 헥사하이드로 또는 6, 7, 8, 9-테트라하이드로이다.Wherein R _A and R _B are each of the general formula

And

Radicals, wherein R ₀ is carboxy or functionally modified carboxy, R ₁ is hydrogen, lower alkyl, amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl or cycloalkyl (lower) alkyl, R ₂ is hydrogen or lower alkyl], and R ₃ and R ₄ are each independently hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R ₃ and R ₄ are Together are lower alkylene dioxy, R ₅ is hydrogen or lower alkyl, X is oxo, two hydrogen, or one hydrogen and one hydroxy, and the carbocyclic ring is hexahydro or 6, 7, 8, 9-tetrahydro.

Examples of functionally modified carboxyl groups in the R ₀ definition include esterified carboxyl groups or carbamoyl groups optionally substituted on a nitrogen atom. One or all of R ₀ , in particular represented by the radicals R _A to COR ₆ and represented by the radicals R _B to COR ₇ , are independently carboxy, esterified carboxy, carbamoyl or substituted carbamoyl.

Salts of compounds of formula (I) are derived from compounds having salt preparation properties, with pharmaceutically acceptable salts being preferred. A carboxyl group, R ₀ is represented by (R _A radical in) R ₆ is hydroxy by the COR ₆ or (radical from R _B) R ₇ is hydroxy is COR _7.

The esterified carboxyl group R ₀ is in particular a lower alkyl or optionally substituted phthalidyl group optionally substituted with an esterification radical, wherein one or both of R ₆ and R ₇ are lower alkoxy; (Amino, mono- or di-lower alkylamino) -substituted lower alkoxy; carboxy substituted lower alkoxy such as α-carboxy substituted lower alkoxy; lower alkoxy lower alkoxy such as α-lower alkoxycarbonyl substituted lower alkoxy; Aryl substituted lower alkoxy such as optionally substituted benzyloxy or pyridylmethoxy; Substituted lower alkoxy (hydroxy, lower alkanoyloxy or lower alkoxy) such as pivaloyloxy methoxy; (Hydroxy, lower alkanoyloxy or lower alkoxy) substituted lower alkoxymethoxy; Bicyclo alkoxycarbonyl substituted lower alkoxy such as bicyclo [2,2,1] heptyloxycarbonyl substituted lower alkoxy, especially bicyclo [2,2,1] heptyloxycarbonyl substituted methoxy; 3-phthalideoxy; (Lower alkyl, lower alkoxy, halo) -substituted-3-phthalideoxy which is represented by partial general formula-COR ₆ (in radical R _A ) or partial general formula -COR ₇ (in radical R _B ).

The optionally N-substituted carbamoyl group R ₀ is in particular one or both of R ₆ and R ₇ is amino; Lower alkylamino; Di-lower alkylamino; Two alkyl groups, such as pyrrolidino, piperidino, or perhydroazino, are bonded by carbon-carbon bonds and together with amino nitrogen form a 5-, 6- or 7-membered heterocycle ring di-lower alkylamino ; (Amino or acylamino) substituted lower alkylamino; α- (carboxy or lower alkoxycarbonyl) substituted lower alkylamino; Aryl is preferably phenyl or indolyl and is an aryl substituted lower alkylamino which may be substituted by carboxy or lower alkoxycarbonyl on the α-carbon; partial formula -COR ₆ (in radical R _A ) or partial formula -COR A group represented by ₇ (in radical R _B ).

Pharmaceutically acceptable esters and monoamides of mono- or di-carboxylic acids prepared according to the invention, which may be converted into carboxylic acids under solvolysis or physiological conditions such as the abovementioned esters and amides, which may be prepared according to the invention The preparation of certain prodrug derivatives of the compounds is particularly an object of the present invention.

Preferred examples of this ester include unsubstituted or suitably substituted straight chains such as pivaloyloxymethyl, bornyloxy carbonylmethyl, benzyl pyridylmethyl, α-carboxyethyl or suitably esterified α-carboxyethyl esters, or the like. And branched lower alkyl esters.

Preferred examples of these amides include simple primary and secondary amides and amides derived from amino acids or derivatives thereof, such as amides derived from alanine, phenylalanine and the like. In particular, the present invention relates to the preparation of the following general formula (IA) compounds or to pharmaceutically acceptable salts thereof:

Wherein R ₁ is hydrogen, lower alkyl, amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl (lower) alkyl, R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ and R ₄ Is hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl or R ₃ and R ₄ together are lower alkylenedioxy, X is oxo, two hydrogens, or one hydrogen And one hydroxy, R ₆ and R ₇ are hydroxy, amino, mono- or di- (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy, (amino, mono Or di-lower alkylamino, carboxy or lower alkoxycarbonyl) -lower alkoxy.

Preferred embodiments of the invention are those in which R ₁ is hydrogen, lower alkyl, amino (lower) alkyl, aryl is lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen or trifluoromethyl. Aryl (lower) alkyl which is mono- or disubstituted or unsubstituted phenyl, R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ and R ₄ are hydrogen, lower alkoxy, lower alkyl, halogen, trifluoro Methyl or R ₃ and R ₄ together are lower alkylenedioxy, X is oxo, one hydroxy and one hydrogen, or two hydrogen, R ₆ and R ₇ are each hydroxy, amino, lower alkoxy, A preparation of the general formula (IA) compound which is phenyl (lower) alkoxy, lower alkoxycarbonyl (lower) alkoxy, or a pharmaceutically acceptable salt thereof.

Useful compounds include those in which R ₁ is hydrogen, lower alkyl, W-amino (lower) alkyl, or aryl (lower) alkyl [where aryl is lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoro Phenyl mono-substituted or unsubstituted by methyl], R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ and R ₄ are hydrogen, lower alkoxy, lower alkyl, halogen or trifluoromethyl or R ₃ and R ₄ together are lower alkylenedioxy, X is oxo, one hydroxy and one hydrogen, or two hydrogen, and R ₆ and R ₇ are hydroxy, amino, lower alkoxy, phenyl (lower) alkoxy, respectively. And the preparation of the general formula (IA) compound which is lower alkoxycarbonyl (lower) alkoxy or a pharmaceutically acceptable salt thereof.

Particularly useful compounds are those in which R ₁ is hydrogen, lower alkyl, W-amino (lower) alkyl, aryl (lower) alkyl, R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ is hydrogen, R ₄ is hydrogen, Lower alkoxy, lower alkyl, halogen or trifluoromethyl, X is oxo, one hydroxy and one hydrogen or two hydrogen, and R ₆ and R ₇ are independently hydroxy, amino, lower alkoxy, phenyl ( Preparation of the general formula (IA) compound which is lower) alkoxy, lower alkoxycarbonyl (lower) alkoxy, or a pharmaceutically acceptable salt thereof.

Very particularly useful compounds are those in which R ₁ is hydrogen, methyl, ethyl, isopropyl, W-aminopropyl, W-aminobutyl, or aryl is one methyl, hydroxy, methoxy, methylenedioxy, acetyloxy, chloro or tri Aryl- (methyl, ethyl, propyl) which is substituted or unsubstituted phenyl as fluoromethyl group, R ₂ and R ₅ are hydrogen or methyl, and R ₃ and R ₄ are hydrogen, methoxy, methyl, chloro or tri Fluoromethyl, X is oxo, one hydroxy, one hydrogen or two hydrogen, R ₆ and R ₇ are independently hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxycarbonylmethoxy Or the preparation of a compound of formula (IA) which is pivaloyloxymethoxy or a pharmaceutically acceptable salt thereof.

More useful compounds include compounds of the general formula (IB) and pharmaceutically acceptable salts thereof;

Wherein n is an integer from 1 to 4, R ₈ is phenyl mono-substituted or unsubstituted by hydrogen or lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, hydroxy or trifluoromethyl, R ₆ And R ₇ is independently hydroxy, lower alkoxy, benzyloxy, or amino of up to 4 carbon atoms.

Particularly valuable compounds are CnH _2n is ethylene, R ₈ is phenyl or lower alkoxy of up to 4 carbon atoms, lower alkyl of up to 4 carbon atoms, phenyl mono substituted as halogen or trifluoromethyl, R ₆ and R ₇ Examples thereof include hydroxy or a general formula (IB) compound which is lower alkoxy having 4 or less carbon atoms, and a pharmaceutically acceptable salt thereof.

The invention also relates to the preparation of stereoisomers of the general formula (I) compound. Numerous racemates are obtained when at least one of R ₁ and R ₂ in the general formula (IA) compound is not hydrogen and / or X is H (OH). Each colon of this racemate can be obtained separately. Certain of these isomers are preferred as angiotensin converting enzyme inhibitors. Remarkable compounds are the following general formula (Ic) compounds or pharmaceutically acceptable salts thereof:

Wherein S is chirality, n is an integer from 1 to 4, R ₈ is hydrogen or monosubstituted or unsubstituted with lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, hydroxy or trifluoromethyl Ring phenyl and R ₆ and R ₇ are independently hydrogen, lower alkoxy having 4 or less carbon atoms, benzyloxy or amino.

The general definitions used herein have the following meanings within the scope of the present invention. Aryl is a carbocycle or heterocycle aromatic radical, preferably phenyl mono- or di-substituted or unsubstituted with lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl to be.

“Cycloalkyl” is preferably a cyclic hydrocarbon radical containing 3 to 8 carbons and examples thereof include cyclopentyl or cyclohexyl. Preferred as “aryl (lower) alkyl” are benzyl in which the phenyl ring is mono- or di-substituted or unsubstituted with lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen or trifluoromethyl, 1 Or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, 1-, 2-, 3- or 4- phenylbutyl.

Preferred as ＂cycloalkyl (lower) alkyl＂ are 1- or 2- (cyclopentyl or cyclohexyl) ethyl, 1-, 2- or 3- (cyclopentyl or cyclohexyl) propyl or 1-, 2-, 3- Or 4- (cyclopentyl or cyclohexyl) -butyl.

The term "lower" referred to before or after in connection with an organic radical or compound is defined as having up to seven, preferably up to four, and advantageously one or two carbon atoms. Lower alkyl groups preferably contain 1 to 4 carbon atoms, examples of which are ethyl, propyl, butyl and methyl are advantageous.

Preferred lower alkoxy groups contain 1 to 4 carbon atoms, examples of which are methoxy, propoxy, isopropoxy and ethoxy are beneficial. Preferred mono- (lower) alkylamino groups include 1 to 4 carbon atoms in the alkyl moiety, examples of which include N-methylamino, N-propylamino and N-ethylamino are advantageous.

Preferred di- (lower) alkylamino groups include one to four carbon atoms in each lower alkyl moiety and examples thereof include N, N-dimethylamino, N-methyl-N-ethylamino, advantageously N And N-diethylamino. Preferred lower alkanoyloxy include acetoxy, propionyloxy or pivaloyloxy. Preferred alkylenedioxy includes ethylenedioxy and advantageously methylenedioxy. Beneficial examples of aryl lower alkoxy include benzyloxy or benzyloxy and pyridyl methoxy substituted by methyl, methoxy or chloro.

An advantageous example of carboxy lower alkoxy is 1-carboxyethoxy. Lower alkoxycarbonyl An advantageous example of lower alkoxy is 1- (ethoxycarbonyl) ethoxy. Examples of beneficial examples of amino (lower) alkoxy, mono- (lower) alkylamino loweralkoxy and di- (lower) alkoxyamino loweralkoxy include aminoethoxy, ethylaminoethoxy and diethylamino ethoxy, respectively. An advantageous example of lower alkanoyloxymethoxy is pivaloyloxymethoxy.

Bicycloalkyloxycarbonyl- (lower) alkoxy preferred is bicyclo [2,2,1] heptyloxycarbonyl- (lower) alkoxy unsubstituted or substituted with lower alkyl. There is. As amino (lower) alkyl and W-amino (lower) alkyl, preferred are amino (ethyl, propyl or butyl) and W-amino (ethyl, propyl or butyl), respectively. Preferred halogens may be chlorine, bromine, fluorine or iodine.

One or both carboxyl groups of the dicarboxylic acids, such as compounds of formula (IA) or (IB), wherein R ₆ and R ₇ are hydroxy may be modified with esters or amides according to the invention. Preferred such functional group derivatives are mono or bis lower alkyl esters such as methyl, ethyl n- or i-propyl, butyl or benzyl esters; Mono- or di-N-alkylated amides such as mono- or diethylamide; Mono or bissubstituted lower alkyl esters such as W- (amino, mono- or dimethylimino, carboxy or carethoxy)-(ethyl, propyl or butyl) esters. Very preferred functional derivatives are monoesters of the general formula (IA) wherein one of R ₆ and R ₇ is hydroxy and the other is lower alkoxy.

Preferred pharmaceutically acceptable salts are metal salts or ammonium salts of the general formula (I) compounds of which R ₀ is carboxy or of the general formula (IA) compounds of COR ₆ and / or COR ₇ of carboxy, in particular sodium, potassium, magnesium or calcium salts. Alkali or alkaline earth metal salts such as these; Mono-, di- or tris-lower such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris- (hydroxymethyl) aminoethane or benzyltrimethylammonium hydroxide There are easy crystalline ammonium salts derived from ammonia or freeamines such as alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkylenediamine or lower (hydroxyalkyl or aralkyl) -alkylammonium bases. Such compounds of the general formula (I) include halogenic acids such as hydrochloric acid and bromic acid: strong inorganic acids such as sulfuric acid, phosphoric acid, nitric acid or perchloric acid; Formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid Anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid; Aliphatic or aromatic carboxylic acids or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, β-toluenesulfonic acid and naphthylenesulfonic acid; It forms the preferred acid addition salts of therapeutically acceptable inorganic or organic acids such as sulfanilic acid or cyclohexylsulfamamic acid.

Compounds of formula (I) exhibit valuable pharmacological properties, such as cardiovascular effects, by inhibiting the release of angiotensin II, in particular through selective inhibition of angiotensin converting enzymes in mammals.

Compounds of general formula (I) primarily exhibit hypotension / hypertension and cardiac effects. These properties can be proved by performing in vivo or in vitro tests using rats, cats, dogs and other mammals or their extraction organs as subjects. These animals may be hypertension, such as normal or genetically spontaneous, hypertensive rats or renal hypertensive rats and dogs and sodium depleted dogs. The compound may be enterally administered or parenterally administered to experimental animals, and may be advantageously administered orally or intravenously in the form of gelatin capsules or starch suspensions or aqueous solutions. The dosage range used is about 0.01 to 100 mg / kg / day, preferably about 0.05 to 50 mg / kg / day, and advantageously about 0.1 to 25 mg / kg day.

In vivo measurement of blood pressure can be achieved by direct positioning using a catheter placed in the femoral artery of a laboratory animal or indirectly by a blood pressure monitor and a transducer in the rat tail. Blood pressure is reported in mmHg before and after dosing.

Therefore, the antihypertensive effect was proved by measuring heart contraction pressure indirectly in spontaneous hypertensive rats. Conscious rats are placed in each of the cages in a warmed chamber. The pulse detector is placed at the end of the inflatable occulsive cuff on each rat tail. The cuff is inflated periodically to close the tail artery. The pressure in the cuff continues to decrease and the contraction pressure coincides with the pressure in the cap where the pulse wave reappears. After adjusting blood pressure and heart rate to the required values, the test compound is administered orally once a day for 4 days. Blood pressure is additionally usually measured 2.0, 4.0 and 23.5 hours after the media compound administration and the results are compared with the measurements of rats administered with therapeutic excipients only.

As in the description of the present invention, the “high melting point” 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro- of Example 1 1H- [1] benzazin-2-one has proven to be an antihypertensive agent. At 3 mg / kg oral administration, blood pressure was lowered by 40 mm Hg as an average value measured 2 hours and 4 hours after the last 2 days. The corresponding S, S enantiomer of Example 12 had a 30 mmHg lowered blood pressure at 1 mg / kg oral administration.

Formula (I) compounds administered intravenously or orally also have an inhibitory effect on angiotensin I induced blood pressure elevation in normal blood pressure rats. Angiotensin I is hydrolyzed in response to this converting enzyme, resulting in a powerful blood pressure booster Angiotensin II. Inhibition of this enzyme prevents the production of angiotensin II from angiotensin I, and in this way reduces the increase in tongue pressure induced by angiotensin I.

Elevated in vivo experiments on intravenous administered compounds were performed with rat males of normal blood pressure anesthetized with sodium 5-ethyl-5- (1-methylpropyl) -2-thiobarbituate-rate. A cannula was connected for direct blood pressure measurement to the femoral artery and saphenous vein and for intravenous administration of angiotensin I and the compound of the present invention. After the basal blood pressure has stabilized, the blood pressure rise is measured for three intravenous doses of 333 mg / kg angiotensin I at 5 minute intervals. Such blood pressure response is usually measured again 5, 10, 15, 30 and 60 minutes after intravenous administration of test compound and compared with initial value. The decrease in anterior blood pressure response measured indicates angiotensin I converting enzyme inhibitory action. As in the description of the present invention, the “high melting point” 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H [ 1] Benzazin-2-one and the corresponding S and S optical enantiomers of Example 12 responded to an angiotensin I achievement for 30 minutes after intravenous administration of 1 mg / kg of any of these compounds. Suppress completely.

Inhibition of the living body of angiotensin converting enzyme according to the general formula (I) compound is described in Biochim. Biophys. Acta 293, 451 (1973). According to this method, the compound is dissolved in phosphate buffer at a concentration of about 1 mmol. To 100 microliters of the test compound solution in phosphate buffer diluted to the required concentration, add 100 microliters of 5 mmol of hypofuryl-histidillucin in phosphate buffer, followed by tris buffer containing potassium and magnesium chloride as well as sucrose ( A solution of 50 microliters of angiotensin converting enzyme (extracted from male rabbits) was dissolved in Tris buffer. The solution is incubated at 37 ° C. for 30 minutes and mixed with 0.75 ml of 0.6N aqueous sodium hydroxide solution to prevent further reaction. At room temperature, add 100 microliters of a 0.2% solution of O-phthalaldehyde in methanol and after 10 minutes add 100 microliters of 6N hydrochloric acid. The sample is contrasted with water to read the spectrophotometer scale at 360 nm and to calculate its optical density. This value is calibrated to a standard curve using a conversion factor expressed in nanomoles of histidyl-leucine produced during the 30 minute incubation period. The results obtained are plotted against drug concentration to determine IC ₅₀ , which is the drug concentration that has half the activity of the control sample containing no drug. ＂High melting point＂ 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazine- of Example 9 in the present invention; The 2-on and rising S, S optical enantiomers of Example 19 have IC ₅₀ of 5.2 × 10 ⁻⁹ M and 1.7 × 10 ⁻⁹ M, respectively. Low Melting Point 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one of Example 8 Has an IC ₅₀ of 5.8 × 10 ⁻⁸ M.

Angiotensin-converting enzymes not only participate in the conversion of angiotensin I to angiotensin II, but also regulate the levels of bradykinin and aldosterone. The effects of the general formula (I) compounds on these factors also contribute to the antihypertensive and cardiac effects of these newly prepared compounds.

Because of the beneficial properties described above, the general formula (I) compounds are of great value as special therapeutic agents for mammals, including humans. Thus, the compounds of general formula (I) are valuable products in particular which are particularly useful for alleviating heart conditions and / or other edema or ascitic diseases, such as hypertension and / or congestive heart failure, irrespective of the etiology. Useful as a manufacturing intermediate of pharmaceutical compositions.

The compound of the general formula (I) is subject to a ring-closing reaction of the compound of the general formula (IX) or an ester thereof, and, if desired, the obtained compound of the general formula (I) described above with other compounds of the general formula (I) And / or optionally convert the obtained compound of formula (I) having salting properties into a salt, liberate a free compound from such a salt, and / or, if necessary, one or more chiral centers. The optical isomers of special electron arrangements having the formula (I) can be prepared according to the invention in a manner known per se, such as by manipulating them to supplement from stereoisomer mixtures of the compounds obtained of general formula (I).

Wherein the carbocyclic ring is hexahydro or 3, 4, 5, 6-tetrahydro, and R _A, R _B, R _3, R _4, R _5, and X are as defined above. Alkylation reactions, which may each serve to introduce residues R _A and R _B, are used to determine the corresponding starting material, as defined by the R _A or R _B hypothetical group, and with Z being (lower alkanesulfonic acids, in particular methanesulfonic acid, trifluorine). Strong organic acids such as aliphatic or aromatic sulfonic acids such as romethanesulfonic acid, in particular benzenesulfonic acid, β-toluenesulfonic acid, β-bromobenzenesulfonic acid and β-nitrobenzenesulfonic acid); Or an alkylating agent of the general formula R _A -Z (IIIA) which is a reactive esterified hydroxyl group such as hydrochloric acid or most preferably a hydroxyl group esterified with hydrofluoric acid such as iodic or bromic acid or a strong inorganic acid such as sulfuric acid. Proceed according to the usual method of treatment.

The alkylation reaction proceeds under conventional general conditions ranging from about 0 ° C. to the boiling point of the reaction mixture, preferably from room temperature to about 100 ° C. The reaction is carried out with chlorinated lower alkanes (e.g. chloroform or methylene chloride), bicyclic or cyclic ethers (e.g. diethyl ether, 1, 2) -dimethoxyethane, dioxane or tetrahydrofuran), in particular low molecular weight 3 Inert to reactants such as tertiary amines (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethylphosphoric acid triamide) It proceeds advantageously in the presence of a solvent. The strong acid HZ released during the reaction is advantageously bonded by the addition of an acid binder. Preferred examples of the acid binder include inorganic acid scavengers such as alkali metal bicarbonates, carbonates or hydroxides, free quaternary ammonium salts such as tetrabutyl ammonium salts, or Organic tertiary bases such as triethylamine, N-ethylpiperidine, pyridine or quinoline.

The alkylation reaction can also proceed under reducing alkylation reaction conditions known and used in the art. In proceeding with the alkylation reaction, the compounds of the general formula R ₁ -CO-R ₀ (IV) wherein R ₁ and R ₀ are as described above are reacted with the starting bicyclic compound and simultaneously with or with the reducing agent in the subsequent process. Reducing agents used simultaneously with alkylating agents include complex metal hydrides such as formic acid and sodium cyanoborohydride; Reducing agents that are excellently used in separate subsequent processes such as the reduction of previously prepared schiff's bases include sodium cyanoborohydride and sodium, which are added to the primary reaction mixture without separating intermediates such as diborane and imine. And complex metal hydrides such as borohydride. In this case, the alkylation reaction may be aliphatic or cyclic ether (diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, etc.) or aliphatic alcohol (methanol, ethanol, isopropanol, glycol, glycol mono It is advantageous to proceed in an organic solvent which is inert to reducing agents such as ethyl ether or diethylene glycol) and is preferably about 0 to 80 ° C. The first reducing agent which can be used simultaneously and also in subsequent processes is hydrogen, in particular catalytically activated hydrogen.

The catalyst is a catalyst commonly used as a hydrogenation catalyst, and examples thereof include rare metal catalysts (palladium, platinum, and the like) on carriers (calcium carbonate, aluminum oxide, barium sulfate, etc.) in the form of a microdispersion suspension without a carrier or a complex in homogeneous acid. Rhodium) is preferred. In addition, Raney metal, in particular, finely dispersed transition metals such as Raney nickel is a very suitable catalyst for reducing alkylation reaction. The intrinsic reaction conditions depend greatly on the hydrogenation catalyst and its exact activity and are not influenced by what is generally known in the hydrogenation reaction. According to standard procedures in the art, temperatures in the range of 150 ° C. to room temperature and hydrogen pressure in the range of atmospheric to about 300 atmospheres are used.

In addition to the inert solvents described above in connection with hydride reduction, also low molecular weight amides except formamide and acetamide, in particular N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethyl Tertiary amides such as piperidone, hexamethylphosphoric acid triamide can be used as a suitable solvent. Special consideration should be given to using starting materials of the general formula (II) having functional groups which are easily reduced, such as 5-oxo groups. To preserve these groups, selective reducing conditions as known in the prior art must be applied. In addition, when co-reduction of these groups is required or required, intensive reaction reagents and / or conditions may be used.

The above-mentioned preliminary imines are formulated in general in an inert solvent such as toluene or methylenechlora in the presence of a dehydrogenation catalyst such as boron trifluoride etherate, p-toluene sulfonic acid or molecular sieve. It is preferably prepared by condensation with the compound of (IV).

Alkylation that can be performed for the introduction of R _B is an alkali metal hydride (such as sodium or potassium hydride), an alkoxide (such as sodium methoxide or ethoxide, potassium tert-butoxide), or (lithium diiso) It proceeds preferably in the presence of very strong bases, such as amides) such that the ethers and amides described above are used as preferred solvents.

nsch(editor) : Synthese von Peptiden(Georg Thieme Verlag, Stuttgart : 1974)].In any alkylation process, the primary and secondary amino groups in the starting material, except for the secondary amino group to be alkylated, must be present in a temporarily protected form during the alkylation reaction. Appropriate protecting groups as well as methods for introducing and removing protecting groups are known in the art and are described in detail as a general method of peptide synthesis of Houben-Weyl in particular. See Methoden der Organischen Chemie: 4th edition, Vol 15 / I. and II, E, W

nsch (editor): Synthese von Peptiden (Georg Thieme Verlag, Stuttgart: 1974)].

The scope of protection group selection depends on the inherent purpose, which must take into account in particular the intrinsic properties of the specific starting material and the reaction conditions of the intrinsic reaction. If several working groups are to be protected, an advantageous combination can be selected. For example, it is preferred to use similar or better identical amino protecting groups in the R ₀ radical and the R ₁ radical and the group is removed at the same time following the alkylation reaction.

Suitable as amino protecting groups are, in particular, amino protecting groups which can be removed by reduction, examples of which in particular the aromatic moieties of benzyloxycarbonyl groups are P-chloro- and -P-bromobenzyloxycarbonyl, p-methoxy Benzyloxycarbonyl forms which may be substituted by halogen atoms, lower alkoxy groups and / or lower alkyl groups, in particular nitro groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl and especially p-nitrobenzyloxy carbonyl groups Protection groups. Advantageous as amino protecting groups are ethoxy carbonyl groups carrying triphenylsilyl, dimethyl tert-butylsilyl or especially trimethylsilyl substituted with three hydrocarbon radicals at the β-position of the silyl group. In particular, this type of β- (trihydrocarbonylsilyl) -ethoxycarbonyl group such as β- (trilower alkylsilyl) -ethoxycarbonyl group such as β- (trimethylsilyl) -ethoxycarbonyl is amino Protected by the formation of the corresponding β-trihydrocarbysilyl ethoxy carbonylimino groups (e.g. β-trimethylsilyl ethoxycarbonylamino groups) with the group, which is very fluorine under very specific and mixed reaction conditions. It can be separated and removed by the action of ions.

Also groups in the form of aralkyl such as benzhydryl, di- (4-methoxy) -benzhydryl and triphenylmethyl (trityl), or 2- (p-biphenyl as described in switch patent specification 509,266 Groups such as tertiary butoxycarbonyl groups as well as certain aralkoxycarbonyl groups in the form of aryl) -2-propoxycarbonyl can be removed by acidolysis. Protective groups derived from carboxylic acid esters can in most cases also be removed by base hydrolysis.

For the temporary temporary protection of hydroxy groups, as can be seen from the above-mentioned literature (Houben-weyl) and the like can be reduced and removed, and also 2-tetrahydropyranyl, tert-butoxycarbonyl and tertiary- It is advantageous to use protecting groups, such as butyl, which can be removed by acid hydrolysis. Preferred examples of hydroxy protecting groups which can be prepared by reduction include benzyl groups, in particular 4-nitrobenzyl groups, in which the aromatic moiety may be substituted as halogen, lower alkyl, lower alkoxy and / or nitro in particular. It is also possible to use acyl groups which can be removed under weak base conditions such as formyl or trifluoroacetyl.

For the optional protection of the oxo groups these groups may be converted to ketals, in particular lower alkanols such as methanol or ethanol or advantageously ketals derived from ethylene glycol, or preferably ketals of 1,2-ethanoldithiol. It is preferable to protect as an octal. All these groups can release an oxo group under the conditions described below.

Subsequent process removal of the protecting group according to the invention depends on these properties and in each case proceeds according to the prior known method taking into account the general nature of the product derived. Where protection groups for amino, hydroxy and oxo are selected for removal under similar conditions, it is advantageous to remove all of these protection groups in a single process: however, in special cases, different types of protection groups may be employed for each of them. Can be removed individually.

Groups which can be removed by reduction, in particular halogenated lower alkyl (such as 2,2,2-trichloroethyl radical), isonicotynyl radicals (such as isonicotinyloxycarbonyl) and especially substituted benzyl radicals, in particular all Groups containing 4-nitrobenzyl radicals of the kind are usually preferably removed by adding an inert organic solvent at room temperature or by zinc reduction in the absence of added acid, preferably in the presence of acetic acid. Removal of the protecting group by addition decomposition can be carried out with water and optionally polyhalogenated lower alkanols or lower alkanes such as 1,1,1,3,3,3-hexafluoropropan-2-ol or hexafluoroacetone. In the presence of discussion, in the case of tert-butyl type groups, hydrogen chloride, hydrogen fluoride or trifluoroacetic acid is used, and in the case of acid-sensitive protecting groups, lower aliphatic carboxylic acids such as formic acid and / or acetic acid are mainly used. Proceed. In this way, for example, the N-trityl group is an organic acid such as formic acid, acetic acid, chloroacetic acid or trifluoroacetic acid in water-soluble or anhydrous trifluoroethanol as a solvent (cf. JP DT 2 346 147). Or water soluble acetic acid can be used and removed; The 2- (p-biphenylyl) -isopropoxycarbonyl group can be prepared by using water-soluble acetic acid or by using a 7: 1: 2 mixture of glacial acetic acid, formic acid (82.8% concentration) and water, or JP DT 2,346,147. Can be removed. The β-silylethyl ester group is preferably removed using a fluoride ion feed reagent such as a fluoride of a quaternary organic base such as tetraethyl ammonium fluoride.

In the latter case, the ketal oxalate group and the terokate oxalate group can be converted to the free oxo group by adding and decomposing it with a conventional inorganic strong acid or oxalic acid in the presence of water by treatment with mercury (II) salt and / or cadmium carbonate. Under basic conditions, protecting groups such as unstable formyl, trifluoroacetyl and carboxylic acid ether groups can be carefully removed by acting with sodium bicarbonate or potassium bicarbonate aqueous solution or sodium carbonate or potassium carbonate aqueous solution or ammonia water in an organic solvent at room temperature. have. The protecting group is preferably removed under the reaction conditions or similar conditions in the examples.

Final products which can be prepared according to the invention containing basic groups are obtained in the form of bases or acid addition salts according to the separation process; Similarly, the final product with acidic groups may also be obtained in the form of salts. Each form can be converted into another form according to a well-known method. The base can be obtained from acid addition salts according to known methods, and from the base this time can be reacted with an acid, for example an acid in the form of the salts below, to give acid addition salts, especially acid addition salts useful for treatment. Acids and salts thereof are also in a similar relationship to each other described above. Compounds having both free carboxyl groups and basic groups may exist in the form of internal salts, which are obtained, for example, by setting isoelectric points.

Starting materials of the general formulas (IIIA), (IIIB) and (IV), which may be referred to as alkylating agents, are known compounds or may be readily prepared according to the preceding synthesis methods even if they are not known.

The starting material to be alkylated can be prepared by conventional synthetic methods and can be advantageously obtained according to the methods which are then illustrated as specific intermediates and described in more detail.

The ring closure reaction according to the manufacturing method can also be advanced by a known method such as dehydration. Particularly useful methods for this purpose include the work cited in Houben-Weyl et al. Vol. Methods developed in connection with the formation of amide bonds in peptides as described in 15/1 and 15/2. According to one preferred embodiment, the amino group to be cyclized is protonated to be inert (eg in the form of acid addition salts) and the carboxyl group is 2,4,5-trichlorophenol, pentachlorophenol. , Pentafluorophenol, 2-nitrophenol or especially 4-nitrophenol: or N-hydroxy succiamino, 1-hydroxybenz triazole or N-hydroxy piperidine; Or in particular N, N'-di-substituted isoureas such as N, N'-dicyclo hexylisourea; Or conversion to activating esters using generally known similar activators. The ring closure reaction involves quaternary ammonium salts in order to convert amino groups into deprotonated forms to achieve reactivation for the ring closure reaction; Or, in particular, by basicizing by adding an organic base such as a tertiary amine such as triethylamine, N-ethylmorpholine or N-methylpiperidine. The reaction temperature is -20 to + 50 ° C., preferably around room temperature, and examples of the material used as a common solvent include chloroform and methylene chloride, as well as dioxane, tetrahydrofuran, acetonitrile, pyridine, and dimethyl. Formamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphosphoric acid triamide and suitable mixtures thereof. In certain forms of preparation (in some cases N-hydroxysuccinimide, unsubstituted or halogen-, methyl- or methoxy-substituted 1-hydroxy-benztriazole or 4-hydroxy benzo-1,2 Carbodiimide, such as N, N'-dicyclohexyl carbonyldiimide, with the addition of, 3-triazine-3-oxide or H-hydroxy-5-norbornene-2,3-dicarboxamide Alternatively, the free acid can be treated with N, N'-carbonyldiimidazole to directly activate the carboxy group.

Starting materials of the general formula (IX) can be obtained according to the general known methods as described in the Examples below.

Obtaining the general formula (I) In any internal transformation of the final product into other compounds within the definition of the general formula (I), the following transition reaction proceeds; Alkylate the amino group and / or reduce the oxo group, in particular the oxo group at position X, to hydroxyl (and hydrogen) or two hydrogens and / or oxidize the hydroxyl to oxo or reduce to hydrogen And / or liberate the free hydroxyl or carboxyl group from the ester and form by hydrolysis or plasticization and / or acylate the hydroxyl or amino group and / or esterify the free carboxyl, and / or general Hydrogenating the aromatic carbocyclic ring of formula (I) with hexahydro or 6,7,8,9-tetrahydro and / or the hexahydro carbocyclic ring with 6,7,8,9-tetrahydro or aromatic carbo The dehydrogenation reaction is carried out with a cyclic ring.

Any of these internal conversions can be carried out according to known prior methods. Lower alkyl represented by R ₅ can be introduced into the final product of formula (I) wherein R ₅ is hydrogen by an alkylation reaction using the modifications mentioned in detail in connection with the preparation. Both substitutional and reductive alkylation reactions can be used, with the former advantageously using alkyl halides, the latter by lower aliphatic aldehydes and ketones and catalytically activated hydrogen or, in the case of formaldehyde, formic acid. The lower alkyl group can also be introduced into the amino group, which is the carbamoyl group component represented by R ₀ , by a substitutional alkylation reaction. The reduction of the 5-oxo group to hydroxy can also be carried out using particularly mild complex metal hydrides such as alkali metal protective hydrides (e.g. sodium borohydride) or the Meerwein-Ponndorf reaction. Or according to a variant, it proceeds according to a conventional method using a metal alkoxide corresponding to an alkanol, in particular isopropyl alcoholol for solvents and reducing agents, and preferably a reducing alcohol such as aluminum isopropoxide as catalyst. It is advantageously carried out by treatment with two hydrogen atom-reducing amalgamated zincs of oxo group and hydrochloric acid or by a Raney-nickel desulfurization reaction of the corresponding dithioketal. Oxidation of hydroxyl to oxo is aluminum isopropoxide as a catalyst with acetone or cyclohexanone as oxidant under hexavalent chromium derivatives such as chromic acid and salts thereof, permanganate (particularly potassium permanganate) or Oppenenauer oxidizing conditions Can be preferably proceeded with. The esterified hydroxyl group can be released according to the method described in detail above in particular with regard to hydroxyl-protecting group removal; The acylation reaction of both hydroxyl and amino groups is preferably carried out in accordance with conventional methods using the corresponding acid anhydrides or halides. For esterification reactions, carboxyl groups can be reacted directly with diazoalkanes, in particular diazomethane, or with the corresponding alcohols in the presence of strong acid catalysts (such as sulfuric acid or organosulfonic acid) and / or dehydrating agents (such as dicyclohexyl carbodiimide). You can. Alternatively, carboxyl groups can be converted to their reactive derivatives, such as active esters, or mixed with anhydrides such as acid halides (especially acid chlorides) or trifluoro acetic acid and reacted with the required alcohols.

Free carboxyl groups can be obtained from esterified carboxyl by known methods, in particular by base-catalyzed hydrolysis. Of interest, however, is the method of selectively obtaining one carboxyl group from among the carboxyl groups represented by -COR ₆ and -COR ₇ . In such cases, Houben-weyl. In the peptide synthesis of Volumes 15/1 and 15/2, it is possible to use a suitable combination of the diversified ester groups. Suitable radicals for selective removal in obtaining carboxyl groups are esters derived from alcohols which produce radicals which can be removed by acid hydrolysis, examples of which are cyano methylalkyl, benzoyl methyl alcohol or tert-butyl alcohol. But in particular 2,2,2-trichloroethanol, benzyl alcohol and especially 4-nitrilobenzyl alcohol or alternatively alcohols that produce radicals which can be removed by reduction, such as isonicotinyl alcohol. A particularly advantageous class of substituted alcohols are ethyl alcohols which carry a trisubstituted silyl group such as triphenylsilyl, dimethylbutylsilyl or especially trimethylsilyl at the β-position. As described in Belgian Patent No. 851,576, the corresponding β-silylethylesters of these alcohols, such as β- (trimethylsilyl) -ethylester, have the same stability as conventional alkylesters but by acting under fluorine ions under mild conditions These alcohols are particularly suitable for selective removal as they can be selectively removed while leaving other esterified carboxyl groups such as alkoxycarbonyl groups.

The removal of esterified groups depends on these properties and in each case proceeds according to prior known methods taking into account the nature of the other radicals involved. And in the case of groups containing groups which can be removed by reduction, in particular halogenated lower alkyl radicals (such as 2,2,2-trichloroethyl radicals) and isicotinyl radicals (such as isonicotinyl oxycarbonyl) Benzyl radicals thus substituted, in particular all kinds of 4-nitrobenzyl radicals, are preferably removed by zinc reduction in the presence of an acid at room temperature, preferably acetic acid, with or without conventional inert organic solvents; Benzyl esters, in particular unsubstituted benzyl esters, are also removed by the hydrolysis methods commonly used for benzyl groups.

Removal of ester groups by addition decomposition can be carried out using hydrogen chloride, hydrogen fluoride or trifluoroacetic acid, especially in the case of tert-butyl form groups. The β-silyl ethyl ester group is preferably removed with a fluorine ion generating reagent such as fluoride of a quaternary organic base such as tetraethylammonium fluoride. Base-labile ester groups can be carefully removed by the rapid action of aqueous ammonia or potassium aqueous solution or aqueous ammonia, preferably in an organic solvent, at room temperature. The ester group is preferably removed under reaction conditions or similar conditions in the examples. It is desirable to remove under similar conditions.

Suitable combinations of ester groups are selected at the beginning of the synthesis or by appropriate selection of starting and reactants, and by introducing a selectively removable ester group into the carboxyl obtained at the final stage. The conversion process to other compounds which can be prepared according to the invention is carried out using chemical methods known in the art.

Compounds of formula (I) or (IA), wherein R ₆ and / or R ₇ is lower alkoxy, are amidated with ammonia mono- or di- (lower) alkylamines to unsubstitute R ₆ and / or R ₇ , Compounds of the general formula (I) or (IA) which are mono- or di- (lower) alkylamino are prepared.

Formula (I) or (IA) compounds wherein R ₆ and / or R ₇ is lower alkoxy, aryl (lower) alkoxy, amino, mono- or di- (lower) amino, are those in which R ₆ and / or R ₇ is hydroxy The conversion reaction to phosphorus general formula (I) or (IA) compounds can be carried out by hydrolysis with an inorganic acid or alkaline aqueous solution such as hydrochloric acid or sulfuric acid, preferably as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.

A compound of formula (I) or (IA) wherein R ₆ and / or R ₇ is an α-aryl (lower) alkoxy such as benzyloxy, or a compound of formula (I) wherein R ₆ and / or R ₇ is hydroxy; The selective conversion reaction to IA) compound can be proceeded by hydrogenolysis using hydrogen in the presence of a catalyst such as palladium.

Compounds of formula (I) or (IA) in which both R ₆ and R ₇ are not hydroxy can be converted to monocarboxylic acids of formula (I) or (IA), wherein one of R ₆ and R ₇ is hydroxy. have. Such conversion reactions proceed based on the selective hydrolysis or hydrolysis processes known in the art and on the chemical properties of the R ₆ and R ₇ substituents.

The free carboxylic acid of formula (I) or (IA) or a salt thereof, wherein R ₆ and / or R ₇ is hydroxy is esterified with a suitable alcohol or reactive derivative thereof well known in the art to give the corresponding mono- or Prepares a compound of formula (I) or (IA) wherein the bis-ester, ie R ₆ and / or R ₇ is lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethyl or lower alkoxycarbonyl (lower) alkoxy . The free carboxylic acid may also be converted via the reactive intermediate to mono- or bis-amides of formula (I) wherein R ₆ and / or R ₇ is amino, mono- or di- (lower) alkylamino.

Catalytic hydrogenation reaction such as hydrogen in the presence of a compound of formula (I) or (IA) in which X is oxo and a palladium catalyst as an intermediate thereof, or reduction of a metal hydride reducing agent such as sodium borohydride, etc. May be converted to the corresponding compound which is hydroxy. The obtained compounds wherein X is one hydrogen and one hydroxy are described in Chem, Ber. 107, 1353 (1974), carbodiimides such as adducts prepared by condensation with dicyclohexyl carbodiimide in the presence of cuprous chloride, in which X is one hydrogen and one hydroxy The catalytic hydrogenation reaction of the adduct may be converted to a compound wherein X is two hydrogens.

In contrast, compounds in which X is one hydrogen and one hydroxy are first converted to the corresponding compounds in which X is one hydrogen and one acyloxy (eg acetoxy), followed by catalytic hydrogenation in the presence of a palladium catalyst. Reduction by reaction or the like yields a compound wherein X is two hydrogens.

The reactions mentioned above are preferably diluents, catalysts, condensers or other reagents which are inert to the reagents and preferably solvents of these reagents at low temperature, room temperature or elevated temperature, preferably at atmospheric pressure or pressure at the solvent boiling point and / or under an inert airflow or In the absence, proceed according to the standard formulation.

The present invention further uses the intermediate product obtained in the specific step of the present invention as a starting material and proceeds with the remaining reaction step or is stopped in the middle of the reaction step, or the starting material is produced under the reaction conditions and the reactive component thereof is All variants of the inventive recipes used in salt form or in optically pure colon form are included. Starting materials for the preparation of the above general formula (I) compounds which are mainly particularly useful should be used in this reaction.

The invention also relates to a process for the preparation of the novel starting materials.

Depending on the choice of starting materials and preparation, the newly prepared compounds may be in the form of possible isomers or one possible mixture of these, e. It may be the same optical isomer mixture or stereoisomer mixture.

The obtained racemate is either recrystallized in an optically active solvent using microorganisms or the acidic end product is reacted with an optically active base forming a salt with racemic acid, and the solubility difference is used to separate the obtained salt into stereoisomers. And it can be further separated into an optical colon according to a known method for obtaining a colon by reacting a suitable reagent to this. Similarly, the basic racemic product can be separated into the colon by the separation method of these stereoisomers such as fractional crystallization of d- or l-tartrate.

It is advantageous to separate the more active of the two colones.

Finally, the compounds which can be prepared according to the invention are obtained in free form or in salt form thereof. The obtained base is preferably converted to the corresponding acid addition salt using a pharmaceutically acceptable acid or anion exchange method or the obtained salt is a metal such as alkali metal hydroxide or carbonate or a strong base or cation such as ammonium hydroxide or basic salt. Exchange methods can be used to convert to the corresponding freebases. Thus compounds of formula (I) wherein R ₀ is carboxy or compounds of formula (IA) wherein COR ₆ and / or COR ₇ are carboxy can also be converted to the corresponding metal or ammonium salts. These salts and other salts such as picrates can also be used in the obtained base purification. The base is converted to a salt, the salt is separated and a base is prepared from this salt. Given the close relationship between the free compound and its salt form compounds, whenever one compound is mentioned in this regard, the corresponding salt should also be considered to be mentioned, as the situation permits.

Including these salts, these compounds also contain other solvents obtained in hydrate form or used in the determination.

Pharmaceutical compositions which can be prepared according to the invention consist of an effective amount of a pharmacologically active compound of formula (I) or a pharmaceutically acceptable salt thereof alone or in combination with one or more pharmaceutically acceptable carriers, Inhibition of angiotensin converting enzymes such as hypertension and congestive heart failure and cardiovascular diseases is a composition suitable for enteral and parenteral administration, such as oral or rectal, to mammals, including humans, for effective treatment or prevention of diseases.

The pharmacologically active compounds of formula (I) are suitable for enteral or parenteral administration and are useful for preparing pharmaceutical compositions prepared by mixing or combining an effective amount of a pharmacologically active compound with an excipient or carrier. Preferred are tablets and capsules wherein the active ingredient is (a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and or glycine, (b) silica, talc, stearic acid, magnesium or calcium thereof Salts and / or suspending agents such as polyethylene glycols, and in the case of tablets also include (c) magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone; Prepared by mixing with a binder such as (d) starch, agar, alginic acid or its sodium salt or boiling mixture and / or (e) adsorbents, colorants, flavors and sweeteners if necessary. Injectable compositions are preferably aqueous isotonic solutions and suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. These compositions may be sterilized or may contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution accelerators, osmotic pressure regulating salts and / or buffers. In addition, these compositions may also contain other therapeutic substances. These compositions are each prepared by conventional mixing, granulating or coating processes and contain about 0.1 to 75%, preferably about 1 to 50% of the active ingredient. For mammals of about 50 to 70 kg, the unit dosage may contain about 10 to 200 mg of active ingredient.

The following examples are intended to illustrate the invention and are not intended to limit the invention thereto. Temperature is in degrees Celsius and all parts are parts by weight. All evaporations are carried out under reduced pressure of about 15 to 100 mm Hg unless otherwise indicated.

In the case of compounds of formula (I) or (IA) in which one or more asymmetric centers exist, the stereoisomer compounds obtained are denoted by A, B and the like in this example. Each stereoisomeric compound is characterized by physical properties such as melting point, chromatographic relative shift, infrared or NMR spectral properties.

In the case of compounds of general formula (I) or (IA) in which X is H ₂ and one asymmetric center is on a carbon atom in a side chain containing nitrogen atoms, the A and B marks are respectively determined on the basis of the relative movement speed on the chromatography. It is given to isomers. Fast moving isomers are referred to as isomer A, and slow moving isomers are referred to as isomer B based on the moving speed in thin layer chromatography using silica gel as a fixed phase and normal phase high pressure liquid chromatography. In reverse phase high pressure liquid chromatography, slow moving isomers are referred to as isomer A, and fast moving isomers are referred to as isomer B.

Example 1

1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H [1] benzazin-2-one

(High melting point isomer)

0.9 g of 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2- in 150 ml ethanol On hydrochloride (racemic isomer B) and 10 ml of propylene oxide are stirred for 18 hours under a stream of nitrogen. The solution is evaporated to dryness and the residue is dissolved in 3 ml ethanol. 75 ml ether is added to precipitate a small amount of starting hydrochloride. The filtrate is evaporated to dryness and stirred with 1: 9 ether / petroleum ether. The solid was filtered to give 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- [1] benz at a melting point of 139 to 141 ° C. Azepin-2-one is obtained which is the high melting racemic isomer B of the general formula (IB) compound wherein CnH _2n is ethylene, R ₆ is ethoxy and R ₇ is hydroxy or R ₈ is phenyl.

1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5 of Example 11 by digestion with optically active amine and separation of diastereomeric salts under standard conditions A pure colon such as -tetrahydro-1H- [1] benzazin-2-one is prepared.

High pressure liquid chromatography separation on a reverse phase columm (solvent system: 1: 1 methanol: water mixture containing 0.025% acetic acid) moved isomer B more rapidly than the low melting racemic isomer A of Example 4. .

Starting material 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride It is prepared similar to that described in Example 28. Starting materials can also be prepared as follows.

48.3 g of 2,3,4,5-tetrahydro-1H- [1] benzazin-2-one [Briggs et al. J. Chem. Soc. 1937, 456], 188 g of phosphorus pentachloride 1300 ml xylene mixture was heated to 90 ° C. (oil bath temperature) for 30 minutes with stirring under a nitrogen stream, and 30 ° C. (to allow the phosphorus pentachloride to dissolve) during the elevated temperature. The temperature is stopped briefly at 50 ° C. At this time, a large amount of hydrogen chloride is released. The temperature is kept at 90 ° C. for 30 minutes. The reaction mixture is filtered when hot to remove small amounts of suspended solids and the filtrate is evaporated under reduced pressure until all solvent is removed. The residue is added to 100 ml saturated aqueous sodium carbonate solution with stirring. After the solidification process was completed, the product was filtered, slurried in 150 ml ethanol, filtered, washed with 50 ml ethanol and 50 ml ether, and dried to dry 3,3-dichloro-2,3,4,5- with a melting point of 185 to 187 ° C. Obtain tetrahydro-1H- [1] benzazin-2-one.

To 920 ml glacial acetic acid add 20 g of 3,3-dichloro-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.174 mole) and 15.4 g of anhydrous sodium acetate (0.188 mole). The solution added is 1.72 g of 5% Pd-c as catalyst and hydrogenated at atmospheric pressure until the consumption of hydrogen is complete. The catalyst is filtered and acetic acid is evaporated under reduced pressure. The residue is equilibrated between 900 ml of 10% NaHCO ₃ aqueous solution and 300 ml dichloromethane, and the aqueous layer (pH8) is further extracted with 3 × 300 ml of dichloromethane, and the mixed organic solution is dried over anhydrous sodium sulfate and evaporated to a melting point. 3-chloro-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one at 163 to 167 ° C is obtained.

15.9 g of 3-chloro-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.08 mol) and 6.36 g of sodium azide (0.10 mol) in 320 ml of dimethyl sulfoxide ) Is maintained at 80 ° C. for 3 hours under a stream of nitrogen. At this time, the IR spectrum of an aliquot shows a strong peak at 215 cm <^{-1> which} is a characteristic of an azide group. The reaction mixture is poured into 1000 ml of ice / water and the suspension is stirred for 30 minutes. The solids were filtered, washed with 250 ml of water and dried to prepare 3-azido-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one with a melting point of 142-145 ° C.

8.7 g of 3-azido-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.043 mol) was added to 75 ml of anhydrous dimethylformamide under a stream of nitrogen. The solution is added to the stirred suspension with sodium hydride (from 1.9 g of 60% mineral oil dispersion washed with 3 x 150 ml of petroleum ether) in 250 ml dry dimethylformamide maintained at &lt; RTI ID = 0.0 &gt; Stirring was continued for an additional 1.5 hours, followed by addition of 10.8 g benzyl bromo-acetate (0.047 mol) in 75 ml anhydrous dimethylformamide over 45 minutes while maintaining the temperature at 0 ° C. The reaction mixture is then allowed to warm to room temperature and stirred for a further 18 hours. Dimethylformamide is removed under reduced pressure and the residue is dispersed in 500 ml water and 500 ml dichloromethane. The aqueous phase is further extracted with 3x500 ml dichloromethane, the combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure to give crude ester-azide as an oily substance. This material is dissolved in 500 ml of toluene and 48 g of silica gel is added. 3-azido-1-benzyloxy-carbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one as an oily substance by filtration and solvent removal under reduced pressure It is used in the next synthetic step without further purification.

15 ml of water was added to the suspension of Ranickel activation catalyst with 5 x 100 ml of ethanol, and 5.0 g of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetra in 300 ml of ethanol. Hydro-1H- [1] benzazin-2-one was added to the stirred mechanical solution, and the suspension was stirred for 18 hours at room temperature under a nitrogen stream. The catalyst is filtered off and the solvent is removed under reduced pressure. The residue is dissolved in 200 ml of 2N hydrochloric acid and the solution is extracted with 2 x 250 ml ether. The aqueous solution is made basic (pH9) with concentrated aqueous ammonia solution and the solution is extracted with 3 x 200 ml of ether. The mixed ether solution was dried over sodium sulfate and evaporated under reduced pressure to afford 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one. Obtained as a routine material and used in the next synthesis step without further purification.

3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is also prepared as follows: 5.0 in 100 ml of dimethylformamide. 1 g of tetrabutyl ammonium bromide (0.031 mol) was added to a solution to which g of 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.028 mol) was added under a stream of nitrogen. ) Is added to a sodium hydride stirred suspension (prepared from 1.2 g 60% mineral oil dispersion) in 400 ml dimethylformamide to which it is added. The reaction mixture is kept at 50 ° C. for 15 minutes, followed by the addition of 7.2 g of benzylbromoacetate (0.031 mol) in 25 ml of dimethylformamide. The reaction mixture is further stirred at 50 ° C. for 18 hours, then cooled to room temperature and the dimethylformamide is removed under high vacuum. The residue is stirred with 500 ml of 1: 1 toluene / dichloromethane to precipitate an inorganic salt. After filtration, the solution is evaporated under reduced pressure and the residue is chromatographed on 200 g of silica gel. 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one as the main product eluting with 0-15% ethyl acetate-toluene solution To obtain.

0.2 g of 10 g of a solution of 1.3 g of 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 250 ml of ethanol was added. % pd-C is used as catalyst to hydrogenate at room temperature and atmospheric pressure until hydrogen consumption is stopped. The catalyst is filtered and the solvent is removed under reduced pressure to yield 0.90 g of white foam. This material is triturated with ether to give 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one with a melting point of 147 to 150 ° C.

14.0 g of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.04 mol) in 300 ml of ethanol Was hydrogenated under a pressure of 3.1 atmospheres at room temperature using 2.0 g of 5% pd-C as a catalyst. The catalyst is filtered off and the solvent is removed under reduced pressure. The residue is dissolved in 500 ml of water and the solution is extracted with 2 x 400 ml dichloromethane. The aqueous solution is filtered and evaporated under reduced pressure. 50 ml of ethanol are added and the solution is evaporated under reduced pressure. Add 50 ml more methanol and repeat evaporation. The residue was recrystallized from ethanol / ethyl acetate to give 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one at a melting point of 147 to 150 ° C. To obtain.

10 g 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one and 26.4 g ethyl benzylpyruvate in 75 ml of acetic acid and 75 ml of methanol The added solution is stirred at room temperature under nitrogen for 1 hour. 3.4 g sodium cyanocarbohydride in 25 ml ethanol is added dropwise over 4 hours. The reaction mixture is stirred at room temperature for 24 hours, and 4 ml of concentrated hydrochloric acid is added dropwise, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness and the residue is partitioned between 150 ml water and 50 ml ether and adjusted to pH 9 with 40% aqueous sodium hydroxide solution. Separate the layers and discard the ether layer. The aqueous layer is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with 3 x 75 ml ethyl acetate. The organic portion is dried (magnesium sulfate) and concentrated to dryness. The crude product solution in 310 ml methylene chloride was passed through hydrogen chloride gas for 5 minutes and the solution was evaporated to stir the residue in 225 ml ether. The product was collected by filtration and measured by high pressure liquid chromatography to give a 70:30 diastereomeric mixture. The product was recrystallized in 1: 3 ethanol / ethyl acetate to give 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4 at a melting point of 246 to 248 캜 (decomposition). Compounds corresponding to, 5-tetrahydro-1H- [1] benzazin-2-one hydrochloride and racemic isomer B are obtained.

Example 2

1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

0.364 g of 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazine in 15 ml of dimethylacetamide A solution of 2-one (0.00075 mol), 0.190 g sodium bicarbonate and 0.315 g ethyl iodide (0.002 mol) was stirred for 72 hours at room temperature under a stream of nitrogen. The reaction mixture is filtered and evaporated under reduced pressure, then 100 ml of water are added and the resulting solution is extracted with 4 × 50 ml of dichloromethane. The mixed extract is dried over sodium sulfate and the solvent is removed under reduced pressure to give a diester as an oily substance. This material is separated into three fractions by high pressure liquid chromatography using 30:70 ethylacetate / toluene as solvent. In the first fraction isomer A of the title compound is obtained as an oily substance, the second fraction contains a mixture of isomers A and B, and in the third fraction isomer B of the title compound. Isomer A moves more slowly than isomer B using high pressure liquid chromatography on a reverse phase column (solvent: containing 0.025% acetic acid, methanol of 3: 1).

Starting material, 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one It may be prepared similarly as described in Example 28. Starting materials can also be prepared as follows: 0.152 g sodium cyanoborohydride (0.0014 moles), 0.45 g 1-benzyloxycarbonylmethyl-3-amino-2,3, in 35 ml methanol. 4,5-tetrahydro-1H- [1] benzazin-2-one (0.0014 mol) and 0.48 g of benzylpyruvic acid (0.0028 mol) are added to the solution prepared. The reaction mixture is stirred at room temperature under a nitrogen stream for 2 hours. Further 0.48 g benzylpyruvic acid (0.0028 mol) is added and the reaction mixture is stirred for an additional 18 hours. 0.5 ml of concentrated hydrochloric acid is added and the resulting solution is stirred for 1 hour. The solvent is removed under reduced pressure and the residue is treated with 100 ml of dichloromethane to precipitate sodium chloride. After filtration, the solvent is removed under reduced pressure and the residue is chromatographed on 30 g of silica gel. Elution with 90: 10: 0.2 ethyl acetate / methanol / acetic acid yielded 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] Benzazin-2-one is obtained as an oily substance: NMR (CDCl ₃ ) δ 7.35 (m, 14H), 5.10 (s, 2H), 4.60 (m, 2H), 3.00 (m, 12H)

Example 3

1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (high melting point isomer)

0.9 g of 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase in 150 ml ethanol The solution to which pin-2-one (isomer B of Example 2) was added was subjected to hydrogenation at room temperature under atmospheric pressure using 0.5 g of 10% pd-C as a catalyst. After the end of the hydrogen absorption, the catalyst is filtered off and the solvent is removed under reduced pressure to give a solid. This material was triturated with 8 ml of ether to afford the same title compound as the compound obtained in Example 1 at melting points of 138 to 140 ° C.

Example 4

1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (low melting point isomer)

1.2 g 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase in 125 ml ethanol The solution to which pin-2-one (Isomer A of Example 3) was added was hydrogenated at room temperature under atmospheric pressure using 0.5 g of 10% pd-C as a catalyst. After the hydrogen absorption capacity has ceased, the catalyst is filtered and the solvent is removed under reduced pressure to give a solid. The foreign material was polished with 8 ml of ether to give 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [. 1] Benzazin-2-one is obtained which is the low melting racemic isomer A.

Performing high pressure liquid chromatography on a reverse phase column [Solvent system: 3: 1 methanol / water containing 0.025% acetic acid] isomer A moves more slowly than the high melting racemic isomer B of Example 1.

Example 5

1-benzyloxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

The title compound can be prepared similarly as described in Example 28 to yield isomer mixtures (isomers A and B). This was chromatographed on silica gel, eluted with 3: 1 toluene / ethyl acetate, initially 1-benzyloxycarbonylmethyl-3- (2-ethoxycarbonyl-3-phenylpropylamino) -2,3, Isomer A of 4,5-tetrahydro-1H- [1] benzazin-2-one is subsequently obtained. Isomers A and B are the same as those of Example 2, as measured by high pressure liquid chromatography separation on a reverse phase column (solvent system: 0.025% acetic acid, 3: 1 methanol / water).

The isomeric mixture is also prepared as follows: A solution of 33.2 g of diethylacetamide maloneate in 150 ml ethanol is added to a solution of sodium ethoxide in ethanol [prepared from 3.8 g of sodium and 200 ml of ethanol]. The reaction mixture was stirred for 30 minutes at room temperature and 40.0 g of 2-nitrophenethyl bromide [J. Med. Chem. 20, 1020 (1977)] is added dropwise over 20 minutes. After completion of the dropwise addition, the reaction mixture was heated to reflux for 18 hours and then cooled to room temperature and evaporated under reduced pressure. The residue is dissolved in 350 ml of water and the solution is extracted with 2 x 350 ml of ethyl acetate. The combined ethyl acetate extracts are washed with 200 ml of water and dried over magnesium sulfate. The solvent is removed under reduced pressure to give diethyl 2-acetamido-2- (0-nitrophenethyl) -malonate as a low melting solid that is used as such in the next synthetic step without further purification.

80 g of diethyl-2-acetamido-2- (O-nitrophenethyl) -malonate was added to 900 ml of 3N hydrochloric acid for 12 hours. The solution is cooled and extracted with 200 ml of ethyl acetate. The aqueous solution is filtered and evaporated to dryness under reduced pressure. The residue is recrystallized in ethanol / ether to give 2-amino-4- (2-nitrophenyl) butyric acid hydrochloride at melting point 219-221 ° C. (decomposition).

A solution of 38.0 g of 2-amino-4- (2-nitrophenyl butyric acid hydrochloride) was added to 1200 ml of 10% ethanolic hydrochloric acid under reflux for 18 hours with stirring The reaction mixture was evaporated to dryness under reduced pressure and 250 ml of water 2N sodium hydroxide is added to make the aqueous solution basic, the solution is extracted with 2 x 500 ml of dichloromethane, the mixed dichloromethane solution is washed with 2 x 150 ml of water and dried over anhydrous magnesium sulfate. Ethyl-2-amino-4- (2-nitrophenyl) butyrate is obtained which is used in the next synthetic step without purification.

27 g of ethyl-2-amino-4- (2-nitrophenyl) butyrate was added to 600 ml of ethanol using 2.5 g of 10% pd-C as a catalyst to hydrogenate at atmospheric pressure and room temperature until hydrogen absorption was stopped. React. The catalyst is filtered and evaporated to dryness to afford ethyl-2-amino-4- (2-aminophenyl) butyrate which is used in the next synthetic step without purification.

35.0 g of ethyl-2-amino-4- (2-aminophenyl) butyrate in 100 ml of methanol was added to a solution of sodium methoxide in methanol [prepared with 400 ml of methanol and 1.0 g of sodium] under nitrogen stream. Add while stirring. The reaction mixture is heated to reflux for 65 hours and evaporated under reduced pressure. The residue is partitioned between 100 ml of water and 400 ml of dichloromethane and the aqueous solution is extracted with 400 ml of dichloromethane. The mixed organic solution is washed with 100 ml of water and dried over magnesium sulfate. After evaporation to dryness, trituration with 250 ml of ether yields 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one having a melting point of 161 to 162 캜.

In contrast, a solution of 2.5 g of 2-amino-4- (2-nitrophenyl) -butyric acid hydrochloride in 200 ml of water was hydrogenated at atmospheric pressure and room temperature using 0.5 g of 10% pd-C as a catalyst. . After the hydrogen uptake has ceased, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 50 ml of water and the pH is adjusted to 7 by addition of 10% sodium hydroxide. The solid is filtered off, washed with water and dried to afford 2-amino-4- (2-aminophenyl) butyric acid. A solution containing 1.0 g of 2-amino-4- (2-aminophenyl) butyric acid, 5.4 g of hexamethyldisilazine and 0.1 g of chlorotrimethylsilane in 125 ml xylene was heated to reflux for 65 hours. The reaction mixture is cooled, poured into 200 ml of ethanol and evaporated under reduced pressure. 100 ml of water are added and the solution is extracted with 2 x 125 ml of dichloromethane. The mixed dichloromethane solution was washed with 50 ml of water, dried over magnesium sulfate and evaporated under reduced pressure to obtain 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one as described above. To obtain.

3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is also prepared as follows.

Under nitrogen stream, 27 g of 3-azido-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (see Example 1) was added to 3500 g of ethanol while stirring at room temperature. To the solution is added a Ranickel suspension in 50 ml of water (washed with 10 volumes of ethanol).

The mixture is stirred at room temperature for 2 hours before additional 30 ml of Ranickel suspension is added. After stirring for an additional 30 minutes, the catalyst is filtered and the solvent is removed under reduced pressure to yield an oily material which solidifies by addition of ether to 3-amino-2,3,4,5- of melting point 161 to 162. Tetrahydro-1H- [1] benzazin-2-one is obtained.

To a solution of 8.0 g of 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one and 18.0 g of benzylpyruvic acid were added to 450 ml of methanol at room temperature under a nitrogen stream. Stir for minutes. 4.5 g sodium cyanoborohydride is added and the resulting solution is stirred for 48 hours at room temperature. 7 ml of concentrated hydrochloric acid is added dropwise over 10 minutes and stirring is continued for an additional hour. The reaction mixture is evaporated to dryness and 150 ml of dichloromethane is added and the mixture is stirred for 30 minutes. The solid was filtered, stirred with 100 ml of water for 15 minutes, then filtered and washed with 50 ml of water and dried to give 3- (1-carboxy-3-phenylpropylamino) -2,3,4, having a melting point of 173 to 175 ° C. 5-Tetrahydro-1H- [1] benzazin-2-one is obtained as an isomer mixture.

In 200 ml of dimethylacetamide, 6.0 g of 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one, 4.0 g A solution to which sodium bicarbonate and 11.6 g of ethyl iodide were added was stirred at room temperature under a nitrogen stream for 72 hours. The reaction mixture is filtered and evaporated under high vacuum. 250 ml of water are added and the resulting solution is extracted with 2 x 400 ml of dichloromethane. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to afford 3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- [1] benzase Pin-2-one is obtained as an isomer mixture.

NMR (CDCL ₃ ) δ 9.22 (s, 1 H), 4.10 (double overlapped triplet, 2H), 1.13 (double overlapped triplet, 3H).

5.0 g of 3-) 1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 20 ml of anhydrous dimethylformamide The solution to which the solution was added was washed with [3 × 75 ml of petroleum ether] in 85 ml of anhydrous dimethylformamide to which 4.4 g of tetrabutylammonium bromide was added to a solution to which hydro-1H- [1] benzazin-2-one was added. 0.6 g of sodium hydride prepared from a 60% mineral oil dispersion were added under a nitrogen stream to a stirred suspension. The reaction mixture is stirred at room temperature for 30 minutes, and then a solution added with 3.2 g of benzyl bromoacetate in 10 ml anhydrous dimethylformamide is added. The reaction mixture is stirred for an additional 30 minutes at room temperature, heated to 60 ° C. and held at this temperature for 18 hours. The reaction mixture is cooled to room temperature and the solvent is removed under high vacuum. 150 ml water is added and the resulting solution is extracted with 2 × 250 ml of ethyl acetate. The mixed ethyl acetate extracts are washed with 100 ml water, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the desired isomeric mixture.

Example 6

1-benzyloxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

The title compound can be prepared similarly as described in Example 28, so that an isomer mixture consisting of isomers A and B is obtained and chromatographed on silica gel. Elution with 1: 1 toluene / ethylacetate affords an oily substance with the isomer A properties of the title compound. : NMR (CDCl ₃ ) δ 5.12 (s, 4H), 4.50 (q, 2H), eluted with a further solvent mixture to give an oily material with the isomeric B properties of the title compound. NMR (CDCl ₃ ), 5.17 (s, 2H), 5.03 (d, 2H), 4.60 (q, 2H)

Isomer mixtures are also prepared as follows:

13.0 g of 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] -benzazin-2-one in 750 ml of dimethylacetamide (Example As described in 5), a solution of 10.0 g of sodium bicarbonate and 19.0 g of benzyl bromide is stirred for 72 hours at room temperature under a stream of nitrogen. The reaction mixture is filtered and evaporated under high vacuum. 150 ml of water are added and the resulting solution is extracted with 2 x 400 ml of dichloromethane. The mixed extract is washed with 100 ml water, dried over magnesium sulfate and evaporated under reduced pressure to give crude benzyl ester. Recrystallization in ethyl acetate, melting point 139-141 ° C. 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2- Obtain a warm.

A solution of 4.0 g of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in anhydrous dimethylformamide was prepared. To a stirred suspension with sodium hydride [from a 60% mineral oil dispersion (0.42 g) washed with 3x80 ml petroleum ether] in 100 ml anhydrous dimethylformamide at room temperature to which 3.1 g of tetrabutylammonium bromide was added under nitrogen stream was added. do. Stirring was further performed at room temperature for 30 minutes, and a solution to which 2.2 g of benzyl bromoacetate was added in 10 ml of anhydrous dimethylformamide was added. After an additional 30 minutes at room temperature, the reaction mixture is heated to 50 ° C. and maintained at this temperature for 18 hours. The reaction mixture is cooled to room temperature and the solvent is removed under high vacuum. 150 ml of water are added and the solution is extracted with 2 x 300 ml of ethyl acetate. The mixed ethyl acetate solution is washed with 100 ml water, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the desired isomeric mixture.

Example 7

1-carboxymethyl-3- (10carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (low melting point isomer)

2.7 g 1-benzyloxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase in 800 ml ethanol The solution to which pin-2-one (Isomer A of Example 6) was added was hydrogenated at room temperature under atmospheric pressure using 0.5 g of 10% pd-C as a catalyst. After the hydrogen adsorption capacity has ceased, the catalyst is filtered and the solvent is removed under reduced pressure to yield the title diacid, which is characterized by isomer A having a melting point of 256 to 259 ° C.

The same compound is obtained by hydrolyzing the compound of Example 4.

Example 8

1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] -benzazin-2-one (high melting point isomer)

5.0 g of 1-benzyloxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase in 950 ml of ethanol The solution to which pin-2-one (isomer B of Example 6) was added was hydrogenated at room temperature under atmospheric pressure using 0.5 g of pd-C as a catalyst. After the hydrogen adsorption capacity has ceased, the catalyst is filtered and the solvent is removed under reduced pressure to yield the title diacid specified by Isomer B at melting points of 280 to 282 ° C.

The same compound is prepared by hydrolyzing the Example 1 (Isomer B) compound or the Example 9 (Isomer B) compound.

Example 9

Title of 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one Compounds can be prepared similarly as described in Example 28, yielding an isomeric mixture consisting of isomers A and B. This material is chromatographed on silica gel and eluted with 1: 1 toluene / ethylacetate to give Isomer A of the desired product. Elution with additional solvent mixture gives high pressure liquid chromatography analysis (see Example 5) to give an oily substance which is isomer B of the main component required product and contains a small amount of isomer A. Elution with an additional solvent mixture affords an oily material that is almost pure isomer B (comfort). This material is dissolved in methanol and converted to the maleate salt by addition of a solution containing the same amount of maleic acid in methanol. Evaporate the solvent and recrystallize the residue in methanol / ether to yield 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H Pure isomer B of-[1] benzazin-2-one is obtained as maleate salt at melting point 114-116 ° C. The maleate salt of isomer A can be prepared similarly. The isomeric mixtures described above may also be prepared as follows:

3.0 g 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] in 10 ml anhydrous dimethylformamide Benzazin-2-one (see Example 5) was added 0.36 g from 60% mineral oil dispersion washed with 3x75 ml petroleum ether in 100 ml anhydrous diethylformamide over 10 minutes at room temperature under nitrogen stream. Sodium hydride is added to the stirred suspension. Stirring was further performed for 30 minutes, and a solution of 1.4 g of ethyl bromoacetate added in 15 ml dimethylformamide was added and the reaction mixture was maintained at 60 ° C. for 48 hours. The reaction mixture is cooled to room temperature and the solvent is removed under high vacuum. 100 ml of water are added and the solution is extracted with 2 × 200 ml ethyl acetate. The mixed ethyl acetate solution is washed with 50 ml water, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the desired isomeric mixture.

It also reacts ethyl 2-amino-4-phenylbutyrate with 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazene-2,3-dione under reductive alkylation conditions. 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H as a starting material for the preparation of maleate salts by reaction with -[1] benzazin-2-one is obtained.

The dione is prepared as follows.

1.0 g of 3,3-dichloro-2,3,4,5-tetrahydro-1H- [1 in 30 ml tetrahydrofuran to a solution in which sodium hydride (4.76 mmol) was added to 20 ml tetrahydrofuran at room temperature under a nitrogen stream. ] Benzazin-2-one (4.32 mmol) and 0.51 ml of ethyl bromoacetate were added dropwise with stirring over 15 minutes. Stirring is continued for a further 2 hours, the solution is quenched by addition of saturated aqueous ammonium chloride solution and the solution is removed under reduced pressure. The residue is extracted with 3x20 ml ether and the mixed ether solution is washed with 20 ml saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent is removed under reduced pressure to afford 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

NMR (CDCl), δ 1.27 (t, 3H); 3.22 (m, 4 H); 4.25 (q, 2H) 4.65 (s, 2H) and 7.3 (m, 4H)

0.315 ml morpholine (3.6 mmol) and 0.5 g 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one The mixture of was stirred at 10 ° C. under a nitrogen stream for 18 hours. The solution is diluted to 10 ml with chloroform and cooled to 0 ° C. 1 ml of 20% sulfuric acid is added and stirred at 0 ° C. for 2 hours. The solution is extracted with 2 x 20 ml chloroform and the extract is washed with 2 x 10 ml 2N hydrochloric acid and 5 ml saturated aqueous sodium chloride solution. The solution is dried over magnesium sulphate and evaporated under reduced pressure to afford 1-ethoxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazene-2,3-dione.

NMR (DCD1 ₃ ): δ 1.25 (t, 3H); 2.6 (m, 2 H); 3.6 (m, 2H); 4.2 (q, 2H) and 7.3 (m, 4H).

Also in the presence of potassium carbonate in methylene chloride, ethyl 2-amino-4-phenylbutyrate is converted to 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzase Reacted with pin-2-one to produce 1-ethoxy-carbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1 ] Benzazin-2-ones can be obtained.

The 3-bromo compound is prepared as follows.

To a solution of 2.5 g of 2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 30 ml chloroform, 3.2 g of phosphorus tachloride was temporarily maintained while maintaining a temperature of 0 to 5 ° C. Add to When the addition is complete, 30 mg of iodine is added followed by the dropwise addition of 2.5 g bromine over 5 minutes. The mixture is then heated to reflux for 4 hours, the chloroform solution is evaporated and the residue is dispersed in 30 ml ice water and 75 ml dichloromethane. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is eluted with 7: 3 ether / hexane and purified by chromatography using silica gel. Suitable fractions yield 3-bromo-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one with a melting point of 146-148 ° C.

300 mg of 3-bromo-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 90 ml of potassium hydroxide and 40 mg in 10 ml tetrahydrofuran maintained at 0 ° C. under a nitrogen stream. Tetrabutylammonium bromide was added to the stirred suspension at a time. Stirring is continued for 5 minutes and then 20 mg of ethyl bromoacetate is added all at once. The reaction mixture is allowed to warm to room temperature with stirring for an additional 3 hours. Tetrahydrofuran is removed under reduced pressure and the residue is dispersed in 5 ml of water and 25 ml ether. The organic phase was washed with 5 ml of 2N hydrochloric acid, dried over magnesium sulfate and the solvent removed under reduced pressure to yield 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetra at a melting point of 114 to 116 ° C. Hydro-1H- [1] benzazin-2-one is obtained.

Furthermore, 3- (1-carboxy-3-phenylpropylamino) -1-cyanomethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one was 48 hours at room temperature. Treated with 1: 1 ethanol / ether saturated with hydrogen chloride, and subjected to the prescribed operation to 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4 , 5-tetrahydro-1H- [1] benzazin-2-one is obtained.

The 1-cyanomethyl compound is prepared as follows:

Bromoa in 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in dimethylformamide in the presence of sodium hydride Acylation with a cetonitrile solution and through a predetermined operation, 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2- Obtain a warm.

Example 10

1-carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

4.0 g 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.01 mol) in 550 ml ethanol ) Was added to a solution of 0.85 g of 5% pd-C as a catalyst and hydrogenated at room temperature under atmospheric pressure until the hydrogen adsorption capacity was stopped. 300 ml of water are added to filter the catalyst and the solvent is evaporated under reduced pressure. The residue is triturated with ether to give the title diacid at melting point 232-236 ° C.

Starting materials are prepared as follows.

To a solution of 5.0 g of 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (0.028 mol) in 100 ml of dimethylformamide was added 10.9 g of nitrogen. In 400 ml of dimethylformamide to which tetrabutylammonium bromide (0.031 mol) was added 1.2 g of sodium hydride [prepared from 60% mineral oil dispersion by washing with 3x150 ml petroleum ether] was added to a stirred suspension. The reaction mixture is held at 50 ° C. for 15 minutes and then a solution is added 7.2 g of benzylbromoacetate (0.031 mol) in 25 ml dimethylformamide. The reaction mixture is stirred for an additional 18 hours at 50 ° C., then cooled to room temperature and the dimethylformamide is removed under high vacuum. The residue is stirred with 500 ml of 1: 1 toluene / dichloromethane to precipitate an inorganic salt. After filtration the solution is evaporated under reduced pressure and the residue is chromatographed on 200 g of silica gel. 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- [1] benzase as eluted with 0-15% ethyl acetate in toluene Obtain pin-2-one. Elution was continued to yield 3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (see Example 1) at a melting point of 124 to 127 ° C. do.

Example 11

1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

0.035 g of 1-carboxymethyl (S)-(1 (S) -methoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz in 4 ml ethanol The solution to which azepin-2-one hydrochloride and 0.5 ml of propylene oxide were added is stirred overnight at room temperature under a nitrogen stream. The solution was evaporated to dryness, 2 ml ether added and the solid filtered off to 1-carboxymethyl-3S- (1S-ethoxy with melting point 148-149 ° C., [α] _D = -159 ° C. (C = 1.2 in ethanol). Carbonyl-3-phenylpropylamino) -2,3,4,5-tatrahydro-1H- [1] benzazin-2-one is obtained.

Optically active starting materials can be prepared similarly as described in Example 28. It may also be prepared as described below.

(a) 0.4 g of 3 (S) -t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- [1] benzazene-2,5- in 30 ml of anhydrous tetrahydrofuran Dion [Australian J. Che mistry Vol. 33, 633-40 (1980) prepared from S-kinurein] and a solution to which 0.23 g of ethyl bromoacetate was added are stirred at 0 ° C. under anhydrous nitrogen stream. 0.254 g of potassium t-butoxide is added at a time, after 1 h at 0 ° C., an additional 0.23 g of ethyl bromoacetate is added and the reaction mixture is further stirred at 0 ° C. for 1 h. 100 ml of water are added and the mixture is extracted with 2 x 50 ml of ethyl acetate. The combined ethyl acetate solution is washed with 100 ml water and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a yellow gum, which was then ground with ether / petroleum ether (boiling point 30-60 ° C.) and melting point 86-88 ° C., [α] _D = -203 ° C. (C in dimethylformamide). = 1) to obtain 3 (S) -t-butyloxycarbonyl-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro 1H- [1] benzazene-2,5-dione do.

0.14 g 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2,5 in 10 ml ethanol -The solution added with dione and 7 mg of sodium borohydrate is stirred at room temperature for 18 hours. Ethanol is removed under reduced pressure and the residue is dissolved in 25 ml dichloromethane. The solution is extracted with 2 x 20 ml of 2N hydrochloric acid, followed by 20 ml saturated aqueous saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with ether to give 3 (S) -t-butyloxycarbonylamino- at a melting point of 167-169.5 ° C. [α] _D = -193 ° C. (C = 0.52 in dimethylformamide). 1-Ethoxy-carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is obtained. This material can also be obtained by hydrogenation of benzazine-2,5-dione derivatives as H ₂ / Pt in ethanol.

0.076 g of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-S-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2 -On, a mixture of 0.064 g of dicyclohexyl carbodiimide and 7 mg of cuprous chloride is heated for 32 hours under a stream of nitrogen at 60 ° C. The reaction mixture is left to cool to room temperature. The residue is dissolved in 50 ml methylene chloride and washed with 2 x 15 ml of dilute ammonium hydroxide and then with 20 ml water. The organic phase is dried over sodium sulphate and evaporated to afford the required adduct and excess dichlorohexyl carbodiimide.

0.100 g of this mixture is dissolved in 40 ml of ethyl acetate and placed in a pressure vessel. 0.010 g of 10% pd / C catalyst is added and the mixture is hydrogenated at 3 atmospheres, 40 ° C. for 16 hours. The catalyst is filtered off and the filtrate is evaporated. The residue was triturated with ether and the ether solution was evaporated to give 3 (S) -t-butyloxycarbonylamino- with a melting point of 115 to 116.5 [α] _D = -182 ° C (C = 2.6 in dimethylformamide). 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is obtained.

(b) 200 ml of 12.6 g of tartaric acid and 22 g of racemate 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one In hot ethanol. The solution is cooled and left overnight at room temperature. The precipitated solid was filtered, collected and recrystallized twice in 200 ml ethanol to give 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazine Obtain the 2-one tartrate salt. This salt is dissolved in 100 ml of water and the pH is adjusted to 9 with dilute ammonium hydroxide and extracted with 2 x 50 ml of methylene chloride. The mixed extract was washed with 75 ml water, dried (magnesium sulphate) and evaporated to 3 (S) -amino-1-ethoxycarbonyl with a melting point of 104-106 ° C., [α] _D = -285.5 ° C. (C = 0.99 in ethanol). Obtain methyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

(c) 0.225 g of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzase in 25 ml of ethyl acetate Hydrogen chloride gas was passed through the solution to which pin-2-one (prepared in (a)) was added for 45 minutes. This solution is then supplied with nitrogen gas for 30 minutes.

Ethyl acetate is washed with 30 ml of water and 30 ml of 1N hydrochloric acid. Discard the ethyl acetate layer and mix the aqueous phase. The aqueous solution was adjusted to pH 9 with dilute ammonium hydroxide, extracted with 3 × 50 ml of ethyl acetate, the organic phases were mixed, dried (sodium sulfate) and evaporated to a melting point of 101 to 102 ° C., [α] _D = -298 ° C. (in ethanol). C = 0.46) to give 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

Treatment with ethanedithiol / borontrifluoride etherate or trifluoroacetic acid / anisole to remove the protecting group 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5- Obtain tetrahydro-1H- [1] benzazin-2-one.

Alternatively, 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is also prepared as follows:

(d) 1.0 g of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- in 20 ml of acetic anhydride [1] Benzazin-2-one is maintained at 80 ° C. for 3 hours. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. 100 ml of ether is added and the resulting solution is washed with 50 ml of water and dried over magnesium sulfate. Solvent was removed under reduced pressure to yield 5-acetoxy-3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzase Pin-2-one is obtained as a pale yellow oily material which is used without further purification.

0.7 g 5-acetoxy-3 (S) -butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazine in 50 ml of ethanol The solution to which 2--2-one was added was hydrogenated using 0.5 g of 10% pd-C as a catalyst for 24 hours at 70 캜 and 2.9 atmospheres. The catalyst was filtered off and the solvent was removed under reduced pressure to afford 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazine 2-one is obtained, which, without further purification, 3 (S) -amino-1 with a melting point of 99-101 ° C., [α] _D = -297 ° C. (C = 1 in ethanol) according to the method described above. -Ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

(e) 12.5 g of 3 (S) -t-butyloxycarbonylamino- made from L-kynurenine as described in Australian J. Chemistry Vol 33, 633-40 (1980) in 700 ml of acetone. A solution obtained by adding 2,3,4,5-tetrahydro-1H- [1] benzazene-2,5-dione and 10.1 g of t-butylbromo acetate is stirred at room temperature under anhydrous nitrogen stream. 12.5 g of calcium carbonate are added in one portion and the resulting suspension is stirred for 16 hours at room temperature. The potassium salt is filtered off and the filtrate is evaporated to dryness. The residue is partitioned between 250 ml ethyl acetate and 250 ml water and the two layers are separated to dry the organic phase (sodium sulfate). The residue was triturated with 350 ml (boiling point 30-60 ° C.) petroleum ether to give 3 (S) -t-butyl at melting point 75-77 ° C., [α] _D = -172 ° C. (C = 0.96 in dimethylformamide). Oxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzasepin-2,5-dione is obtained.

8.0 g of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [in 500 ml ethanol containing 800 mg of platinum oxide. 1] The solution to which benzazine-2,5-dione was added is hydrogenated at atmospheric pressure at room temperature for 2 hours. The catalyst was filtered off and the filtrate was evaporated to afford 3 (S) -t-butyloxy-carbonylamino-1-t-butyloxycarbonylmethyl at [α] = -173 ° C (C = 1.8 in dimethylformamide). Obtain -5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

3.0 g of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazine 2-one, 5.0 g of dicyclohexylcarbodiimide and 500 mg of cuprous chloride suspension are mechanically stirred and heated to 80 ° C. for 16 hours under anhydrous nitrogen stream. The mixture is cooled, diluted with 100 ml methylene chloride and filtered. The solids are discarded and the filtrate is washed with 4 x 75 ml of 7% ammonium hydroxide and then with 1 x 100 ml water followed by 100 ml saturated aqueous sodium chloride solution. The organic phase is dried (sodium sulfate) and evaporated to afford a mixture of the required adduct and excess dicyclohexylcarbodiimide.

5.5 g of this mixture are dissolved in 200 ml ethyl acetate and placed in a pressure vessel. 3.0 g of 10% pd / C catalyst is added and the mixture is hydrogenated at 3 atmospheres, 40 ° C. for 16 hours. The catalyst is filtered off and the filtrate is evaporated. The residue was triturated with 75 ml ether to give a white solid having a melting point of 145 to 147 캜, [α] _D = -194 캜 (C = 0.46 in dimethylformamide), 3 (S) -t-butyloxycarbonylamino-1 -t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is obtained.

3.0 g of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [in 50 ml of acetic anhydride. The solution to which 1] -benzazin-2-one was added is heated to 80 degreeC for 2 hours under anhydrous nitrogen stream. Acetic anhydride is evaporated. The residue is dissolved in 75 ml of ethyl acetate and washed with 50 ml of saturated aqueous bicarbonate solution, 50 ml of water and 50 ml of saturated aqueous sodium chloride solution. The organic phase is dried (sodium sulfate) to evaporate and the residue is triturated with 50 ml ether to give a melting point of 164-166.5 ° C., [α] _D = -169 ° C. (C = 0.36 3 (S) -t-butyloxy in dimethylformamide). Carbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is obtained.

2.2 g of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3, in 300 ml ethanol containing 2.0 g of 10% pd-C catalyst The solution to which 4,5-tetrahydro-1H- [1] benzazin-2-one was added is put into a pressure vessel, and hydrogenated at 3 atmospheres and 70 degreeC for 3 days. The catalyst was filtered off and the filtrate was evaporated to 3 (S0-t-butyloxycarbonylamino-1-t- with melting point 164-165 ° C., [α] _D = -200.6 ° C. (C = 0.64 in dimethylformamide). Butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is obtained.

0.85% of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazene- in 40 ml ethyl acetate Hydrogen chloride gas is passed through the 2-ion solution for 2 hours. Nitrogen is passed through this solution for 30 minutes. Ethyl acetate is evaporated and the white solid residue is soon dissolved in 40 ml ethanol. 5 ml of propylene oxide are added and the mixture is stirred for 16 hours at room temperature. The white solid precipitated was collected by filtration and 3 (S) -amino-1-carboxymethyl-2,3,4,5-tetra with a melting point of 275 to 276 캜 and [α] _D = -287 (C = 0.71 in 1N hydrochloric acid). Hydro-1H- [1] benzazin-2-one is obtained, which is condensed with ethylbenzylpyruvate in the presence of sodium cyanoborohydride, as described below.

2.1 g of sodium hydroxide was added to 5 ml of water and 14.0 g of 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [in 150 ml methanol at room temperature. 1] Benzazin-2-one is added to the added solution and the solution is stirred for 2 hours. The solvent was evaporated and the residue was completely dried and then slurried with ether to give 3 (S) -amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2 -Warm sodium salt is obtained. It is used without further purification.

A solution of the sodium salt (12.9 g) and ethylbenzylpyruvate (31 g) in acetic acid (100 ml) and methanol (75 ml) is stirred for 1 hour at room temperature under anhydrous nitrogen atmosphere. Then, a solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) is added dropwise over 4 hours. The combined solution is stirred overnight at room temperature. Concentrated hydrochloric acid (10 ml) is added dropwise and the mixture is stirred at room temperature for 1 hour before evaporating the solvent. The residue is partitioned between water (400 ml) and ether (100 ml) and the pH adjusted to 9.3 with 40% sodium hydroxide. The layers are separated and the ether layer is removed. The aqueous layer is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3 × 100 ml). The combined organic phases are dried (magnesium sulfate) and evaporated. This material is further purified and hydrogen chloride gas is passed through a crude solution in methylene chloride (150 ml) for 5 minutes. The solvent is evaporated and the resulting foam is dissolved in 100 ml of hot methyl ethyl ketone. The precipitated solid was collected by filtration to give a diastereomeric mixture of 95: 5 as determined by high pressure liquid chromatography. The product was recrystallized in 3-pentanone / methanol of 10: 1 to give a melting point of 188 to 190 ° C. of Formula (Ib) wherein CnH ₂ n is ethylene, R ₆ is ethoxy, R ₇ is hydroxy and R ₈ is phenyl 1-carboxymethyl-3 (S) -1 (S) -ethoxycarbonyl-3-fetylpropylamino) -2,3,4- with [α] _D = -141.0 ° C. (C = 0.9 in ethanol) Tetrahydro-1H- [1] benzazin-2-one hydrochloride is obtained.

Example 12

1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

1.00 g of 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,5-dihydro-1H- [1] benzazin-2,5- in 50 ml of glacial acetic acid 0.10 g of platinum oxide is added to the dione solution. The resulting mixture contained in a pressure vessel is hydrogenated at 2.9 atm for 5 hours. The catalyst is filtered off, the filtrate is concentrated and the oily substance obtained is triturated with anhydrous ethanol. The solid obtained is collected, dried and suspended in 10 ml of water. After the suspension was stirred for 1.5 hours, the solid was collected and dried to impure 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -5-hydroxy-2,3 having a decomposition melting point at 179 ° C. Obtain 4,5-tetrahydro-1H- [1] benzazin-2-one.

Starting materials can be prepared similarly as described in Example 28. It may also be prepared as follows: 8.13 g of 3-methoxy-2,5-dihydro-1H- [1] benzazin-2,5-dione [0.04 mol, Canadian J in 1000 ml of acetonitrile Prepared according to the method described in Chem., 52, 610 (1974), 9.16 g of a mixture of 2.24 g of powdered potassium hydroxide (0.04 mol) and 1.29 g of tetrabutyl ammonium bromide (0.004 mol) was stirred at room temperature with stirring. g benzylbromoacetate (0.04 mol) was added dropwise. At the end of the dropwise addition, the suspension was stirred for 64 hours at room temperature, filtered and the filtrate was concentrated under reduced pressure to give a partially crystalline oily material. The oily material is triturated with ether to give a solid, which is suspended in 100 ml ethyl acetate and stirred for 1.5 hours. The insoluble material was filtered and the filtrate was concentrated to give crude 1-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro-1H- [1] benzazene-2,5-dione, This is used for the next reaction step.

1.02 g of (+)-homophenylalanine (0.0057 mol) was added to a solution in which 0.64 g of 1.0 M potassium t-butoxide solution (0.0057 mol) was added to 5.7 ml of t-butanol while stirring at room temperature under a nitrogen stream. Add. The resulting suspension and 4.3 ml of t-butanol are heated until most of the suspended solids are dissolved. Cooling to give a suspension, which is 2.00 g of 1-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro- in 40 ml of t-butylol under stirring with a pipette under a nitrogen stream. A small amount is added to the reflux solution to which 1H- [1] benzazine-2,5-dione is added over 10 minutes. Yellow precipitates form during the addition. After the addition is complete, the resulting suspension is heated to reflux for 3 hours. The gum solid obtained by filtration of the suspension is washed with petroleum ether and dissolved in 20 ml water. The solution was filtered, acidified to pH 5 with 3N hydrochloric acid, and the resulting crude 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,5-dihydro-1H- [1 ] Benzazin-2,5-dione is collected and used directly in preparing the title compound.

Example 13

Similar to the methods described herein, the following compounds of formula (IA) are prepared wherein X is H ₂ , R ₂ and R ₅ is H, R ₆ is OC ₂ H ₅ , and R ₇ is OH:

TABLE 1

2,3,4,5-tetrahydro-1H- [1] benzazin-2-one having the first moiety of the compound Nos. 2 to 5 was prepared as follows.

7-Chloro-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (melting point 164-165 ° C.) is prepared according to the method described in British Patent No. 1,359,285.

8-methyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (melting point 153 to 154 ° C.) is described in Liebigs Ann. Chem, 574, 171 (1951).

7,8-dimethoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is prepared as follows.

24 g of 6,7-dimethoxy-α-tetralone in 300 ml ethanol and 60 ml water [Snider, T. et al, Org. Prep. Proced, Int., 5, 291 (1973)] was prepared by refluxing with 16 g of hydroxylamine hydrochloride and 25 g of sodium hydroxide, for 2 hours to prepare an oxime. The reaction mixture is poured into 500 ml of ice / water mixture and extracted with 3 × 300 ml of dichloromethane. The mixed extract is washed with 200 ml water, dried over anhydrous magnesium sulfate and evaporated to give 25 g of oxime having a melting point of 154 to 156 캜.

Oxime is redissolved in 170 ml of dichloromethane and 170 ml of polyphosphate ester is added [Fieser and Fieser: Reagents for Organic Synthesis, Wiley N. Y. 1967, 892]. The reaction mixture was heated to reflux for 18 hours, the dichloroform layer was separated, subjected to char-call treatment, dried over magnesium sulfate, and 7, 8-di-methoxy-2,3,4,5 having a melting point of 153 to 156 캜. -Tetrahydro-1H- [1] benzazin-2-one is obtained.

Similarly prepared from 7-methoxy-tetralon of 8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (melting point 132-134 ° C.).

3-amino-7-chloro-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is synthesized as follows.

4.0 g 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one, 6.1 g 2-t-butyloxycarbonyloxy in 20 ml water and 25 ml dioxane The solution added with mino-2-phenylacetonitrile and 5 ml of triethylamine is stirred at room temperature for 18 hours. The solid obtained is filtered and washed with water. Recrystallization from ethyl acetate affords 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one with a melting point of 199 to 201 ° C.

Chlorine gas was added to a solution of 1.5 g of 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 20 ml acetic acid for 10 minutes. give. The reaction mixture is stirred for a further 10 minutes and the precipitated solids are collected, suspended in 30 ml water and ammonia water is added until basic. Filtration yields 3-amino-7-chloro-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one with a melting point of 170 to 171 ° C.

Example 14

Preparation of 10,000 tablets in which each tablet contains 10 mg of the active ingredient of Example 1.

Formulation

1-carboxymethyl-3- (1-ethoxycarbonyl-

3-phenylpropylamino) -2,3,4,5-

Tetrahydro-1H- [1] benzazine-

2-on 100 g

Lactose 1,157g

75 g of corn starch

Polyethylene Glycol 6,000 75 g

Talc Powder 75g

Magnesium Stearate 18g

Purified water

quite

All powders are given through a screen with a 0.6 mm opening. The drug substance, lactose, talc, magnesium stearate and 1/2 starch are then mixed in a suitable mixer. The remaining 1/2 starch is suspended in 40 ml water and the suspension is added to 150 ml water in a boiling point solution of polyethylene glycol. The resulting paste is granulated by the addition of powder and, if necessary, granulated with an additional amount of water. The granules are dried overnight at 35 ° C. for 1 night, cut into a 1.2 mm aperture screen, and the tablets are compressed with a concave surface knitting having a diameter of 6.4 mm to bisect the top.

Example 15

Preparation of injectables containing 25 mg of the active ingredient of Example 1 per 5 ml liquid.

Formulation

1-carboxymethyl-3- (1-ethoxycarbonyl-

3-phenylpropyl-amino) -2,3,4,5-

Tetrahydro-1H- [1] benzazine-

25.0 g 2-on-hydroclyde

Profile Pyraben 1.0g

Suitable amount of water for injection 5000.0ml

Legislation

The active ingredient and preservative are dissolved in 3500 ml water for injection and diluted to 5,000 ml. The solution is filtered using sterile filter and the vial for injection is filled so that the vial contains 5 ml solution under sterile conditions.

Example 16

Preparation of 10,000 capsules in which each capsule contains 20 mg of the active ingredient of Example 8.

Formulation

1-carboxymethyl-3- (1-carboxy-3-

Phenylpropyl-amino) -2,3,4,5-

Tetrahydro-1H- [1] benz

Azepin-2-one 200 g

Lactose 1,700g

Talc Powder 100g

quite

All powders pass through a screen with a 0.6 mm aperture. The drug substance is then placed in a suitable mixer and first mixed with talc and then with lactose until homogeneous. Capsule 3 is filled with 200 mg each using a capsule filling machine. Similarly, other compounds of the invention, such as those described in the Examples herein, may be used to prepare tablets, injections, or capsules.

Example 17

1-carboxymethyl-3S- (1R-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

1-carboxymethyl-3S (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride in Example 11 The crystallized methyl ethyl ketone filtrate was evaporated and the residue was dispersed in 50 ml ethyl acetate and 100 ml water and adjusted to pH 4.3 with concentrated hydrochloric acid. The two layers are separated, the aqueous layer is extracted with 2 x 100 ml of ethyl acetate and the combined ethyl acetate solution is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is separated into its constituents by using high pressure liquid chromatography separation using 0.05% acetic acid containing 3: 7 water / methanol as the solvent and using a C18 reverse phase preparation column. In this way, the S, R isomer addition amount of S, S isomer addition of Example 11 can be obtained. Substances corresponding to S and R isomers are dissolved in 75 ml dichloromethane and run through hydrogen chloride gas for 5 minutes. The solvent was evaporated under reduced pressure and the residue was recrystallized in methyl ethyl ketone to yield 1-carboxymethyl-3S- (1R-ethoxy) having a melting point of 181 to 183 ° C, [α] _D = -188 ° C (C = 0.8 in ethanol). Carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride is obtained.

Example 18

1-carboxymethyl-3S (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazenphen-2-one

To a solution of 0.27 g sodium hydroxide in 2 ml water was added 1 g of 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro- in 10 ml methanol. 1 H [1] benzazin-2-one hydrochloride is added to the solution. The reaction mixture is stirred for 18 hours at room temperature and the solvent is removed under reduced pressure. The residue is dissolved in 25 ml water and the pH is adjusted to 3 by addition of 4N hydrochloric acid. The solid obtained was filtered, washed with water and then dried to give 1-carboxymethyl-3S (1S-carboxy-3) having a melting point of 270-272 ° C., [α] _D = -200.5 ° C. (C = 1 in 3% aqueous ammonium). -Phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazenphen-2-one is obtained.

Example 19

1-ethoxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

The title compound can be prepared similarly as described in Example 28, so that an isomer mixture consisting of isomers A and B is obtained and the material is subjected to chromatographic separation on silica gel. Elution with 9: 1 toluene / ethyl acetate affords the oily material specified as isomer A of the title compound. Elution with further solvent mixtures affords an oily substance specified as isomer B of the title compound. Isomer mixtures can also be prepared as follows:

5.0 g of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one was added to anhydrous dimethylformamide. The solution is added to a stirred suspension with 0.5 g of sodium hydride (prepared from 60% mineral oil washed with 3x80 ml petroleum ether) in 100 ml of anhydrous dimethyl formamide at room temperature under nitrogen stream. Stirring was continued for another 30 minutes at room temperature, and a solution added with 2.0 g of ethyl bromoacetate in 10 ml anhydrous dimethyl formamide was added. After an additional 30 minutes at room temperature the reaction mixture is heated to 50 ° C. and held at this temperature for 18 hours. The reaction mixture is cooled at room temperature and the solvent is removed under high vacuum. 150 ml of water are added and the solution is extracted with 2 x 300 ml of ethyl acetate. The mixed methyl acetate solution is washed with 100 ml water, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the desired isomeric mixture.

Example 20

1-ethoxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

1.1 g of 1-ethoxycarbonyl methyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino-2,3,4,5-tetrahydro-1H- [1] benzazene- in 150 ml ethanol The 2-one (isomer B of Example 19) is hydrogenated at room temperature and atmospheric pressure using 0.5 g pd-C as a catalyst. semi-solid), and triturated with 30 ml ether to give Isomer B of the title compound at melting point 175-177 ° C.

Example 21

1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (Isomer B)

The title compound can be prepared similar to that described in Example 28. The crude product can be converted to hydrochloride by bubbling hydrogen chloride for 5 minutes with a solution of the crude product in dichloromethane. The solution is evaporated and the residue is stirred in ether. After filtration the product was recrystallized in 3-pentanone to give 1-carboxymethyl-8-methoxy-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2, having a melting point of 240 to 245 캜 (decomposition), 3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride (isomer B) is obtained.

Starting materials are prepared as follows. 7.0 g of 8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one (described in Example 13) and 30.0 g of phosphorus pentachloride in 200 ml xylene The solution was heated to 90 ° C. (oil bath temperature) under a nitrogen stream of solution, stirred for 30 minutes, and the temperature was briefly stopped at 30 ° C. and 50 ° C. during the elevated temperature.

At this time, a large amount of hydrogen chloride gas is generated, the temperature is maintained at 90 ℃ 30 minutes. The reaction mixture is filtered while hot to remove small amounts of suspension solids and the filtrate is evaporated under reduced pressure until all solvent is removed. The residue was added to 20 ml saturated aqueous sodium carbonate solution under stirring, and after the solidification process was completed, the product was filtered to make a slurry in 30 ml ethanol, washed with 10 ml ethanol and 10 ml ether and dried, and the melting point was 148 to 150 ° C. Obtain, 3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

A solution of 20 g of 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one and 13.2 g of anhydrous sodium acetate in 250 ml glacial acetic acid was added. Using 1 g of 10% pd-C as a catalyst, the hydrogenation reaction is performed under atmospheric pressure until the hydrogen adsorption capacity is stopped. The catalyst is filtered and acetic acid is evaporated under reduced pressure. 100 ml water is added to the residue and the suspension is stirred for 1 hour. The solid was filtered, washed with 50 ml of water and dried to 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one at a melting point of 162 to 163 ° C. To obtain.

A solution of 12.5 g of 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one and 4.3 g of sodium azide in 150 ml dimethyl sulfoxide Is maintained at 80 ° C. for 3 hours under a nitrogen stream. The reaction mixture is poured into 300 ml ice / water and the suspension is stirred for 30 minutes. The solid was filtered, washed with 50 ml water and dried to afford 3-azido-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one at a melting point of 136 to 138 ° C. To obtain.

5 g of 3-azido-8-methoxy-2,3,4,5 to a stirred suspension in which 0.7 g of tetrabutylammonium bromide and 1.3 g of potassium hydroxide were added in 50 ml tetrahydrofuran maintained at 0 ° C. under a nitrogen stream. Tetrahydro-1H- [1] benzazin-2-one is added at a time. Stirring was continued for 5 minutes, followed by the addition of 3.6 g of ethyl bromoacetate in 15 ml tetrahydrofuran over 5 minutes. The reaction mixture is allowed to warm at room temperature with stirring for an additional 2 hours. The reaction mixture is filtered and tetrahydrofuran is removed under reduced pressure. The residue was partitioned between 50 ml water and 100 ml ether, the organic phase was washed with 10 ml of 2N hydrochloric acid, dried over magnesium sulfate and then removed under reduced pressure to remove 3-azido-1-ethoxycarbonyl at 90-91 ° C. Obtain methyl-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

Suspension with 13.8 g of 3-azido-1-ethoxycarbonylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 75 ml methanol Is treated with a solution of 1.9 g of sodium hydroxide in 75 ml of water. The reaction mixture is stirred at 40-45 ° C. for 2 hours. 100 ml of water are added and the mixture is acidified with 10 ml of concentrated hydrochloric acid and extracted with 3 x 75 ml of methylene chloride. The mixed methylene chloride solution was dried over magnesium sulfate and evaporated under reduced pressure to 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- having a melting point of 145 to 147 ° C. [1] benzazin-2-one is obtained.

11 g of 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 250 ml ethanol and 50 ml mixture 0.5 g of 10% pd-C is used as a catalyst for 3 hours under hydrogen at room temperature at 3 atmospheres. 50 ml of 2N hydrochloric acid is added and the catalyst is filtered off. The solvent is removed under reduced pressure and the residue is dissolved in 50 ml water and 50 ml ethanol mixture. 25 ml of propylene oxide are added and the mixture is stirred for 1 hour. The solvent is removed under reduced pressure to give 3-amino-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one having a melting point of 300 ° C. or higher. .

9.4 with 4.0 g of 3-amino-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in a mixture of 35 ml acetic acid and 35 ml methanol A solution of g ethylbenzylpyruvate was stirred for 1 hour. Then, a solution of 1.1 g of sodium cyano borohydride in 50 ml methanol was slowly added over 5 hours. After a further 16 hours of stirring, 4 ml of concentrated hydrochloric acid are added and stirring is continued for 1 hour. The solvent is removed under reduced pressure and the residue is dispersed in 75 ml of water and 35 ml of ether. The pH is adjusted to 9.4 and the ether layer is separated off. The aqueous layer is acidified to pH 4.3d and extracted with 3 x 50 ml of ethyl acetate. The mixed ethyl acetate solution is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the crude product.

Example 22

1- (1-carboxyethyl) -3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydro Chloride

Hydrogen chloride is passed through a crude base solution of the title compound in methylene chloride for 2 minutes. The solution was evaporated to produce 1- (1-carboxyethyl) -3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- having a melting point of 87-94 ° C. [1] Benzazin-2-one hydrochloride is obtained as a mixture of diastereomers.

Crude bases are prepared similarly as described in Example 28. It is also manufactured as follows:

5 g of 3-azido-2,3,4,5-tetrahydro-1H was added to a stirred suspension of 1.8 g of potassium hydroxide and 0.8 g of tributylammonium bromide in 50 ml tetrahydrofuran maintained at 0 ° C. under a nitrogen stream. -[1] benzazin-2-one (prepared in Example 1) was added temporarily, and stirring was continued for 5 minutes, followed by 5.2 g of (R) -t- in 15 ml tetrahydrofuran. Butyl-2-bromopropionet (J. Am Chem. Soc 76, 6054 (1954), H. Niedrich and G. Koller. J. Prakt. Chem. 729 (1974) by JP Greenstein) Add over.

The reaction mixture is warmed at room temperature with stirring for a further 2 hours. The reaction mixture is filtered and tetrahydrofuran is removed under reduced pressure. The residue was partitioned between 50 ml water and 100 ml ether, the organic phase was washed with 10 ml 2N hydrochloric acid, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to afford 3-azido-1- (1-t-butyloxycarbonyl Ethyl) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one is obtained as an oily substance, which can be used without further purification.

7 g of 3-azido-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one in 70 ml ethanol 0.5 g of 10% pd-C as a catalyst was hydrogenated under 3 atmospheres for 3 hours. The catalyst was filtered off and the ethanol was removed under reduced pressure to afford 3-azido-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- [1] benzase Pin-2-one is obtained as an oily substance. High pressure liquid chromatography (HPLC) indicates that the product is a diastereomeric mixture of about 1: 1. This material is used without further purification.

4.7 g of said 3-amido-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- [1] benzazine- in 25 ml of trifluoroacetic acid The 2-one solution is stirred at room temperature for 1 hour. Trifluoroacetic acid is removed under reduced pressure and the residue is dissolved in 10 ml ether. Hydrogen chloride gas was added to the solution until the formation of precipitate stopped, and the solids were filtered and 3-amino-1- (1-carboxyethyl) -2,3,4,5-tetrahydro-1H- [ 1] benzazin-2-one hydrochloride is obtained. HPLC showed that the product was a diastereomeric mixture of about 1: 1.

6.5 g of 3 amino-1- (1-carboxyethyl) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride and 6.5 g in 30 ml acetic acid and 30 ml ethanol. The solution to which ethylbenzylpyruvate was added was stirred at room temperature for 1 hour, and 0.8 g sodium cyanoborohydrate was added dropwise in 10 ml methanol over 4 hours. The reaction mixture is stirred at room temperature for 24 hours. 2 ml of concentrated hydrochloric acid are added and the mixture is stirred for 1 hour. The solvent is removed under reduced pressure and the residue is partitioned between 50 ml water and 30 ml ether. The pH is adjusted to 9.4 and the ether layer is separated off. The aqueous solution is adjusted to pH 4.3 and extracted with 3 x 50 ml of ethyl acetate. The mixed ethyl acetate solution is dried over magnesium sulfate and the solvent is removed under reduced pressure to give a crude base.

Example 23

1-ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

The title compound can be prepared similar to that described in Example 28. Thus Example 9 1-ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [ 1] benzazin-2-one [NMR (CDCl ₃ ) δ4.52 (q, 2H)] and its diastereomer 1-ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3- Phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one [NMR (CDCl ₃ ) δ4.50 (q, 2H)] is obtained. TLC: (silica gel, ethyl acetate / hexane (40:60): Rf of the (S, S) isomer is 0.24 and Rf of the (S, R) isomer is 0.33.

Example 24

1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

0.25 g of 1-ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetra in 5 ml ethanol while stirring at room temperature under a nitrogen stream. 0.26 ml of 2N potassium hydroxide was added dropwise to the solution to which hydro-1H- [1] benzazin-2-one was added. After stirring for 1 hour, the ethanol is evaporated and the residue is dissolved in 5 ml of water, acidified to pH 2 with 2N hydrochloric acid and extracted with 2 x 30 ml ethyl acetate. The mixed ethyl acetate solution was washed with 5 ml of saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to dryness. The compound of Example 11 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) Obtain -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one.

Example 25

1-carboxymethyl-7-chloro-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one, Isomer B

1.5 g 1-carboxymethyl-7-chloro-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase in 25 ml acetic acid The solution of pin-2-one, isomer B) is added through chlorine gas with stirring at room temperature. White solids will precipitate and chlorine is passed through the reaction mixture until the reaction is complete. The solid is filtered off and separated by reverse phase HPLC using 1: 1 methanol / 0.1% ammonium carbonate aqueous solution as solvent and using C ₁₈ column. The appropriate fractions are dissolved in 50 ml of 1: 1 methanol / ethyl acetate and hydrogen chloride bubbles are passed through this solution.

After evaporation of the solution the residue is suspended in 100 ml ether and the suspension is filtered to give 1-carboxy methyl-7-chloro-3- (1-ethoxycarbonyl-3-phenylpropylamino) at a melting point of 149-151 ° C. Obtain -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride (Isomer B).

Example 26

1880 g of 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride relatively Pure title compound (hydro chloride salt) is mixed with 18000 ml of dichloromethane. The suspension is treated with hydrogen chloride gas to make the solution completely. 7200 ml of diethyl ether are added and the suspension is stirred for 3 hours and then filtered. The collected solids were washed with 2 x 1000 ml of dichloromethane and 2 x 1000 ml of diethyl ether and dried to give a product having a melting point of 183 to 185 ° C. (HPLC indicated product purity of about 96%).

1280 g of the salt are mixed with 4000 ml chloroform and the mixture is heated at reflux for 10 minutes. The heating is stopped and the mixture is stirred for 4 hours and then filtered. The solid was washed with 2 × 200 chloroform 3 × 500 ml of diethyl ether, dried and filtered through a molecular sieve to carry a melting point of 184 to 186 ° C., [α] ²⁵ _D = -139.26 ° C. (anhydrous ethanol C = 0.92). 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylbrofilamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2 identical to the hydrochloride of Example 11 Obtain -on hydrochloride.

The relatively pure title compound (hydrochloride salt) can be prepared similarly as described in Example 31. It may also be prepared as follows: 619 g of 3 (S) -amino-1carboxymethyl-2,3,4,5 with [α] ²⁵ _D = -304,4 ° C. (C = 1.08 in water) Tetra hydro-1H- [1] benzazin-2-one sodium salt, 1960 g of ethylbenzylpyruvate, 5880 ml of anhydrous ethyl alcohol and 5880 ml of glacial acetic acid are mixed and stirred at 20 to 25 ° C. for 1.5 hours. A solution in which 179 g of sodium cyanoborohydride was added to 2200 ml of anhydrous ethyl alcohol was added in small portions over a 24-hour period. After the addition is complete, the reaction mixture is stirred for 24 hours.

500 ml of 12N hydrochloric acid is added to the reaction mixture and the solvent is evaporated at 35-40 ° C./3 mmHg. The remaining oily material is mixed with 3000 g ice, 300 ml water and 3000 ml diethyl ether and the pH of the mixture is adjusted to 9-9.5 using 1735 ml 10N sodium hydroxide solution. The aqueous portion is removed and 8000 ml of diethyl ether is added to the ether portion to make additional product an oily material. The ether immiscible moiety is separated and mixed with the water soluble moiety. The ether extract is then washed with 2 x 1000 ml of water, and the wash is combined with the above water-soluble / oil portion and the pH of the mixture is adjusted to 4.25-4.35 using 550-650 ml of 12N hydrochloric acid. The mixture is extracted with 3 x 2000 ml of ethyl acetate, and the mixed ethyl acetate portion is washed with 200 ml of water and dried over 500 g of anhydrous magnesium sulfate. The desiccant is removed by filtration and the solvent is removed completely by evaporation at 40 ° C./3 mmHg. The oily material obtained is dissolved in 4500 ml ethyl acetate and subjected to 309 g of 28% ethereal hydrogen chloride with vigorous stirring. 1500 ml of diethyl ether are added and the mixture is stirred for 1 hour. The solids are collected and washed with 2 x 500 ml of ethyl acetate and 3 x 1000 ml of diethyl ether. It was dried at 50 ° C./3 mmHg and measured as reversed phase HPLC on C ₁₈ column using a mixture of methanol, water and acetic acid 75: 25: 0.02 as eluent, and required 1- Crude containing about 65% of carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetra hydro-1H- [1] benzazin-2-one Obtain the product.

Hydrogen chloride gas is added to the crude product suspension in 26900 ml of dichloromethane in a continuous flow. The solution is obtained after 40 minutes, and when the solution is stopped, gas addition is stopped. The solution is filtered off to remove extremely insoluble matter and 10750 ml of diethyl ether are added.

The suspension is stirred overnight at ambient temperature and the solids are filtered off and washed with 4 x 500 ml of dichloromethane and 3 x 1000 ml of diethyl ether. On drying, a relatively pure product having a melting point of 175-178 ° C. is obtained in the form of hydrochloride.

Example 27

3- (1-benzyloxycarbonyl-3-phenylpropylamino) -1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2-one hydrochloride (Isomer B )

4 g of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) 1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] -benz in 100 ml ethyl acetate The solution to which azepin-2-one was added is given through anhydrous hydrogen chloride bubbles while stirring at 0 ° C. The reaction mixture is evaporated under reduced pressure and the resulting solid is triturated with 50 ml ether. The solid is filtered off, washed with 15 ml ether and 15 ml ethyl acetate and then boiled with 50 ml ethyl acetate. The product is recrystallized in ethanol / ethyl acetate to afford the title compound (isomer B) at melting points 197-199 ° C.

Starting materials are prepared as follows:

3.0 g of 3- (1-benzyloxycarbonyl-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazine- in 100 ml tetrahydrofuran while stirring at room temperature under a nitrogen stream. To a solution of 2-one and 2.2 g of t-butylbromoacetate, 1.2 g of potassium t-butoxide is added. The reaction mixture is stirred at rt for 20 h and then poured into 250 ml water and extracted with 2 x 150 ml dichloromethane. The mixed dichloromethane solution is washed with 100 ml water and dried over magnesium sulfate. Evaporate the solvent to 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -1-t-butyloxy carboxymethyl-2,3,4,5, -tetrahydro-1H- [1] benzazine 2-one is obtained.

Example 28

1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one

5.6 g of ethyl 2- (1-ethoxy carbonyl-3-phenylpropylamino) -4- [0- (ethoxycarbonylmethylthio) -phenyl] -butyrate was added to 100 ml methanol under a stream of nitrogen To a sodium methoxide solution of methanol [prepared with 0.25 g sodium and 50 ml methanol].

The reaction mixture is heated to reflux for 65 hours and then distilled under reduced pressure.

The residue is partitioned in 50 ml water and 200 ml dichloromethane. The aqueous solution is extracted with 200 ml dichloromethane and the mixed organic solution is washed with 50 ml water and dried over potassium carbonate.

Evaporate solvent to 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2 It is obtained as a mixture of isomers A and B of -one and can also be converted to the respective maleate salts as described in Example 9.

Starting materials are prepared as follows.

To a solution of 17.4 g of ethyl 2-amino-4- (O-nitrophenyl-butyrate) in 130 ml of 50% water-soluble dioxane was added 10.5 g of triethylamine and 18.7 g of 2- (3-butyloxycarbonyl Add oxyimino-2-phenylacetonitrile Stir the reaction mixture at room temperature for 4 hours and then dilute with 300 ml water Extract the mixture with 3 x 150 ml ether, acidify the aqueous phase with ice-cold 2N hydrochloric acid Extract with 2 x 250 ml ethyl acetate, ethyl acetate layer is mixed, washed with 150 ml water and dried over sodium sulfate Ethyl 2-t-butyloxycarbonylamino- is used without further purification by removing the solvent under reduced pressure. 4- (O-nitrophenyl) -butyrate is obtained.

13.0 g of ethyl 2-t-butyloxycarbonylamino-4- (O-nitrophenyl) -butyrate was added to 300 ml ethanol using 1 g of 10% pd-C as a catalyst until the hydrogen adsorption was stopped. And hydrogenation under atmospheric pressure. The catalyst is filtered off and the solvent is evaporated to give ethyl 2-t-butyloxycarbonylamino-4- (O-aminophenyl) -butyrate which is used without further purification in the next reaction step.

A solution of 4.2 g ethyl glyoxylate and 10.0 g ethyl 2-t-butyloxycarbonylamino-4- (0-aminophenyl) -butyrate in 120 ml ethanol was catalyzed by 3 g of 10% pd-C. Hydrogenated at 80 DEG C for 3 hours at 3 atmospheres.

The reaction mixture is cooled to room temperature and the catalyst is filtered off. The solvent is removed under reduced pressure and the residue is dispersed in 150 ml ethyl acetate and 75 ml water. Ethyl 2-t-butyloxycarbonylamino-4- (O-ethoxycarbonylmethylamino) -phenyl- used for drying the organic phase over magnesium sulfate and removing the solvent under reduced pressure without further purification in the next synthesis process. Butyrate is obtained.

150 g of ethyl acetate was added to 8.5 g of ethyl 2-t-butyloxycarbonylamino-4- [O-ethoxycarbonylmethylamino) phenyl] -butyrate through a bubble of hydrogen chloride at room temperature for 30 minutes. The solution is evaporated under reduced pressure and the residue is dissolved in 100 ml ethyl acetate.

The solution is washed with 3 x 100 ml water and dried over sodium sulfate.

The solvent is removed under reduced pressure to afford ethyl 2-amino-4- [O- (ethoxycarbonylmethylamino) -phenyl] -butyrate, which is used in the next step without further purification.

To a solution of 35 ml acetic acid and 35 ml methanol was added 4.7 g of ethyl 2-amino-4- [O- (ethoxycarbonylmethylamino) phenyl] butyrate and 12.4 g of ethylbenzylpyruvate for 1 hour at room temperature under nitrogen stream. Stir. 1.6 g sodium cyanoborohydrate in 15 ml methanolysis was added dropwise over 4 hours and the reaction mixture was stirred at room temperature for 24 hours. 2 ml concentrated hydrochloric acid is added dropwise and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness and the residue is partitioned between 75 ml water and 75 ml ether and adjusted to pH = 2 with 6N hydrochloric acid. The layers are separated and the aqueous phase is extracted with 2 x 75 ml ether. Discard the ether extract and adjust the pH to 9 with 40% sodium hydroxide and extract with 3 x 50 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and the solvent was removed under reduced pressure to yield ethyl 2- (1-ethoxycarbonyl-3-phenylpropylamino) -4- (O-ethoxycarbonylmethylamino) phenylbutyrate. This is used directly to prepare the final product.

Example 29

1-carboxymethyl-3S- (1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2one

3 g of 1-benzyloxycarbonylmethyl-3S- (1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin- 2-one is dissolved in 50 ml ethanol and 0.3 g of 10% pd-C is added and the solution is hydrogenated at 1 atmosphere at room temperature for 2 hours. The reaction mixture was filtered and evaporated to 1-carboxymethyl-3S- (1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz Azepin-2one is obtained.

Starting materials are prepared as follows:

5 g of 1-benzyloxycarbonyl methyl-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one [(implementation Example 2)] is dissolved in 5.15 ml of 2N potassium hydroxide and the solution is evaporated to dryness. 2.3 g of iodomethyl pivalate and 50 ml of dimethylformamide are added and the reaction mixture is stirred for 18 hours at room temperature under a stream of nitrogen. Dimethylformamide is evaporated and the residue is taken up with 100 ml ethyl acetate, washed with 3 x 25 ml of saturated sodium bicarbonate, 3 x 25 ml of water and 25 ml of saturated sodium chloride and dried over magnesium sulfate. Evaporation to 1-benzyloxycarbonylmethyl-3S- (1S-pivaloyloxy-methoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase Obtain pin-2-one.

Similarly, the following materials can be prepared.

(a) 1-carboxymethyl-3S- (1S-1-bornyloxycarbonylmethoxycarbonyl-3-phenylpropylamino) -2,3,4, using 1-bornyl iodoacetate as starting material 5-tetrahydro-1H- [1] benzazin-2one, (b) β-methoxyethoxymethylchloride as starting material, (c) 3-bromophthalimide as starting material 1-carboxymethyl-3S- (1S-β-methoxyethoxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2 -One, (d) 1-carboxymethyl-3S- (1S- (3-pyridylmethoxycarbonyl-3-phenylpropylamino) -2,3,4, using 3-pyridylmethylchloride as starting material 5-tetrahydro-1H- [1] benzazin-2-one.

Example 30

1-carboxymethyl-3S- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5,5a, 6,7,8,9,9a-tecahydro-1H- [1] Benzazin-2-one

The title compound can be prepared similar to that described in Example 28. This can be converted to hydrochloride by bubbling hydrogen chloride with a solution of the title compound in tichloromethane for 5 minutes. The solution was evaporated and the residue was recrystallized in ethanol / ether to give 1-carboxymethyl-3S- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5,5a, 6,7 , 8,9,9a-tecahydro-1H- [1] benzazin-2-one-hydride is obtained as an isomer mixture.

Starting materials are also prepared as follows:

3.6 g 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydroho-1- [1] benzazin-2, in 50 ml acetic acid, The solution to which 5-dione was added was hydrogenated using 1.2 g of platinum oxide as a catalyst for 120 hours at 3 atmospheres. The catalyst is filtered and the filtrate is evaporated under reduced pressure. The residue is dispersed in 200 ml dichloromethane and 100 ml saturated aqueous sodium bicarbonate solution. The dichloromethane solution is washed with 50 ml water, dried over sodium sulphate and the solvent is removed under reduced pressure. The residue was eluted with 0 to 50% ethyl acetate in toluene to collect the fractions, which were then purified by 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- [1] benzazin-2,5-dione is obtained, which is used in the next synthetic step without further purification.

2.7 g 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8,9,9a-decahydro- in 100 ml ethanol The solution to which 1H- [1] benzazine-2,5-dione and 0.2 g sodium borohydride was added is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is dissolved in 100 ml dichloromethane. The solution is extracted with 2 x 500 ml of ice-cold 2N hydrochloric acid and 50 ml of saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with ether to give 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5,5a Obtain 6,7,8,9,9a-decahydro-1H- [1] benzazin-2-one.

2.1 g of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-S-hydroxy-2,3,4,5a, 6,7,8,9,9a-decahydro- A mixture of 1H- [1] benzazin-2-one, 1.8 g of dicyclohexylcarbodiimide and 0.2 g of cuprous chloride was heated to 80 ° C. for 32 hours under a stream of nitrogen. The reaction mixture is cooled to room temperature and the residue is dissolved with 200mlapxlffps chloride and washed with 2x50 ml dilute ammonium hydroxide and 50 ml water. The organic phase is dried over sodium sulfate and evaporated to afford a mixture of the required adduct and excess dicyclohexylcarbodiimide. This mixture is dissolved in 100 ml of ethyl acetate and equipped with a pressure vessel. 0.4 g of 10% pd / C is added and the mixture is hydrogenated at 3 atmospheres and 40 ° C. for 16 hours. The catalyst was filtered and the filtrate was distilled to give 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8,9, 9a-decahydro-1H- [1] benzazin-2-one is obtained, which is used in the next synthetic process without further purification.

1.1 g of the compound was added to 50 ml of ethyl acetate, followed by hydrogen chloride bubbles for 45 minutes. The reaction mixture is evaporated under reduced pressure. The residue is dissolved in 50 ml ethyl acetate and washed with 3 x 30 ml water. The ethyl acetate solution was dried over sodium sulfate and the solvent was removed under reduced pressure to afford 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8,9,9a- Decahydro-1H- [1] benzazin-2-one is obtained, which is used in the next process without further purification.

0.1 g sodium hydroxide in 0.25 ml water is added to a solution in which 0.6 g of upper pin is added to 7.5 ml methanol at room temperature and the solution is sry for 2 hours. After evaporating the solvent and completely drying the residue, slurry was made with ether to give 3 (S) -amino-1-carboxymethyl-2,3,4,5,5a, 6,7,8,9,9a-deca Hydro-1H- [1] benzazin-2-one is obtained.

0.6 g 3 (S) -amino-1-carboxymethyl-2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- [1] -benz in 5 ml acetic acid and methanol A solution of azepin-2-one sodium salt and 1.5 g of ethylbenzylpyruvate was stirred for 1 hour at room temperature under a stream of dry nitrogen. Then, a solution obtained by adding 0.2 g of sodium cyanoborohydride to 2 ml methanol is added over 4 hours. The reaction mixture is stirred at rt for 18 h. 0.5 ml concentrated hydrochloric acid is added and the mixture is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure and the residue is dispersed in 20 ml water and 20 ml ether. The pH is adjusted to 9.3 using 40% sodium hydroxide, the liquid layer is separated and the ether layer is discarded. The aqueous phase is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with 3 × 25 ml ethyl acetate. The extract is dried over magnesium sulfate and the solvent is removed under reduced pressure to afford the title compound.

Example 31

N- [1- (1-carboxymethyl) -2,3,4,5-tetrahydro-2-oxo-1H- [1] benzazin-3S-ylamino) -3-phenylpropyl-1-carbo Nyl] -L-phenylaniline

L-phenylalaninemethylester hydrochloride was dissolved in methylene chloride at room temperature in the presence of 1- (3-dimethylaminopropyl) 3-methylcarbodiimide hydrochloride in 1-benzyl-oxycarbonylmethyl-3S- (1S-carboxy-3- N- [1- (1-benzyloxycarbonyl-) by condensation with phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one and undergoing a predetermined operation. Obtain methyl-2,3,4,5-tetrahydro-2-oxo-1H- [1] benzazin-3S-ylamino) -3-phenylpropyl-1-carbonyl] -L-phenylalanine methylester do.

Hydrogenation reaction with 10% pd / C catalyst in ethanol gave N- [1- (1-carboxymethyl-2,3,4,5-tetrahydro-2-oxo-1H- [1] benzazin-3S- Monoamino) -3-phenylpropyl-1-carbonyl] -L-phenylalanine methylester.

Hydrolyze with dilute aqueous sodium hydroxide solution for 18 hours at room temperature to yield N- [1- (1-carboxymethyl-2,3,4,5-tetrahydro-2-oxo-1H- [1] benzazin-3S- Monoamino) -3-phenylpropyl-1-carbonyl] -L-phenylalanine is obtained.

Example 32

Preparation of 10,000 Tablets Each Tablet Containing 10mg of the Active Material of Example 11

[Formulation]

1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropyl

Amino) -2,3,4,5-tetrahydro-1H- [1] benzazine

2-one 100 g

Lactose 1,157g

75 g of corn starch

Polyethylene glycol 6,000 75 g

Talc Powder 75g

Magnesium Stearate 18g

Purified water

[quite]

The preparation described in Example 14 is followed.

Example 33

Preparation of 10,000 capsules in which each capsule contains 20 mg of hydrochloride of the active ingredient of Example 11.

[Formulation]

1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropyl

Amino) -2,3,4,5-tetrahydro-1H- [1] benzazine

2-one 200 g

Lactose 1,700g

Talc Powder 100g

[quite]

The preparation described in Example 16 is followed.

Cardiovascular pharmacological action of compounds prepared according to the invention

The test of the compound is carried out by measuring the degree of inhibition of angiotensin converting enzyme (ACE). Biochemical evaluation of ACE inhibitors (ACEI) in vivo is to measure the inhibition of peptide degradation of compounds in rabbit lung tissue.

In an in vivo test, rats were inhibited for angiotensin I (AI) blood pressure elevation reaction of this compound.

In in vivo testing, angiotensin I (AI) is first administered to test animals to raise blood pressure. The inhibitory action of each compound on this blood pressure rise is then measured.

[Biochemical test method]

For ACE evaluation by Cheung and Cushman method [Cheung and Cushman, Biochim, Biophys, Acta 293: 451, (1973)] rabbit lung tissue [Das and Saffer., J. Biol, Chem. 250: 6762, (1975). This test method measures the amount of histidyl-leucine released from the synthetic substrate after incubation at 37 ° C. for 30 minutes by spectrophotometer. The IC ₅₀ value of ACE inhibition is determined on a graph, which is expressed as the concentration of test agent required to reduce the amount of histidyl-leucine produced to 50% of the amount produced in the absence of test compound.

[Inhibition method of Angiotensin I (AI) blood pressure elevation response by intravenous injection of test compound (% AI)]

Catheters are connected to the femoral artery and saphenous vein of anesthetized rats as described above in these tests. The arterial pressure is continuously recorded with the arterial catheter, while AI and test compound are injected through the venous catheter. The suppression of AI-hypertension response is expressed in% response to pretreatment controls and is tabulated with the mean inhibition recorded within 30 minutes of the study drug administration.

TABLE 2

result

Claims (15)

3-amino- [1] benzazin-2-one-1-alkanoic acid of formula (I), or a stereoisomer or salt thereof, characterized by ring closure of a compound of formula (IX) or an ester thereof How to prepare.

Wherein R _A is

And R _B is

And, R ₀ is a COR ₆ from R _A, in R _B is COR _7, R ₆ and R ₇ are independently hydroxy, lower alkoxy, (amino, mono-or di-lower alkylamino) substituted lower alkoxy, Carboxy-substituted lower alkoxy, lower alkoxycarbonyl-substituted lower alkoxy, aryl-substituted lower alkoxy, (hydroxy, lower alkanoyloxy or lower alkoxy) -substituted lower alkoxymethoxy, bicycloalkoxycarbonyl- Substituted lower alkoxy, 3-phthalidoxy, (lower alkyl, lower alkoxy or halo) -substituted 3-phthalidoxy, amino, lower alkyl amino, di-lower alkylamino, two alkyl groups are attached to the carbon-carbon bond. Di-lower alkylamino, (amino or lower alkanoylamino) -substituted lower alkylamino, α- (carboxy or lower) which are linked together and form together with the amino nitrogen a 5,6- or 7-membered saturated heterocyclic ring Alkoxycarbonyl) -substituted lower alkyl Amino or aryl-substituted lower alkyl amino, which may be substituted with carboxy or lower alkoxy carbonyl on α-carbon, R ₁ is hydrogen, lower alkyl, amino (lower) alkyl, aryl, aryl (lower) alkyl , Cycloalkyl or cycloalkyl (lower) alkyl, R ₂ is hydrogen or lower alkyl, R ₃ and R ₄ are each independently hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen or trifluor Rhomethyl, or R ₃ and R ₄ together are lower alkylenedioxy, R ₅ is hydrogen or lower alkyl, X is oxo, two hydrogen, or one hydrogen and one hydroxy, and the carbocycle ring is also It may be hexahydro or 6,7,8,9-tetrahydro for formula (I), hexahydro or 3,4,5,6-tetrahydro for formula (IX), aryl Silver lower alkyl, hydroxy, lower It is selected from alkoxy, lower alkylenedioxy, lower alkanoyloxy, phenyl mono- or di-substituted or unsubstituted by halogen or trifluoromethyl, and pyridyl. The method of claim 1, wherein the compound of formula (IA) or a salt thereof is prepared.

Wherein R ₁ is hydrogen, lower alkyl, amino (lower) alkyl, or aryl (lower) alkyl, wherein aryl is lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen or tri Phenyl mono- or di-substituted or unsubstituted with fluoromethyl), R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ and R ₄ are hydrogen, lower alkoxy, lower alkyl, halogen or trifluoro Methyl or R ₃ and R ₄ together are lower alkylenedioxy, X is oxo, one hydroxy and one hydrogen, or two hydrogen, and R ₆ and R ₇ are independently hydroxy, amino, lower Alkoxy, phenyl (lower) alkoxy, lower alkoxy carbonyl (lower) alkoxy. The compound of claim 1, wherein R ₁ is hydrogen, lower alkyl, ω-amino (lower) alkyl or aryl (lower) alkyl, wherein aryl is loweralkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluor Phenyl mono-substituted or unsubstituted with romoxy), R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ and R ₄ are hydrogen, lower alkoxy, lower alkyl, halogen or trifluoromethyl, or R ₃ and R ₄ together are lower alkylenedioxy, X is oxo, one hydroxy and one hydrogen, or two hydrogen, and R ₆ and R ₇ are independently hydroxy, amino, lower alkoxy, phenyl ( A process for preparing a compound of formula (IA) as defined in claim 2 or a salt thereof, wherein the compound is lower alkoxy or lower alkoxycarbonyl (lower) alkoxy. The process of claim 1, wherein the compound of formula (IB) or a salt thereof is prepared.

Wherein n is an integer from 1 to 4, R ₆ and R ₇ are independently hydroxy, lower alkoxy, benzyloxy or amino having 4 or less carbon atoms, R ₈ is hydrogen, or lower alkyl, lower alkoxy, lower alkoxy Phenyl mono-substituted or unsubstituted with noyloxy, halogen, hydroxy or trifluoromethyl. The method of claim 1, wherein 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2- On, or a salt or stereoisomer thereof. The process of claim 1, wherein the high melting racemic compound, or enantiomer or salt thereof, of the compound as defined in claim 5 is prepared. The process of claim 1, wherein the low melting racemic compound of the compound as defined in claim 5, or an enantiomer or salt thereof. The method of claim 1, wherein 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2- Method of preparing a ions or salts thereof. The compound of claim 1, wherein 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one or its Process for preparing salts or stereoisomers. 2. The compound of claim 1 wherein 1-carboxymethyl-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2-one or thereof How to prepare a salt. The method of claim 1, wherein 1-ethoxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazin-2- On, or a salt or stereoisomer thereof. The process of claim 1, wherein the racemic isomer compound B or salt thereof of the compound as defined in claim 11 is prepared. The method of claim 1, wherein the 1-carboxymethyl-7-chloro-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzase A process for preparing racemic isomer compound B or a salt thereof of pin-2-one. The compound of claim 1, wherein 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazin-2- On, or a salt or stereoisomer thereof. The process of claim 1, wherein the compound as defined in claim 8 is prepared in the form of a hydrochloride salt.