CA2019005C - Antiherpes pentapeptide derivatives having a cycloalkyl substituted aspartic acid side chain - Google Patents

Abstract

Disclosed herein are pentapeptide derivatives of the formula X-NR1-CH(R2)-C(W1)-NH-CR3(R4)-C(W2)-NR5-CH¢CH2C(O)-Y!- C(W3)-NH-CR6-¢CR7(R8)-COOH!-C(W4)-NH-CR9(R10-Z wherein X is a terminal group, for example, alkanoyl or phenylalkanoyl radicals, R1 is hydrogen, alkyl or phenylalkyl, R2, R4 and R10 are selected from amino acid or derived amino acid residues, R3, R5, R6 and R9 are hydrogen or alkyl, R7 and R8 are joined to form a cycloalkyl, W1, W2, W3 and W4 are oxo or thioxo, Y is, for example, an alkoxy or a mono or disubstituted amino, and Z is a terminal group, for example, COOH or CH2OH. The derivatives are useful for treating herpes infections.

Description

13-BG-D-23b Antihert~es Pentaueptide Derivatives Having a Cycloalkyl Substituted Asyartic Acid Side Chain Field of the Invention This invention relates to peptide derivatives having antiviral properties and to means for using the derivatives to treat viral infections. More specifically, the invention relates to peptide derivatives (hereinafter called "peptides") exhibiting activity against herpes viruses, to pharmaceutical compositions comprising the pep-tides, and to a method of using the peptides to treat herpes infec-tions.
Background of the Invention The family of herpes viruses is responsible for a wide range of infections that afflict humans and many important domestic ani-mals. The diseases caused by these viruses range from bothersome cold sores to highly destructive infections of the central nervous system (encephalitis). The more common members of this family include herpes simplex virus (types 1 and 2) responsible for cold sores and genital lesions; varicella zoster virus which causes chicken pox and shingles; and Epstein-Barr virus which causes infectious mononucleosis. Although some significant advances have been made in the last decade in antiviral therapy, the need for effective, safe therapeutic agents for treating herpes viral infections continues to exist. For a recent review of current therapeutic agents in this area, see M.C. Nahata, "Antiviral Drugs: Pharmacokinetics, Adverse Effects and Therapeutic Use", J. Pharm. Technol., 3, 100 (1987).
The present application discloses a group of peptide derivatives having activity against herpes viruses. The relatively selective action of these peptides against herpes viruses, combined with a wide margin of safety, renders the peptides as desirable agents for combating herpes infections.

2 The association of peptides with anti-herpes activity is uncommon. Instances of reports of such an association include B.M.
Dutia et al., Nature, 321, 439 (1986), E.A. Cohen et al., Nature, 321, 441 (1986), J.H. Subak-Sharpe et al., UK patent application 2185024, published July 8, 1987, E.A. Cohen et al., European patent application 246630, published November 25, 1987, R. Freidinger et al., European patent application 292255, published November 23, 1988, and R. Freidinger et al., U.S, patent 4,814,432, issued March 21, 1989. The subject peptides of the previous reports can be distin-guished from the peptides of the present application by characteristic structural and biological differences.
Summar3~ of the Invention:
The peptides of this invention are represented by formula 1 XNR'-CH(RZ)-C(W')-NH-CR3(R°)-C(Wi)-NRS-CH[CHxC(O)-Y]-C(VV~)-NH-CR6-[CR'(Ra)-COOH]-C(W4)-NH-CR9(R'°)-Z 1 wherein X is (1-lOC)alkanoyl, (1-lOC)alkoxycarbonyl, benzoyl, benzoyl monosubstituted or disubstituted with a substituent selected from halo, hydroxy, lower alkyl, lower alkoxy, phenyl, 2-carboxy-phenyl or benzyl, 2,2-diphenylacetyl, phenyl(2-lOC)alkanoyl or phenyl(2-lOC)alkanoyl monosubstituted or disubstituted on the aro-matic portion thereof with a substituent selected from halo, hydroxy, lower alkyl, lower alkoxy or phenyl;
R' is hydrogen, lower alkyl or phenyl(lower)alkyl;
RZ is lower alkyl, hydroxy(lower)alkyl or mercapto(lower)alkyl;
R', R5, R6 and R9 each independently is hydrogen or lower alkyl;
R4 is hydrogen, lower alkyl, hydroxy(lower)alkyl, mercapto(lower)alkyl, methoxy(lower)alkyl, methylthio(lower)alkyl, lower cycloalkyl or (lower cycloalkyl)methyl;

3 R' and Ra together with the carbon atom to which they are attached form a lower cycloalkyl;
R'° is lower alkyl, lower alkenyl or (lower cycloalkyl)-(lower alkyl);
W', WZ, W3 and W' each independently is oxo or thioxo;
Y is a. (1-14C)alkoxy, (3-14C)alkenyloxy, CH3(OCHZCH~a O wherein n is the integer 1, 2 or 3, lower cycloalkyloxy, lower alkoxy monosubstituted with a lower cycloalkyl, phenoxy, phenoxy monosubstituted with hydroxy, halo, lower alkyl or lower alkoxy, phenyl(lower)alkoxy or phenyl(lower)alkoxy in which the aromatic portion thereof is substituted with hydroxy, halo, lower alkyl or lower alkoxy, or b. NR"R'z wherein R" is lower alkyl and R'2 is lower alkoxy, or c. NR"R'2 wherein R" is hydrogen or lower alkyl and R'Z is (1-14C)alkyl, lower cycloalkyl, lower alkyl monosubstituted with a lower cycloalkyl; phenyl, phenyl monosubstituted with halo, lower alkyl or lower alkoxy; phenyl(lower)alkyl, phenyl(lower)alkyl in which the aromatic portion thereof is substituted with halo, lower alkyl or lower alkoxy; or (Het)-lower alkyl wherein Het represents a five or six membered heterocyclic radical containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, or d. NR"R'Z wherein R" and R'2 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or 4-(lower alkyl) piperazino; and Z is hydrogen; COOH; CHZCOOH; CHZOH; 5-1H-tetrazolyl; COOR'3 wherein R" is lower alkyl; CONR'4R's wherein R'4 and R'S each independently is hydrogen or lower alkyl; or CON(R'6)OH wherein

4 R'6 is hydrogen or lower alkyl; or a therapeutically acceptable salt thereof.
A preferred group of the peptides of this invention is represented by formula 1 wherein X is (1-lOC)alkanoyl; (1-lOC)alkoxycarbonyl; benzoyl; benzoyl monosubstituted with halo, hydroxy, lower alkyl, lower alkoxy, phenyl, 2-carboxyphenyl or benzyl; phenyl(2-lOC)alkanoyl or phenyl(2-lOC)alkanoyl monosub-stituted or disubstituted on the aromatic portion thereof with a substituent selected from halo, hydroxy, lower alkyl, lower alkoxy or phenyl; R' to R'°, inclusive, and W' to W', inclusive, are as defined hereinabove; Y is (1-14C)alkoxy, (3-14C)alkenyloxy, CH3(OCHZ
CH2)3 O, lower cycloalkyloxy, lower cycloalkylmethoxy, phenyl-(lower)alkoxy, NRl'R~z wherein R" is lower alkyl and R'Z is lower alkoxy, or NR11R12 wherein R'1 is hydrogen or lower alkyl and R'Z is (1-14C)alkyl, lower cycloalkyl, lower cycloalkylmethyl, phenyl, phenyl monosubstituted with halo, lower alkyl or lower alkoxy, phenyl(lower)alkyl, phenyl(lower)alkyl monosubstituted with halo, lower alkyl or lower alkoxy, (Het)-lower alkyl wherein Het is a heterocyclic radical selected from 2-pyrrolyl, 2-pyridinyl, 4-pyridinyl, 2-furyl, 2-isoxazolyl and 2-thiazolyl, or NR'IR'Z wherein R" and R'2 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino; and Z is as defined hereinabove; or a therapeutically acceptable salt thereof.
A more preferred group of the peptides is represented by formula 1 wherein X, R', R8 and R'° are as defined hereinabove; Rl is lower alkyl; RZ is lower alkyl or hydroxy(lower)alkyl; R3, R5, R6 and R9 each independently is hydrogen or methyl; R4 is hydrogen, lower alkyl, hydroxy(lower)-alkyl, methoxy(lower)alkyl, lower cycloalkyl or (lowercyclo-alkyl)methyl; Wl, WZ and W3 are oxo, W' is oxo or thioxo, Y is (1-14C)alkoxy, (3-14C)alkenyloxy, CH3(OCH2CH~3 O, lower cycloalkyloxy, lower cycloalkylmethoxy, phenyl(lower)alkoxy, N(Me)OMe, NR"R'2 wherein R" is hydrogen or s lower alkyl and R'2 is (1-14C)alkyl, lower cycloalkyl, lower cycloalkylmethyl, phenyl, phenyl(lower)alkyl or pyridinyl(lower alkyl), or NRllRlz wherein R" and R'Z together with the nitrogen to which they are attached form a pyrrolidino, piperidino or morpholino; and s Z is hydrogen, COOH, CHZCOOH, s-1H-tetrazolyl, CHZOH, CONR'4Rls wherein R'4 and R's each independently is hydrogen or lower alkyl, or CON(R'6)OH wherein R'6 is hydrogen or lower alkyl;
or a therapeutically acceptable salt thereof.
A most preferred group of the peptides is represented by formula 1 wherein X is acetyl, 4-methylpentanoyl, octanoyl, Boc, benzoyl, 2-biphenylylcarbonyl, 2-(2'-carboxy)biphenylylcarbonyl, phenylacetyl, phenylpropionyl, (4-hydroxyphenyl)propionyl or (3,4-dihydroxyphenyl)propionyl; R' is methyl; RZ is 1-methylethyl, 1-methylpropyl, 1,1-dimethylethyl or 1-hydroxyethyl; R3 is hydrogen or is methyl; R' is hydrogen, lower alkyl, hydroxymethyl, 1-hydroxyethyl, 1- methoxyethyl, cyclopentyl or cyclohexylmethyl; Rs is hydrogen or methyl; R6 is hydrogen; R' and R8 together with the carbon atom to which they are attached form a lower cycloalkyl; R9 is hydrogen or methyl; R'° is 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, 2,2-dimethylpropyl or 2-cyclohexylethyl; W', VV~ and W3 are oxo; W4 is oxo or thioxo; Y is hexyloxy, 1-methylheptyloxy, decyloxy, dodecyloxy, trans-3-heptenyloxy, cis-3-octenyloxy, CH3(OCHZCHZ)3 O, cyclopentyloxy, cyclohexyloxy, cyclohexylmethoxy, phenylpropoxy, N(Me~Me, ethylamino, phenylamino, phenylethylamino, N-methyl-2s N-phenylethylamino, 2-pyridinylethyl, N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-methyl-N-octylamino, pyrroli-dino, piperidino or morpholino; and Z is hydrogen, COOH, CHZCOOH, s-1H-tetrazolyl, CHZOH, CONRI4Rls wherein Rl° and Rls each independently is hydrogen, methyl, ethyl or propyl, or CON(R'6)OH wherein Rlb is hydrogen or methyl; or a therapeutically acceptable salt thereof.

Included within the scope of this invention is a pharma-ceutical composition comprising an anti-herpes virally effective amount of a peptide of formula 1, or a therapeutically acceptable salt thereof, and a pharmaceutically or veterinarily acceptable carrier.
Also included within the scope of this invention is a cosmetic composition comprising a peptide of formula 1, or a therapeutically acceptable salt thereof, and a physiologically acceptable carrier suitable for topical application.
An important aspect of the invention involves a method of treating a herpes viral infection in a mammal by administering to the mammal an anti-herpes virally effective amount of the peptide of formula 1, of a therapeutically acceptable salt thereof.
Another important aspect involves a method of inhibiting the replication of herpes virus by contacting the virus with a herpes viral ribonucleotide reductase inhibiting amount of the peptide of formula 1, or a therapeutically acceptable salt thereof.
Processes for preparing the peptides of formula 1 are described hereinafter.

~01900~
Details of the Invention GENERAL
Alternatively, formula 1 can be illustrated as:
COY
Rj Wi qty R 9 R ~o X ~ ~ :YH
j.~i Z
R~ ~ R ~ Rs R 7 ~ Rs i R
R ~ COOH
The term 'residue' with reference to an amino acid or amino acid derivative means a radical derived from the corresponding a-amino acid by eliminating the hydroxyl of the carboxy group and one hydrogen of the a-amino group.
In general, the abbreviations used herein for designating the amino acids and the protective groups are based on recommenda-tions of the IUPAC-IUB Commision of Biochemical Nomenclature, see European Journal of Biochemistry 138, 9 ( 1984). For instance, Gly, Val, Thr, Ala, Ile, Asp, Ser and Leu, represent the residues of glycine, L-valine, L-threonine, L-alanine, L-isoleucine, L-aspartic acid, L-serine and L-leucine, respectively.
The asymmetric carbon atoms residing in the principal linear axis (i.e. the backbone) of the peptides of formula 1, exclusive of the terminal groups, have an S configuration. Asymmetric carbon atoms residing in the side chain of an amino acid or derived amino acid residue, including those in terminal groups, may also have the R
configuration. Furthermore, with respect to disubstituted benzoyl and disubstitued phenyl(1-lOC)allcanoyl as defined for X of peptides of formula 1, the substituents are selected on the basis that they do not interfere with each others presence.
The term 'halo' as used herein means a halo radical selected from bromo, chloro, fluoro or iodo.

20.9005 s The term "lower alkyl" as used herein, either alone or in combination with a radical, means straight chain alkyl radicals containing one to six carbon atoms and branched chain alkyl radicals containing three to six carbon atoms and includes methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.
The term "lower alkenyl" as used herein means straight chain alkenyl radicals containing two to six carbon atoms and branched chain alkenyl radicals containing three to six carbon atoms and includes vinyl, 1-propenyl, 1-methylethenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and 2-butenyl.
The term "lower cycloalkyl" as used herein, either alone or in combination with a radical, means saturated cyclic hydrocarbon radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "lower alkoxy" as used herein means straight chain alkoxy radicals containing one to four carbon atoms and branched chain alkoxy radicals containing three to four carbon atoms and includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter radical is known commonly as tertiary-butyloxy.
The term "(1-14C)alkyl" as used herein means straight and branched chain alkyl radicals containing from one to fourteen carbon atoms, respectively. The terms "(1-lOC)alkoxy" and "(1-14C)alkoxy"
as used herein, either alone or in combination with a radical, mean straight and branched chain alkoxy radicals containing from one to ten carbon atoms and one to fourteen carbon atoms, respectively.
The term "(3-14C)alkenyloxy" means straight and branched chain alkenyloxy radicals containing from three to fourteen carbon atoms in which the double bond may be cis or trans and is positioned more ~01900~

than one carbon atom away from the oxygen atom of the radical; for example, 3-heptenyloxy and 3-octenyloxy. The term "(1-lOC)alkanoyl" as used herein means a straight or branched chain 1-oxoalkyl radical containing from one to ten carbon atoms; for example, acetyl, 4-methyl-1-oxopentyl (or 4-methylpentanoyl) or 1-oxooctyl (or octanoyl). The term "phenyl(2-10)alkanoyl as used herein means phenyl substituted 1-oxoalkyl radicals wherein the 1-oxoalkyl portion thereof is a straight or branched chain 1-oxoalkyl containing from two to ten carbon atoms; for example, 1-oxo-3-phenylpropyl and 1-oxo-S-methyl-6-phenylhexyl.
Additional abbreviations or symbols used hereafter are:
Boc 1,1-dimethylethoxycarbonyl or tertiary butyloxycarbonyl DAT desaminotyrosyl or 1-oxo-3-(4-hydroxy-phenyl)propyl Ph phenyl PhCH2CHZC0 1-oxo-3-phenylpropyl N-Me-Val N-methylvalyl residue Tbg 2(S)-amino-3,3-dimethylbutanoic acid residue Tba 2(S)-amino-4,4-dimethylpentanoic acid residue N-Me-Tbg 2(S)-methylamino-3,3-dimethylbutanoic acid residue NMe(octyl) N-methyl-N-octylamino NMe(decyl) N-methyl-N-decylamino Asp(cyPr) (S)-a-amino-1-carboxycyclopropaneacetic acid residue Asp(cyBu) (S)-a-amino-1-carboxycyclobutaneacetic acid residue Asp(cyPn) (S)-a-amino- 1-carboxycyclopentaneacetic acid residue to Asp(cyHx) (S)-a-amino-1-carboxycyclohexaneacetic acid residue The symbol "y[CSNH]" used between the three letter representations of two amino acid residues means that the normal amide bond between those residues in the peptide, being represented, has been replaced with a thioamide bond.
The term "pharmaceutically acceptable Garner" or "veterinarily acceptable carrier" as use herein means a non-toxic, generally inert vehicle for the active ingredient which does not adversely affect the ingredient.
The term "physiologically acceptable carrier" as used herein means an acceptable cosmetic vehicle of one or more non-toxic excipients which do not react with or reduce the effectiveness of the active ingredient contained therein.
The term "veterinarily acceptable carrier" as used herein means a physiologically acceptable vehicle for administering drug substances to domestic animals comprising one or more non-toxic pharmaceutically acceptable excipients which do not react with the drug substance or reduce its effectiveness.
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 viral organisms in vivo.
The term "coupling agent" as used herein means an agent capable of effecting the dehydrative coupling of an amino acid or peptide free carboxy group with a free amino group of another amino acid or peptide to form an amide bond between the reactants.
Similarly, such agents can effect the coupling of an acid and an alcohol to form corresponding esters. The agents promote or facilitate the dehydrative coupling by activating the carboxy group.
Descriptions of such coupling agents and activated groups are included in general text books of peptide chemistry; for instance, E.
Schroder and K.L. Lubke, "The Peptides", Vol. 1, Academic Press, New York, N.Y., 1965, pp 2-128, and K.D. Kopple, "Peptides and Amino acids", W.A. Benjamin, Inc., New York, N.Y., 1966, pp 33-51. Examples of coupling agents are thionyl chloride, diphenylphosphoryl azide, 1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide, N-hydroxysuccinimide, or 1-hydroxy-benzotriazole in the presence of dicyclohexylcarbodiimide. A very practical and useful coupling agent is (benzotriazol-1-yloxy)tris (dimethylamino)-phosphonium hexafluorophosphate, described by B.
Castro et al., Tetrahedron Letters, 1219 (1975), see also D. Hudson, J. Org. Chem., 53, 617 ( 1988), either by itself or in the presence of 1-hydroxybenzotriazole.
Process The peptides of formula 1 can be prepared by processes which incorporate therein methods commonly used in peptide synthesis such as classical solution coupling of amino acid residues and/or peptide fragments, and if desired solid phase techniques. Such methods are described, for example, by E. Schrbder and K. Liibke, cited above, in the textbook series, "The Peptides: Analysis, Synthesis, Biology", E. Gross et al., Eds., Academic Press, New York, N.Y., 1979-1987, Volumes 1 to 8, and by J.M. Stewart and J.D. Young in "Solid Phase Peptide Synthesis", 2nd ed., Pierce Chem. Co., Rockford, IL, USA, 1984.
A common feature of the aforementioned processes for the peptides is the protection of the reactive side chain groups of the various amino acid residues or derived amino acid residues with suitable protective groups which will prevent a chemical reaction from occurring at that site until the protective group is ultimately 20i900~

removed. Usually also common is the protection of an a-amino group on an amino acid or a fragment while that entity reacts at the carboxy group, followed by the selective removal of the a-amino protective group to allow subsequent reaction to take place at that location. Usually another common feature is the initial protection of the C-terminal carboxyl of the amino acid residue or peptide fragment, if present, which is to become the C-terminal function of the peptide, with a suitable protective group which will prevent a chemical reaction from occurring at that site until the protective group is removed after the desired sequence of the peptide has been assembled.
In general, therefore, a peptide of formula 1 can be prepared by the stepwise coupling in the order of the sequence of the peptide of the amino acid or derived amino acid residues, or fragments of the peptide, which if required are suitably protected, and eliminating all protecting groups, if present, at the completion of the stepwise coupling to obtain the peptide of formula 1. More specific processes are illustrated in the examples hereinafter.
With reference to the preparation of peptides of formula 1 in which Z is 5-1H-tetrazolyl, the derived amino acid residue containing the tetrazole can be prepared as follows: Boc-Leu-NHZ, for example, was converted to its corresponding nitrite derivative by treatment with p-toluenesulfonyl chloride in methylenedichloride in the presence of excess pyridine and a catalytic amount of 4-dimethylaminopyridine (Fieser and Fieser, "Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, NY, USA, 1967, vol 1, p 1183). The nitrite derivative then was mixed with tributyl tin azide, J.G.A. Luijten et al., Rec. Trav., 81, 202 (1962), giving a tetrazole tin intermediate [cf.
K. Sisido et al., Journal of Organometallic Chemistry, 33, 337 (1971) and J. Dubois et al., J. Med. Chem., 27, 1230 (1984)]. The latter was treated with hydrogen chloride in diethyl ether to afford the desired tetrazole residue as a hydrochloride salt, for example, zo~~oo~

NHZCH[CHZCH(CH3)Z]-5-1H-tetrazole dihydrochloride. The tetrazole residue, or its hydrochloride salt, was used for coupling with the appropriate amino acid or protected fragment, leading to the desired peptide of formula 1.
The peptide of formula 1 of this invention can be obtained in the form of a therapeutically acceptable salt. In the instance where a particular peptide has a residue which functions as a base, examples of such salts are those with organic acids, e.g. acetic, lactic, succinic, benzoic, salicylic, methanesulfonic or p-toluenesulfonic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and also salts with inorganic acids such as hydrohalic acids, e.g. hydrochloric acid, or sulfuric acid, or phosphoric acid. If desired, a particular acid addition salt is converted into another acid addition salt, such as a non-toxic, pharmaceutically acceptable salt, by treatment with the appropriate ion exchange resin in the manner described by R.A. Boissonnas et al., Helv. Chim. Acta, 43, 1849 (1960).
In the instance where a particular peptide has one or more free carboxy groups, examples of such salts are those with the sodium, potassium or calcium cations, or with strong organic bases, for example, triethylamine or N-methylmorpholine.
Antiheroes Activity The antiviral activity of the peptides of formula 1 can be demonstrated by biochemical, microbiological and biological procedures showing the inhibitory effect of the compounds on the replication of herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), and other herpes viruses, for example, varicella zoster virus (VZV), Epstein-Barr virus (EBV), equine herpes virus (EHV) and cytomegalovirus.

Noteworthy is the fact that all of the aforementioned viruses are dependent on their own ribonucleotide reductase to synthesize deoxyribonucleotides for their replication. Although this fact may not be directly linked with the antiviral activity found for the present peptides, the latter compounds have been shown so far to have antiviral properties against all viruses dependent on ribonucle-otide reductase to synthesis DNA for their replication.
In the examples hereinafter, the inhibitory effect on herpes ribonucleotide reductase is noted for exemplary peptides of formula 1. Noteworthy, in the connection with this specific inhibition of herpes ribonucleotide reductase, is the relatively minimal effect or absence of such an effect of the peptides on cellular ribonucleotide reductase activity required for normal cell replication.
A method for demonstrating the inhibitory effect of the peptides of formula 1 on viral replication is the cell culture technique; see, for example, T. Spector et al., 1'roc. Natl. Acad. Sci.
USA, 82, 4254 (1985).
The therapeutic effect of the peptides can be demonstrated in laboratory animals, for example, by using an assay based on genital herpes infection in Swiss Webster mice, described by E.R. Kern, et al., Antiviral Research, 3, 253 (1983).
When a peptide of this invention, or one of its therapeutically acceptable salts, is employed as an antiviral agent, it is administered topically or systemically to warm-blooded animals, e.g. humans, pigs or horses, in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the peptide, chosen route of administration and standard biological practice. For topical adminis-tration, the peptide can be formulated in pharmaceutically accepted vehicles containing 0.1 to 10 percent, preferably 0.5 to 5 percent, of the active agent. Such formulations can be in the form of a solution, cream or lotion.
For systemic administration, the peptide of formula 1 is administered by either intravenous, subcutaneous or intramuscular

5 injection, in compositions with pharmaceutically acceptable vehicles or carriers. For administration by injection, it is preferred to use the peptide 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 of glucose 10 to make the solution isotonic.
Suitable vehicles or carriers for the above noted formulations are described in standard pharmaceutical texts, e.g. in "Remington's Pharmaceutical Sciences", 16th ed, Mack Publishing Company, Easton, Penn., 1980.
15 The dosage of the peptide will vary with the form of administration and the particular active agent chosen. Furthermore, it will vary with the particular host under treatment. Generally, treat-ment is initiated with small increments until the optimum effect under the circumstances is reached. In general, the peptide is most desi-rably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
With reference to topical application, the peptide is administered cutaneously in a suitable topical formulation to the infected area of the body e.g. the skin or part of the oral or genital cavity, in an amount sufficient to cover 1 the infected area. The treatment should be repeated, for example, every four to six hours until lesions heal.

With reference to systemic administration, the peptide of formula 1 is administered at a dosage of 10 mcg to 1000 mcg per kilogram of body weight per day, although the aforementioned varia-tions will occur. However, a dosage level that is in the range of from about 50 mcg to 500 mcg per kilogram of body weight per day is most desirably employed in order to achieve effective results.
Another aspect of this invention comprises a cosmetic composition comprising a herpes viral prophylactic amount of the peptide of formula 1, or a therapeutically acceptable salt thereof, together with a physiologically acceptable cosmetic carrier. Addi-tional components, for example, skin softeners, may be included in the formulation. The cosmetic formulation of this invention is used prophylactically to prevent the outbreak of herpetic lesions of the skin. The formulation can be applied nightly to susceptible areas of the skin. Generally, the cosmetic composition contains less of the peptide than corresponding pharmaceutical compositions for topical application. A preferred range of the amount of the peptide in the cosmetic composition is 0.01 to 0.2 percent by weight.
Although the formulation disclosed hereinabove are indicated to be effective and relatively safe medications for treating herpes viral infections, the possible concurrent administration of these formulations with other antiviral medications or agents to obtain beneficial results is not excluded. Such other antiviral medications or agents include acyclovir and antiviral surface active agents or antiviral interferons such as those disclosed by S.S. Asculai and F.
Rapp in U.S. patent 4,507,281, March 26, 1985.
The following examples illustrate further this invention.
Solution percentages or ratios express volume to volume relationship, unless stated otherwise. Abbreviations used in the examples include Ac: acetyl; Boc: t-butyloxycarbonyl; BOP: (benzotriazol-1-yloxy)tris-(dimethylamino)-phosphonium hexafluorophosphate; Bzl: benzyl;

CHZC12: methylenedichloride; DIPEA: diisopropylethylamine; DCC:
N,N-dicyclohexylcarbodiimide; DMF: dimethyl formamide; Et~O:
diethyl ether; EtOH: ethanol; HOBt: 1-hydroxybenzotriazole; HPLC:
high performance liquid chromatography; i-Pr: 1-methylethyl; MeOH:
methanol; NMM: N-methylmorpholine; TFA: trifluoroacetic acid;
THF: tetrahydrofuran. Temperatures are given in degrees centrigrade.
Example 1 Preparation of the Intermediate BOC-Aspf 1(S)-methylheytyloxyl-OH
A solution of Boc-Asp-OBzI (10.2 g, 31.6 mmol) in acetonitrile was added at 0 ° to a mixture of N,N'-carbonyldiimi-dazole (5.6 g, 34.7 mmol), DIPEA (8 ml, 46 mmol) and 2(S)-octanol (6 ml, 37.9 mmol) and 4-dimethylaminopyridine (200 mg).
The mixture was stirred for 3 h and then concentrated to dryness.
The residue was dissolved in EtOAc. The solution was washed with 1N aqueous HC1, 1N aqueous NaHC03, dried (MgSO,) and concentrated. The resultant oil was purified by chromatography (Si02, eluent: hexane-EtOAc, 7:3) to give Boc-Asp[1(S)-methyl-heptyloxy]-OBzI. Hydrogenation of the latter compound in the presence of 20% Pd(OH)~/C in ethanol solution afforded the title compound as a solid. NMR(200 MHz, CDC13)S 0.9(m,3H), 1.25(m,lOH), 1.45(s,9H), 2.8(dd,lH), 3.0(dd,lH), 4.6(m,lH), 4.95(m,lH) and 5.55(d,lH).
Analogous esters of Boc-Asp-OH were prepared in the same manner.
Example 2 Preparation of the Intermediate Boc-Asp(NEt,)-OH
BOP (2.20 g, 5.0 mmol) was added under N2 to a cooled (0 °) solution of Boc-Asp-OBzI (1.90 g, 4.6 mmol) in CH2C12 (50 ml).

1s 2019005 After 3 min NHEt~.HCI (0.55 g, 5.0 mmol) and DIPEA (2.4 ml, 13.8 mmol) were added. The resultant solution was stirred at 20-22 ° for 18 h. The solution was washed with 1096 aqueous citric acid (2 7~, 1096 aqueous NaHCO, (2 ?n and brine (2 7~. The organic layer was dried (MgSOa and concentrated to give an oil.
After SiO, chromatography of the oil using hexane-EtOAc (7:3) as the eluent, Boc-Asp(NEt~-OBzI (1.55 g, 8996) was obtained as an oil.
Under a Nl atmosphere, a solution of the latter compound (1.55 g, 4.09 mmol) in MeOH (100 ml) was mixed with 596 PdlC (155 mg).
The mixture was shaken on a Park apparatus under Hs (50 psi) for 90 min. The mixture was filtered through a 45~m membrane and the filtrate concentrated to give Boc-Asp(NEt~-OH (1.15g, 9896) as an oil. The structure of the product was confirmed by NMR.
In the same manner, corresponding N-substituted asparagine analogs were obtained by replacing NHErz.HCl with the appropriate amine or amine salt (e.g, pynolidine or N,O-dimethylhydroxylamine hydrochloride).
Example _3 Preparation of (S)-a-Amino-l-carboxycvcloalkvlacetic Acid Intermediates These intermediates, which can be used to prepare peptides of formula 1 in which R' and R' are- joined to form a lower cycloalkyl can be prepared according to the method of M. Bochenska and J.F.
Biernat, Rocz. Chem., 0 1195 (1976); see Chem. Abstr., 86, 43990r ( 1977).
More specifically exemplified, (t)-Boc-Asp(cyPn)(OBzI)-OH
was prepared as follows: To a solution of 1-bromocyclopentane-carboxylic acid ethyl ester [17.1 g, 77.3 mmol, described by D.N. Harpp et al., J. Org. Chem., 46, 3420 (1975)] and freshly distilled ethyl isocyanoacetate (12.7 g, 122 mmol) in a mixture of * Trade-mark A

f. 201900 dimethylsulfoxide and EtzO (1:1, 120 ml) was added sodium hydride (4.5 g, 60% dispersion in mineral oil, 122 mmol) in small portions over 5 h. The resulting red slurry was stirred at room temperature for 16 h after which time it was treated with a saturated aqueous solution of ammonium chloride (5 ml). The mixture was diluted with water (500 ml). The resulting mixture was extracted (2X) with ethyl acetate. The ethyl acetate layers were combined and washed with water (2X) and then with brine. Drying (MgS04), filtering and concentration of the extract afforded a dark red oil. This material was subjected to flash chromatography through a 5 x 25 cm column of silica gel [eluent: EtOAc-hexane (1:10)]. Concentration of the appropriate fractions provided a-cyano-1-carboxycyclopentaneacetic acid diethyl ester as a clear colorless viscous liquid (13 g, 66 %).
The latter compound (13 g, 51 mmol) was mixed with 6 N
aqueous HCl (60 ml) at 0 °. After dissolution, the reaction mixture was heated in a oil bath at 120 ° for 24 h. After this time water was removed from the mixture using a dry ice rotory evaporator.
The resulting white solid was dried under high vacuum for 18 h.
The dried material was dissolved in a mixture of dioxane (50 ml) and 3N aqueous NaOH (52 ml). A solution of di(tertiarybutyl) Bicarbonate ( 14.6 g, 67 mmol) in dioxane (25 ml) was added to the solution. The mixture was stirred at room temperature for 16 h.
Additional 3N aqueous NaOH was added at intervals insuring a pH
of about 10. The mixture was diluted with water (500 ml) and extracted (2X) with EtzO (200 ml). The aqueous phase was rendered acidic (pH = 3) with solid citric acid and extracted (2X) with EtOAc (300 ml). The combined EtOAc extracts were washed with water (3x) and brine. Drying, filtering and concentration of the extract afforded Boc-Asp(cyPn)-OH as a white solid ( 14 g, 96%).
To a solution of the latter compound (7.2 g, 25 mmol) in dry DMF (50 ml) was added K2CO3 (7.6 g, 55 mmol) and benzyl bromide (6.6 ml, 55 mmol). The reaction mixture was stirred at room temperature for about 7 h. Thereafter, the reaction mixture was poured into a mixture of water (500 ml) and ethyl acetate (350 ml).
The organic phase was washed with water (2X) and brine. Drying, filtering and concentration of the extract provided a pale yellow 5 viscous liquid. This material was subjected to flash chromatography through a 5 x 20 cm column of silica gel, eluting with hexane-ethyl acetate (12:1). Concentration of the appropriate fractions provided the dibenzyl derivative of Boc-Asp-(cyPn)-OH as a low melting white solid (11 g, 94%). The dibenzyl product was dissolved in THF (100 10 ml) and an aqueous solution of LiOH (23.5 ml, 1N) was added.
After 4 h, the reaction mixture was poured into water and extracted (3X) with EtzO. The aqueous phase was rendered acidic with 10%
aqueous citric acid and extracted (2X) with ethyl acetate. The ethyl acetate layers were combined, dried (MgS04), filtered and 15 concentrated to provide Boc-Asp(cyPn)(OBzI)-OH as a clear color less gum (7.3 g, 82%).
Example 4 Preparation of the Intermediate Boc-Asp(cyPn)(OBzI)ytfCSNHILeu-OB zl 20 The title compound is obtained by stirring a mixture of the protected dipeptide Boc-Asp(cyPn)(OBzI)-Leu-OBzI (5.5 mol) and Lawesson's reagent (2.7 mmol), see U. Pederson et al., Tetrahedron, 38, 3267 (1982), in toluene at reflux temperature for 2 h; followed by pouring the cooled reaction mixture onto a column of silica gel (3.15 x 20 cm) and eluting the column with CH2C12.
Analogous thioamide intermediates are prepared in the same manner by replacing Boc-Asp(cyPn)(OBzI)-Leu-OBzI with the appropriate protected dipeptide.

_~ 2019005 Example 5 General Procedure for the Solid Phase Preparation of Peptides of Formula 1 A modified version of the solid phase method of R.B.
Merrifield, J. Am. Chem. Soc., 85, 2149 ( 1963) was used to prepare the peptides preferably using a BHA-photoresin such as [4-(2-chloropropionyl)phenoxy]acetamidomethyl-copoly(styrene-1% divinyl-benzene) resin, see D. Bellof and M. Mutter, Chemia, 39, 317 (1985). Protection of free carboxy groups and hydroxy groups was provided by the Bzl protective group. Typically, a Boc-amino acid, representing the C-terminal unit of the desired peptide, e.g. Boc-Leu-OH, was linked to the above noted BHA-photoresin by the potassium fluoride method of K. Horiki et al., Chem. Lett., 165 (1978), using 9 molar equivalents of KF and 3.6 molar equivalents of Boc-Leu-OH, for example in DMF at 70 ° C for 24 hours, to give [4- { 2-(Boc-leucyl } propionyl } phenoxy]acetamidomethyl-copoly(styrene-1 % divinylbenzene) resin. The dried amino acid-solid support typically showed a leucine content of 0.6 to 0.8 mmol/g for the product, as determined by deprotection of an aliquot, followed by picric acid titration, B.F. Gisin, Anal. Chim. Acta, 58, 248 (1972).
The latter amino acid-solid support was used to build up the required sequence of units (i.e. amino acid residues, derived amino acid residues) of the desired peptide by solid phase methodology. Two molar equivalents (per mole of the amino-acid solid support) of the appropriate amino acid residues were coupled serially to the solid support system using BOP (2 molar equivalents), or BOP (2 molar equivalents)/HOBt (1 molar equivalent), in the presence of N-methyl-morpholine (6 molar equivalents) in dry DMF. Completion of coupling was verified by a negative ninhydrin test, E. Kaiser et al., Anal Biochem., 34, 595 (1979). Double coupling was used when necessary.

2o~oov~
...

Cleavage of the protected peptide from the solid support was accomplished by irradiation at 330 nm in EtOH/DMF (1:4) at 0 °
under an argon atmosphere for 6 to 18 h. Protective groups (Bzl), if present, were removed from the cleavage product by hydrogenolysis over 5% or 10% Pd/C or 20°!o Pd(OH)~/C by standard procedures (c~ example 1). Purification of the final product was performed by reversed-phase HPLC to better than 95% homogeneity using 0.06% aqueous TFA/0.06% TFA in acetonitrile gradients.
Example 6 Preparation of PhCH,CH,CO-N-Me-Val-Tb~-Asp(pyrrolidino)-Asp(cyPn)-Leu-OH
(Example of a solution phase procedure for preparing compounds of formula 1) To a solution of Boc-Asp(cyPn)(OBzI)-OH (5.3 g, 14 mmol, described in example 3) in dry CH2C12 (50 mL), BOP (6.8 g, 16 mmol), NMM (4.6 mL, 42 mmol) and the (4 methyl-phenyl)sulfonic acid salt of LeuOBzl (6.6 g, 16 mmol) were added successively. The reaction mixture was stirred at room temperature for 5 h, after which time it was poured into a two component system of EtOAc (500 mL) and a saturated aqueous solution of NaHC03 (400 mL). The organic phase was washed with water and brine.
Drying (MgS04), filtering and concentrating of the organic phase afforded a dark yellow oil. This material was purified by flash chromatography [Si02, eluent: hexane-EtOAc (6:1)] to provide Boc-Asp(cyPn)(OBzI)-Leu-OBzI as a clear colorless gum (7 g, 86%, mixture of diastereoisomers).
The latter compound (7 g, 12 mmol) was mixed with CH2C12 (4 mL). TFA (6 ml) was added to the mixture and the resulting solution was stirred for 30 min at room temperature. Thereafter, the majority of the solvent was evaporated and the residue was poured into a two component system of EtOAc (200 ml) and a saturated aqueous solution of NaHCO, (400 mL). Drying (MgSOa, filtering, and concentrating of the organic phase afforded the amine dipeptide H-Asp(cyPn)(OBzI)-Leu-OBzI as a clear colorless gum (mixture of diastercoisomers). The mixture was separated on a Waters LC-500 [2 columns of SiO~, eluent: hexane-EtOAc (1.5:1)]. The first diastereomer to elute (ca 2g, white solid) proved to provide the more active end products (peptides of formula 1). 'Ibis observation proved general for all corresponding cycloalkyl aspartic acid derivatives made. For convenient storage of material, the pure amine dipeptidc was treated briefly with 6N HCl/dioxane and concentrated to afford the hydrochloride salt as a white foam.
The latter hydrochloride salt (400 mg, 0.8 mmol) was coupled with Boc-Asp(pyrrolidino~OH (250 mg, 0.87 mmol), following the same general procedure used above for preparing Boc-Asp(cyPn)(OBzI)-L,eu-0Bzl. The crude product was purified by flash chromatography [SiO~, eluent: hexane-EtOAc (1:1)] to provide Boc-Asn(pyrrolidino)-Asp(cyhn)(OBzI)-Leu-0Bzl as a white foam (530 mg, 9196).
The previous material (280 mg, 0.38 mmol) was treated with

6 N HCl/dioxane (4 mL) for 30 min at room temperature. The solvent was removed and the residue was pumped under high vacuum for 18 h. The resulting white foam was coupled to Boc-Tbg-0H
(1.1 eq) in essentially the same manner as was done for the previous coupling. The crude product was purified by flash chromatography [SiO=, eluent: hexane-EtOAc (1:1)] to provide Boc-Tbg-Asp(pyrrolidino)-Asp(cyPn)(OBzl~Leu-0Bzl as a white foam (280 mg, 8596).
The latter compound was coupled to Boc-N-Me-Val-OH in the same manner as was dons for the previous coupling to provide Boc * Trade-mark A

20~.900~

N-Me-Val-Tbg-Asp(pyirolidino)-Asp(cyPn)(OBzI)-Leu-OBzI as a white foam (86% yield).
The latter compound (88 mg, 0.09 mmol) was treated with 6 N HCl/dioxane ( 1.5 mL) for 20 min at room temperature. The solvent was removed and the residue was pumped under vacuum for 2 h. This material was dissolved in CH~C12 (0.8 mL) and NMM
(40 L, 0.36 mmol) was added, followed by a premixed solution of 3-phenylpropionic acid (27 mg, 0.18 mmol) and BOP (80 mg, 0.18 mmol) in CHZCIz (0.35 mL). The reaction mixture was stirred at room temperature for 16 h, after which time it was poured into EtOAc (30 mL) and a saturated aqueous solution of NaHC03 (20 mL). The organic phase was washed with water and brine, dried (MgS04), filtered and concentrated to afford a yellow gum. This material was purified by flash chromatography [Si02, eluent: EtOAc-hexane (2:1)] to provide PhCHZCH2C0-N-Me-Val-Tbg-Asp(pyrrolidino)-Asp(cyPn)(OBzI)-Leu-OBzI (80 mg, 90%).
The latter material (80 mg, 0.08 mmol) was dissolved in MeOH (2 mL). 20% Pd(OH)~/C (50 mg) and ammonium formate (50 mg) were added to the mixture. The mixture was stirred under an atmosphere of hydrogen for about 5 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated.
The residue was dissolved in water (20 mL), (a few drops of saturated aqueous solution of NaHC03 were added to insure basicity).
The solution was washed (2X) with Et~O, acidified with solid citric acid and extracted (2X) with EtOAc. The combined EtOAc extracts were dried (MgS04), filtered and concentrated to afford the title compound of this example as a white solid (55 mg, 83%).
The procedures of examples 5 or 6 were used to prepare the peptides listed in the tables of example 7 with modifications noted therein in some instances. Commercially available Boc-amino acids were used. Unnatural amino acids were used in their Boc protected form; they were either commercially available, readily prepared from commercially available corresponding amino acids by reaction with di-tertiary-butyl carbonate, or prepared by standard methods.
Note that N-alkylated Boc amino acids are commercially 5 available, e.g. Boc-N-methylvaline, or they can be prepared by stan-dard N-alkylation of corresponding Boc-amino acids. For example, Boc-N-Me-Asp(NEt~-OH was obtained by reacting Boc-Asp(NEt~)-OH with 2.5 molar equivalents of methyl iodide and 2.1 molar equivalents of potassium hydride in THF at 0 ° for 18 h to give a 10 mixture of Boc-N-Me-Asp(NEt~-OH and its corresponding methyl ester. The mixture was esterified fully (diazomethane) and then saponified (NaOH/H20/dioxane) to yield the desired compound.
Example 7 Inhibition of Heroes Simplex Virus (HSV, type 1) Ribonucleotide 15 Reductase a) Preparation of Enzvme HSV-1 ribonucleotide reductase (partially purified) was obtained from quiescent BHK-21/C13 cells infected with strain F HSV-1 virus at 10 plaque forming units/cell as described by 20 E.A. Cohen et al., J. Gen. Virol., 66, 733 (1985).
b) Assay and Results for Exemplified Peptides By following the procedure described by P. Gaudreau et al., J. Biol, Chem., 262, 12413 (1987), the assay results listed in following tables 1 to 5 were obtained. The assay result for 25 each peptide is expressed as the concentration of the peptide producing 50% of the maximal inhibition (ICS) of enzyme activity. The number of units of the enzyme preparation used in each assay was constant, based on the specific activity of the enzyme preparation. The results are relative to the activity obtained in control experiments without peptide and represent the mean of four assays that varied less than 10°l0 with each other.
TABLE
peptide FAB/MS ICS
M+Na + , .~M
PhCH2CHZC0-N-Me-Val-Tbg- 835 0.06 Asp(pyrrolidino)-Asp(cyBu)-Leu-OH
PhCHZCHZCO-N-Me-Val-Tbg- 849 0.08 Asp(pyrrolidino)-Asp(cyPn)-Leu-OH
PhCHZCH2C0-N-Me-Val-Tbg- 908 0.18 Asp[1 (S)-methylheptyloxy]-Asp(cyBu)-Tba-OH
(4-Hydroxy-Ph)CH2CH2C0-N-Me- 924 0.18 Val-Tbg-Asp[1(S)-methylheptyloxy]-Asp(cyBu)-Tba-OH
PhCHZCHZCO-N-Me-V al-Ile-Asp(NEtz)-Asp(cyBu)-Leu-OCH3 PhCH2CHZC0-N-Me-Val-Ile-Asp(NEtz)-Asp(cyBu)-Leu-OH
PhCH2CH2C0-N-Me-Val-Ile-Asp(NEt~-Asp(cyPn)-(L-leucinol) PhCH2CHZC0-N-Me-Val-Ile-Asp(NMe2)-Asp(cyHx)-NHCH[CHZCH(CH3)~]-5-1H-tetrazole PhCH2CH2C0-N-Me-Val-Ile-Asp(pyrrolidino)-Asp(cyBu)-NHCH[CHZCH2CH(CH3)~]COOH 1 PhCH2CHZC0-N-Me-Val-Ile-Asp(NEt,~-Asp(cyPr)-NHCH[CHi CCH3(=CHZ)]-COOH 2 PhCHZCH2C0-N-Me-Val-Ile-Asp(pyrrolidino)-Asp(cyPn)-NHCH[CHZC(CH3)3]CHZOH
PhCH2CHZC0-N-Me-Val-Ile-Asp(pyrrolidino)-Asp(cyPn)-NHCH[CHZCH(CH3)~]CHZCOOH 3 [2-(2~-Carboxy)biphenylyl]carbonyl-N-Me-Val-Ile-Asp(pyrroli-dino)-Asp(cyHx)-Leu-OH

2~.~9005 PhCHZCHzCO-N-Me-V al-NHCH(cyclohexylmethyl)-CO-Asp-(pyrrolidino)-Asp(cyPn)-Leu-OH
PhCHZCH2C0-N-Me-Val-Ile-Asp(morpholino)-Asp(cyPr)-Leu-PhCH2CH2C0-N-Me-Val-Ile-Asp(NHCHZCHZPh)-Asp(cyBu)-Leu-NEtz s and PhCH2CHZC0-N-Me-Tbg-Ile-Asp(NMe(decyl)]-Asp(cyPn)-Leu-OH.
1 The 2(S)-amino-5-methylhexanoic acid methyl ester (Boc-homoleucine methyl ester) employed for the preparation of this peptide is obtained by reacting [(CH3)2CHCH~]ZCuLi, prepared by the method of D. Seebach and H. Neumann, Chem. Ber., 107, 847 ( 1974), with the O-tosyl derivative of Boc-Ser-OCH3 according to the conditions reported by A. Bernardini et al., Tetrahedron Letters, 24, 3717 (1983); followed by Boc deprotection with TFA/CHZCIz of the resulting Boc-2(S)-amino-5-methylhexanoic acid methyl ester. Subse-quent coupling of the 2(S)-amino-5-methylhexanoic methyl ester so obtained with PhCHZCHZCO-N-Me-Val-Ile-Asp(pyrrolidino)Asp(cyBu)-(OBzI)-OH and deprotection of the coupling product gave the corres-ponding peptide of formula 1.
2 The 2(S)-amino-4-methyl-5-hexenoic acid methyl ester employed for the preparation of this peptide is obtained by converting Boc-Ser-OH to its corresponding 13-lactone by the method of J.C.
Vederas et al., J. Am. Chem. Soc., 107 7105 (1985) and reacting the B-lactone with the organolithium derivative derived from 2-propylene bromide according to the method of D. Seebach and H. Neumann, Chem. Ber., 107, 847 (1974) to give 2(S)-amino-4-methyl-5-hexenoic acid. Subsequent esterification of the latter compound with diazomethane gave the desired corresponding methyl ester.
3 The Boc-3(S)-amino-5-methylhexanoic acid employed in the preparation of this peptide was obtained by an Arndt-Eistert reaction starting from Boc-Leu-OH, W.E. Bachmann and W.S. Struve, Organic Reactions, 1, 38 (1942).
'' Lucinamide was coupled with the appropriate protected fragment followed by hydrogenolysis to remove the Bzl protecting group. More specifically, by coupling PhCH2CH2C0-N-Me-Val-Ile-Asp(morpholino)-Asp(cyPr)(OBzI)-OH, prepared according to the procedure of example 6, with leucinamide using BOP in the presence of DIPEA, followed by hydrogenation to remove the Bzl on the Asp residue, the desired product is obtained.
5 The corresponding protected C-terminal acid is coupled with diethylamine hydrochloride using BOP/HOBt in the presence of N-methylmorpholine, followed by hydrogenation to remove the Bzl on the Asp residue to give the desired product.

Claims (7)

The embodiments of this invention in which an exclusive property or privilege is claimed are defined as follows:

1. A peptide of formula 1 XNR1-CH (R2)-C(W1)-NH-CR3(R4)-C(W2)-NR5-CH[CH2C(O)_ Y]-C(W3)-NH-CR6-[CR7(R8)-COOH]-C(W4)-NH-CR9(R10)-Z

wherein X is (1-10C)alkanoyl; (1-10C) alkoxycarbonyl; benzoyl; benzoyl mono-substituted with halo, hydroxy, lower alkyl, lower alkoxy, phenyl, 2-carboxyphenyl or benzyl;
phenyl(2-10C)alkanoyl or phenyl(2-10C)alkanoyl monosubtituted or disubstituted on the aromatic portion thereof with a substituent selected from halo, hydroxy, lower alkyl, lower alkoxy or phenyl;
R1 is hydrogen, lower alkyl or phenyl(lower)-alkyl;

R2 is lower alkyl, hydroxy(lower)alkyl or mercapto(lower)alkyl;
R3, R5, R6 and R9 each independently is hydrogen or lower alkyl;
R4 is hydrogen, lower alkyl, hydroxy(lower)alkyl, mercapto(lower)alkyl, methoxy(lower)alkyl, methylthio(lower)alkyl, lower cycloalkyl or (lower cycloalkyl)methyl;
R7 and R8 together with the carbon atom to which they are attached form a lower cycloalkyl; R10 is lower alkyl, lower alkenyl or (lower cycloalkyl)-(lower alkyl);W1, W2, W3 and W4 each independently is oxo or thio; Y is (1-14C) alkoxy, (3-14C)-alkenyloxy, CH3(OCH2CH2)3-O, lower cycloalkyloxy, lower cycloalkylmethoxy, phenyl (lower) alkoxy, NR11R12 wherein R11 is lower alkyl and R12 is lower alkoxy, or NR11R12 wherein R11 is hydrogen or lower alkyl and R12 is (1-14C) alkyl, lower cycloalkyl, lower cycloalkylmethyl, phenyl, phenyl monosubstituted with halo, lower alkyl or lower alkoxy, phenyl(lower)alkyl, phenyl(lower)alkyl monosubstituted with halo, lower alkyl or lower alkoxy, (Het)-lower alkyl wherein Het is a heterocyclic radical selected from 2-pyrrolyl, 2-pyridinyl, 4-pyridinyl, 2-furyl, 2-isoxazolyl and 2-thiazolyl, or NR11R12 wherein R11 and R12 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino; and Z is hydrogen; COOH; CH2COOH;
CH2OH; 5-1H-tetrazolyl; COOR13 wherein R13 is lower alkyl; CONR14R15 wherein R14 and R15 each independently is hydrogen or lower alkyl; or CON (R16) OH wherein R16 is hydrogen or lower alkyl; or a therapeutically acceptable salt thereof.

2. A peptide of formula 1 as recited in claim 1 wherein X, R7, R8 and R10 are as defined in claim 1, R1 is lower alkyl; R2 is lower alkyl or hydroxy (lower) alkyl; R3, R5, R6, and R9 each independently is hydrogen or methyl; R4 is hydrogen, lower alkyl, hydroxy(lower)alkyl, methoxy(lower)alkyl, lower cycloalkyl or (lower cycloalkyl)methyl; W1, W2, and W3 are oxo; W4 is oxo or thioxo; Y is (1-14C)alkoxy, (3-14C) alkenyloxy, CH3(OCH2)3-O, lower cycloalkyloxy, lower cycloalkylmethoxy, phenyl (lower) alkoxy, N (Me) OMe, NR11R12 wherein R11 is hydrogen or lower alkyl and R12 is (1-14C) alkyl, lower cycloalkyl, lower cycloalkylmethyl, phenyl, phenyl(lower)alkyl or pyridinyl (lower alkyl), or NR11R12 wherein R11 and R12 together with the nitrogen to which they are attached form a pyrrolidino, piperidino or morpholino; and Z is carboxy, CH2COOH, 5-1H-tetrazolyl, CH2OH, CONR14R15 wherein R14 and R15 each independently is hydrogen or lower alkyl, or CON (R16) OH wherein R16 is hydrogen or lower alkyl; or a therapeutically acceptable salt thereof.

3. A peptide of formula 1 as recited in claim 2 wherein X is acetyl, 4-methylpentanoyl, octanoyl, Boc, benzoyl, 2-biphenylylcarbonyl, 2-(2~-carboxy)biphenylylcarbonyl, phenylacetyl, phenylpropionyl, (4-hydroxyphenyl)propionyl or (3,4-dihydroxyphenyl)propionyl; R1 is methyl; R2 is 1-methylethyl, 1-methylpropyl, 1,1-dimethylethyl or 1-hydroxyethyl; R3 is hydrogen or methyl; R4 is hydrogen, lower alkyl, hydroxymethyl, 1-hydroxyethyl, 1-methoxyethyl, cyclopentyl or cyclohexylmethyl; R5 is hydrogen or methyl; R6 is hydrogen; R7 and R8 together with the nitrogen to which they are attached form a lower cycloalkyl; R9 is hydrogen or methyl; R10 is 2-methylpropyl, 3-methylbutyl or 2,2 -dime thylpropyl ; W1, W2 and W3 are oxo; W4 is oxo or thioxo; Y is hexyloxy, 1-methylheptyloxy, decyloxy, trans-3-heptenyloxy, cis-3-octenyloxy, CH3(OCH2CH2)3-O, cyclopentyloxy, cyclohexyloxy, cyclohexylmethoxy, phenylpropoxy, N(Me)OMe, ethylamino, phenylamino, phenylethylamino, N-methyl-N-phenylethylamino, 2-pyridinylethyl, N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-methyl-N-octylamino, pyrrolidino, piperidino or morpholino; and Z is COON, CH2COOH, 5-1H-tetrazolyl, CH2OH, CONR14R15 wherein R14 and R15 each independently is hydrogen, methyl, ethyl or propyl, or CON(R16)OH
wherein R16 is hydrogen or methyl; or a therapeutically acceptable salt thereof.

4. A peptide of claim 1 selected from the group consisting of PhCH2CH2CO-N-Me-Val-Tbg-Asp(pyrrolidino)-Asp (cyBu)-Leu-OH
PhCH2CH2CO-N-Me-Val-Tbg-Asp(pyrrolidino)-Asp (cyPn)-Leu-OH
PhCH2CH2CO-N-Me-Val-Tbg-Asp[1 (S)-methylheptyloxy]-Asp(cyBu)-Tba-OH and (4-Hydroxy-Ph)CH2CH2CO-N-Me-Val-Tbg-Asp[1 (S)-methylheptyloxy]-Asp(cyBu)-Tba-OH

5. The use of a peptide as defined in claim 1, or a therapeutically acceptable salt thereof, for treating a herpes viral infection in a mammal.

6. The use of a peptide as defined in claim 5 wherein the herpes viral infection is a herpes simplex viral infection.

7. The use of a peptide as defined in claim 1, or a therapeutically acceptable salt thereof, for inhibiting herpes viral ribonucleotide reductase.