SI9210090A - Substituated hydroxycarbamoylmethyl- or substituated hydroxyphosphonyl- derivatives of N-/4-methylvaleryl/,3-methyl-L-valinamide - Google Patents

Abstract

Compounds of Formula (R) represent hydrogen, amino, protected amino, acylamino or lower alkyl optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2, 3-dihydro-1,3-dioxo-1H-benz (d, e) isoquinol-2-yl, carboxyl, protected carboxyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, di (lower alkylamino, carboxy-lower alkanoylamine, pyrrolidino or morpholino; R2 represents hydrogen or lower alkyl optionally substituted by aryl, amino, protected amino, di (lower alkylamino, guanidino, carboxyl, protected carboxyl, carbamoyl, mono (lower alkylcarbamoyl, di (lower alkyl) carbamoyl, di (lower alkoxy) phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino; R3 represents hydrogen or lower alkyl optionally substituted by hydroxy, protected hydroxy, amino or protected amino; R4 represents hydrogen, hydroxy, lower alkoxy or benzyloxy, and R 5 represents hydrogen or halogen and the pharmaceutical acceptable salts. Products are used for preparation of drugs for the treatment or prevention of degenerative diseases joint disease or treatment for invasive tumors, atherosclerosis or multiple sclerosis. You can they are obtained by known methods.

Description

The invention relates to amino acid derivatives, the process for their production and the medicaments they contain.

The amino acid derivatives obtained by the present invention are compounds of the general formula

R1 represents hydrogen, amino, protected amino, acylamino or lower alkyl, which is optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3- dioxo-1Hbenz [d, e] isoquinol-2-yl, carboxyl, protected carboxyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, di (lower alkyl) amine, carboxy-lower alkanoylamine, pyrrolidino or morpholino ;

R ² represents hydrogen or lower alkyl optionally substituted by aryl, amino, protected amino, di (lower alkyl) amine, guanidine, carboxyl, protected carboxyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl , di (lower alkoxy) phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino;

R3 represents hydrogen or lower alkyl optionally substituted by hydroxy, protected hydroxy, amino or protected amino;

R 4 represents hydrogen, hydroxy, lower alkoxy or benzyloxy, and R 4 represents hydrogen or halogen, and pharmaceutically acceptable salts thereof.

The compounds of formula I have important pharmacological properties. They are collagenase inhibitors in particular and can be used to regulate or prevent degenerative joint diseases such as rheumatic arthritis and osteoarthritis, or to treat invasive tumors, atherosclerosis, or multiple sclerosis.

The subject of the present invention are the compounds of formula I and their pharmaceutically acceptable salts alone or for use as therapeutically active substances; a process for the preparation of said compounds and salts; medicines containing said compounds and salts, and the preparation thereof; as well as the use of these compounds and salts to regulate or prevent disease or to improve health, especially to regulate and prevent joint degeneration disease or in the treatment of invasive tumors or atherosclerosis, or to obtain drugs for the regulation or prevention of joint degeneration disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis.

For the purposes of this specification, the term lower alkyl, alone or in combination, denotes a straight- or branched-chain alkyl group containing up to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like. Similarly, the term lower alkoxy denotes a straight or branched chain alkoxy group containing up to six carbon atoms, such as e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. The term aryl denotes a optionally substituted phenyl or naphthyl group, the substituents being selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, phenyl and the like. The acyl moiety of the acylamino group is derived from alkanoic acid containing up to six carbon atoms, such as e.g. acetyl, propionyl, butyryl, pivaloyl and other optionally substituted benzoic or naphthalenecarboxylic acids, such as e.g. benzoyl, 4-chlorobenzoyl, 2carboxybenzoyl, 1- or 2-naphthoyl, and the like, or aryl substituted alkanoic acid containing up to six carbon atoms, e.g. phenylacetyl and others. The lower alkanoyl portion of the carboxy-lower alkanoylamino group is derived from alkanoic acid containing up to six carbon atoms, such as e.g. acetyl, propionyl, butyryl and others. The term halogen means fluorine, chlorine, bromine or iodine.

The term protected amino, protected hydroxy and protected carboxy denotes amino, hydroxy and carboxy groups that are protected in a known manner, such as e.g. usually in peptide chemistry. The amino group may e.g. is protected with benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or the like, or in the form of phthalimido or a similar group. The hydroxy group can be protected e.g. in the form of readily fissile ether, such as e.g. tert-butyl ether or benzyl ether, or in the form of an easily fissionable ester, such as e.g. acetate. So e.g. the carboxy group may be protected in the form of an easily fissionable ester such as methyl, ethyl, benzyl or the like.

The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali metal hydroxides (eg sodium hydroxide or potassium hydroxide), alkaline earth metal hydroxides (eg calcium hydroxide and magnesium hydroxide), ammonium hydroxide and the like. The compounds of formula I, which are basic, form pharmaceutically acceptable salts with acids. As such salts, not only salts with inorganic acids, such as hydrohalic acids (eg hydrochloric and hydrobromic acid), sulfuric acid, hydrochloric acid, phosphoric acid, etc., are considered, but also salts with organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, ptoluenesulfonic acid and others.

The compounds of formula I contain at least two asymmetric carbon atoms and may therefore exist as optically active enantiomers, as diastereoisomers or as racemates. It is an object of the invention to use all these forms.

In the compounds of formula I provided by the present invention, R1 preferably represents hydrogen, amino, acetylamino, benzyloxycarbonylamino or lower alkyl, optionally substituted by amino, phenyl, phthalimido, succinimido, carboxy, alkoxycarbonyl, morpholino, hydroxy or acetoxy, especially hydrogen , amino, acetylamino, benzyloxycarbonylamino, methyl, 5-amino-pentyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 5-hydroxypentyl, 5-acetoxypentyl, aminomethyl, phthalimidomethyl, succinimidomethyl, benzyl, 3-phenylpropyl, 3-carbonylpropyl, 3-carbonyl , benzoylaminomethyl, morpholinomethyl, acetylaminomethyl,

2-phthalimidoethyl, 3-hydroxypropyl or 3-acetoxypropyl. R ² preferably represents lower alkyl, optionally substituted by amino, aryl, guanidino, carboxy, di (lower alkoxy) phosphinyl, dihydroxyphosphinyl or morpholino, in particular methyl, 4-aminobutyl, 1-phenylethyl, 5-carboxypentyl, diethoxyphosphinylmethyl, dihydroxyphosphinyl, or dihydroxyphosphinyl morpholinopentyl. R4 preferably represents hydrogen, hydroxymethyl, 2-aminoethyl or 4-aminobutyl, especially hydrogen. R4 preferably represents hydrogen, hydroxy or benzyloxy, especially hydrogen or hydroxy. R4 preferably represents hydrogen or bromine.

The most preferred compounds of formula I of the present invention are:

N ² - [(R) - [hydroxycarbamoylmethyl] -4-methylvaleryl] -Nl'3-dimethyl-L-valinamide,

N ² -2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] N1, 3-dimethyl-L-valinamide (isomer 2),

N ² - [2 (R or S) - [[[(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2yl) methyl] ( hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide,

N ² - [2 (R or S) - [[(R) - (amino) [(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -N, 3-dimethyl-lvalinamide,

N ² - [(2R or S) - [[(R) - (amino) [(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] -isoquinol2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide, N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl ] -4-methylvaleryl] -Nl, 3-dimethylL-valinamide,

N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4- (methoxycarbonyl) -butyl] -4-methylvaleryl N, 1,3-dimethyl-L-valinamide,

N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvaleryl] -N, 3-dimethyl-lvalinamide and

N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-succinimidoethyl] -4-methylvaleryl] -N1, 3dimethyl-L-valinamide.

The process of the invention provides compounds of formula I and pharmaceutically acceptable salts thereof

a) by reaction of an acid of the general formula

R ¹⁰ (ID wherein R.10 represents hydrogen, protected amino, acylamino or lower alkyl, which is optionally substituted by aryl, protected hydroxy, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3 -dioxo-1H-benz- [d, e] isoquinol-2-yl, protected carboxy, carbamoyl, mono (lower alkylcarbamoyl, di (lower alkyl) carbamoyl, di (lower alkyl) amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino And R ^ O represents hydrogen or lower alkyl which is optionally substituted by aryl, protected amine, di (lower alkylamine, protected carboxyl, carbamoyl, mono (lower alkylcarbamoyl, di (lower alkyl) -carbamoyl, di (lower alkoxy) phosphinyl, pyrrolidino, piperidino or morpholino, with a compound of the general formula

H ₂ N-OZ (III) wherein Z represents hydrogen, tri (lower alkyl) silyl or diphenyl (lower alkyl) silyl, or, if necessary, cleaving any diphenyl (lower alkyl) silyl group present in the reaction product, or

b) by catalytic hydrogenation of a compound of the general formula

(IV) where benzyloxyformamido, R1 has the above meaning and R1 has any preceding value for R4O or represents a nitroguanidine, or

c) by reaction of an amine of the general formula

(V)

H ₂ N

CO-NH-R ²⁰ wherein R 10 is as defined above, with an acid of the general formula

(VI) wherein R 1, R 5 and R 10 have a previously defined meaning and R 4 represents hydrogen or lower alkyl, optionally substituted by a protected hydroxy or protected amino group, or

d) by treating a compound of the general formula

(H) where Rl, R ^, R3, R4, R5 j _n p _re j given meaning, and R represents lower alkyl, with an acid or a halotri (lower alkyl) silane, or

e) by reaction of a compound of general formula (VHD

wherein R 1, R 5 and R 5 O have the meanings given above, with a compound of the general formula

(IX) where R 10 and R 4 O have the meaning given earlier, or

f) by brominating a compound of formula I in which A represents a group of formula (b) in which R4 is hydroxy and R4 is hydrogen, or

g) cleaving off the protecting groups from the compound of formula I, wherein R represents protected amino or lower alkyl substituted by protected hydroxy or protected amino and / or R ² represents a lower alkyl substituted with protected amino or protected carboxyl and / or R represents a lower alkyl substituted with protected hydroxy or protected amino, or

h) by treating a compound of formula I in which R ² represents di (lower alkoxy) phosphinyl- (lower alkyl), with an acid or with halotri (lower alkyl) silane, or

i) by acylating a compound of formula I in which R1 represents amino or amino-lower alkyl, or

j) by opening a ring of a compound of formula I in which R1 represents phthalimido (lower alkyl) or succinimido- (lower alkyl), and

k) as necessary by converting the resulting compound of formula I into a pharmaceutically acceptable salt.

The reaction of an acid of formula II with a compound of formula III according to embodiment a) of this process can be carried out in a known manner, e.g. in an inert organic solvent such as dimethylformamide or the like, using hydroxybenzotriazole in the presence of a condensing agent, such as e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, at a temperature from about 0 ° C to room temperature. Preferred compounds of formula III are those wherein Z is hydrogen, tert-butyldimethylsilyl or tert-butyldiphenylsilyl. When a compound of formula III is used in which Z represents three (lower allyl) silyl, this group is cleaved during the reaction and directly obtained is a compound of formula I. On the other hand, when a compound of formula III is used in which Z represents diaryl (lower alkyl) silyl, this group remains in the reaction product and must then be cleaved in a known manner, e.g. using fluoride ions.

The catalytic hydrogenation of a compound of formula IV according to embodiment b) of this process can be carried out in a known manner; e.g. in an inert organic solvent, using hydrogen in the presence of a precious metal as a catalyst. Suitable organic solvents are, for example, lower alkanols such as methanol, ethanol, and the like, and the catalyst may be platinum, palladium, or rhodium, which are on a suitable carrier material. Palladium on charcoal is the best catalyst. Temperature and pressure are not critical, although it is common for catalytic hydrogenation to be carried out at room temperature and under atmospheric pressure.

The reaction of an amine of formula V with an acid of formula VI according to embodiment c) by this process may be carried out by heating the amine with an acid in an inert organic solvent, such as an aromatic hydrocarbon, especially toluene or xylene, at a temperature of from about 30 ° C to 150 ° C, and most preferably at the reflux temperature of the reaction mixture. If necessary, heating may be carried out in the presence of a tertiary organic base. Alternatively, the reaction may be carried out in a known manner, first by reacting an acid of formula VI with a reagent such as oxalyl chloride, and then by condensation with an amine of formula V, in the presence of a tertiary organic base. This process can be carried out, for example, in an inert organic solvent, such as e.g. halogenated aliphatic hydrocarbon, e.g. dichloromethane or the like, in an aromatic hydrocarbon such as toluene or the like, or in a mixture of such solvents, at a temperature between -25 ° C and room temperature and most preferably at room temperature.

Treatment of a compound of formula VII with an acid or with halotri (lower alkyl) silane, most preferably with halotrimethylsilane, such as bromotrimethylsilane, in accordance with embodiment d) of this process, is carried out in a known manner. So e.g. the compounds of formula VII can be treated with a hydrogen halide, most preferably hydrogen bromide, in lower alkanoic acid, most preferably in acetic acid at room temperature, or with trifluoroacetic acid in an inert organic solvent, e.g. a halogenated hydrocarbon such as dichloromethane or the like, preferably at room temperature. Likewise e.g. the compound of formula VII can be treated with halotri (lower alkylsilane in an inert organic solvent, e.g., halogenated aliphatic hydrocarbon, such as dichloromethane or the like, most preferably at room temperature.

The reaction of a compound of formula VIII with a compound of formula IX in accordance with embodiment e) of this process can be carried out in a known manner. The reaction may be e.g. is carried out in an inert organic solvent such as a halogenated aliphatic hydrocarbon, e.g. chloroform or the like, in the presence of a silylating agent, such as e.g. bis (trimethylsilyl) acetamide, wherein the mixture is acidified, e.g. with a mineral acid such as hydrochloric acid after the reaction has taken place. This reaction is suitably carried out at elevated temperature, e.g. at about 50-60 ° C.

Bromination according to embodiment f) of this process can be carried out in a known manner. Bromination is suitably carried out using bromine in an inert organic solvent such as alkanoic acid, e.g. acetic acid and the like, with bromine in a halogenated hydrocarbon e.g. dichloromethane and the like. Bromination is rapidly carried out at room temperature.

The cleavage of protecting groups according to embodiment g) of this process can be performed using known methods in peptide chemistry. So e.g. cleavage of a protected amino group into an amino group can be carried out by acidolysis using a mineral acid, e.g. hydrochloric acid or trifluoroacetic acid when the protecting group is tert.-butoxycarbonyl, with catalytic hydrogenolysis when the protecting group is benzyloxycarbonyl, or by hydrazinolysis when the protecting group is phthaloyl. Likewise e.g. the cleavage of a protected hydroxy group into a hydroxy group may be carried out by acidolysis when the protecting group is tert-butyl, by catalytic hydrogenolysis when the protecting group is benzyl, or by alkalinity when the protecting group is in the form of an ester e.g. acetate. Likewise e.g. cleavage of the protected carboxy group can be carried out by calcining, e.g. with an aqueous solution of an alkali metal hydroxide, such as an aqueous solution of sodium hydroxide or potassium hydroxide.

Processing according to embodiment h) of this process can be carried out in a known manner. So e.g. the treatment can be carried out using a halogen, most preferably hydrobromic, in lower alkanoic acid, most preferably acetic acid at room temperature, or by using trifluoroacetic acid in an inert organic solvent, e.g.

a halogenated hydrocarbon such as dichloromethane or the like, preferably at room temperature. Likewise e.g. the treatment may be carried out in an inert organic solvent such as a halogenated hydrocarbon such as dichloromethane or the like, most preferably at room temperature.

Acylation according to embodiment i) of this process can be carried out in a known manner; e.g. using an acid halide, e.g. acetyl halide, or preferably acid anhydride e.g. acetic anhydride, etc., in an inert organic solvent and in the presence of a base. Preferably, the organic base is especially pyridine, which can be suitably used in excess and thus serves as a solvent at the same time. Acylation is conveniently carried out at room temperature.

Opening the rings of compounds of formula I in which phthalimido (lower alkyl) or succinimido (lower alkyl) according to embodiment j) of this process leads to a corresponding compound of formula I in which R1 represents (2-carboxybenzoyl) amino- (lower) alkyl) or 3-carboxypropionamido- (lower alkyl). The opening of the rings can be carried out in a known manner, e.g. by treatment with lithium hydroxide under known conditions, e.g. in lower alkanol and most preferably at about room temperature.

According to an embodiment of k) of this process, acidic compounds of formula I can be converted to pharmaceutically acceptable salts by treatment with bases, and basic compounds of formula I can be converted to pharmaceutically acceptable salts by treatment with acids. Such treatment can be carried out in the usual manner.

The acids of formula II used for starting material in embodiment a) of this process are novel and another object of the present invention.

The acids of formula II can be prepared according to the procedure shown in reaction scheme I, wherein R 10 and R 10 have a previously defined meaning and R 4 represents a protecting group such as e.g. tert-butyl, benzyl or the like:

Reaction Scheme I

R ¹⁰ (X)

HOOC

R ⁷ OOC

CO - NH

CO— NH — R ²⁰ (ΧΠ) (Π)

With respect to reaction scheme I, in the first step, the acid of formula X is condensed with an amine of formula XI. This condensation is carried out in a manner known in the chemistry of peptides. So e.g. condensation is carried out by a well-known method with an acid halide, acid anhydride, activated amide, mixed anhydride or activated ester. In a preferred embodiment, the condensation is carried out by an ester-activated method, in particular using hydroxybenzotriazole in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide.

In the next step, the compound of formula XII is converted to the acid of formula II by cleavage of the protecting group R ² . This cleavage is carried out in a known manner, e.g. by treatment with an acid such as hydrobromic acid in glacial acetic acid or trifluoroacetic acid, wherein R ² represents tert-butyl, or by hydrogenolysis when R ² represents benzyl.

The compounds of formula III to be used as starting material in embodiment a) of this process are known compounds.

The compounds of formula IV, which are used as starting materials in embodiment b) of this process, are novel and are further objects of the present invention.

Compounds of formula IV may be prepared by reacting an acid of formula II or the corresponding acid in which R ² 0 represents nitroguanidino with O-gt; benzylhydroxylamine. This reaction can be carried out in a conventional manner, for example in an inert organic solvent such as a chlorinated aliphatic hydrocarbon, for example dichloromethane or the like, in the presence of a condensing agent such as di (l-benzotriazolyl) carbonate, and at room temperature.

The amines of formula V to be used as starting material in embodiment c) of this process are known compounds or analogs of known compounds which are prepared in an analogous manner as known compounds.

The acids of formula VI used as starting material in embodiment c) of this process are novel and are also contemplated by the present invention.

The acids of formula VI may be prepared according to the procedure illustrated in Reaction Scheme II, wherein R ^ and R ⁵ and R ¹⁰ previously defined meaning, R represents a lower alkyl or aryl (lower alkyl), and R represents hydrogen or lower alkyl; optionally substituted by protected hydroxy or protected amino:

Reaction Scheme II

COOR®

(VI)

With respect to reaction scheme II in the first stage, hypophosphoric acid of formula XIII is reacted with a compound of formula XIV in a known manner, for example in an inert organic solvent such as a halogenated aliphatic hydrocarbon, for example dichloromethane or the like, in the presence of a silylating agent, such as is bis (trimethylsilyl) acetamide, and an amine such as 1,1,3,3-tetramethylguanidine at a temperature from 0 ° C to room temperature, whereby the reaction mixture is acidified e.g. with hydrochloric acid after completion of the reaction.

The compound of formula XV is then converted to the compound of formula XVI by reaction with isobutyl bromide or iodide. This reaction is carried out in a conventional manner, e.g. in an inert organic solvent such as dimethyl sulfoxide and the like, and in the presence of a base e.g. an alkali metal hydride such as sodium hydride at a temperature of 5 ° C to room temperature.

The compound of formula XVI can be converted either to another compound of formula XVII or to a compound of formula XVIII. In addition, the compound of formula XVI is a suitable step for performing resolution on optical isomers.

The conversion of a compound of formula XVI to a compound of formula XVII may be carried out in an analogous manner as described previously in the reaction of a compound of formula VIII with a compound of formula IX in embodiment d) of the process of the present invention.

The compound of formula XVII is converted to an acid of formula VI by hydrolysis and decarboxylation by known methods. The methods used depend on the nature of the substituents present in the molecules and are common to one skilled in the art. In addition, hydrolysis and decarboxylation can be performed stepwise in certain circumstances.

The conversion of a compound of formula XVI to a compound of formula XVIII may be carried out in an analogous manner as described for the conversion of a compound of formula XVII to an acid of formula VI, and the conversion of a compound of formula XVIII to an acid of formula VI may proceed in an analogous manner as have been described for the conversion of a compound of formula XVI to a compound of formula XVII.

The resulting acid of formula VI can be functionally modified if necessary. For example, an acid of formula VI in which R 4 represents benzyloxy and R 4 represents hydrogen can be catalytically hydrogenated to give an acid of formula VI in which R 4 represents hydroxy and R 4 represents hydrogen and the latter can be brominated to give an acid of formula VI, wherein R1 represents hydroxy and R8 represents bromine. Bromination may be carried out in an analogous manner as previously described in connection with carrying out e) of the process of the invention.

Compounds of formula VII, which are used as starting material in embodiment c) of this process, are novel and are a further object of the present invention.

The compounds of formula VII can be prepared according to the procedure shown in reaction scheme III. wherein R 1, R ² , R ⁴ , R 10, R 20 and R 4 have a previously defined meaning.

Reaction Scheme III

Oh,

H

OR ⁶

(XIX) /

COO-benzyl

(XX) (XXI) (VH)

With respect to reaction scheme III in the first step, a compound of formula XIX is reacted with compound VIII to give a compound of formula XX. This reaction is carried out in an analogous manner as previously described in the reaction of Formula VIII with a compound of Formula IX.

The compound of formula XX is then debenzylated by catalytic hydrogenation in the usual manner to give the compound of formula XXI.

The compound of Formula XXI is then coupled to the amine of Formula V by methods known in the chemistry of peptides and optionally converted, by known methods, by the known methods, if possible, to a protected amino, protected hydroxy or protected carboxy group present in the product, to an amino, hydroxy or carboxy group.

An alternative process for the preparation of compounds of formula XXI, wherein the lower alkyl is substituted by protected hydroxy or protected amino, as shown in the following reaction scheme IV, wherein R1, R4, R4 and R10 have the aforementioned meaning and R16 represents lower alkyl substituted with protected hydroxy or protected amino, where the protecting group cannot be such that the siege is hydrolytically removed.

Reaction Scheme IV

(XIX) (XXII) (xxm) (XXIa)

With respect to Reaction Scheme IV, the compound of Formula XIX is converted into a compound of Formula XXII by reaction with an aldehyde of Formula R 1 -CHO, wherein R 1 has the aforementioned meaning, upon activation of the hydroxy group in the product obtained and by reacting the activated of an alkali metal azide product. We do these steps in a familiar way. So e.g. the reaction of a compound of formula XIX with an aldehyde may be carried out in an inert organic solvent such as an aromatic hydrocarbon e.g. toluene or the like, in the presence of a base such as 1,1,3,3-tetramethyl guanidine at room temperature. Activation of the hydroxy group is carried out by conversion to the corresponding alkanesulfonyloxy e.g. methanesulfonyloxy compound using alkansulfonyl halide e.g. methanesulfonyl chloride, in the presence of an acid-binding agent, for example pyridine or similar, and in an inert organic solvent, for example a halogenated aliphatic hydrocarbon such as dichloromethane or the like, at a temperature of 0 ° C to room temperature. The reaction with an alkali metal azide, most preferably sodium azide, is preferably carried out in an inert organic solvent, such as dimethylformamide or the like, at an elevated temperature, for example 60-80 ° C.

Thereafter, the compound of formula XXII is converted to the compound of formula XXIII in a known manner, for example by treatment in an inert organic solvent such as lower alkanol for example methanol and the like, with alkanedithiol, for example 1,3-propan-dithiol, in the presence of three (lower alkyl) amines, e.g. triethyl amine or the like, at room temperature.

The compound of formula XXIII is then reacted with the compound of general formula

where R 1 and R 2 have the meanings defined above and the resulting reaction product is debenzylated.

The reaction of a compound of formula XXIII with a compound of formula XXIV can be carried out in a known manner, for example in an inert organic solvent such as a halogenated aliphatic hydrocarbon, for example dichloromethane and the like, and in the presence of a tertiary amine such as N-ethylmorpholine or the like, at room temperature. temperature. Subsequent debenzylation is carried out in the usual manner.

The resulting compound of formula XXI or XXIa can be functionally modified as necessary.

For example, a compound of formula XXI or XXIa in which R represents benzyloxy and ^R5 represents hydrogen can be catalytically hydrogenated to give a compound of formula XXI or

XXIa, where R4 represents hydroxy and R4 represents hydrogen and the second compound can be brominated in an analogous manner as described in embodiment e) of the process of the invention to give a compound of formula XXI or XXIa, wherein R4 represents hydroxy and R ^ represents bromine.

In addition, the protecting group present in R1 can be replaced at any stage of the process shown in Scheme IV.

Compounds of formula VIII, which represent starting materials in embodiment d) of this process, are known compounds or analogues of known compounds that can be prepared in a similar manner to known compounds.

The compounds of formula IX, which also represent starting materials in embodiment d) of this process, are novel and are also the subject of this invention.

Compounds of formula IX can be prepared, for example, by reaction of a compound of formula XVIII with an amine of formula V. This reaction can be carried out in the analogous manner previously described in the reaction of an amine of formula V with an acid of formula VI in embodiment c) of the process, contemplated by this invention.

Compounds of formulas X, XI, XIII, XIV and XIX, which are used as starting materials in the preceding reaction schemes, and compounds of formula XXIV are known compounds which can be prepared in a similar manner to known compounds or as described in the following cases or by analogy with them.

As mentioned above, the compounds of Formula I and their pharmaceutically acceptable salts are collagenase inhibitors. The inhibitory activity on collagenases of these compounds and salts in vitro can be demonstrated using collagenase obtained from culture of human synovial fibroblasts according to the method of Dayer J-M et al, Proc. Natl. Acad. Sci. USA (1976), 73 945, after activation of pro-collagenase in conditioned medium by trypsin treatment. Collagenase activity was measured using ^ C-acetylated collagen type I from the rat tail tendon as substrate and using a plate microtiter test method according to Johnson-Wint, B, Anal. Biochem. (1980), 104,175. IC50 represents that concentration of a compound or salt according to the invention in enzyme digestion that reduces the cleavage of the substrate and solubilization to 50% of the value obtained by the enzyme alone.

The results obtained from the study of representatives of the compounds and salts of the present invention are summarized in

Table I:

Table I

A compound of formula I IC ₅₀ (nM) A 4 B 4 C 9 D 2 E 0.5 F 0.9 Mr 1.9 H 0.5

Compound A: N ² - [(R) - [hydroxycarbamoylmethyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide;

Compound B: N ² - [2 (R or S) - [[[(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1 H -benz [d, e] isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide;

Compound C: N ² - [(R or S) - [[(R) - (amino) [5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1 H -benz [d, e] isoquinol -2-yl) methyl] - (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -N, 1-dimethyl-lvalinamide hydrobromide;

Compound D: N ² - [2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] -N1, 3dimethylvalinamide;

Compound E: N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide;

Compound F: N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4- (methoxycarbonyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide;

Compound G: N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4-phenylbutyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide;

Compound H: N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-succinimidoethyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide;

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally for example in the form of suppositories or parenterally for example in the form of injection solutions.

For the manufacture of pharmaceutical preparations, the compounds of formula I and their pharmaceutically acceptable salts may be formulated with therapeutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts may be used, for example, as tablet carriers, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols and the like. Depending on the nature of the active ingredient, a carrier for soft gelatin capsules is not usually required. Suitable carriers for making solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for the preparation of injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. Natural and hardened oils, waxes, greases, semi-liquid polyols and the like are suitable carriers for making suppositories.

Pharmaceutical preparations may also contain protective agents, stabilizers, moisturizers, emulsifiers, sweeteners, paints, flavor enhancers, osmotic pressure regulating salts, buffers, coating agents and antioxidants.

Medicaments containing compounds of formula I or their pharmaceutically acceptable salts, as well as a process for producing such medicaments, are also an object of the present invention. This process involves converting a compound of Formula I or its pharmaceutically acceptable salts into a form for galenic administration together with a therapeutically inert carrier material and, if necessary, one or more other therapeutically active substances.

As mentioned above, the compounds of Formula I and their pharmaceutically acceptable salts can be used for the treatment or prevention of diseases, especially for the treatment or prevention of degenerative joint diseases or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis. The dosage can vary over a wide range and is, of course, tailored to the requirements of the individual case. In general, in the case of administration, the daily dose is 5 to 30 mg, most preferably 10 to 15 mg, with the upper limit being exceeded if this is useful. The daily dosage amount can be administered at one time or divided into smaller dosage amounts.

The following Examples illustrate the invention in more detail. The following Examples are all temperatures in degrees Celsius.

Example 1

A solution of 1.93 g of N ² - [2 (R) - [benzyloxycarbamoylmethyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide in 150 ml of ethanol was hydrogenated in the presence of 590 mg of 5% palladium on charcoal for 1.5 hours. The catalyst was removed by filtration and the solution was evaporated with the addition of 1.52 g of N ² - [(R) - [hydroxycarbamoyl-methyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide as a white solid; nmr (MeOD): 4.22 (s, 1H); 3.0-2.9 (m, 1H), 2.73 (s, 3H); 2.3 (d, d, 1H, J = 14.8); 2.16 (d, d, 1H, J = 14.6); 1.62-1.42 (m, 2H); 1.24-1.13 (m, 1H); 0.99 (s, 9H); 0.94 (d, 3H); 0.88 (d, 3H); MS: 316 (M + H) < + >.

The starting material was obtained as follows:

i) 3.3 g of 4-tert-butyl 2 (R) -isobutyl succinate and 2.1 g (S) -tert-butylglycine methylamide were dissolved in 50 ml of dimethylformamide and the solution cooled to 0 ° C. 2.66 g of hydroxybenzotriazole and 3.25 g of Ν, Ν'-dicyclohexylcarbodiimide were added. The mixture was allowed to warm to room temperature and stirred overnight. The dicyclohexylurea was removed by filtration and the mixture was evaporated to a pale orange-colored oil which was dissolved in dichloromethane. The organic phase was washed with 5% citric acid solution, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to give an orange-colored foam. Purification by silica gel chromatography using 3% methanol / dichloromethane for elution gave 4.49 g of N ² - [2 (R) - [tert-butoxycarbonylmethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form of white foam; nmr (CDCl3) 6.55-6.48 (m, 2H); 4.32 (d, 1H, J = 10); 2.8 (d, 3H, J = 5); 2.76-2.65 (m, 1H), 2.58 (d, d, 1H, J = 15.10); 2.34 (d, d, 1H, J = 15.5); 1.6-1.45 (m, 2H); 1.43 (s, 9H); 1.3-1.27 (m, 1H); 1.0 (s, 9H); 0.9 (d, 3H, J = 5); 0.86 (d, 3H, J = 5).

ii) N ² - [2 (R) - [tert-butoxycarbonylmethyl] -4-methyl] valeryl] -Nl, 3-dimethyl-L-valinamide was dissolved in 7 ml glacial acid and treated with 10.5 ml 4M hydrogen bromide solution in glacial acetic acid. After stirring for 1.5 hours at room temperature, the mixture was evaporated and the resulting gum was re-evaporated three times with 100 ml of toluene each time. The residue was dissolved in diethyl ether and extracted twice with 5% sodium hydrogen carbonate solution. The aqueous extracts were acidified to pH 2 with hydrochloric acid and extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give 3.26 g of crude white foam containing N ² - [2 (R) -carboxymethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide .

iii) 2.4 g of the white foam above was dissolved in 60 ml of dry dichloromethane and cooled to 0 ° C. Then 0.65 ml of pyridine and 3.38 g of di (1-benzotriazolyl) carbonate were added sequentially. The mixture was stirred for 1 hour at 0 ° C and then 1.18 g of O-benzyl hydroxylamine was added. The solution was allowed to warm to room temperature and stirred overnight. The mixture was extracted three times with 5% sodium hydrogen carbonate solution, 2M hydrochloric acid and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give a white foam. Purification by flash chromatography on silica gel using 2% methanol / dichloromethane for elution gave 2.26 g of N2- [2 (R) - [benzyloxycarbamoylmethyl] -4methylvaleryl] -Nl, 3-dimethylvalinamide as a white foam; nmr (CDCl3): 9.3 (s, 1H); 7.35 (s, 5H); 6.78 (d, 1H, J = 8); 6.28 (br.s, 1H); 4.86 (s, 2H); 4.24 (d, 1H, J = 8); 3.0-2.8 (m, 1H), 2.76 (d, 3H, J = 5); 2.42-2.14 (m, 2H); 1.56-1.42 (m, 2H); 1.27-1.15 (m, 1H); 0.99 (s, 9H); 0.88 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 406 (M + H) < + >.

Example 2

In an analogous manner, as described in the first paragraph of Example 1, 300 mg of N, N - [2 (R or S) - [1 (S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl -L-valinamide, isomer 1, gave 230 mg of N ^ - [2 (R or S) - [1- (S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3dimethyl-valinamide, isomer 1, v as a white solid and from 300 mg of N, N - [2 (R or S) - [1 (S) - (benzyloxycarbamoyl) ethyl) -4-methylvaleryl] -N, 3-dimethyl-L-valinamide, isomer 2, 215 mg of N ^ - [2 (R or S) - [1- (S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] -N ^, 3dimethyl-L-valinamide, isomer 2, as a white solid, were obtained .

The nuclear magnetic resonance and mass spectra data for these isomers are as follows:

Isomer 1:

Nmr (CD3OD): 4.1 (s, 1H); 2.75-2.64 (m, 4H); 2.36-2.27 (m, 1H); 1.65-1.42 (m, 2H); 1,321.12 (m, 4H); 1.02 (s, 9H); 0.95 (d, 3H, J = 5); 0.9 (d, 3H, J = 5); MS: 330 (M + H) < + >.

Isomer 2:

Nmr (CD3OD): 4.27 (s, 1H); 2.72-2.62 (m, 4H); 2.32-2.2 (m, 1H); 1.58-1.45 (m, 1H); 1,431.28 (m, 1H); 1.13-1.05 (m, 4H); 1.02 (s, 9H); 0.89 (d, 3H, J = 5); 0.83 (d, 3H, J = 5); MS: 330 (M = H) < + >.

The starting materials were prepared as follows:

i) 18.78 g of trifluoromethanesulfonic acid anhydride were added dropwise while stirring a solution of benzyl (S) -lactate and 3.51 g of pyridine in 190 ml of dichloromethane at 0 ° C. The mixture was stirred at 0 ° C for 2.5 hours, then washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to 100 ml. This solution was added dropwise to a stirred solution containing 9.6 g of di-tert-butyl malonate and 1.33 g of 80% sodium hydride in 110 ml of dimethylformamide at 0 ° C. The mixture was stirred for 72 hours at room temperature. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The solution was washed with 5% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to an oil. Purification by flash chromatography on silica gel using 5% ethyl acetate / n-hexane for elution gave 9.75 g of 1-benzyl-3-tert-butoxycarbonyl-4-tert-butyl-2 (S) -methylsuccinate as yellow oils, nmr (CDCl3): 7.38-7.34 (m, 5H); 5.15 (dd, 2H, J = 20.15); 3.55 (d, 1H, J = 15); 3.17-3.07 (m, 1H); 1.45 (s, 9H); 1.43 (s, 9H); 1.23 (d, 3H, J = 7); MS: 379 (M + H) < ⁺ >.

ii) 1.16 g of 80% sodium hydride was added with stirring to a solution of 9.72 g of 1-benzyl-3-tert-butoxycarbonyl-4-tert-butyl-2 (S) -methylsuccinate in 75 ml of dimethylformamide. After complete foaming, 7.09 g of isobutyl iodide were added and the solution was stirred at 80 ° C for 5 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The mixture was washed with 5% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to an oil. Purification by flash chromatography on silica gel gave 4.9 g of 1-benzyl-4-tert-butyl-3-tert-butoxycarbonyl-3-isobutyl-2 (S) -methylsuccinate as an oil; nmr (CDCl3): 7.38-7.30 (m, 5H); 5.14 (dd, 2H, J = 20.12); 3.16 (q, 1H, J = 7); 1.92-1. 7 (m, 3H); 1.45 (s, 18H); 1.34 (d, 3H, J = 7); 0.9 (d, 3H, J = 6); 0.86 (d, 3H, J = 6); MS: 435 (M + H) < + >.

iii) 6.67 g of 1-Benzyl-4-tert-butyl-3-tert-butoxycarbonyl-3-isobutyl-2 (S) -methylsuccinate were stirred with 40 ml of trifluoroacetic acid for 2 hours, then the mixture was evaporated and the residue dissolved in toluene and refluxed for 3 hours. The solvent was removed by evaporation to give 4.2 g of 1-benzyl-3 (RS) -isobutyl-2 (S) -methylsuccinate as a yellow oil; Rf 0.83.

iv) In an analogous manner to that described in Example l) -ii), from 5.3 g of 1-benzyl-3 (RS) isobutyl-2 (S) -methylsuccinate 2.4 g of N ² - [2 (RS) - [ 1- (S) - (Benzyloxy-carbamoyl) ethyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a mixture of diastereoisomers.

The isomers were separated by preparative HPLC on a Dynamax 60A column using 10% isopropanol in n-hexane as the mobile phase and at a flow rate of 15ml / min. 908 mg of isomer 1 (retention time of 14 minutes) and 300 mg of isomer 2 (retention time of 17 minutes) were obtained.

The nuclear magnetic resonance and mass spectra data for these isomers are as follows:

Isomer 1:

Nmr (CDCl ₃ ): 9.63 (br.s, 1H) 7.43-7.30 (m, 5H); 6.45-6.30 (m, 2H); 4.35 (br.s., 2H), 4.12 (d, 1H, J = 8); 2.66 (d, 3H, J = 5); 2.58-2.48 (m, 1H); 2.43-2.30 (m, 1H); 1.65-1.48 (m, 2H);

1.3-1.2 (m, 1H); 1.16 (d, 3H, J = 7); 1.02 (s, 9H); 0.96-0.88 (m, 6H); MS: 420 (M + H) < + >.

Isomer 2:

Nmr (CDCl3): 9.43 (s, 1H); 7.43-7.32 (m, 5H); 6.85 (d, 1H, J = 9); 6.5 (br.q, 1H, J = 4); 4.93 (s, 2H); 4.3 (d, 1H, J = 9); 2.74 (d, 3H, J = 4); 2.72-2.63 (m, 1H); 2.43-2.33 (m, 1H); 1,571.32 (m, 2H); 1.18-1.05 (m, 4H); 1.01 (s, 9H); 0.85 (d, 3H, J = 7); 0.8 (d, 3H, J = 7);

MS: 420 (M + H) < + >.

Example 3

A mixture of 132 mg of N ^ - [2 (R or S) - [[(RS) - (ethoxy) - [(5-bromo-2,3-dihydro-6-hydroxy-1,1, dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] phosphinyl] methyl] -4-methylvaleryl] -N ¹ , 3-dimethyl-lvalinamide and 2 ml of trifluoroacetic acid in 2 ml of dry dichloromethane were stirred at room temperature overnight. The solvent was removed by evaporation and the residue was evaporated twice from a 1: 1 mixture of methanol and dichloromethane and then twice from dichloromethane. The remaining solid was triturated in dry diethyl ether and dried in vacuo to give 90 mg of N ² - [2 (R or S) - [[[(5-bromo-2,3-dihydro-6-hydroxy-1, 3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methyl-valeryl] -Nl, 3-dimethyl-lvalinamide as a yellow solid; nmr (dgDMSO): 8.68 (d, 1H, J = 8); 8.52 (d, 1H, J = 8); 8.49 (s, 1H); 7.92-7.83 (m, 2H); 7.63 (d, 1H, J = 10); 4.42 (d, 2H, J = 8); 4.15 (d, 1H, J = 10); 3.95-3.05 (br); 2.95-2.8 (m, 1H); 2.55 (d, 3H, J = 4); 2.12-1.98 (m, 1H); 1,861.73 (m, 1H); 1.55-1.32 (m, 3H); 0.96-0.75 (m, 15H); MS: 624, 626.

The starting material was prepared as follows:

i) 1.37 g of 2 (R or S) - [[(RS) - (ethoxy) - (phthalimidomethyl) phosphinyl] methyl] -4-methyl-valeric acid in 20 ml of dichloromethane was cooled to 0 ° C and then 0.29 was added successively ml of pyridine and 1.52 g of di (1-benzotriazolyl) carbonate. The mixture was stirred for 1 hour at 0 ° C and then 0.52 g (S) -tert.-butylglycine N-methylamide was added. The mixture was allowed to warm to room temperature and stirred overnight. The solution was diluted with dichloromethane, washed three times with 5% sodium hydrogen carbonate solution, once with 2M hydrochloric acid and once with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using 3% methanol / dichloromethane for elution to give 952 mg of N ² - [2 (R or S) - [[(RS) - (ethoxy) phthalimidomethyl] ) (phosphinyl)] methyl] 4-methylvaleryl] -Nl, 3-dirnetyl-L-valinamide in white foam form;

nmr (CDCl3): 7.94-7.72 (m, 4H); 6.85-6.55 (m, 1H); 6.18-6.0 (m, 1H); 4.3-4.05 (m, 5H);

2.94-2.76 (m, 4H); 2.36-2.13 (m, 1H); 2.05-1.85 (m, 2H); 1.7-1.58 (m, 1H), 1.56-1.46 (m, 1H); 1.45-1.26 (m, 3H); 1.06-0.85 (m, 15H); MS: 508 (M + H) < ⁺ >.

ii) A solution of 820 mg of N ² - [2 (R or S) - [[(RS) - (ethoxy) - (phthalimidomethyl) (phosphinyl)] methyl] -4methylvaleryl] -N, 3-dimethyl-L-valinamide and 0.23 ml of hydrazine hydrate in 10 ml of ethanol was stirred overnight at room temperature. The solvent was removed by evaporation and the residue was evaporated three times from toluene. The residue was dissolved in a mixture consisting of 10 ml of dichloromethane and 0.4 ml of glacial acetic acid, and the resulting solution was stirred for 2 hours at room temperature. The mixture was evaporated and the residue partitioned between diethyl ether and 5% citric acid solution. The aqueous phase was washed with diethyl ether, neutralized with concentrated ammonia solution and the aqueous phase extracted twice with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, evaporated and redissolved in 10 ml of dichloromethane. 0.13 ml of N-ethyl-morpholine and 300 mg of 4-benzyloxy-1,8-naphthoic acid anhydride were added sequentially and the mixture was stirred at room temperature for 2 days. The solution was washed with 2M hydrochloric acid, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using 3% methanol / dichloromethane for elution to give 433 mg of N ² - [2 (R or S) - [[(RS) - (ethoxy) - [(6-benzyloxy2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl-methyl] phosphinyl] methyl] -4-methylvaleryl] N, 3-dimethyl-L -valinamide as a yellow solid; nmr (CDCl3): 8.68-8.58 (m, 3H); 7.76-7.7 (m, 1H); 7.56-7.4 (m, 4H); 7.16 (d, d, 1H, J = 8.4); 7.08 (d, 0.6H, J = 10); 6.9 (d, 0.4H, J = 10); 6.23-5.96 (m, 1H); 5.4 (s, 2H); 4.78-4.7 (m, 1H ); 4.56-4.48 (m, 1H); 4.344.15 (m, 3H); 3.08-2.85 (m, 1H); 2.8 (d, 1H, J = 5); 2.72 (d, 2H, J = 5) ; 2.45-2.28 (m, 1H); 2.21.95 (m, 1H); 1.8-1.66 (m, 2H); 1.63-1.4 (m, 2H); 1.34 (q, 2H, J = 6); 1.0 ( s, 6H); 0.95 (s, 3H); 0.92-0.85 (m, 6H); MS: 664 (M + H) +.

iii) A solution of 400 mg of N ² - [2 (R or S) - [[(RS) - (ethoxy) - [6-benzyloxy-2,3-dihydro-1,2-dioxo-1H-benz [d, e] - isoquinol-2-yl) methyl] phosphinyl] methyl-4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide in 40 ml of ethanol was hydrogenated in the presence of 100 mg of 10% palladium on carbon as a catalyst. The catalyst was removed by filtration, the filtrate was re-evaporated and the residue was evaporated twice from toluene to give 334 mg of N ² - [2 (R or S) - [[(RS) (ethoxy) [(2,3-dihydro-6- hydroxy-1,3-dioxo-1H-benz [d, e] -isoquinol-2-ylmethyl] phosphinyl] methyl] -4-methyl-aryl] -Nl, 3-dimethyl-L-valinamide as a white solid; nmr (CDCl3): 11.1 (brs.lH); 8.38-8.32 (m, 1H); 7.83-7.72 (m, 2H); 7.23-6.95 (m, 3H); 6.64-6.56 (m, 1H); 6.06- 5.9 (m, 1H); 4.88-4.73 (m, 1H); 4.45-4.26 (m, 2H); 4.25-4.13 (m, 2H); 3.05-2.9 (m, 1H); 2.8-2.75 (m, 3H ); 2.72-2.52 (m, 1H,); 2.4-2.08 (m, 1H); 1.8-1.4 (m, 6H); 1.02-0.88 (m, 15H); MS: 574 (M + H) +.

iv) 300 mg solution of N ² - [2 (R or S) [[(RS) - (ethoxy) [(2,3-dihydro-6-hydroxy-1,3 dioxo-1H-benz [d, e] -isoquinol-2 -yl) methyl] -phosphinyl] methyl] -4-methylvaleryl] -Nl-, 3-dimethyl-lvalinamide in 10 ml of dry dichloromethane was cooled to 0 ° C and a solution of 83 mg of bromine in 2 ml of dichloromethane was added. After 10 minutes, the solution was washed twice with 5% sodium thiosulphate solution, dried over anhydrous magnesium sulfate and evaporated to give 350 mg of N ² - [2 (R or S) [[(RS) - (ethoxy) [(5-bromo- 2,3-dihydro-6-hydroxyl, 3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] -phosphinyl] methyl] -4-methylvaleryl] -N, - 3-dimethyl- valinamide as a yellow solid; nmr (CDCl3): 10.5-10.2 (br s.lH); 8.5-8.42 (m, 1H); 8.3 (d, 1H, J = 9); 7.53-7.46 (m, 1H); 6.95 (d, 0.6H, J = 8); 6.68 (d, 0.4H, J = 8); 6.025.85 (m, 1H); 4.92-4.77 (m, 1H); 4.46-4.22 (m, 4H); 3.08-2.95 (m, 1H); 2.83 (d, 3H, J = 5);

2.7-2.51 (m, 1H,); 2.43-2.12 (m, 1H); 1.84-1.45 (m, 8H, (6H + H ₂ O)); 1.06-0.92 (m, 15H); MS: 651,653.

Example 4

In the analogous manner as described in the first paragraph of Example 3, 600 mg of N ² [2 (R or S) [[(RS) - (ethoxy) [(2,3-dihydro-6-hydroxy-1,3) -dioxo-1H-benz [d, e] -isoquinol-2yl) -methyl] -phosphinyl] methyl] -4-methylvaleryl] -Nl-, 3-dimethyl-L-valinamide prepared as described in Example 3iii), obtained 411 mg of N ² - [2 (R or S) [[[[(2,3-dihydro-6-hydroxy-1, 3dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy ) phosphinyl] methyl] -4-methylvaleryl] -N ^ -, 3dimethyl-L-valinamide in the form of a yellow foam; nmr (d ^ DMSO): 11.98 (brs, 1H); 8.56 (d, 1H, J = 8); 8.52 (d, 1H, J = 8); 8.4 (d, 1H, J = 8); 7.9 (q, 1H, J = 5); 7.8 (t, 1H, J = 6); 7.63 (d, 1H, J = 10); 7.18 (d, 1H, J = 8); 4.44 (d, 2H, J = 9); 4.15 (d, 1H, J = 10); 4.10-3.10 (brs);

2.95-2.82 (m, 1H); 2.56 (d, 3H, J = 5); 2.12-2.0 (m, 1H); 1.85-1.72 (m, 1H); 1.55-1.32 (m, 3H); 0.86-0.78 (m, 15H); MS: 546 (M + H) < + >.

Example 5

A solution of 550 mg of N1- (N-benzyloxycarbonyl-4-aminobutyl) -N ² - [2 (R or S) [[(RS) 29 (ethoxy) [(2,3-dihydro-1,3-dioxo-1H- benz [d, e] -isoquinol-2-ylmethyl] phosphinylmethyl] -4-methylvaleryl] -3-methyl-L-valinamide in 2 ml of 4M hydrochloric acid in acetic acid was stirred for 1 hour at room temperature. The solvent was removed by evaporation and the remaining oil was evaporated from toluene. Then methanol and subsequently diethyl ether were added, the resulting precipitate was filtered off, washed with diethyl ether and dried in vacuo to give 462 mg of N1- (4-aminobutyl-N2- [2 (R or S) - [[[(2, 3-Dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -3-methyl-L-valinamide hydrobromide in the form light orange-colored solids; nmr (d ^ DMSO): 8.53 (t, 4H, J = 7); 8.04 (t, 1H, J = 5); 7.94 (t, 2H, J = 7); 7.72 (brs. 2H); 7.65 (d, 1H, J = 9); 5.26 (brs); 4.48 (d, 2H, J = 9); 4.15 (d, 1H, J = 9); 3.15-2.72 (m, 5H); 2.16-2.0 (m, 1H); 1.9-1.75 (m, 1H); 1.58-1.35 (m, 7H); 0.92-0.78 (m, 15H); MS: 586 (M + H) +.

The starting material was prepared as follows:

i) A solution of 5g of N- (tert-butoxycarbonyl) -tert-butyl glycine and 1.75 ml of pyridine in 100 ml of dry dichloromethane was cooled to 0 ° C and 9.14 g of di- (1-benzotriazolyl) carbonate was added with stirring. After 1 hour, a solution of 5.42 g of N, N-benzyloxycarbonyl-1,4diaminobutane was added and 1.75 ml of pyridine in 10 ml of dichloromethane was added and the mixture was stirred overnight at room temperature. The mixture was washed twice with 5% sodium hydrogen carbonate solution, once with 2M hydrochloric acid and once with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to give 8.4 g of N ^1- (4- (benzyloxycarbonylamino) butyl) -N 2 - (tert-butoxycarbonyl) -3-methyl-valinamide as a white foam; nmr (CDCl3): 7.35 (s, 5H); 6.38 (br.s, 1H); 5.4-5.08 (m, 4H); 3.97-3.83 (m, 1H); 3.30-3.1 (m, 4H); 1.5 (br.s, 4H); 1.42 (s, 9H); 0.96 (s, 9H); MS: 436 (M + H) < + >.

ii) A solution of 1.6 g of N ¹ - (4-benziIoksikarbonilamino) -butyl-N ^ - (tert-butoxycarbonyl) -3metilvalinamida in 50 ml of 4M hydrochloric acid / ethyl acetate was stirred at room temperature for 2 hours. The solvent was removed by evaporation to give 1.42 g of white foam, which was then reacted with 1.58 g of 2 (R or S) - [[(RS) - (ethoxy)] (2,3-dihydro-1,3-dioxo -1H-benz [d, e] isoquinol-2-yl) methyl] phosphinyl] methyl] -4-methyl valeric acid in an analogous manner as described in Example 3i) to give 1.54 g of N1- (N-benzyloxycarbonyl) -4aminobutyl-N ^ - [2 (R or S) [[(RS) - (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol2-yl) methyl ] phosphinyl] methyl] -4 [methylvaleryl] -3-methyl-L-valinamide in the form of white foam;

nmr (CDCl3): 8.64 (d, 2H, J = 6); 8.27-8.22 (m, 2H); 7.82-7.74 (m, 2H); 7.38-7.27 (m, 5H);

6.77 (d, 0.33H, J = 9); 6.84 (d, 0.66H, J = 9); 6.25 (br.s, 0.33H); 6.07 (br. S, 0.66H); 5.13-4.95 (m, 3H); 4.78-4.67 (m, 1H); 4.55-4.43 (m, 1H); 4.3-4.06 (m, 3H); 3.29-3.07 (m, 4H); 3.0530

2.8 (m, 1H); 2.43-2.26 (m, 1H); 2.17-1.94 (m, 1H); 1.78-1.62 (m, 3H); 1.6-1.25 (m, 8H); 1.00.83 (m, 15H); MS: 749 (M + H) < + >.

Example 6

300 mg solution of NL (4-nitroguanidinobutyl) -N ² - [2 (RaliS) - [[(RS) - (ethoxy) [2,3-dihydrol, 3-dioxo-1H-benz [d, e] -isoquinol- 2-yl) methyl] phosphinyl] methyl] -4-methylvaleryl] -3-methyl-Lvalin-amide in 20 ml of 80% acetic acid was hydrogenated in the presence of 30 mg of 10% palladium on carbon as a catalyst. The catalyst was removed by filtration, the filtrate was evaporated to dryness and the residue was dissolved in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid and the solution was stirred overnight at room temperature. The solvent was removed by evaporation and the residue was evaporated twice with 2 ml of methanol and 2 ml of dichloromethane and 2 times with 2 ml of dichloromethane. The remaining solid was triturated with diethyl ether, filtered and dried in vacuo to give 180 mg of trifluoroacetate N1- (4-guanidinobutyl) -N ² - [2 (R or S) - [[[2,3-dihydro-1] , 3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] phosphinyl] methyl] -4methyl valeryl] -3-methyl-L-valinamide; nmr (dgDMSO): 8.53 (t, 4H, J = 8) 8.03 (t, 1H, J = 7);

7.92 (t, 2H, J = 8); 7.75 (br.s, 1H); 7.1 (br.s, 3H); 4.42 (d, 2H, J = 10); 4.07 (d, 1H, J = 7); 3.142.72 (m, 5H); 2.12-1.98 (m, 1H); 1.85-1.72 (m, 1H); 1.6-1.25 (m, 8H); 0.95-0.7 (m, 15H); MS: 629 (M + H) < + >.

The starting material was prepared as follows:

i) A solution of 1 g of NL (N-benzyloxycarbonyl-4-aminobutyl) methyl valinamide in 10 ml of ethanol was hydrogenated for 1 hour in the presence of 100 mg of 5% palladium on carbon as a catalyst. The catalyst was removed by filtration and 342 mg of 3.5dimethyl-N-nitro-1H-pyrazole-1-carboximidamide was added to the filtrate and the mixture was heated under reflux for 12 hours. The solvent was removed by evaporation and the residue was dissolved in dichloromethane. The solution was washed with 2M hydrochloric acid and 5% sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated to give a white foam. It was purified by flash chromatography on silica gel using 5% methanol / dichloromethane for elution to give 538 mg of N ² - (tert-butoxycarbonyl) N 1- [4- (nitroguanidino) butyl] -3-methylvalinamide as white foam; nmr (CDCl3): 8.55 (br.s, 1H); 7.68 (br. S, 2H); 6.66 (br.s, 1H); 5.26 (br.s, 1H); 3.95 (br. S, 1H), 3.55-3.2 (m, 4H); 1.66-1.54 (m, 4H); 1.43 (s, 9H); 1.0 (s, 9H); MS: 389 (M + H) < + >.

ii) 500 mg of N ² - (tert-butoxycarbonyl) -nl [4- _(n itrogvanidino) butyl] -3-metilvalinamida was treated with 554 mg of 2 (R or S) - [[(RS) - (ethoxy) [ (2,3-dihydro-1,3-dioxo-1H-benz [d, e) isoquinolyl-2-yl) methyl] phosphinyl] methyl-4-methyl valeric acid in an analogous manner as described in Example 3i), that 322 mg of N1- (4-nitroguanidinobutyl) -N2 - [2 (R or S) - [[(RS) - (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz] was obtained d, e] -isoquinol-2-yl) methyl] phosphinyl] methyl] -4-methylvaleryl] -3-methyl-L-valinamide in the form of white foam; nmr (CDCl3): 8.62 (d, 2H, J = 7); 8.32-8.25 (m, 2H); 7.83-7.75 (m, 2H); 7.55 (br, 1H); 7.15-6.88 (m, 2H); 4.844.72 (m, 1H); 4.52-4.4 (m, 1H); 4.3-4.15 (m, 3H); 3.48 (q, 2H, J = 7); 3.3-2.8 (m, 3H); 2.52.22 (m, 2H); 1.6-1.18 (m, 14H); 1.02-0.8 (m, 15H); MS: 702 (M + H) < + >.

Example 7

Solution 500 mg [N ^ - [2 (R or S) - [[(RS) - (ethoxy) [5-tert-butoxycarbonylamino-1- (RS) (2,3-dihydro-1H-benz- [d , e] isoquinolin-2-yl) pentyl] phosphinyl] methyl] -4-methylvaleryl] -Nl-, 3dimethyl-L-valinamide in 1 ml glacial acetic acid and 4 ml 45% hydrobromic hydrochloric acid was stirred for 4 hours at room temperature . The solvent was removed by evaporation and the residue was evaporated twice from toluene to give a pale yellow powder as a mixture of diastereoisomers. The diastereoisomers were determined by preparative reverse phase HPLC on a Sphensorb S5 column using 50% methanol / 0.05M ammonium formate at a flow rate of 8 ml / min as the mobile phase and obtained:

i) 78 mg [N2- [2 (R or S) - [[[5-amino-1 (R or S) - (2,3-dihydro-1H-benz- [d, e] isoquinolin-2yl) pentyl] ] (hydroxy) phosphinyl] methyl] -4-methylvaleryl-N, N -, 3-dimethyl-L-valinamide, isomer 1; retention time 22 min; nmr (CD3OD): 8.56 (d, 1H, J = 6); 8.50 (d, 1H, J = 6); 8.32 (t, 2H, J = 7); 7.81 (t, 1H, J = 7); 7.73 (t, 1H, J = 7); 5.36-5.25 (m, 1H); 4.16 (s, 1H); 3.02-2.82 (m, 3H); 2.7 (s, 3H); 2.48-2.33 (m, 1H); 2.2-1.98 (m, 3H); 1.78-1.64 (m, 3H); 1.60-1.35 (m, 4H); 0.97 (s, 9H); 0.9 (d, 3H, J = 6); 0.85 (d, 3H, J = 6) MS: 601 (M + H) +;

and ii) 70 mg of N - [2 (R or S) - [[[5-amino-1 (R or S) - (2,3-dihydro-1H-benz [d, e] isoquinolin-2yl) pentyl 1] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -N 1,3-dimethyl-L-valinamide, isomer 2: retention time = 34 minutes; nmr (CD3OD): 8.58 (d, 2H, J = 7); 8.36-8.29 (m, 2H); 7,857.75 (m, 2H); 5.4-5.26 (m, 1H); 4.18 (s, 1H); 2.96-2.84 (m, 3H); 2.68 (s, 3H); 2.47-2.32 (m, 2H); 2.19-2.04 (m, 1H); 1.92-1.65 (m, 4H); 1.63-1.37 (m, 4H); 1.01 (s, 9H); 0.87 (t, 6H, J = 6); MS: 601 (M + H) < + >.

The starting material was obtained as follows:

i) A solution of 11.7 g of benzyl 2 (R or S) - [(ethoxyphosphinyl) methyl] -4-methylvalerate and 13.0 g of 5-phthalimido-pentan-1-ala in 100 ml of toluene was treated with 4.7 ml of 1,1,3,3 -tetramethylguanidine and the mixture was stirred at room temperature for 12 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using ethyl acetate / n-hexane (2: 1) for elution to give 8.8 g of a white foam. This foam was dissolved in 150 ml of ethanol, 2.36 ml of hydrazine hydrate was added and the mixture was stirred overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in dichloromethane. 5 ml of glacial acetic acid was added and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, evaporated to dryness and the residue partitioned between diethyl ether and 2M hydrochloric acid. The aqueous phase was basified with concentrated ammonia solution and extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, evaporated and redissolved in 100 ml of dioxane and 100 ml of water. Subsequently, 2.49 g of sodium hydrogen carbonate was added and then 3.87 g of diter-butyl dicarbonate was added and the mixture was stirred overnight at room temperature. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate. The organic phase was washed with 5% citric acid solution, dried over anhydrous magnesium sulfate, evaporated and redissolved in 100 ml of dry dichloromethane. The solution was cooled to 0 ° C and treated with 10.93 ml of pyridine and then dropwise with 1.58 ml of methanesulfonyl chloride. The resulting mixture was stirred at 0 ° C for 2 hours and then at room temperature overnight. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using ethyl acetate / n-hexane (3: 1) for elution to give 5.5 g of benzyl (2- (R or S)) - [[(RS) - (Ethoxy) [1 (RS) -methanesulfonyloxy-5- (tert-butylcarbonylamino) pentyl] phosphinyl] methyl] -4-methylvalerate in the form of white foam.

The above benzyl ester was dissolved in 100 ml of dimethylformamide and 1.21 g of sodium azide was added to the solution. The mixture was heated to 70 ° C for 48 hours, the solvent was removed by evaporation and the residue was dissolved in 50 ml of dichloromethane. The organic layer was washed with 50 ml of sodium hydrogen carbonate solution and 50 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give an oil of yellow color. Purification by flash chromatography on silica gel using ethyl acetate / n-hexane (3: 1) for elution gave 3.65 g of benzyl 2- (R or S) - [[(RS) - (ethoxy) [1- (RS) -azido-5 (tert-butoxycarbonylaminopentyl] phosphinyl] methyl] -4-methylvalerate in white foam form; nmr (CDCl ₃ ): 7.37 (s, 5H); 5.2-5.1 (m, 2H); 4.56 (brs.lH ); 4.17-4.03 (m, 2.5H); 3.43-3.33 (m, 0.5H); 3.25-3.05 (m, 2H); 3.02-2.87 (m, 1H); 2.39-2.15 (m, 1H); 1.98 -1.75 (m, 2H); 1.71.23 (m, 20H); 0.92 (d, 3H, J = 6); 0.87 (d, 3H, J = 6); MS: 539 (M + H) +.

ii) 2.04 ml of 1,3-propanedithiol were added dropwise and stirring was added to a solution of 3.65 g of benzyl 2 (R or S) - [[(RS) - (ethoxy) [- 1- (RS) -azido-5-tert. -butoxycarbonylaminopentylphosphonyl] -methyl] -4-methylvaIerate and 2.83 ml of triethylamine in 80 ml of methanol. The mixture was stirred overnight at room temperature, the solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using 4% methanol / dichloromethane for elution to give 3.25 g of benzyl 2 (R or S) - [[(RS) - (ethoxy) [- 1- (RS) 33 amino-5-tert-butoxycarbonylaminopentyl] phosphinyl] methyl] -4-methylvalerate in the form of white foam; nmr (CDCl3): 7.36 (s, 5H); 5.2-5.08 (m, 2H), 4.6 (brs, 1H), 4.2-3.98 (m, 2H), 3.173.08 (m, 2H); 3.0-2.76 (m, 2H); 2.4-2.13 (m, 1H), 2.0-1.25 (m, 25H); 0.98-0.86 (m, 6H);

MS: 513 (M + H) < + >.

iii) A solution of 3.25 g of benzyl 2- (R or S) - [[(RS) - (ethoxy) [1- (RS) -amino-5-tert-butoxycarbonylaminopentyl] phosphinyl] methyl] -4-methylvalerate and 1.52 g The 1,8-naphthalene anhydride anhydride in 50 ml of dimethylformamide was treated with 0.96 ml of 1,1,3,3-tetramethylguanidine. The mixture was heated at 50 ° C for 48 hours, the solvent was removed by evaporation and the residue was dissolved in dichloromethane. The solution was washed with 2M hydrochloric acid, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a gum-like yellow substance. Purification by flash chromatography on silica gel using 2% methanol / dichloromethane for elution gave 1.78 g of benzyl 2- (R or S) - [[(ethoxy) -5 tert-butoxycarbonylamino-1- (RS) - (2, 3-Dihydro-1H-benz [d, e] -isoquinolin-2-yl) pentylphosphinyl] methyl] -4-methylvalerate in the form of a yellow foam.

The previous benzyl ester was dissolved in 20 ml of isopropanol and the solution was hydrogenated in the presence of 300 mg of 10% palladium on charcoal. The catalyst was removed by filtration and the filtrate was evaporated and the residue was dissolved in dry dichloromethane and cooled to 0 ° C. The solution was treated with 0.2 ml of pyridine and then with 1.09 g of di- (1-benzotriazolyl) carbonate. The mixture was stirred for 1 hour at 0 ° C and then 0.4 g of Nl, 3-dimethyl-Lvalinamide in 1 ml of dichloromethane was added. The mixture was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was diluted with dichloromethane, washed three times with 5% sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated to give a yellow foam.

Purification by flash chromatography on silica gel using 3% methanol / dichloromethane for elution gave 1.12 g of [N ² - [2 (R or S) - (ethoxy) [5-tert.butoxycarbonylamino-1- (RS) - ( 2,3-Dihydro-1H-benz [d, e] isoquinolin-2-yl) pentyl] phosphinylrnethyl] -4-phenylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form of pale yellow foam; nmr (CDCl3): 8.66-8.46 (m, 2H); 8.3-8.22 (m, 2H); 7.83-7.72 (m, 2H), 7.12-6.73 (m, 1H), 6.286.17 (m, 1H), 5.68-5.4 (m, 1H); 4.6-4.48 (m, 1H); 4.3-4.06 (m, 3H), 3.1-2.96 (m, 2H); 2,932.73 (m, 4H); 2.6-2.04 (m, 3H); 1.78-1.3 (m, 18H); 1.28-0.82 (m, 15H); MS: 729 (M + H) < + >.

Example 8

In the analogous manner as described in the first paragraph of Example 3, 120 mg of N2 - [2 (R or S) - [[(RS) - (ethoxy) [1- (RS) - (2,3-dihydro) -1H-benz [d, e] isoquinolin-2-yl) -2-hydroxyethyl] -phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide gave 105 mg of N ^ - [2 (R or S) - [[[1 (RS) - (2,3-dihydro-1H-benz- [d, e] isoquinolin-2-yl) -2-hydroxyethyl] - (hydroxy) -phosphinylmethyl] -4-methylvaleryl ] -Nl, 3-dimethyl-L-valinamide as a mixture of 2: 1 diastereoisomers in the form of white foam; nmr (CD3OD): 8.78-8.66 (m, 2H); 8.43-8.35 (m, 2H); 7.90-7.8 (m, 2H),

5.93-5.8 (m, 0.5H), 5.72-5.6 (m, 0.5H); 5.15-5.06 (m, 1H); 4.32-4.13 (m, 2H); 3.13-2.9 (m, 1H); 2.72 (s, 3H); 2.64-1.95 (m, 3H); 1.72-1.37 (m, 3H); 1.05-0.84 (s, 15H); MS: 558 (M-H) < + >.

The starting material was obtained as follows:

In an analogous manner to that described in Example 7 (i-iii), N- - [2 (R or S) - [[(RS) -] was obtained from 1- (diphenyl-tert-butylsilyloxy) ethan-1-ala. (ethoxy)] 1 (RS) - (2,3-dihydro-1Hbenz [d, e] isoquinolin-2-yl) -2-hydroxyethyl] phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide in the form of white foam; nmr (CDCl3): 8.66-8.58 (m, 2H); 8.3-8.23 (m, 2H); 7.837.75 (m, 2H), 6.99-6.8 (m, 1H), 6.11-5.9 (m, 1H); 5.8-5.57 (m, 1H); 4.58-4.35 (m, 1H); 4,324.05 (m, 4H); 3.52 (brs, 0.5H); 3.16 (br. S, 0.5H); 2.96-2.72 (m, 4H); 2.7-2.3 (m, 2H); 2.251.92 (m, 1H); 1.55-1.23 (m, 5H); 1.05-0.82 (m, 15H); MS: 588 (M + H) < + >.

Example 9

In the analogous manner as described in the first paragraph of Example 7, 250 mg of N2 - [2 (R or S) - [[(RS) - (ethoxy) [3-tert-butoxycarbonylamino-1- (RS) - (2,3-dihydro-1,3-dioxolH-benz- [d, e] isoquinol-2-yl) propyl] phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide obtained 205 mg N N - [2 (R or S) - [[[3-amino-1- (RS) - (2,3-dihydro-1,3-dioxo-1H-benz- [d, e] isoquinol-2-yl) propyl ] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-Lvalin-amide as a mixture of 1: 1 diastereoisomers as white foam; nmr (CD3OD): 8.55 (t, 2H, J = 7); 8.34 (d, 2H, J = 7); 7.82-7.74 (m, 2H), 5.42-5.26 (m, 1H); 4.34 (d, 1H, J = 5);

3.02-2.85 (m, 3H); 2.63-2.44 (m, 5H); 2.42-2.14 (m, 2H); 2.01-1.98 (m, 1H); 1.65-1. 3 (m, 3H); 0.95-0.76 (m, 15H); MS: 573 (M + H) < + >.

In an analogous manner as described in Example 7 (i-iii), N ^ '[2 (R or S) - [[(RS) - (-) is obtained from 3- (tert-butoxycarbonylamino) -propan-1-ala. ethoxy) [3-tert-butoxycarbonylamino-1- (RS) - (2,3) -dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) propyl] phosphinyl] methyl] - 4-methylvaleryl] -N, N, 3-dimethyl-L-valinamide as a 1: 1 mixture of diastereo35 isomers as white foam; nmr (CDCl3): 8.63-8.56 (m, 2H); 8.3-8.22 (m, 2H); 7.85-7.74 (m, 2H); 7.07 (d, 0.5H, J = 9); 6.92 (d, 0.5H, J = 9); 6.71 (No q, 0.5H, J = 4); 6.17 (No.

q, 0.5H, J = 4), 5.57-5.4 (m, 1H); 5.2 (no. T, 1H, J = 5); 4.3-4.07 (m, 3H); 3.49 (br. S, 1H);

3.02-2.46 (m, 5H); 2.4-2.22 (m, 1H); 2.18-2.06 (m, 1H); 1.89-1.56 (m, 4H); 1.46-1.32 (m, 12H); 1.06-0.86 (m, 15H); MS: 701 (M + H) < + >.

Example 10

Mixture of 0.276 g [2 (R or S) - [(R) - (benzyloxyformamido) [[(2,3-dihydro-1,3-dioxo-1Hbenz [d, e] isoquinol-2-yl) -) methyl] - (hydroxy) phosphinyl] methyl] -4-methylvaleric acid and 0.144 g of L-2- (tert-butyl) glycine methylamide in 25 ml of toluene were heated at reflux (bath temperature 140 ° C) for 7 hours under a nitrogen atmosphere. The solvent was removed by evaporation and the residue was dissolved in 15 ml of dichloromethane containing 0.3 g of trifluoroacetic acid and evaporated again. After two further evaporations of 10 ml of ethanol, the residue was dissolved in 4 ml of ethanol and the product precipitated by the gradual addition of 10 ml of water. Thus, 0.26 g of N ² - [2 (R or S) - [(R) - (benzyloxyformamido) [[(2,3-dihydro-1, 3dioxo-1H-benz [d, e] isoquinol-2-yl) ) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3dimethyl-L-valinamide as a white solid; MS: 679 (M + H) < ⁺ >.

The starting material was obtained as follows:

i) A mixture of 19.8 g of crystalline hypophosphoric acid and 36 g of trimethyl orthoformate was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. 27.6 g of diethyl acetamidomethylene malonate were added to the solution and the mixture was cooled to 0 ° C. Then the solution was added

11.5 g of 1,1,3,3-tetramethyl-guanidine in 20 ml of dichloromethane while maintaining the temperature between 0 and 10 ° C. After complete addition, the mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane and poured onto a mixture of 250 ml of 2M hydrochloric acid and ice. The organic phase was decided and the aqueous phase extracted three times with dichloromethane. The organic solutions were combined and evaporated to give 40 g of a pale yellow oil which was dissolved in a mixture of 70 ml of dichloromethane and 60 ml of trifluoroacetic acid. The solution was allowed to stand at room temperature for 24 hours and then evaporated. Toluene was added to the residue and the resulting solution was evaporated. The residue was dissolved in ether and allowed to crystallize for 24 hours. The solid was filtered and dried in vacuo to give 29.34 g of diethyl 2 - [(acetamido) (hydroxyphosphinyl) methyl] malonate as a white solid, m.p. 113-114 ° C.

ii) 12.0 g of Diethyl 2 - [(acetamido) (hydroxyphosphinyl) methylmalonate were dissolved in 100 ml of dry dimethyl sulfoxide and the solution cooled to 10 ° C under stirring and under a nitrogen atmosphere. 3.2 g of 60% sodium hydride in mineral oil were added and the mixture was stirred at room temperature for 2 hours and then 8 g of isobutyl iodide was added. The mixture was stirred at room temperature and in the dark for 20 hours and then 20 ml of glacial acetic acid were added. The volatiles were removed by evaporation under high vacuum and the resulting semi-solid residue was dissolved in 100 ml of water containing 15 ml of 50% hypophosphoric acid. The solution was extracted eight times with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution was gradually washed with water and saturated sodium chloride solution. The solution in dichloromethane was dried over sodium sulfate and evaporated and the residue was crystallized from diethyl ether / nhexane to give 6.28 g of diethyl 2 - [(acetamido) (hydroxyphosphinyl) methyl] -2-isobutylmalonate as a white solid; MS: 352 (M + H) < ⁺ >.

The combined washings of water and sodium chloride formed in the previous paragraph were extracted with dichloromethane to give an additional 1.68 g of product after evaporation of the solvent and crystallization of the diethyl ether / n-hexane residue.

iii) 1.5 g of S - (-) -? - methylbenzylamine and 0.2 g of water were added while stirring a suspension of 3.51 g of diethyl 2 - [(acetamido) (hydroxyphosphinyl) methyl] -2-isobutylmalonate in 50 ml of diethyl ether. The mixture was stirred and allowed to crystallize for 4 hours. The white solid was collected and recrystallized from 50 ml of ethyl acetate containing 0.2 g of water. 1.7 g of 1 (S) phenylethylamine salt of diethyl 2 - [(R) -acetamido) (hydroxyphosphinyl) methyl] -2-isobutylmalonate in the form of white crystals with a melting point of 108-110 ° C were obtained; [a] ²⁰ 5g9 = -13.3 ° (c = 0.5% in methanol).

A suspension containing 15 g of the above salt in 150 ml of ethyl acetate was stirred with 200 ml of 4% aqueous sodium hydrogen carbonate solution until all the solid had dissolved. The aqueous phase was decided and the ethyl acetate phase was extracted twice with 4% aqueous sodium hydrogen carbonate solution. The combined aqueous extracts were acidified with concentrated hydrochloric acid to a pH below 1 and extracted eight times with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a colorless gum which crystallized from diethyl ether / n-hexane. After 2 hours, the solid was collected and dried to give 10.1 g of diethyl 2 - [(R) - (acetamido) (hydroxyphosphinyl) -methyl] -2-isobutylmalonate as white crystals, mp 105-106 ° C; [o] ²⁰ 589 ⁼ '8.1 ° (c = 0.5% in methanol).

iv) A mixture of 0.58 g of N-bromomethyl-1,8-naphthalimide and 0.7 g of diethyl 2 - [(R) - (acetamido) (hydroxyphosphinyl) -methyl] -2-isobutylmalonate in 20 ml of dry chloroform was treated with 10 ml of 1; 1,1,3,3,3-hexamethyldisilazine and 10 ml bis (trimethylsilyl) acetamide. The mixture was stirred for 20 hours at 50 ° C under a nitrogen atmosphere, cooled and poured onto a mixture of 2M hydrochloric acid.

3Ί acid and ice. After stirring, the chloroform phase was separated and the aqueous phase extracted twice with chloroform. The extracts were combined, dried over magnesium sulfate and evaporated to give a residue which was purified by silica gel chromatography using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) for elution. Crystallization of the product from ethyl acetate gave 0.64 g of diethyl 2 - [(R) - (acetamido) [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] methyl] -2-isobutylmalonate in the form of a white powder, mp 202-203 ° C.

v) 2.8 g of diethyl 2 - [(R) - (acetamido) [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) - phosphinyl] methyl] -2-isobutylmalonate was dissolved in 25 ml of dimethyl sulfoxide containing 0.09 g of water and 0.88 g of lithium chloride. The mixture was heated at 180 ° C for 3.5 hours with stirring and under a nitrogen atmosphere. After cooling, the mixture was poured into 150 ml of 2M hydrochloric acid and extracted four times with dichloromethane. The combined extracts were washed twice with water, dried over magnesium sulfate and evaporated to give an orange-colored foam which was chromatographed on silica gel using dichloromethane / methanol / acetic acid / water (120: 15: 3: 2) for elution. 2.03 g of ethyl 2 (R or S) - [(R) - (acetamido) [[(2,3-dihydro-1,3-dioxo-1H-benz- [d, e] isoquinol-2-yl) was obtained methyl] (hydroxy) phosphinyl] methyl] -4-methylvalerate, which was dissolved in a mixture of 27 ml of acetic acid, 24.5 ml of concentrated hydrochloric acid and 16 ml of water. The solution was heated to reflux for 8 hours, cooled and evaporated. The residue was evaporated several times in the presence of 10% methanol in toluene and the resulting residue triturated with acetonitrile. 1.6 g of 2 (R or S) - [(R) - (amino) [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) -methyl] was obtained ( hydroxy) phosphinyl] methyl] -4-methyl valeric acid, which was suspended in a mixture of 120 ml of water and 20 ml of tetrahydrofuran. 3.4 g of potassium carbonate and 2.34 ml of benzyl chloroformate were added and the mixture was stirred for 20 hours at room temperature under a nitrogen atmosphere. 100 ml of 10% methanol in dichloromethane were added and the pH of the aqueous layer was adjusted to below 1 by the addition of concentrated hydrochloric acid. The organic phase was decided and the aqueous phase extracted three times with dichloromethane. The combined organic solutions were washed with water, dried over magnesium sulfate and evaporated to give a brown residue which was crystallized from ethyl acetate / diethyl ether. 1.2 g of 2 (R or S) - [(R) - (benzyloxyformamido) [[(2,3-dihydro-1,3-dioxo-1H-benz- [d, e] isoquinol2-yl) -methyl] was obtained - (hydroxy) phosphinyl] methyl] -4-methyl valeric acid as a white solid; MS: 553 (M + H) < + >.

Example 11

Suspension of 0.6 g of N ² - [2 (R or S) - [(R) - (benzyloxyformamido) [[(2,3-dihydro-1,3-dioxolH-benz- [d, e] isoquinol-2-yl) -methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L38 valinamide and 0.2 g of 10% palladium on charcoal in 150 ml of methanol were stirred for 20 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was evaporated to give a white foam, which was triturated with diethyl ether, filtered and washed with n-hexane. After drying in vacuo, 0.47 g of N ² - [2 (R or S) - (R) - (amino) [[(2,3-dihydro-1,3-dioxo-1Hbenz- [d, e] isoquinol) is obtained. 2-yl) -methyl (hydroxy) phosphinyl] methyl] -4-methylvaleryl-N, 3-dimethyl-lvalinamide as a white powder; MS: 545 (M + H) < ⁺ >.

Example 12 mg N ² - [2 (R or S) - (R) - (amino) [[(2,3-dihydro-1,3-dioxo-1H-benz- [d, e] isoquinol-2-yl) ) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl-N1, 3-dimethyl-L-valinamide was dissolved in 2 ml of dry pyridine and 100 mg of acetic anhydride was added. The solution was stirred for 3 hours at room temperature under a nitrogen atmosphere and then poured into a mixture of 50% hydrochloric acid and diethyl ether with stirring. The resulting precipitate was filtered and dried in vacuo to give 95 mg of N ² - [2 (R or S) - (R) - (acetamido) [[(2,3-dihydro-1,3-dioxo-1H-benz) [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl-N1, 3-dimethyl-L-valinamide as a white powder; MS: 587 (M + H) < ⁺ >.

Example 13

Mixture of 0.568 g of [2 (R or S) - (R) - (benzyloxyformamido) - [[(2,3-dihydro-6-hydroxy-1,2dioxo-1H-benz- [d, e] isoquinol-2-yl) ) methyl] (hydroxy) phosphinyl] methyl-4-methylvaleric acid and 0.29 g of L-2- (tert-butyl) glycine methylamide in 45 ml of toluene and 10 ml of 3-methyl-3pentanol were refluxed for 21 hours (bath temperature was 140 ° C) under a nitrogen atmosphere. The solvents were removed by evaporation, the residue was dissolved in methanol and the solution filtered. The filtrate was concentrated to 5 ml and added dropwise while stirring 10 ml of 5M hydrochloric acid. After 30 minutes, the solid precipitate was collected by filtration, washed with water, diethyl ether and n-hexane and dried in vacuo at 60 ° C. 0.506 g of N ² - [2 (R or S) - (R) - (benzylcarbonyloxyamino) - [[(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz- [d, e] isoquinol) was obtained -2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a yellow solid; MS: 695 (M + H) < ⁺ >.

The starting material was prepared as follows:

i) In an analogous manner as described in Example 10 (iv), 1.76 g of diethyl 2 - [(R) (acetamido) (hydroxyphosphinyl) -methyl] -2-isobutylmalonate and 2.0 g of 4-benzyloxy-N-bromomethyl are obtained -1,8-Naphthalimide gave 1.51 g of 2 - [(R) - (acetamido) [[(6-benzyloxy-2,3-dihydro-1,339 dioxo-1H-benz [d, e] isoquinol-2-yl ) -methyl] - (hydroxy) phosphinyl] methyl] -2-isobutylmalonate as a yellow solid; MS: 667 (M + H) < ⁺ >.

ii) A mixture of 5.29 g of diethyl 2 [(R) - (acetamido) [[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) -methyl] - (hydroxy) phosphinyl] methyl] -2-isobutylmalonate and 1.0 g of 10% palladium on carbon in 100 ml of ethanol were stirred under a hydrogen atmosphere until hydrogen absorption had ceased. The catalyst was removed by filtration and the filtrate was evaporated to give 4.48 g of diethyl 2 [(R) - (acetamido) [[(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e ] isoquinol-2-yl) -methyl] - (hydroxy) phosphinyl] methyl] -2-isobutylmalonate as a yellow foam; MS: 577 (M + H) < + >.

In an analogous manner as described in Example 10 (v), using 1-methyl-2-pyrrolidinone instead of dimethylsulfoxide as solvent in the first step was obtained from 7.89 g of diethyl 2 [(R) - (acetamido) [[(2,3- dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl (hydroxy) phosphinyl] methyl] -2-isobutylmalonate 2.8 g 2- [2 (R or S) - [(R) - (benzyloxyformamido) [[(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) -methyl (hydroxy) phosphinyl] methyl ] -4-methyl valeric acid as a yellow solid;

MS: 569 (M + H) < + >.

Example 14

Mixture of 0.284 g N ² - [2 (R or S) - [(R) - (benzyloxyformamido) (hydroxyphosphinyl) methyl] -4methyl valeryl] -Nl, 3-dimethyl-L-valinamide and 0.48 g 4-benzyloxy-N-bromomethyl -1,8-Naphthalimide in 16 ml of dry chloroform was heated at 60 ° C for half an hour with stirring and under an argon atmosphere. 0.7 ml of bis (trimethylsilyl) acetamide was added and heating continued for 4.9 hours. The solution was cooled and poured into 50 ml of dilute hydrochloric acid. The mixture was extracted three times with dichloromethane and the combined extracts were evaporated to give a residue which was purified by chromatography on silica gel with dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) for elution. 0.4 g of N ² '[2 (R or S) - [[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] was obtained. - (hydroxy) phosphinyl] - (R) - (benzyloxyformamido) -methyl-4-methylvaleryl] -Nl, 3-dimethylL-valinamide as a yellow powder; MS: 785 (M + H) < ⁺ >.

The starting material was obtained as follows:

i) 7.02 g of diethyl 2 [(R) - (acetamido) (hydroxyphosphinyl) -methyl] -2-isobutylmalonate were suspended in 20 ml of water and 1.76 g of lithium hydroxide monohydrate was added. The mixture was stirred at room temperature for 3 days and then acidified by the addition of 6 ml of concentrated hydrochloric acid. The solution was then saturated with sodium chloride and extracted ten times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give 6.0 g of ethyl hydrogen 2 [(R) (acetamido) (hydroxyphosphinyl) -methyl] -2 (RS) -isobutylmalonate as a white foam mixture of 3: 1 diastereoisomers; MS 324 (M + H) < ⁺ >.

ii) A mixture of 13.47 g of ethyl hydrogen 2 [(R) - (acetamido) (hydroxyphosphinyl) methyl] -2 (RS) isobutylmalonate and 8.42 g of triethylamine in 420 ml of dry toluene was refluxed for 2 hours. After cooling, the solvent was removed by evaporation and the residue was dissolved in a mixture of 96 ml of water and 144 ml of concentrated hydrochloric acid and the solution was heated under reflux and nitrogen for 4 hours. The solution was evaporated to dryness and the resulting 2 - [(R) - (amino) (hydroxyphosphinyl) -methyl] -4-methyl valeric acid was dissolved in 225 ml of aqueous saturated sodium hydrogen carbonate solution and 45 ml of tetrahydrofuran. 30 g of solid sodium hydrogen carbonate and 45 ml of benzyl chloroformate were added and the mixture was stirred at room temperature for 48 hours under a nitrogen atmosphere. The solution was extracted twice with diethyl ether and the aqueous solution acidified by careful addition of hydrochloric acid and extracted five times with dichloromethane containing 10% methanol. The extracts were dried over magnesium sulfate and evaporated to give a colorless gum that crystallized from ethyl acetate. 7.0 g of 2 (R or S) - [(R) -benzyloxyformamido) (hydroxyphosphinyl) methyl] -4-methyl valeric acid were obtained as a single diastereoisomer as a white solid;

MS: 344 (M + H) < + >.

A further 0.52 g of said diastereoisomer was obtained from the mother liquor of said crystallization by means of fractionated crystallizations from ethyl acetate.

Mixture of 1.37 g of 2 (R or S) - [(R) -benzyloxyformamido) (hydroxyphosphinyl) methyl] -4-methyl valeric acid, 0.67 g of L-2- (tert-butyl) glycine N-methylamide and 0.24 g of N-ethyl -morpholine in 40 ml of dry toluene was heated for 12 hours under reflux (bath temperature 140 ° C) and under nitrogen. The solution was cooled and the solvent was removed by evaporation. The residue was dissolved in 30 ml of ethyl acetate and the solution was mixed with 30 ml of 50% hydrochloric acid. The aqueous layer was separated and extracted eight times from dichloromethane. The organic solutions were combined and evaporated and the residue triturated with 25 ml of hot ethyl acetate. After cooling, the insoluble material was filtered and dried in vacuo. 1.74 g of N2-2 (R or S) - [(R) benzyloxyformamido) (hydroxyphosphinyl) methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide was obtained as a white solid; MS: 493 (M + Na) < + >.

Example 15

In an analogous manner as described in Example 11, 0.5 g of N ² -2 (R or S) - [(R) benzylcarbonyloxyamino [(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-) was obtained. benz [d, e] isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] methyl] -4-methylvaleryl-N1, 3-dimethyl-L-valinamide was obtained (as described in the first paragraph of Example 13), 0.29 g N ² -2 (R or S) - [[(R) - (amino) - [(2,3-dihydro6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) -methyl] - (hydroxy) phosphinyl] methyl] -4-methylvaleryl-N, 3-dimethyl-L-valinamide; MS: 561 (M + H) < ⁺ >.

Example 16

In an analogous manner as described in the first paragraph of Example 11, 0.28 g of N ² -2- (R or S) - [[[(6-benzyloxy) -2,3-dihydro-1,3-dioxo-1H] is obtained * benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] - (R) - (benzyloxyformamido) -methyl] -4-methylvaleryl-N, 3-dimethyl-lvalinamide, obtained as described in Example 14, 0.19 g of N ² -2 (R or S) - [[(R) (amino) -2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] was obtained isoquinol-2-yl) -methyl] (hydroxy) phosphinyl] -methyl] -4-methylvaleryl-N, 3-dimethyl-L-valinamide as a yellow powder; MS: 561 (M + H) < + >.

Example 17

0.45 g of N ² -2 (R or S) - [[(R) - (amino) -2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, isoquinol-2-yl] -methyl] - (hydroxy) phosphinyl] -methyl] -4-methylvaleryl-N1, 3-dimethyl-L-valinamide was dissolved in 10 ml of glacial acetic acid and 7.6 ml of bromine solution prepared dropwise over 10 minutes by dissolving 2 g of bromine in 100 ml of dichloromethane. The mixture was stirred for 4 hours at room temperature and the solvent was removed by evaporation. The residue was dissolved in methanol and evaporated. The process was repeated twice and the solid residue was then triturated with ethyl acetate, filtered and dried in vacuo to give 595 mg of N2-2 (R or S) - [[(R) - (amino) - [(5-bromo-). 2,3-dihydro-6hydroxy-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) -methyl] - (hydroxy) phosphinyl] -methyl-4methylvaleryl-Nl, 3-dimethyl-L -valinamide hydrobromide in the form of a yellow powder;

MS: 639/641 (M + H) < ⁺ >.

Example 18

0.062 g 3 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] 2-isobutyl-8-phthalimido- of octanoic acid (diastereoisomer 1) was suspended in a mixture of 2 ml of dichloromethane and 4 ml of toluene. 0.5 ml of oxalyl chloride and a dimethylformamide drop were added and the mixture was stirred for 5 hours at room temperature. The solvent was removed by evaporation and the residue was dissolved in dry dichloromethane. A solution of 0.1 g of Nethylmorpholine and 0.04 g of L-2- (tert-butyl) glycine methylamide in 1 ml of dichloromethane was added and the mixture was stirred at room temperature for 1 hour. It was then poured into 10 ml of 1M hydrochloric acid, stirred and the dichloromethane phase separated. The aqueous phase was extracted twice with dichloromethane and the combined dichloromethane solutions were evaporated. 0.058 g of a 1: 1 mixture of diastereoisomers 1A and IB N2-3 (R, S) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) was obtained methyl] - (hydroxy) phosphinyl] -2-isobutyl-8-phthalimido-octanoyl] -N, 3-dimethyl-lvalinamide as a white foam; MS: 745 (M + H) < ⁺ >.

The starting material was obtained as follows:

i) A solution of 2.95 ml of titanium tetrachloride in 8 ml of carbon tetrachloride was added dropwise under stirring and under a nitrogen atmosphere in 50 ml of dry tetrahydrofuran at 0 ° C. The resulting yellow suspension was treated with a solution of 2.45 g of 6-phthalimidohexan-1-ala and 3.55 g of dibenzyl malonate in 40 ml of tetrahydrofuran, and the mixture was stirred for 2 hours at 0 ° C. A solution of 4.5 g of dry pyridine in 12 ml of dry tetrahydrofuran was added dropwise to give a blood-red suspension. The mixture was allowed to reach room temperature and stirred for 18 hours while maintaining the nitrogen atmosphere. 200 ml of 2M sulfuric acid were added and the mixture was extracted four times with dichloromethane. The combined extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using ethyl acetate / n-hexane (1: 2) to elute to give 3.6 g of dibenzyl 2- (6-phthalimidohexylidene) malonate as a colorless oil.

ii) 3.6 g of dibenzyl 2- (6-phthalimidohexylylidene) malonate was added to a solution of 0.88 g of crystalline hypophosphoric acid in 10 ml of dry dichloromethane, the solution was cooled to C and 2.8 g of triethylamine and 2.8 g of trimethylsilyl chloride were added. After stirring for 3 hours at room temperature, the mixture was poured into 60 ml of 1M hydrochloric acid and the resulting solution extracted four times with dichloromethane. The combined extracts were dried and evaporated to give 3.9 g of a colorless gum containing crude dibenzyl 2- [l (RS) (hydroxyphosphinyl) -6-phthalimidohexyl] malonate, which was dissolved in 40 ml of dry dimethyl sulfoxide and reacted with isobutyl iodide in an analogous manner as described in Example 10 (ii). Purification of the crude product by chromatography on silica gel using dichloromethane / methanol / acetic acid / water (240: 24: 3: 2) for elution gave 2.0 g of dibenzyl 2- [l (RS) - (hydroxyphosphinyl) -6-phthalimidohexyl ] -2-isobutylmalonate in the form of a colorless gum.

iii) 5.85 g of dibenzyl 2- [1 (RS) - (hydroxyphosphinyl) -6-phthalimidohexyl] -2-isobutylmalonate and

2.7 g of N-bromomethyl-1,8-naphthalimide were reacted in an analogous manner as described in Example 10 (iv) to give 3.74 g of dibenzyl 2- [l (RS) - [[(2,3-dihydro) -1, 3dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] -6-phthalimidohexyl] -2-isobutylmalonate as a white foam; MS: 843 (M + H) < ⁺ >.

iv) 1.0 g of dibenzyl 2- [1 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -6-phthalimidohexyl] -2-isobutylmalonate was dissolved in 40 ml of dry chloroform and 4 ml of trimethylsilyl bromide were added. The mixture was heated at 60 DEG C. for 1.5 hours under a nitrogen atmosphere, cooled and poured into 50 ml of water. The mixture was stirred and the chloroform layer was separated. The aqueous layer was extracted twice with dichloromethane and the combined organic phases were evaporated. The residue was purified by chromatography on silica gel using chloroform- / methanol / acetic acid / water (240: 24: 3: 2) for elution. Crystallization of the product from ethyl acetate gave 0.57 g of a single diastereoisomer of benzyl hydrogen 2- [1 (RS) - [[(2,3-dihydro-1,3-dioxo-1-benz [d, e] -isoquinol-2) -yl) methyl] (hydroxy) phosphinyl] -6-phthalimidohexyl-2-isobutylmalonate in the form of white crystals;

MS: 753 (M + H) < + >.

v) 0.2 g benzyl hydrogen 2- [1 (RS) - [[(2,3-dihydro-1,3-dioxo-1-benz [d, e] -isoquinol-2yl) methyl] (hydroxy) phosphinyl] - 6-Phthalimidohexyl] -2-isobutylmalonate was suspended in 2 ml of dry chloroform and 3 ml of trimethylsilyl bromide were added. The mixture was then treated with 2 drops of water and 2 drops of 48% hydrobromic acid in acetic acid. The solution was allowed to stand for 3 days at room temperature and then poured into 50 ml of water. The product was extracted three times with dichloromethane and the combined extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in a mixture of 16 ml of xylene and 4 ml of nhexane containing 4 drops of water and then heated at 145 ° C for 4 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel using chloroform / methanol / acetic acid / water (240: 24: 3: 2) for elution. Crystallization from ethyl acetate gave 0.09 g of 3 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2yl) methyl] (hydroxy) phosphinyl] -2-isobutyl -8-phthalimidooctanoic acid (96% diastereoisomer 1) as a white powder; MS: 641 (M + Na) < + &^gt;.

Example 19

In an analogous manner as described in the first paragraph of Example 18, 0.15 g of 3 - [[(2,3dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] ( hydroxy) phosphinyl] -2-isobutyl-8-phthalimido-octanoic acid (diastereoisomer 2) and 0.12 g of L-2- (tert-butyl) glycine methylamide gave 0.197 g of a 1: 1 mixture of diastereoisomers 2A and 2B N ² - [3 (RS ) - [[(2,344 dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl-2-isobutyl-8-phthalimidooctanoyl] -Nl, 3-dimethyl-L -valinamide in the form of pale yellow foam;

MS: 745 (M + H) < + >.

The starting material was obtained as follows:

i) 0.5 g benzyl hydrogen 2- [1 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2yl) methyl] (hydroxy) phosphinyl] - The 6-phthalimidohexyl] -2-isobutylmalonate prepared as described in Example 18 (iv) was suspended in a mixture of 40 ml of xylene, 10 ml of dioxane and 0.25 ml of water and the suspension heated for 4.5 hours at 145 ° C under a nitrogen atmosphere. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel using chloroform / methanol / acetic acid / water (240: 24: 3: 2) for elution. Crystallization from ethyl acetate afforded 0.44 g of a single diastereoisomer of benzyl 3 - [[(2,3-dihydro-1,1-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -2-Isobutyl-8-phthalimidooctanoate as a white solid, mp 144-145 ° C.

ii) 0.3 g benzyl 3 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -2-isobutyl-8 -phthalimidooctanoate was suspended in a mixture of 100 ml of methanol and 20 ml of dichloromethane containing 0.1 g of 10% palladium on charcoal. The mixture was stirred for 20 hours under a hydrogen atmosphere, the catalyst was filtered off and the filtrate was evaporated. The remaining gum was crystallized from ethyl acetate to give 0.2 g of 3 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, eisoquinol-2-yl) methyl] (hydroxy) -phosphinyl] -2-Isobutyl-8-phthalimidooctanoic acid (95% diastereoisomer 2) as a white solid; MS: 641 (M + H) < + >.

Example 20

Mixture of 0.1 g diastereoisomer 1 and 0.1 g diastereoisomer 2 of compound 3 - [[(2,3-dihydrol, 3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] -2-Isobutyl-7-phthalimidoheptanoic acid and 0.049 g of L-2- (tert-butyl) glycine methylamide in 10 ml of xylene were heated at 140 ° C for 2 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel with chloroform / methanol / acetic acid / water (240: 24: 3: 2) for elution. 0.216 g of a mixture of diastereoisomers 1A, IB, 2A and 2B of the compound N2- [3 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-) were obtained yl) methyl] (hydroxy) phosphinyl] -2-isobutyl-7-phthalimidoheptanoyl] -Nl, 3-dimethyl-L-valinamide in the form of pale yellow foam.

In an analogous manner as described in the previous paragraph, from 0.278 g of diastereoisomer 2 of compound 3 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) 45 methyl] - (hydroxy) -phosphinyl] -2-isobutyl-7-phthalimidoheptanoic acid and 0.068 g of L-2- (tert-butyl) glycine methylamide gave 0.242 g of a mixture of diastereoisomers 2A and 2B of formula N ² [3 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] -2-isobutyl-7-phthalimidoheptanoyl] -Nl, 3 -dimethyl-L-valinamide in the form of a yellow foam.

The starting material was obtained as follows:

In the analogous manner as described in Example 18 (iv), diastereoisomers 1 and 2 of compound 3 - [[(2,3-dihydro-1,3-dioxolH-benz [d, e] were obtained from dibenzyl malonate and 5-phthalimidopentan-al) ] -isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] -2-isobutyl-7-phthalimidoheptanoic acid as a white solid.

Example 21

0.17 g of a 1: 1 mixture of diastereoisomers 2A and 2B N ² - [3 (RS) - [[(2,3-dihydro-1,3-dioxo-1 H -benz [d, e] -isoquinol-2-yl) methyl] ( hydroxy-phosphinyl] -2-isobutyl-8-phthalimidooctanoyl] -N1, 3dimethyl-L-valinamide, prepared as described in the first paragraph of Example 19, was dissolved in 2 ml of ethanol containing 0.08 g of hydrazine hydrate. The mixture was stirred for 24 hours at room temperature and then filtered. The filtrate was evaporated and the foam obtained was partitioned between distilled water and ethyl acetate. The aqueous phase was washed several times with 15 ml portions of ethyl acetate and then evaporated to give 0.12 g of a mixture of diastereoisomers 2A and 2B N ² [8-amino-3 - [[(2,3-dihydro-1,3-dioxo-1H) -benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -2-isobutyloctanoyl] -Nl, 3-dimethyl-L-valinamide as a yellow foam; MS: 615 (M + H) < + >.

Example 22

In an analogous manner to that described in Example 21, 0.245 g of a 1: 1 mixture of diastereoisomers IA and IB N ² - [3 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz) [d, e] -isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] -2-isobutyl-8-phthalimidooctanoyl] -Nl, 3-dimethyl-L-valinamide gave 0.18 g of a mixture of isomers IA and IB N ² - [8-amino-3 - [[(2,3-dihydro-1,3-dioxolH-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] -2-isobutyl-octanoyl] -Nl, 3-dimethyl-Lvalinamide in yellow foam form; MS: 615 (M + H) < ⁺ >.

Example 23

In an analogous manner to that described in the first paragraph of Example 10, 0.414 g 2 (R or

S) - [(R) - (benzyloxyformamido) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) 46 methyl] (hydroxy) phosphinyl] methyl-4-methylvaleric acids, prepared as described in

Example 10 (i-v), and 0.552 g of L-2 (tert-butyl) glycine α (S) -methylbenzylamide gave 0.484 g

N ² - [2 (R or S) - [(R) - (benzyloxyformamido) [[(2,3-dihydro-1,3-dioxo-1H-benz [d, eisoquinol-2-yl) methyl] (hydroxy ) phosphinyl] -methyl] -4-methylvalery] -3-methyl-N1 (cy (S) -methylbenzyl) -L-valinamide as a white solid; MS: 769 (M + H) < ⁺ >.

The L-2- (tert-butyl) glycine α (S) -methylbenzylamide used as starting material was prepared as follows:

i) A solution of 1.76 g of N-benzyloxycarbonyl-L-2- (tert-butyl) -glycine in 30 ml of dry dichloro-methane was cooled to-5 ° C and 2.8 g of di (1-benzotriazolyl) carbonate were added and 0.54 ml of pyridine. The mixture was stirred for 2.5 hours at -5 ° C and then 1.6 g (S) -a-methylbenzylamine was added dropwise, maintaining the temperature in the range - 5 to 0 ° C. After stirring overnight at room temperature, the solution was washed twice with saturated sodium hydrogen carbonate solution, twice with 1M hydrochloric acid and finally with saturated sodium hydrogen carbonate solution. After removal of the solvent, evaporation gave a solid which was triturated with n-hexane to give 2.05 g of N ² '(benzyloxycarbonyl) -3-methyl-N1- (a (S) -methylbenzyl) -L-valinamide in the form of a white solid with a melting point of 137 - 139 ° C.

ii) 0.5 g of N ² '(benzyloxycarbonyl) -3-methyl-N1- (a (S) -methylbenzyl) -L-valinamide was treated in an analogous manner as described in Example 11 to give 0.31 g of L-2 (tert-butyl) -glycine α (S) -methylbenzylamide as a colorless gum.

Example 24

In an analogous manner as described in Example 33, 0.1 g of N ² - [2 (R or S) [(R) (benzyloxyformamido) [[(2,3-dihydro-1,3-dioxo-1H-benz) is obtained from 0.1 g. [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -methyl] -4-methylvaleryl] -3-methyl-N1 (a (S) -methylbenzyl) -L-valinamide 0.045 g of hydrobromide N was obtained. ^2- [2 (R or S) [(R) - (amino) [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -methyl] -4-methylvaleryl] -3-methyl-N1 (a (S) methylbenzyl) -L-valinamide as a white solid; MS: 635 (M + H) < ⁺ >.

Example 25

In an analogous manner, as described in the first paragraph of Example 18, racemic 2- [1 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol) was obtained from 0.6 g of diastereoisomer 2 -2-yl) methyl] (hydroxy) phosphinyl] -ethyl] -4-methylvaleric acid and 0.45 g of L-2- (tert-butyl) glycine methylamide gave 0.9 g of a crude mixture of diastereoisomers 2 (i) and 2 (ii) N ² - [2- [1 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -ethyl] -4- methylvaleryl] -Nl, 3-dimethyl-L-valinamide in white foam form.

The diastereoisomer mixture was chromatographed on silica gel using chloroform // methanol / acetic acid / water (120: 15: 3: 2) for elution. The first eluted product is 0.12 g of white foam isomer 2 (i); MS: 544 (M + H) < ⁺ >.

The starting material was prepared as follows:

i) In the analogous manner as described in Example 18 (ii to iii), diethyl 2- [1- (RS) - [[(2,3-dihydrol, 3-dioxo-) is obtained from diethyl ethylidenmalonate and crystalline hypophosphoric acid. 1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] ethyl] isobutylmalonate as a white solid, mp 172-174 ° C.

ii) 1 g Diethyl 2- [1 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -ethyl] isobutylmalonate was dissolved in a mixture of 5 ml of concentrated sulfuric acid, 5 ml of water and 10 ml of acetic acid and the solution heated at 110 ° C for 20 hours. After cooling, the solution was extracted five times with 10% methanol in dichloromethane. The combined extracts were washed with saturated sodium chloride solution and evaporated. The residue was triturated with 20 ml of ethyl acetate and the solid filtered off. 0.54 g of a mixture of diastereoisomers 1 and 2 of 2- [1 [[(2,3-dihydro-1,3-dioxo-1Hbenz [d, e] -isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] was obtained -ethyl] -4-methylvaleric acid as a white solid. The mixture was separated by chromatography on silica gel using chloroform / methanol / acetic acid / water (120: 15: 3: 2) for elution. 75 mg of diastereoisomer 1 racemic 2- [1 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] were obtained -ethyl] -4-methyl valeric acid as a white solid with a melting point of 192-194 ° C and 225 mg of diastereoisomer 2 racemic 2- [1 - [[(2,3-dihydro-1, 3dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] -ethyl] -4-methylvaleric acid as a white solid, mp 202-204 ° C.

Example 26

0.13 g Mixtures of the four isomers of N ² '[7-acetoxy-3 (RS) - [[(2,3-dihydro-1,3-dioxo-1 H -benz [d, e] -isoquinol-2-yl) methyl] (hydroxy ) phosphinyl] -2 (RS) -isobutyl-heptanoyl] -Nl, 3-dimethyl-valinamide was added to 20 ml of methanol containing 0.06 g of 60% sodium hydride in mineral oil. The mixture was stirred for 2.5 hours at room temperature and then the methanol was removed by evaporation. The residue was dissolved in 30 ml of dichloromethane and the solution was washed twice with 1 N hydrochloric acid and twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether and the solid filtered off to give 0.071 g of a white solid which was purified by chromatography on silica gel using chloroform / methanol / acetic acid / water (120: 15: 3: 2) for elution. 0.026 g of a mixture of four diastereoisomers of N2- [3 (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] -hydroxy was obtained phosphinyl] -7-hydroxy-2 (RS) -isobutylheptanoyl] -Nl, 3-dimethyl-L-valinamide as a white solid. MS: 602 (M + H) < ⁺ >.

Example 27

In an analogous manner, as described in the first paragraph of Example 10, 0.283 g of a mixture of two diastereoisomers of 7-acetoxy-3 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] - isoquinol-2yl) methyl] hydroxyphosphinyl] -2-isobutylheptanoic acid and 0.16 g of L-2- (tert-butyl) glycine methylamide were obtained by purification by silica gel chromatography using chloroform / methanol / acetic acid / water (240 : 24: 3: 2) for elution, 0.133 g of a mixture of four diastereoisomers of N2- [7-acetoxy-3- (RS) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e ] -isoquinol-2-yl) methyl] hydroxyphosphinyl] -2 (RS) -isobutylheptanoyl] -Nl, 3-dimethyl-L-valinamide as a white solid: MS: 644 (M + H) ⁺ .

The starting material was prepared as follows:

i) In an analogous manner to that described in Example 18 (i-iii), dibenzyl 2- [5-benzyloxy-1 - [[(2,3-dihydro-1, d) was obtained from 5-benzoyloxy-pentanal and dibenzyl malonate. 3-dioxo-1Hbenz [d, e] -isoquinol-2-yl) methyl] hydroxyphosphinyl] -pentyl] -2-isobutyl malonate; MS: 790 (M + H) < + >.

ii) In an analogous manner to that described in Example 25 (ii), 0.625 g of dibenzyl 2- [5-benzyloxy-1 - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e ] -isoquinol-2-yl) methyl] hydroxy) phosphinyl] -pentyl] -2-isobutylmalonate gave 0.33 g of a 1: 1 mixture of 2 diastereoisomers of 7-acetoxy-3 - [[(2,3-dihydro-1,3-dioxo-1H) -benz [d, e] -isoquinol-2-ylmethyl] -hydroxy) -phosphinyl-2-isobutylheptanoic acid as a rubber compound; MS: 540: (M + Na) < ^{+ &gt};.

Example 28

Solution of 0.3 g of N - [2 (R or S) - [[(RS) - (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz [d, isoquinol-2-yl) methyl] ] phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in a mixture of 10 ml of trifluoroacetic acid and 10 ml of dichloromethane was stirred overnight at room temperature. The solvent was removed by evaporation and the residue triturated with a mixture of isopropanol and diethyl ether. The resulting solid was filtered off and dried to give

0.195 g of N2- [2 (R or S) - [[[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl (hydroxy) -phosphinyl] methyl ] -4-methylvaleryl] -N \ 3-dimethyl-L-valinamide as a white solid; MS: 530 (M + H) < ⁺ >.

The starting material was prepared as follows:

i) A mixture of 0.3 g of benzyl 2 (R or S) - [(ethoxyphosphinyl) methyl] -4-methylvalerate and 0.13 g of diisopropylethylamine in 10 ml of dichloromethane was cooled in an ice bath with stirring and under a nitrogen atmosphere. 2 ml of 1,1,1,3,3,3-hexamethyldisilazane and 1 ml of bis (trimethylsilyl) acetamide were added followed by 0.3 g of N-bromomethyl-1,8-naphthalimide. The cooling bath was removed and the mixture stirred for 18 hours at room temperature, washed with 10% sulfuric acid and sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 0.6 g of a yellow gum which was purified by flash chromatography on silica gel. using ethyl acetate / n-hexane (3: 1) for elution. 0.15 g of benzyl 2 (R or S) - [[(RS) (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz [d, eisoquinol-2-yl) methyl] phosphinyl] was obtained methyl] -4-methylvalerate as a white solid;

MS: 522 (M + H) < + >.

ii) 1 g Benzyl 2 (R or S) - [[(RS) (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2yl) methyl] phosphinyl ] Methyl] -4-methylvalerate was suspended in a mixture of 10 ml methanol and 10 ml ethanol containing 60 mg 10% palladium on charcoal. The mixture was shaken for 24 hours under a hydrogen atmosphere and the solvent was removed by evaporation and the residue triturated with diethyl ether. The solid was filtered off and dried to give 0.61 g of 2 (R or S) - [[(RS) (ethoxy) [(2,3dihydro-1,3-dihydro-1,3-dioxo-1H-benz] [d , e] -isoquinol-2-yl) methyl] phosphinyl] methyl] -4-methylvaleric acid as a white solid; MS: 432 (M + H) < ⁺ >.

iii) 0.43 g 2 (R or S) - [[(RS) (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2yl) methyl] phosphinyl] methyl] -4-methylvaleric acid was suspended in 10 ml of dichloromethane containing 0.095 g of pyridine. The mixture was cooled to 0 ° C and 0.48 g of di- (1-benzotriazolyl) -carbonate was added. After stirring at 0 ° C for 1.75 hours, a solution of 0.15 g of L-2- (tert-butyl) glycine in 10 ml of dichloromethane was added. The mixture was allowed to reach room temperature and stirred for an additional 24 hours. The solution was washed with saturated sodium hydrogen carbonate solution and 1M hydrochloric acid and then evaporated. The residue was purified by flash chromatography on silica gel using a 3% methanol solution in dichloromethane for elution. 0.319 g of N - [2 (R or S) - [[(RS) 50 (ethoxy) [(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-) was obtained yl) methyl] phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in white foam form; MS: 558 (M + H) < ⁺ >.

Example 29

In the analogous manner as described in Example 28, 0.436 g of 6 - [[N- [2 (R or S) [[(RS) - (ethoxy)] (2,3-dihydro-1,3-dioxo- 1H-benz [d, e] isoquinol-2-yl) methyl] phosphinyl] methyl] -4methyl valeryl] -3-methyl-L-valyl] aminohexanoic acid gave 0.42 g of 6 - [[N- [2 (R or S) [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl] -4methyl valeryl] -3-methyl-L-valyl] aminohexanoic acids in the form of a white solid;

MS: 630 (M + H) < + >.

The starting material was prepared as follows:

i) A solution of 9.04 g of N-tert-butoxycarbonyl-L-2- (tert-butyl) glycine in 200 ml of dichloromethane was cooled to 0 ° C and 4.52 g of N-hydroxysuccinimide was added. After stirring for 10 minutes, 8.07 g of dicyclohexylcarbodiimide was added and the mixture was stirred at room temperature for 20 hours. The solid was filtered off, the filtrate was evaporated and the residue was dissolved in 110 ml of dimethylformamide. To the solution was added dropwise a cooled solution of 5.14 g of 6 aminoacaproic acid and 4.52 g of tetramethylguanidine in a mixture of 42 ml of dimethylformamide and 17 ml of water. The resulting mixture was allowed to stand at room temperature and stirred for an additional 20 hours. The solvent was removed by evaporation and the residue partitioned between 10% hydrochloric acid and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic solutions were dried over anhydrous magnesium sulfate and evaporated to give 6 - [[N ² - (tert-butyl-oxycarbonyl) -3-methyl-Lvalillamino-hexanoic acid as white solids.

ii) 2.58 g of the precursor acid was dissolved in 25 ml of dry tetrahydrofuran containing 0.57 g of benzyl alcohol. 1.08 g of dicyclohexylcarbodiimide and 0.064 g of N, N-dimethylaminopyridine were added and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of ethyl acetate and the solution was washed with 10% hydrochloric acid, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and sodium chloride solution. After drying over anhydrous magnesium sulfate, the solution was evaporated to give a colorless oil which was purified by flash chromatography on silica gel using ethyl acetate / nhexane (2: 3) for elution. 1.73 g of benzyl 6 - [[N ² - (tert-butyloxycarbonyl) -3methyl-L-valyl] amino] hexanoate was obtained as a colorless gum.

iii) 10 ml of hydrogen chloride-saturated dioxane was added to a solution containing 1.05 g of benzyl 6 - [[N ² - (tert-butyloxycarbonyl) -3-methyl-L-valyl] amino] hexanoate in 5 ml of dichloromethane . The solution was stirred for 20 minutes and then evaporated. The residue was dissolved in 25 ml of 1M hydrochloric acid and the solution was washed with diethyl ether. The aqueous phase was treated with solid sodium hydrogen carbonate to saturation and extracted three times with dichloromethane. The combined extracts were evaporated to give 0.565 g of oil and an oil was added to the mixture containing 0.729 g (R or S) - [[(RS) (ethoxy) [2,3-dihydro-1,3-dioxo-1Hbenz [ d, e] isoquinol-2-yl) methyl] phosphinyl] methyl] -4-methyl-valeric acid prepared as described in Example 28 (ii), 0.134 g of pyridine and 0.716 g of di- (1-benzotriazolyl) of carbonate previously shaken at 0 ° C for 1 hour. The mixture was shaken for 24 hours at room temperature, diluted with saturated sodium hydrogen carbonate solution, 1M hydrochloric acid and saturated sodium hydrogen carbonate solution. The dichloromethane phase was dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by chromatography on silica gel using ethyl acetate for elution. 0.65 g of benzyl 6 - [[N [2- (R or S) - [[(RS) (ethoxy) (2,3dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-) was obtained yl) methyl] -phosphinyl] methyl] -4-methylvaleryl] -3methyl-L-valyl] aminohexanoate, which was dissolved in 50 ml of ethanol containing 0.1 g of palladium on charcoal. After stirring under hydrogen atmosphere for 7 hours, the catalyst was filtered off and the filtrate was evaporated to give 0.436 g of 6 - [[N [2- (R or S) - [[(RS) (ethoxy) (2,3-dihydro-1; 3dioxo4H-benz [d, e] isoquinol-2-yl) methyl] -phosphinyl] methyl] -4-methylvaleryl] -3-methyl-L-valyl] aminohexanoic acid as a colorless foam; MS: 658 (M + H) < + >,

Example 30

In an analogous manner as described in Example 28, 0.25 g of N - [(R or S) - [[(RS) ethoxy) (2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-ylmethyl) phosphinyl] methyl] -4-methylvaleryl] -3-methyl-N- (5-morpholinopentyl) -L-valinamide hydrochloride gave 0.21 g of N- [2 (R or S) - [[( 2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-ylmethyl) - (hydroxy) phosphinyl] methyl] -4methyl valeryl] -3-methyl-N- (5-morpholinopentyl) - L-valinamide hydrochloride as a colorless solid; MS: 522 (M + H) < ⁺ >.

The starting material was obtained as follows:

i) A solution of 5.81 g of 6 - [[N ² - (tert-butyloxycarbonyl) -3-methyl-L-valyl] amino] hexanoic acid in dry tetrahydrofuran was cooled to - 30 ° C and treated with 2.15 g of N-ethylmorpholine and then 2.54 g of isobutylchloroformiate in 5 ml of tetrahydrofuran was added dropwise. The solution was stirred for 0.25 hours at -25 ° C and then 2.12 ml of 33% aqueous ammonium hydroxide solution was added. The mixture was stirred for 3 hours and then evaporated.

The product was extracted with dichloromethane and the extracts were dried over anhydrous magnesium sulfate and evaporated to give 5.44 g of 6 - [[N ² - (tert-butoxycarbonyl) -3methyl-L-valyl] amino] hexanamide as a gum. This substance was dissolved in a mixture of acetonitrile and water, the solution was stirred and 10.25 g of bis (trifluoroacetoxyodobenzene was added. The mixture was stirred in the dark for 20 hours and then poured into 5% hydrochloric acid. The solution was washed twice with diethyl ether, which was back extracted with 5% hydrochloric acid The combined acid fractions were treated with 14.18 g of solid sodium hydrogen carbonate, 2.96 g of benzyl chloroformate were added and the mixture was stirred for 4 hours at room temperature, the solution was extracted three times with dichloromethane and the extracts were washed with 50 ml of 1M hydrochloric acid and water. After drying over anhydrous magnesium sulfate, the solvent was removed and 6.07 g of N ² - (tert-butyloxycarbonyl) -3-methyl-N 1- [5- (benzyloxyformamido) pentyl] -L-valinamide was obtained in the form of a gum.

ii) In an analogous manner to that described in Example 29 (iii), 3.06 g of N ² - (tert-butoxycarbonyl) -3-methyl-N1- [5- (benzyloxyforamido) pentyl] -L-valinamide and 2.198 g are obtained 2 (R or S) - [[(RS) (ethoxy) (2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methylphosphinyl] methyl] -4-methylvalerian acids prepared according to the method described in Example 28 (ii) gave 1.68 g of N- [2 (R or S) - [[(RS) (ethoxy) (2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2yl) methyl] -phosphinyl] methyl] -4-methylvaleryl] -3-methyl-N - [(5-benzyloxyformamido) pentyl] -valinamide as a colorless foam.

iii) 0.254 g of the foam mentioned above was dissolved in 20 ml of ethanol containing 0.35 g% hydrochloric acid and 0.05 g 10% palladium on charcoal. The mixture was shaken for 6 hours under hydrogen atmosphere, the catalyst was filtered off and the filtrate was evaporated to give N- [2 (R or S) [[(RS) (ethoxy) (2,3-dihydro-1,3-dioxo-1H- benz [d, e] isoquinol-2-ylmethyl) phosphinyl] methyl] -4methyl valeryl] -3-methyl-N- (5-aminopentyl) -L-valinamide. This was dissolved in a mixture of 2 ml of dichloromethane and 1.05 g of bis (2-iodoethyl) ether and 0.247 g of diisopropylethylamine was added. The solution was stirred in the dark for 3 days and then poured into 5% hydrochloric acid. The aqueous solution was washed with diethyl ether and then neutralized by the addition of solid sodium hydrogen carbonate. Sodium chloride was added until the solution became saturated and the mixture was extracted three times with dichloromethane. The extracts were evaporated to give a gum which was purified by flash chromatography on silica gel using 6% methanol in dichloromethane for elution. After adding a few drops of 2M hydrochloric acid and evaporating the solvent, 0.131 g of N- [2 (R or S) [[(RS) (ethoxy) (2,3-dihydro-1,3-dioxo-1H-benz [d] was obtained). e] isoquinol-2-ylmethyl) phosphinyl] methyl] -4methylvaleryl] -3-methyl-N- (5-morpholinopentyl) -L-valinamide hydrochloride in the form of pale yellow foam; MS: 699 (M + H) < ⁺ >.

Example 31

In the analogous manner as described in the first paragraph of Example 28, 0.317 g of 5 - [[N [2 (R or S) - [[(RS) (ethoxy) (2,3-dihydro-1,3-dioxo) -1H-benz [d, e] isoquinol-2-ylmethyl) phosphinyl] -methyl] -4-methyl valeryl] -3-methyl-L-valyl] amino] pentylamine hydrochloride gave 0.298 g of 5 - [[N- [2 ( R or S) - [[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-ylmethyl) (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -3-methyl -L-valyl] amino] pentylamine hydrochloride as a white solid; MS: 601 (M + H) < ⁺ >.

Example 32

In the analogous manner as described in the first paragraph of Example 28, 0.5 g of diethyl [[N [2 (R or S) - [[(RS) (ethoxy) - (2,3-dihydro-1,3-dioxo) are obtained from 0.5 g -1H-benz [d, e] isoquinol-2-yl) methyl) phosphinyl] methyl] -4-methyl valeryl] -3-methyl-L-valyl] aminomethyl] phosphonate gave 0.318 g of diethyl [[N- [2 (R or S) - [[[[(2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl) - (hydroxyphosphinyl] -methyl] -4-methylvaleryl] - 3-methyl-L-valyl] aminomethyl] phosphonate as a white solid having a melting point above 120 ° C (decomposition) MS: 666 (M + H) ⁺ .

The starting material was obtained as follows:

i) In an analogous manner to that described in Example 28 (i) - (ii), diethyl [N- (diethyl) aminomethyl phosphonate hydrochloride and N-benzyloxycarbonyl-L-2- (tert-butyl) glycine were obtained. 3methyl-L-valyl) aminomethyl] phosphonate in the form of rubber.

ii) In an analogous manner as described in Example 29 (iii), 1.1 g of diethyl [N- (3-methylL-valyl) aminomethyl] phosphonate and 1.5 g of 2 (R or S) - [[(RS) ( ethoxy) (2,3-dihydro-1,3-dioxolH-benz [d, e] isoquinol-2-yl) methyl] phosphinyl] methyl] -4-methyl valeric acid gave 1.6 g of diethyl [[N- [2 (R or S) - [[(RS) - (ethoxy) ((2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] -phosphinyl] methyl] -4-methylvaleryl] -3-methyl-L-valyl] -aminomethyl] phosphonate as a white solid; MS: 694 (M + H) +.

Example 33

0.5 g Diethyl [[N- [2 (R or S) - [[(RS) (ethoxy) (2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol2-yl) methyl] phosphinyl] methyl] -4-methylvaleryl] -3-methyl-L-valyl] aminomethyl] phosphonate was dissolved in 15 ml of 45% hydrobromic acid solution in acetic acid. After 3 hours the mixture was evaporated and the residue was re-evaporated four times with toluene. The resulting residue was triturated with diethyl ether and the solid filtered off to give 0.35 g [[N- [2 (R or S) - [[[[2,3-dihydro54,3,3-dioxo-1H-benz]], d ] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl-4-methylvaleryl] -3methyl-L-valyl] -aminomethyl] -phosphonic acid as a white solid with a melting point above 150 ° C (decomposition); MS: 610 (M + H) < + >.

Example 34

In an analogous manner as described in the first paragraph of Example 10, 0.51 g of 2 (R or S) - [(R) - [[(6-benzyloxy-1,3-dihydro-1,3-dioxo-1H-) is obtained. benz [d, e] isoquinol-2-yl) methyl (hydroxy) -phosphinyl] (benzyloxyformamido) methyl] -4-methyl valeric acid and 0.32 g of 3-methyl-N1- (3-morpholinopropyl) -L-valinamide were obtained by the addition of hydrogen chloride 0.416 g N ² [2 (R or S) - [(R) - [[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl ] (hydroxy) -phosphinyl] (benzyloxyformamido) methyl] -4-methylvaleryl] -3-methyl-N1- (3-morpholinopropyl) -L-valinamide hydrochloride as a yellow solid; MS: 898 (M + H) < ⁺ >.

The starting material was obtained as follows:

i) In an analogous manner to that described in Example 23 (i) - (ii), 3-methyl-N was obtained from N-benzyloxycarbonylL-2- (tert-butyl) glycine and 4- (3-aminopropyl) morpholine N - (3-morpholinopropyl) -L-valinamide.

ii) In an analogous manner as described in Example 14, 4-benzyloxy-N-bromomethyl 1,8-naphthalimide and 2 (R or S) - [(R) (benzyloxyformamido) (hydroxyphosphinyl) methyl] -4-methylvalerian acids prepared as described in Example 14 (ii) gave 2 (R or S) - [(R) [[6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] (benzyloxyformamido) methyl] -4-methyl valeric acid as a yellow solid; MS: 659 (M + H) < + >.

Example 35

In an analogous manner to that described in Example 11, 0.75 g of N ² - [2- (R or S) - [(R) - [[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H) is obtained -benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl (benzyloxyformamido) methyl] -4-methylvaleryl] -3-methyl-N1- (3-morpholinopropyl) -valinamide hydrochloride gave 0.596 g of N ² - [2- (R or S) - [(R) - (amino) [[(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl-4-methylvaleryl] -3-methyl-N1- (3-morpholinopropyl) -L-valinamide hydrochloride as a yellow solid; MS: 674 (M + H) < ⁺ >.

Example 36

In an analogous manner to that described in the first paragraph of Example 10, 0.349 g of 2 (R or S) - [[[(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H- benz [d, e] isoquinol-2-yl) methyl (hydroxy) phosphinyl] methyl-4-methyl valeric acid and 0.18 g of 3-methyl-N- (3-morpholinopropyl) -L-valinamide were obtained after the addition of hydrogen chloride 0.532 g of N ^ - [2- (R or S) - [[[(5bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] - ( hydroxy) phosphinyl] methyl-4-methylvaleryl] -3-methyl-N1- (morpholinopropyl) -L-valinamide hydrochloride as a yellow solid; MS: 737 (M + H) < ⁺ >.

Example 37

In an analogous manner, as described in the first paragraph of Example 10, 0.051 g of 2 (R or S) - [[[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz] is obtained from d. e] isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] methyl-4-methyl valeric acid and 0.055 g (2 equivalents) of 3-methyl-N1- (3morpholinopropyl) -L-valinamide were obtained after the addition of hydrogen chloride 0.081 g of N ^ - [2 (R or S) [[[(6-benzyloxy-2,3-dehydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] methyl-4-methylvaleryl] -3-methyl-N ^ - (3-morpholinopropyl) -L-valinamide hydrochloride as a pale yellow solid; MS: 749 (M + H) < ⁺ >.

Example 38

Suspension of 0.354 g 2 (R or S) - [[[(2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, eisoquinol-2-yl) methyl] - (hydroxy) phosphinyl] methyl-4-methyl valeric acid and 0.217 g of 3-methylN1- (3-morpholinopropyl) -L-valinamide in a mixture of 25 ml of toluene, 5 ml of 3-methyl-3-pentanol and 0.32 ml of N-ethylmorpholine were refluxed for 24 hours . The solution was cooled, the solvent was removed by evaporation and the residue was purified by chromatography on silica gel using chloroform / methanol / acetic acid / water (60: 18: 2: 3) for elution. 0.301 g of N2-2 (R or S) - [[[(2,3-dihydro-6-hydroxyl, 3-dioxo-1H-benz [d, e] isoquinol-2-) was obtained (after addition of hydrochloric acid). yl) methyl] - (hydroxy) phosphinyl] methyl-4-methylvaleryl] -3methyl-N1- (3-morpholinylpropyl) -L-valinamide hydrochloride as a yellow solid; MS: 659 (M + H) < + >.

Example 39

In an analogous manner as described in Example 11, 0.775 g of N2-2 (R or S) - [[[6benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz] [d, e] isoquinol-2-yl) methyl] - (hydroxy) -phosphinyl] methyl-4-methyl valeryl] -3-methyl-N- (morpholinopropyl) -L-valinamide hydrochloride gave 0.6 g

N2-2 (R or S) - [[[2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl-4-methylvaleryl] -3-methyl-N- (3-morpholinopropyl) -L-valinamide hydrochloride as a yellow solid; MS: 659 (M + H) < ⁺ >.

Example 40

In an analogous manner as described in Example 38, 0.59 g of 2 (R or S) - [[[(6benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol) 2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methyl-valeric acid and 0.38 g of 4 - [(3-methyl-L-valyl) -amino] butyric acid gave 0.775 g of 4 - [[N ^ - [2 (R or S) - [[[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl -4-methylvaleryl] -3-methyl-L-valyl-amino] butyric acid as a pale yellow solid; MS: 708 (M + H) < ⁺ >.

Example 41

In an analogous manner as described in Example 38, 0.51 g of 2 (R or S) - [[[(6-benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] isoquinol- 2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methyl-valeric acid and 0.38 g of benzyl [4 - [(3-methyl-L-valyl) -amino] propyl] carbamate gave 0.616 g of benzyl [4- [[N ^ -2 (R or S) - [[[[(6-benzyloxy-2,3-dihydro-1, 3dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] (hydroxy ) phosphinyl] methyl-4-methyl-valeryl] -3-methyl-valyl] amino] propyl] carbamate as a pale yellow solid;

MS: 813 (M + H) < + >.

Example 42

In an analogous manner as described in Example 11, 0.8 g of 4 - [[N ^ -2 (R or S) - [[[(6benzyloxy-2,3-dihydro-1,3-dioxo-1H-benz)] was obtained from 0.8 g. [d, e] -isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] methyl-4-methyl valeryl] -3-methyl-L-valyl] amino] butyric acid gave 0.57 g of 4 - [[N ^ -2 (R or S) - [[[(6-hydroxy-2,3-dihydro-1,3-dioxo-1H-benz [d, e] -isoquinol-2-yl) methyl] - (hydroxy) phosphinyl] methyl -4-methylvaleryl] -3-methyl-L-valyl] amino] butyric acid as a yellow solid; MS: 618 (M + H) < ⁺ >.

Example 43

In an analogous manner as described in the first paragraph of Example 1, 0.223 g of N ^ [2 (R) - [(benzyloxycarbamoyl) methyl-4-methylvaleryl] -3-methyl-N1- (3-morpholinopropyl) -valinamide were obtained 0.12 g of N2- [2 (R) - [hydroxycarbamoyl) methyl] -4-methylvaleryl] -3-methyl-N1 (3-morpholinopropyl) -L-valinamide as a white solid; nmr (MeOD): 4.20 (s, 1H);

3.70 (t, 4H, J = 5.5); 3.23 (t, 2H, J = 7.5); 2.95 (m, 1H); 2.54 (br, s, 4H); 2.45 (t, 2H, J = 9); 2.33 (dd, 2H, J = 14.9); 2.18 (dd, 2H, J = 14.7); 1.80-1.66 (m, 2H); 1.63-1.42 (m, 2H), 1.25-1.13 (m, 1H); 0.99 (s, 9H); 0.92 (d, 3H, J = 6); 0.87 (d, 3H, J = 6); MS: 429 (M + H) < + >.

The starting material was prepared as follows:

In an analogous manner as described in Example 1 (i) - (ii), 1.109 g of 4-tert-butyl 2 (R) isobutylsuccinate and 1.264 g of 3-methyl-N1- (3-morpholinopropyl) -L- valinamide gave 1,128 g of N2- [2 (R) - [(benzyloxycarbamoyl) methyl-4-methylvaleryl] -3-methyl-N1- (3-morpholinopropyl) -valinamide as a white foam; MS: 519 (M + H) < ⁺ >.

Example 44

6.3 g of n2- [2 (R or S) - (carboxy) -4-phenylbutyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide, isomer 1 prepared as described in Example 45 (i) - (iv), and 4.5 g of o- (tert-butyldimethylsilyl) hydroxylamine were dissolved in 70 ml of dry dimethylformamide and the solution cooled to 0 ° C under stirring and under a nitrogen atmosphere. 3.75 g of hydroxybenzotriazole, 3.0 ml of N-methylmorpholine and 4.13 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added and the mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed by evaporation and the residue was treated with 200 ml of 5% aqueous sodium hydrogen carbonate solution. The product was extracted three times with ethyl acetate and the combined extracts were washed with 5% citric acid aqueous solution and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was removed by evaporation and the residue triturated with a mixture of ethyl acetate and diethyl ether. The solid was filtered and dried to give 4.6 g of N2- [2 (R) [1 (R or S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvaleryl] -Nl'3-dimethyl-L-valinamide in the form of white powder; nmr (MeOD): 8.14 (d, exch, 1H, J = 9); 7.95 (m, exch, 1H); 7.18 (m, 2H); 7.09 (m, 3H,); 4.20 (d, 1H, J = 9); 2.67 (d, 3H, J = 5); 2.64 (m, 1H); 2.58-2.47 (m, 2H); 2.21-2.13 (m, 1H); 1.65-1.45 (m, 4H); 1.41-1.28 (m, 2H); 1.08-1.00 (m, 1H); 0.94 (s, 9H); 0.85 (d, 3H, J = 6); 0.80 (d, 3H, J = 6); MS: 434 (M + H) < + >.

Example 45

In an analogous manner, as described in the first paragraph of Example 1, 0.19 g of N2- [2 (R) - [1 (R or S) (benzyloxycarbamoyl) -4-phenylbutyl] methylvaleryl] -N1> 3-methyl- Of L-valinamide gave 0.115 g of N2- [2 (R) - [1 (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvaleryl] -N1> -3-dimethyl-L-valinamide as a white solid; MS: 434 (M + H) < ⁺ >.

The starting material was prepared as follows:

i) 0.048 g of 60% sodium hydride was added while stirring a solution of 0.45 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2 (R) -pentantricarboxylate in 10 ml of dry dimethylformamide under nitrogen atmosphere. The mixture was stirred for 0.75 hours at 0 ° C and again for 2.5 hours at room temperature. The mixture was cooled again to 0 ° C before adding 0.236 g of cinnamyl bromide. The mixture was allowed to reach room temperature and stirred for 2 days at room temperature. The mixture was poured into 5% citric acid aqueous solution and the product was extracted four times with diethyl ether. The combined ether extracts were washed with water and sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using hexane / ether (9: 1) for elution. 0.542 g of 1,2-dibenzyl 1-tert-butyl-4-methyl-1- (3-phenylprop-2-en-1-yl) -1, 1,2 (R) -pentantricarboxylate were obtained as a colorless oil; MS: 571 (M + H) < ⁺ >.

ii) 2.5 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (3-phenylprop-2-en-1-yl) -1,2,2 (R) -pentantricarboxylate were dissolved in 100 ml. methanol containing 0.55 g of 10% palladium on charcoal as catalyst. The mixture was stirred under a hydrogen atmosphere until the absorption of hydrogen was completed. The catalyst was filtered off and the solvent removed by evaporation to give 1.94 g of 1-tert-butyl 4-methyl 1- (3-phenylprop-1-yl) -1,2,2 (R) -pentane-tricarboxylate as a colorless rubbery substances. This substance was dissolved in 120 ml of toluene containing 0.6 g of N-ethylmorpholine. The mixture was refluxed for 5.5 hours, cooled, washed twice with citric acid solution and once with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / diethyl ether (10: 1) for elution. After an initial elution of 0.524 g of anhydride corresponding to the initial diacid, 0.74 g of 4-tert-butyl 2 (R) -isobutyl 3 - [(R or S) - (3-phenylprop-1-yl)] - succinate, isomer 1 was obtained , in the form of a colorless rubber and 0.126 g of a mixture of isomers 1 and 2 in the form of a rubber.

iii) In an analogous manner to that described in Example 1 (i), 0.741 g of 4-tert-butyl 2 (R) isobutyl 3 - [(R or S) - (3-phenylprop-1-yl)] -succinate, isomer 1, and 0.32 g of (S) -tert-butyl-glycine methylamide gave 0.93 g of N2- [2 (R) - [1- (tert-butoxy-carbonyl) -4-phenylbutyl] 4-methylvaleryl ] -Nl, 3-dimethyl-L-valinamide in the form of a colorless foam.

iv) 0.93 g of N ² - [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -4-phenylbutyl] -4-methylvaleryl] -Nl, 3dimethyl-L-valinamide was dissolved in a mixture of 28 ml of dichloromethane and 4 ml of trifluoroacetic acid and the solution was stirred for 6 hours at room temperature. The solvent was removed by evaporation and the residue was again evaporated with a mixture of methanol and ethyl acetate. After further evaporation with ethyl acetate, the residue was triturated with diethyl ether to give 0.7 g of N ² [2 (R) - [1 (R or S) - (carboxy) -4-phenylbutyl] -4-methylvaleryl] -Nl, 3 -Dimethyl-L-valinamide, isomer 1, as a white solid; MS: 419 (M + H) < ⁺ >.

v) In an analogous manner as described in Example l (iii), 0.228 g of N ² - [2 (R) - [1 (R or S) - (carboxy) -4-phenylbutyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide and 0.077 g of o-benzylhydroxylamine gave 0.192 g of N ² - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -4-phenylbutyl] -4methylvaleryl] -Nl. White foam 3-dimethyl-L-valinamide; MS: 524 (M + H) < ⁺ >.

Example 46

In an analogous manner as described in the first paragraph of Example 1, 0.135 g of N ² [2 (R) - [(R or S) - (benzyl) (benzyloxycarbamoyl) methyl] -4-methylvaleryl] -Nl, 3- dimethyl-Lvalinamide gave 0.097 g of N ² - [2 (R) - [1 (R or S) - (benzyl) (hydroxycarbamoyl) methyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; nmr (MeOD): 7.287.07 (m, 5H); 4.34 (s, 1H); 2.89-2.63 (m, 3H); 2.72 (s, 3H); 1.62-1.48 (m, 1H); 1.47-1.34 (m, 1H); 1.18-1.07 (m, 1H); 1.04 (s, 9H), 0.91 (d, 3H, J = 6); 0.84 (d, 3H, J = 6); MS: 406 (M + H) < + >.

The starting material was prepared as follows:

In an analogous manner as described in Example 45 (iv), 0.77 g was obtained from 2.0 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 0.53 ml of benzyl bromide. N ² [2 (R) - [(R or S) - (benzyl) (benzyloxycarbamoyl) methyl] -4-methylvaleryl] -N 1,3-dimethyl-lvalinamide as a white solid; MS: 496 (M + H) < ⁺ >.

Example 47

In an analogous manner, as described in the first paragraph of Example 1, 0.135 g of N ² [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -4- (methoxycarbonyl) butyl] -4-methylvaleryl is derived from - N, 1,3-dimethyl-L-valinamide gave 0.10 g of N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4- (methoxycarbonyl) -butyl] -4-methylvaleryl] -N1, 3- dimethyl-L-valinamide as a white solid; nmr (MeOD); 4.25 (s, 1H); 3.62 (s, 3H); 2.74-2.62 (m, 4H); 2.28 (2H, t, J = 7); 2.21-2.11 (m, 1H); 1.70-1.29 (m, 6H); 1.12-1.04 (m, 1H); 1.02 (s, 9H), 0.89 (d, 3H, J = 6); 0.83 (d, 3H, J = 6); MS: 416 (M + H) < + >.

The starting material was prepared as follows:

In an analogous manner as described in Example 45 (i-v), 1.82 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 0.8 g of methyl 4-bromo crotonate were obtained

0.37 g N ² - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -4- (methoxycarbonyl) butyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide as a white solid substances; MS: 506 (M + H) < ⁺ >.

Example 48

In an analogous manner as described in the first paragraph of Example 1, 0.135 g of N ² [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -Nl, 3 -dimethyl-lvalinamide gave 0.07 g of N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid ;

nmr (MeOD); 7.88-7.75 (m, 4H); 4.33 (s, 1H); 4.08 (dd, 1H, J = 14.10); 3.57 (dd, 1H, J = 14.4); 2.93-2.75 (m, 2H); 2.74 (s, 3H); 1.66-1.55 (m, 1H); 1.52-1.37 (m, 1H); 1.18-1.09 (m, 1H); 1.08 (s, 9H); 0.93 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 475 (M + H) < + >.

The starting material was obtained as follows:

i) In an analogous manner to that described in Example 45 (i-iv), 1.82 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 0.96 g of N- bromomethylphthalamide gave 0.73 g of N ² - [2 (R) - [1 (R or S) - (carboxy) -2-phthalimidoethyl] -4-methylvaleryl] -N1, 3dimethyl-L-valinamide as a white solid; MS: 460 (M + H) < ⁺ >.

ii) In an analogous manner to that described in Example 1 (iii), 0.17 g of N ² - [2 (R) - [1 (R or S) - (carboxy) -2-phthalimidoethyl] -4-methylvaleryl] is obtained. -Nl, 3-dimethyl-L-valinamide and 0.061 g of Obenzylhydroxylamine gave 0.161 g of N ² - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -Nl, 3- dimethyl-L-valinamide as a white solid;

MS: 565 (M + H) < + >.

Example 49

In an analogous manner as described in Example 44, 6.44 g of N ² - [2 (R) - [1 (R or S) (carboxy) -2-phthalimidoethyl] -4-methylvaleryl] -Nl, 3-dimethyl -L-valinamide obtained 4.74 g of N ² [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -N, 3-dimethyl-lvalinamide as a white solid .

Example 50

In an analogous manner as described in the first paragraph of Example 1, 0.115 g of a mixture of N, N - [2 (R) - [1 (benzyloxycarbamoyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide isomers obtained 0.06 g of N2- [2 (R) - [1 (hydroxycarbamoyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide as a white solid; MS: 358 (M + H) < + >.

The starting material was obtained as follows:

In an analogous manner as described in Example 45 (iv), N2- [2 (R) was obtained from 1,2-dibenzyl 1-tert-butyl 4methyl-1,1,2,2 (R) -pentantricarboxylate and allyl bromide. - [1 (benzyloxycarbonyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a mixture of isomers.

Example 51

In an analogous manner to that described in the first paragraph of Example 1, 0.198 g of N 2 - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,6-dimethylphenyl) ethyl] -4 -methylvaleryl] -N, N, 3dimethyl-L-valinamide gave 0.139 g of N - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (2,6-dimethylphenyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; nmr (MeOD); 6.92 (s, 3H); 4.32 (s, 1H); 3.11 (dd, 1H, J = 14.12); 2.92-2.82 (m, 1H); 2.72 (s, 3H); 2.64 (dd, 1H, J = 14.3); 2.52-2.43 (m, 1H); 2.27 (s, 6H); 1.61-1.50 (m, 1H); 1.48-1.33 (m, 1H); 1.17-1.08 (m, 1H); 1.07 (s, 9H); 0.93 (d, 3H, J = 6); 0.83 (d, 3H, J = 6); MS: 434 (M + H) < + >.

The starting material was obtained as follows:

In an analogous manner to that described in Example 45 (iv), N, -, - - - - - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,6-dimethylphenyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide as a white solid; MS: 524 (M + H) < + >.

Example 52

In an analogous manner to that described in the first paragraph of Example 1, 0.18 g of N ^ [2 (R) - [2- (4-ethylphenyl) -1 (R or S) - (benzyloxycarbamoyl) ethyl-4-methylvaleryl] is obtained. -N1, 3-dimethyl-Lvalinamide gave 0.132 g of N2- [2 (R) - [2- (4-ethylphenyl) -1 (R or S) - (hydroxycarbamoyl) ethyl-4methylvaleryl] -N, 3-dimethyl- L-valinamide as a white solid;

nmr (MeOD): 7.18-6.96 (m, 4H); 4.33 (s, 1H); 2.84-2.70 (m, 5H); 2.65-2.52 (m, 3H); 2,442.35 (m, 1H); 1.58-1.50 (m, 1H); 1.46-1.35 (m, 1H); 1.18 (t, 3H, J = 7); 1.17-1.05 (m, 1H);

1.04 (s, 9H); 0.90 (d, 3H, J = 6); 0.84 (d, 3H, J = 6); MS: 434 (M + H) < + >.

The starting material was obtained as follows:

In an analogous manner as described in Example 45 (iv), N ² - [2 was obtained from 1,2-dibenzyl 1-tert-butyl 4methyl-1,1,2,2 (R) -pentantricarboxylate and 4-ethylbenzyl bromide (R) - [2- (4-ethylphenyl) -1 (R or S) - (benzyloxycarbamoylethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS: 524 (M + H) ⁺ .

Example 53

In an analogous manner as described in the first paragraph of Example 1, 0.1 g of N ² - [2 (R) 1 (R or S) - (benzyloxycarbamoyl) -3-methylbutyl-4-methylvaleryl] -Nl, 3-dimethyl -L-valinamide gave 0.057 g of N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -3-methylbutyl] -4-methylvaleryl] N, 3-dimethyl-L-valinamide as a white solids;

nmr (MeOD): 4.35 (s, 1H); 4.70 (s, 3H); 4.68-4.57 (m, 1H); 2.31-2.19 (m, 1H); 1.75-1.29 (m, 4H); 1.14-0.95 (m, 1H); 0.91-0.78 (m, 12H); MS: 372 (M + H) < + >.

In an analogous manner as described in Example 45 (iv), N ² - [2 (R) was obtained from 1,2-dibenzyl 1-tert-butyl 4methyl-1,1,2 (R) -pentantricarboxylate and methylyl bromide. ) -1 (R or S) (benzyloxycarbamoyl] -3-methylbutyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS: 462 (M + H) ⁺ .

Example 54

In an analogous manner as described in the first paragraph of Example 44, 0.127 g of N ² · [2 (R) - [1 (R or S) - (carboxy) -2- (1-naphthyl) ethyl] -4- methylvaleryl] -Nl, 3-dimethyl-L-valinamide gave 0.033 g of N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -1-naphthyl) ethyl] -4-methyl-valeryl] Nl , 3-dimethyl-L-valinamide as a white solid; nmr (MeOD): 7.99 (m, 1H); 7.83 (m, 1H); 7.71 (d, 1H, J = 7); 7.52-7.23 (m, 4H); 4.46 (s, 1H); 3.16 (t, 1H, J = 12); 3.00-2.88 (m, 1H); 2.77 (s, 3H); 2.75-2.62 (m, 2H); 1.62-1.38 (m, 2H); 1.21-1.10 (m, 1H); 1.08 (s, 9H); 0.95 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 456 (M + H) < + >.

The starting material was obtained as follows:

In an analogous manner as described in Example 45 (i-iv), 1,2-dibenzyl 1-tert-butyl

4-methyl-1,2,2 (R) -pentantricarboxylate and 1- (bromomethyl) naphthalene gave N ² - [2 (R) -1 (R or S) - (carboxy) -2- (1-naphthyl) ethyl ] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS: 441 (M + H) < ⁺ >.

Example 55

In an analogous manner as described in Example 45 (iv), 1,2-dibenzyl 1-tert-butyl 4methyl-1,1,1,2 (R) -pentantricarboxylate and 2- (bromomethyl) naphthalene were used and using O - (tert-butyldiphenylsilyl) hydroxylamine in part (v) gave N ² - [2 (R) -1 (R or S) - (tert-butyldiphenylsilyloxycarbamoyl) -2- (2-naphthyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS: 694 (M + H) < ⁺ >.

0.102 g N ² - [2 (R) -1 (R or S) - (tert-butyldiphenylsilyloxycarbamoyl) -2- (2-naphthyl) ethyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide was dissolved in 3 ml of dry tetrahydrofuran and 0.15 ml of IM tetrabutylammonium fluoride was added. After stirring at room temperature for one hour, the mixture was poured into 1 N hydrochloric acid and the product extracted several times with ethyl acetate. The extracts were combined and washed with IM hydrochloric acid and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was removed by evaporation and the residue triturated with diethyl ether. 0.049 g of N ² [2 (R) -1 (R or S) - (hydroxycarbamoyl) -2- (2-naphthyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide as a white solid were obtained ;

nmr (MeOD): 7.76 (m, 3H); 7.57 (s, 1H); 7.42 (m, 2H); 7.26 (dd, 1H, J = 7.2); 4.39 (s, 1H); 3.01 (t, 1H, J = 12); 2.92-2.79 (m, 2H); 2.73 (s, 3H); 2.61-2.49 (m, 1H); 1.65-1.52 (m, 1H); 1.50-1.37 (m, 1H); 1.19-1.09 (m, 1H); 1.07 (s, 9H); 0.92 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 456 (M + H) < + >.

Example 56

In the analogous manner as described in the first paragraph of Example 44, 0.127 g of N ² [2 (R) - [1 (R or S) - (carboxy) - (2,3-dihydro) -1,3-dioxo -1H-benz [d, e] isoquinol-2-yl) ethyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide gave 0.055 g of N ² - [2 (R) - [2- (2,3- dihydro) -1, 3dioxo-1H-benz [d, e] isoquinol-2-yl) -1 (R or S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] N, 3-dimethyl-L-valinamide in the form white solids; nmr (MeOD): 7.99 (d, 2H, J = 7.5); 8.28 (d, 2H, J = 7.5); 7.75 (t, 2H, J = 7.5); 4.72 (dd, 1H, J = 14.10), 4.42 (s, 1H); 4.02 (dd, 1H, J = 14.4); 3.03-2.93 (m, 1H); 2.90-2.80 (m, 1H), 2.74 (s, 3H9, 1.70-1.57 (m, 1H), 1.53-1.38 (m, 1H); 1.23-1.14 (m, 1H), 1.10 (s, 9H); 0.94 (d, 3H, J = 6), 0.85 (d, 3H, J = 6);

MS: 525 (M + H) < + >.

The starting material was prepared as follows:

In the analogous manner as described in Example 45 (i) - (iv), 1,2-dibenzyl 1-tert-butyl

4-methyl-1,1,2 (R) - (carboxy) -2,3-dipentantricarboxylate and N- (bromomethyl) -naphthalimide gave N2- [2 (R) - [1 (R or S) - (carboxy) - (2,3-dihydro) -1,3-dioxo-1H-benz [d, e] isoquinol-2yl) ethyl] -4-methylvaleryl] -Nl, 3-dirnetyl-L-valinamide as a white solid; MS: 570 (M + H) < + >.

Example 57

In an analogous manner as described in the first paragraph of Example 1, 0.15 g of N ^ [2 (R) - [2-benzamido-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl are obtained. 3-dimethyl-L-valinamide gave 0.112 g of N2- [2 (R) - [2-benzamido-1 (R or S) - (hydroxycarbamoyl) ethyl-4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid ; nmr (MeOD): 7.77 (m, 2H); 7.56-7.40 (m, 3H); 4.28 (s, 1H); 3.60-3.46 (m, 2H); 2.86-2.76 (m, 1H); 2.72 (s, 3H), 2.70-2.58 (m, 1H) 1.66-1.55 (m, 1H9, 1.50-1.36 (m, 1H); 1.20-1.08 (m, 1H); 1.04 (s, 9H); 0.92 (d, 3H, J = 6.5); 0.85 (J = 6.5); MS: 449 (M + H) +.

The starting material was obtained as follows:

i) A solution of 0.226 g of N2- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2-phthalimidoethyl] -4methyl valeryl] -Nl, 3-dimethyl-L-valinamide in 5 ml of methanol was treated with 8 ml of 0.33M hydrazine hydrate solution in methanol. The mixture was stirred at room temperature overnight and the solvent was removed by evaporation. The residue was mixed with 4 ml of chloroform / methanol / acetic acid / water (120: 15: 3: 2) and the insoluble solid filtered off. The filtrate was purified by chromatography on silica gel using chloroform / methanol / acetic acid / water (120: 15: 3: 2) for elution. The fractions containing the product were evaporated and re-evaporated several times in the presence of toluene to remove water and acetic acid. 0.203 g of N2- [2 (R) - [2-amino-1 (R or S) benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide were obtained as a white solid;

nmr (MeOD); 7.50-7.33 (m, 5H); 4.93 (m, 2H); 4.23 (s, 1H); 3.03 (dd, 1H, J = 14.9); 2.832.70 (m, 2H); 2.68 (s, 3H); 2.44-2.32 (m, 1H); 1.58-1.47 (m, 1H); 1.45-1.29 (m, 1H); 1.101.02 (m, 1H); 0.99 (s, 9H); 0.88 (d, 3H, J = 7); 0.84 (d, 3H, J = 6);

ii) 0.2 g of N ^ - [2 (R) - [2-amino-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -N1, 3dimethyl-L-valinamide were dissolved in 5 ml of dry dimethylformamide, containing 0.05 g of Nmethylmorpholine. The solution was cooled to 0 ° C and 0.077 g of benzoyl chloride was added. After stirring for 20 hours at room temperature, the mixture was poured into 5% aqueous sodium hydrogen carbonate solution and the product extracted with ethyl acetate. The extracts were washed with 5% citric acid aqueous solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate for elution. 0.145 g of N ^ 65 was obtained

0.145 g of N ² - [2 (R) - [2-benzamido-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] N, 3-dimethyl-L-valinamide as a white solid;

nmr (MeOD): 7.80 (m, 2H), 7.59-7.42 (m, 3H); 7.33-7.19 (m, 5H); 4.86 (d, 1H, J = 12); 4.70 (d, 1H, J = 12); 4.28 (s, 1H); 3.61-3.46 (m, 2H); 2.88-2.77 (m, 1H); 2.71 (s, 3H); 2.65-2.55 (m, 1H); 1.60-1.48 (m, 1H); 1.46-1.31 (m, 1H); 1.11-0.96 (m, 10H); 0.90 (d, 3H, J = 6); 0.83 (d, 3H, J = 6);

Example 58

In an analogous manner as described in Example 57 (i), after treatment of the product with hydrogen chloride to form hydrochloride from 0.1 g of N ² - [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) 2- phthalimidoethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide gave 0.08 g of N ² - [2 (R) - (2 amino- l (R or S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] - N, 3-dimethyl-L-valinamide hydrochloride as a white solid;

nmr (MeOD): 4.24 (s, 1H); 3.23 (dd, 1H, J = 12.5,10); 2.92 (dd, 1H, J = 12.5, 3); 2.84-2.76 (m, 1H); 2.69 (s, 3H); 2.61-2.53 (m, 1H), 1.66-1.55 (m, 1H); 1.20-1.12 (m, 1H); 1.01 (s, 9H); 0.89 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 345 (M + H) < + >.

Example 59

In an analogous manner, as described in the first paragraph of Example 1, 0.105 g of N ² [2 (R) - [2-acetamido-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl. 3-Dimethyl-Lvalinamide gave 0.08 g of N ² - [2 (R) - (2-acetamido-1 (R or S) - (hydroxycarbamoyl) ethyl] -4methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solids;

nmr (MeOD): 4.16 (s, 1H); 3.29 (dd, 1H, J = 14.3.5); 3.14 (dd, 1H, J = 14.9); 2.66-2.57 (m, 4H); 2.42-2.33 (m, 1H); 1.80 (s, 3H), 1.51-1.43 (m, 1H); 1.36-1.25 (m, 1H); 1.04-0.95 (m, 1H), 0.93 (s, 9H); 0.80 (d, 3H, J = 6); 0.74 (d, 3H, J = 6); MS: 387 (M + H) < + >.

The starting material was prepared as follows:

In an analogous manner, as described in Example 57 (ii), N ^{2 is} - [2 (R) - [2-amino-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl. 3-dimethyl-L-valinamide and acetic anhydride gave N ² - [2 (R) - [2-acetamido-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4methylvaleryl] -Nl, 3-dimethyl-L- valinamide as a white solid; MS: 477 (M + H) < ⁺ >.

Example 60

In an analogous manner to that described in the first paragraph of Example 1, 0.18 g of N2- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (morpholino) ethyl] -4-methylvaleryl] is obtained. N, 1,3-dimethyl 1 L-valinamide gave 0.11 g of N 2 - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (morpholino) ethyl 4-methyl valeryl] -N1, 3-dimethyl-L- valinamide as a white solid; nmr (MeOD): 4.23 (s, 1H); 3.60 (m, 4H); 2.74 (t, 1H, J = 12); 2.68 (s, 3H); 2.63 (dt, 1H, J = 10.4); 2.53-2.42 (m, 3H); 2.27-2.20 (m, 2H); 2.14 (dd, 1H, J = 14.3.5); 1.55-1.45 (m, 1H); 1.42-1.30 (m, 1H); 1.14-1.05 (m, 1H), 1.01 (s, 9H); 0.86 (d, 3H, J = 6); 0.82 (d, 3H, J = 6); MS: 415 (M + H) < + >.

The starting material was prepared as follows:

A mixture of 0.27 g of N - [2 (R) - [2-amino-1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] N, 3-dimethyl-L-valinamide, 0.25 g Ν. Of Ν-diisopropylethylamine and 0.5 ml of bis (2-iodoethyl) ether in 4 ml of dimethylformamide were allowed to stand for 3 days at room temperature in the dark. The mixture was poured into water and the product extracted with ethyl acetate. The ethyl acetate extract was washed successively with water, aqueous sodium thiosulphate solution, water and saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and evaporated. Treatment with diethyl ether yielded 0.18 g of N - [2 (R) - [1 (R or S) (benzyloxycarbamoyl) -2- (morpholino) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form of a white solid .; MS: 505 (M + H) < ⁺ >.

Example 61

0.04 g of lithium hydroxide monohydrate was added to a solution of 0.141 g of N ^ - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (phthalimidoethyl) -4-methylvaleryl] -Nl, 3-dimethyl-L- of valinamide in a mixture of 4 ml of methanol and 8 ml of water After 15 minutes the mixture was poured into 1M hydrochloric acid and the solution extracted several times with ethyl acetate containing 5% methanol The combined extracts were washed with water and then evaporated. diethyl ether gave 0.121 g of N - [2 (R) - [2-carboxybenzamido) -1 (R or S) (hydroxycarbamoyl) ethyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide in the form white solids; nmr (MeOD): 7.98 (dd, 1H, J = 7.5,2); 7.59 (dt, 1H, J = 7.5,2) 7.52 (dt, 1H, J = 7.5,2); 7.44 (dd, 1H, J = 7.5,2); 4.28 (s, 1H); 3.55 (dd, 1H, J = 14.6.5); 3.45 (dd, 1H, J = 14.4); 2,952.87 (m, 1H); 2.71 (s, 3H); 2.70-2.62 (m, 1H); 1.63-1.54 (m, 1H); 1.44-1.34 (m, 1H), 1.151.06 (m, 1H); 1.03 (s, 9H); 0.88 (dd, 1H, J = 6); 0.84 (dd, 1H, J = 6); MS: 493 (M + H) < + >.

Example 62

In an analogous manner as described in the first paragraph of Example 1, 0.11 g of N '[2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-carboxypropionamido) ethyl] -4-methylvaleryl ] -Nl, 3-dimethyl-L-valinamide gave 0.075 g of N ^ - [2 (R) - [2- (3-carboxy-propionamido) -1 (R or S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl ] -Nl, 3-dimethyl-L-valinamide as a white solid;

nmr (MeOD): 4.23 (s, 1H); 3.39-3.21 (m, 2H); 2.77-2.69 (m, 1H); 2.68 (s, 3H); 2.55 (t, 2H, J = 7); 2.49-2.37 (m, 3H); 1.58-1.49 (m, 1H); 1.42-1.321 (m, 1H); 1.12-1.03 (m, 1H); 0.99 (s, 9H); 0.86 (d, 3H, J = 6); 0.81 (d, 3H, J = 6); MS: 445 (M + H) < + >.

The starting material was prepared as follows:

In an analogous manner as described in Example 57 (ii), N2- [2 (R) -2-amino-1 (R or S) - (benzyloxycarbonyl) -ethyl-4-methylvaleryl] -N2,3 -dimethyl-L-valinamide and succinic anhydride provided N ^ - [2 (R) -1 (R or S) - (benzyloxycarbonyl) -2- (3-carboxypropionamido) -ethyl] -4-methylvaleryl] -Nl, 3 -dimethyl-L-valinamide as a white solid; MS: 535 (M + H) < + >.

Example 63

In an analogous manner as described in the first paragraph of Example 1, 0.15 g of N ^ [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2-succinimidoethyl] -4-methylvaleryl] -N1, 3dimethyl -L-valinamide gave 0.11 g of N ^ - [2 (R) -1 (R or S) - (hydroxycarbamoyl) -2-succinimidoethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid substances; nmr (MeOD): 3.88 (dd, 1H, J = 14.10); 3.37 (dd, 1H, J = 14.4) 2.80 (dt, 1H, J = 14.3.5); 2.72 (s, 3H); 2.65 (m, 5H); 1.60-1.51 (m, 1H); 1.46-1.35 (m, 1H); 1.14-1.05 (m, 1H); 1.03 (s, 9H); 0.88 (d, 3H, J = 6); 0.82 (d, 3H, J = 6); MS: 427 (M + H) < + >.

The starting material was obtained as follows:

A solution of 0.318 g of N - [2 (R) -1 (R or S) - (benzyloxycarbonyl) -2- (3-carboxy-propionamido) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in 6 ml of dry dimethylformamide were treated sequentially with 0.09 g of hydroxybenzotriazole, 0.09 g of N-methyl-morpholine and 0.144 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. The mixture was stirred at room temperature for 20 hours and then poured into 5% aqueous sodium hydrogen carbonate solution. The product was extracted with ethyl acetate and the extract was washed with a 5% citric acid solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using 5% methanol in dichloromethane for elution. 0.16 g were obtained

N ² - [2 (R) -1 (R or S) - (benzyloxycarbamoyl) -2-succinimidoethyl] -4-methylvaleryl] -N1, 3dimethyl-L-valinamide as a white solid; MS: 517 (M + H) < ⁺ >.

Example 64

In an analogous manner, as described in the first paragraph of Example 1, 0.12 g of N ² [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -4- (carboxy) butyl] -4-methylvaleryl] - N1, 3dimethyl-L-valinamide gave 0.088 g of N ² - [2 (R) - [4-carboxy-1 (R or S) - (hydroxycarbamoyl) butyl-4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form of a white solid; nmr (MeOD): 4.14 (s, 1H); 2.63-2.54 (m, 4H); 2.12 (t, 2H, J = 7) 2.10-2.02 (m, 1H); 1,581.22 (m, 6H); 1.02-0.93 (m, 1H); 0.91 (s, 9H); 0.78 (d, 3H, J = 6); 0.73 (d, 3H, J = 6); MS: 402 (M + H) < + >.

The starting material was prepared as follows:

A mixture of 0.09 g of N ² - [2 (R) -1 (R or S) - (benzyloxycarbamoyl) -4- (methoxycarbonyl) butyl-4methyl valeryl] -N, 3-dimethyl-L-valinamide, 0.012 g of lithium hydroxide monohydrate, 0.55 ml of tetrahydrofuran and 0.36 ml of water were stirred at room temperature for 3 days. The tetrahydrofuran was removed by evaporation and the residue was diluted with ethyl acetate and washed with two portions of 0.5M hydrochloric acid and then with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was removed by evaporation to give 0.078 g of N ² - [2 (R) -1 (R or S) - (benzyloxycarbamoyl) -4 (carboxy) butyl] -4-methylvaleryl] -Nl, 3 -dimethyl-L-valinamide as a white solid;

MS: 492 (M + H) < + >.

Example 65

In an analogous manner, as described in the first paragraph of Example 1, 0.094 g of a mixture of isomers of N ² - [2 (R) - (1-benzyloxycarbamoyl) -4- (1-pyrrolidinyl) butyl] -4-methylvaleryl] -Nl , 3dimethyl-L-valinamide gave 0.066 g of N ² - [2 (R) - (1-hydroxycarbamoyl) -4- (1-pyrrolidinyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form white solids, such as mixtures of diastereoisomers; MS: 441 (M + H) < ⁺ >.

The starting material was prepared as follows:

i) In an analogous manner as described in Example 45 (i), 5.0 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 3.3 g of propargyl bromide were obtained 5.58 g of 1,269 dibenzyl 1-tert-butyl 4-methyl-1- (prop-2-yn-1-yl) -1,2,2 (R) -pentantricarboxylate as a colorless oil; MS: 493 (M + H) < ⁺ >.

ii) A mixture consisting of 0.501 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (prop-2-yn-1-yl) -1, 1,2 (R) -pentantricarboxylate, 0.17 ml of pyrrolidine, 0.083 g of paraformaldehyde, 0.39 ml of glacial acetic acid and 0.004 g of copper chloride in 7 ml of dioxane were stirred for 15 minutes at room temperature and under a nitrogen atmosphere and then heated to reflux for 2 hours. The mixture was stirred at room temperature for another 2 hours and evaporated and the residue partitioned between water and dichloromethane. The pH of the aqueous phase was adjusted to 10 by the addition of ammonium hydroxide and the dichloromethane layer was decided. The aqueous phase was extracted with three parts of dichloromethane and the combined extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to give a brown oil which was purified by flash chromatography on silica gel using ethyl acetate / hexane (4: 1) to give elution. 0.489 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (4-pyrrolidinyl) but-2-yn-1-yl) -1,2,2 (R) pentantricarboxylate were obtained as a colorless oil ; MS: 576 (M + H) < ⁺ >.

iii) In an analogous manner as described in Example 45 (ii-v), from 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (4-pyrrolidinylbut-2-yn-1-yl) - 1,1,2 (R) -pentantricarboxylate gave N ² [2 (R) -1- (benzyloxycarbamoyl) -4- (1-pyrrolidinyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide in the form of white solids, such as mixtures of diastereoisomers; MS: 531 (M + H) < ⁺ >.

Example 66

In an analogous manner as described in the first paragraph of Example 44, 0.14 g of N ² [2 (R) - [1 (R or S) - (carboxy) -6-phenylhexyl] -4-methylvaleryl] -Nl, 3 -dimethyl-L-valinamide gave 0.046 g of N ² - [2 (R) - [1- (R or S) - (hydroxycarbamoyl) -6-phenylhexyl] -4-methylvaleryl-N, 3-dimethyl-L-valinamide in the form white solids; nmr (MeOD); 7.24 (m, 2H); 7.13 (m, 3H); 4.25 (s, 1H); 2.69 (s, 3H); 2.3 (m, 1H); 2.55 (t, 2H, J = 7); 2.17-2.09 (m, 1H); 1.641.45 (m, 4H); 1.42-1.13 (m, 6H); 1.10-1.02 (m, 1H); 0.98 (s, 9H); 0.88 (d, 3H, J = 6); 0.83 (d, J = 6); MS: 462 (M + H) < + >.

The starting material was prepared as follows:

i) In an analogous manner as described in Example 45 (i), 7.28 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2 (R) -pentantricarboxylate and 3.88 g of allyl bromide were obtained 7.234 g of 1,2dibenzyl 1-tert-butyl 4-methyl-1- (prop-2-en-1-yl) -1,2,2 (R) -pentantricarboxylate as a colorless oil; MS: 495 (M + H) < ⁺ >.

ΊΟ ii) A mixture of 1.23 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (prop-2-en-1-yl) -1,2,2 (R) -pentantricarboxylate, 3 ml 1 % of an aqueous solution of osmium tetroxide, 2.44 g of sodium periodate, 15 ml of diethyl ether and 15 ml of water were stirred for 1 hour at room temperature. 3.25 g of sodium periodate was added and the mixture was stirred at room temperature for 24 hours. The ether layer was separated and the aqueous layer was extracted with diethyl ether. The combined ether layers were washed several times with 5% aqueous ascorbic acid and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solution was evaporated and the residue purified by flash chromatography on silica gel using hexane / diethyl ether (8: 1) for elution. 0.955 g of 1,2-dibenzyl 1-tert-butyl 1 (formylmethyl) -4-methyl-1,2,2 (R) -pentane tricarboxylate were obtained as a colorless oil;

MS: 497 (M + H) < + >.

iii) A mixture of 0.496 g of 1,2-dibenzyl 1-tert-butyl (1-formylmethyl) -4-methyl-1,2,2 (R) -pentane tricarboxylate, 0.176 g of potassium carbonate and 0.576 g of 3-phenylpropylphenylphosphonium bromide in 8 ml of dry tetrahydrofuran was heated at reflux under a nitrogen atmosphere for 3 days. The solvent was removed by evaporation and stirred with diethyl ether. The solid was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (6: 1) for elution. 0.397 g of 1,2dibenzyl 1-tert-butyl 4-methyl-1- (5-phenylpent-2-en-1-yl) -1,2,2 (R) -pentantricarboxylate were obtained as a colorless oil.

iv) In an analogous manner as described in Example 45 (ii-iv), from 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (5-phenylpent-2-en-1-yl) - 1,1,2 (R) -pentantricarboxylate gave N ² - [2 (R) [1 (R or S) - (carboxy) -6-phenylhexyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form of a white solid; MS: 447 (M + H) < ⁺ >.

Example 67

In an analogous manner to that described in the first paragraph of Example 44, 0.15 g of N ² [2 (R) - [4-acetoxy-1 (R or S) - (carboxy) -butyl] -4-methylvaleryl] -Nl , 3-dimethyl-L-valinamide gave 0.043 g of N ² - [2 (R) - [4-acetoxy-1 (R or S) - (hydroxycarbamoyl) -butyl] -4-methylvaleryl] N 1, 3-dimethyl-L -valinamide as a white solid;

nmr (MeOD): 4.22 (s, 1H); 4.02-3.68 (m, 2H); 2.68-2.60 (m, 4H); 2.2 (dt, 1H, J = 11.3.5);

1.93 (s, 3H); 1.65-1.37 (m, 5H); 1.36-1.26 (m, 1H); 1.06-0.98 (m, 1H); 0.96 (s, 9H); 0.84 (d, 3H, J = 7); 0.77 (d, 3H, J = 7); MS: 416 (M + H) < + >.

The starting material was prepared as follows:

i) A solution of 2.47 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (prop-2-en-1-yl) -1, 1,2 (R) pentantricarboxylate in 5 ml of dry diethyl ether was cooled to 0 ° C and 0.325 ml of the monochloroborane complex with methyl sulfide were added. The mixture was stirred at room temperature for 2 hours, then cooled to 0 ° C and 0.5 ml of water, 2.3 ml of 1.5M aqueous sodium hydroxide solution and 2.3 ml of 30% aqueous hydrogen peroxide solution were added. The mixture was stirred at room temperature for 3 hours and then acidified with 5% citric acid aqueous solution. The product was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (5: 1) for elution. 1,098 g of 1,2-dibenzyl 1-tert-butyl 1- (3-hydroxypropyl) -4-methyl, 1,2 (R) -pentantricarboxylate are obtained as a colorless oil; MS: 513 (M + H) < ⁺ >.

iii) A solution of 1.069 g of 1,2-dibenzyl 1-tert-butyl 1- (3-hydroxypropyl) -4-methyl-1,1,2 (R) pentantricarboxylate in 10 ml of pyridine at 0 ° C was treated with 0.643 g acetic anhydride. The mixture was stirred at room temperature for 20 hours and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with 1 N hydrochloric acid and saturated aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to give 1.155 g of 1,2-dibenzyl 1-tert-butyl 1- (3-acetoxypropyl) -4methyl-1,2,2 (R) -pentantricarboxylate as an oil.

iv) In an analogous manner as described in Example 45 (ii-iv), 1,2-dibenzyl 1-tert-butyl 1- (acetoxypropyl) -4-methyl-1,2,2 (R) -pentantricarboxylate obtained N ² - [2 (R) - [4acetoxy-1 (R or S) - (carboxy) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS 401 (M + H) < ⁺ >.

Example 68

In an analogous manner to that described in the first paragraph of Example 1, 0.058 g of N ² [2 (R) - [1- (R or S) - (benzyloxycarbamoyl) -4-hydroxybutyl] -4-methylvaleryl] -Nl. Of 3-dimethyl-Lvalinamide gave 0.027 g of N ² - [2 (R) - [4-hydroxy-1- (R or S) - (hydroxycarbamoyl) -butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in white solid form; nmr (MeOD): 4.25 (s, 1H); 3.46 (t, 2H, J = 6); 2.70 (s, 3H); 2.67 (dt, 1H, J = 11.4); 2.16 (dt, 1H, J = 11.3.5); 1,671.31 (m, 6H); 1.12-1.04 (m, 1H); 1.01 (s, 9H); 0.88 (d, 3H, J = 6); 0.83 (d, 3H, J = 6);

MS: 374 (M + H) < + >.

The starting material was prepared as follows:

i) In an analogous manner as described in Example l (iii), N2- [2 (R) - [4-acetoxy-1- (R or S) - (carboxy) butyl] -4-methylvaleryl] is derived from - N, 3-dimethyl-L-valinamide gave N ² - [2 (R) - [4-acetoxy-1- (R or S) - (benzyloxycarbamoyl) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L -valinamide as a white solid.

ii) In an analogous manner to that described in the last paragraph of Example 64, 0.1 g of N ² [2 (R) - [4-acetoxy-1- (R or S) - (benzyloxycarbamoyl) butyl] -4-methylvalery] is obtained from 0.1 g. -Nl, 3-dimethyl-Lvalinamide gave 0.058 g of N ² - [2 (R) - [(R or S) - (benzyloxycarbamoyl) -4-hydroxybutyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in the form white solids; nmr (MeOD); 7.46 (m, 2H), 7.37 (m, 3H); 4.88 (m, 2H); 4.23 (s, 1H); 3.44 (t, 2H, J = 7); 2.74-2.65 (m, 4H); 2.142.06 (m, 1H); 1.63-1.55 (m, 1H); 1.50-1.29 (m, 6H); 1.04-0.95 (m, 10H); 0.87 (d, 3H, J = 7); 0.82 (d, 3H, J = 7).

Example 69

In an analogous manner to that described in the first paragraph of Example 44, 0.1 g of N ^{2 is} [2 (R) - [1- (R or S) - (carboxy) -3-phthalimidopropyl] -4-methylvaleryl] -Nl. Of 3-dimethyl-L-valinamide gave 0.060 g of N ² - [2 (R) - [1- (R or S) - (hydroxycarbamoyl) -3-phthalimidopropyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide in white solid form; nmr (MeOD): 7.877.76 (m, 4H), 4.20 (s, 1H); 3.68-3.51 (m, 2H); 2.74-2.65 (m, 4H9, 2.22 (dt, 1H, J = 10.3,5); 2.05-1.93 (m, 1H); 1.85-1.75 (m, 1H); 1.54-1.45 (m, 1H); 1.41- 1.29 (m, 1H); 1.13-1.04 (m, 1H); 1.06 (s, 9H), 0.86 (d, 3H, J = 6); 0.81 (d, 3H, J = 6); MS: 489 (M + H) +.

The starting material was prepared as follows:

i) 8.2 ml IM solution of borane in tetrahydrofuran was added to a solution of 4.055 g of 1,2dibenzyl 1-tert-butyl 1- (formylmethyl) -4-methyl-1,2,2 (R) -pentantricarboxylate in 40 ml of dry tetrahydrofuran. After stirring for 5 minutes, the mixture was acidified with 5% citric acid aqueous solution and extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate for elution. 2.518 g of 1,2-dibenzyl were obtained

tert-butyl 1- (hydroxymethyl) -4-methyl-1,2,2 (R) -pentantricarboxylate as a colorless oil.

ii) A mixture of 2,911 g of 1,2-dibenzyl 1-tert-butyl 1- (hydroxymethyl) -4-methyl-1,2,2 (R) -pentantricarboxylate, 3.04 g of triphenylphosphine and 1.755 g of phthalimide in 50 ml of dry tetrahydrofuran cooled to 0 ° C and 2.047 g of diethyl azodicarboxylate were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (5: 1) for elution. 3.001 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (2-phthalimidoethyl) -1, 1,2 (R) -pentantricarboxylate were obtained as a colorless gum.

iii) In an analogous manner as described in Example 45 (ii-iv), 1,2-dibenzyl 1-tert-butyl 4-methyl-1- (2-phthalimidoethyl) -1, 1,2 (R) -pentantricarboxylate gave N2- [2 (R) - [1- (R or S) - (carboxy) -3-phthalimidopropyl] -4-methyl] -N, 3-dimethyl-L-valinamide as a white solid; MS 474 (M + H) < ⁺ >.

Example 70

In an analogous manner to that described in the first paragraph of Example 1, 0.075 g of a 1: 1 mixture of N2- [2 (R) - [1- (benzyloxycarbamoyl) -2-methylpropyl] -4-methyl-valeryl] -Nl isomers , 3dimethyl-L-valinamide gave 0.041 g of N2- [2 (R) - [1- (hydroxy-carbamoyl) -2-methylpropyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS 358 (M + H) < + >.

The starting material was prepared as follows:

i) In an analogous manner as described in Example 45 (i), 1-benzyl 4-tert-butyl- was obtained from 1-benzyl 4-tert-butyl 3-tert-butoxycarbonyl-2 (R) isobutylsuccinate and isopropyl iodide. 3-tert-butoxycarbonyl-2 (R) -isobutyl-3-isopropyl succinate;

MS: 463 (M + H) < + >.

ii) In the analogous manner as described in Example 2 (iii), 1-benzyl 2 (R) -isobutyl 3- was obtained from 1-benzyl 4-tert-butyl 3-tert-butoxycarbonyl-2 (R) -isobutylsuccinate. (RS) -isopropylsuccinate as a colorless oil; MS: 306 (M) < ^{+ &gt};.

iii) 0.19 g of 1-Benzyl 2 (R) isobutyl 3- (RS) -isopropylsuccinate was dissolved in 5 ml of dichloromethane and the solution was cooled to -70 ° C. 5 ml of isobutene was added followed by two drops of concentrated sulfuric acid. The flask was sealed and the mixture was stirred at room temperature for 3 days. The mixture was poured into 5% aqueous sodium hydrogen carbonate solution and the product extracted four times with diethyl ether. The combined extracts were washed with 5% aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and evaporated and the residue was purified by flash chromatography on silica gel using hexane / diethyl ether (8: 1) for elution. 0.134 g of 1-benzyl 4-tert-butyl 2 (R) isobutyl-3- (RS) -isopropylsuccinate are obtained as a colorless oil, MS: 363 (M + H) ⁺ .

iv) 0.134 g of 1-Benzyl 4-tert-butyl 2 (R) -isobutyl-3- (RS) -isopropylsuccinate was dissolved in 10 ml of methanol containing 0.08 g of 10% palladium on charcoal. After stirring under hydrogen for 8 hours, the catalyst was filtered off and the solvent removed by evaporation to give 4-tert-butyl 2 (R) -isobutyl 3- (RS) -isopropylsuccinate as a colorless gum; MS: 273 (M + H) < + >.

v) In an analogous manner as described in Example l (i-iii), a 1: 1 mixture of isomers of N ² - [2 (2) is obtained from 4-tert-butyl 2 (R) isobutyl 3- (RS) -isopropylsuccinate. R) - [1-Benzyloxycarbamoyl) -2-methylpropyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS: 399 (M + H) < ⁺ >.

Example 71

In an analogous manner as described in the first paragraph of Example 1, 0.115 g of N ² [2 (R) - [2- (4-biphenyl) -1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl ] -Nl, 3-dimethylL-valinamide gave 0.065 g of N ² - [2 (R) - [2- (4-biphenyl) -1 (R or S) - (hydroxycarbamoyl) ethyl 4-methylvaleryl] -Nl, 3-dimethyl -L-valinamide as a white solid; nmr (MeOD): 7.607.17 (m, 9H), 4.36 (s, 3H); 2.94-2.68 (m, 6H); 2.53-2.42 (m, 1H); 1.63-1.52 (m, 1H), 1.501.33 (m, 1H); 1.19-1.08 (m, 1H); 1.07 (s, 9H); 0.94 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 482 (M + H) < + >.

The starting material was obtained as follows:

In an analogous manner as described in Example 45 (iv), N ² - [2 was obtained from 1,2-dibenzyl l-tert-butyl 4methyl-l, 1,2 (R) -pentantricarboxylate and 4-phenylbenzyl bromide. (R) - [2- (4biphenyl) -1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; MS: 572 (M + H) < ⁺ >.

Example 72

In an analogous manner as described in the first paragraph of Example 1, 0.155 g of N ² [2 (R) - [2- (3-biphenyl) -1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvalery ] -Nl, 3-dimethylL-valinamide gave 0.105 g of N ² - [2 (R) - [2- (3-biphenyl) -1 (R or S) - (hydroxycarbamoyl) ethyl4-methylvaleryl] -Nl, 3-dimethyl -L-valinamide as a white solid; nmr (MeOD): 7.58 (m, 2H), 7.46-7.28 (m, 6H); 7.05 (m, 1H); 4.34 (s, 1H); 2.98-2.68 (m, 6H), 2.54-2.43 (m, 1H); 1.62-1.52 (m, 1H); 1.49-1.37 (m, 1H); 1.23-1.10 (m, 1H); 1.07 (s, 9H); 0.93 (d, 3H, J = 6H); 0.85 (d, 3H, J = 6H); MS: 482 (M + H) < + >.

The starting material was prepared as follows:

In an analogous manner as described in Example 45 (iv), N2- [2 (2) was obtained from 1,2-dibenzyl 1-tert-butyl 4methyl-1,1,2,2 (R) -pentantricarboxylate and 3-phenylbenzyl bromide. R) - [2- (3biphenyl) -1 (R or S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide as a white solid; MS: 572 (M + H) < ⁺ >.

Example 73

In an analogous manner, as described in the first paragraph of Example 1, 5.52 g of N2- [2 (R) - [1- (S) - (benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L -valinamide obtained

3.92 g of N2- [2 (R) - [1- (S) - (hydroxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide as a white solid; nmr (CD3OD): 4.27 (s, 1H), 2.72-2.62 (m, 4H), 2.32-2.2 (m, 1H); 1.58-1.45 (m, 1H); 1.43-1.28 (m, 1H); 1.13-1.05 (m, 4H); 1.02 (s, 9H); 0.89 (d, 3H, J = 5); 0.83 (d, 3H, J = 5); MS: 330 (M + H) < + >.

The starting material was prepared as follows:

i) 400 g of D-leucine were dissolved in 5 L of water containing 296 ml of concentrated sulfuric acid and cooled to -2 ° C. A solution of 421 g of sodium nitrite in 1.25 l of water was slowly added while maintaining the temperature at - 2 ° C. The mixture was stirred for 1.5 hours at 0 ° C and then allowed to stand overnight to warm to room temperature. The mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 168 g of pale yellow oil as a pale yellow oil.

The aqueous phase obtained as described in the previous paragraph was cooled to - 2 ° C and treated with sodium nitrite in the same manner as described in the same paragraph by the addition of 222 g of D-leucinic acid as yellow oils (total yield 390

g) · ii) 278 g of benzyl bromide was added while stirring a solution of 215 g of D-leucinic acid and 246 g of triethylamine in 2.5 L of ethyl acetate. The mixture was then refluxed for 5 hours, cooled and filtered to remove triethylamine hydrobromide. The filtrate was washed twice with 2M hydrochloric acid, water, saturated sodium hydrogen carbonate solution, and finally with saturated sodium chloride solution. The organic extract was dried over anhydrous magnesium sulphate and evaporated to give 225 g of Dleucinic acid benzyl ester as a yellow liquid.

iii) A solution of 177 g of D-leucinic acid benzyl ester and 69.5 g of pyridine in 500 ml of dichloromethane was added to a stirred solution of 248 g of trifluoromethanesulfonic acid anhydride in 1 L of dichloromethane for 1.5 hours at 0 ° C. The mixture was stirred at 0 ° C overnight and then washed twice with water, saturated sodium hydrogen carbonate solution and saturated brine. The organic extracts were dried over anhydrous magnesium sulfate and evaporated to give 258 g of a brown oil. Flash chromatography on silica gel using 2% ethyl acetate in hexane for elution gave 223 g of benzyl 2- (R) trifluoromethanesulfonyl-4-methyl valerate as a yellow oil; Rf = 0.52 (10% ethyl acetate / hexane).

iv) A solution of 147 g of benzyl t-butylmalonate in 150 ml of dry Ν, dim-dimethylformamide was added dropwise and with stirring, a suspension of 14.9 g of sodium hydride in 800 ml of imet dimethylformamide for 30 minutes. The solution was stirred at room temperature for 1 hour until turbulent gas evolution ceased. The solution was cooled to 0 ° C and treated with a solution of benzyl 2- (R) -trifluoromethanesulfonyl-4-methylvalerate in 750 ml of dry dichloromethane. The solution was stirred for 1 hour at 0 ° C and then overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in 2 L of dichloromethane. The solution was washed with water, saturated sodium hydrogen carbonate solution and sodium chloride solution. The organic extracts were dried over anhydrous magnesium sulfate and evaporated to give 276 g of yellow oil. Flash chromatography on silica gel using 5% ethyl acetate in hexane for elution gave 230.5 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate as a colorless oil.

v) A solution of 17.05 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2 (R) -pentantricarboxylate in 212 ml of isopropanol was hydrogenated in the presence of 5.2 g of 10% palladium on charcoal. The catalyst was removed by filtration, the filtrate was treated with 10.36 ml of piperidine and 43.7 ml of 40% aqueous formaldehyde solution. The mixture was stirred at room temperature for 4 days, evaporated to dryness and the residue dissolved in ethyl acetate. The solution was washed with 5% citric acid solution and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the resulting oil was purified by flash chromatography on silica gel using 1.5% methanol / dichloromethane for elution to give 7.98 g of 4-tert-butyl-2 (R) -isobutyl-3-methylensuccinate as an oil. MS: 243 (M + H) < + >.

vi) A solution of 7.92 g of 4-tert-butyl-2 (R) -isobutyl-3-methylenesuccinate in 400 ml of ethyl acetate was hydrogenated in the presence of 790 mg of 10% palladium on carbon. The catalyst was removed by filtration and the filtrate volume was reduced to 70 ml. The solution was heated to 70 ° C and then treated with 6 ml of dicyclohexylamine. The solid was dissolved in 150 ml of ethyl acetate and the solution was allowed to cool overnight. The solid was filtered off, washed with a small amount of dry diethyl ether and recrystallized once from ethyl acetate. The solution was washed twice with 0.5M sulfuric acid, water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give 3.32 g of 4-tert-butyl-2 (R) -isobutyl-3 (S) -methylsuccinate; MS: 245 (M + H) < + >.

vii) In an analogous manner as described in Example l (i-iii), 5.52 g of N ² - [2 (R) were obtained from 3.32 g of 4-tert-butyl 2 (R) -isobutyl-3 (S) -methylsuccinate. ) - [1- (S) - (Benzyloxycarbamoyl) ethyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide as a white solid;

MS: 420 (M + H) < + >.

Example 74

In an analogous manner to that described in the first paragraph of Example 44, 1.34 g of N ² [2 (R) - [1- (RS) - (carboxy) -5-phthalimidopentyl] -4-methylvaleryl] -N 4, 3 -dimethyl-L-valinamide prepared in an analogous manner as described in Example 45 (i-iv) gave 0.42 g of N ² [2 (R) - [1- (R or S) - (hydroxycarbamoyl) -5- phthalimidopentyl] -4-methylvaleryl] -Nl, 3-dimethyl-lvalinamide as a white solid; MS: 517 (M + H) < ⁺ >. nmr (CD3OD): 8.07 (d, 1H, J = 10); 7.95 (m, 1H); 7.84-7.75 (m, 4H); 4.24 (m, 1H); 3.59 (t, 2H, J = 7), 2.7-2.63 (m, 4H); 2.13 (m, 1H); 1.68-15.4 (m, 3H); 1.52-1.46 (m, 1H); 1.4-1.28 (m, 3H); 1.24-1.13 (m, 1H); 1.09-1.02 (m, 1H); 1.00 (s, 9H); 0.85 (d, 3H, J = 6); 0.80 (d, 3H, J = 6).

Example 75

In the analogous manner as described in the first paragraph of Example 1, 125 mg of N ² [2 (R) - [(R or S) amino (benzyloxycarbamoyl) methyl] -4-methylvaleryl] -N 1,3-dimethyl- L-valinamide hydrochloride prepared in an analogous manner as described in Example 45 (iv) afforded 62 mg of N ² - [2 (R) - [(R or S) amino) (hydroxycarbamoyl) methyl] -4-methylvaleryl] -Nl, 3dimethyl-L-valinamide hydrochloride as a brownish solid; MS: 331.2345.

Example 76

In the analogous manner as described in the first paragraph of Example 1, 60 mg of N ² · [2 (R) - [(R or S) - (benzyloxycarbamoyl) - (2-phenacetylamido) methyl] -4-methylvaleryl] - N 1,3dimethyl-L-valinamide prepared in an analogous manner as described in Example 45 (i78

v), 46 mg of N2- [2 (R) - [(R or S) - (hydroxycarbamoyl) (2-phenacetylamido) methyl] -4methyl valeryl] -Nl, 3-dimethyl-L-valinamide was obtained as a brownish-colored solid ;

MS: 449 (M + H) < + >. nmr (CD ₃ OD): 7.32-7.20 (m, 5H); 4.45 (d, 1H, J = 8); 4.23 (s, 1H); 3.58-3.46 (m, 2H); 3.07-2.90 (m, 1H); 2.72 (s, 3H); 1.52-1.26 (m, 3H); 1.21-1.02 (m, 1H); 0.98 (s, 9H); 0.86-0.78 (m, 6H).

Example 77

In the analogous manner as described in the first paragraph of Example 1, 200 mg of 4 - [[N [2 (R) - (benzyloxycarbamoylmethyl) -4-methylvaleryl] -3-methyl-L-valyl] amino] -butyric acid prepared in an analogous manner as described in Example l (i-iii) gave 162 mg of 4 - [[N [2 (R) - (hydroxycarbamoylmethyl) -4-methyl valeryl] -3-methyl-L-valyl] amino ] -butyric acids in the form of white powder; MS: 388 (M + H) < ⁺ >. nmr (CD3OD): 7.83 (d, 1H, J = 9); 4.22 (m, 1H); 3.26-3.15 (m, 2H); 2.98-2.90 (m, 1H); 2.35-2.26 (m, 3H); 2.20-2.13 (m, 1H); 1.83-1.74 (m, 2H); 1.62-1.42 (m, 2H); 1.24-1.14 (m, 1H); 1.0 (s, 9H); 0.92 (d, 3H, J = 7); 0.86 (d, 3H, J = 7).

Example 78

In an analogous manner as described in the first paragraph of Example 1, 200 mg of methyl-4 [[N- [2 (R) - [(benzyloxycarbamoyl) methyl] -4-methylvaleryl] -3-methyl-L-valyl] amino] -butyrate, prepared in an analogous manner as described in Example l (i-iii), gave 156 mg of methyl4 - [[N- [2 (R) - [(hydroxycarbamoyl) methyl] -4-methylvaleryl] -3 -methyl-L-valyl] amino] -butyrate as a white powder; nmr (CD3OD): 4.22 (s, 1H); 3.66 (s, 3H); 3.26-3.13 (m, 2H); 2,982.89 (m, 1H); 2.38-2.26 (m, 3H); 2.20-2.13 (m, 1H); 1.85-1.71 (m, 2H); 1.62-1.42 (m, 2H); 1.22-1.13 (m, 1H); 1.0 (s, 9H); 0.91 (d, 3H, J = 8); 0.86 (d, 3H, J = 8).

Example 79

In an analogous manner to that described in the first paragraph of Example 1, 200 mg of 4 - [[N [2 (R) - [(benzyloxycarbamoyl) methyl] -4-methylvaleryl] -3-methyl-L-valyl] amino] -N-methyl butyramide prepared in an analogous manner as described in Example l (i-iii) gave 139 mg of 4 - [[N- [2 (R) - [(hydroxycarbamoyl) methyl) -4-methylvaleryl] - 3-methyl-L-valyl] amino] -Nmethyl butyramide as a white solid; nmr (CD3OD): 4.19 (s, 1H); 3.25-3.10 (m, 2H); 3.0-2.89 (m, 1H); 2.62 (s, 3H); 2.35-2.27 (m, 1H); 2.22-2.15 (n, 2H); 1.82-1.72 (m, 2H); 1.62-1.41 (m, 2H); 1.23-1.14 1.0 (s, 9H); 0.91 (d, 3H, J = 8); 0.86 (d, 3H, J = 8).

Example 80

In an analogous manner to that described in the first paragraph of Example 1, 0.165 g of N ² [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -4- (carbamoyl) butyl] -4-methylvaleryl] is obtained. N, 3-dimethyl-L-valinamide gave 0.11 g of N ² - [2 (R) -4-carbamoyl-1 (R or S) - (hydroxycarbamoyl) butyl-4-methylvaleryl] -N, 3-dimethyl-L -valinamide, in the form of a white solid; nmr (MeOD); 4.15 (s, 1H); 2.61 (s, 3H); 2.58 (dt, 1H, J = 11.3), 2.12-2.02 (m, 3H); 1.58-1.45 (m, 4H); 1.33-1.18 (m, 2H); 1.02-0.93 (m, 1H); 0.92 (s, 9H); 0.78 (d, 3H, J = 6); 0.73 (d, 3H, J = 6); MS: 401 (M + H) < + >.

The starting material was prepared as follows:

Mixture of 0.177 g N ² - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -4- (carboxy) butyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide, 0.062 g ammonium salts of 1-hydroxybenzotriazole, 0.05 ml of N-methylmorpholine and 0.078 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 5 ml of dry dimethylformamide were stirred at 0 ° C for 1 hour and then at room temperature for 2 days. The solution was poured into aqueous sodium hydrogen carbonate solution and the product was extracted with four parts of ethyl acetate. The combined ethyl acetate extracts were washed sequentially with aqueous sodium hydrogen carbonate solution, 1M hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give 0.166 g of N ² - [2 (R) - [1 (R or S) - (Benzyloxycarbamoyl) -4 (carboxy) butyl] -4-methylvaleryl] -N, 3-dimethyl-L-valinamide as a colorless gum; MS: 491 (M + H) < ⁺ >.

The following Examples illustrate pharmaceutical preparations containing amino acid derivatives of the present invention:

Example A

Tablets containing the following ingredients can be prepared in the usual way:

Ingredient On the tablet Amino acid derivative 10.0 mg Lactose 125.0 mg Corn starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg Total mass 215.0 mg

Example B

Capsules containing the following ingredients can be prepared in the usual way:

Ingredient To the capsule Amino acid derivative 10.0 mg Lactose 165.0 mg Corn starch 20.0 mg Talc 5.0 mg Capsule fill weight 200.0 mg

For:

Claims (31)

PATENT APPLICATIONS 1. Amino acid derivatives of the general formula R1 represents hydrogen, amino, protected amino, acylamino or lower alkyl, which is optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3- dioxo-1Hbenz [d, e] isoquinol-2-yl, carboxyl, protected carboxyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, di (lower alkyl) amine, carboxy-lower alkanoylamine, pyrrolidino or morpholino ; R ^ represents hydrogen or lower alkyl, which is optionally substituted by aryl, amino, protected amino, di (lower alkyl) amino, guanidino, carboxyl, protected carboxyl, carbamoyl, mono (lower alkylcarbamoyl, di (lower alkyl) carbamoyl, di (lower alkoxy) phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino; R3 represents hydrogen or lower alkyl optionally substituted by hydroxy, protected hydroxy, amino or protected amino; R4 represents hydrogen, hydroxy, lower alkoxy or benzyloxy, and R 5 represents hydrogen or halogen, and pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein hydrogen, amino, acetylamino or lower alkyl, optionally substituted by hydroxy, protected hydroxy, amino or protected amino, and R ² represents hydrogen or lower alkyl optionally substituted by aryl, amino, protected amino, acetylamino, di (lower alkylamino, guanidino, carboxy, protected carboxy, di (lower alkoxy) phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino. Compounds according to claim 1 or 2, characterized in that R1 represents hydrogen, amino, acetylamino, benzyloxycarbonylamino, or lower alkyl optionally substituted by amino, phenyl, phthalimido, succinimido, carboxy, alkoxycarbonyl, morpholino, hydroxy or acetoxy. Compounds according to claim 3, characterized in that R 4 represents hydrogen, amino, acetylamino, benzyloxycarbonylamino, methyl, 5-amino-pentyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 5-hydroxypentyl, 5-acetoxy-pentyl, aminomethyl, phthalimidomethyl , succinimidomethyl, benzyl, 3-phenylpropyl, 3-carboxy-propyl, 3-methoxycarbonylpropyl, benzoylaminomethyl, morpholinomethyl, acetylaminomethyl, 2-phthalimidoethyl, 3-hydroxypropyl or 3-acetoxypropyl. Compounds according to any one of claims 1 to 4, characterized in that R ² represents lower alkyl optionally substituted by amino, aryl, guanidino, carboxy, di (lower alkoxy) phosphinyl, dihydroxyphosphinyl or morpholino. Compounds according to claim 5, characterized in that R ² represents methyl, 4-aminobutyl, 1-phenylethyl, 5-carboxypentyl, diethoxyphosphinylmethyl, dihydroxyphosphinylmethyl or 5morpholinopentyl. Compounds according to any one of claims 1 to 6, characterized in that R 1 represents hydrogen, hydroxymethyl, 2-aminoethyl or 4-aminobutyl. Compounds according to claim 7, characterized in that R1 represents hydrogen. Compounds according to any one of claims 1 to 8, characterized in that R 1 represents hydrogen, hydroxy or benzyloxy. Compounds according to claim 9, characterized in that R 1 represents hydrogen or hydroxy. Compounds according to any one of claims 1 to 10, characterized in that R 1 represents hydrogen or bromine. A compound according to claim 1, wherein N 2 is - [(R) - [hydroxycarbamoylmethyl4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide. A compound according to claim 1, characterized in that N 2 - [2 (R or S) - [1 (S) (hydroxycarbamoyl) ethyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide ( isomer 1). A compound according to claim 1 wherein N is N - [2 (R or S) - [[[(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz] d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] -methyl] 4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide. A compound according to claim 1, wherein N 2 - [2 (R or S) - [[(R) - (amino) [(5 bromo-2,3-dihydro-6-hydroxy-1,3) -dioxo-1H-benz [d, e] isoquinol-2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide. A compound according to claim 1, wherein N 2 - [2 (R or S) - [[(R) - (amino) [(2,3-dihydro-6-hydroxy-1,3-dioxo-1H) -benz [d, e] isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] methyl] 4-methylvaleryl] -Nl, 3-dimethyl-L-valinamide. A compound according to claim 1, characterized in that N 2 - [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -N 1, 3-dimethyl-L -valinamide. A compound according to claim 1, characterized in that N 2 - [2 (R) - [1 (R or S) (hydroxycarbamoyl) -4- (methoxycarbonyl) butyl] -4-methylvaleryl] -N 1, 3- dimethyl-L-valinamide. A compound according to claim 1, characterized in that N 2 - [2 (R) - [1 (R or S) (hydroxycarbamoyl) -4-phenylbutyl-4-methylvaleryl] -N, 3-dimethyl-L- valinamide. A compound according to claim 1, characterized in that N 2 - [2 (R) - [1 (R or S) · (hydroxycarbamoyl) -2-succinimidoethyl] -4-methylvaleryl] -N 1, 3-dimethyl- L-valinamide. 21. Acids characterized by having a general formula R ¹⁰ where R 10 represents hydrogen, protected amino, acylamino or lower alkyl, which is optionally substituted by aryl, protected hydroxy, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-1H -benz- [d, e] isoquinol-2-yl, protected carboxy, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, di (lower alkyl) amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino, R And O represents hydrogen or lower alkyl, which is optionally substituted by aryl, protected amino, di (lower alkyl) amino, protected carboxyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) -carbamoyl, di (lower alkoxy) phosphinyl, pyrrolidino, piperidino or morpholino. Compounds characterized in that they have the general formula wherein benzyloxyformamido, R1 has the meaning set forth in claim 21, and R1b has any value for R4O indicated in claim 21, or represents nitroguanidine. 23. The acids having the general formula wherein R1 and the meaning given in claim 1 and R10 in claim 21 have the defined meaning are hydrogen or lower alkyl optionally substituted by protected hydroxy or protected amino. (Vlij CO-NH-R ² Compounds characterized in that they have the general formula wherein R1, R4, r3, r4 _and n5 are as defined _in claim 1 and R4 represents lower alkyl. Compounds characterized in that they have the general formula wherein R 1 and R 4 O have the meanings indicated in claim 21. Compounds according to any one of claims 1 to 20, characterized in that they are intended for use as therapeutically active substances. Compounds according to any one of claims 1 to 20, for use in the treatment or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis. A process for the preparation of compounds according to any one of claims 1 to 20, characterized in that it is carried out a) by reaction of an acid of the general formula HOOC R ¹⁰ (ID wherein RJO represents hydrogen, protected amino, acylamino or lower alkyl, optionally substituted by aryl, protected hydroxy, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo -1H-benz- [d, e] isoquinol-2-yl, protected carboxy, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, di (lower alkylamino, carboxy-lower alkanoylamino, pyrrolidino or morpholino, R ² ^ represents hydrogen or lower alkyl, which is optionally substituted by aryl, protected amino, di (lower alkyl) amino, protected carboxyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) -carbamoyl, di (lower alkoxy) phosphinyl, pyrrolidino, piperidino or morpholino, with a compound of the general formula H ₂ N-OZ (III) wherein Z represents hydrogen, tri (lower alkyl) silyl or diphenyl (lower alkyl) silyl 1, or, if necessary, cleaving any diphenyl (lower alkyl) silyl group present in the reaction product, or b) by catalytic hydrogenation of a compound of the general formula A ¹ R ¹⁰ CO - NH CO - NH-R ²¹ (IV) wherein benzyloxyformamido, R- ^ θ has the aforementioned meaning and R ² ^ has any of the preceding values given to R ² Q or represents nitroguanidine, or c) by reaction of an amine of the general formula H ₂ N NH-R ²⁰ (V) wherein R ² has the meaning given earlier in this claim, with an acid of the general formula (VI) wherein R 2 and R 4 have the meaning given in claim 1, R 2 has the previously defined meaning, R- ^ θ represents hydrogen or lower alkyl optionally substituted by protected hydroxy or protected amino. or d) treating the compound of general formula (VII) in which Rl, R ^2, R ^2, R and R in defined Claim 1 and R represents lower alkyl, with an acid or a halotri (lower alkyl) silane, or e) by reacting a compound of the general formula wherein R 1 and R ^{2 have the} meaning indicated in claim 1 and R 1 has a previously defined meaning in this claim, with a compound of the general formula R ¹⁰ (IX) wherein R ² and R ^{2 have the} meanings defined in this claim, or f) by brominating a compound of formula I in which A represents a group of formula (b) in which R4 is hydroxy and R4 is hydrogen, or g) cleaving off the protecting group or groups from a compound of formula I, wherein R represents protected amino or lower alkyl substituted by protected hydroxy or protected amino and / or R ² represents a lower alkyl substituted with protected amino or protected carboxyl and / or R ² represents lower alkyl substituted with protected hydroxy or protected amino, or h) by treating a compound of formula I wherein R ² represents di (lower alkoxy) phosphinyl- (lower alkyl), with acid or with halotri (lower alkyl) silane, or i) by acylating a compound of formula I in which R ¹ represents amino or amino-lower alkyl, or j) by opening a ring of a compound of formula I in which R1 represents phthalimido (lower alkyl) or succinimido- (lower alkyl), and k) as necessary by converting the resulting compound of formula I into a pharmaceutically acceptable salt. A process according to claim 28, characterized in that the compounds of claim 2 are produced by the process b), c), d), e), f), g), h), i) and / or k) of the process. Pharmaceutical compositions characterized in that they contain compounds according to any one of claims 1 to 20 and a therapeutically acceptable material as a carrier of the mixture. A process for the manufacture of a pharmaceutical composition comprising formulating an effective amount of a compound of any one of claims 1 to 20 into a galenic form together with a therapeutically acceptable carrier material.