MXPA00003451A - 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 C1-3 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 with C(O)OR7 wherein R7 is lower alkyl or phenyl(lower alkyl);or R6 is 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 benzyloxycarbonyl or with phenyl optionally substituted among other group with C(O)OR7 wherein R7 is lower alkyl or (lower alkyl)phenyl;X is selected from the group consisting of O, S, SO, SO2, NR8, wherein R8 is H or lower alkyl;and Y is C1-10 non-cyclic or cyclic alkyl;[(CH2)0-1]-phenyl, said phenyl ring optionally substituted;Het or Het(lower alkyl);or when X is NR8, wherein R8 is lower alkyl and Y is lower alkyl or lower alkoxy, X and Y are joined together to form a morpholino or piperidino ring;or a therapeutically acceptable acid addition salt thereof.

Description

DERIVATIVES OF AZETIDINONE FOR THE TREATMENT OF INFECTIONS BY THE HUMAN CITOMEGALOVIRUS FIELD OF THE INVENTION This invention relates to azetidinone derivatives having activity against herpes infections. More specifically, the invention relates to azetidin-2-one derivatives that exhibit anti-herpes activity, to pharmaceutical compositions comprising the derivatives and to methods for using the derivatives to inhibit the replication of the herpes virus and to treat herpes infections. BACKGROUND OF THE INVENTION Herpes viruses inflict a wide range of diseases against humans and animals. By For example, the herpes simplex virus, types 1 and 2 (HSV-1 and HSV-2) are responsible for afta and genital lesions, respectively; the varicella zoster virus (VZV) causes varicella and zoster; and human cytomegalovirus (CMVH) is a leading cause of opportunistic infections in individuals lacking the system.

REF; 119050 During the last two decades, researchers have received the greatest attention 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 current therapeutic agents in this sector, see R.E. Boeheme et al., Annual Reports in Medicinal Chemistry, 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 azetidin-2-one have been reported in I; * bibliography for having a variety of biological activities; mainly antibacterial, anti-inflammatory, antidegenerative, etc. However, the azetidin-2-one derivatives have not been reported to be. antiviral antibodies against herpes virus. The following references describe azetidin-2-ones with biological activity, S.K. Shah et al., 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. 5,100,880, March 31, 1992, P.L. Durette and M. Maccoss, U.S. Pat. 5,104,862, April 14, 1992, W.K. Hagmann et al., Bioorg. Med. Chem. Lett. 1992, 2, 681, W.K. Hagmann et al., J. Med. Chem. 1993, 36, 771, J.B. Doherty et al., U.S. Pat. ,229,381, issued July 20, 1993, S.K. Shah et al., Bioorg. Med. Chem. Lett. 1993, 3, 2295 ', G. Crawley, PCT Patent WO 99/02579, published January 26, 1995, P.E. FinKe et al., J. Med, Chem. 1995, 38, 2449, and K. Kobayashi et al., Japanese Patent Application 07242624, published September 19, 1995; Chem. Abstr. 1996, 124, 29520.

The present azetidin-2-one derivatives are distinguished from the prior art compounds because they possess different chemical structures and biological activities.

DESCRIPTION OF THE INVENTION The azetidin-2-ena derivatives are represented by formula 1: wherein Ri is hydrogen, methyl, ethyl, methoxy or methylthio; R2 and R3, each independently, is hydrogen or alkyl of 1 to 3 carbon atoms; R "is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; 5 is lower alkyl, lower cycloalkyl, (CH2) mC (0) OR6, where is the integer 1 or 2, and Re, 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 alkylamino, di (lower alkyl) amino, lower acylamino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl, and C (0) OR7, wherein R7 is lower alkyl or phenyl (lower alkyl); Het or Het (lower alkyl) wherein Het represents a five or six element 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 [l, 3] dioxolyl) methyl, (1 (R) -1-naphthalenyl) ethyl, 2-benzothiazolyl or 2-thiazolo [4, 5-b] pyridinyl; or R and R5 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-isoquinolonilo) or 2- (3, 4-dihydro-lH-isoquinolinyl), or a pyrrolidino ring, optionally substituted with benzyloxycarbonyl or with phenyl, wherein said phenyl ring optionally mono- or disubstituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di (lower alkyl) amino, lower acylamino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl and C (O) OR7, wherein R7 is as defined above; X is selected from the group consisting of 0, S, SO, SO2, NRβ, where Re is H or lower alkyl; and Y is an alkyl of 1 to 10 carbon atoms, non-cyclic or cyclic; phenyl (lower alkyl), said phenyl ring being optionally mono- or di-substituted with a lower alkyl or lower alkoxy, said phenyl ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing a heteroatom selected from the group consisting of N, O and S; Het or Het (lower alkyl) containing one or more heteroatoms selected from the group consisting of N, O and S, said Het being optionally mono- or di-substituted with a lower alkyl or lower alkoxy group; said heterocyclic ring optionally being condensed with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing one or two heteroatoms selected from the group consisting of N, 0, and S; C (0) R9 wherein Rg is lower alkyl or phenyl (lower alkyl); or when X is NRβ, where Re is lower alkyl and Y is lower alkyl or lower alkoxy, X and Y are linked together to form a morpholino or piperidino ring; or a salt by addition of the pharmaceutically acceptable acid thereof.

Preferred compounds of the invention include compounds of the formula (1), wherein Ri is hydrogen or alkyl of 1 to 2 carbon atoms; R2 and R3 each independently, is hydrogen, methyl or ethyl; 4 is hydrogen or lower alkyl; Rs is phenyl optionally substituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy; phenyl (lower alkyl) optionally mono- or di-substituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C (0) OR7 wherein R7 is lower alkyl or phenyl (lower alkyl); Het (lower alkyl), wherein Het represents a monovalent, five or six element heterocyclic ring containing a heteroatom selected from the group consisting of N, O, or S, said ring optionally being substituted with lower alkyl or lower alkoxy; or R4 and R5 together with the nitrogen atom to which they are attached, form a pyrrolidino ring, optionally substituted with benzyloxycarbonyl or phenyl, said phenyl ring being optionally mono- or di-substituted with halo, nitro, cyano or trifluoromethyl; X is selected from the group consisting of 0, S, NRβ, where Re is H or lower alkyl; and Y is alkyl of 1 to 10 carbon atoms, non-cyclic or cyclic; phenylcarbonyl; phenyl or benzyl optionally mono- or di-substituted with lower alkyl or lower alkoxy, said phenyl ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing a heteroatom selected from the group consisting of N, O and S; and Het or CH2-Het containing one or more heteroatoms selected from the group consisting of N, O, and S, said Het being optionally mono- or di-substituted with a lower alkyl or lower alkoxy group; said heterocyclic ring optionally being condensed with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing one or more heteroatoms selected from the group consisting of N, O, and S; or when X is NRβ, where Re is lower alkyl and Y is lower alkyl, X and Y are linked together to form a piperidino ring.

The most preferred compounds of the invention include compounds of formula 1, wherein Ri, R2 and R3, each independently, is hydrogen, methyl or ethyl; R "is hydrogen or alkyl of 1 to 3 carbon atoms; Rs is phenyl optionally substituted with a substituent independently selected from the group consisting of lower alkyl or lower alkoxy; (alkyl of 1 to 2 carbon atoms) phenyl optionally mono- or di-substituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C ( 0) OR7 wherein R7 is lower alkyl or (lower alkyl) phenyl; X is selected from the group consisting of O, S, NRβ, where Re is H or lower alkyl; Y And it is noncyclic or cyclic lower alkyl; phenyl optionally mono- or di-substituted with lower alkyl or lower alkoxy; or Het containing one or more heteroatoms selected from the group consisting of N, O and S, said Het being optionally mono- or di-substituted with a lower alkyl; said heterocyclic ring being optionally fused to an aromatic ring to form a bicyclic ring, said aromatic ring optionally incorporating one or more heteroatoms selected from the group consisting of N, O. and S; or when X is NRβ, where Re is lower alkyl and Y is lower alkyl, X and Y are linked together to form a piperidino ring.

The most preferred compounds of the invention include compounds of the formula (1), wherein Ri, R2 and R3 each independently, is hydrogen; R is hydrogen or methyl; Rs is benzyl optionally mono-substituted on its phenyl portion with nitro or trifluoromethyl, or 1 (R) -phenylethyl; X is S; and Y is pyrimidine optionally substituted with lower alkyl; pyridine; N-Me-tetrazole; or benzoxazole.

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, which comprises administering thereto an effective amount of the compound of formula 1 or a therapeutically acceptable salt thereof. Also included within the scope is a method of protecting human cells against cytomegalovirus pathogenesis, 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. The processes for the preparation of the compounds of the formula 1 are described below.

DETAILED DESCRIPTION OF THE INVENTION General As used herein, the following definitions apply, unless otherwise indicated: With reference to the cases in which it was used (R) or (S) to designate the configuration of a radical, for example Rs of the compound of 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 from the α-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 text on Biochemistry (see chapter 4). The term "halo", as used herein, means a halo radical selected from bromine, chlorine, fluorine or iodine. The term "lower alkyl" or (lower alkyl) 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-methylethyl, 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, -metheretoxy, butoxy and 1,1-dimethylethoxy. This last radical is commonly known as tert-butoxy. The term "lower alkanoyl", as used herein, alone and in combination with another radical, means a straight-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-ethylpropionyl and 2-ethylbutyryl. The term "lower cycloalkyl", as used herein, 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 alkylamino", as used herein, means alkylamino radicals containing from one to six carbon atoms and includes methylamino, propylamino, (1-methylethyl) amino and (2-methylbutyl) 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 element, 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, (1-3C) alkyl phenyl, lower alkoxy, halo, amino or lower alkylamino. Again optionally, the five or six element heterocycle may be fused to a phenyl. Examples of suitable heterocycles and optionally substituted heterocycles include pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, 1H-imidazole, 1-methyl-1H-imidazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, 2-methylthiazole, 2-aminothiazole, 2 - (methylamino) -thiazole, piperidine, 1-methylpiperidine, 1-methylpiperazine, 1,4-dioxane, morpholine, pyridine, pyridine-N-oxide, pyrimidine, 2,4-dihydroxypyrimidine, 2,4-dimethylpyrimidine, 2,6 -dimethylpyridine, 1-methyl-lH-tetrazole, 2-methyl-2H-tetrazole, benzothiazole, benzoxazole 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 azetidin-2-one derivatives of the formula 1 can be obtained in the form of addition salts 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, p-toluenesulfonic acids, as well as acids polymers such as tannic acid and carboxymethyl cellulose, and salts with inorganic acids such as hydrohalic acids, for example hydrochloric acid, or sulfuric acid, or phosphoric acid.

Procedures 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, Ed., VCH Publishers Inc., New York, N.Y., USA, 1992, pp. 1 to 48 and 257 to 293). The compounds of formula 1, wherein Ri to inclusive R, X and Y are as defined in the summary of the invention, can be prepared by the following generic procedure illustrated in Scheme A: Ksqui Step a: Intermediate V is prepared according to known processes, starting from suitably protected D-aspartic acid (ref P.E. Finke et al., J. Med. Chem. 1995, 38, 2449).

Step b: The acid function of intermediate V is reduced to give alcohol IV.

Step c: When X is O or S, and Y is aryl or Het, the primary alcohol IV is converted to intermediate II, using Mitsunobu reaction conditions (Ref DL Hughes, Org Reaction 1992, 42, 335; JR Dor oy, Synthesis 1982, 753).

Alternatively, when X and Y are as defined in the summary of the invention, the process is carried out by an alternative route using steps b 'and e': Step b ': The alcohol IV becomes a "LG" separation group (eg, mesylate, iodide, bromide) to give the intermediate compound III.

Step c ': Intermediate III is then reacted with a nucleophile (for example alkylthiolate or amine) to provide an intermediate intermediate compound II'.

Step d: The key intermediates II or II 'are converted to the desired inhibitor via deprotection using fluoride ions (eg cesium fluoride), followed by condensation with the appropriate reagent.

In the case of the compounds of formula 1, wherein R is hydrogen, the appropriate reagent is an isocyanate of the formula R5 '-NCO, wherein R5' is as defined above, but not pyridine, and the condensation was carried out in the presence of a tertiary amine (for example diisopropylethylamine) or, preferably, lithium bis (trimethylsilyl) amide. Alternatively, in the case of compounds of the formula 1, wherein R is a lower alkyl, then the appropriate reagent is an activated carbamate of formula VI: SAW and the condensation is carried out in the presence of a Base, such as lithium bis (trimethylsilyl) amide. Still, as a further alternative to the general procedure of scheme A, compounds of formula 1, wherein R5 is pyridine, can be produced by the condensation of a intermediate compound of formula II or II 'with 2 an activated carbamate of the formula VI ' SAW' In addition, the activated carbamate of formula VI or VI 'can be used in the condensation of intermediate II or II' when the appropriate isocyanate Rs' -NCO is not commercially available.

To further illustrate the method according to the invention, specific examples of the alternative methods described in Scheme A are provided.

SCHEME B As a first alternative, a method is provided in which compounds of formula 1 (where Ri, R », and Rs, are as defined above, and R2 and R3 are both H, X is O or S, and Y is phenyl or Het) were prepared as illustrated in Scheme B: Scheme B R = t-BuMe2Si R - t-Bu e ^ i 2 R »t-BuMe ^ St 4 1 a) ßlenrofor »i« to de i.obutilo. 1HK, TH ?, M.ÍH ,. H.O »b) Ph.l ?. DMD, THF. 2- - «• raaftaplr ± midiB? J c) Ce». M «OH > d) lluros, l.oo ± «n * fco«, carb «» »to, THT. a) The reduction of acid 2 was achieved with borane in tetrahydrofuran or via the formation of a mixed anhydride with isobutyl chloroformate in the presence of an organic tertiary amine, for example N-methylmorpholine or diisopropylethylamine, and subsequent treatment of the mixed anhydride with borohydride of sodium. b) The conversion of alcohol 3 to aryl ether or aryl thioether 4 ^ was achieved using the Mitsunobu reaction conditions (Ref DL Hughes, Org Reaction 1992, 42, 335, JR Dormoy, Synthesis 1982, 753), for example using triphenylphosphine and diethyl azodicarboxylate in a solvent such as tetrahydrofuran and in the presence of an arylthiol or aryl alcohol. c, d) Intermediate 4_ was converted to the desired inhibitor 1 via deprotection, using - a source of fluoride ions such as cesium fluoride, followed by condensation with the appropriate isocyanate R5-NCO, in the presence of a tertiary amine such as diisopropylethylamine or, preferably, lithium (or potassium) bis (trimethylsilyl) amide [when R4 is H]. Alternatively, an activated carbamate such as phenoxycarbamate could be used. When R is not hydrogen, an appropriate carbamoyl chloride derivative could be used.

SCHEME C Alternatively, the compounds of formula 1, wherein Ri to inclusive Rs are as defined above, X is NRβ (where Re is as defined in the summary of the invention) or X and Y are linked to form a morpholino ring or piperidino, were prepared by the procedure as illustrated in Scheme C: Scheme C * > Ph, P, ixlanol, I "CH.CN; b > plp.ridtn », reflux; o) C »F, M« 0H; d) lBHDS, oaiautß or ouiiuuto, THF The alcohol 3 became a separation group such as an iodide 5_. b) The iodide 5 was then reacted with a secondary amine such as piperidine or morpholine to give 6 where X and Y are linked to form a piperidino or morpholino ring, respectively. c) Intermediate 6_ was then worked up as described above to provide a compound of formula 1.

SCHEME D Turning now to a further specific embodiment of the process of the invention, there is provided a process for producing compounds of formula 1, wherein R 2 is alkyl of 1 to 3 carbon atoms such as methyl, Y is phenyl or Het, R 3 is H , and Ri, R, R5, and X are as defined in the summary of the invention. These compounds were prepared by the procedure as illustrated in Scheme D: Esquena Z > *} olßruro da ßxelilo, DMßO, CH-C1, b) MaMgBr, HP »c) Mi, *, DMU > , THF, 3- - «• rcaptopirimidin»; d) separation of diaatereoiedmaroa; • > c «F, MeOHí f) iHHDS. laociagata or earbamate, THF. a, b) The primary alcohol 3_ was oxidized to the corresponding aldehyde using activated oxalyl-dimethylsulfoxide chloride (K. Omura and D. Swern, Tetrahedron 1978, 34, 1651) or triacetoxy periodinane (DB Dess and JC Martin, J. Org Chem. 1983, 48, 4155). Next, this aldehyde was reacted with an appropriate Grignard reagent such as methylmagnesium bromide, to give the addition product 7 in the form of a mixture of diastereoisomers.

C, d) The conversion of the secondary alcohols 1_ to aryl ether or aryl thioether 8 ^ was achieved using Mitsunobu reaction conditions as exemplified in Scheme B, step b. The two diastereoisomers could then be separated using chromatography on silica gel or by preparative HPLC. e, f) The desired inhibitor 1 was obtained via deprotection and condensation as described above.

SCHEMES E, F, G, and H The activated isocyanates or carbamates used in this invention, which were not commercially available, were prepared as described in Schemes E, F, G or H.

Scheme E: Isocyanates such as 1 (R) -phenylpropyl isocyanate 1_0 were prepared from commercially available amine via formation of the hydrochloride salt and reaction with tri-phosgene in toluene under reflux.

Scheme, fi a) HCl / Be, 0; b) trlfoa ezio, toluene Scheme F: Alternatively, secondary benzylic amines not commercially available from the corresponding substituted benzyl bromides could be prepared as follows: a) The benzyl bromide 1_1 was reacted with ethylamine in ethanol to provide the corresponding secondary amine 12_, which was isolated in the form of the hydrochloride salt. b) Further reaction with phosgene in the presence of a tertiary organic base such as diisopropylethylamine in dichloromethane gave the desired carbamoyl chloride 13.

Scheme F a) MaltK ,, HtOH, HCl / St, 0, J > ) foagaao, DIB ?, CH.C1, Scheme G, alternatively, preactivation could be achieved via formation of the N-phenoxycarbamate derivative i5, by reacting the amine I4 with phenyl chloroformate in the presence of a tertiary amine such as triethylamine in dichloromethane.

Scheme ß a) PhOCOCl, St, «r, CH, C1, Scheme H: Alternatively, non-commercially available pyrrolidine derivatives such as J9 could be prepared as follows: a, b) The 1-6 amine was protected by the reaction with di-tert-butyl carbonate in the presence of a lime aqueous base such as hydroxide. sodium. The protected amine was reacted with a benzyl halide such as bromide or benzyl chloride in the presence of a base such as sodium hydride in tetrahydrofuran to give intermediate 17. c) Cyclization of intermediate compound 1_7 was achieved using a base strong such as n-butyllithium in the presence of tetramethylethylenediamine in tetrahydrofuran to give the pyrrolidine derivative 18. d) e) Cleavage of the tert-butyloxycarbonyl group was carried out under anhydrous acid conditions, followed by reaction with phosgene in the presence of a tertiary organic base such as diisopropylethylamine in dichloromethane to give the desired carbamoyl chloride 1. Ka? Ruama H 18 19 ») Bß, 0, TBT, HaOH; b) H «B, THF, BnSr; o) n-BuId., THMD1, T »j d)« Cl / dioxanß ».i fb? geno, DIEA, CH2Ct2 SCHEME I The sulfoxides and sulfones are readily accessible from thioether intermediates such as 20, using oxidation with peroxide or preferably, the reaction with oxone in a methanol / water mixture, as shown.

Ksqußma z ?, N =? or 2 «> n- 1, ««. (0, 5 -quiv.), Naos, H.O, a. 2. oxon. (1 aq ».,, .OH» ^ Q, b) X-IHKM, leoe ± aaefco or aajcbamate, TKF SCHEME J __ _ For compounds of formula 1, wherein Y is lower alkyl, the introduction of a lower alkyl thioether could be achieved via intermediate 3. a, b) The hydroxy group of the primary alcohol 3 was converted to a separation group such as 4-nitrobenzenesulfonate, followed by displacement with potassium thioacetate to generate the corresponding thioacetate 21. c, d) Saponification of the acetate 21. in the presence of lithium hydroxide in methanol, followed by the addition of methyl iodide gave the desired methylthioether derivative. Deprotection and ureido formation as described above led to the desired compound 1.

Scheme J a) 4-HOJ-Ph. ~ S01Cl. t-β, CK-C1 ,, b) AeSK, MeCN; c) LiOH, MeOH. lh, lueffo Kel, d > LIBMDS, iaocyanate or arabamate, THF Antiherpes activity The anti-herpes activity of the aforementioned azetidinone derivatives of formula 1 (inhibitors of HCMV processes) can be demonstrated by biochemical, microbiological and biological processes.

A biochemical process to demonstrate the anti-cytomegalovirus activity of the 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 the activity (IC50) of HCMV processes. More specifically, in the assay described herein, the inhibitory activity of the test compound is evaluated on the basis of its ability to interfere with the cleavage of the non-HCMV protease from a fluorogenic peptide substrate which, in turn, is based on the excision site of enzyme maturation.

Methods for demonstrating the inhibitory effect of the azetidinone derivatives of formula 1 on CMV replication involving cell culture techniques (EC50) are described in the examples set forth herein.

When the HCVH protease inhibitor is used as an antiviral agent, it is administered orally or systemically to human beings 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, of the chosen administration route 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 active ingredient, 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., Eds., Williams & Wilkins, Baltimore, Meryland, 1995.

The dosage of the CMVH protease inhibitor will vary with the form of administration and the particular active agent chosen. In addition to this, it will vary with the particular receiver undergoing treatment. Generally, treatment starts with small increments until the optimal 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 relationship, unless otherwise stated. Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz spectrometer; chemical shifts (d) se. They report in parts per million. Abbreviations or symbols used herein include: Boc: tert-butyloxycarbonyl; DEAD: diethyl azodicarboxylate; DIEA: diisopropylethylamine; DMF: dimethylformamide; Et: ethyl; EtOAc: ethyl acetate; Et20: diethyl ether; LiHMDS: lithium bis (trimethylsilyl) amide; Me: methyl, MeOH: methanol; MeCN: acetonitrile; Ph: phenyl; THF: tetrahydrofuran; TMEDA: tetramethylethylenediamine; MS (EN): mass spectrometry by electroprojection; MS (FAB): mass spectrometry with fast atom bombardment; HRMS: high resolution mass spectrometry; PFU: plate forming units.

Example 1 Preparation of 1 (R) -phenylpropyl isocyanate To a solution of 1 (R) -phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mol) was added a 1.0 M solution of HCl / Et2O (212 mL, 212 mmol). The mixture was stirred for 30 minutes and the crude solution was 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 stirred at reflux for 3 hours at room temperature overnight. 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. 1 H NMR (400 MHz, CDC13) d 7.36-7.22 (m, 5H), 4.50 (t, J = 6.7 Hz, 1H), 1.82 (g, J = 7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz , 2H).

Example 2 Preparation of 4-. { . { (phenoxycarbonyl) amino} ethyl} pyridine To a solution of 4- (aminomethyl) pyridine (10.7 g, 98.5 mmol) in CH2C12 (245 ml) at 0 ° C was added Et3N; (14.2 ml, 19.9 g, 197 mmol), followed by the dropwise addition of phenyl chloroformate (14.8 ml, 18.5 g, 118 mmol). After stirring for 1 hour, the resulting mixture was diluted with EtOAc (1.5 1), the organic phase was washed twice with water and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography (Si02, gradient of EtOAc to 10% MCOH / CHC13) gave a yellow solid which was recrystallized from EtOAc: hexane (2: 1) to give the desired compound (9.55 g, 41.85 mol, 42% yield). 1E NMR (400 MHz, CDC13) d 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 3 Preparation of N-methyl-N- chloride. { [4- (trifluoromethyl) phenyl] methyl} Carbamoyl To a bromide solution of. { 4- (trifluoromethyl) phenyl} methyl (20.0 g, 83.7 mmol) in EtOH was added MeNH2 (100 mL of a 40% aqueous solution, 1290 mmol). After 2 hours, the reaction was concentrated in vacuo. The aqueous phase was extracted with EtOAc (2 x 100 ml). The combined organic phase was washed with NaHCO 3 and brine, dried over magnesium sulfate, filtered and evaporated to dryness. The resulting residue was dissolved in HCl / dioxane (4 N, 100 ml), and the solvent was removed in vacuo. The resulting solid was triturated with Et20 and collected by suction filtration to provide N-methyl- hydrochloride salt. { 4- (trifluoromethyl) phenyl} methylamine (17.0 g, 90% yield) as a white solid.

The salt was suspended in CH 2 Cl 2 (150 mL), cooled to 0 ° and DIEA (30.2 mL, 173 mmol) was added followed by a solution of phosgene in toluene (1.93 M, 55 mL, 105.7 mmol). After 2 hours at 0 °, the reaction mixture was concentrated. The resulting thick gum was extracted with Et20 and evaporation of the extract gave a pale yellow oil. This oil was further purified by flash chromatography (Si02, eluent: 10% EtOAc in hexane) to give a pale yellow oil (16.0 g, 84% yield). 'H NMR (400 MHz, CDC13) d 7.59 (m, 2H), 7.33 (m, 2H), 4.72 and 4.58 (2 x s, 2H), 3.04 and 2.97 (2 x s, 3H).

Example 4 Preparation of 2-oxo-4 (R) - (pyrimidin-2-ylsulfanylmethyl) azetidine-1-carboxylic acid (1) (R) -phenylpropyl) amide (Table 1, entry no. 104) Stage A To a solution of l- (tert-butyldimethylsilyl) -4-oxoazetidine-2 (R) -carboxylic acid (15.0 g, 65.40 mmol) in THF. (367 ml) at 0o 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 0o, a solution of NaBH4 (9.9 g, 261.61 mmol) in H20 (98 mL) was added portionwise. The reaction was stirred for 45 mm and 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, gradient 25% to 50% EtOAc / hexane) to provide "1- (tert-butyldimethylsilyl) -4 (R) - (hydroxymethyl) azetidin-2-one (8.46 g, 60% yield) in the form of a white solid XH NMR (400 MHz, CDC13) d 3.74-3.69 (m, 1H), 3.65-3.56 (m, 2H), 3.1-2.98 (m, 1H), 2.81-2.76 (m, 1H), 2.01 (s, 1H), 0.89 (s, 9H), 0.18 (s, 3H), '0.16 (s, 3H), FAB MS m / z 216.2 (MH +).

Stage B To a solution of 1- (tert-butyldimethylsilyl) -4 (R) - (hydroxymethyl) azetidin-2-one (2.75 g, 12.77 mmol) in THF (80 ml) was added PPh3 (6.70 g, 25.54 mmol). The reaction was cooled to 0 ° and DEAD (3.3 ml, 25.54 mmol) was added dropwise. After 5 minutes, 2-mercaptopyrimidine (3.60 g, 31.92 mmol) was added. After stirring for 15 minutes at 0o and for 60 hours at room temperature, the reaction mixture was concentrated. The residue was treated with EtOAC / hexane (1/1), and the resulting solid was filtered and rinsed with Et20. The filtrate was concentrated and purified by flash chromatography (Si02, 25% EtOAc / hexane) to give 1- (tert-butyldimethylsilyl) -4 (R) - (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one (3.75 g, 95% yield) as a transparent oil. "H NMR (400 MHz, CDC12) d 8.70 (d, J = 4.8 Hz, 2H), 7.20 (t, J = 4.9 Hz, 1H), 4.08-4.01 (m, 2H), 3.41-3.36 (m, 1H), 3.99 (dd, J = 14.3, 10.8 Hz, 1H), 2.98 (dd, J = 15.6 , 2.5 Hz, 1H), 1.18 (s, 9H), 0.53 (s, 3H), 0.49 (s, 3H).

Stage C To a solution of 1- (tert-butyldimethylsilyl) -4 (R) - (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one (280 mg, 0.905 mmol) in MeOH (4.5 ml) was added cesium fluoride (206 mg 1.36 mmol). The reaction mixture was stirred for 1.5 hours at room temperature and then concentrated in vacuo. The residue was dissolved in CH 2 Cl 2, washed with H 2 O and brine, dried (MgSO 4), filtered and evaporated to give 4 (R) - (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one (184 mg) which was used as such. . 'H NMR (400 MHz, CDCl 3) d 8.52 (d, J = 5.1 Hz, 2H), 7.02 (t, J = 5.1 Hz, 1H), 6.13-5.93 (m, 1H), 4.04-3.99 (m, 1H ) 3.54 (dd, J = 14.0, 5.4 Hz, 1H), 3.27 (dd, J = 14.0, 7.0, 1H), 3.14 (ddd, J = 15.0, 5.1, 1.9 Hz, 1H), 2.78 (ddd, J 15.0 , 2.2, 1.3 Hz, 1H).

Stage D To a solution of 4 (R) - (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0 ° LiHMDS was added dropwise. (1M / THF) (0.33 ml, 0.331 mmol). After the reaction mixture had been stirred for 15 mm at 0 °, then cooled to -78 °, isocyanate of 1 (R) -phenylpropyl (Example 1) (0.53) was added dropwise.

M / toluene, 0.63 ml, 0.315 mmol) and the mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SIO2, 30% EtOAc / hexane) to give (1 (R) -phenylpropyl) 2-oxo-4 (R) - (pyrimidin-2-ylsulfanylmethyl) azetidine 1-carboxylic acid (75 mg, 67% yield) in the form of a viscous gum. 'H NMR (400 MHz, CDCl 3) d 8.45 (d, J = 4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J = 4.8 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.71 (q, J = 7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J = 14.2, 3.3 Hz, 1H), 3.39 (dd, J = 14.2, 8.3 Hz , 1H), 3.03 (dd, J = 16.0, 5.6 Hz, 1H), 2.89 (dd, J = 16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); IR (pure) v 1758, 1692 cm- '; FAB MS m / z 357.3 (MH +); HRMS calculated for C? 8H2? N402S (MH +) 357.1385, found 357.1379.

Example 5 (1 (R) -phenylpropyl) 2-oxo-4 (R) - [1- (R) - (pyrimidin-2-ylsulfanyl) ethyl] azetidine-1-carboxylic acid y (1 (R) -phenylpropyl- 2-Oxo-4 (R) [1- (S) - (pyrimidin-2-ylsulfanyl) ethyl] azetidine-1-carboxylic acid amide (Table 2, mixture of entries Nos. 208 and 209).

To a solution of oxalyl chloride (0.31 ml, 3.58 mmol) in CH 2 Cl 2 (22 ml) at -78 ° was added dropwise a solution of DMSO (0.48 ml, 6.83 mmol) in CH 2 Cl 2 (1.4 ml). After 15 minutes, a solution of 1- (tert-butyldimethylsilyl) -4 - (R) - (hydroxymethyl) azetidin-2-one (700 mg, 3.25 mmol) in CH 2 Cl 2 (3.3 ml) was added, and the reaction was stirred for an extra 45 minutes. Finally, DIEA (2.8 mL, 16.25 mmol) was added and the reaction was stirred at room temperature for 2 hours. The resulting mixture was diluted with H2O and extracted with CH2C12. The organic phase was washed with aqueous HCl (10%), saturated NaHCO 3 and brine, dried (MgSO 4), filtered and concentrated. The crude aldehyde was used immediately in the next step. To the crude aldehyde dissolved in THF (29 ml) was added dropwise MeMgBr (3M / Et20, 2.7 ml, 8.18 mmol). The reaction mixture was stirred for 1 hour at 0o and for 1 hour at room temperature, followed by the addition of saturated aqueous solution of NH C1. After. extraction with EtOAc, the organic phase was washed with HCl (10%), saturated aqueous NaHC 3 and brine, dried (MgSO), filtered and evaporated. The resulting mixture was purified by flash chromatography (Si02, 40% EtOAc / hexane) to give 1- (tert-butyldi-methylsilyl) -4- (R) - (1-hydroxyethyl) azetidin-2-one (580 mg, 77% yield for the two steps) in form of a mixture of isomers. 'H NMR (400 MHz, CDC13) d 4.02-3.96 (m, 1H), 3.81 (q, J = 6.5 Hz, 1H), 4.33-4.27 (m, 1H), 3.50-3.43 (m, 2H), 3.01 (dd, J = 15.6, 5.6 Hz, 1H), 2.95 (dd, J = 15.3, 2.9 Hz, 1H), 2.84 (dd, J = 15.1, 5.6 Hz, 1H), 2.58 (dd, J = 15.6, 2.9 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.92-0.91 (, 18H), 0.22-0.11 (m, 6H).

The process of Example 4, step B, was followed to give 1- (tert-butyldimethylsilyl) -4 (R) - [1- (pyrimidin-2-ylsulfanyl) azetidin-2-one as a mixture of isomers. The separation of the two isomers was carried out by preparative HPLC (5% to 100% C3 CH 3 CN / H 2 O / 0.06% TFA column).

Diastereoismer without (13.4 minutes): ""? NMR (400 MHz, CDCl 3) d 8.46 (d, J = 4.8 Hz, 2H), 6.94 (t, J = 4.8 Hz, 1H), 3.82 (q, J = 3.0 Hz, 1H), 3.08 (dd, J = 15.6, 5.7 Hz, 1H), 2.85 (dd, J = 15.6, 2.9 Hz, 1H), 1.38 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H), 0.18 (s, 3H), 0.12 ( s, 3H).

Anti diastereoisomer (15 minutes): 'H NMR (400 MHz, CDCl 3) d 8.46 (d, J = 4.8 Hz, 2H), 6.96 (t, J = 4.9 Hz, 1H), 4.26-4.21 (m, 1H), 4.07-4.02 (m, 1H), 2.98 (dd, J = 15.7, 5.6 Hz, 1H), 2.81 (dd, J = 14. 6, 2.9 Hz, 1H), 1.31 (d, J = 7.3 Hz, 3H), 0.94 (s, 9H), 0.32 (s, 3H), 0.24 (s, 3H).

The process of Example 4, Steps C and D, was followed to give the desired compounds: (1 (R) -phenylpropyl) 2-oxo-4 (R) - [1 (R) - (pyrimidin-2-aramid) ilsulfanyl) ethyl] azetidine-1-carboxylic acid. XH NMR (400 MHz, CDCl 3) d 8.45 (d, J = 4.8 Hz, 2H), 7.29-7.18 (m, 5H), 6.93-6.89 (m, 2H), 4.76-4.66 (m, 2H), 4.53- 4.49 8m, 1H), 3.00 (dd, J = 16.2, 5.7 Hz, 1H), 2.90 (dd, J = 16.3, 2.9 Hz, 1H), 1.86-1.79 (m, 2H), 1.37 (d, J = 7.3 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); IR (CHCl3) v 1764, 1700 cm "1; FAB MS m / z 371 (MH +); HRMS calculated for C? 9H23N 02S: 371.1542 (MH +) found: 371.1535. (1 (R) phenylpropyl) 2-acid amide oxo-4 (R) - [1 (S) - (pyrimidin-2-ylsulfanyl) ethyl] azetidine-1-carboxy 1-yl. XH NMR (400 MHz, CDCl 3) d 8.50 (d, J = 4.8 Hz, 2H) , 7.30-7.16 (m, 5H), 6.96 (t, J = 4.8 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.66-4.60 (, 2H), 4.25-4.19 (m, 1H) , 3.05 (dd, J = 16.0, 5.6Hz, 1H), 2.94 (dd, J = 16.2, 2.6 Hz, 1H), 1.70 (q, J = 7.3 Hz, 2H), 1.48 (d, J = 7.0 Hz, 3H), 0.75. (T, J = 7.5 Hz, 3H); (pure) v 1764, 1702 cm -1; FAB MS m / z 371 (MH +); HRMS calculated for C? 9H23N402S: 371.1542 (MH +); found: 371.1535.

Example 6 Preparation of 2-oxo-4 (R) - (phenylsulfanylmethyl) -zetidine-1-carboxylic acid (pyridin-4-ylmethyl) amide (Table 2, entry no 201).

Stage A 1- (tert-butyldimethylsilyl) -4 (R) - (hydroxymethyl) azetidin-2-one (from Example '4, step A) was deprotected using the same process as in Example 4, step C, to give 4 (R ) - (hydroxymethyl) azetidin-2-one. 'H NMR (400 MHz, CDC13) d 6.86-6.67 (broad s, 1H), 3.77 (dd, J = 11.5, 3.4 Hz, 1H), 3.72-3.68 (m, 1H), 3.54 (dd, J = 11.51 6.0 Hz), 3.34-3.07 (broad s, 1H), 2.91 (ddd, J = 14.9, 5.1, 1.3 Hz, 1H), 2.66 (d, J = 14.9 Hz, 1H). a solution of 4 (R) - (hydroxymethyl) azetidin-2-one (502 mg, 4.96 mmol) in CH2Cl2 (7 mL) at 0 ° was added Et3N (0.83 mL, 5.96 mmol), followed by methanesulfonyl chloride (0.46 mL). , 6.0 mmol) and stirred for 5 hours at 0o. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The combined solids were purified by flash chromatography (Si02, 10% MeOH-CHCl3) to give the pure mesylate (610 mg, 3.40 mmol, 61% yield) as a white solid. * H NMR (400 MMz, CDCI3) d 6.07-5.90 (s broad, 1H), 4.38 (dd, J = 11.0, 3.7 Hz, 1H), 4.17 (dd, J = 11.0, 7.2 Hz, 1H), 3.99-3.89 (m, 1H), 3.10 (ddd, J = 15.2, 5.4, 2.0 Hz, 1H), 3.02 (s, 3H), 2.72 (ddd, J = 15.2, 2.5, 1.3 Hz, 1H).

To a cold (0 °) suspension of sodium hydride (54.0 mg, 2.24 mmol) in DMF (4 ml) was added thiophenol (223 ml, 2.17 mmol), and the reaction mixture was stirred at 0 ° C for 1 hour. The mesylate (300 mg, 1.67 mmol) was then added and stirring was continued at room temperature overnight. The reaction mixture was diluted with a 1: 1 mixture of Et20 / EtOAc 25 (40 ml) and washed with H2O, saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Si02, 70% EtOAc-hexane) to give 4 (R) - (phenylsulfanylmethyl) azetidin-2-one (118 mg, 65% yield) as a colorless gum . 1 NMR (400 MHz, CDC13) d 7.38-7.31 (m, 2H), 7.29-7.15 (m, 3H), 5.97-5.80 (s broad, 1H), 3.76-3.69 (m, 1H), 3.12 (dd, J = 13.7, 5.1 Hz, 1H), 3.02 (ddd, J = 15.0, 5.0, 1.9 Hz, 1H), 2.98 (dd, J = 13.7, 7.6 Hz, 1H), 2.60 (ddd, J = 15.0, 2.4, 1.5 Hz, 1H).

Stage B Following the same procedure as in Example 4, step D, but using 4- (phenylsulfanylmethyl) azetidin-2-one and phenyl ester of (pyridin-4-methylmethyl) carbamic acid as reactants was obtained (pyridin-4-ylmethyl) amide of 2-oxo-4 (R) - (phenylsulfanylmethyl) azetidine-1-carboxylic acid as a white solid. 'H NMR (400 MHz, CDC13) d 8.56-8.50 (m, 2H), 7.39-7.34 (m, 2H), 7.31-7.14 (m, 5H), 6.90-6.84 (m, 1H), 4.43 (dd, J = 16.5, 6.4 Hz, 1H), 4.38 (dd, J = 16.5, 6.4 Hz, 1H), 4.28-4.21 (m, 1H), 3.61 (dd, J = 14.3, 2.9 Hz, 1H), 3.19 (dd) , J 14.3, 7.9 Hz, 1H), 3.11 (dd, J = 16.2, 5.7 Hz, 1H), 2.87 (dd, J = 16.2, 2.9 Hz, 1H); IR (KBr) v 3347, 1763, 1701 cm -1; FAB MS m / z 328 (MH +); HRMS calculated for C? 7H? 7N302S 328.1119 (MH +); found: 328.1129.

Example 7 Preparation of benzylamide of 4- (R) benzenesulfini Ímeti 1-2 -oxoazetidine-1-carboxylic acid benzylamide (Table 2, entry no 202).

Stage A A solution of 4 (R) - (phenylsulfanylmethyl) azetidin-2-one (from Example 6, step A) (105 mg, 0.543 mmol) in MeOH (3 ml) was treated with an aqueous solution of oxone (167 mg, 0.272). mmol, 3 ml). After stirring at room temperature for 24 hours, the reaction mixture was quenched with aqueous Na 2 S 2 3 3 (10%, 1 ml) and concentrated. The concentrate was diluted with EtOAc (5 ml) and brine (5 ml) and the two layers were separated. The aqueous layer was re-extracted three times with CHCl3 (20 ml) and the combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Si02, EtOAc) to give 4 (R) - (benzenesulfinylmethyl) azetidin-2-one (89.6 mg, 79% yield). 1 H NMR (400 MHz, CDC13) d (1: 1 mixture of diastereomers) 7.61-7.45 (m, 10H), 6.29-6.14 (broad s, 1H), 5.70-5.58 (broad s, 1H), 4.16-4.08 ( m, 1H), 3.88-3.80 (m, 1H), 3.27-3.05 (m, 4H), 2.92 (dd, J = 13.3, 9.2 Hz, 1H), 2.90 (dd, J = 13.3, 3.5 Hz, 1H) , 2.75-2.67 (m, 1H), 2.66-2.58 (m, 1H).

Stage B Following the same procedure as in Example 4, step D, but using 4 (R) - (benzenesulfinylmethyl) azetidin-2-one and benzyl isocyanate as the starting material, 2 (R) -benzenesulfinylmethyl-4-benzylamide was obtained -oxoazetidine-1-carboxylic acid. ^ "H NMR (400 MHz, CDCl 3) d (1: 1 mixture of diastereoisomers) 7.62-7.55 (m, 4H), 7.54-7.45 (m, 6H), 7.31-7.24 (m, 4H), 7.24-7.17 ( m, 6H), 6.85-6.70 (m, 2H), 4.57-4.49 (m, 1H), 4.43-4.30 (m, 4H), 4.18-4.11 (m, 1H), 3.66 (dd, J = 13.0, 3.5 Hz, 1H), 3.51 (dd, J = 13.7, 3.2 Hz, 1H), 3.33 (dd, J = 16.5, 2.9 Hz, 1H), 3.25-3.16 (m, 1H), 3.24 (dd, J = 16.0, 5.4 Hz, 1H), 3.20 (dd, J = 13.7, 8.9 Hz, 1H), 3.06 (dd, J = 16.5, 2.9 Hz, 1H), 2.89 (dd, J = 13.0, 10.0 Hz, H); IR ( KBr) v 3325, 1774, 1691, 1036 cm "1; FAB MS m / z 343 (MH +); HRMS calculated for C? S i8N2? 3S: 343.1116, found: 343.1129.

Example 8 Preparation of 2 (R) benzenesulfonyl eti 1-4 -oxoazetidine-1-carboxylic acid benzylamide (Table 2, entry no. 203).

Following the two-step process as in Example 7, but using an excess of aqueous oxone in step A, 4 (R) -benzenesulfonylmethyl-2-oxo-azetidine-l-carboxylic acid benzylamide was obtained as a solid White. 1 H NMR (400 MHz, CDC13) d 7.90-7.84 (m, 2H), 7.67-7.61 (m, 1H), 7.58-7.51 (m, 2H), 7.30-7.16 (m, 5H), 6.74-6.66 (m , 1H), 4.38-4.25 (m, 3H), 4.14 (dd, J = 14.0, 2.9 Hz, 1H), 3.22-3.17 (m, 3H); IR (KBr) v 3328, 1779, 1693, 1303, 1150 cm "1; FAB MS m / z 359 (MH +); HRMS calculated for C? 8H? 8N202S: (MH +) 359.1066, found: 359.1074 Example 9 Preparation of 4- (R) - (Methylsulfanyl) methyl-2-oxazetidine-l-carboxylic acid (1) (R) -phenylpropyl) (Table 1, entry n 127 1- (tert-butyldimethylsilyl) -4 (R) - (hydroxymethyl) azetidin-2-one (from Example 4, step A) (2.0 g, 9.29 mmol) was dissolved in CH2C12 (14 mL) and cooled to 0o. Et3N (1.55 mL, 11.1 mmol) was added, followed by 4-nitrobenzene sulfonyl chloride (2.47 g, 11.1 mmol) and stirred at 0 ° C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Et20 was added to the residue, and the salt was separated by filtration. The filtrate was concentrated and the crude product was purified by flash chromatography (SiO2, 30% EtOAc-hexane) to give the desired product as a yellow solid (2.98 g, 80% yield). To a solution of the 4-nitrobenzenesulfonate derivative (1.0 g, 2.50 mmol) in MeCN (12 mL) was added potassium thioacetate (342 mg, 3.00 mmol). The reaction mixture was stirred at room temperature overnight and the orange suspension was evaporated in vacuo. The residue was diluted with EtOAc (25 mL), washed with H20 and brine, dried (MgSO), filtered and concentrated. The residue was purified by flash chromatography (Si02, 20% EtOAc-hexane) to give the thioacetate derivative (586 mg, 86% yield) as a yellow oil. 1 H NMR (400 MHz, CDC12) d 3.65-3.57 (m, 1H), 3.42 (dd, J = 13.7, 3.2 Hz, 1H), 3.08 (dd, J = 15.6, 5.4 Hz, 1H), 2.69 (dd, J = 13.7, 9.2 Hz, 1H), 2.56 (dd, J = 15.6, 2.7 Hz, 1H), 2.31 (s, 3H), 0.91 (s, 9H), 0.24 (s, 3H), 0.20 (s, 3H) ). To a solution of the thioacetate (151 mg, 0.552 mmol) in MeOH (3 mL) was added a solution of LiOH (16.0 mg, 0.664 mmol) in MeOH (4 mL). The reaction mixture was stirred for 1 hour at room temperature, Mel (41 ml, 0.659 mmol) was added, and stirring was continued for 1 hour. The reaction mixture was evaporated to dryness and purified by flash chromatography (Si02, 80% EtOAc-hexane) to give 4 (R) - (methylsulfanylmethyl) azetidin-2-one as a colorless oil (41.1 mg , 57% yield). 1 H NMR (400 MHz, CDC13) d 6.10-5.92 (broad s, 1H), 3.79-3.72 (m, 1H), 3.06 (ddd, J = 14.9, 5.0, 2.2 Hz, 1H), 2.73 (dd, J = 13.6, 5.3 Hz, 1H), 2.66-2.59 (m, 1H), 2.58 (dd, J = 13.6, 8.0 Hz, 1H), 2.10 (s, 3H). Following the same procedure as in Example 4, step D, but using 4 (R) - (methylsulfanylmethyl) azetidin-2-one as the starting material, 2 (R) -methylsulfanyl (1-phenylpropyl) amide was obtained) methyl-4-oxoazetidine-1-carboxylic acid in the form of a yellowish oil. 1M NMR (400 MHz, CDC13) d 7.31-7.24 (m, 2H), 7.23-7.16 (m, 3H), 6.83 (d, J = 8.0 Hz, 1H), 4.68 (ddd, J = 8.0, 7.6, 7.6 Hz, 1H), 4.18-4.10 (m, 1H), 3.14 (dd, J = 14.0, 3.2 Hz, 1H), 3.08 (dd, J = 16.0, 5.6 Hz, 1H), 2.83 (dd, J = 16.0, 2.9 Hz, 1H), 2.77 (dd, J = 14.0, 8.3 Hz, 1H), 2.10 (s, 3H), 1.83-1.73 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); IR v (CHCl3) 1764, 1698 cm "1; FAB MS m / z (MH +); HRMS calculated for C? 5H2 or 2? 2S (MH +) 293.1324, found: 293.1311.

Example 10 Preparation of 2-oxo-4 (R) - (piperidin-1-ylmethyl) azetidine-1-carboxylic acid (1) (R) -phenylpropyl) (Step nos. 206) Step A Iodine (4.25 g, 16.7 mmol) was added to a solution of 1- (tert-butyldimethylsilyl) -4 (R) - (hydroxymethyl) azetidin-2-one (2.25 g, 10.47 mmol), Ph3P (5.48 g, 20.93 mmol ) and imidazole (1.64 g, 24.07 mmol) in MeCN (100 ml) at 0o. After stirring at room temperature for four days, the mixture was concentrated and suspended in EtOAc-hexane (1: 1). The suspension was filtered through a pad of silica gel and washed with EtOAc-hexane (1: 1). Concentration of the filtrate and purification by flash chromatography (SIO2, 10% EtOAc-hexane) gave pure 1- (tert-butyldimethylsilyl) -4 (R) - (iodomethyl) azetidin-2-one as a solid white (2.73 g, 80% yield). X H NMR (400 MHz, CDCl 3) d 3.72-3.66 (m, 1 H), 3.50 (ddd, J = 9.8, 3.2, 0.6 Hz, 1 H), 3.21 (ddd, J = 15.6, 5.4, 0.6 Hz, 1 H), 3.11 (dd, J = 9.8, 9.8 Hz, 1H), 2.76 (dd, J = 15.6, 2.5 Hz, 1H), 0.96 (s, 9H), 0.27 (s, 3H), 0.22 (s, 3H).

Stage B 1- (tert-Butyldimethylsilyl) -4 (R) - (iodomethyl) azetidin-2-one (202 mg, 0.62 mmol) was heated to reflux in piperidine (5 mL) for 2 hours. The solution was concentrated, dissolved in CH 2 Cl 2 and washed with saturated NaHCO 3 and brine, dried (MgSO 4) and concentrated. The residue was purified by flash chromatography (Si02, EtOAc) to give 1- (tert-butyldimethylsilyl) -4 (R) - (piperidin-1-ylmethyl) azetidin-2-one (116 mg, 71% yield) . X H NMR (400 MHz, CDCl 3) d 3.70-3.63 (m, 1 H), 3.16 (dd, J = 15.3, 5.4 Hz, 1H), 2.70-2.61 (, 2H), 2.45-2.26 (m, 5H), 1.60-1.53 (m, 4H), 1.46-1.38 (m, 2H), 0.96 ( s, 9H), 0.24 (s, 6H).

Stage C Following the same processes as in Example 4, Steps C and D, (2 (R) -phenylpropyl) 2-oxo-4 (R) - (piperidin-1-ylmethyl) azetidine-1-carboxylic acid amide was obtained in shape of a yellow rubber. 1R NMR (400 MHz, CDCl 3) d 7.39-7.22 (m, 5H), 7.14-7.09 (m, 1H), 4.79 (q, J = 7.6 Hz, 1H), 4.13-4.06 (m, 1H), 3.09 ( dd, J = 15.9, 5.7 Hz, 1H), 3.01 (dd, J = 13.2, 3.5 Hz, 1H), 2.86 (dd, J = 15.9, 2.5 Hz, 1H), 2.56 (dd, J = 13.2, 7.6 Hz , 1H), 2.50-2.39 (m, 4H), 1.60-1.50 (m, 4H), 1.88-1.80 (m, 2H), 1.45-1.35 (m, 2H), 0.92 (t, 7.3 Hz, 3H); IR v (pure) 3354, 1798, 1763, 1703 cm "1; FAB MS m / z 330 (MH +); HRMS calculated for Ci9H28N302 (MH +) 330.2181, found: 330.2172.

Example 11 Preparation of 1 (2 (R) -phenyl-pyrrolidine-1-carbonyl) -4- (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one and 1- (2 (S) -phenyl-pyrrolidine-1-carbonyl) - 4- (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one (Table 4, mixture of entries n ° 402 and 403).

Stage A To a solution of 3-chloropropylamine hydrochloride (10 g, 77.0 mmol) and NaOH (10 N, 7.6 mL, 76 mmol) in THF (50 mL) was added di-tert-butyl dicarbonate (15.9 g, 73 mmol) in THF (10 ml), followed by a mixture of MeOH / H20 (20/10 ml). The resulting solution was stirred for 2 hours, then concentrated to approximately 15 ml and Et20 was added. The organic phase was washed twice with aqueous HCl (1.0 N), water and brine, dried (MgSO), filtered and concentrated to give N-Boc-3-chloropropyl sheet (14.2 g, 96% yield) as a yellow oil XH NMR (400 MHz, CDC13) d 4.70 (m, 1H), 3.59 (t, J = 6.3 Hz, 2H), 3.25 (m, 2H), 1.91 (m, 2H), 1.42 (s, 9H).

Stage B To a solution of N-Boc-3-chloropropylamine (10.0 g, 51.8 mmol) in TMF was added sodium hydride (1.87 g, 78 mmol). After 20 min benzyl bromide (9.24 ml, 78 mmol) was added, and the reaction mixture was heated to reflux for 16 hours. After cooling, the reaction mixture was diluted with Et20 (150 ml) and H20 (50 'ml), the layers were separated and the aqueous layer was extracted twice with Et20. The combined organic phases were washed with H20 and brine, dried (MgSO), filtered and concentrated. The resulting yellow oil was purified by flash chromatography (Si02, 10% EtOAc-hexane) to give N-Boc-N-benzyl-3-chloropropylamine (1.97 g, 13% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3) d 7.29-7.19 (m, 5H), 4.40 (broad s, 2H), 3.45 (broad m, 2H), 3.25 (wide m, 2H), 1.90 (broad m, 2H), 1.44, 1.39 (2s, 9H).

Stage C To a solution of tetramethylethylenediamine (0.83 ml, 5.47 mmol) and n-BuLi (1.6 M / hexane, 3.31 ml, 5.3 mmol), cooled to -78 °, was added dropwise N-Boc-N-benzyl-3-chloropropylamine (1.0 g, 3.53 mmol) in THF. The resulting yellow solution was stirred at -78 ° for 5 hours. Then, the reaction mixture was quenched with aqueous NH C1 (20 ml) and diluted with Et20 (150 ml), the layers were separated and the aqueous layer was extracted twice with Et20. The combined organic phases were washed with H20 and brine, dried (MgSO), filtered and concentrated. The resulting yellow oil was purified by flash chromatography (Si02, 10% EtOAc-hexane) to give 2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.57 g, 65% yield). 1R NMR (400 MHz, CDC13) d 7.31-7.14 (m, 5H), 4.90-4.71 (m, 1H), 3.59 (m, 2H), 2.29 (m, 1H), 1.92-1.84 (, 3H), 1.43, 1.16 (2s, 9H).

Stage D A solution of tert-butyl ester of 2-phenyl-pyrrolidine-1-carboxylic acid (0.55 g, 2.23 mmol) in HCl / dioxane (4 M, 5 mL) was stirred for 30 min and then evaporated to dryness. To the resulting oil was added CH2Cl2 (25 ml) and diisopropylethylamine (0.90 ml, 5.13 mmol), and the mixture was cooled to 0o. Phosgene (1.93 M in toluene, 1.62 ml, 3.12 mmol) was quickly added, and the reaction mixture was stirred for 1 hour and then concentrated. The resulting solid was extracted with Et20, the undissolved residue was filtered and discarded. The ether solution was concentrated and the resulting oil was purified by flash chromatography (SiO2, 10% EtOAc-hexane) to give 2-phenylpyrrolidine-1-carbamoyl chloride (0.43 g, 95% yield). X H NMR (400 MHz, CDCl 3) d 7.36-7.18 (m, 5H), 4.95-4.76 (m, 1H), 3.71 (m, 2H), 2.31 (m, 1H), 1.97-1.86 (m, 3H).

Stage E Following the same procedure as Example 4, step D, using 4 - (R) - (pyrimidin-2-ylsulfanylmethyl) azetidin-2-one and 2-phenylpyrrolidine-1-carbamoyl chloride as reactants the compounds of the form of a 1/1 mixture. The separation of the isomers was achieved by rapid resolution chromatography (Si02, 50% EtOAc-hexane) to give isomer A (less polar, 0.047 g, 18% yield) and isomer B (more polar 0.059 g, 31% yield).

Isomer A (mixture of rotamers): 1 H NMR (400 MHz, CDC13) d 8.44 (d, J = 4.8 Hz, 2H), 7.27-7.06 (m, 5H), 6. 94 (t, J = 4.8 Hz, 1H), 5.50-4.80 (broad m, 1H), 4. 40-3.50 (width, 5H), 3.36 (m, 1H), 3.00-2.15 (broad m, 3H), 1.95-1.72 (m, 3H); IR v (pure) 1776, 1665 cm "1; FAB MS m / z 369 (MH +); HRMS calculated for C? 9H2? N20 S 369.1385; found: 369.1398. Isomer B (mixture of rotamers) ': 1 H NMR (400 MHz, CDCI3) d 8.45 (broad s, 2H), 7.25-7.16 (m, 5H), 6.94 (m wide, 1H), 5.49 and 4.99 (2 m wide, 1H), 4.44-3.45 (m broad, 4H), 3.11-2.76 (broad m, 2H), 2.44-2.29 (broad m, 1H), 2.18-1.10 (broad m, 4H); IR v (pure) 1776, 1665 cm "1; FAB MS m / z 369 (MH +); HRMS calculated for C? 9H2? N204S 369.1385; found: 369.1402.

Example 12 Anti-herpes activity The following two assays (A and B) were used to evaluate anti-CMVH activity.

A. Non-HCMV Protease Assay Material and methods: Fluorescence measurements were recorded on a Perkin-Elmer LS-50B spectrofluorimeter equipped with a plate reading accessory. UV measurements were recorded on a Thermornax® microplate reader from Molecular Devices Corporation, Menlo Park, CA, USA. Non-HCMV protease was assayed with a fluorocoustic substrate that was abruptly cooled internally based on the maturation cleavage site (Abz-VVNASSRLY (3-NO2) R-0H, Kcat / KM = 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 IC50 values of the inhibitors.

In synthesis, no CMVH was incubated for 2.5 hours 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 fluorescence measurement, since the total scan time by the plate reader accessory was short 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 Na2SO4, 50 mM NaCl, 0.1 mM EDTA, tris (2-carbo-xylethyl) phosphine. 1 mM HCl, 3% v / v DMSO and 0.05% w / v casein. The final concentrations of the non-HCMV protease (expressed in terms of total monomer concentration) and 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 IC 50 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 (assay 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 adsorb to the cells for 2 hours at 37 °. After viral adsorption, 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 hours after infection. After 4 days of incubation at 31 °, 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 20% ethanol 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 EC50 values obtained according to this test for certain azetidine derivatives of this invention are listed in the following Table under heading EC50.

Example 13 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 Tables 1, 2, 3 and 4 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 were determined according to the metabolic assay of the tetrazolium salt (MTT), F. Denizot and F. Lang, J. Immun. Meth., 1986, 89, 271. The symbols used in the following Tables include P: phenyl, Bn: benzyl; Py: pyridinyl; CF3: tri luoromethyl; MS: FAB mass spectrometry, unless otherwise stated (such as ES). r p Cp O in o TABLE 1 fCw MS input p ° μM μM μM (M + H) * -J or ro Cp p O Oí TABLE 1 input n ° μM μM μM (M + H) ' -J 10 twenty r l- > -1 p or cp O Cp TABLE 2 -J to t H Cp cp O cp O TAB 2 -4 t t-1 cp or cp or cp TABLE 3 00 t t r- »Cp O in Cp O TABLE 3 ro Cp or Cp Cp TABLE 4 15 20 Conclusion From the results presented in Tables 1 to 4, it can be concluded that the compounds of formula 1 are active against the CMVH virus protease. In addition, several of these compounds also inhibit the replication of the virus in cells infested with virus, thereby indicating that these compounds are active in vivo in mammals, particularly humans. The TC50 reported in Tables 1 to 4 also indicate that these compounds are non-toxic and have a therapeutic window that allows the safe use of these compounds in mammals, including humans.

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, the content of the following is claimed as property

Claims (20)

1. A compound of formula 1: characterized in that Ri is hydrogen, methyl, ethyl, methoxy or methylthio; R2 and R3, each independently, is hydrogen or alkyl of 1 to 3 carbon atoms; s is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; Rs is lower alkyl, lower cycloalkyl, (CH2) mC (0) 0R6, wherein m is the integer 1 or 2, and Re, 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 alkylamino, di (lower alkyl) amino, lower acylamino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) thio, (trifluoromethyl) sulfinyl, (trifluoromethyl) sulfonyl, and C (0) 0R7, wherein R7 is lower alkyl or IL® phenyl (lower alkyl); Het or Het (lower alkyl) wherein Het represents a five or six element heterocyclic ring, monovalent, unsubstituted, monosubstituted or disubstituted, containing one or two heteroatoms selected from A 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, (1 (R) -1-naphthalenyl) ethyl, 2-benzothiazolyl or 2-thiazolo [4, 5-b] pyridinyl; or R4 and R5 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-isoquinolonilo) or 2- (3 , 4-dihydro-lH-isoquinolinyl), or a pyrrolidino ring, optionally 25 substituted with benzyloxycarbonyl or with phenyl, wherein said phenyl ring optionally mono- or disubstituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di (lower alkyl) amino, lower acylamino, 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); X is selected from the group consisting of 0, S, SO, S02, NRβ, where Re is H or lower alkyl; Y Y is an alkyl of 1 to 10 carbon atoms, non-cyclic or cyclic; phenyl [(CH2) 0-1], said phenyl ring being optionally mono- or di-substituted with a lower alkyl or lower alkoxy, said phenyl ring being optionally condensed with an aromatic ring to form a bicyclic ring, said ring containing said ring optionally a heteroatom selected from the group consisting of N, O and S; Het or Het (lower alkyl) containing one or more heteroatoms selected from the group consisting of N, O and S, said Het being optionally mono- or di-substituted with a lower alkyl or lower alkoxy group; said heterocyclic ring being optionally fused to an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing one or two heteroatoms selected from the group consisting of N, O, and S; and C (0) Rg wherein R9 is lower alkyl or phenyl (lower alkyl); or when X is NRβ, where Re is lower alkyl and Y is lower alkyl or lower alkoxy, X and Y are linked together to form a morpholino or piperidino ring; or a salt by addition of the pharmaceutically acceptable acid thereof.

2. The compound of the formula according to claim 1 characterized in that Ri is hydrogen or alkyl of 1 to 2 carbon atoms; R2 and R3 each independently, is hydrogen, methyl or ethyl; 4 is hydrogen or lower alkyl; R5 is phenyl optionally substituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy; phenyl (lower alkyl) optionally mono- or di-substituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C (O) OR7 wherein R7 is lower alkyl or phenyl (lower alkyl); Het (lower alkyl), wherein Het represents a monovalent, five or six element heterocyclic ring containing a heteroatom selected from the group consisting of N, O, or S, said ring optionally being substituted with lower alkyl or lower alkoxy; or and R5 together with the nitrogen atom to which they are attached form a pyrrolidino ring, optionally substituted with benzyloxycarbonyl or phenyl, said phenyl ring being optionally mono- or di-substituted with halo, nitro, cyano or trifluoromethyl; X is selected from the group consisting of O, S, NRβ, where Re is H or lower alkyl; Y Y is alkyl of 1 to 10 carbon atoms, non-cyclic or cyclic; phenylcarbonyl; phenyl or benzyl optionally mono- or di-substituted with lower alkyl or lower alkoxy, said phenyl ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing a heteroatom selected from the group consisting of N, O and S; and Het or CH2-Het containing one or more heteroatoms selected from the group consisting of N, 0, and S, said Het being optionally mono- or di-substituted with a lower alkyl or lower alkoxy group; said heterocyclic ring optionally being condensed with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing one or more heteroatoms selected from the group consisting of N, O, and S; or when X is NRβ, where Re is lower alkyl and Y is lower alkyl, X and Y are linked together to form a piperidino ring.

3. The compound of formula 1, according to claim 2, characterized in that Ri, R2 and R3, each independently, is hydrogen, methyl or ethyl; R 4 is hydrogen or alkyl of 1 to 3 carbon atoms; Rs is phenyl optionally substituted with a substituent independently selected from the group consisting of lower alkyl or lower alkoxy; (alkyl of 1 to 2 carbon atoms) phenyl optionally mono- or di-substituted on its phenyl portion with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C ( 0) 0R7 wherein R7 is lower alkyl or (lower alkyl) phenyl; X is selected from the group consisting of O, S, NRβ, where Re is H or lower alkyl; Y And it is noncyclic or cyclic lower alkyl; phenyl optionally mono- or di-substituted with lower alkyl or lower alkoxy; or Het containing one or more heteroatoms selected from the group consisting of N, O and S, said Het being optionally mono- or di-substituted with a lower alkyl; said heterocyclic ring being optionally fused to an aromatic ring to form a bicyclic ring, said aromatic ring optionally incorporating one or more heteroatoms selected from the group consisting of N, O and S; or when X is NRβ, where Re is lower alkyl and Y is lower alkyl, X and Y are linked together to form a piperidino ring.

4. The compound of formula 1 according to claim 3 characterized in that, Rx, R2 and R3 each independently, is hydrogen; R is hydrogen or methyl; Rs is benzyl optionally mono-substituted on its phenyl portion with nitro or trifluoromethyl, or 1 (R) -phenylethyl; X is S; and Y is pyrimidine optionally substituted with lower alkyl; pyridine; N-Me-tetrazole; or benzoxazole.

5. The compound of formula 1 according to claim 1 characterized in that it is selected from the group consisting of: , ß ton ocp »M« tifinßn abara: ßhbWÓ? tf Ri XY 101 í H ° 2-pyridinite 102 Me O fßníio ... - • 3 -? - HS 2-p? idinß '104 YH 5 2- piripv l? ulo 1 ios' "" H S 4,6-Met-2-pipmJdin? Lo i .. _... fifteen 20, "'" 120' Me S "!" '"Tito: í" 25 55 ßpdßndt R », i ßntachin * * Ri X Y i" 'Me s aotopemito 25

6. The compound according to claim 5 characterized in that, it is selected from the group consisting of the entries #: 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 138, 139, 140, 141, 143, 144 and 145.

7. The compound according to claim 6 characterized in that it is selected from the group consisting of the entries #: 11, 112, 123, 125 and 133.

8. The compound of formula 1 according to claim 1 characterized in that it is selected from the group consisting of:

9. The compound according to claim 8 characterized in that it is selected from the group consisting of the entries #: 204, 206, 208, 20 ^, and 212.

10. The compound of formula 1 according to claim 1 characterized in that it is selected from the group consisting of:

11. The compound according to claim 10 characterized in that it is selected from the group consisting of the entries #: 301, 302, 304, 307, 309, 310, 311, 312, 316, 319, 320, and 322.

12. The compound according to claim 11 characterized in that it is selected from the group consisting of the entries #: 309, 311, 320, and 322.

13. The compound of formula 1 according to claim 1 characterized in that it is selected from the group consisting of:

14. The compound according to claim 13 characterized in that it is selected from the group consisting of the entries #: 407 and 408.

15. The compound according to claim 14 characterized in that it is selected as entry # 407.

16. A pharmaceutical composition for the treatment of cytomegalovirus infections in a mammal, including humans, characterized in that it comprises a compound of formula 1 according to claim 1, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method for the treatment of cytomegalovirus infections in a mammal, including humans, characterized in that it comprises administering therein an effective amount of the compound of formula 1 according to claim 1, or a therapeutically acceptable salt thereof.

18. A method for the protection of human cells against cytomegalovirus pathogenesis, characterized in that it comprises treating said cells with an effective amount of anti-cytomegalovirus of a compound of formula 1 according to claim 1, or a therapeutically acceptable salt thereof. .

19. The compound of formula 1 according to claim 1 in combination with another anti-herpes compound, characterized in that it is selected from the group consisting of ganciclovir, foscarnet, acyclovir, valaciclovir, famciclovir, cidofovir, penciclovir and lobucavir.

20. The compound of formula 1 according to claim 1 in combination with another anti-ritroviral compound, characterized in that it is selected from the group consisting of reverse transcriptase inhibitors and protease inhibitors. AZETIDINONE DERIVATIVES FOR THE TREATMENT OF INFECTIONS BY THE HUMAN CITOMEGALOVIRUS "SUMMARY OF THE INVENTION A compound of the formula (1) wherein Ri is hydrogen, methyl, ethyl, methoxy or methylthio; Bj and R3 each independently, is hydrogen or alkenyl of 1 to 3 carbon atoms; is hydrogen, lower alkoyl, methoxy, ethoxy, or benzyloxy; R5 is lower alkyl, lower cycloalkyl, (CH2) «C (0) ORß, wherein m is the integer 1 or 2, and Re is lower alkyl or phenyl optionally substituted with C (0) 0R7 wherein R7 is lower alkyl or phenyl (lower alkyl); or e is Het or Het (lower alkyl); or R§ and R5 together with the nitrogen atom to which they are attached, form a nitrogen-containing ring optionally substituted with benzyloxycarbonyl or with phenyl optionally substituted by another group with C (O) OR7 wherein R7 is lower alkyl or phenyl (alkyl) lower); X is selected from the group consisting of O, S, SO, SO2, NRβ / where Re is H or lower alkyl; and Y is an alkyl of 1 to 10 carbon atoms, non-cyclic or cyclic; [(CH2) o-i] -phenyl, said phenyl ring being optionally substituted; Het or Het (lower alkyl); or when X is NRβ, where Re is lower alkyl and Y is lower alkyl or lower alkoxy, X and Y are linked together to form a morpholino or piperidino ring; or a salt by addition of the pharmaceutically acceptable acid thereof.