MXPA00003450A - Azetidinone derivatives for the treatment of hcmv infections - Google Patents

Abstract

A compound of formula (I) wherein R1 is hydrogen, methyl, ethyl, methoxy or methylthio;R2 and R3 each independently is hydrogen or lower alkyl;R4 is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy;R5 is lower alkyl, lower cycloalkyl, (CH2)mC(O)OR6 wherein m is the integer 1 or 2 and R6 is lower alkyl, phenyl optionally substituted;optionally Het or Het(lower alkyl);or R4 and R5 together with the nitrogen atom to which they are attached form a nitrogen containing ring optionally substituted with C(O)O-benzyl or with phenyl optionally substituted with C(O)OR7 wherein R7 is lower alkyl or (lower alkyl)phenyl;and Z is lower alkyl or optionally substituted phenyl or Het;with the proviso that when Z is (CH2)p-(Het), then R2 and R3 each is hydrogen;or a therapeutically acceptable acid addition salt thereof.

Description

DERIVATIVES OF AZETID INONA FOR THE TREATMENT OF INFECTIONS BY THE HUMAN CITOMEGALOVTRUS FIELD OF THE INVENTION This invention relates to a? Ethidinone derivatives having activity against herpes infections. More specifically, the invention relates to azetidin-2-one derivatives that exhibit antiherpe activity, to pharmaceutical compositions comprising the derivatives and to methods of using the derivatives to inhibit the replication of herpes viruses and to treat herpes infections.

BACKGROUND OF THE INVENTION Herpes viruses inflict a wide range of diseases against humans and animals. For example, herpes simplex virus, types 1 and 2 (HSV-1 and VH? -2) are responsible for afta and genital lesions, respectively; Varicella-oster virus (VVZ) causes chickenpox and oster and human cytomegalovirus. { CMVH) is a leading cause of opportunistic infections in individuals lacking the immune system.

REF.:119049 Over the past two decades, it has received the greatest attention from researchers in the search for new therapeutic agents for the treatment of herpes virus infections, a class of compounds known as the purine and pyrimidine nucleoside analogues. As a result, several nucleoside analogs have been developed as antiviral agents. The most successful to date is acyclovir, which is the agent of choice to treat genital HSV infections. Another nucleoside analogue, ganciclovir, has been used with some success in the treatment of CMVH infections. However, despite some significant advances, there continues to be a need for effective and safe therapeutic agents to treat viral herpes infections. For a review of the current therapeutic agents in this sector, see R »E« - Boeheme et al., Annual Reports in Medicinal Ghemistry, 1995, 30, 139. The present application describes a group of azetidin-2-one derivatives, particularly active against cytomegalovirus. This activity, linked to a wide margin of safety, makes these derivatives Desirable agents to fight herpes infections, Derivatives of azet idin-2-one have been reviewed in the literature for having a variety of biological activities; mainly antibacterial, anti-inflammatory, antidegenerative, etc. However, azet idin-2-one derivatives have not been reported as antiviral agents against herpes viruses. The following references describe azetidin-2-ones with biological activity: S, K. Shah et al, r European patent application 0. 199,630, October 29, 1986 S, K, Shah et al, European patent application 0,377,549, October 18, 1989, P.L. Durette and M. Maccoss, U.S. Pat. ,100,880, March 31, 1992, P, L, Durette and M, Maccoss, US patent, ,104,862, April 14, 1992, W, K, Hagmann et al, Bioorg, Med, Chem, Lett, 1-992, 2, 681, W, K, Hagmann et al, J Med, Chem, 1-993-, 36, 771, J, B, Doherty et al, U.S. Patent, 5,229,381, issued July 20, 1993, S.K. Shah et al., Bioorg. Med. Chem. Lett. 1993, 3, 2295, G. Crawley, PCT patent WO 95/02579, published January 26, 1995, P, E, Finke et al, J Med, Chem, 1-995, 38, 2449 and K. Kobayashi et al., Japanese patent application 07242624, published September 19, 1995; Chem, Abstr, 1-99G 124, 29520, The present azet idin-2-one derivatives are distinguished from the prior art compounds because they possess different chemical structures and biological activities.

Br e desirripsién de 1-a invenaión The azet idin-2-one derivatives are represented by formula 1: wherein Ri is hydrogen, methyl, ethyl, methoxy or methylthio; * and R-3 -, - each independently, is hydrogen or lower alkyl; R 4 is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy; R5 is lower alkyl, lower cycloalkyl, (CH2) mC (0) ORir, where m is the integer 1 or 2, and R-β is lower alkyl or phenyl (lower alkyl); phenyl, monosubstituted phenyl, disubstituted or trisubstituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; phenyl (lower alkyl), phenyl (lower alkyl) monosubstituted or disubstituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkyl-amino , di (lower alkyl) amino, lower amino acyl, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl, and C (0) 0R7, wherein R7 is lower alkyl or phenyl (lower alkyl); Het or Het (lower alkyl), wherein Het represents a five or six membered heterocyclic ring-monovalent, unsubstituted, monosubstituted or disubstituted, containing one or two heteroatoms selected from the group consisting of N, O or S, wherein each substituent is independently selected from the group consisting of lower alkyl, lower alkoxy, halo and hydroxy; 5- (benzo [1,3] dioxolyl) methyl, (l (R) -l-naphthalenyl) ethyl, 2-benzothiazoli or 2-thiazolo [4, 5-b] pyridinyl; or -4 and R5, together with the nitrogen atom to which they are attached, form a ring of piperidino, morpholino, thiomor-olino, piperazino, N-methylpiperazino, l- (3,4-dihydro-lH-isoquinolinyl), or - (3, 4-dihydro-lH-isoquinolinyl), or a pyrrolidino ring, optionally substituted with benzyloxycarbonyl or with phenyl, said phenyl ring being optionally mono- or. It is substituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkyl-amino, di (lower alkyl) amino, acyl lower-amino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and C (0) 0R7, wherein R7 is lower alkyl or (lower alkyl) phenyl; and Z is lower alkyl, phenyl, phenyl monosubstituted or disubstituted with a substituent independently selected from lower alkyl, lower alkoxy, halo, hydroxy and amino; phenylmethyl, phenylmethyl monosubstituted or disubstituted in its phenyl portion with a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, hydroxy and amino; or (CH2) P-Het, where p is the integer 0 or 1 and Het is as defined herein; with the proviso that when Z is (CH2) P-Het as defined herein, then R2 and R3 is each hydrogen; or a pharmaceutically acceptable acid addition salt thereof. A preferred group of compounds is represented by the formula (1), wherein Ri? R2 and R ^ are as defined herein above; R-4 is hydrogen or lower alkyl; R5 is lower alkyl, lower cycloalkyl, CH2C (0) CR6, wherein R6 is methyl, ethyl or phenylmethyl; phenyl, monosubstituted phenyl, disubstituted or trisubstituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; phenyl (lower alkyl), phenyl (lower alkyl) monosubstituted or disubstituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkyl-amino , di (lower alkyl) amino, lower amino acyl, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and C (0) OR, where R7 is methyl, ethyl or phenylmethyl; Het or Het (lower alkyl), wherein Het is 2-furyl, 2-methyl-3-furyl, 2-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-methyl-2-pyrrolyl, -thiazolyl, 4-thiazolyl, 2-isoxazolyl, 2-pyrimidinyl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 4-pyrimidinyl, 2,6-dimethyl-2-pyrimidinyl, 4- methyltetrazolyl, 2-benzothiazole, ilo or 2-thiazolo [4, 5-b] pyridinyl; (5-benzo [1,3] dioxolyl) methyl, 1 (R) (1-naphthalenyl) ethyl; or R4 and R5, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino. morpholino, N-methylpiperazino, 1- (3, -dihydro-lH-isoquinolinyl) or 2- (3,4-dihydro-lH-isoquinolinyl); and Z is as defined herein above. A more preferred group of compounds is represented by formula 1, wherein R-i is hydrogen, methyl, ethyl, methoxy or methylthio; R-2 and R-3- each independently, is hydrogen or methyl; R-4 is hydrogen, methyl or ethyl; s is methyl, ethyl, 1-methylethyl, cyclobutyl, cyclopentyl, cyclohexyl, CH 2 C (0) OR 6, wherein R 6 is methyl or phenylmethyl; phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxy-phenyl, 4-methylphenyl, 4- (methylthio) phenyl, phenylmethyl, 1-phenylpropyl, 1-phenylbutyl, phenylmethyl monosubstituted in the position 3 or 4 of its phenyl part with a substituent selected from the group consisting of methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, methoxy, ethoxy, methylthio, bromine, chlorine, fluorine, nitro, acetylamino, C (0) NMe2, C (0) NMe2 C (0) Net2, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromet il) sulfonyl and C (0) 0R7, wherein R7 is methyl, ethyl or benzyl; 5- (benzo [1,3] dioxolyl) methyl, (1 (R) -l-naphthalenyl) ethyl, 2-pyridinyl, 4-pyridinyl, 2-pyridinylmethyl, 4-pyridinylmethyl, 1- (4-pyridinyl) ethyl or 1- (4-pyridinyl) propyl; or R-4 and R-5, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, morpholino, 1- (3,4-dihydro-lH-isoquinolinyl) or 2- (3,4-dihydro) -IH-isoquinolinyl); Z is phenyl or phenylmethyl Another more preferred group of compounds is represented by formula 1, wherein Ra is hydrogen, methyl or methylthio; R-2 and? each independently, is hydrogen or methyl; R is hydrogen, methyl or ethyl; Rs is methyl, ethyl, 1-methylethyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2C (0) OR6, wherein R6 is methyl or phenylmethyl; phenyl, 4-fluorophenyl, 4- methoxyphenyl, 3,5-dimethyl-4-methoxy-phenyl, 4-methylphenyl, 4- (methytthio) phenyl, phenylmethyl, 1-phenylpropyl, 1-phenylbutyl, phenylmethyl monosubstituted in the 3- or 4-position of its part phenyl with a substituent selected from the group consisting of methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, methoxy, ethoxy, methylthio, bromo, chloro, fluoro, nitro, acetylamino, C (0) NMe2, C (0) NEt2, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and C (0) 0R7, wherein R7 is methyl, ethyl or benzyl; 5- (benzo [1, 3] ioxolyl) methyl, (1 (R) -1-naphthalenyl) ethyl, 2-pyridinyl, 4-pyridinyl, 2-pyridinylmethyl, 4-pyridinylmethyl, 1- (4-pyridinyl) ethyl or 1- (4-pyridinyl) propyl; and Z is lower alkyl. Yet another more preferred group of compounds is represented by formula 1, wherein Ri is hydrogen, methyl, methylthio or methoxy; R2 and R3 each independently, is hydrogen or methyl, R-4 is hydrogen, methyl or ethyl; Rs is methyl, ethyl, 1-met i let ilo, cyclobutyl, cyclopentyl, cyclohexyl, CH 2 C (0) ORß, wherein R 6 is methyl or phenylmethyl; phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxy-phenyl, 4-methylphenyloyl 4- (methylthio) phenyl, phenylmethyl, 1-phenylpropyl, 1-phenylbutyl, phenylmethyl monosubstituted at the position 3 or 4 of its phenyl part with a substituent selected from the group consisting of methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, methoxy, ethoxy, methylthio, bromo, chloro, fluoro, nitro, acetylamino , C (0) NMe2, c (0) NEt2, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and c (0) 0R7, wherein R7 is methyl, ethyl or benzyl; 5- (benzo [1,3] dioxolyl) methyl, 1 (R) - (1-naphthalenyl) ethyl, 2-pyridinyl, 4-pyridinyl, 2-pyridinylmethyl, 4-pyridinylmethyl, 1- (4- pyridinyl) ethyl or 1- (4-pyridinyl) propyl; and Z is 2-furyl, 2-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-methyl-2-pyrrolyl, 2-thiazolyl, 2-isoxazolyl, 2-pyrimidinyl; 4,6-Dimethyl-2-pyrimidinyl, 5- (1-methyl-1H-tethexyl), 5- (2-methyl-2H-tetrazolyl), 2-benzothiazolyl or 2-thiazolo [4,5-b] ] pyridinyl.

A more preferred group of compounds is represented by formula 1, wherein i is hydrogen, methyl, methoxy or methylthio; 2 and R3- is each hydrogen; it is hydrogen or methyl; R5 is CH2C (0) OR6, wherein R6 is phenylmethyl; or R5 is 4- fluorophenyl, 4-methoxyphenyl, 3,5-dimet and 1-4-methoxy-phenyl, 4- (methylthio) phenyl, phenylmethyl, 1 (R) -phenylethyl, 1 (S) -phenylethyl, 1 ( R) -phenylpropyl, 1 (R) -phenylbutyl, (4-methylphenyl) methyl,. { 4- (1-methylethyl) phenyl} metyl, (4-methoxyphenyl) metyl, (4-chlorophenyl) methyl, (2-nitrophenyl) methyl, (3-nitrophenyl) methyl,. { 4 - (acetylamino) phenyl} met ilo,. { 4- (trifluoromethyl) phenyl} I put it,. { 4-. { (trifluoromethyl) uncle} phenyl Jmetilo,. { 4- . { (trifluoromethyl) sulfinil} phenyl } methyl,. { 4-. { (trifl oromethyl) sulfonyl} phenyl } met ilo,. { 4 - (methoxycarbonyl) phenyl} methyl, (5-benzo [l, 3] dioxolyl) methyl, 1 (R) - (1-naphthalenyl) ethyl, 4-pyridinyl, 4-pyridinylmethyl or l- (4-pyridinyl) ropyl; or R4 and R5 together with the nitrogen to which they are attached, form a pyrrolidino, morpholino, 1- (3, 4-dihydro-lH-isoquinolinyl) or 2- (3,4-dihydro-lH-isoquinolinyl); And Z is phenyl or phenylmethyl. Included within the scope of this invention is a pharmaceutical composition for treating cytomegalovirus infections in a human, comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The scope of the invention also includes a method for treating cytomegalovirus infections in a human being, comprising administering thereto an effective amount of the compound of formula 1 or a therapeutically acceptable salt thereof. A method for protecting human cells against cytomegalovirus pathogenesis is also included within the scope. , which comprises treating said cells with an effective anti-cytomegaloviric amount of a compound of formula 1 or a therapeutically acceptable salt thereof,. The compounds of formula 1 according to the present invention can also be used in co-therapies with other conventional anti-herpes compounds such as, but not limited to ganciclovir, foscarnet, acyclovir, valaciclovir, famciclovir, cidofovir, penciclovir and lobucavir. The compounds of formula 1 according to the present invention can also be used in co-therapies with anti-retroviral compounds such as reverse transcriptase inhibitors (ie AZT, 3TC) or protease inhibitors. In the following, methods for preparing the compounds of formula 1 are described, Dfr &detailed description of the invention General As used herein, the following definitions apply, unless otherwise indicated: With reference to the cases in which (R) or (S) is used to designate the configuration of a radical, for example Rs of the compound of the formula 1, the designation is made in the context of the compound and not in the context of the radical alone. The term "residue", with reference to an amino acid or amino acid derivative, means a radical derived from the corresponding α-amino acid by removing the hydroxyl from the carboxy group and a hydrogen of the a-amino group »For example, the terms Gln, Ala, Gly, Lie, Arg, Asp, Phe, Ser, Leu, Cys, Asn, Sar and Tyr represent the" residues "of L-glutamine, L-alanine , glycine, L-isoleucine, L-arginine, L-aspartic acid, L-phenylalanine, L-serine, L-leucine, L-cysteine, L-asparagine, sarcosine and L-tyrosine, respectively. The term "side chain", with reference to an amino acid or amino acid derivative, means a residue attached to a carbon atom of the α-amino acid. For example, the side chain of the R group for glycine is hydrogen, for alanine it is methyl and for valine it is isopropyl. For the specific R groups or the side chains of the α-amino acids reference is made to A, L. Lehninger's text on Biochemistry (see Chapter 4). The term "halo", as used herein, means a halo radical selected from bromine, chlorine, fluorine or iodine, the expression "lower alkyl" or (alkyl) (C? _6), as used herein, alone or in combination with another radical, means straight or branched chain alkyl radicals containing up to six carbon atoms and includes methyl, ethyl, propyl, butyl, hexyl, 1-methylthiol, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. The term "lower alkoxy," as used herein, means straight-chain alkoxy radicals containing one to four carbon atoms and branched-chain alkoxy radicals containing three to four carbon atoms, and includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy, The latter radical is commonly known as tert-butoxy, The term "lower alkanoyl", as used herein, alone or in combination with another radical, means a Linear chain 1-oxoalkyl containing from one to six carbon atoms or a branched chain 1-oxoalkyl containing from four to six carbon atoms; for example, acetyl, propionyl (1-oxopropyl), 2-met yl-l-oxo-propyl, 2-methypropyl and 2-ylbutyl-iryl, The term "lower cycloalkyl", as used herein, is used, alone or in combination with another radical, means saturated cyclic hydrocarbon radicals containing from three to seven carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "amino", as used herein, means an amino radical of the formula -NH2. The term "lower alkyl amino", as used herein, means alkylamino radicals containing from one to six carbon atoms and includes methylamino, propylamino, (1-methylethyl) amino and (2-met ilbutyl) amino. The term "di (lower alkyl) amino" means an amino radical having two lower alkyl substituents, each of which contains one to six carbon atoms, and includes dimethylamino, diethylamino, ethylmethylamino, and the like. The term "Het", as used herein, means a monovalent radical derived from the separation of a hydrogen from a five- or six-membered, saturated or unsaturated heterocycle, containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur. Optionally, the heterocycle can carry one or two substituents; for example, N-oxide, lower alkyl, phenyl-alkyl (C? _3), lower alkoxy, halo, amino or lower alkyl-amino. Again optionally, the five or six heterocycle members may be condensed to a phenyl. Examples of suitable heterocycles and optionally substituted heterocycles include pyrrolidine, tetrahydrofuran, thiazolidine, pyrrol-lH-imidazole, 1-methyl-1H-imidazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, 2-methyltolyazole, 2-aminothiazole , 2- (methylamino) -thiazole, piperidine, 1-methylpiperidine, 1-methyl-piperazine, 1,4-dioxane, morpholine, pyridine, pyridine-N-oxide, pyrimidine, 2,4-dihydroxypyrimidine, 2,4-dimet ilpyrimidine, 2,6-dimethyl-pyrimidine, 1-methyl-1H-tet-razol, 2-methyl-2H-tetrazole, benzothiazole and thiazolo [4, 5-b] -pyridine. The term "pharmaceutically acceptable carrier", as used herein, means a vehicle for the active ingredient, non-toxic and generally inert, which does not adversely affect the ingredient. The term "effective amount" means a predetermined antiviral amount of the antiviral agent, i.e., an amount of the agent sufficient to be effective against the virus in vivo. The azet idin-2-one derivatives of formula 1 can be obtained in the form of salts per addition of therapeutically acceptable acids. In the case where a particular derivative has a residue that functions as a base, examples of salts of this type are those with organic acids, for example acetic, lactic, succinic, benzoic, salicylic, methanesulfonic or p-toluenesulfonic acid, as well as as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as hydrohalic acids, for example. hydrochloric acid, or sulfuric acid, or phosphoric acid.

Process The compounds of formula 1 can be synthesized from commercially available amino acids, suitably protected, as exemplified hereinafter. (For general synthesis processes, see: The Organic Chemistry of beta-Lactams, Gunda I. Georg, comp., VCH Publishers Inc., New York, NY, USA, 1992, pp. 1 to 48 and 257 a 293). Compounds of formula 1, wherein R1 through R5, inclusive, and Z are as defined herein may be prepared by a process selected from one of the following methods: A) reacting a key intermediate of formula 2: wherein R1, R2, R3 and Z are as defined herein, either (a) with an isocyanate of the formula R5NC0, wherein R5 is as defined herein, in the presence of a proton acceptor, or (b) with a phenoxycarbamate of formula R5NHC (0) 0Ph in the presence of a proton acceptor, to obtain the corresponding compound of formula 1! where a ', R2? R3, R5 and Z are as defined herein and R4 is hydrogen, or B) reacting the key intermediate of formula 2, wherein R1, R2, R3 and Z are as defined herein, with a Carbamoyl chloride derivative of the formula R4R5NC (0) C1, wherein R4 is lower alkyl, methoxy, ethoxy or benzyloxy, and R5 is as defined herein, or R4 and R5, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, morpholino, N-met ilpipera-zino, 1- (3,4-dihydro-lH-isoquinolinyl) ) or 2- (3,4-dihydro-lH-isoquinolinyl) in the presence of a proton acceptor, to obtain the corresponding compound of formula 1, wherein R1, R2, R3 and R5 are as defined herein and R 4 is lower alkyl, methoxy, ethoxy or benzyloxy, or R 4 and R 5, together with the nitrogen atom to which they are attached, are as defined herein, and Z is as defined herein. The key intermediate compound of formula 2, mentioned above, can be prepared by a process illustrated by Scheme A as follows: Scheme A (3) (4) Intermediate compound of formula 2 wherein PG is an amino protecting group and R, R and Z are as defined herein. The starting material of formula 3 is commercially available or can be prepared by known methods. With reference to Scheme A, the protected amino acid (3) is homologated by well known processes to give the benzyl ester of the corresponding β-amino acid (4). This latter benzyl ester is deprotected to provide the corresponding free amino acid that is cyclodehydrate according to known processes, see, for example, M.F. Loe et al., Tetrahedron Letters 1991, 32, 2299; and S. Kobayashi et al., J. Am. Chem. Soc., 1981, 103, 2406, to give the key intermediate of formula 2. The preparation of the compound of formula 1 can be further illustrated with reference to Scheme B, wherein PG, R2, R3 and R5 are as defined herein and R1, R1 and R4 are as defined here below in the description of Scheme B.

Scheme B . lower alkoxy or (lower alkyl) thio and Zes Ph) With reference to Scheme B, the amino acid (3a), commercially available and suitably protected, is homologated by conventional processes to give the benzyl ester of the corresponding b-amino acid (4a). This latter benzyl ester is deprotected to provide the corresponding free amino acid that is cyclodehydrated by known processes to give a key intermediate of the formula 5. The condensation of the key intermediate (5) with an appropriate isocyanate of the formula R NCO in the presence of a proton acceptor provides a corresponding ureido derivative which is the compound of formula 1, wherein R1, R4 are hydrogen and R2, R3 and R5 inclusive are as defined herein. Alternatively, a primary or secondary amine, or its salts, can be preactivated with triphosgene in the presence of a base, for example diisopropylethylamine; or via the formation of the phenoxycarbamate derivative which, in turn, is reacted with the intermediate compound of the formula 5; to provide the foregoing compound of formula 1, wherein R1 is hydrogen. Optionally, the key intermediate of formula 5 can be functionalized at the 3-position of the azet idin-2-one ring; namely, the nitrogen atom of the intermediate of the formula 5 is protected first with a suitable N-protecting group and then the resulting N-protected derivative is alkylated by conventional methods in the 3-position. The subsequent deprotection gives the compound intermediate (6) functionalized. After that, the intermediate compound (6) can be transformed into the desired ureido compound of the formula 1, wherein R 1 is lower alkyl, alkoxy lower or (lower alkyl) thio in the same manner as that described above for the transformation of the key intermediate (5) into the ureido compound of the formula 1, wherein R1 is hydrogen and R2 to R5 inclusive are as defined in this memory. The process of this invention can be further illustrated by more specific reference to the process described by Scheme B. Accordingly, an amino-protected phenylalanine derivative of the formula 3a is homologated to the benzyl ester (4a) according to the following process (a) reacting an amino-protected phenylalanine derivative of the formula 3a, wherein PG is an amino protecting group and R2 and R3 are as defined herein, in the presence of an alkyl chloroformate, preferably isobutyl chloroformate, and a tertiary organic base,. for example N-methylmorpholine or triethylamine, to obtain a corresponding mixed anhydride, (b) reacting the mixed anhydride with diazomethane to obtain a corresponding diazomethyl ketone, and (c) reacting transposition the diazomethyl ketone with a silver benzoate in the presence of benzyl alcohol and a tertiary organic base, for example N-methylmorpholine or triethylamine, to obtain a corresponding benzyl ester (4a). After that, the benzyl ester (4a) is subjected to of deprotection, for example hydrogenation in the presence of a catalytic amount of palladium hydroxide on carbon when PG is a benzyloxycarbonyl protecting group, to give the corresponding β-amino acid. The latter compound is subjected to cyclodehydration conditions, for example methanesulfonyl chloride / sodium bicarbonate, in a suitable solvent, for example acetonitrile, to give the key intermediate of formula 5, wherein R2 and R3 are as defined in this memory. The key intermediate of formula 5 can be converted into the azetidinone derivative of formula 1, wherein R 1 and R 4 are each hydrogen, R 2, R 3, R 5 are as defined herein and Z is phenyl, by reacting the key intermediate of the formula 5 with an appropriate isocyanate of the formula R5NC0, wherein R5 it is as defined in this report, in the presence of a base (proton acceptor). A convenient and practical base is triethylamine or, preferably, lithium bis (trimethylsilyl) amide. In this manner, the ureido residue is incorporated into the desired azetidinone (ie, the compound of formula 1, wherein R1 and R4 is each hydrogen, R2, R3 and R5 are as defined herein and Z is phenyl ). A method for introducing the ureido residue so that azetidinone derivatives of the formula 1 can be obtained for those derivatives wherein R 1 is hydrogen, R 2 and R 5 are as defined herein, R 4 is lower alkyl, methoxy, ethoxy or benzyloxy, or R4 and R5, together with the nitrogen atom to which they are attached, are as defined herein, and Z is phenyl, is as follows: react the key intermediate (5) with a derivative of carbamoyl chloride of the formula RR5NC (0) C1 wherein R4 is lower alkyl, methoxy, ethoxy or benzyloxy, and R5 is as defined herein, or R4 and R5, together with the nitrogen atom to which they are attached , are as defined herein, in the presence of a suitable tertiary amine, for example diisopropylethylamine or, preferably, lithium bis (trimethylsilyl) amide. The required carbamoyl chloride derivative can be prepared by preactivating the appropriate secondary amine with triphosgene. This particular method for the formation of the ureido residue is especially suitable for the preparation of azetidinone derivatives in which R4 is lower alkyl, and for the preparation of azetidinone derivatives, in which R4 and R5, together with the nitrogen atom To which they are united, they are as defined in this report. Another method for forming the ureido residue to obtain the desired azetidinone derivatives of the formula 1, in which R1 and R4 is each hydrogen, R2, R3 and R5 are as defined herein and Z is phenyl, involves reacting the key intermediate compound (5) with a phenoxycarbamate of. the formula R5HNC (0) 0Ph, wherein R5 is as defined herein, in the presence of a suitable base (proton acceptor), for example triethylamine or, preferably, lithium bis (trimethylsilyl) amide, thereby obtaining the desired product. Turning now to the preparation of the azetidinones of the formula 1, wherein R 1 is methyl, ethyl, methoxy or methylthio, R2 to R5, inclusive, are as defined herein and Z is phenyl, the versatile intermediate of formula 5 can be functionalized at the 3-position of the azetidinone ring as follows: firstly, a protecting group of N such as benzyl, (4-methoxyphenyl) methyl or, preferably, tert-butyldimethylsilanyl (Me3C-Si (Me2) -), is introduced into position 1 of intermediate (5). The resulting amino-protected derivative of formula 5 is then subjected to conventional alkylation conditions with the appropriate electrophilic reagent. More explicitly, the formation of the enolate is carried out in the presence of a suitable proton acceptor, for example lithium diisopropylamide or lithium bis (trimethylsilyl) amide. After that, the enolate is reacted with a) a methyl or ethyl halide, for example methyl iodide or ethyl iodide; or b) with oxygen in the presence of trimethyl phosphite to provide the corresponding one substituted with 3-hydroxy which, in turn, is reacted with diazomethane in the presence of silica gel; or c) with dimethyl disulfide; followed by the deprotection of N in conditions conventional to give the corresponding functionalized intermediate compound of formula 6, wherein R 1 is methyl or ethyl, or methoxy, or methylthio, respectively, and R 2 and R 3 are as defined herein. After that, the functionalized intermediate compound of formula 6 is converted to the desired compound of formula 1, wherein R 1 is methyl, ethyl, methoxy or methylthio, R 2 to R 5, inclusive, are as defined herein and Z is phenyl, in the same manner as that described above for the introduction of the ureido residue in the transformation of the key intermediate of the formula 5 into the compound of the formula 1, in which R1 is hydrogen, R2 to R5 inclusive are as define in this memory and Z is phenyl. Finally, the preparation of the azetidinones of the formula 1, wherein R2 and R3 are each hydrogen, R1, R4, R5 are as defined herein and Z. is (CH2) p- (Het), wherein Het are as defined herein, can be illustrated by Scheme C, where PG, R1, R, R5, Het and p are as defined in this specification: Scheme C With reference to Scheme C, 4-carboxyazet idinones of formula 7, suitably N-protected, wherein R 1 is as defined herein and PG is an amino protecting group are well known Q can be prepared by known methods such as methods for functionalizing position 3 of azetidinones described hereinabove. For example, the 4-carboxyazetidinone of the formula 7, N-protected, where PG is the group Protector Me3CSi (Me) 2- has been described by P.E. Finke et al., J, Med. Chem. 1995, 38, 2449. The N-protected idinone 4-carboxyazet of formula 7 is reduced in the corresponding 4- (hydroxymethyl) azetidinone derivative of formula 8 with an agent reducer capable of converting an acid into its corresponding alcohol. The 4- (hydroxymethyl) azetidinone is then oxidized to give the aldehyde of formula 9 with a reagent capable of converting a primary alcohol into its corresponding aldehyde. The latter aldehyde, thus obtained, is reacted with an appropriate Grignard reagent of the formula Het (CH2) P- (halo) Mg, where Het and p are as defined herein and halo is bromo, chloro or iodo, or with an appropriate organolithium reagent of the formula Het (CH2) P-Li, for the product (10). Subsequent separation of the secondary hydroxy in the side chain at the 4-position of the product (10) by conventional methods, for example by conversion of the hydroxy moiety to a reducible group which is subsequently removed by reduction, followed by cleavage of the N-protecting group from the resulting protected b-lactam provides the desired intermediate b-lactam of formula 11.

More explicitly, the transformation of 4-carboxyzetineinone (7) into the desired intermediate (11) can be exemplified as follows: the reduction of 4-carboxyazetidinone (7), wherein PG is Me 3CSiMe 2 - and R 1 is as defined herein, with borane in tetrahydrofuran, or via the formation of a mixed anhydride with isobutyl chloroformate in the presence of a tertiary organic base, for example N-methylmorpholine or diisopropylethylamine, followed by reduction of the mixed anhydride with sodium borohydride in water, provides 4- (hydroxymethyl) azetidinone (8), where PG is Me3CSiMe2- and R1 is as defined herein.

The latter compound is oxidized with an appropriate oxidizing agent, for example oxalyl-activated dimethyl sulfoxide chloride (K. Omura and D. Swern, Tetrahedron 1978, 34, 1651) or triacetoxi-periodinano (D.B. Dess and J.C. Martin, J. Org. Chem. 1983, 48, 4155) to give the corresponding aldehyde of the formula 9 .. This aldehyde is subsequently reacted with the appropriate Grignard reagent Het (CH2) P-Mg- (halo) as defined herein above, or with the organolithium reagent Het ( CH2) P-Li as defined herein above, for give the addition product (10) in the form of a mixture of diastereoisomers. The deoxygenation of the hydroxy-bearing side chain of the addition product (10) can be achieved in two stages. First, the corresponding diastereomeric xanthates can be formed by reacting the product (10) with carbon disulfide in the presence of a tertiary amine or with 1,1'-thiocarbonyldiimidazole; the diastereoisomeric xanthates thus obtained are reacted with tributyltin hydride in the presence of 2,2'-azo-bisisobutyl ironityl (AIBN) in refluxing benzene. In this manner, deoxygenation of the hydroxy-bearing side chain is effected, followed by removal of the N-protecting group to provide the desired intermediate b-lactam of formula 11. The latter intermediate compound can be transformed into a compound of formula 1, wherein R2 and R3 are each hydrogen, R1, R4 and R5 are as defined in this specification, and Z is (CH2) P-Het, wherein py and Het are as defined herein, in the same manner as described above for the introduction of the ureido residue to give the intermediate compound of formula 5.

More specifically, when Het is a tetrazole derivative, the intermediate compound (11) was obtained from the derivative (8) using published processes (J. Fetter, E. Keskeny, T. Czuppon, K. Lempert, M. Kaj tar -Peredy, J. Tamas, J. Chem. Soc. Perkin Trans., 1992, 1, 3061-3067 and LT Giang, J. Fetter, K. Lempert, M. Kaj tar-Peredy, A, Gomory, Tetrahedron, 1996, 52, 10169-10184).

Anti-herpes activity The anti-herpes activity of the aforementioned azetidinone derivatives of formula 1, (CMVH protease inhibitors) can be demonstrated by biochemical, microbiological and biological processes. A biochemical process for demonstrating anti-cytomegalovirus activity of azetidinone derivatives of formula 1 is described in the examples set forth below. This particular assay determines the ability of a test compound to inhibit HCVH protease activity. More specifically, in the assay described herein, the inhibitory activity of the compound of The assay is evaluated on the basis of its ability to interfere with the cleavage of the HCVH N0 protease from a fluorogenic peptide substrate which, in turn, relies on the maturation cleavage site of the enzyme. Methods to demonstrate the inhibitory effect of azetidinone derivatives of formula 1 on CMV replication involving cell culture techniques are described in the examples set forth herein. When the HCMV protease inhibitor is used as an antiviral agent it is administered orally or systemically to humans in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, the chosen route of administration and conventional biological practice. For oral administration, the compound or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets, each of which contains a predetermined amount of the ingredient. active, ranging from about 50 to 500 mg, in a pharmaceutically acceptable carrier. For parenteral administration, the HCMV protease inhibitor is administered by intravenous, subcutaneous or intramuscular injection, in compositions with pharmaceutically acceptable carriers or carriers. For administration by injection, it is preferred to use the compounds in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives, as well as sufficient quantities of pharmaceutically acceptable salts or glucose to render the solution isotonic. Suitable carriers or carriers for the aforementioned formulations are described in conventional pharmaceutical texts, for example in "Remington's, The Science and Practice of Pharmacy," 19th ed., Mack Publishing Company, Easton, Penn., 1995, or in "Pharmaceutical Dosage. Forms and Drug Delivery Systems ", 6th ed., HC Ansel et al., Comps. , Williams & Wilkins, Saltimore, Maryland, 1995. The dosage of the CMVH protease inhibitor will vary with the form of administration and the particular active agent chosen. In addition to that, it will vary with the particular host undergoing treatment. Generally, treatment starts with small increments until the optimum effect is reached under the circumstances. In general, the inhibitor compound is administered, in the most desirable manner, at a level of concentration which, generally, will provide antivirally effective results without causing harmful or deleterious side effects. For oral administration, the HCMV protease inhibitor is administered in the range of 20 to 200 mg per kilogram of body weight per day, with a preferred range of 25 to 100 mg per kilogram. For ocular administration, the HCMV protease inhibitor is administered topically or infraocularly (injection or implant) in a suitable preparation. For example, an implant containing the compound in a suitable formulation can be implanted surgically in the posterior segment of the eye through a small incision. With reference to systemic administration, the HCMV protease inhibitor is administered at a dosage of 10 mg to 150 mg per kilogram of body weight per day, although the aforementioned variations will occur. However, in order to achieve effective results, a dosage level in the range of about 10 mg to 100 mg per kilogram of body weight per day is most desirably employed.

EXAMPLES The following examples further illustrate this invention. All reactions were carried out in a nitrogen or argon atmosphere. Temperatures are given in degrees Celsius. The percentages or relationships in solution express a volume-to-volume ratio, unless otherwise stated. Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz spectrometer; chemical shifts (d) are reported in parts per million. Abbreviations or symbols used -in this memory include; Abz: 2-aminobenzoic acid; Bzl: benzyl (also known as phenylmethyl); DIEA: diisopropylethylamine; DMF: dimethylformamide; EDTA: ethylenediaminetetraacetic acid; Et: ethyl; EtOAc: acetate of ethyl; Et20; diethyl ether; HRMS: high resolution mass spectrometry; MS (ES) mass spectrometry by electroprojection; FBS: fetal bovine serum; Me; methyl, MeOH: methanol; MeCN: acetonitrile; PFU: plate forming units; Ph: phenyl; THF: tetrahydrofuran.

Example 1 Benzylamide of 4 (S) -benzyl-3 (S) -met-il-2-oxoazetidine-1-carboxylic acid (1: R1 = Me, R2, R3 and R4 each = H, R5 = Bzl and Z = Ph ) (Table 2, entry n ° 207).

Step A: To a solution of N- (benzyloxycarbonyl) -L-phenylalanine (18.7 g, 62 mmol) in THF (300 mL) was added Et3N (6.9 g, 9.5 mL, 68 mmol). The mixture was cooled to -10 °. Isobutyl chloroformate (11.0 g, 10.5 ml, 81 mmol) was added dropwise over 10 min. After 30 mm at -10 °, and for 30 min at room temperature (20-22 °), a solution of diazomethane in Et20 (0.3-0.5 M, 500 ml) was added. The reaction mixture was stirred for 10 min and then purged with nitrogen for 2 h. He The resulting white precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 20% EtOAc in hexane) to give 15.9 g (83% yield) of the desired diazoketone as a yellow solid. The diazoketone (11.2 g, 43 mmol) was dissolved in THF (150 mL). Benzyl alcohol (4.66 ml, 45 mmol) was added at room temperature. Silver benzoate (977 mg, 4.29 mmol) in triethylamine (8.92 mL, 64 mmol) (vigorous gas evolution) was added dropwise. After 30 min at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc. The solution was washed with H20 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (Si02, 15% EtOAc in hexane) to give benzyl ester of 3 (S) - acid. { . { (benzyloxy) carbonyl} Not me } -4-phenylbutyric (11 g, 63% yield) as a white solid.

XH-NMR (400 MHz, CDC13) d 7.40-7.10 (m, 15H), 5.27 (d wide, J = 8.0 Hz, ÍH) 5.14 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.06 (s, 2H), 4.30-4.20 (m, ÍH), 2.93 (dd, J = 13 , 3, 6.5 Hz, ÍH), 2.82 (dd, J = 13.3, 7.6 Hz, 1H), 2.57 (dd, J = 16, 5.5 Hz, HH), 2.50 (dd, J = 16, 5.0 Hz, HH). Step B The benzyl ester of 3 (S) - acid. { . { (benzyloxy) carbonyl} Not me } -4-phenylbutyric (from step A) (10.97 g, 27.2 mmol) in MeOH (11) was stirred at room temperature for 7 h under an atmosphere of hydrogen (1 atmosphere) in the presence of Pd ( 0H) 2 to 20% / C (50 mg). The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to provide 4.53 g (93% yield) of 3 (S) -amino-4-phenylbutyric acid as a white solid. A suspension of NaHCO3 (12.74 g, 152 mmol) in MeCN (1.55 L) was stirred and heated to gentle reflux. Mesyl chloride (2.15 mL, 27.8 mmol) was added, followed by portionwise addition of the preceding acid (4.53 g, 25.3 mmol) over 5 h. After .16 h under reflux, the solid was removed by filtration at 60 ° and the filtrate was concentrated under reduced pressure. The residual solid was triturated with EtOAc and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (Si02, 40% EtOAc in hexane) to give 4 (S) -benzylazet idin-2-one (2.20 g, 54% yield) as a white solid. X-NMR (400 MHz, CDC13) 57.35-7.17 (m, 5H), 5.83 (broad s, HI), 3.88-3.82 (m, 1H), 3.08 (ddd) , J = 14.8, 5.0, 2.2 Hz, ÍH), 2.98 (dd, J = 13.7, 5.7 Hz, ÍH), 2.84 (dd, J = 13.7 , 7.9 Hz, ÍH), 2.70 (ddd, J = 14.9, 2, 0, 1, 3 Hz, ÍH).

Step CA: a solution of 4 (S) -benzylazetidin-2-one (400 mg, 2.48 mmol) in CH2C12 (8 mL) was added DIEA (648 μL, 3.72 mmol), followed by tert-butyl chloride ildimethylsilyl (411 mg, 2.73 mmol). The reaction mixture was stirred for 16 h at room temperature. The CHC12 was evaporated and the residue was purified by flash chromatography (SiO2, 12% EtOAc in hexane) to give 4 (S.) - benzyl-1- (tert-butyldimethylsilyl) azetidin-2-one (647 mg 95% yieldj as a white solid: 1 H-NMR (400 MHz, CDC13) 57.34-7.15 (m, 5H), 3.77-3.70 (m, 1H), 3.25 (dd, J = 13.5, 3.5 Hz, 1H), 2.99 (dd, J = 15.5 Hz, 5 Hz, ÍH), 2.70 (dd, J = 15.5, 2, 5 Hz, HH), 2.59 (dd, J = 13.5, 11 Hz, HH), 1.01 (s, 9H), 0.31 (s, 3H), 0.29 (s 3H) Step D To a solution of diisopropylamine (705 μL, 5.03 mmol) in anhydrous THF (12 mL) at -20 ° was added butyllithium (2.87 mL, 4.60 mmol, 1.6 M in hexane). After cooling the reaction mixture to -78 °, a solution of 4 (S) -benzyl-1- (tert-butyldimethylsilyl) azet idin-2-one (640 mg, 2.32 mmol) in THF was added. (4 mL), and the mixture was stirred at -78 ° for 15 min followed by the addition of methyl iodide (488 mg, 214 μL, 3.44 mmol). After 10 min, the reaction mixture was poured into EtOAc (125 mL). The organic phase was washed with aqueous NaHS04 (1 M) and brine, dried (MgSO), filtered and concentrated. The residual oil was purified by flash chromatography (Si02, 6% EtOAc in hexane) to give 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) -methylazetidin-2-one (557 mg, 83% yield) in the form of a pale yellow solid. XH-NMR (400 MHz, CDC13) 5 7.33-7.15 (m, 5H), 3.25 (ddd, J = 10.8, 3.8, 2.5 Hz, 1H), 3.21 (dd, J = 13.4, 3.8 Hz, ÍH), 2.88 (qd, J = 7.5, 2.5 Hz, ÍH), 2.60 (dd, J = 13.4, 10 , 8 Hz, 1H) 1.02 (d, J = 7.5 Hz, 3H), 1.00 (s, 9H), 0.31 (s 3H), 0.27 (s, 3H) Step EA: a solution of 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) -methylazetidin-2-one (557 mg, 1.92 mmol) in MeOH (25 ml) at 0 ° C. added cesium fluoride (439 mg, 2.89 mmol). After 1 h, the MeOH was evaporated under reduced pressure, and the residue was dissolved in EtOAc. The organic phase was washed with H20 and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Si02, 50% EtOAc in hexane) to give 4 (S) -benzyl-3 (S) -methylazet idin-2-one (239 mg, 71% yield) in shape of a white solid. X-NMR (400 MHz, CDC13) 57.35-7.17 (m, 5H), 5.78 (broad s, HI), 3.46 (ddd, J = 8.0, 5.9, 2, 0 Hz, ÍH), 2.98 (dd, J = 13.5, 5.9 Hz, ÍH), 2.91 (qd, J = 7.3, 2.0 Hz, ÍH), 2.84 (dd, J = 13.5, 8.0 Hz, 1H), 1.26 (d, J = 7.3 Hz, 3H).

Step FA: a solution of 4 (S) -benzyl-3 (S) -methylazetidin-2-one (50 mg, 0.28 mmol) in THF (4 ml) at -78 °, bis (trimethylsilyl) amide was added. lithium (280 μl, 280 mmol, 1 M in THF). After 10 min, benzyl isocyanate (37.2 mg, 34.6 μL, 0.28 mmol) was added. Stirring was continued at -78 ° for 45 min. The reaction mixture was diluted with EtOAc (50 ml) and washed with aqueous NaHS0 (1M) and brine, dried (MgSO4) filtered and concentrated. The residue was purified by flash chromatography (Si02, 14% EtOAc in hexane) to give the benzylamide compound of 4 (S) -benzyl-3 (S) -met-il-2-oxoazet idine-1- carboxy 1 ico (23 mg, 27% yield) as a colorless oil. 1 H-NMR (400 MHz, CDC13) 57.38-7.19 (m, 10H), 6.94 (t, J = 5.1 Hz, HH), 4.53 (dd, J = 14.9, 6.0 Hz, 1H), 4.48 (dd, J = 14.9, 6.0 Hz, ÍH), 3.90 (ddd, J = 8.6, 3.2, 2.9 Hz, HI ), 3.53 (dd, J = 13.7, 3.5 Hz, ÍH), 2.95 (qd, J = 7.6, 2.5 Hz, ÍH), 2.92 (dd, J = 13.3, 8.9 Hz, ÍH), 1.14 (d, J = 7.6 Hz, 3H); FAB MS m / z 309.3 (MH +); HRMS calculated for C? 9H2? N202: 309.1603 (MH +); found: 309.1614.

Example 2 Benzylamide of 4 (S) -benzyl-2-oxoazetidine-l-carboxylic acid (1: R1, R2, R3 and R4, each = H, R5 = Bzl and Z = Ph) (Table 1, entry n ° 116).

Following the process of step F of Example 1, but replacing 4 (S) -benzyl-3 (S) -methylazetidin-2-one by an equivalent amount of 4 (S) -benzylazetidin-2-one, described in step B of Example 1, the title compound was obtained. 1 H-NMR (400 MHz, CDC13) 57.46 (t, J = 6.4 Hz, 1H), 7.36-7.21 (m, 10H), 4.36 (d, J = 6.4 Hz , 2H), 4.21 (m, 1H), 3.27 (dd, J = 11.8, 3.8 Hz, ÍH), 3.06 (dd, J = 15.8, 5.6 Hz, ÍH), 2.93 (dd, J = 11.8, 8.9 Hz, 1H), 2.73 (dd, J = 15.8, 3.0 Hz, 1H) GO CDC13) v 1769, 1700 c "1; FAB MS m / z 295.2 (MH +) HRMS calculated for C? 8H? 9N202; 295.1447 (MH +); found: 295.1452.

Example 3 Isocyanate of 1 (R) -phenylpropyl (intermediate compound to introduce the group 1 (R) -phenylpropyl in R ° of the compound of the formula 1) To a solution of 1 (R) -phenylpropylamine 14.33 g, 10.6 mmol) in Et20 (102 mL) was added a 1.0 M HCl / Et20 solution (212 mL, 212 mmol). The resulting solution was stirred for 30 min and then evaporated to dryness in a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 ml). Triphosgene (11.67 g, 39.3 mmol) was added and the resulting suspension was refluxed for 3 h and at room temperature for 18 h. The reaction mixture was concentrated, and the final volume was adjusted to 200 ml with toluene, giving a final concentration of 0.53 M. The resulting isocyanate solution was used as such. An aliquot (170 ml) was concentrated to give a colorless oil: XH-NMR (400 MHz, CDC13) 5 7.36-7.22 (m, 5H), 4.50 (t, J = 6.7 Hz , ÍH), 1.82 (q, J = 7.3 Hz, 2H), 0.94 (t, J = 7, 3 Hz, 2H).

Example 4 4- . { . { (phenoxycarbonyl) amino} met il} pyridine (intermediate compound for introducing the 4- (aminomethyl) pyridinyl group in Rb of the compound of the formula 1) To a solution of 4- (aminomethyl) pyridine (10.7 g, 98.5 mmol) in CH2C12 (245 mL) at 0 ° was added Et3N (14.2 mL, 19.9 g, 197 mmol), followed by a dropwise addition of phenyl chloroformate (14.8 ml, 18.5 g, 118 mmol). After stirring for 1 h, the resulting mixture was diluted with EtOAc (1.5 1). The organic phase was washed twice with water, then with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by chromatography (Si02, gradient of EtOAc to 10% MeOH / CHC13) gave a yellow solid which was recrystallized from EtOAc: hexane (2: 1) to give the desired compound (9.55 g, 41.85 mmol, 42% yield). X-NMR (400 MHz, CDC13) 5 8.61 (d, J = 5.7 HZ, 2H), 7.40-7.15 (m, 7H), 5.61 (broad s; 1H), 4 , 50 (d, J = 6, 4 Hz, 2H).

Example 5 N-met il-N- chloride. { . { 4- (trifluoromet il) phenyl} methyl } carbamoyl (intermediate compound for introducing methyl into R 4 and. {4- (trifluoromethyl) phenyl) methyl into R 5 of the compound of Formula 1 To a bromide solution of. { 4- (trifluoromethyl) phenyl} methyl (20.0 g, 83.7 mmol) in EtOH was added methylamine (100 mL of a 40% aqueous solution, 1290 mmol). After 2 h, the reaction was concentrated under reduced pressure. The aqueous phase was separated and extracted with EtOAc (2 x 100 ml). The combined organic phase was washed with aqueous 5% NaHC03 solution and then with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The resulting residue was dissolved in HCl / dioxane (4 N, 100 ml). The solvent was removed under reduced pressure. The resulting solid was triturated with Et20 and collected by suction filtration to provide N-methyl-1-hydrochloride salt. { 4- (trifluoromet il) phenyl} methylamine (17.0 g, 90% yield) as a white solid. The salt was suspended in CH2C12 (150 ml) and the suspension was cooled to 0 °. To the cooled solution was added DIEA (30.2 mL, 173 mmol), followed by the addition of a solution of phosgene in toluene (1.93 M, 55 mL, 105.7 mmol). After 2 h at 0 °, the reaction mixture was concentrated and the resulting thick gum extracted with Et20. Evaporation of the Et20 extract gave a light yellow oil which was purified by flash chromatography (Si02: 10% EtOAc in hexane) to give the title compound as a pale yellow oil (16.0 g, 84% of performance). 1 H-NMR (400 MHz, CDC13) 5 7.59 (m, 2H) 7.33 (m, 2H), 4.72 and 4.58 (2 xs, 2H), 3.04 and 2.97 (2 xs, 3H).

Example 6 (1 (R) -phenylpropyl) 4 (S) -terc-butyl-2-oxoazetidine-1-carboxylic acid amide (1: Ri = H, R2 = R3 = Z = Me, R4 = H, R5 = 1- (R) Ph-Pr) (Table 2, entry no. 215).

Step A Following the same procedure as in Example 1, step A, but using 2 (S) - acid. { (benzyloxycarbonyl) amino} -3,3-dimeticbutanoic as starting material is obtained benzyl ester of 3 (S) - acid. { (benzyloxycarbonyl) amino} -4,4-dimethyl-tartanoic acid in the form of a colorless oil. ^ • H-NMR (400 MHz, CDC13) 5 7.28-7.19 (m, 10H), 5.01-4.93 (m, 4H), 4.80 (d, J = 10.2 Hz, ÍH), 3.94 (td, J = 9.9, 3.8 Hz, HH), 2.59 (dd, J = 14.6, 4.1 Hz, HH), 2.24 (dd, J = 14.3, 9.9 Hz , ÍH), 0.85 (s, 9H). Step B The benzyl ester of 3 (S) - acid. { (benzyloxycarbonyl) amino} -4, 4-dimethylenic (from step A) (490 ml, 1.33 mmol) in EtOH (13.3 ml) was stirred at room temperature for 16 h under a hydrogen atmosphere (1 atmosphere) in the presence of Pd (0H) 2 at 20% / C (50 mg). The catalyst was removed by filtration over diatomaceous earth. The filtrate was concentrated under reduced pressure to provide 186 mg (96% yield) of the expected amino acid in the form of a white solid. To a suspension of the amino acid (169 mg, 1.16 mmol) in MeCN (116 ml) and H20 (20 drops) was added 2-chloro-l-met ilpyridinium iodide (356 mg, 1.39 mmol), followed by Et 2 N (405 μl, 2.90 mmol). The resulting yellow suspension was stirred for 6 h at reflux and then at room temperature for 18 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (Si02, 75% EtOAc in hexane) to provide 4 (S) -t-er-butylazet idin-2-one (93 mg, 63% of performance) in the form of a white solid. ^ -H-NMR (400 MHz, CDC13) 55.83-5.67 (broad s, HI) 3.45 (dd, J = 5.1, 2.6 Hz, 1H), 2.85 (ddd, J = 14.9, 5.1, 2.5 Hz, ÍH), 2.69 (ddd, J = 14.9, 2.5, 1.0 Hz, 1H), 0.93 (s, 9H) .

Step C Following the same procedure as in Example 1, step F, but using 4 (S) -tert-butylazetidin-2-one as starting material and isocyanate of 1 (R) -phenolpropyl as reactant, (1 ( R) -phenylpropyl) 4 (S) -terc-butyl-2-oxoazet idine-1-carboxylic acid amide in the form of a waxy solid. XH-NMR (400 MHz, CDCl 3) 5 7.35-7.24 (m, 5H), 7.21 (d, J = 10.2 Hz, HH), 4.76 (dd, J = 15.3 , 7.6 Hz, HH), 3.91 (dd, J = 6.0, 3.9 Hz, HH), 2.96 (dd, J = 16.2, 6.0 Hz, HH), 2 , 76 (dd, J = 16.2, 3.2 Hz, ÍH), 1.91-1.79 (m, 2H), 1.03 (s, 9H), 0.93 (t, J = 7 , 3 Hz, 3H) j IR (CHCl3) v 3361, 1752, 1693 cm "1, FAB MS m / z 2.89.1 (ME +); HRMS calculated for C? 7H2SN202: 289.1916 (MH +); found: 289 , 1921.

Example 7 N-methyl-N-. { . { 4- (trifluoromethyl) phenyl} methyl } 4 (S) -benzyl-2-oxoazetidine-l-carboxylic acid amide (1: R? = R2 = R3 = H, R4 = Me, R5 = CH2 (4-CF3) -Ph, Z = Ph) ( Table 1, entry n ° 135). To a solution of 4 (S) -benzyl azetidin-2-one (110 mg, 0.68 mmol) (from Example 1, step B) in THF (6 ml) at -50 ° was added bis (trimethylsilyl) ) potassium amide (1.43 ml, 0.717 mmol, 0.5 M in toluene). After 20 min, the reaction mixture was added via a cannula to a solution of N-met il-N- chloride. { . { 4- (trifluoromethyl) phenyl} carbamoyl lo (from Example 5) (860 mg, 3.4 mmol) in THF (6 ml). The reaction mixture was stirred for 2 h, during which time the temperature was raised to -20 °. The reaction was then quenched with brine (2 ml) and diluted with EtOAc (25 ml). The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography (Si02, 20% EtOAc in hexane) to give the title compound (102 mg, 40% yield) as an oil uncolored gold X-NMR (400 MHz, CDC13) 5 7.58 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.26-7.10 (m 5 H), 4.80-4.53 (m, 2H), 4.41 (m, ÍH), 3.15 (dd, J = 14.8, 3.8 Hz, ÍH), 2.85 (s, 3H), 2.84 (m, 2H), 2.65 (dd, J = 14.8, 3.5 Hz, 1H); IR (pure) v 1778, 1665 cm "1, FAB MS m / z 377 (MH +); HRMS calculated for c20H2oF3N202: 377.1477; found: 377.1488.

Example 8 4 (S) -benzyl-2-oxoazet idine-1-carboxylic acid (4-pyridinylmethyl) amide (1: Ri. = R2 = R3 = R4 = H, R5 = CH2- (4-Py), Z = Ph) (Table 1, entry n ° 136).

Following the same process as in Example 1, stage F, but using 4-. { . { (phenoxycarbonyl) amino} methyl } pyridine (from Example 4) as the reactant in place of benzyl isocyanate, "the title compound is obtained in the form of a white solid X-NMR (400 MHz, CDC13) 5 8.55 (m, 2H), 7, 38-7.12 (m, 7H) 7.01 (m, HH), 4.47 (m, 2H), 4.29 (m, HH), 3.41 (dd, J = 14.0, 3.0 Hz, ÍH), 2.99 (dd, J = 16.2, .8 Hz, HH), 2.93 (dd, J = 14.0, 8.4 Hz, HH), 2.73 (dd, J = 16.2, 2.9 Hz, HH); IR (CDC13) v 3357, 1764, 1694 cm "1, FAB MS m / z 296.1 (MH +); HRMS calculated for C? 7H? 8N302: 296.1399; found: 296.1408.

Example 9 (1 (R) phenylpropyl) 4 (S) -benzyl-3 (S) (methylthio) -2-oxoazetidine-l-carboxylic acid amide (1: Ri = MeS, R2 = R3 = R4 = H, R5 = 1 (R) -Ph-Pr, Z = Ph) (Table 2, entry nü 209).

Following the same procedure as in Example 1, step D, but replacing methyl iodide with dimethyl disulfide, we obtain 4 (S) -benzyl 1-1- (tert-but i Idimet i Isiil) -3 (S) - (methylthio) azetidin-2-one. X-NMR (400 MHz, CDC13) 5 7.36-7.20 (m, 5H), 3.75 (d, J = 2.6 Hz ', ÍH), 3.66 (ddd, J = 10, 5, 3.8, 2.2 Hz, HH), 3.29 (dd, J = 13.7, 3.8, ÍH), 2.67 (dd, J = 13.7, 10.5 Hz, ÍH), 1.82 (s, 3H), 1.03 (s, 9H), 0.34 (s, 3H), 0.31 (s, 3H). Following the process of deprotection described in Example 1, step E, but using 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) - (methylthio) azetidin-2-one as the starting material, followed by the formation of urea as shown in Example 1, step F, but using 1 (R) -phenylpropyl isocyanate (from Example 3) as the reactant, the title compound is obtained in the form of a colorless oil. X-NMR (400 MHz, CDC13) 5 7.38-7.21 (m, 10H), 6.90 (d, J = 8.6 Hz, ÍH), 4.82 (dd, J = 15.4 , 7.5 Hz, 1H), 4.13 (ddd, J = 8.3, 2.5, 2.5 Hz, ÍH), 3.77 (d, J = 2.5 Hz, ÍH), 3 , 49 (dd, J = 14.3, 3.5 Hz, ÍH), 3.08 (dd, J = 14.3, 8.3 Hz, ÍH), 1.93 (s, 3H), 1, 93-1.84 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); IR (CHCl3) v 3359, 1763, 1702 cm "1, FAB MS m / z 369.2 (MH +) HRMS calculated for C2? H25N202S: 369.1637 (MH +) found: 369, 1646.

Example 10 4 (S) -benzyl-3 (S) methoxy-2-oxoazetidine-l-carboxylic acid (4-pyridinylmethyl) amide (1: R ± = MeO, R2 R3 = R4 = H, R5 = CH2- (4 -Py) (Table 2, entry n ° 210).

To a solution of diisopropylamine (800 μl, 5.7 mmol) in anhydrous THF (40 ml) at -20 ° was added butyllithium (3.56 ml, 5.7 mmol, 1.6 M in hexane). After 15 min, the reaction was cooled to -78 ° and freshly distilled trimethyl phosphite (1.12 ml, 7.6 mmol) was added, followed by a solution of 4 (S) -benzyl-1- (tert-butyl). but i Idimet i Isi lil) azetidin-2-one (from Example 1 step C, 1.05 g, 3.8 mmol) in THF (10 ml). A constant stream of oxygen was introduced, and the mixture was stirred at -78 ° during 3 h. The reaction mixture was quenched with NH 4 Cl saturated aqueous and extracted with EtOAc (120 mL).

The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Si02, 10% EtOAc-hexane to 30% EtOAc in hexane) to give 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) -hydroxyazetidine. -2-one (671 mg, 60% yield) as a white solid. 1R-NMR (400 MHz, CDC13) 5 7.25-7.21 (m, 5H), 4.51 (d, J = 2 Hz, ÍH), 3.75-3.71 (m, 1H) , 3.26 (broad s, 1H), 3.20 (dd, J = 14, 3.8 Hz, ÍH), 2.66 (dd, J = 14, 11.1 Hz, ÍH), 1.00 (s, 9H), 0.30 (d, J = 3.5 Hz, 6H).

To a solution of 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) -hydroxyazetidin-2-one (150 mg, 0.51 mmol) in Et20 (70 mL) at 0 ° was added silica gel (40-60 μm, 9 g). The vigorously stirred mixture was treated with diazomethane in Et20 (50 ml, 0.3-0.5 M solution). Once the yellow color had almost disappeared after approximately 15 min, additional diazomethane solution was added. (20 ml). This process was repeated several times until more starting material could no longer be detected by TLC (approximately 1.5 h). The reaction mixture was stirred for an additional hour at room temperature and then filtered and concentrated to give 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) -methoxyazetidin-2-one (157 mg, 99% yield) in the form of a white solid that was sufficiently pure for further handling. XH-NMR (400 MHz, CDC13) 5 7.27-7.20 (m, 5H), 4.16 (d, J = 1.9 Hz, HH), 3.67 (ddd, J = 11.1, 3.8, 1.9 Hz, HH), 3.23 fdd, J = 13.5, 3.8 Hz, 1H), 2.94 (s, 3H), 2.57 (dd, J = 13.4, 11.1 Hz, ÍH), 1.01 (s, 9H), 0.32 (d, J = 6 Hz, 6H).

Following the same process as in the Example 1, step E, but using 4 (S) -benzyl-1- (tert-butyldimethylsilyl) -3 (S) -methoxyazet idin-2-one as the starting material, 4 (S) -benzyl-3 was obtained (S) -methoxyazet idin-2-one. XH-NMR (400 MHz, CDC13) 5 7.36-7.18 (m 5H), 6.00 (broad s, IH), 5.26 (t, J = 1.9 Hz, ÍH), 3, 80 (ddd, J = 7.8, 6.2, 1.6 Hz, HH), 3.34 (s, 3H), 2.98 (dd, J = 14, 6.2 Hz, HH), 2 , 88 (dd, J = 14, 7.8 Hz, ÍH).

Following the same process as in the Example 1, step F, but using 4 (S) -benzyl-3 (S) -methoxyazetidin-2-one as starting material and 4-. { . { (phenoxycarbonyl) amino} methyl Jpiridine as the reactant was obtained 4 (S) -benzyl-3 (S) -methoxy-2-oxoazetidine-l-carboxylic acid (4-pyridinylmethyl) amide in the form of a light pale yellow oil. 1 H-NMR (400 MHz, CDC13) 5 8.60-7.22 (m, 9H), 7.06-7.04 (m, HH), 4.52-4.50 (m, 2H), 4 , 28 (d, J = 2.2 Hz, 1H), 4.21-4.17 (m, 1H), 3.57 (dd, J = 14, 3.5Hz, ÍH), 3.15 (s, 3H), 2.93 (dd, J = 14.2, 8.9 Hz, ÍH); IR (neat) v 1773, 1770 cm "1; FAB-MS m / z 329 (MH +); HRMS calculated for C? 6H20N303: 326.1504 (MH +); found: 326.1519.

Example 11 N-methyl-N-. { . { (4-trifluoromethyl) phenyl} methyl } 4 (R) - (2-thiazolylmethyl) -2-oxoazetidine-l-carboxylic acid amide (1: Ri = R2 = R3 = H;, R4 = Me, R5 = CH2- (4-CF3-Ph), Z = 2-thiazolyl) (Table 2, entry no. 218).

To a solution of 1- (tert-butyldimethylsilyl) -4-oxoazetidine-2 (R) -carboxylic acid (15.0 g, 65.40 mmol) in THF (167 ml) at 0 ° was added N-methylmorpholine (7). , 2 ml, 65.40 mmol) and isobutyl chloroformate (8.5 ml, 65.40 mmol). After stirring for 1.5 h at 0 °, a solution of NaBH4 (9.9 g, 261.61 mmol) in H20 (98 mL) was added portionwise. The reaction was stirred for 45 min, then diluted with EtOAc and quenched with aqueous HCl solution (10%) to pH 5-6. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO 3 and brine, dried (MgSO 4), filtered and concentrated. The residual oil was purified by flash chromatography (Si02, eluent: Gradient 25% to 50% EtOAc / hexane) to provide 1- (tert-butyldimethylsilyl) -4 (R) - (hydroxymethyl) azet idin-2-one (8.46 g, 60% yield) as a white solid. X-NMR (400 MHz, CDC13) 5 3.74-3.69 (m, ÍH), 3.65-3.56 (m, 2H), 3,1-2,98 (m, ÍH), 2,81-2,76 (m, ÍH), 2,01 (s 1H), 0,89 (s 9H) ¡0,18 (s, 3H) 0.16 (s, 3H). FAB MS m / z 216, 2 (MH +).

A solution of 1- (tert-butyldi-ethylsilyl) -4 (R) - (hydroxymethyl) azet idin-2-one (309 mg, 1.44 mmol) and Dess-Martin periodinone (917 mg, 2.16 mmol) CH2C12 (15 ml) was stirred at room temperature for 1 h. A 1: 1 mixture of 10% aqueous NaHSÜ3: saturated aqueous solution of NaHC 3 (20 mL) was added and the mixture was stirred vigorously until the two layers were clear (15 min). After, the mixture was extracted with Et20, washed with NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The resulting aldehyde (263 mg, 85% yield) was immediately dissolved in THF (5 ml) and trickled dropwise to a solution of 2-lithothiazole [prepared by the addition of butyllithium (1.3 mmol, 1 , 04 ml, 1.25 M) to a thiazole solution (1.3 mmol, 115 mg) in THF (15 ml) at -50 °]. The resulting solution was stirred at -50 ° for 45 min and then it was quenched with a saturated aqueous solution of NH4C1. The mixture was extracted with EtOAc. The extract was washed with brine, dried (MgSO), filtered and concentrated. The resulting residue was purified by radial chromatography (40% EtOAc in hexane) to provide the desired mixture of diastereomeric alcohols. 1 H-NMR (400 MHz, CDC13) 5 7.73 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 3.2 Hz, ÍH), 4.98 (d, J = 6.7 Hz, ÍH), 4.20 (broad s, ÍH), 3.93-3.89 (m, ÍH), 3.01 (dd, J = 15.7, 5.7 Hz, ÍH) , 2.77 (dd, J = 15.7, 2.8 Hz, ÍH), 0.99 (s, 9H), 0.30 (s, 3H), 0.24 (s, 3H).

A solution of the diastereomeric alcohols (121 mg, 0.41 mmol) and 1,1'-t -carbonyldiimidazole (216 mg, 1.22 mmol) in CH2C12 was stirred at room temperature for two days. The resulting mixture was then evaporated and subjected to flash chromatography (Si02, 40% EtOAc in hexane) - to provide the desired mixture of diastereomeric xanthates (127 mg, 77% yield). ^ -RM (400 MHz, CDC13) 5 8.40-8.35 (m, 1H), 7.87-7.84 (m, 1H) 7.66-7.58 (m, IH) 7.44-7.40 (m, ÍH), 7.10-7.07 (m, ÍH), 6.90-6.85 (m, ÍH), 6.90-6.85 (m, ÍH), 4.47-4.43 and 4.35-4.33 (2 xm, ÍH), 3.22 (dd, J = 15.8, 5.8 Hz, ÍH), 3.02 (dd, J = 15.8, 2.7 Hz, ÍH), 0.95 and 0.94 (2 xs, 9H), 0.29, 0.27, 0.26 and 0.25 (4 xs, 6H).

This last mixture was dissolved in benzene (2 ml) together with 2, 2 '-azobisisobut ironitrile (AIBN, 1 mg). The solution was added to a refluxing solution of Bu3SnH (0.17 ml, 0.62 mmol) in benzene over a period of 15 min using a syringe pump. The resulting solution was refluxed for 1 h, then cooled to room temperature and the residue subjected to flash chromatography (SiO2, 40% EtOAc in hexane) to provide 4 (R) - (2-t-azole) il) -1- (tert-butyldimethylsilyl) azet idin-2-one (45 mg, 51% yield). XH-NMR (400 MHz, CDC13) 5 7.73 (d, J = 3.2 Hz, 1H), 7.25 (d, J = 3.2 Hz, HI), 4.02-3.97 ( m, HH), 3.58 (dd, J = 14.8, 3.5 Hz, HH), 3.19 (dd, J = 15.6, -5.4 Hz, HH), 3.11 ( dd, J = 14.8, 9.9 Hz, HH), 2.83 (dd, J = 15.6, 2.5 Hz, HH), 1.00 (s, 9H), 0.31 (s) , 3H), 0, 28 (s, 3H).

Following the same procedure as in Example 1, step E, for the deprotection, followed by the formation of the ureide as in Example 7, the compound of the N-me til-N- formulation was obtained. { . { (4-trif-Luoromethyl) phenyl} methyl } 4 (R) - (tiazolylmethyl) -2-oxoazetidine-1-carboxylic acid amide in the form of a yellow gum. 1 H-NMR (400 MHz, CDC13) 5 7.72 (d, J = 3.3 Hz, HH), 7.62 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 3.3 Hz, ÍH), 4.70-4.55 (m, 3H), 3.59 (dd, J = 14.9, 4 , 2 Hz, ÍH), 3.45 (dd, J = 14.9, 6.9 Hz, 1H), 3.10-3.00 (m, 2H), 2.97 (s, 3H); IR (neat) v 1780, 1669 cm "1; FAB-Ms m / z 384.2 (MH +); HRMS calculated for C? 7H? 6F3N302S: 384.0994 (MH +) found: 384.1003.

Example 12 N-methyl-N-. { . { (4-t rifluoromet il) phenyl} methyl } 4 (R) - (2-Methyl-2H-tetrazol-5-ylmethyl) -2-oxoazetidine-1-carboxylic acid amide. (Ri = R2 = R3 = H, R4 = Me, R5 = CH2- (4-CF3-Ph), Z = 2-methyl-2H-tetrazolyl) (Table 2, entry nu 223). The same process as in Example 7 was followed, but using 4 (R) - (2-met1-2H- tet raz- -ylmethyl) azet idine-2-one (this was obtained using published processes of J. Fetter, E. Keskeny, T. Czuppon, K. Lempert, M. Kaj tar-Peredy, J. Tamas J. Chem. Soc Perkin Trans, 1992, 1, 3061-3067 and LT Giang, J. Fetter, K. Lempert, M. Kaj tar-Peredy, A. Gomory, Tetrahedron, 1996, 52, 10169-10184). After the formation of the ureide, the title compound was obtained in the form of a yellow gum. 1 H-NMR (400 MHz, CDC13) 5 7.56 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.70-4.44 ( m, 3H), 4.21 (s, 3H), 3.40 (dd, J = 15.0, 4.1 Hz, ÍH), 3.28 (dd, J = 15.0, 6.5 Hz , ÍH), 3.03 (dd, J = 16.0, 6.0 Hz, HH), 2.90 (s, 3H), 2.83 (dd, J = 16.0, 3.7 Hz, 1 HOUR); IR (neat) v 1779, 1669, 1322 cm "1; FAB MS m / z 383.1 (MH +); HRMS calculated for Ci6H18F3N6? 2: 383.1444; found 383.1452.

Example 13 The following two assays (A and B) were used to evaluate anti-CMVH activity. A. Assay of the protease N0 of CMVH Material and methods: the fluorescence measurements were recorded in a Perkin-Elmer spectrofluorimeter LS-50B equipped with a plate reading accessory. UV measurements were recorded on a Thermomax® microplate reader from Molecular Devices Corporation, Menlo Park, CA, USA. The HCVH N0 protease was assayed with an internally abruptly cooled fluorogenic substrate based on the maturation cleavage site (Abz-VVNASSRLY (3-N02) R-OH, Kca = M = 260 M "1S" 1 ). The increase in fluorescence after excision of the Ala-Ser amide bond was monitored using an excitation? = 312 nm (2.5 nm slot) and one emission? = 415 nm (5 nm slot). An adaptable protocol was designed to a 96-well plate format for the determination of the CI5o values of the inhibitors. In synthesis, N ° of CMVH was incubated for 2 h at 30 ° in the presence of the substrate with a range of sequentially diluted inhibitor concentrations (300 to 0.06 μM, depending on the potency of each compound). After this period, the enzymatic hydrolysis of the fluorogenic substrate in the absence of the inhibitor led to a conversion of about 30%. No quenching was required prior to the fluorescence measurement, since the total scan time on the part of the plate reader accessory was brief in relation to the duration of the reaction. The aqueous incubation buffer contained Tris (hydroxymethyl) aminomethane. 50 mM HCl pH 8.0, 0.5 M Na2SO, 50 mM NaCl, 0.1 mM EDTA, tris (2-carboxyethyl) phosphine. 1 mM HCl, 3% v / v DMSO and 0.05% w / v casein. The final concentrations of protease N0 of CMVH (expressed in terms of total concentration of monomers) and of the substrate were 100 nM and 5 μM, respectively. The IC 50 values were obtained by adjusting the inhibition curve to a competitive inhibition model using the SAS NLIN process. The mode of inhibition was determined by measurements of the initial rates (in cuvettes) at various concentrations of the substrate in the buffer as described above. The IC50 values listed in the following Tables were obtained according to this test.

B. Plaque reduction assay (PRA): Hs-68 cells (ATCC No. CRL 1635) were seeded in 12-well plates at 83,000 cells / well in 1 ml of DMEM medium (Gibco Canada Inc.) supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37 ° to allow the cells to reach a confluence of 80-90% before assay. The medium was removed from the cells by aspiration. Next, the cells were infested with approximately 50 PFU of CMVH (strain AD169, ATCC VR-538) in DMEM medium supplemented with inactivated 5% FBS (test medium) (The DMEM medium is commercially available and has been described by R Dulbecco et al., Virology 1959, 8, 396). The virus was allowed to be absorbed into the cells for 2 h at 37 °. After viral absorption, the medium was removed from the wells by aspiration. The cells were then incubated with or without 1 ml of appropriate concentrations of assay reagent in a test medium. Occasionally, test compounds were added 24 h after infection. After 4 days of incubation at 37 °, the medium was changed by means of fresh addition containing the test compound and, 4 days later, the cells were fixed with 1% aqueous formaldehyde and stained with a purple solution at room temperature. 2% in ethanol at % in water. The microscopic plates were counted using a stereomicroscope. The effects of the drug were calculated as percent reduction in the number of plaques in the presence of each drug concentration compared to the number observed in the absence of drug. As a positive control, ganciclovir was used in all experiments. The CE5o values obtained according to this test for certain azetidine derivatives of e-s-ta invention are listed in the following Table under heading EC50.

Example 14 In conjunction with the appropriate starting materials and intermediates, the processes of Examples 1 to 11 can be used to prepare other compounds of formula 1. Examples of compounds, thus prepared, are listed in the following -Tablas I, II and III together with mass spectral data for the compounds and results of tests A and B of Example 12. The cytotoxic effects reported as CT50 in the following Tables will be determined according to the test metabolite of the tetrazolium salt (MTT) F. Denizot and F. Lang, J. Immun. Meth., 1986, 89, 271. The symbols used in the following Tables include 4-AcNH-Ph: 4- (acetylamino) phenyl; 4-NH2-Ph: 4-amino-phenyl; BTZ: benzathiazolyl, Bu: butyl; 4-CF3-Ph: 4- (tri-fluoromethyl) phenyl; 4-Cl-Ph: 4-chlorophenyl; 4-C00Me-Ph: 4- (methoxycarbonyl) phenyl; Et: ethyl; 4-F-Ph: 4-fluorophenyl; 4-I-Ph: 4-iodophenyl; 4-iosPr-Ph: 4- (1-methylethyl) phenyl; Me: methyl; 4-Me0-3, 5-Me2-Ph: 4-methoxy-3,5-dimethylphenyl; 4-MeO-Ph: 4-methoxyphenyl; 4-Me-Ph: 4-met ilphenyl; 2-N02-Ph: 2-nitophenyl; 4-N02-Ph: 4-nitrophenyl, Ph: phenyl; Pr: propyl; 4-Py: 4-pyridinyl; 1- (4-Py) -Pr: 1- (4-pyridinyl) propyl; 4-sCF3-Ph: 4 -. { (trifluoromet il) t io} feni lo; 4-SOCF3-Ph: 4-. { (trifluoromethyl) sulfinil} phenyl; 4-S02CF3-Ph: 4-. { (trifluoromet il) sulfonyl} phenyl; THZ: thiazolyl. (or TABLE I t o TABLE I 2 o TABLE I (or TABLE I -1 (or TABLE I - 4 (or TABLE I 00 or TABLE II (or TABLE II 00 or (or TABLE II or TABLE II 00 or TABLE II 00 or TABLE II 00 TABLE III It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (1)

1. R E I V I N D I C A C I O N S l.A compound of formula 1 wherein Ri is hydrogen, methyl ethyl, methoxy or methylthio; R2 and R3. each independently, is hydrogen or lower alkyl; R4 is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy, R5 is lower alkyl, lower cycloalkyl, (CH2) mC (0) 0R6, where m is the integer 1 or 2, and R6 is lower alkyl or phenyl (lower alkyl); phenyl, monosubstituted phenyl, disubstituted or trisubstituted with a substituent independently selected from the group consisting of: in lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; phenyl (lower alkyl), phenyl (lower alkyl) monosubstituted or disubstituted in its phenyl part with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkyl-amino, di (lower alkyl) amino, acyl lower-amino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl, and C (0) 0R7, wherein R7 is lower alkyl or phenyl (lower alkyl); Het or Het (lower alkyl), wherein Het represents a five or six membered heterocyclic ring, monovalent, unsubstituted, monosubstituted or disubstituted, containing one or two heteroatoms selected from the group consisting of N, O or S, wherein each substituent is independently selected from the group consisting of lower alkyl, lower alkoxy, halo and hydroxy; 5- (benzo [1,3] dioxolyl) methyl, (l (R) -l-naphthalenyl) ethyl, 2-benzothiazolyl or 2-t-azolo [4, 5-b] iridinyl; or R * and --s r together with the nitrogen atom to which they are attached, form a ring of piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, l- (3,4-dihydro-lH-isoquinolinyl), or 2- (3,4-dihydro-lH-isoquinolinyl), or a pyrrolidino ring, optionally substituted with benzyloxycarbonyl or with phenyl wherein said phenyl ring is optionally mono- or di-substituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkyl-amino, di (lower alkyl) amino, lower-amino acyl, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and C (0) 0R, wherein R is lower alkyl or (lower alkyl) phenyl; and Z is lower alkyl, phenyl, phenyl monosubstituted or disubstituted with a substituent independently selected from lower alkyl, lower alkoxy, halo, hydroxy and amino; phenylmethyl, phenylmethyl monosubstituted or disubstituted in its phenyl portion with a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, hydroxy and amino; or (CH2) P-Het, where p is the integer 0 or 1 and Het is as defined in this specification; with the proviso that when Z is (CHJ.-Het as defined herein, then R2 and R3 .5 each hydrogen, or a salt by the addition of pharmaceutical acid to the acceptable meat thereof. The compound of formula 1 according to claim 1, characterized in that R.sub.2 and 3 are as defined in claim 1, R 4 is hydrogen or lower alkyl, R 5 is lower alkyl, inferred cycloalkyl, CH 2 C (O) CR 6 wherein R6 is methyl, ethyl or phenylmethyl, phenyl, monosubstituted, disubstituted or tris-substituted phenyl with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; lower), phenyl (lower alkyl) monosubstituted or disubstituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkyl-amin or, di (lower alkyl) amino, acyl lower-amino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) t i or, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and C (0) 0R7, wherein R7 is methyl, ethyl or phenylmethyl; Het or Het (lower alkyl), where Het is 2-furyl, 2-methyl-? -furyl, 2-thienyl, 2-pyridinyl, 3-pyridinyl, - '• -pyridinyl, 3-methyl-1-2- pyrrolyl, 2-thiazolyl, -thiazolyl, 2-isoxazolyl, 2-pyrimidinyl, 4-methyl- _. -pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 4-pyrimidinyl, 2,6-dimethyl-2-pyrimidinyl, 4-methyl-tert-butyl, 2-benzo-thiazolyl or -2-thiazolo [4, 5-b] pyridinyl; (5-benzo [1,3] dioxolyl) me t i lo, 1 (R) - (1-naphthalenyl) ethyl; or R4 and R5, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino. morpholino, N-methylpiperazino, 1- (3, 4-dihydro-lH-isoquinolinylc 'or 2- (3,4-dihydro-lH-isoquinolinyl); and Z is as defined in claim 1. 3. - The compound of formula 1 according to claim 2, characterized in that Ri is hydrogen, methyl, ethyl, methoxy or methylthio; R2 and R3 each independently, is hydrogen n I did it R 4 is hydrogen, methyl or ethyl; R5 is methyl, ethyl, 1-methylethyl, cyclobutii. , cyclopentyl, cyclohexyl, CH2C (0) ORß, where Re is methyl or phenylmethyl; phenyl, 4-fluoropheni-1 or, 4-methoxyphenyl, 3,5-dimethyl-4-methoxy-phenyl, k -methylphenyl, 4- (methyl thio) phenyl, phenylmethyl, 1-phenylpropyl, 1-phenylbutyl, phenylmethyl monosubstituted in position 3 or 4 of its a ~ phenyl moiety with a substituent selected from the group consisting of methyl, ethyl, 1-methyl tile, 1,1-dimethylethyl, propyl, methoxy, ethoxy, methylthio, bromo, chloro, fluoro, nitro, acetylamino, C (O) Me ^, C (0) NMe2, C (0) Net2, cyano, trifluoromethyl, (tri fluoromet il) thio, (tri fluromethyl) sui fi ni lo, (tri f luorome til) sui fonilo and C (O) OR7, wherein R7 s-methyl, ethyl or benzyl; 5- (benzo [l, > dioxolyl) methyl, (1 (R) -1-naphthalenyl) ethyl, 1-pyridinyl, 4-pyridinyl, 2-pyridinylmethyl, 4-pyridinylmethyl, 1 - (4-pyridinyl) and ilo or 1- (4-pyridinyl) propyl; or R4 and Rs. together with the nitrogen atom to which they are attached, they form a pyrrolidino, piperidino, morpholino, 1- (3,4-dihydro-l-i soquinol inyl) or 2 - (3, -di h i dr o- lH-i s oqui n ol ini l o); and Z is phenyl or phenylmethyl 4. - The compound of the formula X according to claim 3, characterized in that Ri is hydrogen, methyl or methylthio; R2 and R3. each independently, is hydrogen or methyl; R 4 is hydrogen, methyl or ethyl; R5 is methyl, ethyl, 1-methyl ethyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2C (0) ORe, wherein .6 e -methyl or phenylmethyl; phenyl, 4-f luorofenyl, k -methoxyphenyl, 3,5-dimethyl-4-methoxy-phenyl, 4-methylphenyl, 4- (methyl tio) phenyl, phenylmethyl, 1-phenylpropylo, 1-phenyl Figure imgf000044_0001, phenylmethyl monosubstituted in the 3 or 4 position of its phenyl part with a substituent selected from the group consisting of methyl, ethyl, 1-methyl, 1,1-dimethylethyl, propyl, methoxy, ethoxy , methylthio, bromo, chloro, fluoro, nitro, acetylamino, C (O) Me., C (0) NEt2, cyano, trifluorome ilo, (tri fluoromet i 1) thio, (t r i f luromethyl) sulfinyl, (trifluoromet il) sui fonilo and C (0) 0R7, where R is methyl, ethyl or benzyl; 5- (benzo [1,3] dioxolyl) methyl, (1 (R) -1-naphthalenyl) ethyl, 2-pyridinyl, 4-pyridinyl, 2-pyridinylmethyl, 4-pyridinylmethyl, 1 - (4 - pi ridini 1) ethyl or 1- (4-pyridinyl) ropyl; and Z is lower alkyl, 5. - The compound of formula 1 according to claim 4, characterized in that Ri is hydrogen, methyl, methylthio or methoxy; R2 and R3 each independently, is hydrogen or methyl, R4 is hydrogen, methyl or ethyl; R5 is methyl, ethyl, 1-methylethyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2C (0) OR6, wherein R6 -. methyl or phenylmethyl; phenyl, 4-fluorophenyl, k -me toxy phenyl, 3,5-dimethyl-t-4-methoxy-phenyl, 4-methylphenyloyl 4- (methyl thio) phenyl, phenylmethyl, 1-phenylpropylo, 1-phenylbutyl, phenylmethyl monosubstituted in the 3 or 4 position of its phenyl portion with a substituent selected from the group consisting of methyl, ethyl, 1-methyl, 1,1-dimethylethyl, propyl, methoxy, ethoxy, methylthio, bromo, chloro, fluorine, nitro, acetylamino, C (0) NMe2, c (0) NEt2, cyano, trifluoromethyl, (tri fluoromethoxy, trifluoromethyl) sulphi, (trifluoromethyl) sulfonyl and c (0) 0R7, wherein R7 is methyl, ethyl or benzyl; (benzo [1,3] dioxolyl) methyl, 1 (R) - (1-naphthalenyl) ethyl, 2-pyridinyl, 4-pyridinyl, 2-pi r idinylmethyl, 4-pyridine lme ti 1, -? - pyridinyl) ethyl or 1- (4-pyridinyl) propyl; and Z is 2-furyl, 2-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-methyl-1-2-pyrrolyl, 2-thiazolyl, 2-isoxazolyl, 2-pyrimidinyl; 4,6-dimethyl-2-pyrimidinyl, 5- (1-methyl-1H-tetrazolyl), 5- (2-methyl-2H-tetrazolyl), 2-benzothiazolyl or 2-thiazolo [4, 5-b] pi ri dini 1 o. 6. - The compound of formula 1 according to claim 5, characterized in that Ri is hydrogen, methyl, methoxy or methylthio; R2 and R3 is each hydrogen; R 4 is hydrogen or methyl; R5 is- CH2C (0) OR6, wherein R6 is phenylmethyl; or R5 is 4-f luorofenyl, 4-methoxyphenyl, 3,5-dimethyl-4-methoxy-phenyl, 4- (methylthio) phenyl, phenylmethyl, 1 (R) -phenylethylc, 1 (S) -phenylethyl, 1 ( R) -phenylpropyl, 1 (R) -f-enylbutyl, (4-methylphenyl) methyl,. { 4- (1-methylethyl) fyl Jmethyl, (4- methoxyphenyl) methyl, (4-chlorophenyl) methyl, (2-nitrophenyl) methyl, (3-nitrophenyl) methyl,. { 4- (acetylamino) phenyl} methyl,. { 4- (trifluoromethyl) phenyl} methyl,. { 4- . { (trifluoromethyl) thio} phenyl } methyl, X -. { (trifluoromethyl) sulfinil} phenyl Jmetilo,. { 4-. { (trifluoromethyl) sulfonyl} phenyl } methyl,. { - (methoxycarbonyl) phenyl} methyl, (5-benzo [1,3] dioxolyl) methyl, 1 (R) - (1-naphthalenyl) ethyl, 4-pyridinyl, 4-pyridinylmethyl or 1- (4-pyridinyl) propyl; or R4 and R5 together with the nitrogen to which they are attached, form a pyrrolidino, morpholino, 1- (3, 4-dihydro-lH-isoquinolinyl) or 2- (3,4-dihydro-lH-isoquinolinyl); and Z is phenyl or phenylmethyl. 7. - The compound of formula 1 according to claim 1, characterized in that it is selected from the group consisting of: twenty 10 fifteen twenty ßn where R1, R > R3 is each hydrogen, Z is -5 phenyl and R and R are designated as follows: 8. The compound according to claim 7, characterized in that it is selected from the group consisting of the entries n °: 101, 102, 103, 104, 106, 107, 109, 111, 117, 118, 121, 122, 128, 131, 135 and 139. 9. The compound of formula 1 according to claim 1, characterized in that it is selected from the group consisting of: 10X The compound according to claim 1, characterized in that it is selected from the group consisting of entries no: 203, 204, 206, 208, 209, 210, 212, 216, 19, 222, 224, 225, 226, 227, 228, 229, 230 and 231. 11. - The compound according to claim 10, characterized in that it is selected from the group consisting of the entries NO: 203, 204, 219, 225 and 226. 12. - The compound of formula 1 according to claim 1, characterized in that it is selected from the group consisting of: 13. A pharmaceutical composition for treating cytomegalovirus infections in a mammal, including 1 s human beings, characterized in that it comprises a compound of formula 1 according to claim 1, or a therapeutically acceptable salt thereof, and a pharmaceutical carrier acceptable. 14. A method for treating cytomegalovirus infections in a mammal, including humans, characterized in that it comprises administering thereto an effective amount of the compound of formula 1 according to claim 1, or a therapeutically acceptable salt thereof. 15. - A method to protect human cells against a pathogenesis by cytomegalovirus, ca ra ct er i za u. > because it comprises treating said cells with an effective antimegaloviric amount of a compound of formula 1 according to claim 1, or a therapeutically acceptable salt thereof. 16. - The compound of formula 1 according to claim 1, in combination with another antiherpes compound, selected from the group consisting of ganciclovir, foscarnet, aciclovir, valaciclovir, famciclovi: cidofovir, penciclovir and lobucavir. 17. - The compound of formula 1 according c ::? claim 1, in combination with another ar.t_-retroviral compound, characterized in that it is selected from the group consisting of reverse transcriptase inhibitors and protease inhibitors. SUMMARY OF THE DESCRIPTION A compound of formula 1 wherein Ri is hydrogen, methyl, ethyl, methoxy or methylthio; R2 and R3, each independently, is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy; R5 is lower alkyl, lower cycloalkyl, (CH2) mC (O) OR6, wherein m is the integer 1 or 2, and Re is lower alkyl, optionally substituted phenyl; optionally Het or Het (lower alkyl); or R4 and R5, together with the nitrogen atom to which they are attached, form a nitrogen-containing ring, optionally substituted with (CO) Obencil or with phenyl optionally substituted with C (O) OR7, wherein R7 is lower alkyl or ( lower alkyl) phenyl; and Z is lower alkyl or optionally substituted phenyl or Het; with the proviso that when Z is (CH:], - then R 2 and R 3 is each hydrogen, or a salt by the addition of pharmaceutically acceptable acid thereof.