MXPA00003441A - Azetidinone derivatives for the treatment of hcmv infections - Google Patents

Abstract

A compound of formula (1) wherein Y is S or O;R1 is C1-6 alkyl;(C0-6 alkyl)aryl;(C0-6 alkyl)Het;or R1 is an amino acid analog or dipeptide analog of formula (I) wherein R2 is H, C1-10 alkyl;or an amide or ester group;A is C6-10 aryl, Het or CH-R3 wherein R3 is C1-6 alkyl or (C0-4 alkyl)aryl;and Z is H, C1-6 alkyl, or an acyl;R4 is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy;and R5 is alkyl, cycloalkyl, carboxyl group;an aryl;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 phenyl or C(O)OCH2-phenyl, said phenyl ring optionally mono- or di-substituted with among others C(O)OR7 wherein R7 is lower alkyl or phenyl (lower alkyl);or a therapeutically acceptable acid addition salt thereof.

Description

DERIVATIVES OF AZETIDINONE FOR THE TREATMENT OF INFECTIONS BY THE HUMAN CITQMEGALOVIRUS 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 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 HSV-2) are responsible for afta and genital lesions, respectively; Varicella zoster virus (VZV) causes varicella and zoster and human cytomegalovirus (CMVH) is a leading cause of opportunistic infections in individuals lacking the immune system.

REF.:119048 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 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 azet idin-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 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 aze idin-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. . 100,880, March 31, 1992, P.L. Durette and M. Maccoss, U.S. Pat. . 104,862, April 14, 1992, .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. 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, 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.

BRIEF DESCRIPTION OF THE INVENTION The azetidin-2 -one derivatives are represented by formula 1: U) where Y is S or O; Ri is C? -6 alkyl optionally substituted with NHC (0) -R8 or C (0) -R8, wherein R8 is a C? -6 / 0-C? _6 alkyl, NH-C? -6 alkyl, (C0-4 alkyl) aryl or (C0-4 alkyl) Het, wherein Het represents a five or six membered heterocyclic ring, monovalent, containing a heteroatom selected from the group consisting of N, O or S; (alkyl Co-e) aryl, wherein said aromatic ring is optionally substituted with halo, C? _6 alkyl, C-6 alkyl or NH-R9, wherein Rg is: C? -6 alkyl, C6-? 0 aryl, Het or an acyl of formula C (O) -Rio, wherein Rio is a C? _6 alkyl, O-C? -S alkyl, NH-C? -6 alkyl , (C0-4 alkyl) aryl or (C0-4 alkyl) Het; (Alkyl Co-ß) Het, the carbon atoms of said Het optionally substituted with halo, C? -6 O-Rg or NH-Rg alkyl, wherein Rg is as defined above, or the nitrogen atom of being said Het optionally substituted with R9, wherein Rg is as defined above; Ri is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, C? _? 0 alkyl optionally monosubstituted with (C? _6 alkyl) thio, (alkyl) C? _6) sulfonyl or C6-? Aryl or / or an amide group or mono- or di-sus acid ester with Ca_6 alkyl; A is aryl C6-? O / Het or CH-R3, wherein R3 is alkyl C? -6 or (C0-alkyl) aryl; and Z is H, C? -6 alkyl, or an acyl of the formula C (0) -R8 / wherein R8 is as defined above; i is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy; and R5 is lower alkyl, lower cycloalkyl, (CH2) mC (O) OR6, where m is the integer 1 or 2, and R6 is lower alkyl or phenyl (lower alkyl); phenyl, monosubstituted phenyl, disubstituted or trisituted 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 (O) OR7, 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, in wherein each substituent is independently selected from the group consisting of lower alkyl, lower alkoxy, halo and hydroxy; - (benzo [l, 3] dioxolyl) methyl, (l (R) -l-naphthalenyl) ethyl, 2 -benzotiazolilo or 2 - thiazolo [4, 5 -b] pyridinyl; or R and 5 / together with the nitrogen atom to which they are attached, form a ring of piperidino, morpholino, thiomorpholino, piperazino, N-met ilpiperazino, l- (3,4-dihydro-1H-isoquinolinyl), or 2 - (3, 4-dihydro-1H-isoquinolinyl), or a pyrrolidino ring, optionally substituted with benzyloxycarbonyl or with phenyl, said phenyl ring being 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 alkylamino, di (lower alkyl) amino, acyl lower alkylamino, di (lower alkyl) aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl) uncle (rifluorome il) sulfinyl, (rifluorome il) sulfonyl and C (0) OR7, wherein R7 is lower alkyl or phenyl (lower alkyl); or a therapeutically acceptable acid addition salt thereof Preferred compounds of the invention include compounds of formula (1), wherein Y is S or O; Ri is C? -6 alkyl optionally substituted with C (0) -R8 or NHC (0) -R8, wherein R8 is a C? -6 alkyl / NH-C? -6 alkyl or phenyl; (C0-4 alkyl) phenyl, wherein said phenyl ring is optionally substituted with halo, Ci-g alkyl or NH-Rg, wherein Rg is: C 1-4 alkyl, phenyl or an acyl of formula C (O) -Ra, wherein Rio is a C? -β alkyl # NH-Cl-6 alkyl or phenyl, (alkyl Co-3) Het, wherein said atoms carbon atoms of said Het are optionally substituted with halo, C? _6 alkyl or NH-R9; or said nitrogen atom of said Het is substituted with Rg, wherein R9 is: C? -4 alkyl, phenyl or an acyl of formula C (O) -Rio, wherein Rio is a C? -6 alkyl, NH? -C6 alkyl or phenyl; or Ri is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, the optionally N-alkylated asparagine side chain, or C6-6 alkyl optionally monosubstituted with (C6-alkyl) sulfonyl or phenyl, A is phenyl or CH-R3, wherein R3 is C6-6 alkyl or (C0-4 alkyl) phenyl; Y Z is C (0) -R8, wherein R8 is C1-6 alkyl, C6-6 alkoxy or phenyl; R 4 is hydrogen or C 1-3 alkyl; and 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 selected from the group consisting of lower alkyl, lower alkoxy, halo, cyano, trifluoromethyl and C (O) OR7, wherein R7 is lower alkyl or phenyl (lower alkyl); Het (lower alkyl), wherein Het represents a five or six membered heterocyclic ring, monovalent, 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 C (O) O-benzyl or phenyl, said phenyl ring being optionally mono- or di-substituted with halo, nitro, cyano or trifluoromethyl; or a salt by addition of therapeutically acceptable acid thereof.

More preferred compounds of the invention include compounds of formula 1, wherein Y is S or O; Ri is C? -3 alkyl optionally substituted with C (O) OMe or NH-C (0) -Ph; phenyl, benzyl or phenylethyl, wherein said phenyl ring is optionally substituted with chorus or methoxy; Het, Het-methyl or Het-ethyl, wherein Het is 2-, 3- or 4-pyridinyl optionally substituted on the nitrogen with methyl or C (O) -R 0, where io is CH 2 -t-Bu or phenyl, or Ri is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, CH2-C (O) N (Me) 2, CH2-CH (Me) 2 or methyl optionally monosuted with methylsulfonyl, A is phenyl or CH-t-Bu; and Z is C (0) -R8, wherein R8 is CH2-t-Bu or O-t-Bu; R 4 is hydrogen or lower alkyl '; Y R5 is phenyl optionally substituted with a substituent independently selected from the group consisting of lower alkyl, lower alkoxy; (C 1 -2 alkyl) 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; or a salt by addition of therapeutically acceptable acid thereof.

A more preferred group of compounds is represented by the formula 1 ': where Y is O or S; Ri is phenyl, 4-chloro-phenyl, benzyl, phenylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, CH2 - (S) CH (CH2CH2S02Me) -NH-Tbg-Boc, CH2- (S) CH (CH2CHMe2 ) -NH-Tbg-C (O) CH2-t-Bu; R4 is H or Me; R12 is phenyl, benzyloxy ilo or Het; and R 3 is hydrogen, methyl, ethyl, propyl or hydroxymethyl. 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 antiretroviral 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.

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 R5 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'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? -e), 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-methyl-ethyl, 1-methylpropyl, 2-methypropyl and 1,1-dimethyl-ethyl. The term "C0-6 alkyl" which precedes a radical means that this radical may be optionally linked through an alkyl radical Ci-s or the alkyl may be absent (C0). 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-methoxy, butoxy and 1,1-dimethyletoxy. This last radical is commonly known as tert-butoxy. 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 alkyl amino", as used herein, means alkylamino radicals containing from one to six carbon atoms and includes methylamino, propylamino, (1-methyl-yl-yl) amino and (2-met ilbutyl) ) Not me . 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, et illmethylamino 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-(C? _3) alkyl, lower alkoxy, halo, amino or lower alkyl-amino. Again optionally, the five or six membered heterocycle may be fused 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-methyl-t-thiazole, 2-aminothiazole, 2- (methylamino) -thiazole, piperidine , 1-methyl-piperidine, 1-methyl-piperazine, 1,4-dioxane, morpholine, pyridine, pyridine-N-oxide, pyrimidine, 2,4-dihydroxypyrimidine, 2,4-dimethyl-pyrimidine, 2,6-dimethyl-pyrimidine, 1 -met-1 H-tetrazole, 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 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 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).

A) The compound of formula 1, wherein Y, Ri, R2, R3 and R5 / are as defined above and R4 is hydrogen, can be prepared by the following procedures: Scheme A Ul) (1) (a) reacting a key intermediate compound of the formula II with an isocyanate of the formula R5NC0, wherein R5 is as defined herein, in the presence of a proton acceptor, or (b) reacting an intermediate key of the formula II with a phenoxycarbamate of the formula R5NHC (O) OPh in the presence of a proton acceptor, to obtain the corresponding compound of the formula 1, wherein R4 is hydrogen.

B) The compound of formula 1, wherein Y, Ri, R2, R3, and R5 are as defined herein above and R is not hydrogen can be prepared with the following procedure Scheme B (II) (1) reacting the key intermediate of the formula II with a carbamoyl chloride derivative of the formula R4R5NC (0) C1, wherein R4 is lower alkyl and R5 is as defined herein above, or R and 5 together with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, in the presence of an acceptor proton, to obtain the corresponding compound of formula 1, wherein Ri and R5 are as defined herein above and R4 is lower alkyl or R4 and R5, together with the nitrogen atom to which they are attached, are as defined herein. The key intermediate of the aforementioned formula II, wherein Y is oxygen, can be prepared by a process illustrated by Scheme C as follows: Scheme C (II, Y = 0) as exemplified in step A, Example 4. The above-mentioned key intermediate compound of formula II, wherein Y is sulfur can be prepared by a process illustrated by Scheme D as follows: Scheme D NaOH (II, Y = S) as exemplified by step C of Example 1 Anti-herpes activity The antiherbal activity of the aforementioned azetidinone derivatives of the formula 1. (CMVH protease inhibitors) can be demonstrated by biochemical, microbiological and biological processes. A biochemical process for demonstrating the anti-cytomegalovirus activity of the azetidinone derivatives of the 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 protease. 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 HCVH N0 protease from a fluorogenic peptide substrate which, in turn, is based on at the cleavage site of enzyme maturation. 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 HCVH 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 , of the chosen route of administration and conventional biological practice. For oral administration, the compound or a therapeutically acceptable salt thereof can be formulated into unit dosage forms such as capsules or tablets, each of which contains a predetermined amount of the active ingredient., which ranges 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," 19 * ed., Mack Publishing Company, Easton, Penn., 1995, or in "Pharmaceutical Dosage Forms and Drug Delivery Systems ", 6 * 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 this, 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. In rare ocular administration, the HCMV protease inhibitor is administered topically or intraocularly (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) are reported in parts per million. Abbreviations or symbols used in this report include; DEAD: diethyl azodicarboxylate; DIEA: diisopropylethylamine; DMAP: 4- (dimethylamino) pyridine; DMF: dimethylformamide; Et: ethyl; EtOAc: ethyl acetate; Et20: diethyl ether; Me: methyl; MeOH: methanol; MeCN: acetonitrile; Ph: phenyl; TBTU: 2- (lH-benzotriazol-1-yl) - N, N, N ', N'-tetramethyluronium tetrafluoroborate; THF: tetrahydrofuran; MS (FAB) or FAB / MS: mass spectrometry by bombardment with fast atoms; HRMS: high resolution mass spectrometry; PFU: plate forming units.

EXAMPLE 1 Preparation of (2-oxo-4 (S) - (pyridin-2-ylmethylthio) azetidine-1-carboxylic acid (1) (p) -phenylpropyl) hydrochloride (7) (Table 1, entry nc 114).

Stage A 2-picolyl thioacetate (2) Potassium thioacetate (8.4 g, 73 mmol), 2-picolyl chloride-hydrochloride 1 (6.0 g, 37 mmol) and potassium carbonate (5.0 g, 37 mmol) were stirred in DMF (35 ml. ) at room temperature (20-22 °) for 18 h. The reaction mixture was poured into water (200 ml). The resulting mixture was extracted with Et20 (2 x 50 ml). The combined organic phases were washed with water and brine, dried (MgSO 4), filtered and concentrated to give 2-picolyl thioacetate as a pale brown liquid (5.65 g). The product was used without purification. X H-NMR (400 MHz, CDCl 3) d 8.51 (d, 1 H), 7.62 (t, 1 H), 7.32 (d, 1 H), 7.15 (d, 1 H), 4.25 ( s, 2H), 2.37 (s, 3H). Stage B. Isocyanate of 1 (R) -phenylpropyl (4) To a solution of (1 (R) -phenylpropyl) amine 3 (14.3 g, 106 mmol) in Et20 (102 mL) was added a 1.0 M solution of HCl / Et20 (212 mL, 212 mmol), stirred for 30 min and then the crude solution was evaporated to dryness in a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 ml) and triphosgene (11.7 g, 39.3 mmol) was added, and the resulting suspension was stirred at reflux for 3 h and then at room temperature for 18 h. The reaction mixture was concentrated, and the final volume was adjusted to 200 ml in toluene to give a final concentration of 0.53 M. The resulting isocyanate-solution 4 was used as such. An aliquot (170 μl) was concentrated to give 1 (R) -phenylpropyl isocyanate as a colorless oil. 1 H NMR (400 MHz, CDC13) d7, 36-7, 22 (m, 5H), 4.50 (t, J = 6.7 Hz, 1H), 1.82 (q, J = 7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz, 2H).

Stage C. 4 -. { 2 (2-pyridinylmethyl) thio} azetidin-2 -one (6) JO To a solution of 2-picolyl-2-thioacetate (from step A) (673 mg, 4.00 mmol) in MeOH (8 ml) was added a 5M solution of sodium hydroxide in water (890 μl, 4.40 mmol ). After stirring for 15 min at room temperature, a solution of 4-acetoxyazet idin-2 -one (520 mg, 4.00 mmol) in MeOH (1.5 mL) was added. The reaction mixture was stirred for 2 h at room temperature and then concentrated under pressure. The residue was poured into water (30 ml) and extracted with EtOAc (3 x 15 ml), dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography (Si02, EtOAc) to give 4-. { (2-pyridinylmethyl) uncle} azetidin-2 -one 6 (750 mg, 96% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3) d 8,5 (d, 1 H), 7.68 (t, 1 H), 7.30 (d, 1 H), 7.20 (t, 1 H), 6.42 (s) width, 1H), 4.88 (dd, 1H), 3.91 (s, 3H), 3.35 (dd, 1H), 2.85 (dd, 1H).

Step D: (1 (R) -phenylpropyl) -amide of 4 (S) - acid. { (2 -piridini Imetil) uncle} azetidin-2-one-l-carboxylic acid (7) To a solution of the azetidinone 6 from step C (188 mg, 0.970 mmol), Et3N (150 μL, 1.07 mmol), DMAP (10 mg) in CH2C12 (5 mL) was added an isocyanate solution of 1 (R) -phenylpropyl 4 (172 mg, 1.07 mmol) in CH2C12 (2 mL). The reaction mixture was stirred for 22 h. A second portion of Et3N (150 μL, 1.07 mmol), DMAP (10 mg) and 4 (172 mg, 1.07 mmol) in CH2C12 were added. (2 ml), and the mixture was stirred for another 22 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (Si02, 40% EtOAc-hexane) to provide isomer 4 (S ") 7 (less polar isomer). Treatment with HCl in Et20 (2 mL, 1 M) gave 7 (74 mg, 19% yield) in the form of a white solid The starting material was recovered (90 mg, 48%).

XH NMR (400 MHz, DMSO-D6) d 8.67 (d, J = 4.8 Hz, 1H), 8.13 (t, J = 7.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.36-7.23 (m, 5H), 7.14 (d, J = 8.3 Hz , 1H), 5.28-5.26 (m, 1H), 4.65 (q, J = 7.3 Hz, 1H), 4.48 (d, J = 14.3 Hz, 1H), 3 , 52 (dd, J = 6.0, 16.2 Hz, 1H), 3.02 (dd, J = 3.0, 16.2 Hz, 1H), 1.87-1.71 (m, 2H), 0.83 (t , J = 7.0 Hz, 3H); IR (KBr) v 1768, 1689 cm "1; FAB MS m / z 356 (MH +); HRMS calculated for C? 9H22N302S1: 356.1433 (MH +); found: 356.1421.

Example 2 Preparation of benzylamide of 4 (S) - acid. { . { (2 (S) -. {(N-tert -butyloxycarbonyl-L-tert-butylglycyl) amino} -4-methylpentyl} thio.) Azetidin-2-lone-1-carboxylic acid 13 (Table 1, entry 101).

Stage A N-tert-but-yloxycarbonyl-L-tere-but-il-glycyl-L-leucinol (10) To a suspension of N-tert-butyloxycarbonyl-L-tert-butylglycine 8 (2.43 g, 10.5 mmol), L-leucinol 9 (1.23 g, 10.5 mmol) and TBTU (3.44 g) , 11.5 mmol) in acetonitrile (30 ml) at 0 ° (ice bath) was added N-methylmorphol ina (1.3 ml, 11.5 mmol). The resulting mixture was stirred for 19 h (allowing the ice bath to warm to room temperature) and the white solid was collected on a filter (486 mg, 14% yield). The mother liquors were purified by flash chromatography (Si02, 25-35% EtOAc-hexane) to give N-tert-butyloxycarbonyl-L-tert-butylglycyl-L-leucinol 10 (2.79 g, 80% yield). ) in the form of a solid. white (which includes the filtered solid). 1 H-NMR (400 MHz, CDCl 3) d 5.82 (d, 1H), 5.19 (d, 1H), 4.09-4.00 (m, 1H), 3.76 (d, 1H), 3.69 (dd, 1H), 3.54 (dd, 1H), 1.69-1.59 (m, 1H), 1.44 (s, 9H), 1.43-1.28 (m, 2H), 1.02 (s, 9H), 0.93 (d, 3H), 0.91 (d, 3H).

Stage B N-tere -but iloxycarbonyl-L-tere. -but ilgl icil -S -acet il -L- leucinatol iol (11) PPh, + DEAD 3 To a solution of triphenylphosphine (373 mg, 1.42 mmol) and diethyl azodicarboxylate (225 μL, 1.42 mmol) in THF (6 mL) at 0 ° was added a solution of N-tert-butyloxycarbonyl-L- tert-butylglycyl-L-leucinol 10 (313 mg, 0.950 mmol) and thioacetic acid (100 μl, 1.42 mmol) in THF (4 ml). The mixture was stirred at 0 ° for 2 h and the solvent was removed in vacuo. The residue was purified by flash chromatography (Si02, 10 -30% EtOAc-hexanes) to give the corresponding title compound 11 in 63% yield (232 mg). 1 H NMR (400 MHz, CDC13) d 5.60 (d, 1H), 5.16 (d, 1H), 4.21-4, ll (m, 1H), 3.69. (d, 1H), 3.10-2.99 (m, 2H), 2.35 (s, 3H), 1.66-1.58 (m, 1H), 'l, 44 (S, 9H) , 1.43-1.28 (m, 2H), 0.99 (s, 9H), 0.92 (d, 3H), 0.90 (d, 3H). Stage C 4-. { . { 2 (S) -. { (N-tere-butyloxycarbonyl-L-tert-butylglycyl) amino} -4-methylpentyl} uncle} azetidin-2 -one (12).

Following the same process as in the Example 1, Step C, but using 11 from Step B as starting material and 5 as reagent, compound 12 is obtained in the form of a pale yellow oil. XH NMR (400 MHz, CDC13) d 7.18 (d, 1H), 5.77 (d, 0.5H), 5.59 (d, 0.5H), 5.18-5.03 (m, 1H), 4.83 (dd, 0.5H), 4.70 (dd, 0.5H), 4.09-4.00 (m, 1H), 3.73 (d, 1H), 3.40 (dd, 0.5H), 3.34 (dd, 0.5H), 2.91-2.83 (m, 1H), 2.75 (dd, 0.5H), 2.68-2, 61 (m, 1H), 2.56 (dd, 0.5H), 1.70-1.59 (m, 1H), 1.45 (s', 9H), 1.42-1.28 (m , 2H), 1.03 (s, 4.5 H), 1.01 (s, 4.5 H), 0.94-0.87 (d over d, 6H).

Step D The title compound of this Example (13) Following the same procedure as in Example 1, Step D, but using 12 from Step C as starting material and benzyl isocyanate as reagent, the title compound of this Example 13 is obtained as a white solid ( the most polar diastereoisomer) X H NMR (400 MHz, CDCl 3) d 7.36-7.28 (m, 5H), 6.90 (broad s, 1H), 6.29 (d, J = 8.6 Hz, 1H), 5.23) d, J = 9.2 Hz, 1H), 5.18 (dd, J = 2.9, 5.7 Hz, 1H), 4.53 (dd, J = 6.2 , 14.9 Hz, 1H), 4.44 (dd, J = 6.2, 14.9 Hz, 1H), 4.35-4.25 (m, 1H), 3.81 (d, J = 9.5 Hz, 1H), 3.50 (dd, J = 5.7, 16.2 Hz, 1H), 3.17 (dd, J = 5.1, 13.7 Hz, 1H), 3, 15-3.05 (m, 1H), 2.91 (dd, J = 2.9, 16.2 Hz, 1H), 1.63-1.35 (m, 3H), 1.54 (s, 9H), 1.41 (s, 9H), '0.99 (s, 9H), 0.91 (d, J = 4.8 Hz, 3H), 0.89 (d, J = 4.8 Hz, 3H); IR (KCl) V 1774, 1703 cm -1; FAB MS m / z 549 (MH +); HRMS calculated for C28H45N405S? : 549.3111 (MH +); found: 543,3100.

EXAMPLE 3 Preparation of 3 (R) -methyl- (S) - (pyridin-2-ylmethylthio) azet idin-2 -one-1-carboxylic acid (1) (R) -phenylpropyl) hydrochloride (16) .

(This compound was prepared solely for the purpose of confirming the stereochemistry of the compounds of Examples 1"and 2. The establishment of the stereochemistry of the methylated lactam ring at positions 3 and 4 ensured the assignment of the appropriate stereochemistry (S) by NMR studies at position 4 for compounds of Examples 1 and 2).

Stage A 3 (R) -methyl-4 (S) - (pyridin-2-ylmethylthio) azetidin-2-hydrochloride (15) Following the same procedure as in Example 1, Step C, but using 3 (R) -methyl-4 (S) -acetoxyazetidin-2 -one (PE Finke et al., J. Med. Chem. 1995, 38, 2449 ) as starting material and the 2-picolyl thioacetate 2 from Example 1, Step A as reagent, compound 15 is obtained in the form of a white solid. 1 H NMR (400 MHz, CDC13) d 8.53 (d, 1H), 7.68 (d, 1H), 7.33 (d, 1H), 7.21 (t, 1H), 6.60 (s) width, 1H), 4.51 (d, 1H), 3.95 (s, 2H), 3.06 (q, 1H), 1.33 (d, 3H) Step B 3 (R) -methyl-4 (S) - (pyridin-2-ylmethylthio) azetidin-2-amino-1-carboxylic acid (1) (R) -phenylpropyl) amide (16) Following the same procedure as in Example 1, Step D, but using azetidinone from Step A of this example as starting material and isocyanate of 1 (R) -phenylpropyl 4 as reagent, compound 16 is obtained in the form of a white solid after treatment with HCl in Et2 O. 1 H NMR (400 MHz, DMS0-D6) d 8.63 (d, J = 4.8 Hz, 1H), 8.06 (t, J = 7, 6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 6.0 Hz, 1H), 7.36-7.31 (m, 4H) , 7.27-7.23 (m, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.02 (d, J = 3.2 Hz, 1H), 4.66 ( q, J = 7.6 Hz, 1H), 4.42 (d, J = 14.0 Hz, 1H), 4.26 (d, J = 14.0 Hz, 1H), 3.29 (ddd, J = 3.2, 7.2, 7.2 Hz, 1H), 1.87-1.73 (m, 2H), 1.21 (d, J = 7.3 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H); IR (KBr) and 3359, 1769, 1698 cm "1; FAB MS m / z 370 (MH +) HRMS calculated for C20H24N302S ?: 370.1589 (MH +); found: 370.1602.

Example 4 Preparation of 4 [N-t-butyloxycarbonyl-L-leucinoxy] azetidin-2-one-1-carboxylic acid benzylamide (19) (Table 2, entry 201).

STAGE A: ETAP Step A 4- [N-t-Butyloxycarbonyl-L-leucinoxy] aze i din-2-one (18) To a solution of L-BOC-leucinol 17 (1.0 g, 4.6 mmol) and Pd (0Ac) 2 (155 mg, 0.69 mmol) in toluene (15 ml) was added dropwise a solution of 4-acetoxyazetidinone 5 (654 mg, 5.06 mmol) and triethylamine (700 μl, 5.06 mmol) in toluene (8 ml). The resulting mixture was stirred for 20 h at room temperature and a fresh solution of 4-acetoxyazet idinone 5 (218 mg, 1.70 mmol) and triethylamine (230 μl, 1.70 mmol) in toluene (5 ml) was added slowly. . After stirring for two days, the mixture was filtered on a pad of Celite, then poured into water (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic phases were washed with water (20 ml), dried with MgSO 4 and evaporated in vacuo. The residue was purified by flash chromatography (Si02, 30-40% EtOAc-hexane) to provide 18 (622 mg, 47%) as a pale yellow oil 1 H NMR (400 MHz, CDC13) d 6.75 ( s wide, 1H), 5.06 (ddd, J = 1.3, 2.5, 10.0 Hz, 1H), 4.55 (d, J = 8.0) Hz, 1H), 3.80 (broad s, 1H), 3.53-3.43 (m, 2H), 3.13-3.07 (m, 1H), 2.86 (d, J = 15.9 Hz, 1H), 1.70-1.60 (m, 1H) ', 1.45 (s, 9H) ), 1.41-1.24 (m, 2H), 0.93 (d, J = 7.3 Hz, 6H).

Stage B 4- [N-t-Butyloxycarbonyl-L-leucinoxy] -azetidin-2-one-1-carboxylic acid benzylamide (19) Following the same procedure as in Example 1, Step D, but using 18 from stage A as starting material and benzyl isocyanate as reagent, 4 [N- t -butyloxycarbonyl-L- -leucinoxy benzylamide is obtained. ] -azetidin-2-amino-1-carboxylic acid (19) in the form of a white solid (in the form of a 1: 1 mixture of diastereoisomers). X H NMR (400 MHz, CDCl 3) d 7.36-7.25 (m, 5H), 6.94-6.89 (m, 1H), 5.42-5.40 (m, 1H), 4, 65-4.51 (m, 1H), 4.48-4.45 (m 2H), 4.00-3.66 (m, 3H), 3.27-3.20 (m, 1H), 2 , 93 (dd, J = 1.9, 16.2 Hz, 1H), 1.71-1.61 (m, 1H), 1.44 (s, 9H), 1.37-1.23 (m , 2H), 0.92 (d, J 6.4 Hz, 6H); IR (NaCl) v 3356, 2957, 1773, 1699, 1653 cm "1; FAB MS m / z '420 (MH +); HRMS calculated for C28H45N406: 533.3339 (MH +); found: 533.3347.

Example 5 Preparation of 4- [N-t-butyloxycarbonyl-L-t-butylglycine-L-leucinoxy] azetidin-2-amino-1-carboxylic acid benzylamide (19) (Table 2, entry 202).

STAGE A: NHBoc 22 Step A 4- [N- t -butyloxycarbonyl-L t -butylglycine-L-leucine-oxy], - azet idin-2 -one (21) To a solution of the alcohol from Example 2, Step A, 20 (1, 02 g, 3.09 mmol) and Pd (0Ac) 2 (139 mg, 0.62 mmol) in toluene (10 ml) was added dropwise a solution of 4-acetoxyazet idinone 5 (439 mg, 3.40 mmol ) and triethylamine (475 μl, 3.40 mmol) in toluene (5 ml). The resulting mixture was stirred for 20 h at room temperature and a fresh solution of 4-acetoxyazet idinone 5 (218 mg, 1.70 mmol) and triethylamine (230 μl, 1.70 mmol) in toluene (2 ml) was added slowly. . After stirring for two days, the mixture was filtered on a pad of Celite, then poured into water (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic phases were washed with water (20 ml), dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (Si02i 55% hexane EtOAc) to provide 21 (565 m, 46%) as a pale yellow oil (mixture of diastereomers in C4) 1 H NMR (400 MHz, CDCl 3) d 6 , 95 (S, 0.5H), 6.88 (s, 0.5H), 5.91 (d, J = 7.9 Hz, 1H), 5.30-5.15 (m, 1H) , 5.05 (ddd, J = 1.2, 5.1, 10.5Hz, 1H), 4.25-4.13 (m, 1H), 3.75-3.04 (m, 1H), 2.85 (d, J = 15.0 Hz, 1H), 1.66-1.55 (m, 1H), 1.43 (s, 9H), 1.41-1.26 (m, 2H) , 0.99 (s, 9H), 0.91 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H).

Step B Benzylamide of 4 - [Nt-butyloxycarbonyl-L-butylglycine-L-leucinoxy] -zet idin-2 -one-1-carboxylic acid (22) Following the same procedure as in Example 1, Step D, but using From benzyl isocyanate as starting material and from stage A as starting material, benzylamide of 4 - [Nt-butyloxycarbonyl-L-butylglycine-L-leucinoxy] -azet idin-2 -one-1-carboxylic acid is obtained. 22 in the form of a white solid (in the form of a 1: 1 mixture of diastereoisomers). X H NMR (400 MHz, CDCl 3) d 7.36-7.26 (, 5H), 6.94-6.89 (m, 1H), 6.03 (d, J = 8.6 Hz, 0.4H), 5.64 (d, J = 8.6) Hz, 0.6H), 5.43-5.37 (m, 1H), 5.30-5.24 (m, 1H), 4.50-4.46 (m, 1H), 4.30- 4.17 (m, 1H), 4.06-3.97 (m, 1H), 3.88-3.69 (m, 2H), 3.25 (ddd, J = 1.3, 4.5 , 16.2 Hz, 1H), 2.93 (dd, J = 1.9, 6.4, 16.2 Hz, 1H), 1.65-1.57 (, 1H), 1.43 (s) , 5, H), 1.42 (s, 3.6H), 1.41-1.26 (m, 2H), 0.98 (s, 9H), 0.91 (d, J = 6.4) Hz, 6H); IR (NaCl) V 3356, 2957, 1773, 1699, 1653 cm "1; FAB MS m / z 420 (MH +), - HRMS calculated for C28H45N406; 533/3339 (MH +) found: 533.3347.

Example 6 Anti-herpes activity The following two tests (A and B) were used to evaluate the anti-CMVH activity. A. Assay of protease N0 of HCMV 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 Thermomax microplate reader from Molecular Devices Corporation, Menlo Park, CA, USA. The protease N0 of CMVH was tested with a fluorogenic substrate abruptly cooled internally based on the site of. Maturation cleavage (Abz -VVNASSRLY (3-N02) R-OH, 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). We designed "an adaptable protocol to a 96-well plate format for the determination of the IC 50 values of the inhibitors." In synthesis, Nv of HCvH was incubated for 2.5 h at 30 ° in the presence of the substrate with a range of concentrations of sequentially diluted inhibitor (300 to 0.06 μM, depending on the potency of each compound) After this period, enzymatic hydrolysis of the fluorogenic substrate in the absence of the inhibitor led to a conversion of approximately 30%. before the fluorescence measurement, since the total scan time by the plate reader accessory was short in relation to the duration of the reaction.

Tris (hydroxymethyl) aminomethane. 50 mM HCl pH 8.0, 0.5 M Na2SO4, 50 mM NaCl, 0.1 mM EDTA, 1 mM tris (2-carboxyethyl) phosphine, 1% HCl, 3% v / v DMSO and 0.05% w / w v of 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 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 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 20% ethanol in water 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 7 In conjunction with the appropriate starting materials and intermediates, the processes of Examples 1 and 2 can be used to prepare other compounds of formula 1. Examples of compounds, thus prepared, are listed in the following Table 1, together with data from mass spectra for the compounds and results of tests A and B of Example 6. 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 Table include Ph: phenyl, Bn: benzyl; Boc: tert-butyloxycarbonyl; Me: methyl and Tbg: tere-buti glycine. (or TABLE 1 ND: Not determined *: Configuration in position 4 of the lactam ring TABLE2 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 (15)

R E I V I N D I C A C I O N E S

1. A compound of formula 1: wherein Y is S u 0; Ri is C? -6 alkyl optionally substituted with NHC (0) -R8 or C (0) -R8, wherein R8 is a C? -6 alkyl, O-C? -6 alkyl, NH-C? -6 alkyl , (C0-4 alkyl) aryl or (alkyl Co-4) Het, wherein Het represents a five or six membered heterocyclic ring, monovalent, containing a heteroatom selected from the group consisting of N, O or S; (alkyl Co-e) aryl, wherein said aromatic ring is optionally substituted with halo, C? _6 alkyl O-C 1-6 alkyl or NH-R 9, wherein R 9 is: C 6 alkyl, C 6 aryl, Het or an acyl of formula C (0) -R? O, wherein Ri0 is a C? _6 alkyl, O-alkyl C1-6, NH-alkyl C? -6 / (C0- alkyl) aryl or (alkyl) C0-4) Het; (C0-6 alkyl) Het, the carbon atoms of said Het being optionally substituted with halo, alkyl C? -6, 0-R9 or NH-R9, wherein R9 is as defined above; , or the nitrogen atom of said Het being optionally substituted with R, wherein R9 is as defined above; Ri is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, C1-10 alkyl optionally monosubstituted with (C6-6 alkyl) thio, (C6-6 alkylsulfonyl or C6-6aryl aryl, or a mono- or di-substituted amide or ester group with alkyl C? _6; A is aryl C6-? O / Het or CH-R3, wherein R3 is alkyl C1-6 or (C0-alkyl) aryl; and Z is H, C? -S alkyl, or an acyl of the formula C (0) -R8, wherein R8 is as defined above; R 4 is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy; and Rs is lower alkyl, lower cycloalkyl, (CH) mC (O) ORß, 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 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) sulphonyl, 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, in 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 [, 5-b] pyridinyl; or R and R5, together with the nitrogen atom to which they are attached, form a ring of piperidino, morpholino, t -omorpholino, piperazino, N-met ilpiperazino, l- (3,4-dihydro-lH-isoquinolinyl), or - (3,4-dihydro-lH-isoquinolinyl), or a pyrrolidino ring, optionally substituted with benzyloxycarboni lo or with phenyl, said phenyl ring being optionally mono- or di-substituted with a substituent independently selected from the group it consists 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) sulfyl, (trifluoromethyl) sulfonyl and C (0) OR 7, wherein R 7 is lower alkyl or phenyl (lower alkyl); or a salt by addition of therapeutically acceptable acid thereof.

2. - The compound of formula 1 according to claim 1, characterized in that Y is S or O; Ri is C? _6 alkyl optionally substituted with C (0) -R8 or NHC (0) -R8, wherein R8 is a C? _6 alkyl, NH? -C6 alkyl or phenyl; (alkyl CO-)) phenyl, wherein said phenyl ring is optionally substituted with halo, C? _6 alkyl or NH-Rg, wherein R9 is: C alquilo _ alkyl, phenyl or an acyl of formula C (O) -Rio, wherein R? 0 is a C?-6 alkyl, NH-Cl-6 alkyl or phenyl, (C C-3 alqu alkyl) Het, wherein said carbon atoms of said Het are optionally substituted with halo, C 1-6 alkyl or NH-R 9; or said nitrogen atom of said Het is substituted with R9, wherein R9 is: C? - alkyl, phenyl or an acyl of formula C (0) -Rio, wherein Rx is a C? -6 alkyl, NH? -C6 alkyl or phenyl; or Ri is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, the optionally N-alkylated asparagine side chain, or C? -6 alkyl optionally monosubstituted with (C? -6 alkylsulfonyl or phenyl, A is phenyl or CH-R3, wherein R3 is C6-6 alkyl or (C0-4 alkyl) phenyl; Y Z is C (0) -R8, wherein R8 is C1-6 alkyl, C6-6 alkoxy or phenyl; R4 is hydrogen or C3_3 alkyl; and 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 selected from the group consisting of alkyl lower, lower alkoxy, halo, cyano, trifluoromethyl and C (0) OR7, wherein R7 is lower alkyl or phenyl (lower alkyl); Het (lower alkyl), wherein Het represents a five or six membered heterocyclic ring, monovalent, 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 R 4 and R 5, together with the nitrogen atom to which they are attached, form a pyrrolidino ring optionally substituted with C (0) 0-benzyl or phenyl, said phenyl ring being optionally mono- or di-substituted with halo , nitro, cyano or trifluoromethyl; or a salt by addition of therapeutically acceptable acid thereof.

3. - The compound of formula 1 according to claim 2, characterized in that And it's S or O; Ri is C1-3 alkyl optionally substituted with C (O) 0Me or NH-C (O) -Ph; phenyl, benzyl or phenylethyl, wherein said phenyl ring is optionally substituted with chorus or methoxy; Het, Het-methyl or Het-ethyl, wherein Het is 2-, 3- or 4-pyridinyl optionally substituted on the nitrogen with methyl or C (O) -R? 0 / wherein Rio is CH2-t-Bu or phenyl, or i is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, CH2-C (O) N (Me) 2, CH2-CH (Me) 2 or methyl optionally monosubstituted with methylsulfonyl, A is phenyl or CH-t-Bu; and Z is C (0) -R8, wherein R8 is CH2-t-Bu or O-t-Bu; R 4 is hydrogen or lower alkyl; and R 5 is phenyl optionally substituted with a substituent selected "independently from the group consisting of lower alkyl, lower alkoxy, (C 1 -2 alkyl) phenyl optionally mono- or di-substituted on its phenyl portion with a substituent independently selected from the group which consists of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl and C (0) OR7, wherein R7 is lower alkyl or (lower alkyl) phenyl, or a therapeutically acceptable acid addition salt thereof.

4. - A compound of formula 1 'characterized in that (! ') Y e s O or S; Ri is phenyl, 4-chloro-phenyl, benzyl, phenylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, CH2- (S) CH (CH2CH2S02Me) -NH-Tbg-Boc, CH2- (S) CH (CH2CHMe2) -NH-Tbg-C (O) CH2-t-Bu; R4 is H or Me; R 12 is phenyl, benzyloxyethyl or Het; Y R 13 is hydrogen, methyl, ethyl, propyl or hydroxymethyl.

5. - A compound of the formula. 1 characterized in that it is selected from the group consisting of: in dondßRi, Y R12 and Rwson as defined below: where R ?, and R «and R« are as defined below:

6. . - The compound of formula 1 according to claim 5, characterized in that it is selected from the group consisting of entries n °: 101, 102, 103, 105, 106, 108, 109, 110, 111, 112, 114, 115 and 116.

7. - The compound of formula 1 according to claim 6, characterized in that it is selected from the group consisting of entries n °: 101, 102, 103, 105, 106, 112, and 115.

8. - A compound of the Formula 1 characterized in that it is selected from the group consisting of: where RX / and R? 3 are as defined below:

9. The compound of formula 1 according to claim 8, characterized in that it is selected from the group consisting of entries n °: 202, 203, 204, 205, 206, 207 and 210.

10. - The compound of formula 1 according to claim 9, characterized in that it is selected from the group consisting of entries n °: 202, 203, 204 and 207.

11. A pharmaceutical composition for treating 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, in admixture with a pharmaceutically acceptable carrier.

12. 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.

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

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

15. The compound of formula 1 according to claim 1, in combination with another anti-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 where Y is S or O; Ri is C? _6 alkyl; (C0_6 alkyl) aryl; (C0-6 alkyl) Het; or Ri is an amino acid analog or dipeptide analog of the formula: wherein R2 is H, alkyl C? _? 0; or an amide or ester group; A is aryl C6-? O / Het or CH-R3, wherein R3 is alkyl C? -6 or (C0-alkyl) aryl; and Z is H, C? _6 alkyl, or an acyl; R 4 is hydrogen, lower alkyl, methoxy, ethoxy or benzyloxy; and R5 is an alkyl, cycloalkyl group; carboxyl; an aril; 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 phenyl or C (O) OCH-phenyl wherein said phenyl ring is optionally mono- or di-substituted, inter alia, with C (0) OR7, wherein R7 is lower alkyl or phenyl (lower alkyl); or a salt by addition of therapeutically acceptable acid thereof.