WO1994015909A1 - Amino acids and peptides having modified terminals - Google Patents

Amino acids and peptides having modified terminals Download PDF

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Publication number
WO1994015909A1
WO1994015909A1 PCT/US1994/000335 US9400335W WO9415909A1 WO 1994015909 A1 WO1994015909 A1 WO 1994015909A1 US 9400335 W US9400335 W US 9400335W WO 9415909 A1 WO9415909 A1 WO 9415909A1
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WIPO (PCT)
Prior art keywords
compound
hydrogen
administered
amount
carbon atoms
Prior art date
Application number
PCT/US1994/000335
Other languages
French (fr)
Inventor
U. Prasad Kari
Original Assignee
Magainin Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Magainin Pharmaceuticals, Inc. filed Critical Magainin Pharmaceuticals, Inc.
Priority to JP6516279A priority Critical patent/JPH08505854A/en
Priority to AU61219/94A priority patent/AU681117C/en
Priority to EP94907791A priority patent/EP0679153A4/en
Publication of WO1994015909A1 publication Critical patent/WO1994015909A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/30—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to nitro or nitroso groups
    • C07C279/32—N-nitroguanidines
    • C07C279/36—Substituted N-nitroguanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • This invention relates to biologically active amino acids and peptides. More particularly, this invention relates to biologically active amino acids and peptides having modified C-terminals and modified N-terminals.
  • AA is an amino acid or a chain of two or more amino acids, excluding the N-terminus and C-terminus from the amino acid or chain of two or more amino acids.
  • R 1 is hydrogen or an alkyl group having 1 to 3 carbon atoms.
  • R 2 is selected from the group consisting of (i) a substituted or unsubstituted aliphatic (i.e., alkyl, alkenyl, or alkynl) hydrocarbon having 1 to 20 carbon atoms, and (ii)
  • R 4 is an aliphatic hydrocarbon having 1 to 4 carbon atoms. R 4 may be substituted or unsubstituted.
  • R 3 is selected from the group consisting of (i) hydrogen
  • R 1 is hydrogen. In another embodiment, R 1 is an alkyl group having from 1 to 8 carbon atoms.
  • R 1 is an alkyl group and preferably an alkyl group having from 7 to 16 carbon atoms.
  • R 2 is R 4 , wherein R 4 is
  • R 4 is an alkenyl group, more preferably an alkenyl group having from 2 to 4 carbon atoms, and most preferably R 4 is an alkenyl group having 2 carbon atoms.
  • R 3 is hydrogen. In another embodiment, R 3 is:
  • R 5 is hydrogen, while in another embodiment, R 5 is a nitro group.
  • R 5 is
  • each of R 6 , R 7 , and R 8 is hydrogen. In another embodiment, each of R 6 , R 7 , and R 8 is methyl.
  • amino acid residues which may be contained in the compound can be amino acid residues known to those skilled in the art. Such residues include, but are not limited to, hydrophobic amino acid residues, basic hydrophilic amino acid residues, and neutral hydrophilic amino acid residues.
  • hydrophobic amino acids are Ala, Cys, Gly, lle, Leu, Met, Phe, Pro, Trp, Tyr, Val, cyclohexylalanine (Cha), norleucine (Nle), norvaline (Nva), and aminobutyric acid.
  • the basic hydrophilic amino acids are Lys, Arg, His, ornithine (Orn), p-aminophenylalanine, and 2,4-diaminobutyric acid (Dbu), and homoarginine (Har).
  • the neutral hydrophilic amino acids are Asn, Gln, Ser, Thr, and homoserine (Hse).
  • amino acid residues may contain substituents such as, for example, halogens, amino groups, amidino groups, or NH-C-HN
  • R 5 groups (wherein R 5 is as hereinabove described), at positions other than the carboxyl or amino terminus.
  • the phenylalanine residue may be substituted at one or more positions of the phenyl group with one or more of the substituentL hereinabove described.
  • the phenyl group may be substituted at the para-position with a halogen atom (such as fluorine, for example) or an amino group.
  • AA is an amino acid or a chain of at least two and no greater than 20 amino acids, wherein the C-terminal and the N-terminal of the amino acid or chain of amino acids is excluded.
  • one or more of the amino acid residues which is not a glycine residue is a D-amino acid residue.
  • Compounds in which each of the amino acid residues is a D-amino acid residue or a glycine residue have increased resistance to proteolytic enzymes found in the gut, and thus may be administered orally.
  • AA is an amino acid or a chain or two or more amino acids, excluding the N-terminus and C-terminus from said amino acid or chain of two or more amino acids.
  • R 1 is hydrogen or an alkyl group having from 1 to 8 carbon atoms.
  • R 2 is selected from the group consisting of (i) a substituted or unsubstituted an aliphatic hydrocarbon having from 1 to 20 carbon atoms, and
  • R 4 wherein R 4 is an aliphatic hydrocarbon having
  • R 4 may be substituted or unsubstituted.
  • R 3 is selected from the group consisting of (i) hydrogen;
  • R 1 is hydrogen. In another embodiment, R 1 is an alkyl group having from 1 to 8 carbon atoms.
  • R 2 is an alkyl group, and preferably an alkyl group having from 7 to 16 carbon atoms.
  • R 2 is R 4 , wherein R 4 is an
  • R 4 is an alkenyl group, more preferably an alkenyl group having from 2 to 4 carbon atoms, and most preferably R 4 is an alkenyl group having 2 carbon atoms.
  • R 3 is hydrogen. In another embodiment, R 3 is:
  • R 5 is hydrogen or a nitro group.
  • R 5 is hydrogen, whereas in another embodiment, R 5 is a nitro group.
  • R 3 is : 8 wherein each of R 6 , R 7 , and R 8 is hydrogen or methyl.
  • each of R 6 , R 7 , and R 8 is hydrogen. In another embodiment, each of R 6 , R 7 , and R 8 is methyl.
  • AA is an amino acid or a chain of at least two and no greater than 20 amino acids, excluding the C- terminal and the N-terminal of the amino acid or chain of at least two and no greater than 20 amino acids .
  • the amino acid(s) which are part of the compound may be those hereinabove described.
  • the amino acid residue(s) may be substituted at positions other than the carboxyl terminus or the amino terminus with substituent groups such as those hereinabove described.
  • the amino acid(s) is a hydrophobic amino acid residue, and preferably a phenylalanine residue. When the amino acid residue is a phenylalanine residue, such residue may, in one embodiment, be further modified such that the compound has the following structural formula:
  • R 1 , R 2 , and R 3 are as hereinabove described.
  • R 3 is hydrogen, and in another embodiment, R 3 is:
  • R 5 is as hereinabove described.
  • R 5 is hydrogen, whereas in another embodiment, R 5 is a nitro group.
  • Each of the amino acid residue(s) which is not a glycine residue may be a D-amino acid residue.
  • R 1 , R 2 and R 3 are as hereinabove described.
  • R 1 is hydrogen.
  • R 3 is: wherein R 5 ls hydrogen or a nitro group.
  • R 5 is hydrogen, whereas in another embodiment, R 5 is a nitro group.
  • a representative example of such a compound which may be administered in accordance with the present invention is 1,12 [bis- guanyl] diaminododecane, which has the following structure:
  • such compounds may be prepared from a diaminoalkane, which may be reacted with 1-methyl-3-nitro-1- nitrosoguanidine, and the nitro-guanylated product is the hydrogenated and purified by preparative HPLC to obtain the desired compound.
  • the compounds of the present invention may be administered to a host; for example a human or non-human animal, in an amount effective to inhibit growth of a target cell or virus.
  • the compounds may be used as antimicrobial agents, antiviral agents, anti-bacterial agents, anti-tumor agents, anti- parasitic agents, spermicides, as well as exhibiting other bioactive functions.
  • antimicrobial means that the compounds of the present invention inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, fungi, viruses, or the like.
  • anti-bacterial means that the compounds employed in the present invention produce effects adverse to the normal biological functions of bacteria, including death or destruction and prevention of the growth or proliferation of the bacteria when contacted with the compounds.
  • antibiotic means that the compounds employed in the present invention produce effects adverse to the normal biological functions of the non-host cell, tissue or organism, including death or destruction and prevention of the growth or proliferation of the non-host cell, tissue, or organism when contacted with the compounds.
  • spermicidal means that the compounds employed in the present invention, inhibit, prevent, or destroy the motility of sperm.
  • antiviral means that the compounds employed in the present invention inhibit, prevent, or destroy the growth or proliferation of viruses, or of virally-infected cells.
  • anti-tumor means that the compounds inhibit the growth of or destroy tumors, including cancerous tumors.
  • anti-parasitic means that the compounds employed in the present invention inhibit, prevent, or destroy the growth or proliferation of parasites.
  • the compounds of the present invention have a broad range of potent antibiotic activity against a plurality of microorganisms including gram-positive and gram-negative bacteria, fungi, protozoa, and the like, as well as parasites.
  • the compounds of the present invention allow a method for treating or controlling microbial infection caused by organisms which are sensitive to the compounds. Such treatment may comprise administering to a host organism or tissue susceptible to or affiliated with a microbial infection an antimicrobial amount of at least one of the compounds.
  • antibiotics because of the antibiotic, antimicrobial, antiviral, and antibacterial properties of the compounds, they may also be used as preservatives or sterilants or disinfectants of materials susceptible to microbial or viral contamination.
  • the compounds may be administered in combination with a non- toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • a non- toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • Such pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like.
  • the compositions containing the compounds of the present invention may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses, and the like, as well as by parasites.
  • the compounds of the present invention may be administered to a host; in particular a human or non-human animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or antimicrobial and/or antibacterial and/or anti-parasitic and/or an antispermicidal amount.
  • composition in accordance with the invention will contain an effective anti-microbial amount and/or an effective antispermicidal amount and/or an effective anti-viral amount and/or an effective anti-tumor amount and/or an effective anti-parasitic and/or an effective antibiotic amount of one or more of the hereinabove described compounds which have such activity.
  • the compounds may be administered by direct application of the compounds to the target cell or virus or virally-infected cell, or indirectly applied through systemic administration.
  • the compounds of the present invention may also be employed in promoting or stimulating healing of a wound in a host.
  • wound healing includes various aspects of the wound healing process.
  • These aspects include, but are limited to, increased contraction of the wound, increased deposition of connective tissue, as evidenced by, for example, increased deposition of collagen in the wound, and increased tensile strength of the wound, i.e., the compounds increase wound breaking strength.
  • the compounds of the present invention may also be employed so as to reverse the inhibition of wound healing caused by conditions which depress or compromise the immune system.
  • the compounds of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections.
  • the compounds may be used to treat skin and burn infections caused by organisms such as, but not limited to, P. aeruginosa and S. aureus.
  • the compounds are also useful in the prevention or treatment of eye infections.
  • infections may be caused by bacteria such as, but not limited to, P. aeruginosa, S. aureus, and N. gonorrhoea, by fungi such as but not limited to C. albicans and A. fumigatus, by parasites such as but not limited to A. castellani, or by viruses.
  • the compounds may also be effective in killing cysts, spores, or trophozoites of infection - causing organisms.
  • Such organisms include, but are not limited to Acanthamoeba which forms trophozoites or cysts, C. albicans, which forms spores, and A. fumigatus, which forms spores as well.
  • the compounds may also be administered to plants in an effective antimicrobial or antiviral or antiparasitic amount to prevent or treat microbial or viral or parasitic contamination thereof.
  • the compounds when used in topical compositions, are generally present in an amount of at least 0.1%, by weight. In most cases, it is not necessary to employ the compound in an amount greater than 2.0%, by weight.
  • the compound is present in an amount to achieve a serum level of the compound of at least about 5 ug/ml.
  • the serum level of the compound need not exceed 500 ug/ml.
  • a preferred serum level is about 100 ug/ml.
  • Such serum levels may be achieved by incorporating the compound in a composition to be administered systemically at a dose of from 1 to about 100 mg/kg. In general, the compound need not be administered at a dose exceeding 10 mg/kg.
  • the compounds of the present invention may be prepared by any acceptable methods for modifying the C-terminal and the N-terminal of amino acids or peptides to provide the compounds hereinabove described.
  • an amino acid or peptide may be reacted with an alkyl amine in the presence of 1,3-dicyclohexylcarbodiimide (DCC) to form an amino acid or peptide having an alkyl amide at the C-terminal.
  • DCC 1,3-dicyclohexylcarbodiimide
  • the C-terminal modified amino acid or peptide may then be reacted with a guanyl group to form an amino acid or peptide having an alkyl amide at the C-terminal and a guanyl group at the N-terminal.
  • DCC 1,3-dicyclohexylcarbodiimide
  • the C-terminal modified amino acid or peptide may then be reacted with a guanyl group to form an amino acid or peptide having an
  • the amino acids or peptides may be obtained is substantially pure form.
  • the unmodified peptide may be synthesized on an automatic peptide synthesizer. Journal of the American Chemical Society, Vol. 85, pgs. 2149-54 (1963). It is also possible to produce unmodified peptides by genetic engineering techniques.
  • DNA which encodes the peptides prior to the modification thereof.
  • DNA may be expressed by means known to those skilled in the art.
  • the compounds may be employed in combination with an ion having pharmacological properties for the purposes hereinabove described.
  • An ion having pharmacological properties is one which when introduced into a target cell, virus, or virally-infected cell, inhibits and/or prevents and/or destroys the growth of the target cell, virus, or virally-infected cell.
  • Such an ion having pharmacological properties is one which in the absence of an ion channel-forming peptide is unable to cross a natural or synthetic lipid membrane; in particular a cell membrane, in sufficient amounts to affect a cell or virus adversely.
  • the compound and ion having pharmacological properties may be administered as a single composition or in separate compositions, and the single or separate compositions may include additional materials, actives and/or inactives, in addition to the compound and ion having pharmacological properties.
  • ions having pharmacological properties there may be mentioned fluoride, peroxide, bicarbonate, silver, zinc, mercury, arsenic, copper, platinum, antimony, gold, thallium, nickel, selenium, bismuth, and cadmium ions.
  • the compound and the ion having pharmacological properties are employed in amounts effective to inhibit and/or prevent and/or destroy the growth of the target cell.
  • the ion potentiates the action of the compound, i.e., the amount of ion is effective to reduce the minimum effective concentration of the compound for inhibiting growth of a target cell, virus, or virally-infected cell.
  • the ion having pharmacological properties when used topically, is generally employed in a concentration of from 0.05% to 2.0%. When used systemically, the ion is generally employed in an amount of from 1 to 10 mg. per kg. of host weight. Dosages of the compound may be within the ranges hereinabove described.
  • the compound and ion having pharmacological properties may be delivered or administered in different forms; for example, the ion may be administered orally, while the compound may be administered by IV or IP.
  • the compound could be administered in an amount of up to about 1% weight to weight and the ion delivered in an amount of about 50mM (about 0.1%).
  • the ion, in the form of a salt such as sodium fluoride could be administered orally in conjunction with systemic administration of the compound.
  • the compound may be administered IV or IP to achieve a serum dose of 100 micrograms per milliliter (10 milligrams per kilogram) in conjunction with an oral dose of ion, in particular, sodium fluoride, of 10 meq per kilogram.
  • the compounds of the present invention may be administered to a host in combination with an antibiotic selected from the class consisting of bacitracins, gramicidin, polymyxin, vancomycin, teichoplanin, aminoglycosides, pseudomonic acids, cephalosporins, penem antibiotics, hydrophobic antibiotics, penicillins, monobactams, or derivatives or analogues thereof.
  • an antibiotic selected from the class consisting of bacitracins, gramicidin, polymyxin, vancomycin, teichoplanin, aminoglycosides, pseudomonic acids, cephalosporins, penem antibiotics, hydrophobic antibiotics, penicillins, monobactams, or derivatives or analogues thereof.
  • the bacitracins, gramicidin, polymyxin, vancomycin, teichoplanin, and derivatives and analogues thereof, are a group of polypeptide antibiotics.
  • a preferred bacitracin is bacitracin A.
  • Aminoglycoside antibiotics include tobramycin, kanamycin, amikacin, the gentamicins (e.g., gentamicin C 1 , gentamicin C 2 , gentamicin C 1a ), netilmicin, and derivatives and analogues thereof.
  • the preferred aminoglycosides are tobramycin and the gentamicins.
  • the aminoglycosides, and the bacitracins hereinabove described, tend to be hydrophilic and water-soluble.
  • Penicillins which may be employed include, but are not limited to benzyl penicillin, ampicillin, methicillin (dimethoxyphenyl penicillin), ticaricillin, penicillin V (phenoxymethyl penicillin), oxacillin, cloxacillin, dicloxacillin, flucloxacillin, amoxicillin, and amidinocillin.
  • Preferred penicillins which may be employed are benzyl penicillin and ampicillin.
  • a preferred monobactam which may be employed is aztreonam.
  • hydrophobic antibiotics which may be used in the present invention, there may be mentioned macrolides such as erythromycin, roxythromycin, clarithromycin, etc.; 9-N-alkyl derivatives of erythromycin; midecamycin acetate; azithromycin; flurithromycin; rifabutin; rokitamycin; a 6-0-methyl erythromycin A known as TE-031 (Taisho); rifapentine; benzypiperazinyl rifamycins such as CGP-7040, CGP-5909, CGP-279353 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the C 11 /C 12 position of a macrolide ring known as A-62514 (Abbott); AC-7230 (Toyo Jozo); benzoxazinorifamycin; difficidin; dirithromycin; a 3-N-piperdinomethyl
  • antibiotics which may be used are antibiotics which are 50-S ribosome inhibitors such as lincomycin; clindamycin; and chloramphenicol; etc.; antibiotics which have a large lipid like lactone ring, such as mystatin; pimaricin, etc.
  • the compound and antibiotic may be administered by direct administration to a target cell or by systemic or topical administration to a host which includes the target cell, in order to prevent, destroy or inhibit the growth of a target cell.
  • Target cells whose growth may be prevented, inhibited, or destroyed by the administration of the compounds and antibiotic include Gram- positive and Gram-negative bacteria as well as fungal cells.
  • the antibiotic such as those hereinabove described, or derivatives or analogues thereof, when used topically, is generally employed in a concentration of about 0.1% to about 10%.
  • the antibiotic or derivative or analogue thereof when used systemically, is generally employed in an amount of from 1.25 mg. to about 45 mg. per kg. of host weight per day. Dosages of the compound may be those as hereinabove described.
  • the compound could be administered in an amount of from about 0.1% to about 10% weight to weight, and the antibiotic is delivered in an amount of from about 0.1% to about 10% weight to weight.
  • the compounds of the present invention may be administered in combination with an antiparasitic agent or an antifungal agent.
  • Antiparasitic agents which may be employed include, but are not limited to, anti-protozoan agents.
  • specific anti- parasitic agents include, but are not limited to, pentamidine isethionate, and propamidine isethionate (Brolene).
  • Anti-fungal agents which may be employed include, but are not limited to, ketoconazole. It is also to be understood that certain anti-pairasitic agents, may also have anti-fungal activity, and that certain anti-fungal agents may have anti-parasitic activity.
  • the compounds of the present invention may be administered in combination with an antibiotic which inhibits DNA gyrase, which is an enzyme involved in the formation of bonds between individual coiling strands of replicating bacterial DNA.
  • DNA gyrase is necessary for the normal replication of bacterial DNA, and, therefore, antibiotics which inhibit DNA gyrase inhibit the normal replication of bacterial DNA.
  • antibiotics which inhibit DNA gyrase include nalidixic acid, oxolinic acid, cinoxacin, and quinolone antibiotics which include ciprofloxacin, norfloxacin, ⁇ floxacin, enoxacin, pefloxacin, lomefloxacin, fleroxacin, tosulfloxacin, temafloxacin, and rufloxacin.
  • the compounds of the present invention may be administered for the purpose hereinabove described in combination with biologically active amphiphilic peptides, or in combination with ion channel-forming proteins.
  • N- ⁇ -tert - butyloxycarbonyl (Boc) amino acid(s) was (were) placed into a DMF or DMF/CH 2 Cl 2 (10 ml/g) solvent system, and an equivalent amount of 1-hydroxybenzotriazole (HOBt) was added and the mixture was stirred in an ice-salt temperature bath.
  • a coupling reagent, 1-ethyl-3-dimethylaminopropyl carbodiimide/Hcl (equimolar amounts) was added and stirring continued for 20 minutes at about -15° C.
  • an amino component either as an alkyl amine or a suitably protected amino acid
  • reaction mixture was poured into a cold stirred solution of NaHCO 3 . After stirring for about 30 minutes the precipitate was filtered, washed with water, then 5% citric acid, then water, and then dried. The homogeneity of the product was checked by thin layer chromatography (TLC) in different solvent systems.
  • TLC thin layer chromatography
  • Compound 26 was prepared by following Procedures (i) and (ii).
  • Compound 28 was prepared by reacting N - ⁇ - Boc - p - benzyloxycarbonyl (Z) amino phenylalanine with heptylamine followed by treatment with HBr/hydroxyacetate and neutralization.
  • Compound 29 was prepared from Compound 15 by following Procedure (iii).
  • Compound 30 was prepared by reacting N - ⁇ - Boc - p - NH 2 (Z) phenylalanine with heptylamine after phenylalanine was subjected to Procedure (i), and then subjecting the product to Procedures (ii) and (iii).
  • Boc-phenylalanine was treated with bis-[(2-oxo-3-oxazolidinyl) phosphinic chloride] and triethylamine at ice bath temperature. Dioctylamine was added and stirring continued overnight in a cold room, and then at room temperature for one more day. Solvent was removed and the residue was placed in ethyl acetate and extracted with 0.5 N HCl, water, 5% NaHCO 3 solution, water, and then dried over anhydrous Na 2 SO 4 . The solvent was removed, and the product was characterized by thin layer chromatography.
  • 1,12-diaminododecane was reacted with 1-methyl-3-nitro-1- nitrosoguanidine at about 55°C for several days while following the progress of the reaction by thin layer chromatography. Solvent was removed under reduced pressure, triturated with ether and decanted. The residue then was triturated with water and decanted. The nitroguanylated product was purified in some cases and checked for antibacterial activities.
  • the crude product was placed into a mixture of CH 3 OH:acetic acid:water (9:1:1), and hydrogenated overnight at 40 psi in the presence of 10% Pd/C catalyst (0.5-1.0 equivalent amount by weight). The catalyst was filtered and concentrated in vacuo. The residue was triturated with ether, filtered, washed with ether, and then with petroleum ether, and then dried. The purification of the compound was carried out by preparative HPLC to obtain the desired compound.
  • the stock modified solutions of Compounds 1 through 12, 26 through 36, and 3-D, 9-D, and 12-D are diluted in serial dilutions (1:2) down the wells of a microtiter plate so that the final concentrations of the compounds in the wells are 0.25, 0.50, 1, 2,
  • aureus ATCC 25923, E. coli ATCC 25922, P. aeru ⁇ inosa ATCC 27853, or C. albicans were added to the wells in full strength Mueller Hinton broth (BBL 11443) from a mid-log culture.
  • the inoculum is standardized spectrophotometrically at 600 nm and is verified by colony counts.
  • the plates are incubated for 16-20 hours at 37°C, and the minimal inhibitory concentrations (MIC) for the compounds are determined.
  • Minimal inhibitory concentration is defined as the lowest concentration of amino acid or peptide which produces a clear well in the microtiter plate.
  • Example 2 Example 2 was tested for minimal inhibitory concentration against various organisms listed in Table II according to the assay procedure given m Example 2. The results are given in Table II below.
  • the compounds of the present invention may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • compositions may be used topically or
  • compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses,
  • the compound may be administered to a host in particular an animal, in an effective antibiotic and/or anti-tumor and/or antiviral and/or antimicrobial and/or antispermicidal and/or antifungal and/or antiparasitic amount, or in an amount effective to stimulate wound healing in a host.
  • the compounds may be administered either alone or in combination with an antibiotic or ion channel forming peptide or protein as hereinabove described.
  • the compound When the compound is administered in combination with an agent as hereinabove described, it is possible to administer the compound and agent in separate forms.
  • the agent may be administered systemically and the compound may be administered topically.
  • the compound When the compound is administered topically, it may be administered in combination with a water-soluble vehicle, said water-soluble vehicle being in the form of an ointment, cream, lotion, paste or the like.
  • water-soluble vehicles which may be employed include, but are not limited to, glycols, such as polyethylene glycol, hydroxycellulose, and KY Jelly.
  • the water-soluble vehicle is preferably free of an oily substance.
  • the compounds may also be employed in combination with a ion having pharmacological properties, as hereinabove
  • compositions and materials used for oral hygiene purposes include, but are not limited to, toothpastes, mouthwashes, tooth gels, and tooth powders.
  • Such composition may thus be used to treat or prevent periodontal disease, to prevent or reduce plaque, and/or to prevent or treat or reduce dental caries.
  • the compound and toxic ion may be used to inhibit, prevent, or destroy the growth of Streptococcus mutants, which is associated with dental caries and

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Abstract

Compounds which have one of structural formulae (I) or (II). AA is an amino acid residue or an amino acid chain of two or more amino acid residues, excluding the N-terminal and the C-terminal from said amino acid residue or amino acid chain of two or more amino acid residues; R1 is hydrogen or an alkyl group having from 1 to 8 carbon atoms; R2 is selected from the group consisting of (i) a substituted or unsubstituted hydrocarbon having from 1 to 20 carbon atoms, and (ii) (a). R4 is an aliphatic hydrocarbon having 1 to 4 carbon atoms. R4 may be substituted or unsubstituted. R3 is selected from the group consisting of (i) hydrogen; (ii) (b), wherein R5 is hydrogen or a nitro group; and (iii) (c), wherein each of R6, R7, and R8 is hydrogen or methyl. The above compounds are useful as pharmaceuticals for inhibiting the growth of target cells, viruses, or virally-infected cells.

Description

Amino Acids and Peptides having modified Terminals.
This application is a continuation-in-part of Application Serial No. 004,313, filed January 14, 1993.
This invention relates to biologically active amino acids and peptides. More particularly, this invention relates to biologically active amino acids and peptides having modified C-terminals and modified N-terminals.
Certain peptides, proteins, and dipeptides having C-terminal or N-terminal substitutions have been disclosed previously. Molinero, et al., Peptides (Giralt, et al., eds., pgs. 436-437 (1990)), disclose dipeptides substituted at the N-terminal with a lauroyl group. The dipeptides have surfactant activity, as well as antimicrobial activity. Antimicrobial activity was tested against Bacillus pumilus, Micrococcus lateus, Staphylococcus epidermidis, Corynebacterium agropyri, Micrococcus aurantaleus, Streptococcus faecalis, and Candida albicans. Copending U.S. Patent Application Serial No. 713,716, filed June 12, 1991, discloses amphiphilic ion channel-forming peptides or proteins which have C-terminal substitutions. The C-terminal substitutions may be C-terminal esters, C-terminal hydrazides, C-terminal hydroxylamines, or C- terminal amides. In accordance with an aspect of the present invention, there is provided a compound having the following structural formula:
Figure imgf000004_0001
R3 - N - AA - C - N - R2 - N - C - AA - N - R3.
AA is an amino acid or a chain of two or more amino acids, excluding the N-terminus and C-terminus from the amino acid or chain of two or more amino acids. R1 is hydrogen or an alkyl group having 1 to 3 carbon atoms. R2 is selected from the group consisting of (i) a substituted or unsubstituted aliphatic (i.e., alkyl, alkenyl, or alkynl) hydrocarbon having 1 to 20 carbon atoms, and (ii)
Figure imgf000004_0002
R4 is an aliphatic hydrocarbon having 1 to 4 carbon atoms. R4 may be substituted or unsubstituted.
R3 is selected from the group consisting of (i) hydrogen;
(ii) - C - NH
Figure imgf000004_0004
NH R5 ,wherein R5 is hydrogen or a nitro group; and
(iϋ)
7
wherein each of R6, R7, and R8 is
Figure imgf000004_0003
hydrogen or methyl.
In one embodiment, R1 is hydrogen. In another embodiment, R1 is an alkyl group having from 1 to 8 carbon atoms.
In another embodiment, R1 is an alkyl group and preferably an alkyl group having from 7 to 16 carbon atoms.
In yet another embodiment, R2 is R4 , wherein R4 is
Figure imgf000004_0005
Figure imgf000004_0006
an aliphatic hydrocarbon having from 1 to 4 carbon atoms. Preferably, R4 is an alkenyl group, more preferably an alkenyl group having from 2 to 4 carbon atoms, and most preferably R4 is an alkenyl group having 2 carbon atoms. In one embodiment, R3 is hydrogen. In another embodiment, R3 is:
In one embodiment, R5 is hydrogen, while in another embodiment, R5 is a nitro group.
In yet another embodiment, R5 is
Figure imgf000005_0001
In one embodiment, each of R6, R7, and R8 is hydrogen. In another embodiment, each of R6, R7, and R8 is methyl.
The amino acid residues which may be contained in the compound can be amino acid residues known to those skilled in the art. Such residues include, but are not limited to, hydrophobic amino acid residues, basic hydrophilic amino acid residues, and neutral hydrophilic amino acid residues.
The hydrophobic amino acids are Ala, Cys, Gly, lle, Leu, Met, Phe, Pro, Trp, Tyr, Val, cyclohexylalanine (Cha), norleucine (Nle), norvaline (Nva), and aminobutyric acid.
The basic hydrophilic amino acids are Lys, Arg, His, ornithine (Orn), p-aminophenylalanine, and 2,4-diaminobutyric acid (Dbu), and homoarginine (Har).
The neutral hydrophilic amino acids are Asn, Gln, Ser, Thr, and homoserine (Hse).
Within the scope of the present invention, the amino acid residues may contain substituents such as, for example, halogens, amino groups, amidino groups, or NH-C-HN
Figure imgf000005_0003
NH R5 groups (wherein R5 is as hereinabove described), at positions other than the carboxyl or amino terminus. For example, when a phenylalanine residue is employed, the phenylalanine residue may be substituted at one or more positions of the phenyl group with one or more of the substituentL hereinabove described. As an illustrative example, the phenyl group may be substituted at the para-position with a halogen atom (such as fluorine, for example) or an amino group.
In another embodiment, AA is an amino acid or a chain of at least two and no greater than 20 amino acids, wherein the C-terminal and the N-terminal of the amino acid or chain of amino acids is excluded.
In one embodiment, one or more of the amino acid residues which is not a glycine residue is a D-amino acid residue. Compounds in which each of the amino acid residues is a D-amino acid residue or a glycine residue have increased resistance to proteolytic enzymes found in the gut, and thus may be administered orally.
Representative examples of such compounds of the present invention include, but are not limited to, the following:
1. [1-nitroamidino phenylalanyl-12-nitroamidino phenylalanyl] 1, 12 diaminododecane
O2N-HN-C-HN-HC-CO-NH ( CH2 ) 12NH-CO-CH-NH-C-NH-NO2
Figure imgf000006_0001
2. [1-nitroamidino phenylalanyl-12-amidino-phenylalanyl] 1, 12- diaminododecane.
O2N-NH-C-HN-CH-CO-NH ( CH2 ) n NH-CO-CH-NH-C-NH2
Figure imgf000006_0002
3. 1, 12-[bis-N-α-amidino-phenylalanyl] diammododecane H2N-C-HN-CH-CO-NH(CH2)12 NH-CO-CH-NH-C-NH2
Figure imgf000007_0001
4. 1, 12-[bis-N-α-amidino-tyrosyl] diammododecane.
H2N-C-HN-CH-CONH(CH2)12 NHCO-CH-NH-C-NH2
Figure imgf000007_0002
5. [1-nitroamidino-seryl-12 amidino-seryl]-1,
12 -diammododecane.
O2N-HN-C-NH-CH-CO-NH(CH2)12 NH-CO-CH-NH-C-NH2
Figure imgf000007_0003
6. 1, 7-[bis-N-α-amidino-phenylalanyl] diaminoheptane, H2N-C-HN-CH-CO-NH(CH2)7NH-CO-CH-NH-C-NH2
Figure imgf000007_0004
7. 1, 7-[bis-N-α-amidino-seryl] diaminoheptane.
H2N-C-HN-CH-CO-NH(CH2)7NH-CO-CH-NH-C-NH,
Figure imgf000007_0005
8. 1, 12 - [di-arginyl] diammododecane.
H2N - CH - CO NH(CH2)12 NHCO - CH - NH2
Figure imgf000008_0001
9. 1, 12 - [di-arginyl-phenylalanyl] diammododecane.
H2N - CH - CO - NH-CH-CONH(CH2)12 NHCO - CH - NH - CO - CH - NH2
Figure imgf000008_0002
10. 1, 12 - [di-N-α-amidino-arginyl-phenylalanyl] diaminododecane.
NH2-C-NH-CH-CO-NH-CH-CONH ( CH2 )12NHCO-CH-CONH-CH-NH-C-NH2
Figure imgf000008_0003
11. 1, 12-[bis-N-α -amidino-p-fluoro-phenylalanyl]diaminododecane
Figure imgf000008_0004
12. 1,12-[di-B-alanyl-arginyl-phenylalanyl] diamino dodecane
H2N-CH2CH2CO-NH-CH-CO-NH-CH-CO-NH(CH2)12NH-CO-CH-NH-CO-CH-NH-COCH2CH2NH2
Figure imgf000009_0001
13. 1,12-[di-(N-α-amidino-seryl)] diaminododecane.
NH2-C-NH-CH-CONH(CH2)12 NHCO-CH-NH-C-NH2
Figure imgf000009_0002
14. 1 , 12-[di-amidino-β-alanyl-arginyl-phenylalanyl ) ] diaminododecane.
NH2-C-NH-CH2CH2CONH-CHCONHCH-CONH(CH2)12NHCOCHNHCO-CH-NHCOCH2CH2NHCNH2
Figure imgf000009_0003
15. 1-12, -[di-[Boc-γ-aminobutyryl-arginyl-phenylalanyl) ] diaminododecane.
(CH3)3-C-OC-NH2-(CH2)3-CONH-CH-CO-NH-CH-CONH(CH2)12NHCOCHNHCOCH-NHCO(CH2)3NH- -O-C-(CH3)3
Figure imgf000009_0005
Figure imgf000009_0004
16. 1,12-[di-(Boc-alanyl-arginyl-phenylalanyl)] diaminododecane.
Figure imgf000010_0005
(CH3)3CO-C-NHCHCONHCHCONHCHCONH(CH2)12NHCOCHNHCOCHNHCOCHNH-C-OC(CH3)3
3
Φ 6
Figure imgf000010_0004
17. 1,12-[di ( γ-aminobutyryl-arginyl-phenylalanyl) ] diaminododecane.
NH2(CH2)3CONHCHCONHCHCONH(CH2)12NHCOCHNHCOCHNHCO (CH2)3NH2
Figure imgf000010_0003
18. 1,12-[di(alanyl-arginyl-phenylalanyl)] diaminododecane.
NH2-CHCONHCHCONHCHCONH(CH2)12NHCOCHNHCOCHNHCOCHNH,
Figure imgf000010_0001
19. 1,12-[di-(p-F-phenylalanyl)] diaminododecane.
NH2-CHCONH(CH2)12NHCOCH-NH2
Figure imgf000010_0002
20. 1,12-[di-(arginyl-arginyl-phenylalanyl)]diaminododecane. NH2-CHCONHCHCONH-CHCONH(CH2)12NHCOCHNHCOCHNHCOCH-NH2
Figure imgf000011_0001
21. 1,12-[di-(glutamyl-arginyl-phenylalanyl)]diaminododecane.
NH2-CHCONHCHCONHCHCONH(CH2)12NHCOCHNHCOCHNHCOCH-NH2
Figure imgf000011_0002
22. 1,12-[di-phenyalanyl-arginyl)]diaminododecane.
NH2-CHCONHCHCONH(CH2)12NHCOCHNHCOCH-NH2 -
Figure imgf000011_0003
23. 1,2-[di-(arginyl-phenylalanyl-threonyl-threonyl)]diaminoethane NH2-CHCONHCHCONHCHCONHCHCONH(CH2)2NHCOCHNHCOCHNHCOCHNHCOCH-NH2
Figure imgf000011_0004
24. 4-(N-α-amidino-phenylalany1)-4'-phenylalanyl-diaminostilbene
NH2-C-NH-CHCONH-
Figure imgf000011_0006
-CH=CH-
Figure imgf000011_0007
-NHCOCH-NH2
Figure imgf000011_0005
25. 4,4'-[di-(arginyl-phenylalanyl)]diaminostilbene
NH2-CHCONHCHCONH
Figure imgf000012_0006
-CH=CH-
Figure imgf000012_0007
)-NHCOCHNHCOCH-NH2
>
Figure imgf000012_0002
The above compounds are sometimes hereinafter referred to as Compounds 1 through 25, respectively.
In accordance with another aspect of the present invention, there is provided a compound having the following structural formula:
Figure imgf000012_0001
AA is an amino acid or a chain or two or more amino acids, excluding the N-terminus and C-terminus from said amino acid or chain of two or more amino acids. R1 is hydrogen or an alkyl group having from 1 to 8 carbon atoms. R2 is selected from the group consisting of (i) a substituted or unsubstituted an aliphatic hydrocarbon having from 1 to 20 carbon atoms, and
(ii)
Figure imgf000012_0003
R4 wherein R4 is an aliphatic hydrocarbon having
Figure imgf000012_0004
1 to 4 carbon atoms. R4 may be substituted or unsubstituted. R3 is selected from the group consisting of (i) hydrogen;
(ii)
Figure imgf000012_0005
wherein R5 is hydrogen or a nitro group; and (iii) wherein each of R6, R7, and R8 is
Figure imgf000013_0001
hydrogen or methyl.
In one embodiment, R1 is hydrogen. In another embodiment, R1 is an alkyl group having from 1 to 8 carbon atoms.
In a preferred embodiment, R2 is an alkyl group, and preferably an alkyl group having from 7 to 16 carbon atoms.
In another embodiment, R2 is R4 , wherein R4 is an
Figure imgf000013_0002
Figure imgf000013_0003
aliphatic hydrocarbon having from 1 to 4 carbon atoms. Preferably, R4 is an alkenyl group, more preferably an alkenyl group having from 2 to 4 carbon atoms, and most preferably R4 is an alkenyl group having 2 carbon atoms.
In one embodiment, R3 is hydrogen. In another embodiment, R3 is:
Figure imgf000013_0004
NH R5, wherein R5 is hydrogen or a nitro group. In one embodiment, R5 is hydrogen, whereas in another embodiment, R5 is a nitro group.
In another embodiment, R3 is : 8 wherein each of R6, R7, and R8 is hydrogen or methyl.
Figure imgf000013_0005
In one embodiment, each of R6, R7, and R8 is hydrogen. In another embodiment, each of R6, R7, and R8 is methyl.
In another embodiment, AA is an amino acid or a chain of at least two and no greater than 20 amino acids, excluding the C- terminal and the N-terminal of the amino acid or chain of at least two and no greater than 20 amino acids . The amino acid(s) which are part of the compound may be those hereinabove described. The amino acid residue(s) may be substituted at positions other than the carboxyl terminus or the amino terminus with substituent groups such as those hereinabove described. In one embodiment, the amino acid(s) is a hydrophobic amino acid residue, and preferably a phenylalanine residue. When the amino acid residue is a phenylalanine residue, such residue may, in one embodiment, be further modified such that the compound has the following structural formula:
Figure imgf000014_0001
wherein R1, R2, and R3 are as hereinabove described. In one embodiment, R3 is hydrogen, and in another embodiment, R3 is:
Figure imgf000014_0002
NH R5, wherein R5 is as hereinabove described. In one embodiment, R5 is hydrogen, whereas in another embodiment, R5 is a nitro group.
Each of the amino acid residue(s) which is not a glycine residue, may be a D-amino acid residue.
Representative examples of compounds having the structural formula hereinabove described include the following:
26. phenylalanyl heptylamide
CH2 - CH - CO - NH(CH2)6 CH3
Figure imgf000014_0003
Figure imgf000014_0004
27. N-α - amidino phenylalanyl heptylamide
CH2 - CH - CO - NH(CH2)6 CH3
Figure imgf000015_0001
Figure imgf000015_0002
28. p-amino-pheny lalany 1 heptylamide
H2N CH2 - CH - CO - NH(CH2)6 CH3
Figure imgf000015_0003
Figure imgf000015_0004
29 p-guanyl-N-α-amidino-pheny lalany 1 heptylamide
H2N C - HN -CH2 - CH - CO - NH(CH2)6CH3
Figure imgf000015_0006
Figure imgf000015_0005
Figure imgf000015_0007
30. p-amino-N-α-amidino-phenylalanyl heptylamide H2N - CH2 - CH - CO - NH(CH2)6CH3
Figure imgf000015_0008
Figure imgf000015_0009
31. N-α-amidino-pheynlalanyl dodecylamide
H2N - C - HN - CH - CONH(CH2)11CH3
Figure imgf000015_0010
Figure imgf000015_0011
32. N-α-amidino-phenylalanyl dioctylamide
( CH2 )7CH3
H2N - C-HN - CH - CO - N
Figure imgf000016_0001
( CH2 ) 7CH3
Figure imgf000016_0002
33. N-α-amidino phenylalanyl tetradecylamide
CH2-CH-CO-NH-(CH2)13CH3
Figure imgf000016_0003
Figure imgf000016_0004
34 . N-α-amidino phenylalanyl hexadecylamide
CH2-CH-CO-NH ( CH2) 15CH3
Figure imgf000016_0005
Figure imgf000016_0006
35. arginyl-phenylalanyl dioctylamide H2N-CH-CO-NH-CH-CO-
Figure imgf000016_0007
Figure imgf000016_0008
Such compounds are sometimes hereinafter referred to as
Compounds 26 through 35, respectively. In accordance with another aspect of the present invention, there is provided a process for inhibiting the growth of a target cell, virus, or virally-infected cell in a host. The process comprises administering to a host a compound having the following structural formula:
1 1
Figure imgf000017_0001
R1, R2 and R3 are as hereinabove described. In one embodiment, R1 is hydrogen. In another embodiment, R3 is:
Figure imgf000017_0002
wherein R5 ls hydrogen or a nitro group. In one embodiment, R5 is hydrogen, whereas in another embodiment, R5 is a nitro group.
A representative example of such a compound which may be administered in accordance with the present invention is 1,12 [bis- guanyl] diaminododecane, which has the following structure:
H2 N-C-HN-(CH2)12 - NH-C-NH2
Figure imgf000017_0003
Figure imgf000017_0004
This compound is sometimes hereinafter referred to as Compound 36.
In general, such compounds may be prepared from a diaminoalkane, which may be reacted with 1-methyl-3-nitro-1- nitrosoguanidine, and the nitro-guanylated product is the hydrogenated and purified by preparative HPLC to obtain the desired compound.
The compounds of the present invention may be administered to a host; for example a human or non-human animal, in an amount effective to inhibit growth of a target cell or virus. Thus, for example, the compounds may be used as antimicrobial agents, antiviral agents, anti-bacterial agents, anti-tumor agents, anti- parasitic agents, spermicides, as well as exhibiting other bioactive functions.
The term "antimicrobial" as used herein means that the compounds of the present invention inhibit, prevent, or destroy the growth or proliferation of microbes such as bacteria, fungi, viruses, or the like.
The term "anti-bacterial" as used herein means that the compounds employed in the present invention produce effects adverse to the normal biological functions of bacteria, including death or destruction and prevention of the growth or proliferation of the bacteria when contacted with the compounds.
The term "antibiotic" as used herein means that the compounds employed in the present invention produce effects adverse to the normal biological functions of the non-host cell, tissue or organism, including death or destruction and prevention of the growth or proliferation of the non-host cell, tissue, or organism when contacted with the compounds.
The term "spermicidal" as used herein means that the compounds employed in the present invention, inhibit, prevent, or destroy the motility of sperm.
The term "antiviral" as used herein means that the compounds employed in the present invention inhibit, prevent, or destroy the growth or proliferation of viruses, or of virally-infected cells.
The term "anti-tumor" as used herein means that the compounds inhibit the growth of or destroy tumors, including cancerous tumors.
The term "anti-parasitic" as used herein means that the compounds employed in the present invention inhibit, prevent, or destroy the growth or proliferation of parasites.
The compounds of the present invention have a broad range of potent antibiotic activity against a plurality of microorganisms including gram-positive and gram-negative bacteria, fungi, protozoa, and the like, as well as parasites. The compounds of the present invention allow a method for treating or controlling microbial infection caused by organisms which are sensitive to the compounds. Such treatment may comprise administering to a host organism or tissue susceptible to or affiliated with a microbial infection an antimicrobial amount of at least one of the compounds.
Because of the antibiotic, antimicrobial, antiviral, and antibacterial properties of the compounds, they may also be used as preservatives or sterilants or disinfectants of materials susceptible to microbial or viral contamination.
The compounds may be administered in combination with a non- toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution. Such pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like. The compositions containing the compounds of the present invention may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses, and the like, as well as by parasites.
The compounds of the present invention may be administered to a host; in particular a human or non-human animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or antimicrobial and/or antibacterial and/or anti-parasitic and/or an antispermicidal amount.
Depending on the use, a composition in accordance with the invention will contain an effective anti-microbial amount and/or an effective antispermicidal amount and/or an effective anti-viral amount and/or an effective anti-tumor amount and/or an effective anti-parasitic and/or an effective antibiotic amount of one or more of the hereinabove described compounds which have such activity. The compounds may be administered by direct application of the compounds to the target cell or virus or virally-infected cell, or indirectly applied through systemic administration.
The compounds of the present invention may also be employed in promoting or stimulating healing of a wound in a host.
The term "wound healing" as used herein includes various aspects of the wound healing process.
These aspects include, but are limited to, increased contraction of the wound, increased deposition of connective tissue, as evidenced by, for example, increased deposition of collagen in the wound, and increased tensile strength of the wound, i.e., the compounds increase wound breaking strength. The compounds of the present invention may also be employed so as to reverse the inhibition of wound healing caused by conditions which depress or compromise the immune system.
The compounds of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections. In particular, the compounds may be used to treat skin and burn infections caused by organisms such as, but not limited to, P. aeruginosa and S. aureus.
The compounds are also useful in the prevention or treatment of eye infections. Such infections may be caused by bacteria such as, but not limited to, P. aeruginosa, S. aureus, and N. gonorrhoea, by fungi such as but not limited to C. albicans and A. fumigatus, by parasites such as but not limited to A. castellani, or by viruses.
The compounds may also be effective in killing cysts, spores, or trophozoites of infection - causing organisms. Such organisms include, but are not limited to Acanthamoeba which forms trophozoites or cysts, C. albicans, which forms spores, and A. fumigatus, which forms spores as well.
The compounds may also be administered to plants in an effective antimicrobial or antiviral or antiparasitic amount to prevent or treat microbial or viral or parasitic contamination thereof.
The compounds, when used in topical compositions, are generally present in an amount of at least 0.1%, by weight. In most cases, it is not necessary to employ the compound in an amount greater than 2.0%, by weight.
In employing such compositions systemically (intramuscular, intravenous, intraperitoneal), the compound is present in an amount to achieve a serum level of the compound of at least about 5 ug/ml. In general, the serum level of the compound need not exceed 500 ug/ml. A preferred serum level is about 100 ug/ml. Such serum levels may be achieved by incorporating the compound in a composition to be administered systemically at a dose of from 1 to about 100 mg/kg. In general, the compound need not be administered at a dose exceeding 10 mg/kg.
The compounds of the present invention, having modified C- terminals and modified N-terminals, may be prepared by any acceptable methods for modifying the C-terminal and the N-terminal of amino acids or peptides to provide the compounds hereinabove described. For example, an amino acid or peptide may be reacted with an alkyl amine in the presence of 1,3-dicyclohexylcarbodiimide (DCC) to form an amino acid or peptide having an alkyl amide at the C-terminal. The C-terminal modified amino acid or peptide may then be reacted with a guanyl group to form an amino acid or peptide having an alkyl amide at the C-terminal and a guanyl group at the N-terminal. It is to be understood, however, that the scope of the present invention is not to be limited to any specific moieties at the C-terminal or N-terminal, or to any specific reaction scheme for preparing the compounds.
The amino acids or peptides (including 2 or more amino acids), prior to the modification thereof, may be obtained is substantially pure form. When a peptide is desired to be modified in accordance with the present invention, the unmodified peptide may be synthesized on an automatic peptide synthesizer. Journal of the American Chemical Society, Vol. 85, pgs. 2149-54 (1963). It is also possible to produce unmodified peptides by genetic engineering techniques.
Thus, within the scope of the present invention there may be provided DNA which encodes the peptides prior to the modification thereof. Such DNA may be expressed by means known to those skilled in the art.
In accordance with another embodiment, the compounds may be employed in combination with an ion having pharmacological properties for the purposes hereinabove described.
An ion having pharmacological properties is one which when introduced into a target cell, virus, or virally-infected cell, inhibits and/or prevents and/or destroys the growth of the target cell, virus, or virally-infected cell.
Such an ion having pharmacological properties is one which in the absence of an ion channel-forming peptide is unable to cross a natural or synthetic lipid membrane; in particular a cell membrane, in sufficient amounts to affect a cell or virus adversely.
The compound and ion having pharmacological properties may be administered as a single composition or in separate compositions, and the single or separate compositions may include additional materials, actives and/or inactives, in addition to the compound and ion having pharmacological properties. As representative examples of ions having pharmacological properties which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, silver, zinc, mercury, arsenic, copper, platinum, antimony, gold, thallium, nickel, selenium, bismuth, and cadmium ions.
The compound and the ion having pharmacological properties, whether administered or prepared in a single composition or in separate compositions, are employed in amounts effective to inhibit and/or prevent and/or destroy the growth of the target cell. In effect, the ion potentiates the action of the compound, i.e., the amount of ion is effective to reduce the minimum effective concentration of the compound for inhibiting growth of a target cell, virus, or virally-infected cell.
The ion having pharmacological properties, when used topically, is generally employed in a concentration of from 0.05% to 2.0%. When used systemically, the ion is generally employed in an amount of from 1 to 10 mg. per kg. of host weight. Dosages of the compound may be within the ranges hereinabove described.
It is also to be understood that the compound and ion having pharmacological properties, may be delivered or administered in different forms; for example, the ion may be administered orally, while the compound may be administered by IV or IP.
As representative examples of administering the compound and ion for topical or local administration, the compound could be administered in an amount of up to about 1% weight to weight and the ion delivered in an amount of about 50mM (about 0.1%). Alternatively, the ion, in the form of a salt such as sodium fluoride, could be administered orally in conjunction with systemic administration of the compound. For example, the compound may be administered IV or IP to achieve a serum dose of 100 micrograms per milliliter (10 milligrams per kilogram) in conjunction with an oral dose of ion, in particular, sodium fluoride, of 10 meq per kilogram.
In accordance with another embodiment, the compounds of the present invention may be administered to a host in combination with an antibiotic selected from the class consisting of bacitracins, gramicidin, polymyxin, vancomycin, teichoplanin, aminoglycosides, pseudomonic acids, cephalosporins, penem antibiotics, hydrophobic antibiotics, penicillins, monobactams, or derivatives or analogues thereof.
The bacitracins, gramicidin, polymyxin, vancomycin, teichoplanin, and derivatives and analogues thereof, are a group of polypeptide antibiotics. A preferred bacitracin is bacitracin A. Aminoglycoside antibiotics include tobramycin, kanamycin, amikacin, the gentamicins (e.g., gentamicin C1, gentamicin C2, gentamicin C1a), netilmicin, and derivatives and analogues thereof. The preferred aminoglycosides are tobramycin and the gentamicins. The aminoglycosides, and the bacitracins hereinabove described, tend to be hydrophilic and water-soluble.
Penicillins which may be employed include, but are not limited to benzyl penicillin, ampicillin, methicillin (dimethoxyphenyl penicillin), ticaricillin, penicillin V (phenoxymethyl penicillin), oxacillin, cloxacillin, dicloxacillin, flucloxacillin, amoxicillin, and amidinocillin. Preferred penicillins which may be employed are benzyl penicillin and ampicillin. A preferred monobactam which may be employed is aztreonam.
As representative examples of hydrophobic antibiotics which may be used in the present invention, there may be mentioned macrolides such as erythromycin, roxythromycin, clarithromycin, etc.; 9-N-alkyl derivatives of erythromycin; midecamycin acetate; azithromycin; flurithromycin; rifabutin; rokitamycin; a 6-0-methyl erythromycin A known as TE-031 (Taisho); rifapentine; benzypiperazinyl rifamycins such as CGP-7040, CGP-5909, CGP-279353 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the C11/C12 position of a macrolide ring known as A-62514 (Abbott); AC-7230 (Toyo Jozo); benzoxazinorifamycin; difficidin; dirithromycin; a 3-N-piperdinomethylzaino methyl rifamycin SV known as FCE-22250 (Farmitalia); M-119-a (Kirin Brewery); a 6-0-methyl-1- 4"-0-carbamoyl erythromycin known as A-63075 (Abbott); 3- formylrifamycin SV-hydrazones with diazabicycloalkyl side chains such as CGP-27557 and CGP-2986 (Ciba-Geigy); and 16-membered macrolides having a 3-0-alpha-L-cladinosyl moiety, such as 3-0- alpha-L-cladinosyldeepoxy rosaramicin; tylosins and acyl demycinosyl tylosins.
In addition to the macrolides hereinabove described, rifamycin, carbenicillin, and nafcillin may be employed as well. Other antibiotics which may be used (whether or not hydrophobic) are antibiotics which are 50-S ribosome inhibitors such as lincomycin; clindamycin; and chloramphenicol; etc.; antibiotics which have a large lipid like lactone ring, such as mystatin; pimaricin, etc.
The compound and antibiotic may be administered by direct administration to a target cell or by systemic or topical administration to a host which includes the target cell, in order to prevent, destroy or inhibit the growth of a target cell. Target cells whose growth may be prevented, inhibited, or destroyed by the administration of the compounds and antibiotic include Gram- positive and Gram-negative bacteria as well as fungal cells.
The antibiotic, such as those hereinabove described, or derivatives or analogues thereof, when used topically, is generally employed in a concentration of about 0.1% to about 10%. When used systemically, the antibiotic or derivative or analogue thereof is generally employed in an amount of from 1.25 mg. to about 45 mg. per kg. of host weight per day. Dosages of the compound may be those as hereinabove described.
As representative examples of administering the compound and antibiotic for topical or local administration, the compound could be administered in an amount of from about 0.1% to about 10% weight to weight, and the antibiotic is delivered in an amount of from about 0.1% to about 10% weight to weight.
In accordance with another embodiment, the compounds of the present invention may be administered in combination with an antiparasitic agent or an antifungal agent.
Antiparasitic agents which may be employed include, but are not limited to, anti-protozoan agents. Examples of specific anti- parasitic agents which may be employed include, but are not limited to, pentamidine isethionate, and propamidine isethionate (Brolene).
Anti-fungal agents which may be employed include, but are not limited to, ketoconazole. It is also to be understood that certain anti-pairasitic agents, may also have anti-fungal activity, and that certain anti-fungal agents may have anti-parasitic activity.
In accordance with another embodiment, the compounds of the present invention may be administered in combination with an antibiotic which inhibits DNA gyrase, which is an enzyme involved in the formation of bonds between individual coiling strands of replicating bacterial DNA. Thus, DNA gyrase is necessary for the normal replication of bacterial DNA, and, therefore, antibiotics which inhibit DNA gyrase inhibit the normal replication of bacterial DNA.
Examples of antibiotics which inhibit DNA gyrase include nalidixic acid, oxolinic acid, cinoxacin, and quinolone antibiotics which include ciprofloxacin, norfloxacin, όfloxacin, enoxacin, pefloxacin, lomefloxacin, fleroxacin, tosulfloxacin, temafloxacin, and rufloxacin.
In accordance with another embodiment, the compounds of the present invention may be administered for the purpose hereinabove described in combination with biologically active amphiphilic peptides, or in combination with ion channel-forming proteins.
The present invention will be further described with respect to the following examples; however, the scope of the invention is not to be limited thereby.
Example 1
A. Preparation of Compounds 1-25, 27, 29, 31, 33, and 34
Procedure (i)
N- α -tert - butyloxycarbonyl (Boc) amino acid(s) was (were) placed into a DMF or DMF/CH2Cl2 (10 ml/g) solvent system, and an equivalent amount of 1-hydroxybenzotriazole (HOBt) was added and the mixture was stirred in an ice-salt temperature bath. A coupling reagent, 1-ethyl-3-dimethylaminopropyl carbodiimide/Hcl (equimolar amounts) was added and stirring continued for 20 minutes at about -15° C. To this reaction mixture, an amino component (either as an alkyl amine or a suitably protected amino acid), as a free base, was added and stirring continued overnight at room temperature. After concentrating the solvent to about half the original volume the reaction mixture was poured into a cold stirred solution of NaHCO3. After stirring for about 30 minutes the precipitate was filtered, washed with water, then 5% citric acid, then water, and then dried. The homogeneity of the product was checked by thin layer chromatography (TLC) in different solvent systems.
Procedure (ii)
The compound was then treated with either trifluoroacetic acid (TFA) or 50% TFA in CHCl3 (10 ml/g) for 30 minutes, and concentrated at reduced pressure at about 30°C in order to remove the Boc group. The residue was treated with ether, filtered, washed with ether, petroleum ether, and then dried.
Procedure (iii) - Guanylation
The residue was then treated with 1-methyl-3-nitro-1- nitrosoguanidine at about 55°C for several days while following the progress of the reaction by thin layer chromatography. Solvent was removed under reduced pressure, triturated with ether and decanted. The residue then was triturated with water and decanted. The nitroguanylated product was purified in some cases and checked for antibacterial activities. The crude product was placed into a mixture of CH3OH: acetic acid: water (9:1:1), and hydrogenated overnight at 40 psi in the presence of 10% Pd/C catalyst (0.5-1.0 equivalent amount by weight). The catalyst was filtered and concentrated in vacuo. The residue was triturated with ether, filtered, washed with ether, and then with petroleum ether, and then dried. The purification of the compound was carried out by reverse phase HPLC (C-18 Dynamax, 300A).. The homogeneity of the product was checked by thin layer chromatography and mass spectrophotometry. B. Preparation of Compound 26
Compound 26 was prepared by following Procedures (i) and (ii).
C. Preparation of Compounds 28 and 29
Compound 28 was prepared by reacting N - α - Boc - p - benzyloxycarbonyl (Z) amino phenylalanine with heptylamine followed by treatment with HBr/hydroxyacetate and neutralization.
Compound 29 was prepared from Compound 15 by following Procedure (iii).
D. Preparation of Compound 30
Compound 30 was prepared by reacting N - α- Boc - p - NH2 (Z) phenylalanine with heptylamine after phenylalanine was subjected to Procedure (i), and then subjecting the product to Procedures (ii) and (iii).
E. Preparation of Compound 32
Boc-phenylalanine was treated with bis-[(2-oxo-3-oxazolidinyl) phosphinic chloride] and triethylamine at ice bath temperature. Dioctylamine was added and stirring continued overnight in a cold room, and then at room temperature for one more day. Solvent was removed and the residue was placed in ethyl acetate and extracted with 0.5 N HCl, water, 5% NaHCO3 solution, water, and then dried over anhydrous Na2SO4. The solvent was removed, and the product was characterized by thin layer chromatography.
The product was then treated according to Procedures (ii) and (iii) to provide Compound 32.
F. Preparation of Compound 35
Compound 32 was deblocked according to Procedure (ii), and coupled with BOC-arginine (NO2)-OH. Hydrogenolysis followed by TFA treatment yielded Compound 35.
G. Preparation of Compound 36
1,12-diaminododecane was reacted with 1-methyl-3-nitro-1- nitrosoguanidine at about 55°C for several days while following the progress of the reaction by thin layer chromatography. Solvent was removed under reduced pressure, triturated with ether and decanted. The residue then was triturated with water and decanted. The nitroguanylated product was purified in some cases and checked for antibacterial activities. The crude product was placed into a mixture of CH3OH:acetic acid:water (9:1:1), and hydrogenated overnight at 40 psi in the presence of 10% Pd/C catalyst (0.5-1.0 equivalent amount by weight). The catalyst was filtered and concentrated in vacuo. The residue was triturated with ether, filtered, washed with ether, and then with petroleum ether, and then dried. The purification of the compound was carried out by preparative HPLC to obtain the desired compound.
Example 2
Antimicrobial Assay
The procedure for the antimicrobial assay is based upon the guidelines of the National Committee for Clinical Laboratory Standards, Document M7-T2, Volume 8, No. 8, 1988.
Stock solutions of Compounds 3, 4, 6, and 8 through 12, 26, 27, 29, and 31 through 36, as well as Compounds 3-D, 9-D, 12-D, wherein each of the amino acid residues of Compounds 3, 9 and 12 is D-amino acid residue, are prepared as hereinabove described in Example 1, at a concentration of 512 μg/ml in sterile deionized distilled water and stored at -70°C.
The stock modified solutions of Compounds 1 through 12, 26 through 36, and 3-D, 9-D, and 12-D are diluted in serial dilutions (1:2) down the wells of a microtiter plate so that the final concentrations of the compounds in the wells are 0.25, 0.50, 1, 2,
4, 8, 16, 32, 64, 128, and 256 μg/ml. 1-5 X 105 CFUs/ml of either
5. aureus ATCC 25923, E. coli ATCC 25922, P. aeruσinosa ATCC 27853, or C. albicans were added to the wells in full strength Mueller Hinton broth (BBL 11443) from a mid-log culture. The inoculum is standardized spectrophotometrically at 600 nm and is verified by colony counts. The plates are incubated for 16-20 hours at 37°C, and the minimal inhibitory concentrations (MIC) for the compounds are determined. Minimal inhibitory concentration is defined as the lowest concentration of amino acid or peptide which produces a clear well in the microtiter plate.
The MIC values for each of Compounds 3, 4, 6, and 8 through 12, 26, 27, 29, and 31 through 36, and 3-D, 9-D and 12-D, against S. aureus, P. aeruginosa, E. coli, and C. albicans are given in Table I below.
Figure imgf000030_0001
Example 3 Compounds 9-D, 12-D, 15, 16, 17, and 18 were prepared as
described in Example 1, and were tested for minimal inhibitory concentration against various organisms listed in Table II according to the assay procedure given m Example 2. The results are given in Table II below.
Figure imgf000031_0001
Example 4
Compounds 3-D, 6, 10, 11, 12, and 14 were prepared as described in Example 1, and tested for minimal inhibitory concentration against various organisms according to the assay procedure of Example 2. The results are given in Table III below.
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Example 5
Compounds 3, 4, 9, and 36 were prepared as described in Example 1, and tested for minimal inhibitory concentration against various organisms listed in Table IV below according to the assay procedure of Example 2. The results are given in Table IV below.
Figure imgf000034_0002
Figure imgf000035_0001
Example 6
Compounds 19 through 22, 24, and 25 were prepared as described in Example 1, and tested for minimal inhibitory concentration against various organisms given in Table V below according to the assay procedure of Example 2. The results are given in Table V below.
Figure imgf000035_0002
The compounds of the present invention, whether administered alone or in combination with agents such as antibiotics or biologically active peptides or proteins as hereinabove described, may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution. Such
pharmaceutical compositions may be used topically or
systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule or the like. The compound or agent as hereinabove described may also be used in
combination with adjuvants, protease inhibitors, or
compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses,
parasites, fungi, and the like.
The compound may be administered to a host in particular an animal, in an effective antibiotic and/or anti-tumor and/or antiviral and/or antimicrobial and/or antispermicidal and/or antifungal and/or antiparasitic amount, or in an amount effective to stimulate wound healing in a host. The compounds may be administered either alone or in combination with an antibiotic or ion channel forming peptide or protein as hereinabove described.
When the compound is administered in combination with an agent as hereinabove described, it is possible to administer the compound and agent in separate forms. For example, the agent may be administered systemically and the compound may be administered topically.
When the compound is administered topically, it may be administered in combination with a water-soluble vehicle, said water-soluble vehicle being in the form of an ointment, cream, lotion, paste or the like. Examples of water-soluble vehicles which may be employed include, but are not limited to, glycols, such as polyethylene glycol, hydroxycellulose, and KY Jelly. The water-soluble vehicle is preferably free of an oily substance.
The compounds may also be employed in combination with a ion having pharmacological properties, as hereinabove
described, in the form of an oral composition for oral hygiene. Such a composition may be incorporated into a wide variety of compositions and materials used for oral hygiene purposes, which include, but are not limited to, toothpastes, mouthwashes, tooth gels, and tooth powders. Such composition may thus be used to treat or prevent periodontal disease, to prevent or reduce plaque, and/or to prevent or treat or reduce dental caries. The compound and toxic ion may be used to inhibit, prevent, or destroy the growth of Streptococcus mutants, which is associated with dental caries and
periodontal disease.
Numerous modifications and variations of the present invention are possible in light of the above teachings;
therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described.

Claims

WHAT IS CLAIMED IS:
1. A compound having the following structural formula:
Figure imgf000038_0001
R3 - N - AA - C - N - R2 - N - C - AA - N - R3, wherein AA is an amino acid or a chain of two or more amino acids,
excluding the N-terminus and C-terminus from said amino acid or chain of two or more amino acids; R1 is hydrogen or an alkyl group having 1 to 8 carbon atoms; R2 is selected from the group consisting of: (i) a substituted or unsubstituted aliphatic hydrocarbon having from 1 to about 20 carbon atoms; and (ii) :
( wherein R4 is an aliphatic hydrocarbon having 1
Figure imgf000038_0002
to 4 carbon atoms, and R4 may be substituted or
unsubstituted; and R3 is selected from the group consisting of : (i) hydrogen;
(ii)
5, wherein R5 is hydrogen or a nitro group;
Figure imgf000038_0003
and (iii)
wherein each of R6, R7 and R8 is
Figure imgf000038_0004
hydrogen or methyl.
2. The compound of Claim 1 wherein R1 is hydrogen.
3. The compound of Claim 1 wherein R2 is an alkyl group having from 7 to 16 carbon atoms.
4. The compound of Claim 1 wherein R2 is R4 wherein
Figure imgf000038_0005
Figure imgf000038_0006
R4 is an aliphatic hydrocarbon having 1 to 4 carbon atoms, and R4 may be substituted or unsubstituted.
5. The compound of Claim 4 wherein R4 is an alkenyl group having from 2 to 4 carbon atoms.
6. The compound of Claim 5 wherein R4 is an alkenyl group having 2 carbon atoms.
7. The compound of Claim 1 wherein R3 is hydrogen.
8. The compound of Claim 1 wherein R3 is:
Figure imgf000039_0001
NH R5, wherein R5 is hydrogen or nitro.
9. The compound of Claim 8 wherein R5 is hydrogen.
10. The compound of Claim 8 wherein R5 is nitro.
11. The compound of Claim 8 wherein R3 is:
6
Figure imgf000039_0002
R8, wherein each of R6, R7, and R8 is hydrogen or methyl.
12. The compound of Claim 11 wherein each of R6, R7, and R8 is methyl.
13. The compound of Claim 11 wherein each of R6, R7, and R8 is hydrogen.
14. The compound of Claim 1 wherein said compound is 1, 12-[di-arginyl-phenylalanyl] diaminododecane.
15. A compound having the following structural formula:
Figure imgf000039_0003
wherein AA is an amino acid or a chain of two or more amino acids, excluding the N-terminus and C-terminus from said amino acid or chain of two or more amino acids; R1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R2 is selected from the group consisting of : (i) a substituted or unsubstituted aliphatic hydrocarbon having from 1 to about 20 carbon atoms, and ( ii) :
R4 wherein R4 is an aliphatic hydrocarbon having 1
Figure imgf000040_0003
Figure imgf000040_0004
to 4 carbon atoms, and R4 may be substituted or
unsubstituted; and R3 is selected from the group consisting of: (i) hydrogen;
(ii)
Figure imgf000040_0001
NH R5, wherein R5 is hydrogen or a nitro group; and (iii)
Figure imgf000040_0002
R8, wherein each of R6, R7, and R8 is hydrogen or methyl.
16. The compound of Claim 15 wherein R1 is hydrogen.
17. The compound of Claim 15 wherein R2 is an alkyl group having from 7 to 16 carbon atoms.
18. The compound of Claim 15 wherein R2 is
Figure imgf000040_0006
wherein R4 is an aliphatic hydrocarbon having 1 to 4 carbon atoms, and R4 may be substituted or unsubstituted.
19. The compound of Claim 18 wherein R4 is an alkenyl group having from 2 to 4 carbon atoms.
20. The compound of Claim 19 wherein R4 is an alkenyl group having 2 carbon atoms.
21. The compound of Claim 20 wherein R3 is hydrogen.
22. The compound of Claim 15 wherein R3 is:
Figure imgf000040_0005
NH R5, wherein R5 is hydrogen or nitro.
23. The compound of Claim 22 wherein R5 is hydrogen.
24. The compound of Claim 15 wherein R3 is:
6
Figure imgf000041_0001
R8, wherein each of R6, R7, and R8 is hydrogen or methyl.
25. The compound of Claim 24 wherein each of R6, R7, and R8 is methyl.
26. The compound of Claim 24 wherein each of R6, R7, and R8 is hydrogen.
27. The compound of Claim 15 wherein AA is a
phenylalanine residue without the C-terminus and N-terminus.
28. The compound of Claim 27 wherein said compound has the following structural formula: < N
Figure imgf000041_0002
29. The compound of Claim 28 wherein R3 is hydrogen.
30. The compound of Claim 28 wherein R3 is:
Figure imgf000041_0003
NH R5, wherein R5 is hydrogen or nitro.
31. The compound of Claim 21 wherein R5 is hydrogen.
32. A process for inhibiting the growth of a target cell, virus, or virally-infected cell in a host, comprising:
administering to a host the compound of Claim 1, said compound being administered in an amount effective to inhibit growth of a target cell, virus, or virally-infected cell in a host.
33. The process of Claim 32 wherein said compound is administered in an effective anti-bacterial amount.
34. The process of Claim 32 wherein said compound is administered in an effective antimicrobial amount.
35. The process of Claim 32 wherein said compound is administered in an effective anti-viral amount.
36. The process of Claim 32 wherein said compound is administered in an effective anti-tumor amount.
37. The process of Claim 32 wherein said compound is administered in an effective anti-parasitic amount.
38. The process of Claim 32 wherein said compound is administered in an effective antispermicidal amount.
39. A process for inhibiting the growth of a target cell, virus, or virally-infected cell in a host, comprising:
administering to a host the compound of Claim 15, said compound being administered in an amount effective to inhibit growth of a target cell, virus, or virally-infected cell in a host.
40. The process of Claim 39 wherein said compound is administered in an effective antibacterial amount.
41. The process of Claim 39 wherein said compound is administered in an effective antimicrobial amount.
42. The process of Claim 39 wherein said compound is administered in an effective antibiotic amount.
43. The process of Claim 39 wherein said compound is administered in an effective anti-viral amount.
44. The process of Claim 39 wherein said compound is administered in an effective anti-tumor amount.
45. The process of Claim 39 wherein said compound is administered in an effective anti-parasitic amount.
46. The process of Claim 39 wherein said compound is administered in an effective anti-spermicidal amount.
47. A process for inhibiting the growth of a target cell, virus, or virally-infected cell in a host, comprising:
administering to a host a compound having the following structural formula:
1 1
Figure imgf000043_0001
R3 - N - R2 - N - R3, wherein AA is an amino acid or a chain of two or more amino acids, excluding the N-terminus and C-terminus from said amino acid or chain of two or more amino acids; R1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R2 is selected from the group consisting of: (i) a substituted or unsubstituted aliphatic hydrocarbon having from 1 to about 20 carbon atoms, and (ii):
wherein R4 is an aliphatic hydrocarbon having
Figure imgf000043_0002
1 to 4 carbon atoms, and R4 may be substituted or
unsubstituted; and R3 is selected from the group consisting of : ( i) hydrogen;
(ii)
Figure imgf000043_0003
NH R5, wherein R5 is hydrogen or a nitro group; said compound being administered in an amount
effective to inhibit growth of a target cell, virus, or virally-infected cell in a host.
48. The process of Claim 47 wherein R1 is hydrogen.
49. The process of Claim 47 wherein R3 is:
Figure imgf000043_0004
NH R5, wherein R5 is hydrogen or nitro.
50. The process of Claim 49 wherein R5 is hydrogen.
51. The process of Claim 47 wherein said compound is administered in an effective antibacterial amount.
52. The process of Claim 47 wherein said compound is administered in an effective antimicrobial amount.
53. The process of Claim 47 wherein said compound is administered in an effective antibiotic amount.
54. The process of Claim 47 wherein said compound is administered in an effective anti-viral amount.
55. The process of Claim 47 wherein said compound is administered in an effective anti-tumor amount.
56. The process of Claim 47 wherein said compound is administered in an effective anti-parasitic amount.
57. The process of Claim 47 wherein said compound is administered in an effective anti-spermicidal amount.
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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034137A (en) * 1996-10-22 2000-03-07 Syntex (U.S.A.) Inc. Cationic lipids for gene therapy
US6440690B1 (en) 1995-06-29 2002-08-27 Amram Mor Peptides for the activation of the immune system in humans and animals
FR2842423A1 (en) * 2002-07-18 2004-01-23 Centre Nat Rech Scient COMPOUNDS WITH ANTI-PARASITE ACTIVITY AND MEDICAMENTS CONTAINING SAME
JP2008069175A (en) * 1994-08-19 2008-03-27 La Region Wallonne Compound, pharmaceutical composition and diagnostic device comprising the same and their use
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2015651A1 (en) * 1969-04-02 1970-10-15 Taiho Pharmaceutical Company Ltd., Tokio omega-guanidinoic acid diamide derivatives and their onium salts
US4647693A (en) * 1984-04-16 1987-03-03 Shionogi & Co., Ltd. Antibiotics DO-248-A and B and process for preparing the same
US4954512A (en) * 1987-11-24 1990-09-04 Shosuke Okamoto Anti-ulcer composition
EP0394684A1 (en) * 1989-04-03 1990-10-31 Nippon Kayaku Kabushiki Kaisha Immunopotentiator and spergualin-related compound therefor
US5037808A (en) * 1988-07-20 1991-08-06 Monsanto Co. Indolyl platelet-aggregation inhibitors
US5145872A (en) * 1988-03-16 1992-09-08 Zambon Group, S.P.A. Peptides with pharmaceutical activity

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1377806A (en) * 1962-12-18 1964-11-06 Hoechst Ag Process and product for rendering macromolecular materials antistatic
US4468383A (en) * 1982-09-29 1984-08-28 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Service Dimeric enkephalins
DE3585936D1 (en) * 1984-09-20 1992-06-04 Erba Carlo Spa BIOLOGICALLY ACTIVE PEPTIDES, THEIR METHOD FOR THE PRODUCTION AND PHARMACEUTICAL COMPOSITIONS.
US4906767A (en) * 1987-06-30 1990-03-06 The University Of Southern Mississippi Monomers with urea groups
WO1990005141A1 (en) * 1988-11-10 1990-05-17 Australian Commercial Research & Development Limited Amino acid and peptide inhibitors of human leukocytic elastase and collagenase
JPH02272034A (en) * 1989-04-13 1990-11-06 Fuji Photo Film Co Ltd Polypeptide thin film and production of material carrying same thin film
JP3387948B2 (en) * 1992-12-04 2003-03-17 富山化学工業株式会社 Novel phenylalanine derivative or salt thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2015651A1 (en) * 1969-04-02 1970-10-15 Taiho Pharmaceutical Company Ltd., Tokio omega-guanidinoic acid diamide derivatives and their onium salts
US4647693A (en) * 1984-04-16 1987-03-03 Shionogi & Co., Ltd. Antibiotics DO-248-A and B and process for preparing the same
US4954512A (en) * 1987-11-24 1990-09-04 Shosuke Okamoto Anti-ulcer composition
US5145872A (en) * 1988-03-16 1992-09-08 Zambon Group, S.P.A. Peptides with pharmaceutical activity
US5037808A (en) * 1988-07-20 1991-08-06 Monsanto Co. Indolyl platelet-aggregation inhibitors
EP0394684A1 (en) * 1989-04-03 1990-10-31 Nippon Kayaku Kabushiki Kaisha Immunopotentiator and spergualin-related compound therefor
US4990536A (en) * 1989-04-03 1991-02-05 Nippon Kayaku Kabushiki Kaisha Immunopotentiator and spergualin-related compound therefor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0679153A4 *

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JPH08505854A (en) 1996-06-25
EP0679153A4 (en) 1996-05-15
AU6121994A (en) 1994-08-15
EP0679153A1 (en) 1995-11-02
AU681117B2 (en) 1997-08-21
CA2153987A1 (en) 1994-07-21

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