EP0679153A4 - Endständig modifizierte aminosäuren und peptide. - Google Patents
Endständig modifizierte aminosäuren und peptide.Info
- Publication number
- EP0679153A4 EP0679153A4 EP94907791A EP94907791A EP0679153A4 EP 0679153 A4 EP0679153 A4 EP 0679153A4 EP 94907791 A EP94907791 A EP 94907791A EP 94907791 A EP94907791 A EP 94907791A EP 0679153 A4 EP0679153 A4 EP 0679153A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- hydrogen
- amount
- administered
- effective
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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-terminal ⁇ .
- Certain peptides, proteins, and dipeptide ⁇ having C-terminal or N-terminal sub ⁇ titutions have been disclosed previou ⁇ ly.
- 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 a ⁇ antimicrobial activity.
- AA is an amino acid or a chain of two or more amino acids, excluding the N-terminu ⁇ and C-terminu ⁇ from the amino acid or chain of two or more amino acids.
- R is hydrogen or an alkyl group having 1 to 3 carbon atoms.
- R 2 i ⁇ 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. > may be substituted or unsub ⁇ tituted.
- R 3 is selected from the group consi ⁇ ting of (i) hydrogen
- R i ⁇ hydrogen.
- R j i ⁇ an alkyl group and preferably an alkyl group having from 7 to 16 carbon atom ⁇ .
- R 3 is hydrogen.
- R 5 is hydrogen, while in another embodiment, R 5 is a nitro group.
- each of R ⁇ R 7 , and R 8 is hydrogen. In another embodiment, each of R ⁇ , R 7 , and R 8 is methyl.
- amino acid re ⁇ idue ⁇ which may be contained in the compound can be amino acid re ⁇ idue ⁇ known to those skilled in the art.
- Such re ⁇ idue ⁇ include, but are not limited to, hydrophobic amino acid re ⁇ idues, basic hydrophilic amino acid residues, and neutral hydrophilic amino acid residues.
- hydrophobic amino acids are Ala, Cys, Gly, lie, Leu, Met, Phe, Pro, Trp, Tyr, Val, cyclohexylalanine (Cha), norleucine (Nle), norvaline (Nva), and aminobutyric acid.
- the basic hydrophilic amino acids are Lys, Arg, Hi ⁇ , ornithine (Orn), p-aminophenylalanine, and 2,4-diaminobutyric acid (Dbu), and homoarginine (Har) .
- the neutral hydrophilic amino acid ⁇ are Asn, Gin, Ser, Thr, and homoserine (Hse).
- the amino acid residue ⁇ may contain ⁇ ub ⁇ tituent ⁇ ⁇ uch a ⁇ , for example, halogen ⁇ , amino group ⁇ , amidino group ⁇ , or NH-C-HN
- NH Rs groups (wherein R j is as hereinabove de ⁇ cribed), at po ⁇ ition ⁇ other than the carboxyl or amino terminus.
- the phenylalanine residue may be ⁇ ubstituted at one or more po ⁇ ition ⁇ of the phenyl group with one or more of the substituentL hereinabove described.
- the phenyl group may be substituted at the para-po ⁇ ition with a halogen atom ( ⁇ uch a ⁇ fluorine, for example) or an amino group.
- AA i ⁇ 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 acid ⁇ i ⁇ excluded.
- one or more of the amino acid re ⁇ idue ⁇ which i ⁇ not a glycine residue i ⁇ a D-amino acid residue may be admini ⁇ tered orally.
- Representative example ⁇ of such compounds of the present invention include, but are not limited to, the following:
- AA is an amino acid or a chain or two or more amino acids, excluding the N-terminu ⁇ and C-terminu ⁇ from ⁇ aid amino acid or chain of two or more amino acid ⁇ .
- R j i ⁇ hydrogen or an alkyl group having from 1 to 8 carbon atoms.
- R 2 i ⁇ selected from the group consi ⁇ ting of (i) a ⁇ ub ⁇ tituted or un ⁇ ubstituted an aliphatic hydrocarbon having from 1 to 20 carbon atom ⁇ , and wherein R 4 i ⁇ an aliphatic hydrocarbon having 1 to 4 carbon atom ⁇ .
- R 4 may be substituted or unsubstituted.
- R 3 i ⁇ selected from the group con ⁇ i ⁇ ting of (i) hydrogen;
- R 8 wherein each of Rg, R 7 , and R g i ⁇ hydrogen or methyl.
- R ! is hydrogen.
- R 2 is an alkyl group, and preferably an alkyl group having from 7 to 16 carbon atom ⁇ .
- R 2 is - ⁇ - R t ⁇ " / wherein R, is an aliphatic hydrocarbon having from 1 to 4 carbon atoms.
- R 4 is an alkenyl group, more preferably an alkenyl group having from 2 to 4 carbon atom ⁇ , and most preferably R 4 i ⁇ an alkenyl group having 2 carbon atom ⁇ .
- R 3 i ⁇ hydrogen. In another embodiment, R 3 i ⁇ :
- R 5 wherein R 5 i ⁇ hydrogen or a nitro group. In one embodiment, R 5 i ⁇ hydrogen, wherea ⁇ in another embodiment, R 5 i ⁇ a nitro group.
- R g wherein each of Rg, R 7 , and R 8 i ⁇ hydrogen or 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 lea ⁇ t two and no greater than 20 amino acid ⁇ .
- the amino acid(s) which are part of the compound may be those hereinabove described.
- the amino acid residue(s) may be ⁇ ub ⁇ tituted at po ⁇ ition ⁇ other than the carboxyl terminus or the amino terminus with sub ⁇ tituent group ⁇ ⁇ uch a ⁇ tho ⁇ e hereinabove described.
- the amino acid(s) i ⁇ a hydrophobic amino acid residue, and preferably a phenylalanine residue.
- ⁇ uch residue may, in one embodiment, be further modified such that the compound ha ⁇ the following structural formula:
- R,, R 2 , and R 3 are a ⁇ hereinabove de ⁇ cribed.
- R 3 i ⁇ hydrogen
- R 5 NH R 5 , wherein R 5 i ⁇ a ⁇ hereinabove de ⁇ cribed.
- Each of the amino acid re ⁇ idue( ⁇ ) which i ⁇ not a glycine re ⁇ idue, may be a D-amino acid re ⁇ idue.
- Such compound ⁇ are ⁇ ometimes hereinafter referred to a ⁇
- a proce ⁇ for inhibiting the growth of a target cell, virus, or virally-infected cell in a ho ⁇ t.
- the process comprises administering to a ho ⁇ t a compound having the following ⁇ tructural formula:
- R ] , R 2 and R 3 are a ⁇ hereinabove de ⁇ cribed.
- R 5 l hydrogen or a nitro group.
- R 5 i hydrogen
- R 5 is a nitro group.
- a representative example of ⁇ uch a compound which may be administered in accordance with the present invention is 1,12 [bis- guanyl] diaminododecane, which ha ⁇ the following ⁇ tructure:
- This compound is sometime ⁇ hereinafter referred to a ⁇ Compound 36.
- ⁇ uch compound ⁇ may be prepared from a diaminoalkane, which may be reacted with l-methyl-3-nitro-l- nitrosoguanidine, and the nitro-guanylated product i ⁇ the hydrogenated and purified by preparative HPLC to obtain the desired compound.
- the compound ⁇ 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.
- a host for example a human or non-human animal
- the compound ⁇ may be u ⁇ ed a ⁇ antimicrobial agent ⁇ , anti ⁇ viral agents, anti-bacterial agents, anti-tumor agents, anti- parasitic agents, spermicide ⁇ , as well as exhibiting other bioactive functions.
- tf».rm “antimicrobial” as used herein means that the compounds of the present invention inhibit, prevent, or destroy the growth or proliferation of microbes ⁇ uch a ⁇ bacteria, fungi, viru ⁇ e ⁇ , or the like.
- anti-bacterial a ⁇ u ⁇ ed herein mean ⁇ that the compound ⁇ employed in the pre ⁇ ent invention produce effect ⁇ adver ⁇ e to the normal biological function ⁇ of bacteria, including death or de ⁇ truction and prevention of the growth or proliferation of the bacteria when contacted with the compound ⁇ .
- antibiotic a ⁇ u ⁇ ed herein mean ⁇ that the compound ⁇ employed in the pre ⁇ ent invention produce effect ⁇ adver ⁇ e to the normal biological function ⁇ of the non-host cell, tissue or organi ⁇ m, including death or de ⁇ truction and prevention of the growth or proliferation of the non-ho ⁇ t cell, tis ⁇ ue, or organism when contacted with the compound ⁇ .
- ⁇ permicidal a ⁇ u ⁇ ed herein mean ⁇ that the compounds employed in the pre ⁇ ent invention, inhibit, prevent, or de ⁇ troy the motility of ⁇ perm.
- antiviral means that the compounds employed in the present invention inhibit, prevent, or destroy the growth or proliferation of viru ⁇ e ⁇ , or of virally-infected cell ⁇ .
- anti-tumor a ⁇ used herein mean ⁇ that the compound ⁇ inhibit the growth of or destroy tumors, including cancerou ⁇ tumor ⁇ .
- anti-para ⁇ itic means that the compounds employed in the present invention inhibit, prevent, or de ⁇ troy the growth or proliferation of para ⁇ ite ⁇ .
- the compound ⁇ of the pre ⁇ ent invention have a broad range of potent antibiotic activity again ⁇ t a plurality of microorganisms including gram-positive and gram-negative bacteria, fungi, protozoa, and the like, as well as parasite ⁇ .
- the compound ⁇ of the pre ⁇ ent invention have a broad range of potent antibiotic activity again ⁇ t a plurality of microorganisms including gram-positive and gram-negative bacteria, fungi, protozoa, and the like, as well as parasite ⁇ .
- SUBSTITUTE SHEET present invention allow a method for treating or controlling microbial infection caused by organisms which are sensitive to the compound ⁇ .
- Such treatment may comprise admini ⁇ tering to a ho ⁇ t organi ⁇ m or ti ⁇ sue su ⁇ ceptible to or affiliated with a microbial in ection an antimicrobial amount of at lea ⁇ t one of the compound ⁇ .
- antibiotics because of the antibiotic, antimicrobial, antiviral, and antibacterial propertie ⁇ of the compounds, they may also be used as preservatives or sterilants or di ⁇ infectant ⁇ of material ⁇ susceptible to microbial or viral contamination.
- the compound ⁇ 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 composition ⁇ may be u ⁇ ed topically or ⁇ ystemically and may be in any suitable form such a ⁇ a liquid, ⁇ olid, ⁇ emi- ⁇ olid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like.
- compositions containing the compounds of the present invention may also be used in combination with adjuvant ⁇ , protea ⁇ e inhibitor ⁇ , or compatible drug ⁇ where such a combination is seen to be de ⁇ irable or advantageou ⁇ in controlling infection caused by harmful microorganisms including protozoa, viruse ⁇ , and the like, as well as by para ⁇ ites.
- the compound ⁇ of the pre ⁇ ent invention may be admini ⁇ tered 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 anti ⁇ microbial and/or antibacterial and/or anti-parasitic and/or an antispermicidal amount.
- composition in accordance with the invention will contain an effective anti- icrobial 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 compound ⁇ may be admini ⁇ tered by direct application of the compound ⁇ to the target cell or virus or virally-infected cell, or indirectly applied through systemic administration.
- the compounds of the pre ⁇ ent invention may also be employed in promoting or stimulating healing of a wound in a host.
- wound healing includes variou ⁇ a ⁇ pect ⁇ of the wound healing proce ⁇ .
- the compound ⁇ of the pre ⁇ ent invention may al ⁇ o be employed ⁇ o a ⁇ to rever ⁇ e the inhibition of wound healing cau ⁇ ed by condition ⁇ which depre ⁇ s or compromi ⁇ e the immune ⁇ ystem.
- the compound ⁇ of the pre ⁇ ent invention may be u ⁇ ed in the treatment of external burn ⁇ and to treat and/or prevent ⁇ kin and burn infection ⁇ .
- the compound ⁇ may be u ⁇ ed to treat ⁇ kin and burn infection ⁇ caused by organi ⁇ m ⁇ ⁇ uch a ⁇ , but not limited to, P. aeruginosa and S. aureus.
- the compound ⁇ are al ⁇ o u ⁇ eful in the prevention or treatment of eye infections.
- Such infections may be caused by bacteria ⁇ uch a ⁇ , but not limited to, P. aeru ⁇ ino ⁇ a, S. aureu ⁇ . and N. ⁇ onorrhoea, by fungi ⁇ uch a ⁇ but not limited to C. albican ⁇ and A. fumi ⁇ atu ⁇ , by para ⁇ ite ⁇ ⁇ uch a ⁇ but not limited to A. ca ⁇ tellani, or by viruses.
- the compound ⁇ may al ⁇ o be effective in killing cy ⁇ t ⁇ , ⁇ pore ⁇ , or trophozoite ⁇ of infection - cau ⁇ ing organi ⁇ m ⁇ .
- organi ⁇ m ⁇ include, but are not limited to Acanthamoeba which for ⁇ trophozoite ⁇ or cysts, C. albicans, which forms ⁇ pore ⁇ , and A. fumi ⁇ atu ⁇ . which form ⁇ ⁇ pore ⁇ as well.
- the compound ⁇ may also be administered to plants in an effective antimicrobial or antiviral or antiparasitic amount to
- SUBSTITUTE SHEET prevent or treat microbial or viral or parasitic contamination thereof.
- the compound ⁇ when used in topical compo ⁇ ition ⁇ , are generally pre ⁇ ent in an amount of at least 0.1%, by weight. In most cases, it is not nece ⁇ ary 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 lea ⁇ t about 5 ug/ml.
- the serum level of the compound need not exceed 500 ug/ml.
- Such serum levels may be achieved by incorporating the compound in a composition to be administered sy ⁇ temically at a do ⁇ e of from 1 to about 100 mg/kg.
- the compound need not be admini ⁇ tered at a dose exceeding 10 mg/kg.
- the compound ⁇ of the present invention having modified C- terminal ⁇ and modified N-terminal ⁇ , may be prepared by any acceptable method ⁇ for modifying the C-terminal and the N-terminal of amino acid ⁇ or peptide ⁇ to provide the compound ⁇ 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. It is to be under ⁇ tood, however, that the ⁇ cope of the pre ⁇ ent invention i ⁇ not to be limited to any ⁇ pecific moietie ⁇ at the C-terminal or N-terminal, or to any ⁇ pecific reaction scheme for preparing the compound ⁇ .
- the amino acid ⁇ or peptide ⁇ (including 2 or more amino acid ⁇ ), prior to the modification thereof, may be obtained i ⁇ ⁇ ub ⁇ tantially pure form.
- the unmodified peptide may be ⁇ ynthesized on an automatic peptide synthe ⁇ izer. Journal of the American Chemical Society. Vol. 85, pgs. 2149-54 (1963). It is al ⁇ o possible to produce unmodified peptides by genetic engineering techniques.
- DNA which encodes the peptides prior to the modification thereof.
- DNA may be expres ⁇ ed by mean ⁇ known to tho ⁇ e 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 de ⁇ troy ⁇ the growth of the target cell, virus, or virally-infected cell.
- Such an ion having pharmacological propertie ⁇ is one which in the ab ⁇ ence of an ion channel-forming peptide i ⁇ unable to cro ⁇ s a natural or synthetic lipid membrane; in particular a cell membrane, in sufficient amounts to affect a cell or viru ⁇ adversely.
- the compound and ion having pharmacological propertie ⁇ may be administered as a single compo ⁇ ition or in ⁇ eparate compo ⁇ ition ⁇ , and the ⁇ ingle or separate compositions may include additional materials, actives and/or inactive ⁇ , in addition to the compound and ion having pharmacological propertie ⁇ .
- the compound and the ion having pharmacological propertie ⁇ are employed in a ount ⁇ effective to inhibit and/or prevent and/or de ⁇ troy the growth of the target cell.
- the ion potentiate ⁇ the action of the compound.
- SUBSTITUTE SHEET 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.
- i ⁇ when used topically, i ⁇ generally employed in a concentration of from 0.05% to 2.0%. When used systemically, the ion i ⁇ generally employed in an amount of from 1 to 10 mg. per kg. of ho ⁇ t 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 admini ⁇ tered orally in conjunction with ⁇ y ⁇ temic administration of the compound.
- the compound may be administered IV or IP to achieve a serum dose of 100 microgram ⁇ per milliliter (10 milligram ⁇ per kilogram) in conjunction with an oral do ⁇ e of ion, in particular, ⁇ odium fluoride, of 10 meq per kilogram.
- the compound ⁇ of the present invention may be administered to a host in combination with an antibiotic selected from the cla ⁇ con ⁇ i ⁇ ting of bacitracin ⁇ , gramicidin, polymyxin, vancomycin, teichoplanin, aminoglyco ⁇ ide ⁇ , p ⁇ eudomonic acid ⁇ , cephalosporin ⁇ , pene antibiotic ⁇ , hydrophobic antibiotic ⁇ , penicillin ⁇ , onobactam ⁇ , or derivative ⁇ or analogue ⁇ thereof.
- an antibiotic selected from the cla ⁇ con ⁇ i ⁇ ting of bacitracin ⁇ , gramicidin, polymyxin, vancomycin, teichoplanin, aminoglyco ⁇ ide ⁇ , p ⁇ eudomonic acid ⁇ , cephalosporin ⁇ , pene antibiotic ⁇ , hydrophobic antibiotic ⁇ , penicillin ⁇ , onobactam ⁇ , or derivative ⁇ or analogue ⁇ thereof.
- the bacitracin ⁇ , 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 gentamicin ⁇ (e.g., gentamicin C,, gentamicin C 2 , gentamicin C ), netilmicin, and derivatives and analogues thereof.
- the preferred aminoglyco ⁇ ides are tobramycin and the gentamicins.
- the aminoglyco ⁇ ides, and the bacitracin ⁇ hereinabove de ⁇ cribed, tend to be hydrophilic and water- ⁇ oluble.
- Penicillins which may be employed include, but are not limited to benzyl penicillin, ampicillin, ethicillin (dimethoxyphenyl penicillin), ticaricillin, penicillin V (phenoxymethyl penicillin), oxacillin, cloxaci ' llin, 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 a ⁇ erythromycin, roxythromycin, clarithromycin, etc.; 9-N-alkyl derivative ⁇ of erythromycin; midecamycin acetate; azithromycin; flurithromycin; rifabutin; rokitamycin; a 6-0-methyl erythromycin A known a ⁇ TE-031 (Taisho); rifapentine; benzypiperazinyl rifamycin ⁇ ⁇ uch as CGP-7040, CGP-5909, CGP-279353 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the C ⁇ /C 12 position of a macrolide ring known as A-62514 (Abbott); AC-7230 (Toyo Jozo); benzoxazinorifamycin; difficidin; dirithromycin; a
- antibiotics which are 50-S ribo ⁇ ome inhibitor ⁇ such as lincomycin; clindamycin; and chloramphenicol; etc.; antibiotic ⁇ which have a large lipid like lactone ring, ⁇ uch as mystatin; pimaricin, etc.
- the compound and antibiotic may be admini ⁇ tered by direct admini ⁇ tration to a target cell or by ⁇ y ⁇ temic or topical admini ⁇ tration to a host which include ⁇ the target cell, in order to prevent, de ⁇ troy or inhibit the growth of a target cell.
- Target cells whose growth may be prevented, inhibited, or destroyed by the admini ⁇ tration of the compound ⁇ and antibiotic include Gram- po ⁇ itive and Gram-negative bacteria as well as fungal cell ⁇ .
- the antibiotic, ⁇ uch a ⁇ those hereinabove described, or derivative ⁇ or analogue ⁇ thereof, when used topically, is generally employed in a concentration of about 0.1% to about 10%.
- the antibiotic or derivative or analogue thereof i ⁇ When used ⁇ y ⁇ temically, the antibiotic or derivative or analogue thereof i ⁇ generally employed in an amount of from 1.25 mg. to about 45 mg. per kg. of ho ⁇ t weight per day. Do ⁇ age ⁇ of the compound may be tho ⁇ e a ⁇ hereinabove de ⁇ cribed.
- the compound could be admini ⁇ tered in an amount of from about 0.1% to about 10% weight to weight, and the antibiotic i ⁇ delivered in an amount of from about 0.1% to about 10% weight to weight.
- the compound ⁇ of the pre ⁇ ent invention may be admini ⁇ tered in combination with an antipara ⁇ itic agent or an antifungal agent.
- Antipara ⁇ itic agent ⁇ which may be employed include, but are not limited to, anti-protozoan agents.
- specific anti- parasitic agents which may be employed include, but are not limited to, pentamidine isethionate, and propamidine isethionate (Brolene) .
- Anti-fungal agent ⁇ which may be employed include, but are not limited to, ketoconazole. It is al ⁇ o to be understood that certain anti-pairasitic agent ⁇ , may al ⁇ o have anti-fungal activity, and that certain anti-fungal agent ⁇ may have anti-para ⁇ itic activity.
- the compound ⁇ of the present invention may be administered in combination with an antibiotic which inhibits DNA gyrase, which i ⁇ an enzyme involved in the formation of bond ⁇ between individual coiling ⁇ trand ⁇ of replicating bacterial DNA. Thu ⁇ , DNA gyra ⁇ e i ⁇ nece ⁇ ary 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 antibiotic ⁇ which include ciprofloxacin, norfloxacin, ⁇ floxacin, enoxacin, pefloxacin, lo efloxacin, fleroxacin, to ⁇ ulfloxacin, temafloxacin, and rufloxacin.
- the compounds of the present invention may be admini ⁇ tered for the purpo ⁇ e hereinabove de ⁇ cribed in combination with biologically active amphiphilic peptide ⁇ , or in combination with ion channel-forming proteins.
- N- si / -tert - butyloxycarbonyl (Boc) amino acid( ⁇ ) wa ⁇ (were) placed into a DMF or DMF/CH 2 C1 2 (10 ml/g) solvent system, and an equivalent amount of l-hydroxybenzotriazole (HOBt) was added and the mixture was stirred in an ice-salt temperature bath.
- a coupling reagent, l-ethyl-3-dimethylaminopropyl carbodiimide/Hcl (equimolar amounts) wa ⁇ added and stirring continued for 20 minutes
- the re ⁇ idue wa ⁇ then treated with l-methyl-3-nitro-l- nitro ⁇ oguanidine at about 55°C for ⁇ everal day ⁇ while following the progre ⁇ of the reaction by thin layer chromatography.
- Solvent wa ⁇ removed under reduced pre ⁇ ure, triturated with ether and decanted.
- the re ⁇ idue then was triturated with water and decanted.
- the nitroguanylated product was purified in some case ⁇ and checked for antibacterial activitie ⁇ .
- the crude product wa ⁇ 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).
- Compound 28 wa ⁇ prepared by reacting N - ⁇ - Boc - p - benzyloxycarbonyl (Z) amino phenylalanine with heptyla ine followed by treatment with HBr/hydroxyacetate and neutralization.
- Compound 30 wa ⁇ prepared by reacting N - ⁇ - Boc - p - NH 2 (Z) phenylalanine with heptylamine after phenylalanine wa ⁇ ⁇ ubjected to Procedure (i), and then ⁇ ubjecting the product to Procedure ⁇ (ii) and (iii) .
- Solvent wa ⁇ removed and the residue wa ⁇ placed in ethyl acetate and extracted with 0.5 N HCl, water, 5% NaHC0 3 ⁇ olution, water, and then dried over anhydrou ⁇ Na 2 S0 4 .
- the ⁇ olvent wa ⁇ removed, and the product wa ⁇ characterized by thin layer chromatography.
- 1,12-diaminododecane was reacted with l-methyl-3-nitro-l- nitro ⁇ oguanidine at about 55°C for ⁇ everal days while following the progress of the reaction by thin layer chromatography.
- Solvent wa ⁇ removed under reduced pre ⁇ ure, triturated with ether and decanted. The re ⁇ idue then wa ⁇ triturated with water and decanted.
- the nitroguanylated product wa ⁇ purified in some case ⁇ and checked for antibacterial activitie ⁇ .
- the crude product wa ⁇ placed into a mixture of CH 3 OH:acetic acid:water (9:1:1), and hydrogenated overnight at 40 p ⁇ i in the pre ⁇ ence of 10% Pd/C catalyst (0.5-1.0 equivalent amount by weight).
- the cataly ⁇ t wa ⁇ filtered and concentrated in vacuo.
- the re ⁇ idue was triturated with ether, filtered, washed with ether, and then with petroleum ether, and then dried.-
- the purification of the compound wa ⁇ carried out by preparative HPLC to obtain the de ⁇ ired compound.
- the stock modified solutions of Compound ⁇ 1 through 12, 26 through 36, and 3-D, 9-D, and 12-D are diluted in ⁇ erial dilution ⁇ (1:2) down the well ⁇ of a microtiter plate so that the final concentrations of the compound ⁇ in the well ⁇ are 0.25, 0.50, 1, 2,
- aureu ⁇ ATCC 25923, E. coli ATCC 25922, P. aeru ⁇ ino ⁇ a ATCC 27853, or C. albican ⁇ were added to the well ⁇ in full ⁇ trength Mueller Hinton broth (BBL 11443) from a mid-log culture.
- the inoculum is standardized spectrophoto etrically at 600 nm and i ⁇ verified by colony count ⁇ .
- the plate ⁇ are incubated for 16-20 hour ⁇ at 37°C, and the minimal inhibitory concentration ⁇ (MIC) for the compound ⁇ are determined.
- Minimal inhibitory concentration is defined as the lowest concentration of amino acid or peptide which produce ⁇ a clear well in the icrotiter plate.
- Organism S.aureuB 29313 E. coli 25922 P.aeru ⁇ mosa 27853 E. faec um 26143 E.faecalis 19052 E.faecalis 19290 E.faecalis 23296 E.faecalis 29212 C.difficile TTU614 C.difficile P324
- 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.
- Such pharmaceutical composition ⁇ may be used topically or systemically and may be in any ⁇ uitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule or the like.
- the compound or agent a ⁇ hereinabove de ⁇ cribed may al ⁇ o be used in combination with adjuvants, protease inhibitors, or compatible drug ⁇ where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganism ⁇ including protozoa, viruses, parasites, fungi, and the like.
- the compound may be administered to a ho ⁇ t 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 compound ⁇ may be admini ⁇ tered either alone or in combination with an antibiotic or ion channel forming peptide or protein a ⁇ hereinabove de ⁇ cribed.
- the compound i ⁇ administered in combination with an agent as hereinabove described it i ⁇ po ⁇ sible to administer the compound and agent in separate form ⁇ .
- the agent may be admini ⁇ tered ⁇ y ⁇ te ically and the compound may be administered topically.
- the compound i ⁇ admini ⁇ tered 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- ⁇ oluble vehicle i ⁇ preferably free of an oily ⁇ ubstance.
- 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.
- a composition may be incorporated into a wide variety of composition ⁇ and material ⁇ u ⁇ ed for oral hygiene purposes, which include, but are not limited to, toothpaste ⁇ , mouthwashe ⁇ , tooth gel ⁇ , and tooth powder ⁇ .
- compo ⁇ ition may thu ⁇ 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 u ⁇ ed to inhibit, prevent, or de ⁇ troy the growth of Streptococcu ⁇ mutants. which i ⁇ a ⁇ ociated with dental carie ⁇ and periodontal disease.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US431393A | 1993-01-14 | 1993-01-14 | |
US4313 | 1993-01-14 | ||
PCT/US1994/000335 WO1994015909A1 (en) | 1993-01-14 | 1994-01-11 | Amino acids and peptides having modified terminals |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0679153A1 EP0679153A1 (de) | 1995-11-02 |
EP0679153A4 true EP0679153A4 (de) | 1996-05-15 |
Family
ID=21710154
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94907791A Withdrawn EP0679153A4 (de) | 1993-01-14 | 1994-01-11 | Endständig modifizierte aminosäuren und peptide. |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0679153A4 (de) |
JP (1) | JPH08505854A (de) |
CA (1) | CA2153987A1 (de) |
WO (1) | WO1994015909A1 (de) |
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WO1996005863A1 (fr) * | 1994-08-19 | 1996-02-29 | La Region Wallonne | Composes, composition pharmaceutique et dispositif de diagnostic les comprenant et leur utilisation |
FR2735983B1 (fr) | 1995-06-29 | 1997-12-05 | Centre Nat Rech Scient | Peptide permettant de modifier l'activite du systeme immunitaire humain ou animal |
CA2217550A1 (en) * | 1996-10-22 | 1998-04-22 | F. Hoffmann-La Roche Ag | Cationic lipids for gene therapy |
FR2842423B1 (fr) * | 2002-07-18 | 2005-07-08 | Centre Nat Rech Scient | Composes a activite anti-parasitaire et medicaments les renfermant |
US8143288B2 (en) | 2005-06-06 | 2012-03-27 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
US8329159B2 (en) | 2006-08-11 | 2012-12-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8303944B2 (en) | 2006-08-11 | 2012-11-06 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7745636B2 (en) | 2006-08-11 | 2010-06-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7759495B2 (en) | 2006-08-11 | 2010-07-20 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7659270B2 (en) | 2006-08-11 | 2010-02-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7741347B2 (en) | 2007-05-17 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8629171B2 (en) | 2007-08-08 | 2014-01-14 | Bristol-Myers Squibb Company | Crystalline form of methyl ((1S)-1-((25)-2-(5-(4'-(2-((25)-1((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
US7728027B2 (en) | 2007-08-08 | 2010-06-01 | Bristol-Myers Squibb Company | Process for synthesizing compounds useful for treating hepatitis C |
CA2715400A1 (en) | 2008-02-12 | 2009-08-20 | Bristol-Myers Squibb Company | Heterocyclic derivatives as hepatitis c virus inhibitors |
US7704992B2 (en) | 2008-02-13 | 2010-04-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8147818B2 (en) | 2008-02-13 | 2012-04-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7906655B2 (en) | 2008-08-07 | 2011-03-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8383094B2 (en) | 2008-10-01 | 2013-02-26 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
TWI438200B (zh) | 2009-02-17 | 2014-05-21 | 必治妥美雅史谷比公司 | C型肝炎病毒抑制劑 |
US8394968B2 (en) | 2009-02-17 | 2013-03-12 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8796466B2 (en) | 2009-03-30 | 2014-08-05 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
TW201038559A (en) | 2009-04-09 | 2010-11-01 | Bristol Myers Squibb Co | Hepatitis C virus inhibitors |
US8143414B2 (en) | 2009-04-13 | 2012-03-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8138215B2 (en) | 2009-05-29 | 2012-03-20 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8211928B2 (en) | 2009-05-29 | 2012-07-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US20110274648A1 (en) | 2009-11-11 | 2011-11-10 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20110269956A1 (en) | 2009-11-11 | 2011-11-03 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20110281910A1 (en) | 2009-11-12 | 2011-11-17 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US8377980B2 (en) | 2009-12-16 | 2013-02-19 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8362020B2 (en) | 2009-12-30 | 2013-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8552047B2 (en) | 2011-02-07 | 2013-10-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9546160B2 (en) | 2011-05-12 | 2017-01-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9326973B2 (en) | 2012-01-13 | 2016-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US20150023913A1 (en) | 2013-07-02 | 2015-01-22 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US9717712B2 (en) | 2013-07-02 | 2017-08-01 | Bristol-Myers Squibb Company | Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus |
CN105530933B (zh) | 2013-07-17 | 2018-12-11 | 百时美施贵宝公司 | 用于治疗hcv的包含联苯衍生物的组合产品 |
WO2017023631A1 (en) | 2015-08-06 | 2017-02-09 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
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EP0175323A2 (de) * | 1984-09-20 | 1986-03-26 | FARMITALIA CARLO ERBA S.r.l. | Biologisch aktive Peptide, deren Verfahren zur Herstellung und pharmazeutische Zusammensetzungen |
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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 (ja) * | 1989-04-13 | 1990-11-06 | Fuji Photo Film Co Ltd | ポリペプチド薄膜とこれを担持する材料の製造方法 |
JPH06172288A (ja) * | 1992-12-04 | 1994-06-21 | Toyama Chem Co Ltd | 新規なフェニルアラニン誘導体またはその塩 |
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1994
- 1994-01-11 EP EP94907791A patent/EP0679153A4/de not_active Withdrawn
- 1994-01-11 JP JP6516279A patent/JPH08505854A/ja active Pending
- 1994-01-11 WO PCT/US1994/000335 patent/WO1994015909A1/en not_active Application Discontinuation
- 1994-01-11 CA CA002153987A patent/CA2153987A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
WO1994015909A1 (en) | 1994-07-21 |
CA2153987A1 (en) | 1994-07-21 |
JPH08505854A (ja) | 1996-06-25 |
EP0679153A1 (de) | 1995-11-02 |
AU681117B2 (en) | 1997-08-21 |
AU6121994A (en) | 1994-08-15 |
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