FI76074B - PROCEDURE FOR FRAMSTATION OF ANTIHYPERTENSIVE 3-AMINO- / 1 / BENSAZEPIN-2-ON-1-ALKANSYROR. - Google Patents

Description

76074

Process for the preparation of antihypertensive 3-amino- [1] benzazepin-2-one-1-alkanoic acids - For the preparation of antihypertensive 3-amino- [1] benzazepin-2-on-1-alkanesyror GB patent 1,305,278 describes quinoline -, benzazepine and benzazokine compounds having both an optionally substituted phenyl substituent and an aminoalkylene group in either the 3- or 4-position of the heterocyclic ring. They are suitable as stimulants of the central nervous system and can be used to treat depression. U.S. Patent 3,748,321 describes N- (dialkylalkylamino-lower alkyl) N-lower alkyl-1-benzalkyleneimine-1-carboxamides which can be used as sedatives. Swedish Patent Publication 372,012 describes certain 3-alkoxycarbonyl-3-amino -tetrahydro-quinolin-1-ones which can be used as intermediates for the preparation of pharmaceutically valuable 1,4-benzodiazepine derivatives.

This invention is based on the discovery that certain substituted 3-amino- [1] benzazepin-2-one-1-alkanoic acids and their derivatives constitute a new class of inhibitors that are potent against angiotensin converting enzyme (ACE).

The above properties make the 3-amino- [1] benzazepin-2-ones of the invention particularly valuable when administered alone or in combination to mammals, for example in the treatment or prevention of diseases affected by angiotensin converting enzyme inhibition, e.g. cardiovascular disorders such as hypertension and cardiac disorders. conditions such as congestive heart failure.

The present invention relates to novel 3-amino- [1] benzazepin-2-one-1-alkanoic acids and their derivatives which are valuable as inhibitors of angiotensin converting enzyme, to a process for their preparation, to pharmaceutical compositions containing these compounds and to methods for treating diseases affected by angiotensin converting enzyme. 2,76074 inhibition of the enzyme by administering these compounds and compositions to mammals.

The compounds of the invention have the general formula (I)

R4 X

Λ (le I, y- <„

Re 0 / »1

wherein Ra represents a residue -CH

and Ro represents the residue -CH

\ r

k?

wherein R0 in R8 is CORg and in RB is COR7, wherein Rg and R7 are independently hydroxy, lower alkoxy or enyl-lower alkoxy; and R 1 represents hydrogen or phenyl-lower alkyl; R 2 is hydrogen or lower alkyl; R 3 and R 4 independently represent hydrogen, lower alkoxy or halogen; R 5 is hydrogen and X represents two hydrogen atoms or, simultaneously with the hydrogen atom, a hydroxy group; and stereoisomers and salts thereof.

Salts of the compounds of formula (I) are derived from those compounds which have salt-forming properties and are preferably pharmaceutically acceptable salts.

The esterified carboxyl group is illustrated by the substituent -CORg (at the residue RA) or the sub-formula -COR7 (at the residue Rg), where one of the residues Rg and R7 or both residues denotes lower alkoxy or phenyl-substituted lower alkoxy, e.g. optionally substituted benzyloxy.

Il 3 76074

Derivatives of the compounds according to the invention which form precursors of the active ingredient, e.g. all pharmaceutically acceptable esters of the mono- or dicarboxylic acids according to the invention which can be converted by solvolysis or under physiological conditions into the carboxylic acids according to the invention, e.g.

These esters are preferably, for example, straight-chain or branched, unsubstituted or suitably substituted lower alkyl esters, such as benzyl ester and the like.

The invention relates in particular to compounds of formula (IA) which are CO-Rc R3 CH ° 6 1 * 2 XCO-R? wherein R 1 represents hydrogen or aryl- (lower) alkyl, where aryl means unsubstituted phenyl, R 2 represents hydrogen or lower alkyl, R 3 and R 4 represent hydrogen, Lower alkoxy or halogen, R 5 represents hydrogen, X represents a hydroxy group and a hydrogen atom or two hydrogen atoms, R 9 and R 7 independently represent hydroxy, lower alkoxy or phenyl (lower) alkoxy, or a pharmaceutically acceptable salt thereof.

Particularly valuable are compounds of formula (IA) wherein R 1 represents hydrogen or phenyl- (lower) alkyl, R 2 represents hydrogen or lower alkyl, R 3 and R 5 represent hydrogen, R 4 represents hydrogen, lower alkoxy or halogen, X represents a hydroxy group and a hydrogen atom, or two hydrogen atoms, R 9 and R 7 independently represent hydroxy, lower alkoxy or phenyl (lower) alkoxy, or pharmaceutically acceptable salts thereof.

Of particular value are compounds of formula (IA) wherein R 1 is hydrogen or aryl (methyl, ethyl, propyl), wherein aryl is unsubstituted phenyl, R 2 is hydrogen or methyl, R 3 and R 4 are hydrogen, methoxy -si or chlorine, R 5 is hydrogen, X represents a hydroxy group and a hydrogen atom or two hydrogen atoms, R 8 and R 7 independently represent hydroxy, ethoxy, methoxy or benzyl solutions, or pharmaceutically acceptable salts thereof.

Of paramount value are the compounds of formula (IB) (PV Vnh-CH 2 CnH 2n "* R 8 (IB} '^' C0-Re I o CH 2 -CO-R 7 where n is an integer from 1 to 4, R 8 represents unsubstituted phenyl, Rg and R7 independently represent hydroxy, lower alkoxy having up to 4 carbon atoms or benzyloxy, or pharmaceutically acceptable salts thereof.

Of particular value are compounds of formula (IB) wherein CnH2n is ethylene, R8 is phenyl, R8 and R7 are independently hydroxy or lower alkoxy having up to 4 carbon atoms, or pharmaceutically acceptable salts thereof.

This invention also relates to stereoisomers of the compounds of formula (I). A number of racemates are obtained, for example, when in formula (IA) at least one of the radicals R 1 and R 2 is different from hydrogen and / or X represents the group H (OH).

The individual enantiomers of these racemates can in turn be obtained. Certain specific representatives of these isomers are preferred as inhibitors of the angiotensin converting enzyme.

Preferred are compounds of formula (IC) C H -R_ ^, (S) / n 2n 8 Π T (S) V ~ NH-CH (IC) n \ x> -R 6 I O 6 CH 2 -CO-R?

II

5,76074 wherein S represents chirality, n is an integer from 1 to 4, Rg represents unsubstituted phenyl, Rg and R7 independently represent hydroxy, lower alkoxy having up to 4 carbon atoms or benzyloxy, or pharmaceutically acceptable salts thereof.

The general definitions used herein have the following meanings within the scope of the invention.

Aryl preferably means phenyl.

Aryl- (lower) alkyl preferably means benzyl, 1- or 2-phenethyl, 1-, 2- or 3-phenylpropyl, 1-, 2-, 3- or 4-phenylbutyl, in which the phenyl ring is unsubstituted.

The term "lower" used in connection with the above and below organic residues or compounds defines these as containing up to 7, preferably up to 4 and most preferably 1 or 2 carbon atoms.

The lower alkyl group preferably contains 1 to 4 carbon atoms and means, for example, ethyl, propyl, butyl or preferably methyl.

The lower alkoxy group preferably contains 1 to 4 carbon atoms and is, for example, methoxy, propoxy, isopropoxy or more preferably ethoxy.

Aryl-lower alkoxy preferably means e.g. benzyloxy.

Halogen preferably means chlorine, but may also be bromine, fluorine or iodine.

According to the invention, one or both of the carboxyl groups of the dicarboxylic acids, i.e. the compounds of formula (IA) or (B) in which R 9 and R 7 are hydroxy, may be in the form of functional derivatives as esters. Such functional derivatives are preferably mono- or bis-lower alkyl esters, e.g. methyl, ethyl, n- or iso-propyl, butyl or benzyl ester.

6 76074

Particularly preferred functional derivatives are monoesters of formula (IA), e.g. those in which one of the residues Rg and represents hydroxy and the other Alem-5 pialkoxy.

Pharmaceutically acceptable salts are preferably the metal or ammonium salts of the compounds of formula (I) in which Rq is carboxy, or the metal or ammonium salts of the compounds of formula (IA) in which CORg and / or COR1 are carboxy, in particular alkali. - or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, or preferably readily crystallising ammonium salts derived from ammonia or organic amines, such as mono-, di- or tri-lower (alkyl, cycloalkyl-15 or hydroxyalkyl) ) amines, lower alkylenediamines or lower (hydroxyalkyl or aralkyl) ammonium bases, e.g. These compounds of formula (I) form acid addition salts, which are preferably treated with therapeutically suitable inorganic or organic acids, such as strong mineral acids, e.g. hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, maleic acid, palic acid, citric acid, ascorbic acid, ascorbic acid, ascorbic acid, -aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid; 35 methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic

II

7 76074 with acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfamic acid.

The compounds of formula (I) have valuable pharmacological properties, which are manifested above all in their inhibitory effect on the secretion of angiotensin II. This effect is based on the selective inhibition of the angiotensin-converting enzyme in mammals. The compounds are thus useful in the treatment of diseases that respond to the inhibition of angiotensin converting enzymes in mammals, including humans.

The compounds according to the invention have a primarily hypotensive / antihypertensive effect and affect the heart rate. These properties can be demonstrated in in vivo or in vitro animal experiments, preferably in mammals, such as those used as experimental animals, cats, dogs or their isolated organs for 15 minutes. The animals may be normotensive or hypertensive, e.g., genetically spontaneously hypertensive rats or renally hypertensive rats or moths and dogs with decreased sodium levels. The compounds may be administered to experimental animals enterally or parenterally, preferably orally or intravenously, e.g. as gelatin capsules or in the form of aqueous solutions containing starch-containing suspensions. The dose used may be about 0.01 to 100 mg / kg / day, preferably about 0.05 to 50 mg / kg / day, especially about 0.1 to 15 mg / kg / day.

The antihypertensive effect in vivo is determined either directly by a catheter inserted into the femoral artery of the test animal or indirectly by a sphygmomanometer in the rat tail using a transfer device. Blood pressure is determined before and after administration of the active substance in mm Hg.

Thus, antihypertensive effects can be demonstrated in spontaneously hypertensive rats by indirect measurement of systolic blood pressure. Non-anesthetized rats 35 are placed alone in a cage that restricts their movement in a slightly heated room. A pulse sensor is attached to the inflatable cuff at the tail 8,76074 of each rat. The cuff is inflated to close the tail artery. The pressure in the cuff is continuously reduced and the systolic pressure corresponds to the pressure in the cuff when the pulse pulse 5 occurs again. After recording blood pressure and heart rate control values, test compounds are administered orally once daily for four consecutive days. Additional blood pressure measurements are performed as usual at 2.0, 4.0, and 23.5 hours after each 10 daily doses. The values are compared to the values of rats treated with vehicle alone.

To illustrate the invention, mention should be made of the "higher melting" 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) -15 benzazepin-2-one antihypertensive agent of Example 1. effect: at a dose of 3 mg / kg po blood pressure decreases by an average of 40 mm Hg. Measurements were taken 2 and 4 hours after dosing on the last two days. The corresponding S, S-enantiomeric compound of Example 12 lowers blood pressure at an oral dose of 1 mg / kg at 30 mm Hg.

The compounds of the invention, when administered intravenously or orally, also have an inhibitory effect on angiotensin I-induced hypertension in normotensive rats. Said modifying enzyme hydrolyses angio-25 tensin I and angiotensin II, a potent antihypertensive agent. Inhibition of said enzyme reduces the formation of angiotensin II from angiotensin I. In this way, the increase in blood pressure provoked by angiotensin I is reduced.

Corresponding in vivo tests are performed by intravenous administration of compounds to normotensive male rats anesthetized with the sodium salt of 5-ethyl-5- (1-methylpropyl) -2-thiobarbituric acid. The femoral artery and hypothalamus are in each case subjected to perforation with a perforation of 35 to measure blood pressure directly, as well as intravenous administration of angiotensin I and a compound of the invention.

II

9 76074 for execution. Once baseline blood pressure has stabilized, pressure changes are determined over three, 5-minute periods i.v. after stimulation with 333ng / kg of angiotensin I. Such pressure changes are determined at 5, 10, 15, 30 and 60 minutes after intravenous administration of the test compound. The latter pressure change values are compared with the initial values. Each observed reduction in blood pressure is indicative of inhibition of angiotensin I converting enzymes. To illustrate the invention, reference is made to the "higher melting" 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1] benzazepin-2-one of Example 1 and Example 12. to the corresponding S, S enantiomer These completely prevent an increase in blood pressure after angiotensin I stimulation for 30 minutes after an intravenous dose of 1 mg / kg.

In vitro inhibition of the angiotensin converting enzyme can be detected with the compounds of the invention analogously to Biochem. Biophys. Acta 293, 451 (1973). According to this method, said compounds are dissolved in phosphate buffer at concentrations of about 1 mmol. To 100 microliters of a solution of the test compound in phosphate buffer, which solution is diluted to the desired concentration, is first added 100 microliters of 5 millimolar hippuryl-histidyl-leucine in phosphate buffer and then 50 ul of angiotensin converting enzyme. This enzyme is made from the lungs of adult male rabbits in Tris buffer, which contains potassium and magnesium chloride as well as cane sugar. Said 30 solutions are incubated for 30 minutes at 37 ° C and the reaction is stopped by adding 0.75 ml of 0.6 N aqueous sodium hydroxide solution. Then 100 microliters of a 0.2% solution of o-phthalaldehyde in methanol are added at room temperature and, after 10 minutes, 100 microliters of 6-nor-35-colored hydrochloric acid. These samples are compared in a spectrophotometer at 360 nm with water and their optical titre is determined. These values are converted by a conversion factor to correspond to a standard curve, giving the amount of histidyl-leucine formed during said 30 minutes of incubation in nanomoles. The results are plotted to determine the IC 50 value, plotted against active substance concentrations. The IC 50 value refers to the concentration of active substance that results in half the activity value of the control sample without active substance. To illustrate the invention, reference is made to the "higher melting" 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one of Example 109 and the corresponding example of Example 19. To the S, S enantiomer having an IC 50 of 5.2 x 10 M and 1.7 x 10 M. The corresponding "lower melting" 1-carboxymethyl-3- (1-carbox-15 si-3-phenylpropylamino) -2,3,4,5-tetrahydro-LH (l) benzamide

_ O

azepin-2-one has an IC 50 of 5.8 x 10 M.

The angiotensin converting enzyme is not only involved in the conversion of angiotensin I to angiotensin II but also plays a role in the regulation of bradykinin and aldosterone levels. The effect of the compounds of the invention on these factors may also contribute to their antihypertensive and cardiac properties.

Due to the above-mentioned advantageous properties, the compounds of the invention are very valuable as specific therapeutic agents for mammals, including humans.

Thus, the compounds of the invention are valuable antihypertensive agents, especially for lowering hypertension (regardless of etiology) and / or in cardiac diseases such as heart failure and / or other conditions where edema or dehydration occurs. They can also be used as intermediates in the preparation of other valuable products, especially in the manufacture of pharmacologically effective preparations.

The compounds of formula (I) according to the invention can be prepared in a manner known per se in such a way that e.g.

A) to a compound of formula (II)

R4 X

fr J NH-R 1 - (II) 3 i. ° wherein X, R 1, R 1, R 4 and R 5 have the same meaning as above, R is attached by alkylation of yh-5 with a dyst of formula (IIIA) R -Z (IIIA) / i wherein Z represents a reactive esterified hydroxyl group and RA represents the same as above, or by alkylation with a compound of formula (IV)

Rx - CO - Rq (IV) wherein R1 and Rq are as defined above, in the presence of a reducing agent, while temporarily protecting any primary and secondary amino groups and / or optionally hydroxyl and / or oxo groups which may be present at any residue X, R,, R_, R., R_, R. and Rr, AB 1 3 4 J 5 or 15 b) a compound of formula (V)

'»S H O

wherein X, R 1, R 4 and R 2 are as defined above and R a is hydrogen or is the same as R A above is alkylated with a compound of formula (IIIB) RB "Z (IIIB) wherein Z is reactive, esterified hydroxyl group and RB have the same meaning as above, temporarily protecting any primary and secondary amino groups and / or optionally hydroxyl and / or oxo groups which may be present at any of the radicals X, R1, rb, R3, R4 and R5, or c) a compound of formula (VI) wherein R represents an oxo or a reactive esterified hydroxyl group Z together with a hydrogen atom and X, RB, R3 and R4 have the same meaning as above, is condensed with an amine of formula (VII) RA -NH-R 5 (VII) wherein Ra and R 5 are as defined above wherein when Y is oxo, the coding is carried out in the presence of a reducing agent, or d) in a compound of formula (VIII)

R4 X R

-V R5 / 1

(r Ί V-N-CH

T ^ N-V \ R, R- I O 0

3 CH

Wherein R 1 to R 5 are as defined above, one of R 0 'and R 0 "is cyano and the other is cyano or means the same as R 0 above, the cyano group (s) is (are) subjected to solvolysis, or e) a compound of formula (IX) on

II

COOH A

3 rb 13 76074 wherein X, R1, RB, R3, R4 and R5 are as defined above, or an ester thereof is cyclized, or f) a compound which is structurally identical to a compound of formula I above, except that the compound contains an additional double bond at the C-3 position or between the nitrogen atom and the adjacent carbon atom in the R & group is treated with a reducing agent to saturate this double bond, and the resulting compound of formula I as defined above is converted to another compound of formula I as defined above and / or the resulting compound of formula I as defined above having salt-forming properties is optionally salified or the free compound is liberated from such a salt and / or an optical isomer having a specific configuration at at least one chiral center is optionally liberated from a mixture of stereoisomeric forms of the compound of formula I obtained.

The alkylation according to methods a) and b), which is carried out on the residue R & resp. For the coupling of RB takes place in the customary manner, preferably by treating the corresponding starting material of the formula (II) or (V) with an alkylating agent of the formula R 1 -Z (IIIA) or RB (IIIB), in which R 6 and R B have the same meaning as above and Z is a reactive esterified hydroxyl group, such as a hydroxyl group esterified with a strong organic acid, e.g. a hydroxyl group esterified with an inorganic acid such as, in particular, sulfuric acid or a hydrohalic acid such as hydrochloric acid or most preferably hydroiodic acid or hydrobromic acid. The alkylation is usually carried out under conditions of about 0 ° C to the boiling point of the reaction mixture, preferably at room temperature to about 100 ° C.

Iillä. The reaction is preferably carried out in the presence of a solvent inert to the reactants, such as the acyclic or cyclic ether of a chlorinated lower alkane (e.g. chloroform or methylene chloride) (e.g. diethyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran), and especially teratofuran. in the presence of an amide (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethylphosphoric acid trisamide). The strong acid HZ released during the reaction is best bound by the addition of an acid scavenger, e.g. preferably an inorganic acid scavenger such as alkali metal bicarbonate, carbonate or hydroxide, organic, quaternary ammonium salt (e.g. tetrabutylammonium) or tetrabutylammonium. a base such as triethylamine, N-ethylpiperidine, pyridine or quinoline.

In process a) the alkylation can also be carried out under reductive alkylation conditions known per se and used in the prior art.

To carry out the alkylation, a compound of the general formula (IV) is R ..- CO-R (IV)

1 O

wherein R and R are as defined above, is reacted with a bicyclic starting material of formula (II) and simultaneously or subsequently with a reducing agent in the next process step. Reducing agents used concomitantly with the alkylating agent include formic acid and complex metal hydrides such as sodium cyanoborohydride; reducing agents which are generally used in a separate, subsequent process step, i.e. reduction of a previously formed imine (Schiff's base) include diborane and complex metal hydrides such as sodium borohydride and sodium cyanoborohydride, which are preferably added.

II

is added to the primary reaction mixture without isolation of the intermediate, e.g. imine. In this case, the alkylation is preferably carried out in an organic solvent inert to the reducing agent, such as an aliphatic or cyclic ether (e.g. diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran) or an aliphatic alcohol such as , isopropyl alcohol, glycol, glycol monomethyl ether or diethylene glycol), preferably at about 10-80 ° C. However, an important reducing agent that can be used both simultaneously and afterwards is hydrogen, especially catalytically activated hydrogen. Catalysts are usually used as hydrogenation catalysts, namely preferably noble metal catalysts (such as palladium-15, platinum and rhodium) on a support (such as calcium carbonate, alumina or barium sulphate), as a finely divided suspension without support or in the form of complexes in homogeneous form. Fine transition metals, e.g. Raney metals, in particular Raney-Nikke-20 li, are also particularly suitable for the reductive alkylation of catalysts. The particular reaction conditions depend to a large extent on the hydrogenation catalyst used in each case and its precise activity, and do not differ from the conditions normally used for hydrogenation. According to standard methods of the prior art, temperatures between room temperature - about 150 ° C and hydrogen pressure between atmospheres - about 300 atmospheres are useful. In addition to the inert solvents mentioned above in connection with the hydride reduction, lower molecular amides, in particular tertiary amides (such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone, hexamethylphosphorus) formamide and acetamide are also suitable as solvents. In the case of starting materials of the formula (II) which contain an easily reducible functional group, such as the 5-oxo group, must certain factors be taken into account? 16 7 60 7 4 Selective reduction conditions must be used to preserve these groups, as is known in the art, or when simultaneous reduction of these groups is desirable or necessary, energetically reactive substances and / or conditions are used.

The above-mentioned first-formed imines are preferably prepared by condensing an amine of formula (II) with a compound of formula (IV) in an inert solvent, e.g. toluene or methylene chloride, primarily a dehydration catalyst, e.g. boron trifluoride etherate, p-toluene sulphonyl acid.

Process b) is preferably carried out in the presence of very strong bases, such as alkali metal hydrides (e.g. sodium or potassium hydride), alcoholates (e.g. sodium methylate or ethylate, potassium tert-butylate) or amides (e.g. lithium diisopropylamide), wherein the above-mentioned ethers and amides are most suitable as solvents. In a particular embodiment of process b), starting materials are used in which R 1 represents hydrogen and at least two equivalents of the compound of formula (IIIB) involved in the reaction are used. In the resulting product, both residues and Rg are identical and have the same meaning as Rg.

In each alkylation process, the primary and secondary amino groups in the starting materials, with the exception of the secondary amino group to be alkylated, must be in a temporarily protected form during the alkylation. Suitable protecting groups and methods for their attachment and cleavage are set forth in the prior art Level 30a, which has been developed in detail, in particular as general methods for synthesizing peptides, cf. Houben-Weyl: Methoden der organischen Chemie, 4. Ausgabe, Band 15/1 und II, E. Wiinsch (publisher): Synthese von Peptiden (Georg Thieme-Verlag, Stuttgart, 1974). The closer choice of protecting groups depends in particular on their function, in which case it is necessary to take into account in particular the specific properties of the starting materials used in each case and the reaction conditions of each process. When the functional groups to be protected are different, preferred combinations can be selected. Preferably, e.g., identical or better-identical amino protecting groups are used at both residues Rq and also at the residue and are cleaved off simultaneously at the end of the alkylation.

Suitable amino-protecting groups are, in particular, amino-protecting groups which can be removed by reduction, such as, in particular, protecting groups of the benzyloxycarbonyl type, in which the benzyloxycarbonyl group can be substituted in the aromatic part by halogen atoms, bromooxy and lower alkoxy groups and / or lower alkyl radicals. -, p-methoxy-sibenzyloxycarbonyl, p-methylbenzyloxycarbonyl and especially p-nitrobenzyloxycarbonyl group or alternatively isonicotinyloxycarbonyl group. A preferred amino protecting group is an ethoxycarbonyl group containing a silyl group substituted at the β-position by three hydrocarbon residues, such as triphenylsilyl, dimethyl-tert-butylsilyl or especially trimethylsilyl. This type of β- (trihydrocarbylsilyl) -ethoxycarbonyl group, such as the β- (trialempalkylsilyl) -ethoxycarbonyl group, e.g. in particular β- (trimethylsilyl) -ethoxycarbonyl- ), which can only be cleaved off under very specific, very mild conditions by fluoride ions.

It is also possible to use groups which can be cleaved off by acidolysis, such as tert-butoxycarbonyl groups and the like, as well as aralkyl-type groups, such as benzhydryl, di- (4-methoxy) benzhydryl and triphenylmethyl (trityl) or Certain aralkoxycarbonyl groups of the 2- (p-biphenylyl) -2-propoxy-35 cyclocarbonyl type, as disclosed in CH Patent 509 266. It should be noted that in most cases the protecting groups derived from carbonic acid esters are also subjected to basic hydrolysis. cleavable.

For optional temporary protection of hydroxy groups, protecting groups which can be cleaved off by reduction can be advantageously used, cf. the above text (Houben-Weyl) and also groups that can be removed by acidolysis such as 2-tetrahydropyranyl, tert-butoxycarbonyl and tert-butyl. Preferred hydroxy protecting groups which can be cleaved off by reduction are, for example, benzyl groups which in the aromatic moiety may be substituted by halogen, lower alkyl, lower alkoxy and / or especially nitro, in particular a 4-nitrobenzyl group. It is also possible to use acyl groups which can be cleaved off under weakly basic conditions such as formyl or trifluoroacetyl.

In the optional protection of oxo groups, these groups are preferably protected as ketals, in particular ketals derived from lower alkanols, such as methanol or ethanol, or preferably as ketals derived from ethylene glycol or corresponding thioketals, preferably ketals derived from 1,2-ethanedithiol. All of these groups can be converted to free oxo groups under the conditions set forth below.

Subsequent cleavage of the protecting groups according to the invention depends on the nature of the groups and is carried out in a conventional manner known per se, in which case the general properties of the products formed must be taken into account. When the protecting groups for the amino, hydroxy and oxo groups are selected so that they can be cleaved off under similar conditions (especially in this case, the acid-lytic or, in the case of amino and hydroxy groups, reducing groups which are already cleavable, which are already mentioned in detail) are preferred) , cleaving all such protecting groups, preferably in one process step; However, in specific cases, it is possible to use different

II

19 7 60 7 4 types of groups and each is split off separately.

Groups which can be cleaved off by reduction, in particular those containing all types of halogenated lower alkyl residues (e.g. 2,2,2-trichloro-5 ethyl residues), isonicotinyl residues (e.g. isonicotinyl-oxycarbonyl) and in particular substituted benzyl residues before, nitrobenzyl residues, preferably cleaved off by reduction with zinc, usually in the presence of an acid, preferably acetic acid, and with or without the addition of 10 inert organic solvents, usually at room temperature. Cleavage of the protecting group by acid hydrolysis (acidolysis) is carried out in the case of tert-butyl-type groups with hydrogen chloride, hydrogen fluoride or trifluoroacetic acid, and in the case of acid-sensitive protecting groups mainly with a lower aliphatic polyhydric carboxylic acid such as formic acid and / or formic acid. or in the presence of a lower alkanol such as 1,1,1,3,3,3-hexafluoropropan-2-ol or hexafluoroacetone. In this way, for example, it is possible to cleave off the N-trityl group with an organic acid, such as formic acid, acetic acid, chloroacetic acid or trifluoroacetic acid in aqueous or absolute trifluoroethanol, which acts as a solvent (cf. DE-25 23 46 147) or aqueous acetic acid, trifluoroacetic acid or hydrochloric acid and a 2- (p-biphenylyl) isopropoxycarbonyl group with aqueous acetic acid or, for example, a mixture of glacial acetic acid, formic acid (strength 82.8%) and water (7: 1; 2) or by the method described in DE- 23 46 147. The β-silylethyl ester groups are preferably cleaved off with a fluoride ion generating reagent, for example fluorides of a quaternary organic base such as tetraethylammonium fluoride.

The oxo groups, which are ketals or thioketals, are cleaved into free oxo groups by acidolysis with ordinary strong inorganic acids or oxalic acid in the presence of water, the latter protecting groups preferably being treated with a sulfur-binding agent, e.g. mercury or cadmium salt. Protecting groups which are unstable under basic conditions, for example formyl, trifluoroacetyl and carbonic acid ester groups, can be carefully removed by aqueous sodium or potassium carbonate or carbonate solution or also by aqueous ammonia in an organic Liu-10 solvent, usually at room temperature. The protecting groups are preferably cleaved off under the reaction conditions of the examples or the like.

The final products according to the invention which contain basic groups are obtained, depending on the method of isolation, in the form of bases or acid addition salts. Similarly, products containing acidic groups can also be obtained in the form of salts. Each shape can be changed to another in a known manner. The bases can be obtained from acid addition salts in a manner known per se. From the bases, on the other hand, it is possible to obtain acid addition salts, in particular therapeutically useful acid addition salts, by reaction with acids, for example the salt-forming acids mentioned above. Acids and their salts change with each other in the same proportion. Compounds containing a free carboxy group as well as a basic group may be in the form of internal salts, and these are obtained, for example, by adjusting the solution to an isoelectric point.

Starting materials of formulas (IIIA), (IIIB) and (IV), i.e. alkylating agents, are known or, if unknown, can be prepared in a simple manner according to customary synthetic methods.

The starting materials of formulas (II) and (V) can be obtained according to conventional synthetic methods and preferably in the manner set forth and illustrated in detail below in connection with specific intermediates.

Il 21 76074

Process c), which also involves an alkylation reaction, is carried out in accordance with the same general considerations and under the same experimental conditions as methods a) and b) above, as detailed above for the treatment of formulas (IIIA), (IIIB) or (IV). alkylating agents (namely, substitutive alkylation or reductive alkylation). The starting materials of the formula (VI) can be prepared by a conventional method known per se, e.g. as described in more detail below. The amines of the formula are known or, when new, can be obtained simply by customary synthetic methods.

Process d) is also carried out in the usual manner under conventional solvolysis conditions, which are characterized in that they convert cyanides (nitriles) to free carboxylic acids or their salts or esters.

When converted to the free acid, it is most preferred to carry out the hydrolysis with water in an inert, organic solvent which is at least partially miscible with water, such as ethers (e.g. diethyl or diisopropyl ether, 1,2-dimethoxyethane or especially dioxane or tetrahydrofuran), or lower alkanols. (e.g. methanol, ethanol, isopropyl alcohol, butyl alcohol, especially tert-butyl alcohol), in which case a larger amount of water is required to prevent alcoholysis. Hydrolysis can be catalyzed by both strong acids, in particular inorganic acids such as sulfuric acid or preferably hydrohalic acids (e.g. hydrobromic acid or above all hydrochloric acid) as well as bases, in particular inorganic bases such as alkali metal hydroxides and carbonates, e.g. sodium hydroxide and e.g. The bases are usually used in at least stoichiometric proportions, with the carboxylic acid salt forming the primary product. Acid catalysts are used in the form of a dilute aqueous solution to obtain the best result. The final products of formula (I) in which Rq represents an esterified carboxyl group can be obtained by carrying out the solvolysis of the nitrile with the corresponding alcohol (alcoholysis) using a catalytic amount of anhydrous strong acid, preferably hydrogen chloride in gaseous form. Excess alcohol is usually used as a solvent, however, inert, organic solvents such as acyclic or cyclic ethers (especially those mentioned above) and / or halogenated lower alkanes (especially chloroform and dichloromethane) may be added. When the alcoholysis is performed under absolutely anhydrous conditions, the primary product (imidoester) must be hydrolyzed, preferably by adding water to the reaction mixture. On the other hand, when the alcoholysis is performed using an almost stoichiometric equivalent of water, the desired ester is obtained directly.

The starting materials of formula (VIII) can be obtained according to conventional methods known per se, e.g. by condensation according to method c), wherein the starting material of formula (VI) as defined above is treated with an amine of formula (VII1) i / R1

Rc - NH - CH (VII ') 5 ^ CN 1 2 3 4 5 6 11 wherein and R2 are as defined above and correspond to 2 amines of formula (VII) as defined above. Methods a) and b) can also be used in a similar manner to prepare nitriles of formula 4 (VIII).

5

The cyclization corresponding to process variant e) can also be carried out in a manner known per se, e.g. as a dehydrate. Particularly useful methods for this purpose have been developed in connection with the formation of an amide bond of peptides, as described in compilations, e.g., Houben 23 7 6 0 7 4

Weyl, Volume 15/1 and Volume 15/11, as already outlined above. According to a preferred modification, the amino group to be cyclized is made inactive by protonation (i.e. converted to the acid addition salt form) and the carboxyl group converted to the Akti-5 ointment ester, e.g. with compounds such as 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-fluorophenol or in particular 4-nitrophenolyl, or an N-hydroxy compound such as N-hydroxysuccinimidyl, 1-hydroxybenztriazole or N-hydroxypiperidine-10 or alternatively N, N'-disubstituted isourea, such as in particular N, N'-dicyclohexyl -isourea or a similar, generally known activating agent. The cyclization is carried out by basifying the reaction mixture, preferably by adding an organic base such as a quaternary ammonium salt or especially a tertiary amine such as triethylamine, N-ethylmorpholine or N-methylpiperidine to reactivate the cyclizable amino group to a non-converting moiety. The reaction temperature is usually -20 to + 50 ° C, preferably close to room temperature, and ordinary solvents are used, e.g.

dioxane, tetrahydrofuran, acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphosphoric acid trisamide, and chloroform and methylene chloride, and mixtures thereof. In a particular variant of the process, the carboxy group can be activated directly in situ by the action of the free acid together with a carbodiimide such as Ν, Ν'-dicyclohexylcarbodiimide (optionally at the same time N-hydroxysuccinimide, unsubstituted or substituted by halogen, methyl or nitro, for example hydroxybenztriazole or 4-hydroxybenzo-1,2,3-triazine-3-oxide or N-hydroxy-5-norbornene-2,3-dicarboximide) or in combination with N, N'-carbonyldiimidazole.

The starting materials of the formula (IX) can be prepared by general methods known per se, e.g. as shown in the following specific examples.

The reduction corresponding to method f) can also be carried out in a manner generally known for the saturation of such double bonds. In particular, in the unsaturated starting materials corresponding to formula (I), there may be a double bond between carbon atoms C-3 and C-4 or between carbon atom C-3 and an adjacent nitrogen atom or between a nitrogen atom and an adjacent carbon atom in a group. Saturation of the double bond is preferably carried out by catalytic hydrogenation, for example as detailed above, under preferred conditions as well as by metal reduction such as zinc reduction in a neutral or acidic medium or especially in the case of a CN double bond with diborane or complex hydrides, sodium borohydride, as described above. The unsaturated starting materials for these process variants are obtained according to generally known methods, e.g. according to methods a) and c) and / or in a special form, as described below.

In carrying out the optional conversion of the final product of formula (I) obtained into another compound of formula (I) within the meaning of the above definitions, this conversion takes place as follows:

The symbol X, which represents a hydroxyl group (plus hydrogen), is converted by reduction into two hydrogen atoms, and / or the free hydroxyl or carboxyl group is liberated from their esterified form by hydrolysis or hydrogenolysis, and / or the free carboxyl is esterified.

All of these optional changes are performed according to well-known conventional methods.

To carry out the esterification, the carboxyl group can be reacted directly with a diazoalkane, in particular diazomethane, or a corresponding alcohol in the presence of a strong acid catalyst (e.g. sulfuric acid or organic sulfonic acid) and / or in the presence of a dehydrating agent (e.g. dicyclohexylcarbodiimide). Exchange-

II

Conditionally, the carboxyl group can be converted to its reactive derivative, such as the active ester or mixed anhydride mentioned in process e), e.g. with an acid halide (especially acid chloride) or trifluoroacetic acid, and this activated intermediate is reacted with the desired alcohol.

The free carboxyl group can be liberated from the esterified carboxyl in a generally known manner, especially with a base-catalyzed hydroxyl. Of particular interest, however, are methods suitable for the selective release of a particular carboxyl group represented by the symbols -COR6 and -COR7. In such a case, a suitable combination of ester groups can be used, which are known in the art, in particular as carboxyl-protecting groups, and which have been developed to a greater extent, in particular for the synthesis of peptides, cf. Houben-Weyl, Volume 15/1 and Volume 15/11, as set forth above. Suitable residues for the selective cleavage of the carboxyl group are esters derived, for example, from alcohols which produce residues which can be removed by acidolysis, such as tert-butyl alcohol, but in particular from alcohols which produce cleavable residues, such as benzyl alcohol.

The cleavage of the esterifying groups depends on their nature and is carried out each time in the usual manner known per se, taking into account the properties of the other residues involved. The groups which can be cleaved off by reduction, in particular benzyl residues, are cleaved off preferably by reduction with zinc, usually in the presence of an acid, preferably acetic acid and with or without the addition of an inert organic solvent, usually at room temperature. They are also removed by the hydrogenolysis technique commonly used for benzyl groups.

Removal of the ester group by acid hydrolysis (acidolysis) can be carried out in the case of tert-butyl-type groups with hydrogen chloride, hydrogen fluoride or trifluoroacetic acid. Ester groups which are unstable under basic conditions can be carefully removed by rapid addition of aqueous sodium or potassium bicarbonate solution or, preferably, aqueous ammonia in an organic solvent, usually at room temperature. The ester groups are preferably cleaved off under the reaction conditions set forth in the Examples or the like.

The appropriate combination of ester groups can be selected in the previous steps of the synthesis or by selecting the appropriate starting materials and reactants, e.g. in process a) the selectively cleavable ester group is coupled with a carboxyl which is liberated in the last step.

The compounds of formula (I) in general and the compounds of formula (IA) in particular are preferably prepared according to reaction sequence 1, which comprises the appropriate selection of starting materials and intermediates and the following steps: a) a compound of formula (XI)

pl ** O

R 3 where R 31 and R 4 'represent hydrogen, lower alkoxy or halogen, X 1 represents two hydrogen atoms or simultaneously with the hydrogen atom hydroxy, and R 8 represents amino, azido or acylamino, e.g. lower alkanoylamino or alkoxycarbonylamino, is condensed under basic catalytic conditions , with a compound of formula (III'B) is R '-CH-COR' (III * B) 2 I 7 z wherein R 2 'is hydrogen or lower alkyl, Z is reactively esterified hydroxy and R 1' is hydroxy , di- (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy, b) The intermediate obtained is optionally reduced, hydrogenolysed, hydrolysed or alkylated to give a compound of formula (II) ') is y · V j (Γ jT V NH2 (II ·.) R ~' I °

3 CH

/ R 2 'co-r 7' wherein R 1 ', R 4' and X 'are as defined in formula (XI), R 2' is hydrogen or lower alkyl and R 1 'is hydroxy, amino, mono- or di- (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkano-15-yloxymethoxy, di- (lower alkylamino) lower alkoxy or lower alkoxycarbonyl (lower) alkoxy, c) The compound of formula (II ') above is condensed under reductive alkylation conditions. of formula (IV)

O

R, 1 -C-COR, 1 (IV) 16 76074 28 wherein P .. | 'means hydrogen or phenyl (lower) alkyl and Pg' means hydroxy, di- (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy, or the compound of formula (II ') above is condensed under alkylation conditions with a compound of formula (ΙΙΙΆ) R 1'-CH-COR,' (III'A) wherein R 1 'and R 8' have the same meaning as in formula (IV) and Z represents reactively esterified hydroxy.

d) Optionally, the resulting product is hydrolyzed or derivatized, e) A compound of any of formula (IA) is converted to another compound of the invention.

Compounds of formula (XI) are obtained from the corresponding, optionally substituted and / or derivatized 2,3,4,5-tetrahydro-1H- (1) benzazepin-2-ones (J. Chem. Soc. 1937, 456; GB- Patent 1,359,285, Liebig's Annalen der Chemie, 574, 171 (1951). The novel starting (1) benzazepin-2-ones converted to suitable derivatives are preferably prepared by Beckmann rearrangement of the corresponding derivatives of naphthalen-1-ones using methods known in the art and illustrated above.

Tetrahydro- (1) benzazepin-2-ones are converted to 3-halo-25, e.g. 3-chloro-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one under the conditions illustrated above, e.g., by treatment with phosphorus pentachloride and finally hydrogenation. Substitution of this halogen derivative with a metal azide, e.g. sodium azide, and possible reduction or substitution with ammonia and possible acylation give compounds of formula li 29 7 6 0 7 4 (XI).

Alternatively, compounds of formula (XI) wherein Rg is amino and acylamino are obtained by reduction and cyclization of an appropriately substituted and / or derivatized 4- (o-nitrophenyl) -2-aminobutyric acid and optionally finally N-alkylation. casting or N-acylation.

Another synthesis of the optically active compounds of the invention starts from natural tryptophan.

In particular, L-4- (o-aminophenyl) -4-oxo-2-aminobutyric acid (L-kynurenine, J.Am.Chem.Soc. 76, 1708 (1954) derived from L-tryptophan) is converted to the optically active formula (XI) wherein acylamino, e.g. 3- (S) -tert-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- (1) benzazepine-2,5-dione, as shown in the Australian Journal of Chemistry 33, 633-40 (1980). The lactam alkylation of a compound of formula (XI) with a reagent of formula (III1B) well known in the art is preferably carried out with 20 bases such as alkali metal hydrides, e.g. sodium or potassium hydride, alkali metal alcoholates, e.g. potassium tert-butylate or sodium , in the presence of organometallic reagents, e.g. lithium diisopropylamide under phase transfer catalysis conditions, e.g. in the presence of tetrabutyl-25 ammonium salt, preferably in a solvent, e.g. tetrahydrofuran, dimethylformamide, at a temperature of preferably about 0 to 75 ° C.

Condensation of an intermediate of formula (II ') with a known α-keto acid derivative of formula (IV) 30 (cf. Chem. Ber. 31, 551, 3133) by reductive N-alkylation is carried out under conditions known in the art, e.g. using catalytic hydrogenation with hydrogen. in the presence of a platinum, palladium or nickel catalyst or with chemical reducing agents such as simple or complex light metal hydrides, preferably an alkali metal cyanoborohydride such as sodium cyanoborohydride. The reductive amination is carried out with an alkali metal cyanoborohydride, preferably in an inert solvent, e.g. methanol or acetonitrile, preferably in the presence of an acid, e.g. hydrochloric acid or acetic acid, at a temperature of 0 to 50 ° C, preferably at room temperature.

Alkylation of the intermediate amine of formula (II ') with a reagent of formula (III'A) well known in the art is performed using basic catalysts such as triethylamine or potassium carbonate with or without an inert solvent.

The compounds of formula (I) in general and the compounds of formula (IA) in particular can also be prepared according to reaction series 2 and 3.

Series 2 comprises the following steps: a) a compound of formula (XII) is r4 'X' r5 · (r ^ 'NH (XII) VH ° wherein R ^', R ^ 'and X' have the same meaning as in formula (XI ) and R 1 'is hydrogen are condensed under reductive alkylation conditions with a compound of formula (IV) R 1' - C-CO-R 8 '(IV) 2 O wherein R 1' and R 8 'are as defined above, or under alkylation conditions with a compound of formula (III'A) is R. '-CH-COR,' '(IIIΆ) z wherein R 1', R 9 'and Z are as defined above, to give compound 76074 31, of formula (V) is IV X * r.

.4 K5 R · - \ r / Ki p I YN-CH (V »), (^ CO-R 'r' · HO 6 where R ^ ', Rj', R ^ ', Rs' / Rg' and X * have the same meaning as above, b) the compound of formula (V) obtained is condensed, under 5-base catalysis conditions, with a compound of formula (III'B) R'-CH-COR '(III'B)

Z

wherein R 2 '/ R 2' and Z have the same meaning as above, c) optionally hydrolysing or derivatizing the product obtained, d) optionally converting any compound of formula (I) obtained into another compound of the invention.

Series 3 comprises the following steps: a) a compound of formula (VII1) is R5 "R-1" HN - CH - COR "(VII ·) D1 wherein R1" is hydrogen or phenyl- (lower) alkyl;

Rg "means hydrogen and Rg" means hydroxy, di- (lower) alkylamino, lower alkoxy, aryl (upper) alkoxy, 76074 32 lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy, condensed under reductive alkylation conditions with a compound of formula VI ) is vx "ΓΤ% γ <vi,) V CH 0 R 1" CO-R 7h 5 wherein R 2 "represents hydrogen or lower alkyl, F 3" and R 2 "represent hydrogen, lower alkoxy or halogen, X" means two hydrogen atoms or one hydrogen atom and etherified or esterified hydroxy, R 1 "represents hydroxy, dialkoxyalkoxy, aryl- (lower) alkoxy, loweralkanoyloxymethoxy or loweralkoxycarbonyl- (lower) alkoxy and Y represents oxo or dichloro, or a compound of formula (VII ') is condensed with a compound of formula (VI1) as defined above, wherein X "represents oxo, Y represents hydrogen and reactively esterified or etherified hydroxy, or with a 3,4-dehydro-elimination product of this compound or a compound thereof with a 3,4-dehydro derivative, b) the product obtained is optionally reduced, hydrolysed or derivatized, c) any compound obtained is optionally converted into another compound of the invention.

In series 2 and 3 above, lactam alkylation, reductive N-alkylation, and alkylation of amines are preferably performed under the conditions set forth in Method 1.

In the above reaction series 1, 2 and 3, for example, the compounds of formulas (ΙΙΙ'Α), (ΙΙΙ'Β) and (VII ') can be used.

II

33 76074 the reactants are replaced by the corresponding nitriles, e.g. R 2'CH (Z) CN, R 1'CH (Z) CN or R 1 NHCH (R 2 ') CN. The nitriles thus obtained can be converted into the corresponding carboxylic acids of formula (I) as hindrances using methods known in the art.

The starting materials of formula (VII ') refer to amino acids and derivatives known in the art. It is worth mentioning that optically active compounds of the invention can be prepared starting from an optically active compound of formula (VII '), e.g. L-α-aminophenylbutyric acid, L-phenylalanine and their derivatives.

When using compounds of formulas (ΙΙΙΆ), (III'B), (IV) and 15 (VII1) in which R 1, R 8 or R 11 represent hydroxy, a suitable carboxylate salt may be prepared, preferably in situ, before reaction with the above-mentioned desired intermediate. condensation.

Certain expressions 20 used in the above methods have the meanings defined below.

Reactively esterified hydroxy group means one which has been esterified with a strong, inorganic or organic acid, in particular a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid or p-toluene.

Etherified hydroxy preferably means lower alkoxy, e.g. methoxy, ethoxy or tert-butoxy.

Optional reduction, hydrogenolysis, hydrolysis steps or the step of derivatizing the starting materials of the disclosed process and converting the resulting product to another compound of the invention is accomplished by chemical procedures known in the art and illustrated herein.

6 76074 34

Compounds of formula (I) or (IA) wherein R

and / or R 1 represents lower alkoxy or phenyl- (lower) alkoxy, to compounds of formula (I) or (IA) in which R 1

O

and / or R 1 represents hydroxy, is preferably carried out by hydrolysis with inorganic acids such as hydrohalic acids or sulfuric acid or aqueous alkalis, preferably alkali metal hydroxides such as lithium or sodium hydroxide.

Selective conversion of compounds of formula (I) or (IA) in which R 1 to 15 and / or R 2 represents α-phenyl- (lower) alkoxy, benzyloxy to compounds of formula (I) or (IA) in which R 9 and / or R 2 represents hydroxy, preferably carried out by hydrogenolysis, using hydrogen in the presence of a catalyst, e.g. palladium.

Compounds of formula (I) or (IA) wherein both

Rg and R1 represent hydroxy may be converted to monocarboxylic acids of formula (I) or (IA) wherein one of R8 and R1 represents hydroxy. Such modification is accomplished by selective hydrolytic or hydrogenolytic methods well known in the art and depending on the chemical nature of the R and R substituents.

The free carboxylic acids of the formula (I) or (IA) in which R 9 and / or R 2 represent hydroxy, or their salts, can be esterified with suitable alcohols or their reactive derivatives well known in the art, corresponding mono- or di-esters, that is, to prepare compounds of formula (I) or (IA) wherein R 9 and / or R 2? means lower alkoxy or phenyl (Alem-35 pi) alkoxy.

Il 76074 35

Compounds of formula (I) or (IA) and intermediates therefor, e.g. compounds of formulas (X) and (V) in which X or X 'represents oxo, may be converted to the corresponding compounds in which X or X' represents a hydrogen atom and hydroxy group, by reduction, e.g. by catalytic hydrogenation, e.g. with hydrogen in the presence of a platinum catalyst or with a metal hydride reducing agent such as sodium borohydride. The resulting compounds in which X or X 'represents a hydrogen atom and a hydroxy group can be converted into compounds in which X or X' represents two hydrogen atoms, e.g. by catalytic hydrogenation of a carbodiimide adduct, e.g. an adduct formed when a compound wherein X or X 'represents a hydrogen atom and a hydroxy group, is condensed with dicyclohexylcarbodiimide in the presence of copper (I) chloride according to the general method described in Chem. Ber., 107, 1353 (1974).

Alternatively, compounds in which X or X 'represents a hydrogen atom and a hydroxy group may first be converted to the corresponding compounds in which X or X' represents a hydrogen atom and an acyloxy group (e.g. acetoxy), and then, e.g. by catalytic hydrogenation in the presence of a palladium catalyst, reduced to , where X or X 'represents two hydrogen atoms.

The above reactions are carried out according to standard methods in the presence or absence of diluents, preferably those inert to and reactants with reactants, further reactions are carried out in the presence or absence of catalysts, condensing agents or other substances, and / or in inert atmospheres. , at reduced temperatures, at room temperature, preferably at the boiling point of the solvent used, at atmospheric pressure or above.

36 76074

The invention encompasses all variations of the process disclosed herein in which the intermediate compound is used as a starting material at any stage and the remaining steps are performed, or the process is stopped at any stage, or the starting materials are formed under reaction conditions or the reaction components are used in the form of their salts or optically pure antipodes. In principle, the starting materials from which the compounds mentioned above are particularly valuable must be used in each case.

The invention also relates to novel starting materials and methods for their preparation.

Depending on the choice of starting materials and methods, the novel compounds may be in the form of a possible isomer or mixtures thereof, for example depending on the number of asymmetric carbon atoms, the compounds may be pure optical isomers such as antipodes or mixtures of optical isomers such as racemates or diastereoisomers.

The resulting mixtures of diastereoisomers and mixtures of racemates can be separated into the pure isomers, diastereoisomers or racemates in a known manner on the basis of the physicochemical differences of the components, e.g. by chromatography and / or fractional crystallization.

The racemates obtained can be further separated into the optical antipodes by methods known per se, for example by recrystallization from an optically active solvent, by microorganisms or by reacting the acidic end product with an optically active racemic acid with a salt-forming base, and separating the salts thus obtained. solubilities, into diastereoisomers from which antipodes can be liberated by appropriate agents. Basic, racemic products can be similarly separated into antipodes, e.g., by separation of their diastereoisomeric salts, e.g., by fractional crystallization of their d- or ε-

II

37 76074 tartrates. Any racemic intermediate or starting material can be isolated in the same manner.

It is more appropriate to isolate the more active from the two antipodes.

Finally, the compounds of the invention are obtained either in free form or in the form of their salts. Any base obtained can be converted to the corresponding acid addition salt, preferably a pharmaceutically acceptable acid or anion exchange preparation is used, or the resulting salts can be converted to the corresponding free bases, for example using a stronger base such as a metal or ammonium hydroxide or a basic salt, e.g. alkali metal hydroxide or carbonate, or cation exchange preparation. A compound of formula (I) wherein Rq represents carboxy or a compound of formula (IA) wherein CORg and / or COR1 represents carboxy may also be converted to the corresponding metal or ammonium salt. These or other salts, for example picrates, can also be used to purify the resulting bases. The bases are converted to salts, the salts are separated and the bases are liberated from the salts. Since the free compounds and the compounds in the form of their salts are very similar, it is to be understood in the context of the compound always disclosed in this specification that the corresponding salt is also meant, if possible or suitable under the given conditions.

The compounds, including their salts, may also be obtained in the form of their hydrates or may contain other solvents used for crystallization.

The pharmaceutical preparations of the invention are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including humans, in the treatment or prevention of diseases dependent on angiotensin converting enzyme inhibition, e.g. cardiovascular diseases, and such as hypertension. congestive heart defects, and which contain 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.

38 7 6 0 7 4

The following examples illustrate the invention without, however, limiting it in any way. Temperatures are given in degrees Celsius (° C) and all parts given are by weight. Unless otherwise stated, all evaporations are performed under reduced pressure, preferably at about 15 to 100 mm Hg.

In compounds of formula (I) or (IA) having more than one center of asymmetry, the diastereoisomeric compounds obtained in the examples containing these compounds are denoted by the letters A, B, etc. Each diastereoisomeric compound is characterized by physical properties, e.g. by melting point, chromatographic. distance (R 2) and spectral values obtained in infrared or nuclear magnetic resonance measurements.

In compounds of formula (I) or (IA) in which X 15 represents H 2 and the center of asymmetry is located in the side chain of the carbon atom to which the nitrogen atom is attached, symbols A and B are assigned to the respective isomer as follows, based on their relative chromatographic distance. Based on the distances obtained in thin layer chromatography and normal phase high pressure liquid chromatography, using silica gel as stationary phase, denote the fast-forwarding isomer as isomer A and the slow-progressing isomer as isomer B. the advancing isomer as isomer A and the rapidly advancing isomer as isomer B.

Example 1: 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one (higher melting isomer)

A solution of 3-aminocarboxymethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (10.0 g) and benzyl pyruvic acid ethyl ester (26.4 g) in acetic acid ( 75ml) and methanol (75ml), is stirred under a nitrogen atmosphere at room temperature for one hour. Then to the reaction mixture

II

39 7 6 0 7 4 Sodium cyanoborohydride (3.4 g) in methanol (25 ml) is added dropwise over 4 hours and stirred for 24 hours at room temperature. To the mixture is added dropwise conc. hydrochloric acid (4 ml), stirred for 1 hour at room temperature and evaporated to dryness. The residue is extracted into 150 ml of water and 50 ml of ether and the pH is adjusted to 9 with 40% aqueous sodium hydroxide solution. The layers are separated and the ether layer is discarded. The pH of the aqueous layer is adjusted to conc. hydrochloric acid to pH 10 4.3 and extracted with 3 x 75 ml of ethyl acetate.

The organic extracts are dried over magnesium sulfate and evaporated to dryness. The crude product is dissolved in 310 ml of methylene chloride and hydrogen chloride gas is bubbled into this solution for 5 minutes. The solution is evaporated and the residue is taken up in 225 ml of ether. The product is filtered. A diastereomeric mixture of 70:30 is obtained, which is determined by high-performance liquid chromatography. The product is recrystallized from ethanol / ethyl acetate (1: 3). 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,20-tetrahydro-1H- (1) benzazepin-2-one hydrochloride is obtained, melting at 246-248 ° ( decomposed) and corresponds to the racemic isomer B.

A solution of the hydrochloride salt obtained above (0.9 g) and propylene oxide (10 ml) in ethanol (150 ml) is stirred for 18 hours under a nitrogen atmosphere. The solution is evaporated to dryness and the residue is dissolved in 3 ml of ethanol. Ether (75 ml) is added, which precipitates a small amount of the above hydrochloride. The filtrate is evaporated to dryness, stirred with ether / petroleum ether (1: 9) and the solid is filtered off. 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 139-141 °. This is a compound of formula (IB) wherein C H- is ethylene, R 1 n zn o is ethoxy, R 1 is hydroxy and R 8 is phenyl, the higher melting, racemic isomer B.

76074 40 '

Separation with an optically active amine under standard conditions and resolution of the diastereomeric salts gives pure enantiomers, e.g. 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -5,3,4,5-tetrahydro-1H- (Example 12). l) benzazepin-2-one.

When high pressure liquid chromatography (hereinafter referred to as high pressure liquid chromatography) is used, the isomer passes through a reverse phase column (solvent system: methanol / water (3: 1) containing 0.025% acetic acid). B faster than the lower melting isomer A of Example 5.

The starting material, 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, is prepared as follows: A mixture of 2,3,4,5-tetrahydro -1H- (1) benzazepin-2-one (48.3 g; see Briggs et al., J. Chem. Soc. 1937, 456), phosphorus pentachloride (188 g) and xylene (1300 ml) are heated at 90 ° under nitrogen. (oil bath) within 30 minutes, while stirring. Heating is performed with a pause at 30 ° (allowing the phosphorus pentachloride to dissolve) and at 50 °. Abundant hydrogen chloride is formed. The temperature is maintained at 90 ° for 30 minutes. The reaction mixture is filtered hot to remove a small amount of suspended solid and the filtrate is evaporated to dryness under reduced pressure. The residue is poured, with stirring, into saturated aqueous sodium carbonate solution (100 ml). When the product has cured, it is filtered, then slurried in ethanol (150 ml), washed with ethanol (50 ml) and ether (50 ml) and dried. 3,3-Dichloro-2,3,4,5-tetrahydro-1H-1-benzazazin-2-one is obtained, melting at 185-187 °.

A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-1 benzazepin-2-one (20 g, 0.174 mol) and anhydrous sodium acetate (15.4 g, 0.188 mol) in glacial acetic acid (920 ml ), Is hydrogenated at atmospheric pressure using 5% palladium on carbon catalyst (1.72 g) until hydrogen consumption ceases. catalase

II

The lysator is filtered off and the acetic acid is evaporated off under reduced pressure. The residue is partitioned between 10% sodium hydrogen carbonate solution (900 ml) and dichloromethane (300 ml). The aqueous layer (pH 8) is further extracted with dichloromethane (3 x 300 mL). The combined extracts are dried over anhydrous sodium sulfate and evaporated. 3-Chloro-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 163-167 °.

A solution of 3-chloro-2,3,4,5-tetrahydro-1H- (1) -10 benzazepin-2-one (15.9 g, 0.08 mol) and sodium azide (6.36 g, 0 , 10 moles) in dimethyl sulfoxide (320 mL) is maintained at 80 ° for 3 hours under a nitrogen atmosphere. In this case, the sample taken has a strong maximum in the IR spectrum at 2150 cm -1, which is characteristic of the azide group. The reaction mixture is poured into 1000 ml of ice water and the suspension is stirred for 30 minutes. The solid is filtered, washed with water (250 ml) and dried. 3-Azido-2,3,4,5-tetrahydro-1H- (s) -benzazepin-2-one is obtained, melting at 142-145 °.

A solution of 3-azido-2,3,4,5-tetrahydro-1H- (1) -20 benzazepin-2-one (8.7 g, 0.043 mol) in dry dimethylformamide (75 ml) is added. within 1 minute to a stirred suspension of sodium hydride (prepared from 60% mineral oil dispersion (1.9 g)}, washed with petroleum ether (3 x 150 mL) in dry dimethylformamide 25 (250 mL) at 0 ° under nitrogen. Stirring is continued for 1.5 hours, then bromoacetic acid benzyl ester (10.8 g, 0.047 mol) in dry dimethylformamide (75 ml) is added over 45 minutes, keeping the temperature at 0 °. The reaction mixture is then stirred for a further 18 hours, during which time it is warmed to room temperature. The dimethylformamide is evaporated off under reduced pressure and the residue is partitioned between water (500 ml) and dichloromethane (500 ml). The aqueous phase is extracted with dichloromethane (3 x 500 ml). The combined extracts are dried over sodium sulfate and the solvent is evaporated off under reduced pressure.

The crude ester azide is obtained as an oil. This is dissolved in toluene (500 ml) and silica gel (48 g) is added. Filter and evaporate the solvent under reduced pressure to give 3-azido-1-benzyloxocarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one as an oil which is used crude in the next step of the synthesis.

A suspension of the active Raney nickel catalyst in water (15 mL) is washed with ethanol (5 x 100 mL) and added to a mechanically stirred solution of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5 -tetra-10 hydro-ΙΗ- (1) benzazepin-2-one (5.0 g) in ethanol (300 ml). The suspension is stirred for 8 hours under a nitrogen atmosphere at room temperature. The catalyst is filtered off and the solvent is evaporated off under reduced pressure. The residue is dissolved in 2N hydrochloric acid (200 ml) and the solution is extracted with ether (2 x 250 ml). The aqueous solution is basified (pH 9) with concentrated aqueous ammonia and the solution is extracted with ether (3 x 200 mL). The combined ether extracts are dried over sodium sulfate and evaporated under reduced pressure. 3-Amino-1-benzyloxy-20-carbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained as an oil which is used crude in the next step of the synthesis.

3-Amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one is also prepared as follows:

A solution of 3-amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (5.0 g; 0.028 mol) in dimethylformamide (100 ml) is added to a stirred suspension under nitrogen. with sodium hydride (prepared from a 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3 x 150 mL)) in dimethylformamide (400 mL) supplemented with tetrabutylammonium bromide (10 g; 0.031 mol). The reaction mixture is kept at 50 ° for 15 minutes, after which a solution of bromoacetic acid benzyl ester (7.2 g; 0.031 mol) in dimethylformamide (25 ml) is added. The reaction mixture is further stirred for 18 hours at 50 °, then cooled.

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43 76074 is brought to room temperature and the dimethylformamide is evaporated off under high vacuum. The residue is stirred with toluene / dichloromethane (1: 1, 500 ml) to precipitate inorganic salts. After filtration, the solution is evaporated under reduced pressure and the residue is chromatographed on silica gel (200 g). Elute with 0-15% acetic acid ethyl ester in toluene. The main product is 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one.

A solution of 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (1.3 g) in ethanol (250 ml) is hydrogenated at room temperature and atmospheric pressure. under pressure using 10% palladium on carbon (0.20 g) until hydrogen consumption ceases. The catalyst 15 is filtered off and the solvent is evaporated off under reduced pressure. A white foam (0.90 g) is obtained. This is triturated with ether to give 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one. Mp 147-150 °.

A solution of 3-azido-1-benzyloxycarbonyl-20-methyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (14.0 g; 0.04 mol) in ethanol (300 ml) , hydrogenated for 25 hours at 3.1 atmospheric pressure at room temperature using 5% palladium on carbon catalyst (2.0 g). The catalyst is filtered off and the solvent is evaporated off under reduced pressure. The residue is dissolved in water (500 ml) and the solution is extracted with dichloromethane (2 x 400 ml). The aqueous solution is filtered and evaporated under reduced pressure. The residue is dissolved in ethanol and the solution is evaporated under reduced pressure. The residue is redissolved in ethanol (50 ml) and evaporation is repeated. The residue is recrystallized from ethanol / ethyl acetate. 3-Amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 147-150 °.

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Example 2: 1-Benzyloxycarbonylmethyl-3- (1-carboxy-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H-f] -benzazepin-2-one Sodium cyanoborohydride (0.152 g; 0.0014 mol) 5 is added to a solution of 1-benzyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (0.45 g; 0.0014 mol) and pyruvic acid benzyl ester ( 0.48 g, 0.0028 mol) in methanol (35 ml). The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 2 hours to 10 hours. Thereafter, pyruvic acid benzyl ester (0.48 g; 0.0028 mol) is added again to the reaction mixture and stirring is continued for 18 hours. Add conc. hydrochloric acid (0.5 ml) and the resulting solution is stirred for 1 hour. The solvent is evaporated off under reduced pressure and the residue is taken up in dichloromethane (100 ml) to precipitate sodium chloride. The mixture is filtered, the solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel (30 g). Elution is performed with ethyl acetate / methanol / acetic acid (90: 10: 0.2). 1-Benzyloxycarbon-20-methylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained as an oil. NMR (CDCl 3) δ 7.35 (m, 14H), 5.10 (s, 2H), 4.60 (m, 2H), 3.00 (m, 12H).

Example 3: 1-Benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f) benzazepin-2-one

A solution of 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (0.364 g; 0.00075 mol), sodium bicarbonate (0.190 g; 0.0022 mol) and ethyl iodide (0.315 g; 0.002 mol) in dimethylacetamide (15 ml) are stirred under a nitrogen atmosphere at room temperature for 72 hours. The reaction mixture is filtered and evaporated under reduced pressure. Water (100 ml) is added and the resulting solution is extracted with dichloromethane (4 x 50 ml). The combined extracts are dried over rium sulphate and the solvent is evaporated off under reduced pressure. The diester is obtained as an oil. This material is separated by hplc into three fractions using ethyl acetate / toluene (30:70) as solvent.

The first fraction gives isomer A of the title compound as an oil. The second fraction contains a mixture of isomers A and B and the third fraction comprises isomer B of the title compound. When using a reversed phase column in hplc (solvent system: methanol / water (3: 1), containing 0.025% acetic acid), isomer A slower than isomer B.

Example 4: 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f] benzazepin-2-one (higher melting isomer)

A solution of 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one (Isomer B of Example 3; 9 g) in ethanol (150 ml), hydrogenated at room temperature and atmospheric pressure using 10% palladium on carbon catalyst (0.5 g). When the consumption of hydrogen ceases, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. A solid is obtained which is triturated with ether (8 ml). The title compound is obtained, melting at 138-140 ° and identical to the compound of Example 1.

Example 5: 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (benzazepin-2-one (lower melting isomer))

A solution of 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (Isomer A * 1 of Example 3, 2 g) in ethanol (125 ml), hydrogenated at room temperature 46 76074 and atmospheric pressure using 10% palladium on carbon catalyst (0.5 g). After the consumption of hydrogen has ceased, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. A solid is obtained which is triturated with ether (8 ml). 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 126-129 ° and lower melting racemic isomer A.

When a reversed phase column (solvent-10 system: roethanol / water (3: 1) containing 0.025% acetic acid) is used in hplcr, isomer A proceeds more slowly than the higher melting racemic isomer B which is the compound of Example 1.

Example 6: 1-Benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one

A solution of 3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (5.0 g) in dry dimethylformamide (20 ml) is added under nitrogen. -20 spheres to a stirred suspension of sodium hydride (prepared from a 60% mineral oil dispersion (0.6 g) washed with petroleum ether (3 x 75 mL)) in dry dimethylformamide (85 mL) containing tetrabutylammonium bromide (4.4 g). The reaction mixture is stirred for 30 minutes at room temperature, after which a solution of bromoacetic acid benzyl ester (3.2 g) in dry dimethylformamide (10 ml) is added. The mixture is further stirred for 30 minutes at room temperature, heated to 60 ° and kept at this temperature for 18 hours. The reaction mixture is cooled to 30 room temperature and the solvent is evaporated off under high vacuum.

Water (150 ml) is added and the resulting solution is extracted with ethyl acetate (2 x 250 ml). The combined acetic acid ethyl ester extracts were washed with water (100 ml), dried over magnesium sulphate and evaporated under reduced pressure. 35 brown oil is obtained, which is chromatographed on silica gel (150 g).

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47 7 6 0 7 4 and eluted with toluene / acetic acid ethyl ester (3: 1). First, isomer A of 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained.

Isomers A and B are identical to the compounds of Example 3, as can be seen on a reversed phase column (solvent system: methanol / water (3: 1), containing 0.025% acetic acid).

The starting material is prepared as follows: A solution of acetaminomalonic acid diethyl ester (33.2 g) in ethanol (150 ml) is added to a solution of sodium methoxide in ethanol (prepared from sodium (3.8 g) and ethanol (200 ml). )). The reaction mixture is stirred for 30 minutes at room temperature and a solution of 2-nitrophenylethyl bromide (J. Med. Chem. 20, 1020 (1977); 40.0 g) in ethanol (100 ml) is added dropwise over 15 minutes. At the end of the addition, the reaction mixture is refluxed for 18 hours, then cooled to room temperature and evaporated under reduced pressure. Residue 20 is dissolved in water (350 ml) and the solution is extracted with ethyl acetate (2 x 350 ml). The combined acetic acid ethyl ester extracts are washed with water (200 mL) and dried over magnesium sulfate. The solvent is evaporated off under reduced pressure. 2-Acetamido-2- (o-nitro-phenylethyl) -malonic acid-25-diethyl ester is obtained as a low melting solid which is used crude in the next step of the synthesis.

A solution of 2-acetamido-2- (o-nitro-phenylethyl) -malonic acid diethyl ester (80 g) in 3N hydrochloric acid (900 ml) is refluxed for 12-30 hours. The solution is cooled and extracted with ethyl acetate (200 ml). The aqueous solution is filtered and evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol / ether. 2-Amino-4- (2-nitro-phenyl) -butyric acid hydrochloride is obtained, melting at 219-221 ° 35 (decomposed).

48 7 6 0 7 4

A solution of 2-amino-4- (2-nitrophenyl) butyric acid hydrochloride (38 g) in 10% ethanolic hydrochloric acid (1200 ml) is refluxed for 18 hours. The reaction mixture is evaporated under reduced pressure, water (250 ml) is added and the aqueous solution is basified with 2N sodium hydroxide solution. The solution is extracted with dichloromethane (2 x 500 ml). The combined dichloromethane solutions are washed with water (2 x 150 mL) and dried over anhydrous sodium sulfate. After evaporation, 2-amino-4- (2-nitro-phenyl) -butyric acid ethyl ester is obtained, which is used crude in the next synthetic step.

A solution of 2-amino-4- (2-nitro-phenyl) -butyric acid ethyl ester (27 g) in ethanol (600 ml) was hydrogenated at room temperature and atmospheric pressure using a 10% palladium on carbon catalyst (2, 5 g) until hydrogen consumption ceases. The catalyst is filtered off and the solution is evaporated to dryness. 2-Amino-4- (2-aminophenyl) -butyric acid ethyl ester is obtained, which is used crude in the next synthetic step.

A solution of 2-amino-4- (2-aminophenyl) -butyric acid ethyl ester (35.0 g) in methanol (100 ml) is added, under stirring under nitrogen, to a solution of sodium methoxide in methanol (prepared from sodium). (1.0 g) and methanol (400 ml)). The reaction mixture is refluxed for 65 hours and evaporated under reduced pressure. The residue is partitioned between water (100 ml) and dichloromethane (400 ml). The aqueous solution is extracted with dichloromethane (400 ml). The combined organic solutions are washed with water (100 mL) and dried over magnesium sulfate. The solution is evaporated to dryness and the residue is triturated with ether (250 ml). 3-Amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 161-162 °.

In the second case, the following procedure can be followed: A solution of 2-amino-4- (2-nitrophenyl) butyric acid hydrochloride (2.5 g) in water (200 ml) is hydrogenated at room temperature and atmospheric temperature. under pressure, using a 10% palladium-on-carbon catalyst. After the consumption of hydrogen has ceased, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water (50 ml) and the pH is adjusted to 7 with 10% sodium hydroxide solution. The precipitate is filtered off, washed with water and dried. 2-Amino-4- (2-aminophenyl) butyric acid is obtained. A solution of 2-amino-4- (2-aminophenyl) butyric acid (1.0 g), hexamethyldisilazane (5.4 g) and chlorotrimethylsilane (0.1 g) in xylene 10 (125 ml) is refluxed for 65 hours. . The reaction mixture is cooled, poured into ethanol (200 ml) and evaporated under reduced pressure. Water (100 ml) is added and the solution is extracted with dichloromethane (2 x 125 ml). The combined dichloromethane solutions are washed with water (50 ml), dried over magnesium sulphate and evaporated under reduced pressure.

3-Amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained which is identical to the product obtained above.

3-Amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is also prepared as follows: To a solution of 3-azido-2,3,4,5-tetrahydro-1H- (1) -Benzazepin-2-one (see Example 1) (27 g) in ethanol (3500 ml) is added, under a nitrogen atmosphere at room temperature, with stirring, a suspension of Raney nickel in water (50 ml, washed with 10 volumes of ethanol). The mixture is stirred at room temperature for 2 hours, after which a further 30 ml of Raney nickel suspension are added. The mixture is further stirred for 30 minutes, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. An oil is obtained which solidifies after addition of ether. 3-Amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 161-162 °.

A solution of 3-amino-2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one (8.0 g) and benzylpyruvic acid (450 ml) is stirred under a nitrogen atmosphere at room temperature. minutes. Sodium cyanoborohydride (4.5 g) is added and the resulting solution is stirred for 48 hours at room temperature. To the mixture is added dropwise over 10 minutes conc. hydrochloric acid (7 ml) and stir for a further 1 hour. The reaction mixture is evaporated to dryness, dichloromethane (150 ml) is added and the mixture is stirred for 30 minutes. The solid is filtered, stirred with water (100 ml) for 15 minutes, then filtered, washed with water (50 ml) and dried. 3- (1-Carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained as a mixture of isomers. Mp 173-175 °.

A solution of 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (6.0 g), sodium hydrogen carbonate (4, 0 g) and ethyl iodide (11.6 g) in dimethylacetamide (200 ml), stirred for 72 hours under nitrogen at room temperature, filtered and evaporated under high vacuum. The residue is dissolved in water (250 ml) and the resulting solution is extracted with dichloromethane (2 x 400 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. 3- (1-Ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-20 (1) benzazepin-2-one is obtained as a mixture of isomers. NMR (CDCl 3) δ 9.22 (s, 1H), 4.10 (2 overlapping quartets, 2H), 1.13 (2 overlapping triplets, 3H).

Example 7: 1-Benzyloxycarbonylmethyl-3- (1-benzyloxycarbonyl-2H-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one

A solution of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (4.0 g) in dry dimethylformamide is added under a nitrogen atmosphere. to a stirred suspension of sodium hydride (60% mineral oil suspension (0.42 g), washed with petroleum ether (3 x 80 ml)) in dry dimethylformamide (100 ml) mixed with tetrabutylammonium bromide (3.1 g) at room temperature. The mixture is allowed to react for a further 30 minutes at room temperature, followed by addition

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A solution of bromoacetic acid benzyl ester (2.2 g) in dry dimethylformamide (10 ml) is added. The solution is allowed to stand for 30 minutes at room temperature, after which it is heated to 50 ° and kept at this temperature for 5 to 18 hours. The mixture is cooled to room temperature and the solvent is evaporated off under high vacuum. The residue is dissolved in water (150 ml) and the solution is extracted with ethyl acetate (2 x 300 ml). The combined acetic acid ethyl ester solutions are washed with water (100 ml), dried over magnesium sulphate and evaporated under reduced pressure. A brown oil is obtained which is chromatographed on silica gel (250 g). Elution is performed with toluene / ethyl acetate (1: 1; 600 ml) to give an oil which is the isomer A of the title compound, NMR (CDCl 3) δ 5.12 (s, 4H), 4.50 (q, 2H). Further elution with 2000 ml of solvent mixture gives an oil which is isomer B of the title compound. NMR (CDCl 3) 65.17 (s, 2H), 5.03 (d, 2H), 4.60 (q, 2H).

The starting material is prepared as follows: A solution of 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (as shown in Example 6) 13.0 g), sodium hydrogen carbonate (10.0 g) and benzyl broride (19.0 g) in dimethylacetamide (750 ml) are stirred at room temperature under nitrogen for 7.2 hours. The reaction mixture is filtered and evaporated under high vacuum. The residue is dissolved in water (150 ml) and the resulting solution is extracted with dichloromethane (2 x 400 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulphate and evaporated under reduced pressure. The crude benzyl ester is obtained. Recrystallization from acetic acid ethyl ether gives 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, melting at 139-141 ° .

52 76074

Example 8: 1-Carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f) benzazepin-2-one (lower melting isomer) 5 A solution of 1-benzyloxycarbonylmethyl-3- (1-Benzyloxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one (Isomer A of Example 7; 2.7 g) in ethanol (800 ml), hydrogenated at room temperature and at atmospheric pressure, using 10% palladium on carbon-10 catalyst (0.5 g). After the consumption of hydrogen has ceased, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. There is obtained a diacid (title compound) which is isomer A, m.p. 256-259 °.

The identical compound is obtained by hydrolysis of the compound of Example 15.

Example 9: 1-Carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one (higher melting isomer) 20 A solution of 1-benzyloxycarbonylmethyl-3- (1 -benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (isomer B * 5.0 g of Example 7) in ethanol (950 ml), hydrogenated at room temperature and atmospheric pressure. under pressure, using palladium on carbon-25 catalyst (0.5 g). After uptake of hydrogen, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. The above-mentioned diacid (title compound), which is isomer B, m.p. 280-282 °.

The identical compound is obtained by hydrolyzing the compound of Example 30 1 (isomer B) or the compound of Example 10 (isomer B).

Example 10: 1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one Solution of 3 - (- ethoxycarbonyl-3- phenylpropyl-35-amino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (see

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53 7 6 0 7 4 Example 6; 3.0 g) in dry dimethylformamide (10 ml) is added dropwise at room temperature, under a nitrogen atmosphere, over 10 minutes to a stirred suspension of sodium hydride (prepared from a 60% suspension of mineral oil 5 (0.26 g) washed with petroleum ether (3 x 75 ml)). ) as in dimethylformamide (100 ml). The mixture is further stirred for 30 minutes, a solution of bromoacetic acid ethyl ester (1.4 g) in dimethylformamide (15 ml) is added and the mixture is kept at 60 ° for 48 hours. The reaction mixture is cooled to 10 room temperature and the solvent is evaporated off under high vacuum.

Water (100 ml) is added to the residue and the solution is extracted with ethyl acetate (2 x 200 ml). The combined extracts are washed with water (50 ml), dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. A yellow oil (3.8 g) is obtained. This is chromatographed on silica gel (120 g) and eluted with toluene / ethyl acetate (1: 1; 250 ml). Isomer A of the desired product is obtained. Further elution with 250 ml of a solvent mixture gives an oil.

This consists mainly of isomer B, 20 of the desired product, containing a small amount of isomer A, as can be seen by analytical hplcs (see Example 6). Further elution with 250 ml of solvent mixture gives an oil which is practically pure isomer B (slower progressing). This material is dissolved in methanol (25 mL) and converted to the maleate salt by adding an equivalent amount of maleic acid in methanol. Evaporation of the solvent and recrystallization of the residue from methanol / ether gives pure isomer B of 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one. melting at 114-116 °.

Example 11: 1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-1H-f) benzazepin-2-one

A solution of 1-benzyloxycarbonylmethyl-3-35 benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-54 7 6 0 7 4 (1) benzazepin-2-one (4.8 g? 0.01 mol) in ethanol (550 mL), hydrogenated at room temperature and atmospheric pressure using 5% palladium on carbon catalyst (0.85 g) until hydrogen consumption ceases. Water (300 ml) is added to the mixture, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. The residue is triturated with ether. The title compound (diacid) is obtained, melting at 232-236 °.

The starting material is prepared as follows: A solution of 3-amino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (5.0 g; 0.028 mol) in dimethylformamide (100 ml) is added. to a stirred suspension of sodium hydride (prepared from a 60% suspension of mineral oil (1.2 g) washed with petroleum ether (3 x 150 ml)) in di-15-methylformamide (400 ml) supplemented with tetrabutylammonium bromide (10.9 ml). g; 0.031 mol). The reaction mixture is kept at 50 ° for 15 minutes, after which a solution of benzoate of bromoacetic acid (7.2 g; 0.031 mol) in dimethylformamide (25 ml) is added. The mixture is further stirred for 20 to 18 hours at 50 °, then cooled to room temperature and the dimethylformamide is evaporated off under high vacuum. The residue is stirred with toluene / dichloromethane (1: 1 to 500 mL) to precipitate inorganic salts. After filtration, the solution is evaporated under reduced pressure. The residue is chromatographed on silica gel (200 g) and eluted with 0-15% ethyl acetate in toluene. 1-Benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained as the first fraction. Further elution gives 3-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, m.p. 124-127 ° and 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (see Example 1).

Il 55 76074

Example 12: 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one By treating 3 (S) -amino-1-carboxymethyl 2,3,4,5-5 Tetrahydro-ΙΗ- (1) benzazepin-2-one with benzylpyruvic acid ethyl ester in the presence of sodium cyanoborohydride (as shown in Example 1 for the racemic compound) and purification as follows gives 1-carboxymethyl-3S- (1S -ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-10 tetrahydro-ΙΗ- (1) benzazepin-2-one:

A solution of sodium hydroxide (2.1 g) in water (5 ml) is added at room temperature to a solution of 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (14.0 g) in methanol (150 mL) and Liu-15 buy is stirred for 2 hours. The solvent is evaporated off, the residue is carefully dried and slurried with ether. 3-S-Amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one sodium salt is obtained, which is used without further purification.

A solution of the above sodium salt (12.9 g) and benzylpyruvic acid ethyl ester (31 g) in acetic acid (100 ml) and methanol (75 ml) is stirred under a dry nitrogen atmosphere at room temperature for 1 hour. A solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) is then added dropwise over 4 hours. The combined solutions are stirred overnight at room temperature and added dropwise to conc. hydrochloric acid (10 ml).

The mixture is stirred at room temperature for one hour and evaporated. The residue is partitioned between water (400 ml) and ether 30 (100 ml) and the pH is adjusted to 9.3 with 40% sodium hydroxide solution. The layers are separated and the ether layer is discarded. The pH of the aqueous layer is adjusted to conc. with hydrochloric acid to 4.3 and extracted with ethyl acetate (3 x 100ml). The organic phases are combined, dried over magnesium sulphate and evaporated. The crude product is dissolved in methylene chloride (150 ml) and treated with hydrogen chloride for 5 minutes. The solvent is evaporated and the resulting foam is dissolved in hot methyl ethyl ketone (100 ml). The precipitated precipitate is filtered off. A diastereomeric mixture of 95: 5 is obtained, as can be seen by hplc. The product is recrystallized from 3-pentanone / 5 methanol (10: 1). 1-Carboxymethyl-3 (S) - (1 (S) -ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride, m.p. 188-190 °; (a) D = -141.0 ° (c = 0.9 in ethanol), which is a compound of formula (IIa) wherein CnH2n is ethylene, Rg is ethoxy, hydroxy and Rg is phenyl.

A solution of the above hydrochloride (0.035 g) and propylene oxide (0.5 ml) in ethanol (4 ml) is stirred at room temperature under nitrogen overnight. The solution is evaporated to dryness, ether (2 ml) is added and the precipitate is filtered off. 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 148-149 °. (a) D = -159 ° (c = 1.2 in ethanol).

The optically active starting material is prepared as follows: a) A solution of 0.4 g of 3 (S) -t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- (1) benzazepine-2, 5-Dione (prepared from L-kynurenine according to the method of Australian J. Chemistry, Vol. 33, 633-640 (1980)) and ethyl bromoacetate (0.23 g) in dry tetrahydrofuran (30 ml) are stirred at 0 °: in a dry nitrogen atmosphere. Potassium tert-butoxide (0.254 g) is added in one portion, the mixture is allowed to stand for 1 hour at 0 °, then more ethyl bromoacetic acid (0.23 g) is added and stirred at 0 ° for a further hour. . Water (100 ml) is added to the reaction mixture and extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulphate and evaporated under reduced pressure. A yellow solid is obtained which, after trituration with ether-petroleum ether (b.p. 30-60 °), gives 3 (S) -t-butyl

II

57 76074 oxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepine-2,5-dione, m.p. 86-88 °.

(a) D = -203 ° (c = 1 in dimethylformamide).

A solution of 3 (S) -t-butyloxycarbonylamino-1-5 ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepine-2,5-dione (0.14 g) and sodium borohydride (7 mg) in ethanol (10 ml), stirred for 18 hours at room temperature. The ethanol is evaporated off under reduced pressure and the residue is dissolved in dichloromethane (25 ml). The solution is extracted with 2N hydrochloric acid (2 x 20 ml) and saturated aqueous sodium chloride solution (20 ml) and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the residue is triturated with ether. 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonyl-15-methyl-5-hydroxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 167-169.5 ° :in. (α) β = -193 ° (c = 0.52 in dimethylformamide). This compound is also obtained by hydrogenation of the benzazepine-2,5-dione derivative with H 2 / Pt in ethanol.

A mixture of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (0.076 g), dicyclohexylcarbodiimide (0.064 g) and copper (I) chloride (7 mg) are heated under nitrogen at 60 ° for 32 hours. The reaction mixture is allowed to cool to room temperature. The residue is dissolved in methylene chloride (50 ml) and washed first with dilute ammonium hydroxide (2 x 15 ml) and then with water (20 ml). The organic phase is dried over sodium sulfate and evaporated. A mixture of the desired adduct and excess di-cyclohexylimide is obtained.

The latter mixture (0.100 g) is dissolved in acetic acid ethyl ester (40 ml) and placed in a pressure vessel. 10% Palladium on carbon catalyst (0.010 g) is added and the mixture is hydrogenated for 16 hours at 40 ° and atmospheric pressure.

35 The catalyst is filtered off and the filtrate is evaporated.

The residue is triturated with ether and the ether solution is evaporated. 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 115-116.5 °. (° D = 182 ° (c = 2.6 in dimethylformamide).

5 b) Tartaric acid (12.6 g) and racemic 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (22 g) are dissolved in hot ethanol ( 200 ml). This solution is cooled and allowed to stand at room temperature overnight. The precipitate obtained is filtered off and recrystallized twice from ethanol (200 ml). 3 (S) -Amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one tartrate salt is obtained. This is dissolved in water (100 ml), the pH is adjusted to 9 with dilute ammonium hydroxide and extracted with methylene chloride (2 x 50 ml). The combined extracts are washed with water (75 ml), dried over magnesium sulphate and evaporated. 3 (S) -Amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 104-106 °. (° D = 285.5 ° (c = 0.99 in ethanol)).

C) To a solution of the compound obtained in 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one (a) above ; 0.225 g) in acetic acid ethyl ester (25 ml), first with hydrogen chloride gas for 45 minutes and then with nitrogen for 30 minutes. The ethyl acetate is washed with water (30 ml) and 1N hydrochloric acid (30 ml). The acetic acid-ethyl ester layer is discarded and the aqueous phases are combined. The pH of the aqueous solution is adjusted to 9 with dilute ammonium hydroxide, extracted with ethyl acetate (3 x 50 mL). The organic phases are combined, dried over sodium sulfate and evaporated. 3 (S) -Amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 101-102 °. (° D = 298 ° (c = 0.46 in ethanol)).

The protecting groups are cleaved off by treatment with ethanediol-35 thiol / boron trifluoride etherate or trifluoroacetic acid / anisole. 3 (S) -Amino-1-ethoxycarbonylmethyl

II

76074 2,3,4,5-Tetrahydro-1H- (1) benzazepin-2-one.

3 (S) -Amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one is also prepared as follows: 5 d) A solution of 3 (S) ) t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (compound above; 1.0 g) in acetic anhydride (20 ml ) is maintained at 80 ° for 3 hours. The reaction mixture is cooled to room temperature and evaporated under reduced pressure. Ether (100 ml) is added to the residue, the resulting solution is washed with water (500 ml) and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure. 5-Ethoxy-3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benz-15-azepin-2-one is obtained in the form of a colorless oil which is used without further purification.

A solution of 5-ethoxy-3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1H-benzazepin-2-one (0.7 g) in ethanol (50ml), hydrogenated for 24 to 20 hours at 70 ° and 2.9 atmospheric pressure using a 10% palladium on carbon catalyst (0.5 g), the catalyst is filtered off and the solvent is evaporated off under reduced pressure to give 3 (S) -t -butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, modified, crude, according to the above procedure, 3 (S) -amino-1-ethoxycarbonylmethyl -2,3,4,5-tetrahydro-β- (1) benzazepin-2-one, mp 99-101 °, (a) D = -297 (c = 1 in ethanol).

e) A solution of 3 (S) -t-butyloxycarbonylamino-2,3,4,5,5-tetrahydro-1H- (1) benzazepine-2,5-dione (12.5 g) is prepared from L-kynurenine in Australian J. Chemistry Vol. 33, 633-640 (1980), and bromoacetic acid tert-butyl ester (10.1 g) in acetone (700 ml) is stirred at room temperature under a dry nitrogen atmosphere. Potassium carbonate (12.5 g) is added in one portion and the resulting suspension is stirred for 16,76074 hours at room temperature. The potassium salts are filtered off and the filtrate is evaporated to dryness. The residue is partitioned between acetic acid ethyl ester (250 ml) and water (250 ml). The layers are separated and the organic phase is dried over sodium sulfate.

5 The residue is triturated with petroleum ether (350 ml; boiling point 30-60 °). 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) -benzazepine-2,5-dione is obtained, m.p. 75-77 °. (a) D = -172 ° (c = 0.96 in dimethylformamide).

A solution of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) -benzazepine-2,5-dione (8.0 g) in ethanol (500 ml), hydrogenated for 2 hours at atmospheric pressure and room temperature, using platinum oxide (800 mg). The catalyst is filtered off and the filtrate is evaporated. 3 (S) -t-butyloxycycarbonylamino-tert-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, (a) D = -173 ° (c = 1.8 in dimethylformamide).

A suspension of 3 (S) -t-butyloxycarbonylamino-20-n-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-β- (1) benzazepin-2-one (3 .0 g), dicyclohexylcarbodiimide (5.0 g) and copper (I) chloride (500 mg), are mechanically stirred and heated to 80 ° in a dry nitrogen atmosphere for 16 hours. The mixture is cooled, diluted with methylene chloride (100 mL) and filtered. The solid is discarded. The filtrate is washed with 7% ammonium hydroxide (4 x 75 mL), then 1 x 100 mL of water and saturated aqueous sodium chloride solution (100 mL). The organic phase is dried over sodium sulfate and evaporated. A mixture of the desired adduct and the excess dicyclohexylcarbodiimide is obtained.

This mixture (5.5 g) is dissolved in ethyl acetate (200 ml), placed in a pressure vessel, 10% palladium-on-carbon catalyst (3.0 g) is added and hydrogenated for 16 hours at 40 ° at 35 and 3 atmospheres. The catalyst is filtered off and the filtrate is evaporated. The residue is triturated with ether

II

61 76074 (75 ml). A white solid is obtained which is 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, m.p. 145-147 °, (° D = 194 ° (c = 0.46 in dimethylformamide).

A solution of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one (compound shown above; 3.0 g) in acetic anhydride (50 ml), heated at 80 ° for 2 hours in a dry nitrogen atmosphere. The acetic anhydride is evaporated, the residue is dissolved in ethyl acetate (75 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic phase is dried over sodium sulfate, evaporated and the residue is triturated with ether (50 ml). There is obtained 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, m.p. 164-166.5 °, (a) D = -169 ° (c = 0.36 in dimethylformamide).

Solution of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-β- (1) benzazepin-2-one (2.2 g ) in ethanol (300 ml) is placed together with 10% palladium on carbon catalyst 25 in a pressure vessel. The mixture is hydrogenated for 3 days at 70 ° and 3 atmospheres. The catalyst is filtered off and the filtrate is evaporated. 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 164-165 °, (a) D = -200.6 ° 30 (c = 0.64 in dimethylformamide).

To a solution of 3 (S) -t-butyloxycarbonylamino-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one (0.85 g) in ethyl acetate (40 ml), hydrogen chloride gas is introduced for 2 hours and then nitrogen for 35 minutes. The ethyl acetate is evaporated and the residual white substance is immediately dissolved in methanol (40 ml). Propylene oxide (5 ml) is added and the mixture is stirred for 16 hours at room temperature. The white substance obtained as a precipitate is filtered off. 3 (S) -Amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 275-276 °, (a) D = -287 ° (c = 0.71 in 1N hydrochloric acid). This product is condensed, as described above, with benzylpyruvic acid ethyl ester in the presence of sodium cyanoborohydride.

Example 13; 10 1-Carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -5-hydroxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one

To a solution of 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,5-dihydro-1H- (1) benzazepine-2,5-dione (1.00 g) in acetic acid (50 ml ), 15 platinum oxides (0.10 g) are added. The mixture is hydrogenated in a pressure vessel for 5 hours at 2.9 atmospheric pressure. The catalyst is filtered off, the filtrate is evaporated and the oil obtained is triturated with anhydrous ethanol. The resulting solid is separated, dried and suspended in water (10 ml). The suspension is stirred for 1.5 hours, the solid is separated and dried. There is obtained crude 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -5-hydroxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, melting 179 ° while decomposing.

The starting material is prepared as follows: Bromoacetic acid benzyl ester (9.16 g, 0.04 mol) is added dropwise at room temperature, with stirring, to a mixture of 3-methoxy-2,5-dihydro-1H- (1) benzazepine. -2,5-dione (8.13 g; 0.04 mol; prepared as described in Canadian J. Chem., 52, 610 (1974)), powdered potassium hydroxide (2.24 g; 04 moles) and tetrabutylammonium bromide (1.29 g; 0.004 moles) in 1000 ml of acetonitrile. When the addition is complete, the suspension is stirred for 64 hours at room temperature, filtered and the filtrate is concentrated under reduced pressure. A partially crystallized oil is obtained.

35 This is triturated with ether to give a solid mother 76074 63 ne. This is suspended in ethyl acetate (100 ml) and stirred for 1.5 hours. The insoluble matter is filtered off and the filtrate is concentrated. Crude 1-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro-1H- (1) benzazine-5-siline-2,5-dione is obtained, which is used directly in the next step.

To a 1.0 molar solution of potassium tert-butoxide (0.64 g; 0.0057 mol) in tert-butanol (5.7 ml) under nitrogen was added at room temperature, while stirring, 10 (+) - homophenylalanine (1, 02 g; 0.0057 moles) in one portion. The resulting suspension is heated with tert-butanol (4.3 mL) until most of the solid to be suspended dissolves. After cooling, a suspension is obtained. This suspension is added portionwise, using a 15 pipette, over 10 minutes at reflux to a boiling solution of 1-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro-1H- (1) benzazepine-2,5- dione (2.00 g) in tert-butanol (40 ml). A yellow precipitate forms during the addition. When the addition is complete, the resulting suspension is refluxed for 3 hours, after which it is filtered. The resulting gummy solid was washed with petroleum ether and dissolved in water (20 mL). The solution is filtered and the pH is adjusted to 5 with 3N hydrochloric acid. The crude 1-benzyloxy-25-carbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,5-dihydro-1H- (1) benzazepine-2,5- the dione is isolated and used directly to prepare the title compound.

Example 14:

According to methods analogously shown, the following compounds of formula (IA) are prepared in which X = H 2, Ra and R 5 = H, R 6 = OC 2 H 5 and R 7. = OH: 64 76074

Well. ^%

1 C6H5CH2 H H

2 C6H5CH2CH2 7-OCH3 8-OCH3

3 C6H5CH2CH2 7-C1H

5 4 C6H5CH2CH2 8_CH3 H

5 C6H5CH2CH2 8-OCH3 H

6 p-ClC6H4CH2CH2 H H

7 CH3 H H

The substituted 2,3,4,5-10 tetrahydro-ΙΗ-1 benzazepin-2-one starting materials used for compounds 2-5 are prepared as follows: 7-chloro-2,3,4,5-tetrahydro-1H- (1 ) benzazepin-2-one, m.p. 164-165 °, prepared as described in British Patent 1,359,285.

8-Methyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is prepared by the method of Huisgen,

Liebigs Ann. Chem. 574, 171 (1951). Mp 153-154 °.

7,8-Dimethoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is prepared as follows: To prepare an oxime, a solution of 24 g of 6,7-dimethoxy-α-tetralone (Snider, T. et al., Org. Prep. Proced. Int., 5, 291 (1973)) in ethanol (300 ml) and water (60 ml) are refluxed for 2 hours with hydroxylamine hydrochloride (16 g) and sodium hydroxide. (25 g). The reaction mixture is poured into 25,500 ml of ice / water and extracted with 3 x 300 ml of dichloromethane. The combined extracts are washed with 200 ml of water, dried over anhydrous magnesium sulphate and evaporated. 25 g of oxime are obtained, melting at 154-156 °.

The oxime, in turn, is dissolved in dichloromethane (170 ml) and polyphosphate ester (170 ml) is added (Fieser and Fieser: Reagents for Organic Synthesis, Wiley N.Y. 1967, p. 892). The reaction mixture is refluxed for 18 hours. The di-65 76074 chloromethane layer is separated, treated with activated carbon and dried over magnesium sulfate. 7,8-Dimethoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 153-156 °.

8 8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one, m.p. 132-134 °, is prepared in a similar manner starting from 7-methoxy-α-tetralone.

3-Amino-7-chloro-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is prepared as follows: A solution of 10 is 3-amino-2,3,4,5 -tetrahydro-1H- (1) benzazepin-2-one (4.0 g), 2-tert-butyloxycarbonyloxyimino-2-phenylacetonitrile (6.1 g) and triethylamine (5 ml) in water (20 ml). ) and dioxane (25 ml) are stirred at room temperature for 18 hours. The resulting precipitate is filtered and washed with water. Recrystallize from ethyl acetate to give 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one, m.p. 199-201 °.

A solution of 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (1.5 g) in acetic acid (20 ml) is bubbled with hydrogen chloride for 10 minutes.

The reaction mixture is further stirred for 10 minutes. The precipitate is separated, suspended in water (30 ml) and basified with aqueous ammonia. After filtration, 3-amino-7-chloro-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained which melts at 170-171 °.

Example 15: 1-Carboxymethyl-3S- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H-flibenzazepin-2-one

A solution of 3 (S) -amino-1-carboxymethyl-2,3,4-5,5a, 6,7,8,9,9a-decahydro-1H- (1) benzazepin-2-one sodium salt (0.6 g) and benzylpyruvic acid ethyl ester (1.5 g) in acetic acid (5 ml) and methanol (3 ml) are stirred under a dry nitrogen atmosphere at room temperature for 1 hour. A solution of sodium cyanoborohydride (0.2 g) in methanol (2 ml) is added over 4 hours. The reaction mixture is stirred for 18 hours at room temperature. Add conc. hydrochloric acid and stir the mixture for 1 hour. The solvent is evaporated off under reduced pressure and the residue is extracted into water (20 ml) and ether (20 ml). The pH is adjusted to 9.3 with 40% sodium hydroxide solution. The layers are separated and the ether layer is discarded. The pH of the aqueous phase is adjusted to conc. hydrochloric acid to 4.3 and extracted with acetic acid-5 ethyl ester (3 x 25 mL). The extracts are dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The residue is dissolved in dichloromethane (70 ml) and hydrogen chloride gas is bubbled into the solution for 5 minutes. The solution is evaporated and the residue is recrystallized from ethanol / ether.

10-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- (1) benzazepine is obtained. -2-one hydrochloride as a mixture of isomers.

The starting material is prepared as follows:

A solution of 3 (S) -t-butyloxycarbonylamino-1-15 ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepine-2,5-dione (3.6 g) in acetic acid ( 50 ml), hydrogenated for 120 hours at 3 atmospheres, using platinum oxide (1.2 g) as catalyst. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is extracted into dichloromethane (200 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml). The dichloromethane solution is washed with water (50 ml), dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel, eluting with 25-50% ethyl acetate. The fractions eluted with 50% ethyl acetate in toluene are combined. 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- (1) benzazepine-2,5 -dione, which is used crude in the next synthetic step.

A solution of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- (1) benzazepine-2,5- dione (2.7 g) and sodium borohydride (0.2 g) in ethanol (100 ml) are stirred for 18 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is dissolved in dichloromethane (100 ml). Solution

II

67 76074 is extracted with ice-cold 2N hydrochloric acid (2 x 50 ml) and saturated aqueous sodium chloride solution (50 ml) and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the residue is triturated with ether. 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- (1) benzazepin-2-one is obtained .

A mixture of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5,5a, 6,7,8,9,9a-10 decahydro-1H- (1) benzazepine -2-one (2.1 g), dicyclohexylcarbodiimide (1.8 g) and copper (I) chloride (0.2 g) are heated under nitrogen at 80 ° for 32 hours. The reaction mixture is cooled to room temperature, the residue is dissolved in methylene chloride (200 ml), washed with dilute ammonium hydroxide solution (2 x 50 ml) and water (50 ml). The organic phase is dried over sodium sulfate and evaporated. A mixture of the desired adduct and excess dicyclohexylcarbodiimide is obtained. This mixture is dissolved in ethyl acetate (100 ml) and placed in a pressure vessel. 10% Pd / C catalyst (0.4 g) is added and the mixture is hydrogenated at 40 ° and 3 atmospheres for 16 hours. The catalyst is filtered off and the filtrate is evaporated. 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a, 6,7,8-9,9a-decahydro-1H- (1) benzazepin-2-one is obtained, which used 25 crude in the next synthetic step.

The product obtained above (1.1 g) is dissolved in ethyl acetate (50 ml) and hydrogen chloride gas is introduced into the solution for 45 minutes. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in ethyl acetate (50 ml) and washed with water (3 x 30 ml). The ethyl acetate solution is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 3 (S) -Amino-ethoxycarbonylmethyl-2,3,4,5,52,6,7,8,9,92-decahydro-1H- (1) benzazepin-2-one is obtained, which is used crude in the following procedure or -35 heessa.

68 760 74

A solution of sodium hydroxide (0.1 g) in water (0.25 ml) is added at room temperature to a solution of the amine obtained above (0.6 g) in methanol (7.5 ml) and the solution is stirred for 2 hours. The solvents are evaporated off, the residue is carefully dried and slurried in ether. The sodium salt of 3 (S) -amino-1-carboxymethyl-2,3,4,5,5a, 6,7,8,9,9a-decahydro-1H- (1) benzazepin-2-one is obtained.

Example Nf 1- (1-Carboxymethyl) -2,3,4,5-tetrahydro-2-oxo-1H- [1] -10-benzazepin-3S-ylamino) -3-phenylpropyl-1-carbonyl] -L-phenylalanine L-phenylalanine methyl ester hydrochloride is condensed with 1-benzyloxycarbonylmethyl-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one in methylene chloride 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, at room temperature. Further work gives N- (1- (1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-2-oxo-1H- (1) benzazepin-3S-ylamino) -3-phenylpropyl-1-carbonyl) -L-phenylalanine methyl ester

Hydrogenation in ethanol using 10% Pd / C catalyst gives N- (1- (1-carboxymethyl-2,3,4,5-tetrahydro-2-oxo-1H- (1) benzazepin-3S-amino) -3-phenylpropyl-1-carbonyl) -L-phenylalanine methyl ester.

Hydrolysis with dilute sodium hydroxide solution at room temperature for 18 hours gives N- (1- (1-carboxymethyl-2,3,4,5-tetrahydro-2-oxo-1H- (1) benzazepin-3S-amino) - 3-phenylpropyl-l-carbonyl) -L-phenylalanine ketone.

Example 17: 1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one By treating 3- (1-carboxy- 3-phenylpropylamino) -l-cyanomethyl-2,3,4,5-tetrahydro-LH (l) benzazepin-2-one

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76074 69 with ethanol / ether (1: 1) saturated with hydrogen chloride for 48 hours at room temperature gives, after further reactions, 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2, 3,4,5-Tetrahydro-1H- (1) benz-5 azepin-2-one identical to the compound of Example 10.

The starting material is prepared as follows: 3- (1-Carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is alkylated with bromoacetonitrile-10 in dimethylformamide in the presence of sodium hydride. Further work-up gives 3- (1-carboxy-3-phenyl-propylamino) -1-cyanomethyl-2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one, which is used directly in the next step.

Example 18: 1-Carboxymethyl-3S- (1R-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one The 12-carboxymethyl-3S- The methyl ethyl ketone filtrate from the crystallization of (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride is evaporated and the residue is triturated. with acetic acid ethyl ester (50 mL). The solid obtained is partitioned between ethyl acetate (100 ml) and water (100 ml) and the pH is adjusted to conc. with hydrochloric acid to 4.3. The layers are separated and the aqueous phase is extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate solutions are dried over sodium sulfate and evaporated under reduced pressure. The residue is separated into its components by liquid chromatography (hplc) using a preparative C18 reverse phase column. Water / methanol (3: 7) containing 0.05% acetic acid is used as solvent. Thus, the S, S-isomer of Example 12 is further obtained and also the substance corresponding to the S, R-isomer, S, R-isomer is dissolved in dichloromethane (75 ml) and hydrogen chloride gas is introduced into the solution. The solvent is evaporated off under reduced pressure and the residue is recrystallized from methyl ethyl ketone. 1-Carboxymethyl-3S- (1R-5 ethoxycarbonyl-3-phenylpropylamino-2 / 3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride is obtained, mp 181-183 °, ( a) D = -188 ° (c = 0.8, in ethanol).

Example 19; 1-Carboxymethyl-3S- (1S-carboxy-3-phenylpropylamino) -10 2,3,4,5-tetrahydro-1H-f) benzazepin-2-one

To a solution of 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one hydrochloride (1 g) in methanol (10 ml), a solution of sodium hydroxide (0.27 g) in water (2 ml) is added. The reaction mixture is stirred for 18 hours at room temperature, after which it is evaporated under reduced pressure. The residue is dissolved in water (25 ml) and the pH is adjusted to 3 with 4N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried. 1-Carboxymethyl-20β-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-β- (1) benzazepin-2-one is obtained, melting at 270-272 °: in.

(&) q = -200.5 ° (c = 1.3 in aqueous ammonia).

Example 20; 1-Ethoxycarbonylmethyl-3- (1-benzyloxycarbonyl-3- (2-phenylpropylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one

A solution of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (5.0 g) in dry dimethylformamide is added under a nitrogen atmosphere. to a stirred suspension at room temperature of sodium hydride (prepared from a 60% dispersion of mineral oil (0.5 g), washed with petroleum ether (3 x 80 ml)) in dry dimethylformamide (100 ml). The mixture is further stirred at room temperature for 30 minutes, after which time

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71,76074 is added bromoacetic acid ethyl ester (2.0 g) in dry dimethylformamide (10 ml). The reaction mixture is further kept at room temperature for 30 minutes, after which it is heated to 50 ° and kept at this temperature for 18 hours. The mixture is cooled to room temperature and evaporated under high vacuum. The residue is dissolved in water (150 ml) and the solution is extracted with ethyl acetate (2 x 300 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulphate and the solvent is evaporated off under reduced pressure.

A brown oil is obtained which is chromatographed on silica gel (250 g), eluting with toluene / ethyl acetate (9: 1; 600 ml). An oil is obtained which is isomer A of the title compound. Further elution with 1000 ml of a solvent mixture gives an oil »which is isomer B of the title compound.

Example 21: 1-Ethoxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f] benzazepin-2-one 1-ethoxycarbonylmethyl-3- (1-benzyloxycarbonyl) -20 (1- (3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (Isomer B of Example 20; 1.1 g) is hydrogenated in ethanol (150 ml) at room temperature and at atmospheric pressure, using a palladium on carbon catalyst (0.5 g). When the consumption of hydrogen ceases, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. A semi-solid is obtained which is triturated with ether (30 ml). Isomer B of the title compound, m.p. 175-177 °.

Example 22: 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -8-methoxy-2,3,4,5-tetrahydro-1H-f) benzazepin-2-one (Isomer B)

A solution of 3-amino-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (4.0 g) and 72 7 6 0 7 4 benzylpyruvic acid ethyl ester (9.4 g) in a mixture of acetic acid (35 ml) and methanol (35 ml), stirred for one hour. A solution of sodium cyanoborohydride (1.1 g) in methanol (50ml) is then added slowly over 5 hours. 5 The mixture is further stirred for 16 hours, conc. hydrochloric acid (4 ml) and stir for another hour. The solvent is evaporated off under reduced pressure and the residue is partitioned between water (75 ml) and ether (35 ml). The pH is adjusted to 9.4, the ether layer is separated and discarded. The aqueous layer is adjusted to pH 4.3 and extracted with ethyl acetate (3 x 50 mL). The combined acetic acid ester solutions are dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The crude product is dissolved in methylene chloride (100 ml) and hydrogen chloride gas is bubbled into the solution for 5 minutes.

The solution is evaporated and the residue is taken up in ether (75ml). The product is filtered. A diastereomeric mixture of about 70:30 is obtained, as can be seen by hplc.

The product is recrystallized from 3-pentanone. 1-Carboxymethyl-8-methoxy-3- (1-ethoxycarbonyl-3-phenyl-20-propylamino) -2,3,4,5-tetrahydro-7H- (1) benzazepin-2-one hydrochloride (Isomer B) is obtained melting at 240-245 ° (decomposed).

The starting material is prepared as follows:

A solution of 8-methoxy-2,3,4,5-tetrahydro-1H- (1) -25 benzazepin-2-one (7.0 g; shown in Example 14) and phosphorus pentachloride (30.0 g) in xylene ( 200 ml), heated under a nitrogen atmosphere, with stirring, to 90 ° (oil bath temperature) over 30 minutes. Heating is performed with a pause at 30 ° and 50 °. During the lunar period, considerable hydrogen chloride gas is formed. The temperature is maintained at 90 ° for 30 minutes. The reaction mixture is filtered hot to remove a small amount of suspended solid and the filtrate is evaporated to dryness under reduced pressure. The residue is added, with stirring, to aqueous saturated sodium carbonate solution (20 ml).

Once the product has solidified, it is filtered, followed by it

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73 76074 is slurried in ethanol (30 ml), washed with ethanol (10 ml) and ether (10 ml) and dried. 3,3-Dichloro-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 148-150 °.

A solution of 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (20 g) and anhydrous sodium acetate (13.2 g) in glacial acetic acid (250 ml ), hydrogenated at atmospheric pressure using a 10% palladium on carbon catalyst (1 g) until hydrogen consumption ceases. The catalyst is filtered off and the acetic acid is evaporated off under reduced pressure. Water (100 ml) is added to the residue and the suspension is stirred for 1 hour. The solid is filtered, washed with water (50 ml) and dried. 3-Chloro-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 162-163 °.

A solution of 3-chloro-8-methoxy-2,3,4,5-tetrahydro-β- (1) benzazepin-2-one (12.5 g) and sodium azide (4.3 g) in dimethyl sulfoxide ( 150 ml), kept at 80 ° for 3 hours under a nitrogen atmosphere. The broth mixture is poured into ice / water (300 ml) and the suspension is stirred for 30 minutes. The solid is filtered, washed with water (50 ml) and dried. 3-Azido-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, m.p. 136-138 °.

2-Azido-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazin-25-pin-2-one (5 g) is added in one portion to a stirred suspension of potassium hydroxide (1.3 g) under a nitrogen atmosphere. and tetrabutylanonium bromide (0.7 g) in tetrahydrofuran cooled to 0 °. The mixture is further stirred for 5 minutes, after which a solution of ethyl bromoacetic acid (3.6 g) in tetrahydrofuran (15 ml) is added over 5 minutes. The reaction mixture is allowed to warm to room temperature where it is stirred for a further 2 hours. The mixture is filtered and the tetrahydrofuran is evaporated off under reduced pressure. The residue is extracted into water (50 ml) and ether (100 ml). The organic phase is washed with 2N hydrochloric acid (10 ml), dried over magnesium sulphate 74 76074 and the solvent is evaporated off under reduced pressure. 3-Azido-1-ethoxycarbonylmethyl-8-methoxy-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one is obtained, m.p. 90-91 °.

Suspension of 3-azido-1-ethoxycarbonylethyl-5H-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (13.8 g) in methanol (75 ml) , is treated with a solution of sodium hydroxide (1.9 g) in water (75 ml). The reaction mixture is stirred for 2 hours at 40-45 °, water (100 ml) is added, acidified with conc. hydrochloric acid (10 ml) and extracted with methylene chloride (3 x 75 ml). The combined methylene chloride solutions are dried over magnesium sulfate and evaporated under reduced pressure. 3-Azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting at 145-147 °.

A solution of 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (11 g) in ethanol (250 ml) and water (50 ml) in the mixture, is hydrogenated at room temperature for 3 hours at 3 atmospheres, using 10% Pd-C catalyst. 2N Hydrochloric acid (50 ml) is added to the mixture and the catalyst is filtered off. The solvent is evaporated off under reduced pressure and the residue is dissolved in a mixture of water (50 ml) and ethanol (50 ml). Propylene oxide (25 ml) is added and the mixture is stirred for 1 hour. The solvent is evaporated off under reduced pressure. 3-Amino-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, melting above 300 °.

Example 23; 1- (1-Carboxyethyl) -3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride

A solution of 3-amino-1- (1-carboxyethyl) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride (3 g) and benzylpyruvic acid ethyl ester (6.5 g). g) in acetic acid (30 ml) and methanol (30 ml), stir at room temperature for 35 hours. Add sodium cyanoboron within 4 hours.

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75 7 6 0 7 4 hydride (0.8 g) in methanol (10 ml). The reaction mixture is stirred for 24 hours at room temperature, conc. hydrochloric acid (2 mL) and stir for an hour. The solvent is evaporated off under reduced pressure and the residue is extracted into water (50 ml) and ether (30 ml). The pH is adjusted to 9.4, the ether layer is separated and discarded. The pH of the aqueous solution is adjusted to 4.3 and extracted with ethyl acetate (3 x 50 mL). The combined extracts are dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. Hydrogen chloride gas is bubbled into the methylene chloride solution of the crude product (10 ml) for 2 minutes and the solution is evaporated. Obtained as a mixture of 1- (1-carboxyethyl) -3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride diastereomers, mp 87-94 °.

The starting material is prepared as follows: 3-Azido-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (prepared according to Example 1; 5 g) is added in one portion to a stirred suspension of potassium hydroxide (1 , 8 g) and tetrabutylammonium bromide (1.8 g) in tetrahydro-furan (50 ml) under a nitrogen atmosphere at 0 °. Stirring is continued for 5 minutes, after which (R) -2-bromopropionic acid tert-butyl ester (jPGreenstein et al., J.Am.Chem.Soc. 76, 6054 (1954), H.Niedrich) is added to the mixture over a period of 5 minutes. and G.Roller, J.Prakt.Chem. 316, 25,729 (1974)) (5.2 g) in tetrahydrofuran (15 ml). The reaction mixture is allowed to warm to room temperature over the next 2 hours while stirring. The reaction mixture is filtered and evaporated under reduced pressure. The residue is extracted into water (50 ml) and ether (100 ml).

The organic phase is washed with 2N hydrochloric acid (10 ml), dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. 3-Azido-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one is obtained as an oil which is used without further purification.

76 7 6 0 7 4

A solution of 3-azido-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (7 g) in ethanol (70 ml), hydrogenated at 3 atmospheres for 3 hours using 10% Pd-C catalyst (0.5 g). The catalyst is filtered off and the ethanol is evaporated off under reduced pressure. 3-Amino-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained in the form of an oil. High performance liquid chromatography (hplc) shows that the product is an approximately 1: 1 mixture of diastereomers. This material is used without further purification.

A solution of the above 3-amino-1- (1-t-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (4.7 g) in trifluoroacetic acid (25 ml), stirred for one hour at room temperature. Trifluoroacetic acid is evaporated off under reduced pressure and the residue is dissolved in ether (100 ml). Hydrogen chloride gas is introduced into the solution until the formation of a precipitate ceases. The solid is filtered off. 3-Amino-1- (1-carboxyethyl) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride is obtained, m.p. 165-176 °.

Hplc indicates that the product is an approximately 1: 1 mixture of diastereomers.

Example 24: 1-Ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H-flibenzazepin-2-one

A solution of 3S-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (1.5 g), 2-bromo-4-phenyl- butyric acid ethyl ester (1.6 g) and triethylamine (0.8 ml) in dimethylformamide (37 ml) are stirred for 18 hours at 70 ° under a nitrogen atmosphere. The dimethylformamide is then evaporated off under reduced pressure. The residue is dissolved in ethyl acetate (70 ml), washed with water (5 x 25 ml), dried over magnesium sulphate and evaporated. The product mixture is then separated by silica gel chromatography using ethyl acetate / hexane (40:60) as solvent. Approximately equal amounts of 1-ethoxy-35-bicarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropyl) are obtained.

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76074 77 Liamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (NMR (CDCl 3) δ 64.52 (q, 2H)), which is the S, S enantiomer, and its diastereomer 1-ethoxycarbonylmethyl-3S- (1R-ethoxycarbonyl-3-phenylpropyl-5-amino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one; NMR (CDCl 3): 64.50 (q, 2H).

TLC (thin layer chromatography): (silica gel; ethyl acetate / hexane 40:60): the (S, S) -isomer has an Rf value of 0.24 and the (S, R) -isomer has an Rf value of 0.33.

Example 25: 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f) benzazepin-2-one

Add dropwise 2-normal potassium hydroxide solution (0.26 ml) to a solution of 1-ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one (0.25 g) in ethanol (5 ml) at room temperature under nitrogen with stirring. The mixture is stirred for one hour, after which the ethanol is evaporated off, the residue is dissolved in water (5 ml), the pH is adjusted to 2 with 2N hydrochloric acid and extracted with ethyl acetate (2 x 30 ml). The combined acetic acid ethyl ester solutions are washed with saturated sodium hydroxide solution (5 ml), dried over magnesium sulphate and evaporated to dryness. 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one is obtained, which is the compound of Example 12.

Example 26: 1-Carboxymethyl-7-chloro-3- (1-ethoxycarbonyl-5-phenyl-30-propylamino) -2,3,4,5-tetrahydro-1H-f) benzazepin-2-one (Isomer B)

To a solution of 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (Isomer B; 1.5 g ) in acetic acid 78 7 6074 (25 ml) is introduced at room temperature, with stirring, chlorine gas. A white precipitate forms. Chlorine gas is passed until the reaction is complete. The solid is filtered off and separated into its components by liquid chromatography (hplc), using a preparative C18 reverse phase column. A mixture of methanol / 0.1% aqueous ammonium carbonate solution (1: 1) is used as solvent. The appropriate fractions are dissolved in methanol / acetic acid ethyl ester (1: 1; 50 ml) and hydrogen chloride gas is bubbled into the solution. The solution is evaporated, the residue is suspended in ether (100 ml) and the suspension is filtered. 1-Carboxymethyl-7-chloro-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride is obtained, melting at 149-151 °. (isomer B).

Example 27: 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f) benzazepin-2-one hydrochloride 3 (S) - Amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- (1) -2,5 benzazepin-2-one sodium salt (619 g) having a (oi) D of 20-304.4 ° (c = 1.08 in water), benzylpyruvic acid ethyl ester (1960 g), anhydrous ethanol (5880 ml) and glacial acetic acid (5880 ml) are stirred and the mixture is stirred at 20-25 ° for 1.5 hours. A solution of sodium cyanoborohydride (179 g) in anhydrous ethyl alcohol (2200 ml) is added slowly and evenly over 24 hours to the mixture. When the addition is complete, stir the reaction mixture for an additional 24 hours. To the reaction mixture is added 12N hydrochloric acid (500 ml) and the solvent is evaporated at 35-40 ° under a pressure of 3 ininHg. The residual oil is added to the mixture if there is ice (3000 g), water (3000 ml) and diethyl ether (3000 ml), and the pH of the mixture is adjusted to 9-9.5 with 10N sodium hydroxide solution (1735 ml). . The aqueous phase is separated and a further 6000 ml of ether are added to the ether layer to give even more product as an oil. The layer immiscible with ether 35 is separated and combined with the brine 79 7 60 7 4-containing phase. The ether extract is then washed with water (2 x 1000 ml), the washings are combined with the water / oil portion obtained above and the pH of the mixture is adjusted to 4.25-4.35 with 12N hydrochloric acid (550-650 ml). The mixture is extracted with ethyl acetate (3 x 2000 mL). The combined acetic acid ethyl ester extracts were washed with water (2000 ml) and dried over anhydrous magnesium sulfate (500 g). The desiccant is filtered off and the solvent is carefully evaporated at 40 ° and 3 mm Hg. The resulting oil was dissolved in ethyl acetate (4500 mL) and 28% ethereal hydrogen chloride (309 g) was added with vigorous stirring. Diethyl ether (1500 ml) is added to the mixture, which is then stirred for one hour. The solid is separated and washed with ethyl acetate (2 x 500 mL) and diethyl ether (3 x 1000 mL). Dry at 50 ° and 3 mmHg to give the crude product, which is about 65% of the desired 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4, From 5-tetrahydro-1H- (1H) benzazepin-2-one, which is identical to the product of Example 12. This is confirmed by hplc, using a preparative Cgg reverse phase column. A methanol / water / acetic acid mixture (75: 25: 0.02) is used as solvent.

The crude product obtained above is suspended in dichloromethane (26900 ml) and hydrogen chloride gas is introduced into the solution in a constant stream. After 40 minutes a solution is obtained. In this case, the gas conduction is stopped. The remaining insoluble matter is removed from the solution by filtration and diethyl ether (10,750 ml) is added.

The suspension is stirred overnight at room temperature and the solid is filtered. This is washed with dichloromethane (4 x 500 mL) and diethyl ether (3 x 1000 mL). Dry to give the pure product as the hydrochloride salt, m.p. 175-178 °.

To the hydrochloride salt obtained above (1880 g) is added dichloromethane (18,000 ml). The suspension is treated with chlorine 76074 hydrogen gas to give a solution. To this is added diethyl ether (7200 mL). The resulting suspension is stirred for 3 hours and filtered. The solid is washed with dichloromethane (2 x 1000 mL) and diethyl ether (2 x 1000 mL) and dried. A product is obtained which melts at 183-185 °. (Hplc indicates that the product is 96%).

To the salt obtained above (1280 g) is added chloroform (4000 ml), and the mixture is refluxed for 10 minutes. The heating is stopped, the mixture is stirred for 4 to 10 hours and filtered. The solid was washed with chloroform (2 x 200 mL) and diethyl ether (3 x 500 mL), dried and screened. 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one hydrochloride is obtained, m.p. 184-186 ° :in.

15 (a) ^ = “139.26 ° (c = 0.92 in absolute ethanol).

The product is identical to the hydrochloride salt of Example 12.

Example 28: 3- (1-Benzyloxycarbonyl-3-phenylpropylamino) -1-carboxymethyl-2,3,4,5-tetrahydro-1H-f) benzazepin-2-one hydrochloride (Isomer B)

To a solution of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (4.0 g; see Example 7) in acetic acid ethyl ester (100 ml), hydrogen chloride gas is bubbled in at 20 ° for 20 minutes. The reaction mixture is evaporated under reduced pressure and the solid obtained is triturated with ether (50 ml). The solid is filtered, washed with ether (15 ml) and acetic acid ethyl ester (15 ml) and then boiled with acetic acid ethyl ester 30 (50 ml). The product is recrystallized from methanol / ethyl acetate. The title compound is obtained, melting at 197-199 °. (Isomer B).

The starting material is prepared as follows:

To a solution of 3- (1-benzyloxycarbonyl-3-35 phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (3.0 g) and bromoacetic acid tert-butyl ester

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81 7 607 4 (2.2 g) in tetrahydrofuran (100 ml) are added under a dry nitrogen atmosphere at room temperature, while stirring, potassium tert-butoxide (1.2 g). The reaction mixture is stirred for 20 hours at room temperature, then poured into water (250 ml) and extracted with dichloromethane (2 x 150 ml). The combined extracts are washed with water (100 ml) and dried over magnesium sulfate. The solvent is evaporated to give 3- (1-benzyloxycarbonyl-3-phenyl-propylamino) -1-t-butyloxycarbonylmethyl-2,3,4,5-10 tetrahydro-ΙΗ- (1) benzazepin-2-one.

Example 29: 1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H-fl) -benzazepin-2-one To a solution of sodium methoxide in methanol (prepared from sodium (0.25 g) and methanol (50 ml)), a solution of 2- (1-ethoxycarbonyl-3-phenylpropylamino) -4- (o- (ethoxycarbonylmethylamino) phenyl) butyric acid is added under nitrogen with stirring. ethyl ester (5.6 g) in methanol (100 ml). The reaction mixture is refluxed for 20 to 65 hours and then evaporated under reduced pressure. The residue is partitioned between water (50 ml) and dichloromethane (200 ml). The aqueous solution is extracted with dichloromethane (200 ml). The combined organic solutions are washed with water (50 ml) and dried over potassium carbonate. The solvent is evaporated to give a mixture of isomers A and B of 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one. , which is chromatographed on silica gel and converted according to Example 10 to the individual maleates.

The starting material is prepared as follows:

To a solution of 2-amino-4- (o-nitrophenyl) -butyric acid ethyl ester (17.4 g) in 50% aqueous dioxane (130 mL) was added triethylamine (10.5 g) and 2- (tert. -35-butyloxycarbonyloxyimino) -2-phenylacetoxynitrile 82 7 6 0 7 4 (18.7 g). The reaction mixture is stirred for 4 hours at room temperature and then diluted with water (300 ml). The mixture is extracted with ether (2 x 150 ml), the aqueous phase is acidified with ice-cold 2N hydrochloric acid and extracted with ethyl acetate (2 x 250 ml). The ethyl acetate layers are combined, washed with water (150 mL) and dried over sodium sulfate. The solvent is evaporated off under reduced pressure. 2-t-Butyloxycarbonylamino-4- (o-nitrophenyl) -butyric acid ethyl ester is obtained, which is used without further purification.

A solution of 2-t-butyloxycarbonylamino-4- (o-nitrophenyl) butyric acid ethyl ester (13.0 g) in ethanol (300 ml) was hydrogenated at room temperature and atmospheric pressure using a 10% palladium on carbon catalyst (Ig ), 15 until hydrogen consumption ceases. The catalyst is filtered off and the solvent is evaporated. 2-t-Butyloxycarbonylamino-4- (o-aminophenyl) -butyric acid ethyl ester is obtained, which is used crude in the next step.

A solution of 2-t-butyloxycarbonylamino-4-20 (o-aminophenyl) butyric acid ethyl ester (10.0 g) and glyoxylic acid ethyl ester (4.2 g) in ethanol (120 ml) is hydrogenated at 80 °: and at 3 atmospheres for 72 hours, using a 10% palladium on carbon catalyst. The reaction mixture is cooled to room temperature and the catalyst is filtered off. The solvent is evaporated off under reduced pressure and the residue is partitioned between ethyl acetate (150 ml) and water (75 ml). The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 2-t-Butyloxycarbonylamino-4- (o- (ethoxycarbonylmethylamino) -30-phenyl) -butyric acid ethyl ester is obtained, which is used without purification in the next step.

To a solution of 2-t-butyloxycarbonylamino-4- (o- (ethoxycarbonylmethylamino) -phenyl) -butyric acid ethyl ester (8.5 g) in acetic acid ethyl ester (150 ml) was bubbled hydrogen chloride gas for 30 minutes at room temperature. The solution is evaporated under reduced pressure and the residue is taken up in 83 7 6 0 7 4 in ethyl acetate (100 ml). The solution is washed with water (3 x 100 mL) and dried over sodium sulfate. The solvent is evaporated off under reduced pressure. 2-Amino-4- (o- (ethoxycarbonylmethylamino) -phenyl) -butyric acid ethyl ester-5 is obtained, which is used crude in the next step.

A solution of 2-amino-4- (o- (ethoxycarbonylmethylamino) phenyl) butyric acid ethyl ester (4.7 g) and benzyl lipoic acid ethyl ester (12.4 g) in acetic acid (35 ml) and methanol (35 ml) is stirred for 1 hour under a nitrogen atmosphere at room temperature. Sodium cyanoborohydride (1.6 g) in methanol (15 ml) is added dropwise over 4 hours. The reaction mixture is stirred for 24 hours at room temperature, dropwise is added conc. hydrochloric acid (2 ml) and stirred for 1 hour at room temperature.

The mixture is evaporated to dryness, the residue is partitioned between water (75 ml) and ether (75 ml) and the pH is adjusted to 2 with 6N hydrochloric acid. The layers are separated and the aqueous phase is extracted with ether (2 x 75 ml). The ether extracts are discarded and the pH of the aqueous layer is adjusted to 9 with 40% sodium hydroxide solution and extracted with ethyl acetate (3 x 50 mL). The extracts are dried over sodium sulfate and evaporated under reduced pressure. 2- (1-Ethoxycarbonyl-3-phenylpropylamino) -4- (o- (ethoxycarbonylmethylamino-phenyl) -butyric acid ethyl ester is obtained, which is used directly in the preparation of the final product.

Example 30: 2-Amino-4-phenylbutyric acid ethyl ester is treated, under reductive alkylation conditions as described in the above examples, with 1-ethoxycarbonylmethyl-2,3,4,5-30 tetrahydro-ΙΗ- (1) benzazepine-2,3 -dione. 1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained, which is the compound of Example 10.

The starting material is prepared as follows: A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one (1.0 gf 4.32 mmol) and bromoacetate - O * 76074 Acid ethyl ester (0.51 ml) in tetrahydrofuran (30 ml) is added dropwise over 15 minutes, with stirring, under a nitrogen atmosphere to a solution of sodium hydride (4.76 mmol) in tetrahydrofuran (20 ml). The mixture is further stirred for 2 hours. The solution is decomposed by adding saturated aqueous ammonium chloride solution and the solvents are evaporated off under reduced pressure. The residue is extracted with ether (3 x 20 ml), the combined ether solutions are washed with saturated aqueous sodium chloride solution (20 ml) and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure. 3,3-Dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained. NMR (CDCl 3): 61.27 (t, 3H); 3.22 (m, 4 H) and 4.25 (q, 2 H); 4.65 (s, 2 H) and 7.3 (m, 4 H).

A mixture of morpholine (0.315 g? 3.6 mmol) and 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one (O , 5 g), is stirred under a nitrogen atmosphere at 110 ° for 18 hours. The solution is diluted with chloroform to 10 ml and cooled to 0 °. 20% sulfuric acid (1 ml) is added and the solution is stirred for 2 hours at 0 °. The solution is extracted with chloroform (2 x 20 ml) and the extracts are washed with 2N hydrochloric acid (2 x 10 ml) and saturated aqueous sodium chloride solution (5 ml). The solution is dried over magnesium sulfate and evaporated under reduced pressure. 1-Ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepine-2,3-dione is obtained. NMR (CDCl 3): 61.25 (t, 3H); 2.6 (m, 2H) * 3.6 (m, 2H) ·, 4.2 (q, 2H) and 7.3 (m, 4H).

Example 31; 2-Amino-4-phenylbutyric acid ethyl ester is treated with 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one in the presence of potassium carbonate in methylene chloride. 1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-35H- (1) benzazepin-2-one is obtained, which is the compound of Example 10.

85 7 6 0 7 4 The starting material is prepared as follows:

To a solution of 2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (2.5 g) in chloroform (30 ml) was added portionwise phosphorus pentachloride (3.2 g) 5 is maintained at 0-5 °. When this addition is complete, iodine (30 mg) is added first over 5 minutes, followed by bromine (2.5 g). The mixture is refluxed for 4 hours. The chloroform solution is evaporated and the residue is partitioned between ice water (30 ml) and dichloromethane (75 ml). The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The crude residue is purified by chromatography on silica gel, eluting with ether / hexane (7: 3). After evaporation of the appropriate fractions, 3-bromo-2,3,4,5-tetrahydro-1H- (1) benzazepin-2-2-one is obtained, melting at 146-148 °.

To a stirred suspension of potassium hydroxide (90 mg) and tetrabutylammonium bromide (40 mg) in tetrahydrofuran (10 ml) is added in one portion 3-bromo-2,3,4,5-tetrahydro-1H- (1) benzazepine-2- onion (300 mg), nitrogen atmosphere-20 at 0 °. Stirring is continued for 5 minutes. Bromoacetic acid ethyl ester (200 mg) is added in one portion and the mixture is allowed to warm to room temperature over the next 3 hours while stirring. The tetrahydrofuran is evaporated off under reduced pressure and the residue is extracted into water (5 ml) and ether (25 ml). The organic phase is washed with 2N hydrochloric acid (5 ml), dried over magnesium sulphate and evaporated under reduced pressure. 3-Bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one is obtained, m.p. 114-116 °.

3-Chloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one is prepared in a similar manner.

A solution of 3-chloro-2,3,4,5-tetrahydro-1H- (1) -benzazepin-2-one (1.95 g) in dimethylformamide (10 ml) is added dropwise at 5 ° to a stirred solution. where 35 is potassium tert-butoxide (1.11 g) in dimethylformamide (10 ml). The solution is further stirred for 15 minutes at 5 °, 86 76074, after which bromoacetic acid ethyl ester (1.78 g) in dimethylformamide (5 ml) is added dropwise. Stirring is continued for a further 30 minutes at 5 ° and then for 3 hours at room temperature. The reaction mixture is cooled to 10 ° and water (100 ml) is added. The solution is extracted with chloroform (100 ml), the chloroform solution is washed with water (2 x 10 ml) and dried over sodium sulfate. The solvent is evaporated off under reduced pressure. 3-Chloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- (1) benz-10-azepin-2-one is obtained; NMR (dimethyl sulfoxide-d 6): 61.2 (t, 3H); 2.65 (m. 4H); 4.15 (q, 2 H); 2.6 (d, 2 H) and 7.3 (m).

Example 32: 1-Carboxymethyl-3S- (1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H-f) benzazepin-2-one 1-Benzyloxycarbonylmethyl-3S- (1S-pivaloyloxy) Cimethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-ΙΗ- (1) benzazepin-2-one (3 g) is dissolved in ethanol (50 ml) and 10% palladium on carbon is added. 20 (0.3 g). The solution is hydrogenated at room temperature for 2 hours at 1 atmospheric pressure.

The reaction mixture is filtered and evaporated. 1-Carboxymethyl-3S- (1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one is obtained.

The starting material is prepared as follows: 1-Benzyloxycarbonylmethyl-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one (5 g; Example 2) is dissolved in 2 to normal potassium hydroxide solution (5.15 ml) and the solution is evaporated to dryness.

Pivalic acid iodomethyl ester (2.3 g) and dimethylformamide (50 ml) are added and the mixture is stirred under nitrogen for 18 hours at room temperature. The dimethylformamide is evaporated off, the residue is dissolved in acetic acid ethyl ester 35 (100 ml) and washed with saturated sodium carbonate solution.

II

87 76074 (3 x 25 ml), water (3 x 25 ml) and saturated sodium chloride solution (25 ml) and dried over magnesium sulphate. Evaporation gives 1-benzyloxycarbonylmethyl-3S- (1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino) -5,3,4,5-tetrahydro-1H- (1) benzazepin-2-one.

In a similar manner there are prepared: a) 1-Carboxymethyl-3S- (1S-E-bornyloxycarbonyl-methoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-β- (1) benzazepin-2-one as starting material iodine- 10 whey-ί, -bornylies blades.

b) 1-Carboxymethyl-3S- (1S-p-methoxyethoxymethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one using 8-methoxyethoxymethyl chloride as starting material.

C) 1-Carboxymethyl-3S- (1S- (3-phthalidioxycarbonyl) -3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) benzazepin-2-one using 3-bromophthalide as starting material .

d) 1-Carboxymethyl-3S- (1S- (3-pyridylmethoxycarbonyl) -3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- (1) -20 benzazepin-2-one using 3- pyridylmethyl chloride.

Cardiovascular pharmacology of the compounds of the invention:

The effects of the compounds are tested by methods that take advantage of the inhibition of angiotensin converting enzyme (ACE). A biochemical assay that determines in vitro ACE inhibition (äCE inhibition = ACE1) determines the activity of a compound in rabbit lung tissue.

In an in vivo test method, an increase in blood pressure is first induced in an experimental animal by administration of angiotensin I (AI). The inhibitory effect of the individual compounds on this increase in blood pressure is then determined.

88 7 60 7 4 I. Biochemical test method A rabbit lung tissue preparation (Das and Saffer, J. Biol. Chem. 250: 6762 (1975)) is used to determine ACE by the method of Cheung and Cushman (Cheung and Cushman, Biochim. Biophys Acta 293, 451 (1973) This method determines spectrophotometrically the amount of histidyl leucine released from a synthetic substrate during a 30 minute incubation at 37 ° C. The IC 50 values of ACE inhibition are then calculated graphically. g value is the concentration (in moles) of test compound that reduces the amount of histidyl-leucine formed in the absence of test compound by 50%.

II. Method in which intravenous administration of a test compound prevents angiotensin I (AI) -induced hypertension (% AI inhibition) In this experiment, as described above, a catheter is inserted into both the femoral artery and the fundus vein. Arterial pressure is recorded from the arterial catheter, while angiotensin I (AI) and the respective test compound are injected through the venous catheter. Angiotensin I-induced hypertension inhibition is expressed as the percentage reduction from pre-treatment hypertension control values and is shown in the table as the mean inhibition within 30 minutes of test substance dosing.

Il 89 7 60 7 4

Score;

Prevention of angiotensin I (AI) pressure increase_

The In vitro i.v. dose% AI

compound ACEI (mg / kg) inhibition IC50 (M) 1 6 x 10 ~ 7 10 100 1.0 100 0.1 50 5 2 x 10 "7 0.1 37 9 5 x 10" 9 0.3 93 0, 1 80 0.03 40 10 1 x 10-5 1.0 80 Maleate salt 12 4 x 10 ~ 7 1.0 100 HCl salt 0.3 95 0.1 82 0.06 74 0.03 29 19 2 x 10 ~ 9 0.1 93 0.06 84 0.03 70 0.02 69 0.01 28 0.007 14 28 1 x 10 "7 0.19 92 Isomer B, HCl salt

Claims (5)

90 7 60 7 4 A process for the preparation of antihypertensive 3-amino-11-benzazazin-pin-2-one-1-alkanoic acids of the general formula I of R 4 X 4 R 2 I 3 R 2 Bi wherein Rr is -CH X 10 and R 8 is -CH 2 R 0 wherein R 0 in R 6 is COR 8 and in R B is COR 7, wherein R 8 and Ry are independently hydroxy, lower alkoxy or phenyl lower alkoxy; and R 1 represents hydrogen or phenyl-lower alkyl; R 2 is hydrogen or lower alkyl; R 3 and R 4 independently represent hydrogen, lower alkoxy or halogen; R 5 is hydrogen and X represents two hydrogen atoms or, simultaneously with the hydrogen atom, a hydroxy group; and stereoisomers and salts thereof, characterized in that a) in a compound of formula II is II 91 76074 R4 X «, ίΕ» wherein X, Rg, R3, R4 and Rg are as defined above, RA is coupled with an alkyl label with a compound of formula IIIA is Ra-Z (IIIA) wherein Z represents a reactive esterified hydroxyl group and Ra is as defined above, or by alkylation with a compound of formula IV is RX - CO - Rq (IV) wherein Rx and R0 are as defined above, in the presence of a reducing agent, while temporarily protecting any primary and secondary amino groups and / or optionally hydroxyl and / or oxo groups which may be at any of the residues X, R1, RB, r3, r4 and or or b) a compound of formula V is ftx. - R 30 wherein X, R 3, R 4 and R 8 are as defined above and R 6 'is hydrogen or the same as RA above are alkylated with a compound of formula IIIB 92 76074 Rb-Z (IIIB) wherein Z is a reactive esterified hydroxyl group and R 8 is the same as above, temporarily protecting any primary and secondary amino groups and / or optionally hydroxyl and / or oxo groups which may be at any of the radicals X, RA, Rg, R3, R4 and R5, or c) a compound of formula VI is R3 wherein Y represents an oxo or a reactive esterified hydroxyl group Z together with a hydrogen atom and wherein X, Rg, R3 and R4 have the same meaning as above, is condensed with an amine of formula VII is Ra-NH-R5 (VII) wherein Ra and R 5 has the same meaning as above, wherein when Y represents oxo, the condensation is carried out in the presence of a reducing agent, or d) in a compound of formula VIII is R 4 XBV. Il d ^ 4 - \ | 5/1 [II Vn-ch (Vili) J 1 r »R, IO o / c \ K9 R" 2 o where X and R1-R5 have the same meaning as above, the second sym- II 93 Of the 7 6074 boles, R 0 * and R 0 "are cyano and the other is cyano or has the same meaning as R c above, the cyano groups) are subjected to solvolysis, or e) a compound of formula IX is fccS-O / v A 3 * b wherein X, R 1, R b, R 3, R 4 and R 5 are as defined above, or an ester thereof is cyclized, or f) a compound which is structurally identical to a compound of formula I given above, except that the compound contains an additional a double bond at the C-3 position or between a nitrogen atom and an adjacent carbon atom in the RA group is treated with a reducing agent to saturate this double bond, and the resulting compound of formula I as defined above is optionally converted to another compound of formula I as defined above and / or , of formula I as defined above A compound of formula I having salt-forming properties is optionally salified or the free compound is liberated from such a salt and / or an optical isomer having a specific configuration at at least one chiral center is optionally liberated from a mixture of stereoisomeric forms of the resulting compound of formula I. Process according to Claim 1, characterized in that 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] -benzazepine is prepared. -2-one, a stereoisomer or a salt thereof. Process according to Claim 1, characterized in that a racemic compound of the compound mentioned in Claim 2 which melts at a higher temperature, its enantiomer or a salt is prepared. Process according to Claim 1, characterized in that a racemic compound, an enantiomer or a salt thereof, which melts at a lower temperature and is mentioned below, is prepared. Process according to Claim 1, characterized in that 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1H] benzazepine-2- oni or a salt thereof. tl 76074 95 Patentkrav;