HK1178537B

HK1178537B - High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds

Info

Publication number: HK1178537B
Application number: HK13106282.9A
Authority: HK
Inventors: 于崇曦; 徐丽娜; 陈玉华; 严彬冰; 涂仕前
Original assignee: 上海泰飞尔生化技术有限公司; 于崇曦
Priority date: 2009-06-10
Filing date: 2010-06-10
Publication date: 2016-10-14

Description

Prodrug compositions of antimicrobials and antimicrobial-related compounds with high penetration

Priority declaration

This application is a partially-filed and priority-filed application of united states patent application 12/482,373, filed on 10/6/2009, which is hereby incorporated by reference. This application also claims priority from chinese patent application 200910141944.X, filed on 10/6/2009, which is incorporated herein by reference.

Technical Field

The present invention relates to pharmaceutical compositions that can penetrate one or more biological barriers, and the use of such pharmaceutical compositions for the prevention, diagnosis and/or treatment of any antimicrobial agent and antimicrobial related compound treatable conditions in humans and animals. The invention also relates to the use of these pharmaceutical compositions for screening new drug candidates and the use of these pharmaceutical compositions for diagnosing a condition in a biological subject.

Background

An antimicrobial agent is a substance that kills or inhibits the growth of microorganisms, such as bacteria, fungi, or protozoa, and which also destroys or inhibits the growth of viruses. The major classes of microorganisms include, for example, antibiotics that treat bacterial-related conditions, antiviral drugs that treat viral-related conditions, antifungal drugs that treat fungal-related conditions, and antiprotozoal drugs that treat protozoan-related conditions.

Beta-lactam antibiotics are a class of antibiotics that contain a four-membered cyclic amide core in the molecular structure. A hundred thousand varieties of β -lactam antibiotics have been prepared by semi-synthetic or total synthetic methods (l.a. mitscher, et al, antibiotic and antimicrobial drugs, ind.f. smith, ed., stereoisomerism manual: therapeutic drugs, boca raton, FL, crpress, 1989; r.b. morinnand m.gorman eds., chemistry and biology of β -lactam antibiotics, volumes 1-3, new york academyc press, 1982; and a.l. demainand n.a. solomon, eds., antibiotics containing β -lactam structures, volumes 1 and 2, pharmaceutical test manual, volume 67, new york, Springer, 1983). Examples of beta-lactam antibiotics include penicillin derivatives, cephalosporins, monobactams, carbapenems, beta-lactamase inhibitors, sulfonamides and quinolones.

With the high use of antimicrobials, pathogens mutate over time making drug resistance a common and serious problem. Therefore, the development of new antimicrobial agents is becoming urgent and challenging.

Numerous antimicrobial agents can be used to treat systemic bacterial diseases by intravenous, intramuscular, subcutaneous, oral, and rectal administration. Oral antibiotics suffer from a low absorption rate of the antimicrobial agent from the gastrointestinal tract. Intravenous, subcutaneous or intramuscular injection is not only painful but can be accomplished by only a small percentage of trained individuals, and additionally increases the risk of injury, infection or other injury from the needle.

Another method of using drugs is transdermal delivery, which has many advantages, such as avoiding drug inactivation due to the "first pass" effect of the GI tract and liver. The method can reach optimum local drug concentration at the affected part, and avoid systemic exposure of the drug. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) suggests that oral administration of drugs may create other problems in that the concentration of drugs in the blood required to effectively treat pain or inflammation at a peripheral location may be much higher than actually required. These concentration levels are much higher than would be required if the drug could be delivered accurately to the pain site or injury. However, for most antimicrobial agents, topical administration does not achieve concentrations of the drug that are effective in treating the disease.

Therefore, there is a strong need in the art for novel compositions that can be effectively delivered to the site of action of a condition (e.g., disease) to prevent, alleviate or treat the condition while reducing side effects.

Summary of the invention

In one aspect, the present invention provides a High Permeability Prodrug (HPP) or High Permeability Composition (HPC) comprising a functional unit covalently linked to a transport unit via a linker. The terms "HPP" and "HPC" are used herein individually or collectively and are interchangeable unless otherwise indicated.

In certain embodiments, the functional unit of the HPP or HPC contains a portion (entity) of an agent, wherein it is desirable to efficiently and effectively deliver the agent to a biological subject and/or transport the agent across one or more biological barriers.

In certain embodiments, the functional units may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). For example, the lipophilicity of the functional unit may be intrinsic, or obtained by converting the hydrophilic portion of the functional unit to a lipophilic portion. In certain embodiments, the carboxyl, amino, guanidino, or other hydrophilic groups of the functional units may be protected with hydrocarbyl, aryl, or heteroaryl ester or amide groups to form a more lipophilic HPP or HPC.

In certain embodiments, the functional unit of the HPP or HPC contains an antimicrobial agent or antimicrobial-related compound. Antimicrobial agents are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, protozoa, etc., and that also disrupt viral growth.

An antimicrobial-related compound is a compound having a structure comprising an antimicrobial structure, an antimicrobial metabolite structure, or a therapeutic substance structure that can be metabolized to an antimicrobial or antimicrobial metabolite after HPP or HPC penetrates one or more biological barriers. The antimicrobial-related compound further comprises an analog or mimetic (micic) of an antimicrobial or an antimicrobial metabolite, or is a therapeutic substance, wherein the therapeutic substance is metabolisable to an analog or mimetic of an antimicrobial or an antimicrobial metabolite upon penetration of the HPP or HPC through one or more biological barriers.

Examples of antimicrobial agents include, for example, antibiotics that can treat bacteria-related symptoms, antiviral drugs that can treat virus-related symptoms, antifungal drugs that can treat fungi-related symptoms, and antiprotozoal drugs that can treat protozoan-related symptoms.

Examples of antimicrobial agents include, but are not limited to, beta-lactam antibiotics, sulfonamides, and quinolone antibiotics. Examples of beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penem antibiotics, monobactams, carbapenems, beta-lactamase inhibitors, and combinations thereof. Examples of penicillin derivatives include, but are not limited to, amino-based penicillins (e.g., amoxicillin, ampicillin, and epicillin), carboxy-based penicillins (e.g., carbenicillin, ticarcillin, and temocillin), ureido-based penicillins (e.g., azlocillin, piperacillin, and mezlocillin), mecillin, sulbenicillin, benzathine, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin o (allylmercaptomethylpeniciliinic), procainamycin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, ampicillin-bacampicillin (becampicilin), maytans, phthalampicillin, amoxicillin (amoxicillin + clavulanic acid), and piperacillin. Examples of cephalosporins include, but are not limited to: cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome. Examples of penem antibiotics include, but are not limited to: faropenem. Examples of monoamide ring antibiotics include, but are not limited to: aztreonam and tigemonam. Examples of carbapenem antibiotics include, but are not limited to: biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. Examples of beta lactamase inhibitors include, but are not limited to: tazobactam ([2S- (2 alpha, 3 beta, 5 alpha) ] -3-methyl-7-one-3- (1H-1, 2, 3-triazol-1-ylmethyl) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4, 4 sodium dioxide salt), sulbactam ((2S, 5R) -3, 3-dimethyl-7-one-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4, 4 sodium dioxide) and clavulanic acid ((2R, 5R, Z) -3- (2-hydroxyethylidene) -7-one-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid). Examples of other antibiotics include, but are not limited to: [ (N-benzyloxycarbonylamino) methyl ] -phosphoric acid- (4-nitrophenyl) ester sodium salt, [ (N-benzyloxycarbonylamino) methyl ] -phosphoric acid- (3-pyridyl) ester sodium salt, sulfanilamide, (4-aminobenzenesulfonamide), sulfasalazine (6-one-3- (2- [4- (N-pyrimidin-2-ylsulfamoyl) phenyl ] hydrazono) cycloocta-1, 4-diene carboxylic acid), 1-cyclopropyl-6-fluoro-4-one-7-piperazin-1-yl-quinoline-3-carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-one- [1, 8] naphthyridine-3-carboxylic acid).

Examples of sulfonamide antibiotics include, but are not limited to: sulfamethazine, sulfanilamide, sulfadiazine, sulfamethoxazole, sulfamonomethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamil, furosemide, hydrochlorothiazide, indapamide, mefuside, metolazone, xipamide, dichlorfenamide, dusacamide, acetazolamide, isozolamide, sultam, zonisamide, mafenide, mazone, celecoxib, direprevir, probenecid, sulfasalazine and sumatriptan.

Examples of quinolone antibiotics include, but are not limited to: cinoxacin, flumequine, nalidixic acid, oxolinic acid, pyrric acid, pipemidic acid, roxofloxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, gatifloxacin, enoxacin (ecinofloxacin), delafloxacin (delafloxacin) and nalidixic acid.

Examples of antiviral drugs include, but are not limited to: rifampin, zanamivir, and oseltamivir.

Examples of antifungal drugs include, but are not limited to: polyene antifungal drugs (e.g., natamycin, streptomycin, filipin, nystatin, amphotericin B and candelilla), imidazole antifungal drugs (e.g., miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole and tioconazole), triazole antifungal drugs (e.g., fluconazole, itraconazole, isaconazole, ravuconazole, posaconazole, voriconazole and terconazole), thiazole antifungal drugs (e.g., abafungin), allylamine antifungal drugs (e.g., terbinafine, amorolfine, naftifine and butenafine), echinocandins (e.g., anidulafungin, caspofungin and micin), and other antifungal drugs such as benzoic acid, ciclopirox, tolnaftate, undecylenic acid, flucytosine, Griseofulvin and haloprogin.

Examples of anti-protozoan drugs include, but are not limited to: enlosamide (elornithine), furazolidone, melarsinol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine and tinidazole.

In certain embodiments, the transport unit of the HPP or HPC contains a protonatable amino group, which may facilitate or enhance the transport of the HPP or HPC across one or more biological barriers. In certain embodiments, the protonatable amino group may be substantially protonated at the pH conditions of the biological barrier penetrated by the HPP or HPC. In certain embodiments, the amino group may be reversibly protonated or deprotonated.

In certain embodiments, a linker may covalently link the functional unit to the transport unit of the HPP, the linker comprising a chemical bond that can be cleaved upon penetration of the HPP through the one or more biological barriers. The cleavable bond includes, for example, a covalent bond, an ether bond, a thioether bond, an amide bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, or an oxime bond.

In certain embodiments, the HPP or HPC of the antimicrobial or antimicrobial-related compound contains one or two primary, secondary, or tertiary amino groups that can exist in protonated form at physiological pH. In certain embodiments, the HPP or HPC contains one primary, secondary, or tertiary amino group that can exist in protonated form at physiological pH.

Another aspect of the invention relates to a pharmaceutical composition comprising HPP or HPC of at least one antimicrobial agent or antimicrobial-related compound and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a method of penetration of a biological barrier with HPP or HPC of an antimicrobial agent or antimicrobial agent related compound.

Another aspect of the invention relates to a method of diagnosing the onset, development, or amelioration of a condition in a biological subject using an HPP or HPC of an antimicrobial or antimicrobial-related compound. In some embodiments, the HPP (or HPC) or functional unit thereof may be tested. In certain embodiments, the HPP (or HPC) or functional unit thereof may itself be detectable, or labeled or conjugated with a detectable label.

Another aspect of the invention relates to a method of screening a functional unit, linker, or transport unit for a desired characteristic.

Another aspect of the invention relates to a method of preventing, alleviating, or treating a condition in a biological subject by administering to the biological subject a composition of the invention. In certain embodiments, the methods relate to methods of treating a condition treatable by an antimicrobial agent or antimicrobial related compound in a biological subject by administering to the subject a therapeutically effective dose of an HPP of an antimicrobial agent or antimicrobial related compound, or a pharmaceutical composition thereof. In certain embodiments, the conditions treatable with this method include, but are not limited to, pain, injury, and conditions associated with microorganisms. The symptoms associated with microorganisms refer to symptoms caused by microorganisms such as bacteria, fungi, protozoa, and viruses. For example, symptoms caused by bacteria (bacteria-related symptoms), protozoa (protozoa-related symptoms), fungi (fungi-related symptoms), and viruses (virus-related symptoms). Bacterial-related conditions include, for example, infection (e.g., infection of an organ such as liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gall bladder, duodenum, rectus intestine (rectus tomach), colorectal, intestinal, venous, respiratory system, vascular, anorectal, and anal pruritus, respiratory tract infection, upper respiratory tract infection, urinary tract infection, nosocomial infection, pseudomonas infection, coagulase-positive staphylococcal infection (e.g., skin infection, poisoning, acute infective endocarditis, septicemia, necrotizing pneumonia), infection after implantation of a prosthesis, opportunistic infection with septicemia and pneumonia), plague (e.g., lymphadenitis and pneumonic plague), anthrax (e.g., skin, lung, and gastrointestinal anthrax), Lyme disease, brucellosis, cough, acute enteritis, parrot, pyretic infection, pertussis, and pertussis, Nongonococcal urethritis, trachoma, neonatal inclusion body conjunctivitis, lymphogranuloma veneris, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, dysentery, neonatal meningitis, hemorrhagic colitis, hemolytic uremic syndrome, tularemia, pneumonia, bronchitis, gastric ulcer, legionnaires 'disease, Pompe fever, leptospirosis, Listeria disease, leprosy, tuberculosis, mycoplasmal pneumonia, gonorrhea, neonatal ophthalmia, septic arthritis, successive outbreak of meningococcal disease, Hua-Freund's syndrome (acute fulminant meningococcal bacteraemia), rocky mountain spotted fever, typhus salmonella disease (typhofetid vertyellosis), salmonella accompanied by gastroenteritis and colitis, bacillary dysentery, meningitis, endometritis, Otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever, and cholera. Protozoan-related symptoms include, for example: malaria, narcolepsy, and toxoplasmosis. Fungal-related symptoms include, for example: aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioomycosis, sporotrichosis, and zygomycosis. Virus-related symptoms include, for example: influenza, yellow fever and AIDS.

In certain embodiments, the pharmaceutical composition of HPP or HPC may be administered to a biological subject by a variety of routes, including, but not limited to, oral, intestinal, oral, nasal, topical, rectal, vaginal, aerosol, transmucosal, epithelial, transdermal, ocular, pulmonary, subcutaneous, and/or injectable routes of administration. In certain preferred embodiments, the HPP or HPC may be administered by the oral, transdermal, topical, subcutaneous and/or injectable routes.

Consistent with the advantages of the present invention, and not intended to be limited by any particular mechanism, a therapeutically effective dose of HPP or HPC may be administered locally at the site of symptoms at a lower dose and to achieve a higher concentration. Advantages of the present invention also include, for example, avoidance of systemic administration, reduction of side effects (e.g., injection pain, gastrointestinal or renal reactions, or other side effects), and potential new therapeutic modalities due to high local concentrations of HPP, HPC, or active substance. Advantages of the present invention further include, for example, how rapid and efficient systemic administration of HPP or HPC to a biological subject can achieve bioavailability, penetration of difficult to cross biological barriers (e.g., the blood-brain barrier and the blood-milk barrier), and new therapeutic modalities due to the passage of biological barriers.

Drawings

FIG. 1a 1: 6-p-Acetoxyacetamido-2-diethylaminoethyl penicillin hydrochloride (A), Acrylthiomethyl-2-diethylaminoethyl penicillin hydrochloride (B), 6- (2, 6-dimethoxybenzamide) penicillin acid-2-diethylaminoethyl ester hydrochloride (C), 6- (5-methyl-3-phenyl-2-isoxazoline-4-carboxamido) penicillin acid-2-diethylaminoethyl ester hydrochloride (D), 6- [3- (o-chlorophenyl) -5-methyl-4-isoxazolecarboxamido ] penicillin acid-2-diethylaminoethyl ester hydrochloride (E) through human skin tissue isolated in Franz cell (n ═ 5), cumulative total amount of 6- [3- (2, 6-dichlorophenyl) -5-methyl-4-isoxazolecarboxamido ] penicillanic acid-2-diethylaminoethyl ester hydrochloride (F), penicillin V (G), penicillin O (H), methicillin (I), benzasoxazole penicillin (J), cloxacillin (K), and dicloxacillin (L). In each case, the carrier solution was phosphate buffered (0.2M) at pH 7.4.

FIG. 1a 2: 6- [ D (-) - α -Acetaminophenylacetamido ] penicillanic acid-2-diethylaminoethyl ester hydrochloride (A), D- α - [ (imidazolidin-2-one-1-yl) carboxamido ] benzylpenicillin-2-diethylaminoethyl ester hydrochloride (B), 6R- [2- [3- (methylsulfonyl) -2-one-1-imidazolidincarboxamido ] -2-phenylacetamido ] penicillanic acid-2-diethylaminoethyl ester hydrochloride (C), 6-D (-) - α - (4-ethyl-2, 3-dione-1-piperazinecarboxamido) - α -phenylacetamidopenicillanic acid-2-diethylaminoethyl ester hydrochloride (A), 6-D (-) - α - (3-dione-1-piperazinecarboxamido) - α -phenylacetamidopenicillanic acid-2-diethylaminoethyl ester hydrochloride (B), and the like Cumulative total of ester hydrochloride (D), 7- (2-thiopheneacetamino) cephalosporanic acid-2-diethylaminoethyl ester hydrochloride (E), ampicillin (F), azlocillin (G), mezlocillin (H), piperacillin (I), and cephalosporin (J). In each case, the carrier solution was phosphate buffered (0.2M) at pH 7.4.

FIG. 1a 3: 7- [ (hydroxyphenylacetyl) amino ] -3- [ [ (1-methyl-1H-tetrazol-5-yl) thio ] methyl ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-2-diethylaminoethyl ester hydrochloride (A), 3- [ [ (aminocarbonyl) oxy ] methyl ] -7- [ [ 2-furanyl (methoxyimino) acetamido ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-2-diethylaminoethyl ester hydrochloride (B) separated from human skin tissue in Franz pool (n ═ 5), 3- [ [ (aminocarbonyl) oxy ] methyl ] -7-methoxy-8-one-7- [ (2-thienylacetyl) amino) ] -5-thia-1-azabicyclo- [4.2.0] -oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (C), 7- [ [ [2- (acetamidomethyl) phenyl ] acetyl ] amino ] -3- [ [ [1- (ethoxycarbonylmethyl) -1H-tetrazol-5-yl ] thio ] methyl ] -8-one-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (D), cumulative total of 7- [ (acetamidophenylacetyl) amino ] -3-chloro-8-one-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-2-diethylaminoethyl ester hydrochloride (E), cefamandole (F), cefuroxime (G), cefoxitin (H), cefrex (I), and cefaclor (J). In each case, the carrier solution was phosphate buffered (0.2M) at pH 7.4.

FIG. 1a 4: 3- [ (acetoxy) methyl ] -7- [ [ (2-acetamido-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-2-diethylaminoethyl ester hydrochloride (A), 7- [ [ (2-acetamido-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-2-diethylaminoethyl ester hydrochloride (B), 7- [ [ [ [ (4-ethyl-2), 3-diketo-1-piperazino) carbonyl ] amino ] - (4-acetoxyphenyl) acetyl ] amino ] -3- [ [ (1-methyl-1H-tetrazol-5-yl) thio ] methyl ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (C), 7- [2- (2-acetamido-4-thiazolyl) -2- ((Z) -methoxyimino) acetamido ] -3- (methoxymethyl) -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (D) Cumulative total amount of 7- [2- (2-acetamido-4-thiazole) -2- ((Z) -ethoxycarbonylmethoxy) imino ] acetamido ] -3- (vinyl) -8-one-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-2-diethylaminoethyl ester hydrochloride (E), cefotaxime (F), ceftizoxime (G), cefoperazone (H), cefpodoxime proxetil (I), and cefixime (J). The carrier solutions were all phosphate buffered (0.2M) at pH 7.4.

FIG. 1 b: sodium [2S- (2a, 3b, 5a) ] -3-methyl-7-one-3- (1H-1, 2, 3-triazol-1-ylmethyl) -4-thioxo-1-azabicyclo [3, 2, 0] heptane-2-carboxylic acid-4, 4-dioxide salt (tazobactam, curve F), [2S- (2a, 3b, 5a) ] -3-methyl-7-one-3- (1H-1, 2, 3-triazol-1-ylmethyl) -4-thioxo-1-azabicyclo [3, 2, 0] heptane-2-carboxylic acid-4, 4-dioxide 1-piperidine ethyl ester hydrochloride (tazobactam-PEE, curve A), (2S, 5R) -3, 3-dimethyl-7-one-4-thia-1-azabicyclo [3, 2, 0] heptane-2-carboxylic acid sodium-4, 4-dioxide (sulbactam, Curve G), (2S, 5R) -3, 3-dimethyl-7-one-4-thia-1-azabicyclo [3, 2, 0] heptane-2-carboxylic acid sodium-4, 4-dioxide N, N-diethylaminoethyl ester hydrochloride (sulbactam-DEE, Curve B), 2R- (2a, 3Z, 5a) -3- (2-hydroxyethenyl) -7-one-4-oxa-1-azabicyclo [3.2.0] -heptane-2-carboxylic acid- (clavulanic acid) Curve H), 2R- (2a, 3Z, 5a) -3- (2-hydroxyethenyl) -7-keto-4-oxa-1-azabicyclo [3.2.0] -heptane-2-carboxylic acid 4-piperidineethyl ester hydrochloride (clavulanic acid-PEE, curve C), [ (N-phenoxycarbonylamino) methyl ] -phosphonic acid mono- (4-nitrophenyl) ester sodium salt (curve I), [ (N-phenoxycarbonylamino) methyl ] -phosphonic acid mono- (4-nitrophenyl) (N, N-diethylaminomethyl) ester hydrochloride (curve D), [ (N-phenoxycarbonylamino) methyl ] -phosphonic acid mono- (3-pyridyl) ester sodium salt (curve J) and [ (N-phenoxycarbonylamino) methyl ] -phosphonic acid mono- (3-pyri-dyl) ester Pyridyl) - (1-piperidineethyl) ester hydrochloride (curve E) cumulative total amount of human skin in the Frannz cell (n ═ 5). The carrier solution was 0.2MpH value 7.4 phosphate buffered saline.

FIG. 1 c: the curves are respectively 4-aminobenzenesulfonamide (p-aminobenzenesulfonamide, E), 4- (4-dimethylaminobutyryl) -4-aminobenzenesulfonamide hydrochloride (DMAB-p-aminobenzenesulfonamide, A), 6-keto-3- (2- [4- (N-pyridin-2-ylsulfamoyl) phenyl ] hydrazono) cyclohexa-1, 4-diencarboxylic acid (sulfasalazine, F), 6-keto-3- (2- [4- (N-pyridin-2-ylsulfamoyl) phenyl ] hydrazono) cyclohexa-1, 4-Dienecarboxylic acid N, N-diethylaminopropyl ester hydrochloride (sulfasalazine-DEPE, B), 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-one-7 (1-piperazinyl) -3-quinolinecarboxylic acid (ciprofloxacin, G), 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-one-7 (1-piperazinyl) -3-quinolinecarboxylate butyl ester hydrochloride (ciprofloxacin-BE, C), 1-ethyl-1, 4-dihydro-7-methyl-4-one-1, 8-naphthyridine-3-carboxylic acid (naphthyridine acid, H), 1-ethyl-1, cumulative total amount of 4-dihydro-7-methyl-4-keto-1, 8-naphthyridine-3-carboxylic acid N, N-diethylaminoethyl ester hydrochloride (naphthyridine acid-DEE, D) across human skin in the Frannz pool (N ═ 5). The carrier solution was a phosphate buffered solution at pH 7.40.2M.

Detailed description of the invention

I. High Permeability Prodrugs (HPPs) or high permeability compositions (high) HPC) structure

One aspect of the present invention relates to a High Permeability Prodrug (HPP) or a High Permeability Composition (HPC). "high penetrating prodrug" or "HPP" or "high penetrating composition" or "HPC" in the present invention refers to a composition comprising a functional unit and a transport unit covalently linked by a linker.

The functional unit of an HPP or HPC contains a portion of the parent drug (motif), which has the following properties: 1) it is desirable to deliver the parent drug or HPP/HPC into a biological subject and/or to transport the parent drug across some biological barrier; 2) HPP/HPC can penetrate or cross biological barriers; and 3) HPP/HPC may be cleaved such that a portion of the parent drug is converted to the parent drug or a metabolite of the parent drug.

In certain embodiments, the functional units may be hydrophilic, lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). The lipophilic part of the functional unit may be intrinsic or obtained by converting one or more hydrophilic parts of the functional unit into a lipophilic part. For example, the lipophilic portion of the functional unit can be converted to a lipophilic group by organic synthesis by converting one or more hydrophilic groups of the functional unit. Examples of hydrophilic groups include, but are not limited to, carboxyl, hydroxyl, thiol, amino, phosphate/phosphonate, guanidino, and carbonyl. Lipophilic moieties generated by modification of these hydrophilic groups include, but are not limited to, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates, and or oximes. In certain embodiments, the functional unit may be lipophilic by acetylation or acylation. In certain embodiments, the functional units may be lipophilic by esterification.

In certain embodiments, the parent drug of HPP or HPC may be selected from the group consisting of an antimicrobial agent or an antimicrobial-related compound. A portion of the antimicrobial agent or antimicrobial-related compound can be further converted to a lipophilic moiety according to the methods described previously.

An antimicrobial agent is a substance that kills or inhibits the growth of microorganisms, such as bacteria, fungi, or protozoa, and which also destroys or inhibits the growth of viruses. Antimicrobial agents include, for example, antibiotics which treat bacterial-related conditions, antiviral agents which treat viral-related conditions, antifungal agents which treat fungal-related conditions, and antiparasitic agents which treat parasitic-related conditions.

Antimicrobial-related compounds are compounds that contain an antimicrobial structure, an antimicrobial metabolite structure, or a therapeutic substance structure that can be metabolized into an antimicrobial or antimicrobial metabolite. Antimicrobial-related compounds further include analogs or mimics of antimicrobial agents (micics), or analogs or mimics of metabolites of antimicrobial agents, or are therapeutic substances that are metabolized to antimicrobial agents or analogs or mimics of metabolites of antimicrobial agents after HPP or HPC have penetrated one or more biological barriers.

Examples of antibiotics include, but are not limited to, beta-lactam antibiotics, sulfonamides, and quinolone antibiotics. Beta-lactam antibiotics are well known in the art and are used in a variety of conditions. In the present invention, a beta-lactam antibiotic refers to a compound containing a beta-lactam nucleus.

Examples of beta-lactam antibiotics include, but are not limited to, penicillin derivatives, cephalosporins, penem antibiotics, monobactams, carbapenems, beta-lactamase inhibitors, and combinations thereof. Examples of penicillin derivatives include, but are not limited to, amino-based penicillins (e.g., amoxicillin, ampicillin, and epicillin), carboxy-based penicillins (e.g., carbenicillin, ticarcillin, and temocillin), ureido-based penicillins (e.g., azlocillin, piperacillin, and mezlocillin), mezlocillin, sulbenicillin, benzathine, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), penicillin o (allylmercaptomethylpenilliginic), procainicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, ampicillin-ketacillin, bacampicillin (becampicilin), maytansillin, phthalampicillin, amoxicillin (amoxicillin + clavulanic acid), and piperacillin. Examples of cephalosporins include, but are not limited to: cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime and cefpirome. Examples of penem antibiotics include, but are not limited to: faropenem. Examples of monoamide ring antibiotics include, but are not limited to: aztreonam and tigemonam. Examples of carbapenem antibiotics include, but are not limited to: biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem. Examples of beta lactamase inhibitors include, but are not limited to: tazobactam ([2S- (2 alpha, 3 beta, 5 alpha) ] -3-methyl-7-one-3- (1H-1, 2, 3-triazol-1-ylmethyl) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4, 4 sodium dioxide salt), sulbactam (2S, 5R) -3, 3-dimethyl-7-one-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4, 4 sodium dioxide and clavulanic acid ((2R, 5R, Z) -3- (2-hydroxyethylidene) -7-one-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid). Examples of other antibiotics include, but are not limited to: [ (N-benzyloxycarbonylamino) methyl ] -phosphoric acid- (4-nitrophenyl) ester sodium salt, [ (N-benzyloxycarbonylamino) methyl ] -phosphoric acid- (3-pyridyl) ester sodium salt, sulfanilamide, (4-aminobenzenesulfonamide), sulfasalazine (6-one-3- (2- [4- (N-pyrimidin-2-ylsulfamoyl) phenyl ] hydrazono) cycloocta-1, 4-diencarboxylic acid), 1-cyclopropyl-6-fluoro-4-one-7-piperazin-1-yl-quinoline-3-carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-one- [1, 8] naphthyridine-3-carboxylic acid).

Examples of sulfonamide antibiotics include, but are not limited to: sulfamethoprim, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfamonomethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamil, furosemide, hydrochlorothiazide, indapamide, mefuside, metolazone, xipamide, dichlorfenamide, dusacamide, acetazolamide, isozolamide, sultam, zonamide, mafenide, sulipram, celecoxib, Daralvir, probenecid, sulfasalazine and sumatriptan.

Examples of antifungal drugs include, but are not limited to: polyene antifungal drugs (e.g., natamycin, streptomycin, filipin, nystatin, amphotericin B, camphosine), imidazole antifungal drugs (e.g., miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole), triazole antifungal drugs (e.g., fluconazole, itraconazole, isaconazole, ravuconazole, posaconazole, voriconazole, and terconazole), thiazole antifungal drugs (e.g., abafungin), allylamine antifungal drugs (e.g., terbinafine, amorolfine, naftifine, and butenafine), echinocandins (e.g., anidulafungin, caspofungin, and micin), and other antifungal drugs such as benzoic acid, ciclopirox, tolnaftate, undecylenic acid, Flucytosine, griseofulvin, and haloprogin.

In certain embodiments, the functional unit of the HPP of the antimicrobial or antimicrobial-related compound comprises a structure having the structural formula F-1:

including stereoisomers thereof and pharmaceutically acceptable salts thereof.

Unless otherwise stated in the specification, Y is selected from the group consisting of: H. OH, NHCHO, NHC (═ O) R₆、OC(＝O)CH₃、OC(＝O)R₆、OCH₃、OC₂H₅、OR₆、CH₃SO₃、R₆SO₃、NO₂、CN、CF₃、OCF₃、OC₂F₅、OC₃F₇F, Br, I, Cl, and substituted and unsubstituted alkoxy groups;

selected from the group consisting of structural formula NS-1, structural formula NS-2, structural formula NS-3, structural formula NS-4, and structural formula NS-5:

X₁selected from the group consisting of: H. OH, OCH₃、OC₂H₅、OR₆、C(＝O)NH₂、CH₂OC(＝O)NH₂、CH₂OC(＝O)CH₃、CH₂OC(＝O)CH₆、OC(＝O)CH₃、OC(＝O)R₆、CH₂OCH₃、CH₃、C₂H₅、R₆、Cl、F、Br、I、HC＝CHCH₃、HC＝CH₂、CH₂OCH₃、CH₂OR₆、S(CH₂)_n-NHR₇Structural formula X₁-1, structural formula X₁-2, structural formulaX₁-3, structural formula X₁-4, structural formula X₁-5, structural formula X₁-6, structural formula X₁-7, structural formula X₁-8, structural formula X₁-9, structural formula X₁-10, structural formula X₁-11, structural formula X₁-12, structural formula X₁-13, structural formula X₁-14, structural formula X₁-15, structural formula X₁-16, structural formula X₁-17, structural formula X₁-18, structural formula X₁-19, structural formula X₁-20, structural formula X₁-21, structural formula X₁-22, structural formula X₁-23, structural formula X₁-24, structural formula X₁-25, structural formula X₁-26, structural formula X₁-27, structural formula X₁-28, structural formula X₁-29, structural formula X₁-30, structural formula X₁-31, structural formula X₁-32, structural formula X₁-33, structural formula X₁-34, structural formula X₁-35, structural formula X₁-36, structural formula X₁-37, structural formula X₁-38, structural formula X₁-39, structural formula X₁-40, structural formula X₁-41, structural formula X₁-42, structural formula X₁-43, structural formula X₁-44, structural formula X₁-45, structural formula X₁-46, structural formula X₁-47, structural formula X₁-48, structural formula X₁-49, structural formula X₁-50, structural formula X₁-51, structural formula X₁-52, structural formula X₁-53, structural formula X₁-54, structural formula X₁-55, structural formula X₁-56, structural formula X₁-57, structural formula X₁-58, structural formula X₁-59, structural formula X₁-60, structural formula X₁-61, structural formula X₁-62, structural formula X₁-63, structural formula X₁-64, structural formula X₁-65, structural formula X₁-66, structural formula X₁-67, structural formula X₁-68, structural formula X₁-69, structural formula X₁-70, structural formula X₁-71, structural formula X₁-72, structural formula X₁-73, structural formula X₁-74, structural formula X₁-75, structural formula X₁-76, structural formula X₁-77, structural formula X₁-78, structural formula X₁-79, structural formula X₁-80, structural formula X₁-81 and structural formula X₁-82：

R_sTogether with Y represent R₆OCH2C(R₅) Either, or itself selected from the group consisting of: r₆OOCCH(NHR₇)(CH₂)_nCONH-、R₆OOCCH(NHR₇)(CH₂)_nSCONH-、CF₃SCH₂CONH-、CF₃CH₂CONH-、CHF₂SCH₂CONH-、CH₂FSCH₂CONH-、NH₂COCHFS-CH₂CONH-、R₇NHCH(L₁-L₄-L₂-W)CH₂SCH₂CONH-、CNCH₂SCH₂CONH-、CH₃(CH₂)_nCONH-、R₇N＝CHNR₇CH₂CH₂S-、R₇N＝C(NHR₇)NHCO-、CH₂、CH₃C(Cl)＝CHCH₂SCH₂CONH-、(CH₃)₂C(OR₆)-、CNCH₂CONH-、CNCH₂CH₂S-、R₇HN＝CH(NR₇)CH₂CH₂S-、CH₂＝CHCH₂SCH₂CONH-、CH₃CH(OH)-、CH₃CH(OR₈)-、CH₃CH(Y₁)-、(CH₃)₂CH-、CH₃CH₂-、CH₃(CH₂)nCH＝CH(CH₂)mCONH-，R₇N＝C(NHR₇)NHC(＝O)CH₂Structural formula Rs-1, structural formula Rs-2, structural formula Rs-3, structural formula Rs-4, structural formula Rs-5, structural formula Rs-6, structural formula Rs-7, structural formula Rs-8, structural formula Rs-9, structural formula Rs-10, structural formula Rs-11, structural formula Rs-12, structural formula Rs-13, structural formula Rs-14, structural formula Rs-15, structural formula Rs-16, structural formula Rs-17, structural formula Rs-18, structural formula Rs-19, structural formula Rs-20, structural formula Rs-21, structural formula Rs-22, structural formula Rs-23, structural formula Rs-24, structural formula Rs-25, structural formula Rs-26, structural formula Rs-27, structural formula Rs-28, structural formula Rs-29, structural formula Rs-4, Structural formula Rs-30, structural formula Rs-31, structural formula Rs-32, structural formula Rs-33, structural formula Rs-34, structural formula Rs-35, structural formula Rs-36, structural formula Rs-37, structural formula Rs-38, structural formula Rs-39, structural formula Rs-40, structural formula Rs-41, structural formula Rs-42, structural formula Rs-43, structural formula Rs-44, structural formula Rs-32Rs-45, and structural formula Rs-46;

w is selected from the group consisting of: H. substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, protonatable amino group, pharmaceutically acceptable substituted and substitutable primary amino group, structural formula Wa, structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, structural formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, structural formula W-10, structural formula W-11, structural formula W-12, structural formula W-13, structural formula W-14, structural formula W-15, structural formula W-16, Structural formula W-17 and structural formula W-18:

z is selected from the group consisting of: CH (CH)₂、S、SO、SO₂、NH、NR₆、CHCH₃、CHCH₂CH₃、CHR₆、R₆-C (═ O) -, and O;

AA represents any amino acid;

each m and n may be independently selected from the group consisting of 0 and integers, such as 0, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, …;

HA is selected from the group consisting of: non, pharmaceutically acceptable acids, such as: HCl, HBr, HI, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, acid tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid (gentisic acid), fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid;

r is selected from the group consisting of: none, CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted alkynylHeteroaryl of (a), wherein any CH in R₂Can be O, S, P, NR₆Or any other pharmaceutically acceptable group substitution;

R₁-R₃each may be independently selected from the group consisting of: H. substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;

R₅and R₃₅Each may be independently selected from the group consisting of: H. c (═ O) NH₂、CH₂CH₂OR₆、CH₂CH₂N(CH₃)₂、CH₂CH₂N(CH₂CH₃)₂Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted hydrocarbonyl, substituted and unsubstituted hydrocarbonylamino, -C (═ O) -W, L₁-L₄-L₂-W and W;

R₆、R₃₆and R₄₆Each may be independently selected from the group consisting of: H. f, Cl, Br, I, Na⁺、K⁺、C(＝O)R₅2-keto-1-imidazolidinyl, phenyl, 5-indanyl, 2, 3-dihydro-1H-inden-5-yl, 4-hydroxy-1, 5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxy, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C (═ O) -W, L₁-L₄-L₂-W and W;

R₇and R₃₇Each may be independently selected from the group consisting of: H. f, Cl, Br, I, CH₃NHC(＝O)CH₂CH(NHR₈)C(＝O)、R₅N＝C(NHR₆)NHC(＝O)-、C(＝O)CH₃、C(＝O)R₆、PO(OR₅)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted hydrocarbonoxy, substituted and unsubstituted hydrocarbonamino, L₁-L₄-L₂-W and C (═ O) -W;

R₈and R₃₈Each may be independently selected from the group consisting of: H. f, Cl, Br, I, CH₃、C₂H₅、CF₃、CH₂CH₂F、CH₂CH₂Cl、CH₂CH₂Br、CH₂CH₂I、CH₂CHF₂、CH₂CF₃、CH₂F、CH₂Cl、CH₂Br、CH₂I、CH₂NR₆R₇、CH(NHR₇)CH₂C(＝O)NH₂、C₃H₇、C₄H₉、C₅H₁₁、R₆、C(＝O)R₆、C(＝O)NH₂、CH₂C(＝O)NH₂、CH₂OC(＝O)NH₂、PO(OR₅)OR₆、C(CH₃)₂C(＝O)OR₆、CH(CH₃)C(＝O)OR₆、CH₂C(＝O)OR₆、C(＝O)-W、L₁-L₄-L₂-W, W, substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylamino, substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted haloalkyl, and substituted and unsubstituted hydrocarbonyl;

R_11-16each independently selected from the group consisting of: none, H, CH₂C(＝O)OR₁₁Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;

X₂selected from the group consisting of: none, H, CH₂(CH₂)_nOR₈、Cl、F、Br、I、NO₂、CN、CF₃、C₂F₅、C₃F₇、OCF₃、OC₂F₅、NH₂、NHR₆、CH₃、C₂H₅、R₆、C(＝O)NH₂、CH₂OC(＝O)NH₂、CH₂C(＝O)OR₅、CH₂(CH₂)_nN(CH₃)₂、CH₂(CH₂)_nSO₃R₅Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, and substituted and unsubstituted hydrocarbyloxy;

X₃selected from the group consisting of: none, H, N₃、SO₃W、F、Cl、Br、OH、OCH₃、OR₆、CH₃、R₆、C(＝O)OW、OW、L₁-L₄-L₂-W and I;

X₄selected from the group consisting of: none, N, CH, and CY₁；

X₅And X₃₅Each independently selected from the group consisting of: none, C (═ O), OC (═ O), CH₂CH, S, O and NR₅；

Y₁、Y₃₁、Y₂、Y₃₂、Y₃And Y₄Each independently selected from the group consisting of: H. OH, OW, OC (═ O) W, L₁-L₄-L₂-W、OC(＝O)CH₃、CH₃、C₂H₅、C₃H₇、C₄H₉、R₆、SO₃R₆、CH₂OR₆、CH₂OC(＝O)R₆、CH₂C(＝O)OR₈、OCH₃、OC₂H₅、OR₆、CH₃SO₂、R₆SO₂、CH₃SO₃、R₆SO₃、NO₂、CN、CF₃、OCF₃、CH₂(CH₂)_nNR₅R₆、CH₂(CH₂)_nOR₆、CH(C(＝O)NH₂)NHR₆、CH₂C(＝O)NH₂、F、Br、I、Cl、CH＝CHC(＝O)NHCH₂C(＝O)OW、CH＝CHC(＝O)NHCH₂L₁-L₄-L₂-W、NR₈C(＝O)R₅、SO₂NR₅R₈、C(＝O)R₅、SR₅Substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted hydrocarbyloxy, substituted and unsubstituted hydrocarbylthio, substituted and unsubstituted hydrocarbylamino, substituted and unsubstituted polyfluoroalkyl, substituted and unsubstituted halocarbyl, and substituted and unsubstituted hydrocarbonyl;

L₁selected from the group consisting of: none, O, S, -O-L₃-、-S-L₃-、-N(L₃)-、-N(L₃)-CH₂-O、-N(L₃)-CH₂-N(L₅)-、-O-CH₂-O-、-O-CH(L₃) -O, and-S-CH (L)₃)-O-；

L₂Selected from the group consisting of: none, O, S, -O-L₃-、-S-L₃-、-N(L₃)-、-N(L₃)-CH₂-O、-N(L₃)-CH₂-N(L₅)-、-O-CH₂-O-、-O-CH(L₃)-O、-S-CH(L₃)-O-、-O-L₃-、-N-L₃-、-S-L₃-、-N(L₃)-L₅-and L₃；

L₄Selected from the group consisting of: C-S O, C,

For each L₁、L₂And L₄，L₃And L₅Each may be independently selected from the group consisting of: none, H, CH₂C(＝O)OL₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted polyfluoroalkyl and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further replaced by O, S, P, NL₃Or any other pharmaceutically acceptable group;

L₆may be independently selected from the group consisting of: H. OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted polyfluoroalkyl and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further replaced with O, S, N, P (O) OL respectively₆、CH＝CH、C≡C、CHL₆、CL₆L₇Aromatic hydrocarbonSubstituted with a group, heteroaryl or cyclic group;

L₇may be independently selected from the group consisting of: H. OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted polyfluoroalkyl and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further replaced with O, S, N, P (O) OL respectively₆、CH＝CH、C≡C、CHL₆、CL₆L₇Aryl, heteroaryl or cyclic group substitution; and

any CH₂The group may be substituted with O, S or NH.

In certain embodiments, the functional unit of an HPP or HPC of an antimicrobial or antimicrobial-related compound comprises a certain structure selected from the group consisting of: structural formula FP-1, structural formula FP-2, structural formula FP-3, structural formula FP-4, structural formula FP-5, structural formula FP-6, structural formula FP-7, structural formula FP-8, structural formula FP-9, structural formula FP-10, structural formula FP-11, structural formula FP-12, structural formula FP-13, structural formula FP-14, structural formula FP-15, structural formula FP-16, structural formula FP-17, structural formula FP-18, structural formula FP-19, structural formula FP-20, structural formula FP-21, structural formula FP-22, structural formula FP-23, structural formula FP-24, structural formula FP-25, structural formula FP-26, structural formula FP-27, structural formula FP-28, structural formula FP-29, structural formula FP-6, Structural formula FP-30, structural formula FP-31, structural formula FP-32, structural formula FP-33, structural formula FP-34, structural formula FP-35, structural formula FP-36, structural formula FP-37, structural formula FP-38, structural formula FP-39, structural formula FP-40, structural formula FP-41, structural formula FP-42, structural formula FP-43, structural formula FP-44, structural formula FP-45, structural formula FP-46, structural formula FP-47, structural formula FP-48, structural formula FP-49, structural formula FP-50, structural formula FP-51, structural formula FP-52, structural formula FP-53, structural formula FP-54, structural formula FP-55, structural formula FP-56, structural formula FP-57, structural formula FP-58, structural formula, Structural formula FP-59, structural formula FP-60, structural formula FP-61, structural formula FP-62, structural formula FP-63, structural formula FP-64, structural formula FP-65, structural formula FP-66, structural formula FP-67, structural formula FP-68, structural formula FP-69, structural formula FP-70, structural formula FP-71, structural formula FP-72, structural formula FP-73, structural formula FP-74, structural formula FP-75, structural formula FP-76, structural formula FP-77, structural formula FP-78, structural formula FP-79, structural formula FP-80, structural formula FP-81, structural formula FP-82, structural formula FP-83, structural formula FP-84, structural formula FP-85, structural formula FP-86, structural formula FI-1, structural formula FP-62, structural formula FP-64, structural formula FP-72, structural formula FP, Structural formula FI-2, structural formula FI-3, structural formula FI-4, structural formula FI-5, structural formula FI-6, structural formula FI-7, structural formula FI-8, structural formula FI-9, structural formula FI-10, structural formula FI-11, structural formula FI-12, structural formula FI-13, structural formula FI-14, structural formula FI-15, structural formula FI-16, structural formula FI-17, structural formula FI-18, structural formula FI-19, structural formula FI-20, structural formula FI-21, structural formula FI-22, structural formula FI-23, structural formula FI-24, structural formula FI-25, structural formula FI-26, structural formula FI-27, structural formula FI-28, structural formula FI-29, structural formula FI-31, structural formula FI-32, structural formula FI-33, structural formula FS-1, structural formula FS-2, structural formula FS-3, structural formula FS-4, structural formula FS-5, structural formula FS-6, structural formula FS-7, structural formula FS-8, structural formula FS-9, structural formula FS-10, structural formula FS-11, structural formula FS-12, structural formula FS-13, structural formula FS-14, structural formula FS-15, structural formula FS-16, structural formula FS-17, structural formula FS-18, structural formula FS-19, structural formula FS-20, structural formula FT-1, structural formula FT-2, structural formula FT-3, structural formula FT-4, structural formula FT-5, structural formula FT-6, structural formula FS-3, structural formula FT-4, structural formula FT-5, structural, Structural formula FT-7, structural formula FT-8, structural formula FT-9, structural formula FT-10, structural formula FT-11, structural formula FT-12, structural formula FT-13, structural formula FT-14, structural formula FT-15, and structural formula FT-16:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

n、R₅、R₇、X₅、X₃₅、Y₁、Y₂、Y₃₁、Y₃₂、Y₃and Y₄The definition of (A) is the same as that described above;

L₃₁and the aforementioned L₁Are defined identically, L₃₂And the aforementioned L₂Are defined identically, L₃₄And the aforementioned L₄Definitions are the same, -L in some embodiments₁-L₄-L₂-and-L₃₁-L₃₄-L₃₂-each may be independently selected from the group consisting of: -O-, -X-, -O-X-, -N-X-, -S-X-, -X₅-、-O-X₅-、-N-X₅-、-S-X₅-、-O-X₇-, -O-C (═ O) -, -NH-C (═ O) -, -C (═ O) -O-, -C (═ O) -N-, and C (═ O) -X-,

x is selected from the group consisting of: none, C (═ O), OC (═ O), CH₂、CH、S、NH、NR₅And O;

X₆、X₃₆and X₄₆Each independently selected from the group consisting of: none, C (═ O), C (═ S), OC (═ O), CH₂CH, S, O and NR₅(ii) a And

X₇each may be independently selected from the group consisting of: none, C (═ O), C (═ S), OC (═ O), CH₂CH, S, O and NR₅。

In certain embodiments, the functional unit of an HPP or HPC of an antimicrobial or antimicrobial-related compound comprises a functional unit with a structure selected from the group consisting of: structural formula F-1, structural formula FP-2, structural formula FP-3, structural formula FP-4, structural formula FP-5, structural formula FP-6, structural formula FP-7, structural formula FP-8, structural formula FP-9, structural formula FP-10, structural formula FP-11, structural formula FP-12, structural formula FP-13, structural formula FP-14, structural formula FP-15, structural formula FP-16, structural formula FP-17, structural formula FP-18, structural formula FP-19, structural formula FP-20, structural formula FP-21, structural formula FP-22, structural formula FP-23, structural formula FP-24, structural formula FP-25, structural formula FP-26, structural formula FP-27, structural formula FP-28, structural formula FP-3, structural formula FP-4, structural formula FP-5, structural formula FP-, Structural formula FP-29, structural formula FP-30, structural formula FP-31, structural formula FP-32, structural formula FP-33, structural formula FP-34, structural formula FP-35, structural formula FP-36, structural formula FP-37, structural formula FP-38, structural formula FP-39, structural formula FP-40, structural formula FP-41, structural formula FP-42, structural formula FP-43, structural formula FP-44, structural formula FP-45, structural formula FP-46, structural formula FP-47, structural formula FP-48, structural formula FP-49, structural formula FP-50, structural formula FP-51, structural formula FP-52, structural formula FP-53, structural formula FP-54, structural formula FP-55, structural formula FP-56, structural formula FP-57, structural formula FP-32, Structural formula FP-58, structural formula FP-59, structural formula FP-60, structural formula FP-61, structural formula FP-62, structural formula FP-63, structural formula FP-64, structural formula FP-65, structural formula FP-66, structural formula FP-67, structural formula FP-68, structural formula FP-69, structural formula FP-70, structural formula FP-71, structural formula FP-72, structural formula FP-73, structural formula FP-74, structural formula FP-75,

m＝0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、……；

n＝0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、……；

R₁Can be selected from the group consisting of: H. c₁-C₂₀Hydrocarbyl radical, C₁-C₂₀Hydrocarbyloxy, C₁-C₂₀Alkenyl radical, C₁-C₂₀Alkynyl, aryl, and heteroaryl;

R₂can be selected from the group consisting of: H. c₁-C₂₀Hydrocarbyl radical, C₁-C₂₀Hydrocarbyloxy, C₁-C₂₀Alkenyl radical, C₁-C₂₀Alkynyl, aryl, and heteroaryl;

R₃can be selected from the group consisting of: H. c₁-C₂₀Hydrocarbyl radical, C₁-C₂₀Hydrocarbyloxy, C₁-C₂₀Alkenyl radical, C₁-C₂₀Alkynyl, aryl and heteroaryl;

R₅and R₃₅Each may be independently selected from the group consisting of: H. -C (═ O) NH₂、CH₂CH₂OR₆、CH₂CH₂N(CH₃)₂、CH₂CH₂N(CH₂CH₃)₂、CH₂CH₂OR₆、Cl、F、Br、I、C₁-C₂₀Hydrocarbyl radical, C₁-C₂₀Cycloalkyl radical, C₁-C₂₀Hydrocarbyloxy, C₁-C₂₀Cycloalkyl oxy, C₁-C₂₀Alkenyl radical, C₁-C₂₀Cycloalkenyl radical, C₁-C₂₀Cycloalkynyl group, C₁-C₂₀Alkynyl, aryl, heteroaryl, C (═ O) -W, and W;

R₆、R₃₆and R₄₆Each may be independently selected from the group consisting of: H. f, Cl, Br, I, Na⁺、K⁺、C(＝O)R₅2-keto-1-imidazolidinyl, phenyl, 5-indanyl, 2, 3-dihydro-1H-inden-5-yl, 4-hydroxy-1, 5-naphthyridin-3-yl, C₁-C₁₂Hydrocarbyl radical, C₁-C₁₂Cycloalkyl radical, C₁-C₁₂Hydrocarbyloxy, C₁-C₁₂Cycloalkyl oxy, C₁-C₁₂Alkenyl radical, C₁-C₁₂Cycloalkenyl radical, C₁-C₁₂Cycloalkynyl group, C₁-C₁₂Alkynyl, aryl, heteroaryl, C (═ O) -W, and W,

R₇And R₃₇Each may be independently selected from the group consisting of: H. f, Cl, Br, I, CH₃NHC(＝O)CH₂CH(NHR₈)C(＝O)、R₅N＝C(NHR₆)NHC(＝O)-、C(＝O)CH₃、C(＝O)R₆、PO(OR₅)OR₆、C₁-C₂₀Hydrocarbyl radical, C₁-C₂₀Hydrocarbyloxy, C₁-C₂₀Alkenyl radical, C₁-C₂₀Alkynyl, aryl, heteroaryl, C (═ O) -W, and W;

R₈and R₃₈Each may independently be selected from the group consisting of: H. f, Cl, Br, I, CH₃、C₂H₅、CF₃、CH₂CH₂F、CH₂CH₂Cl、CH₂CH₂Br、CH₂CH₂I、CH₂CHF₂、CH₂CF₃、CH₂F、CH₂Cl、CH₂Br、CH₂I、CH₂NR₆R₇、CH(NHR₇)CH₂C(＝O)NH₂、C₃H₇、C₄H₉、C₅H₁₁、R₆、C(＝O)R₆、C(＝O)NH₂、CH₂C(＝O)NH₂、CH₂OC(＝O)NH₂、PO(OR₅)OR₆、C(CH₃)₂C(＝O)OR₆、CH(CH₃)C(＝O)OR₆、CH₂C(＝O)OR₆、C(＝O)-W；

X₂Can be selected from the group consisting of: none, H, CH₂(CH₂)_nOR₈、Cl、F、Br、I、NO₂、CN、CF₃、C₂F₅、C₃F₇、OCF₃、OC₂F₅、NH₂、NHR₆、CH₃、C₂H₅、R₆、C(＝O)NH₂、CH₂OC(＝O)NH₂、CH₂C(＝O)OR₅、CH₂(CH₂)_nN(CH₃)₂、CH₂(CH₂)_nSO₃R₅、C_1-8Hydrocarbyl radical, C_1-8Mercapto group, C_1-8Hydrocarbylamino, and C_1-8Alkoxy radical,

X₃Can be selected from the group consisting of: none, H, N₃、SO₃W、F、Cl、Br、OH、OCH₃、OR₆、CH₃、R₆C (═ O) OW, and I;

X₄can be selected from the group consisting of: none, N, CH, and CY₁；

X₅And X₃₅Each may be independently selected from the group consisting of: none, C (═ O), OC (═ O), CH₂CH, S, O and NR₅；

Each Y₁、Y₃₁、Y₂、Y₃₂、Y₃And Y₄Are independently selected from the group consisting of: H. OH, OW, OC (O) W, OC (O) CH₃、CH₃、C₂H₅、C₃H₇、C₄H₉、SO₃R₆、CH₂OR₆、CH₂OC(＝O)R₆、CH₂C(＝O)OR₈、OCH₃、OC₂H₅、CH₃SO₂、R₆SO₂、R₆SO₃OR₆、CH₃SO₃、R₆SO₃、NO₂、CN、CF₃、OCF₃、CH＝CHC(＝O)NHCH₂C(＝O)OW、CH₂(CH₂)_nNR₅R₆、CH₂(CH₂)_nOR₆、CH(C(＝O)NH₂)NHR₆、CH₂C(＝O)NH₂、F、Br, I, and Cl;

Z、AA、HA、R、R_s、Y、R₁₁-R₁₆、X、L₁、L₂、L₄、L₃₁、L₃₂、L₃₄and W is as defined above,

any CH₂The group can be O, S, NR₆Or any substituent which is pharmaceutically acceptable.

In the present invention, "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which can be safely used in a subject. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the invention. Pharmaceutically acceptable acidic addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentiopiconate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (e.g., 1, 11-methylene-bis- (2-hydroxy-3-naphthoate)). Certain compounds of the invention may form pharmaceutically acceptable salts with a variety of amino acids. Suitable basic salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For reviews of pharmaceutically acceptable salts see bergeetal, 66j. arm. sci.1-19(1977), incorporated herein by reference.

In the present invention, unless otherwise specified, the term "hydrocarbon group" means a branched or unbranched, saturated or unsaturated, monovalent or polyvalent hydrocarbon group, and includes saturated hydrocarbon groups, alkenyl groups, and alkynyl groups. Examples of hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutenyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecenyl, dodecenyl, methylene, ethylene (ethylene), propylene (propylene), isopropylene (isopropylene), butylene (butylene), isobutylene (isobutenyl), tert-butylene (t-butylene), pentylene (penylene), hexylene (heptylene), heptylene (heptylene), octylene (nonylene), nonylene (nonylene), Decylenyl (decylene), undecylenyl (undecylene), and dodecylenyl (dodecylelene). In certain embodiments, the hydrocarbon group contains from 1 to 30 carbon atoms. In certain embodiments, the hydrocarbon group contains 1 to 20 carbon atoms. In certain embodiments, the hydrocarbon group contains 1 to 12 carbon atoms.

In the present invention, unless otherwise specified, the term "cyclic hydrocarbon group" means a hydrocarbon group containing at least one ring and not containing an aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In certain embodiments, the hydrocarbon group contains from 1 to 30 carbon atoms. In certain embodiments, the hydrocarbon group contains 1 to 20 carbon atoms. In certain embodiments, the hydrocarbon group contains 1 to 12 carbon atoms.

In the present invention, unless otherwise specified, the term "heterocyclic hydrocarbon group" means a cyclic hydrocarbon group in which at least one of the ring atoms is not a carbon atom. Non-carbon atoms on the ring include, but are not limited to, sulfur (S), oxygen (O), and nitrogen N).

In the present invention, unless otherwise specified, the term "hydrocarbyloxy" refers to a hydrocarbyl, cycloalkyl or heterocycloalkyi group containing one or more oxygen atoms. Examples of hydrocarbyloxy groups include, but are not limited to, -CH₂-OH、-OCH₃、-O-R_e、-R_e-OH、-R_e1-O-R_e2-, wherein R_e，R_e1And R_e2Are the same or different hydrocarbyl, cycloalkyl or heterocycloalkyl groups.

In the present invention, unless otherwise specified, the term "halogenated hydrocarbon group" means a hydrocarbon group, a cycloalkyl group or a heterocyclic hydrocarbon group containing one or more halogen atoms. The term "halogen" refers to fluorine, chlorine, bromine or iodine. Examples of halogenated hydrocarbon groups include, but are not limited to, -R_e-F、-R_e-Cl、-R_e-Br、-R_e-I、-R_e(F)-、-R_e(Cl)-、-R_e(Br) -and-R_e(I) -, wherein R_eIs a hydrocarbyl, cycloalkyl or heterocyclic hydrocarbyl group.

In the present invention, unless otherwise specified, the term "alkylthio" refers to a hydrocarbon, cycloalkyl or heterocyclic hydrocarbon group containing one or more sulfur atoms. Examples of hydrocarbylthio groups include, but are not limited to, -CH₂-SH、-SCH₃、-S-R_e、-Re-SH、-R_e-S-R_e1-, wherein R_eAnd R_e1Are the same or different hydrocarbyl, cycloalkyl or heterocycloalkyl groups.

In the present invention, unless otherwise specified, the term "hydrocarbylamino" refers to a hydrocarbyl, cycloalkyl or heterocycloalkyl group containing one or more nitrogen atoms. Examples of hydrocarbylamino groups include, but are not limited to, -CH₂-NH、-NCH₃、-N(R_e)-R_e1、-N-R_e、-R_e-NH₂、-R_e-N-R_e1and-R_e-N(R_e1)-R_e2Wherein R is_e，R_e1And R_e2Are the same or different hydrocarbyl, cycloalkyl or heterocycloalkyl groups.

In the present invention, unless otherwise specified, the term "alkyl (alkyl)" refers to a hydrocarbon, cycloalkyl or heterocyclic hydrocarbon group containing one or more carbonyl groups. Examples of hydrocarbon carbonyl groups include, but are not limited to, aldehyde groups (-R)_e-C (O) -H), keto group (-R)_e-C(O)-R_e1) Carboxylic acid group (R)_e-C (═ O) OH), ester group (-R)_e-C(＝O)O-R_e1) Formylamino group (-R)_e-C(＝O)O-N(R_e1)R_e2) (iii) an alkenoyl group (-R)_e-C(O)-C(R_e1)＝C(R_e2)R_e3) Acyl halide (-R)_e-C (O) -X) and an anhydride group (-R)_e-C(O)-O-C(O)-R_e1) Wherein R is_e，R_e1，R_e2And R_e3May be the same or different hydrocarbyl, cycloalkyl or heterocycloalkyl groups.

In the present invention, unless otherwise specified, the term "polyfluoroalkyl" refers to a hydrocarbon, cycloalkyl or heterocyclic hydrocarbon group containing one or more fluoro groups, including, but not limited to, polyfluoromethyl, polyfluoroethyl, polyfluoropropyl.

In the present invention, unless otherwise specified, the term "aryl" refers to a chemical structure containing one or more aromatic rings. In certain embodiments, one or more of the ring atoms is a non-carbon atom, such as an oxygen atom, a nitrogen atom, or a sulfur atom ("heteroaryl"). Examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, anthracenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, pyrimidinyl, pyridazinyl, cinnamyl, cinn,Cinnoline base(cinnolinyl), imidazolyl, benzimidazolyl, purinyl, indolyl, furyl, benzofuryl, isobenzofuryl, pyrrolyl, indolyl, isoindolyl, thienyl, benzothienyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl (thiaxolyl), guanidinyl, and benzothiazolyl.

In certain embodiments, the transport unit of the HPP contains a protonatable amino group that facilitates the transport of the HPP across or through one or more biological barriers (e.g., at least about 20-fold, about 50-fold, about 100-fold, about 300-fold, about 500-fold, about 1000-fold faster than the parent drug). In certain embodiments, the protonatable amino group is substantially protonated at physiological pH. In certain embodiments, protonation of the amino group is reversible. In certain embodiments, the transport unit may or may not be cleaved from the functional unit after the HPP has passed through the one or more biological barriers. In certain embodiments, the functional unit may comprise a transport unit, particularly for antimicrobial agents and antimicrobial-related compounds that contain at least one free amino group.

In certain embodiments, the protonatable amino group is selected from the group consisting of: pharmaceutically acceptable substituted and unsubstituted primary amino groups, pharmaceutically acceptable substituted and unsubstituted secondary amino groups, and pharmaceutically acceptable substituted and unsubstituted tertiary amino groups.

In certain embodiments, the protonatable amino group is selected from the group consisting of the following structures: the structural formula is W-1, W-2, W-3, W-4, W-5, W-6, W-7, W-8, W-9, W-10, W-11, W-12, W-13, W-14, W-15, W-16, W-17 and W-18, the definitions of which are the same as the above, including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the linker connecting the functional unit and the transport unit of an HPP comprises a bond that can be cleaved after the HPP penetrates through one or more biological barriers. Cleavable linkages include, for example, covalent bonds, ether bonds, thioether bonds, amide bonds, ester bonds, thioester bonds, carbonate bonds, carbamate bonds, phosphate bonds, or oxime bonds.

In certain embodiments, the HPPs of the beta-lactam antibiotics and beta-lactam antibiotic-associated compounds have the structure of structural formula L-1 as follows:

including stereoisomers and pharmaceutically acceptable salts thereof.

F is a functional unit of HPP of the antimicrobial agent or antimicrobial agent related compound. Examples of F include structural formula F-1, structural formula FP-2, structural formula FP-3, structural formula FP-4, structural formula FP-5, structural formula FP-6, structural formula FP-7, structural formula FP-8, structural formula FP-9, structural formula FP-10, structural formula FP-11, structural formula FP-12, structural formula FP-13, structural formula FP-14, structural formula FP-15, structural formula FP-16, structural formula FP-17, structural formula FP-18, structural formula FP-19, structural formula FP-20, structural formula FP-21, structural formula FP-22, structural formula FP-23, structural formula FP-24, structural formula FP-25, structural formula FP-26, structural formula FP-27, structural formula FP-2, structural formula FP-3, structural formula FP-4, structural formula FP-5, Structural formula FP-28, structural formula FP-29, structural formula FP-30, structural formula FP-31, structural formula FP-32, structural formula FP-33, structural formula FP-34, structural formula FP-35, structural formula FP-36, structural formula FP-37, structural formula FP-38, structural formula FP-39, structural formula FP-40, structural formula FP-41, structural formula FP-42, structural formula FP-43, structural formula FP-44, structural formula FP-45, structural formula FP-46, structural formula FP-47, structural formula FP-48, structural formula FP-49, structural formula FP-50, structural formula FP-51, structural formula FP-52, structural formula FP-53, structural formula FP-54, structural formula FP-55, structural formula FP-56, structural formula FP-31, structural formula FP-32, structural formula FP-33, structural formula FP-, Structural formula FP-57, structural formula FP-58, structural formula FP-59, structural formula FP-60, structural formula FP-61, structural formula FP-62, structural formula FP-63, structural formula FP-64, structural formula FP-65, structural formula FP-66, structural formula FP-67, structural formula FP-68, structural formula FP-69, structural formula FP-70, structural formula FP-71, structural formula FP-72, structural formula FP-73, structural formula FP-74, structural formula FP-75, structural formula FP-76, structural formula FP-77, structural formula FP-78, structural formula FP-79, structural formula FP-80, structural formula FP-81, structural formula FP-82, structural formula FP-83, structural formula FP-84, structural formula FP-85, structural formula, Structural formula FP-86, structural formula FI-1, structural formula FI-2, structural formula FI-3, structural formula FI-4, structural formula FI-5, structural formula FI-6, structural formula FI-7, structural formula FI-8, structural formula FI-9, structural formula FI-10, structural formula FI-11, structural formula FI-12, structural formula FI-13, structural formula FI-14, structural formula FI-15, structural formula FI-16, structural formula FI-17, structural formula FI-18, structural formula FI-19, structural formula FI-20, structural formula FI-21, structural formula FI-22, structural formula FI-23, structural formula FI-24, structural formula FI-25, structural formula FI-26, structural formula FI-27, structural, Structural formula FI-29, structural formula FI-30, structural formula FI-31, structural formula FI-32, structural formula FI-33, structural formula FS-1, structural formula FS-2, structural formula FS-3, structural formula FS-4, structural formula FS-5, structural formula FS-6, structural formula FS-7, structural formula FS-8, structural formula FS-9, structural formula FS-10, structural formula FS-11, structural formula FS-12, structural formula FS-13, structural formula FS-14, structural formula FS-15, structural formula FS-16, structural formula FS-17, structural formula FS-18, structural formula FS-19, structural formula FS-20, structural formula FT-1, structural formula FT-2, structural formula FT-3, structural formula FT-4, The structural formula FT-5, the structural formula FT-6, the structural formula FT-7, the structural formula FT-8, the structural formula FT-9, the structural formula FT-10, the structural formula FT-11, the structural formula FT-12, the structural formula FT-13, the structural formula FT-14, the structural formula FT-15 and the structural formula FT-16 are defined as the above;

t is the transport unit for HPP of the antimicrobial agent or antimicrobial agent related compound. For example, T may be selected from the group consisting of: protonatable amino group, pharmaceutically acceptable substituted and unsubstituted primary amino group, pharmaceutically acceptable substituted and unsubstituted secondary amino group, and pharmaceutically acceptable substituted and unsubstituted tertiary amino group, structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, structural formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, structural formula W-10, structural formula W-11, structural formula W-12, structural formula W-13, structural formula W-14, structural formula W-15, structural formula W-16, structural formula W-17, and structural formula W-18, which are as defined above; and

L₁、L₃₁、L₂、L₃₂、L₄and L₃₄As defined above. In certain embodiments, -L₁-L₄-L₂-and-L₃₁-L₃₄-L₃₂-is selected from the group consisting of: -O-, -X-, -O-X-, -N-X-, -S-X-, -X₅-，-O-X₅-，-N-X₅-，-S-X₅-，-O-X₇-, -O-C (═ O) -, -NH-C (═ O) -, -C (═ O) -O-, -C (═ O) -N-, and-C (═ O) -X-; x, X therein₅And X₇As defined above.

In certain embodiments, the HPP or HPC of the antimicrobial or antimicrobial-related compound comprises a structure selected from the group consisting of: structural formula P-1, structural formula P-2, structural formula P-3, structural formula P-4, structural formula P-5, structural formula P-6, structural formula P-7, structural formula P-8, structural formula P-9, structural formula P-10, structural formula P-11, structural formula P-12, structural formula P-13, structural formula P-14, structural formula P-15, structural formula P-16, structural formula P-17, structural formula P-18, structural formula P-19, structural formula P-20, structural formula P-21, structural formula P-22, structural formula P-23, structural formula P-24, structural formula P-25, structural formula P-26, structural formula P-27, structural formula P-28, structural formula P-29, structural formula P-13, Structural formula P-30, structural formula P-31, structural formula P-32, structural formula P-33, structural formula P-34, structural formula P-35, structural formula P-36, structural formula P-37, structural formula P-38, structural formula P-39, structural formula P-40, structural formula P-41, structural formula P-42, structural formula P-43, structural formula P-44, structural formula P-45, structural formula P-46, structural formula P-47, structural formula P-48, structural formula P-49, structural formula P-50, structural formula P-51, structural formula P-52, structural formula P-53, structural formula P-54, structural formula P-55, structural formula P-56, structural formula P-57, structural formula P-58, structural formula P-34, structural formula P-, Structural formula P-59, structural formula P-60, structural formula P-61, structural formula P-62, structural formula P-63, structural formula P-64, structural formula P-65, structural formula P-66, structural formula P-67, structural formula P-68, structural formula P-69, structural formula P-70, structural formula P-71, structural formula P-72, structural formula P-73, structural formula P-74, structural formula P-75, structural formula P-76, structural formula P-77, structural formula P-78, structural formula P-79, structural formula P-80, structural formula P-81, structural formula P-82, structural formula P-83, structural formula P-84, structural formula P-85, structural formula P-86, structural formula I-1, structural formula P-80, structural formula P-62, structural formula P-64, structural formula P-, Structural formula I-2, structural formula I-3, structural formula I-4, structural formula I-5, structural formula I-6, structural formula I-7, structural formula I-8, structural formula I-9, structural formula I-10, structural formula I-11, structural formula I-12, structural formula I-13, structural formula I-14, structural formula I-15, structural formula I-16, structural formula I-17, structural formula I-18, structural formula I-19, structural formula I-20, structural formula I-21, structural formula I-22, structural formula I-23, structural formula I-24, structural formula I-25, structural formula I-26, structural formula I-27, structural formula I-28, structural formula I-29, structural formula I-30, structural formula I-13, structural formula I-14, structural formula I-15, structural formula I-, Structural formula I-31, structural formula I-32, structural formula I-33, structural formula S-1, structural formula S-2, structural formula S-3, structural formula S-4, structural formula S-5, structural formula S-6, structural formula S-7, structural formula S-8, structural formula S-9, structural formula S-10, structural formula S-11, structural formula S-12, structural formula S-13, structural formula S-14, structural formula S-15, structural formula S-16, structural formula S-17, structural formula S-18, structural formula S-19, structural formula S-20, structural formula T-1, structural formula T-2, structural formula T-3, structural formula T-4, structural formula T-5, structural formula T-6, structural formula S-1, structural formula S-4, structural formula S-, Structural formula T-7, structural formula T-8, structural formula T-9, structural formula T-10, structural formula T-11, structural formula T-12, structural formula T-13, structural formula T-14, structural formula T-15, and structural formula T-16:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein, m, n, R₁，R₂，R₅，R₃₅，R₆，R₃₆，R₄₆，R₇，R₈，R₃₈，T，W，X，X₂，X₄，X₅，X₃₅，X₆，X₃₆，X₄₆，X₇，Y₁，Y₂，Y₃₁，Y₃₂，Y₃，Y₄，Z，AA，HA，R，R_sAnd R₁₁-R₁₆And the like are as defined above.

Pharmaceutical compositions containing HPP

Another aspect of the invention relates to a pharmaceutical composition comprising an HPP of at least one antimicrobial agent or an HPP of an antimicrobial agent-related compound, and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable carrier" refers herein to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting an HPP from one location, body fluid, tissue, organ (internal or external), or part of the body to another location, body fluid, tissue, organ (internal or external), or part of the body.

The "pharmaceutically acceptable" plasmids of each carrier are now compatible with other ingredients in the formulation, such as an HPP, and are suitable for use in contact with a tissue or organ of a biological system without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio.

Examples of materials that can serve as pharmaceutically acceptable carriers include: 1) sugars such as lactose, glucose and sucrose; 2) starches, such as corn starch and potato starch; 3) celluloses and their derivatives, such as carboxymethyl cellulose, ethyl cellulose and cellulose acetate; 4) powdered gum tragacanth; 5) malt; 6) gelatin; 7) talc powder; 8) adjuvants, such as cocoa butter and suppository waxes; 9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; 10) glycols, such as propylene glycol; 11) polyhydroxy compounds such as glycerol, sorbitol, mannitol and polyethylene glycol; 12) esters, such as ethyl oleate and ethyl laurate; 13) agar; 14) buffering agents such as magnesium hydroxide and aluminum hydroxide; 15) alginic acid; 16) pyrogen-free water; 17) isotonic saline; 18) ringer's solution; 19) alcohols such as ethanol and propanol; 20) a phosphate buffer solution; and 21) other non-toxic compatible substances such as acetone for use in pharmaceutical formulations.

The pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, such as a buffer salt. In certain embodiments, the pharmaceutically acceptable carrier is a polar solvent such as acetone and alcohols.

The concentration of HPP in these formulations may vary widely and may be selected primarily based on the volume, viscosity, body weight and the like of the fluid, depending on the particular mode of administration selected and the requirements of the biological system. For example, the concentration (by weight) may be 0.0001% to 100%, 0.001% to 50%, 0.01% to 30%, 0.1% to 20%, 1% to 10%.

The compositions of the present invention can be used for prophylaxis, treatment, and/or health care by administration. Such administration may be by topical, mucosal, such as oral, nasal, vaginal, rectal, injection, transdermal, subcutaneous, intramuscular, intravenous, inhalation, ocular, and other suitable routes. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration include powders, tablets, pills, capsules, and lozenges (lozenes), and unit dosage forms suitable for transdermal administration include solutions, suspensions, and gels.

Thus, a typical pharmaceutical composition for transdermal, oral, intravenous administration may be about 10 days per subject^-10Grams to about 100 grams, about 10^-10To about 10^-3Gram, about 10^-9Gram to about 10^-6Gram, about 10^-6From about 0.001 to about 100 grams, from about 0.01 to about 10 grams, or from about 0.01 to about 1 gram. The daily dosage for each subject may range from about 0.01 mg to about 100 g. The actual methods of preparing compositions for injectable administration are well known in the art or will be apparent to those skilled in the art, and are described in more detail in publications such as Remington's pharmaceutical science, 21sted., Mack publishing company, Easton, Pa. (2005).

Use of HPP

i) A method of penetrating a biological barrier.

Another aspect of the invention relates to a method of penetrating one or more biological barriers using the composition of the invention. The method comprises the step of administering to a biological subject an HPP or an antimicrobial agent or antimicrobial agent related compound, or a pharmaceutical composition thereof. In certain embodiments, an HPP may exhibit a penetration rate of one or more biological barriers that is greater than about 20-fold or greater, 50-fold or greater, 100-fold or greater, 200-fold or greater, 300-fold or greater, 500-fold or greater, 1000-fold or greater than its parent drug.

The term "biological barrier" as used herein refers to a biological layer that separates an environment into distinct spatial regions or compartments (compositions) that regulates (e.g., restricts, limits, enhances, or does not act upon) the passage, penetration, or transport of an object (substance) or material (material) from one compartment/region to another. Different spatial regions or compartments in the present invention may have the same or different chemical or biological environments. Reference to a biological layer in the present invention includes, but is not limited to, a biological membrane, a cellular layer, a biological structure, an object, an organism, an inner surface of an organ or a body cavity, an outer surface of an object, an organism, an organ or a body cavity, or any combination or plurality thereof.

Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., nuclear or organelle membranes such as golgi membrane or envelope, rough and smooth endoplasmic reticulum membrane or envelope, ribosomal membrane or envelope, vacuolar membrane or envelope, vesicle membrane or envelope, liposome membrane or envelope, mitochondrial membrane or envelope, lysosomal membrane or envelope, nuclear membrane or envelope, chloroplast membrane or envelope, plastid (plastic) membrane or envelope, peroxisomal membrane or envelope, or microbody membrane or envelope).

The lipid bilayer structure of the present invention is a bilayer structure of lipid molecules, including, but not limited to, phospholipids and cholesterol. In a particular embodiment, the bilayer structured lipid is an amphiphilic molecule consisting of a polar end group and a non-polar fatty acid tail chain. The bilayer structure is composed of two lipid layers, and the hydrocarbon tail chains of the lipid layers are arranged to face each other to form an oily core through hydrophobic effect gathering, and the charged end groups of the lipid layers face the aqueous phase solution on two sides of the membrane. In another particular embodiment, the lipid bilayer structure may contain one or more protein and/or carbohydrate molecules embedded therein.

Examples of cell layers include eukaryotic cell layers (e.g., epithelium, lamina propria (laminapropria) and smooth muscle or mucosal muscularis (in the gastrointestinal tract)), prokaryotic cell layers (e.g., surface layer or S-layer, which refers to a two-dimensional structural monolayer composed of the same proteins or glycoproteins, in particular, S-layer refers to a portion of the cell envelope that is commonly present in bacteria and archaea (archaea)), biofilms (a structured microbial community encapsulated in a spontaneously formed polymer matrix that adheres to biological or inert surfaces), and plant cell layers (e.g., epidermis). The cell can be a normal cell or a diseased cell (e.g., a disease cell, a cancer cell).

Examples of biological structures include structures sealed by tight or closed junctions, which provide a barrier to the entry of toxins, bacteria and viruses, such as the blood milk barrier and the Blood Brain Barrier (BBB). In particular, the BBB consists of a class of impermeable endothelium that forms a physical barrier in conjunction with adjacent endothelial cells through tight junctions and a transport barrier containing efflux transport pumps. Biological structures may also include mixtures of cells, proteins, and carbohydrates (e.g., thrombi).

Examples of the inner surface of the subject, organism, organ or body cavity include buccal mucosa (buccalmucosas), esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (mucosa of uterus, cell wall lining of pollen grains, or lining wall of spores), or a combination or plurality thereof.

Examples of external surfaces of an object, organism, organ, or body cavity include capillaries (e.g., capillaries of cardiac tissue), a membrane of a mucous membrane associated with the skin (e.g., at nostrils, lips, ears, reproductive area, and anus), an external surface of an organ (e.g., liver, lung, stomach, brain, kidney, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum, stomach, large intestine (colonrectum), intestine, vein, respiratory system, vasculature, and anorectum), skin, a stratum corneum (e.g., dead cell layer of epithelial cells or keratinocytes or superficial layer of overlapping cells overlying hair shafts of animals (superficialiayer), a multi-layered structure outside the epidermis of various invertebrates, plant cuticle or polymer cutin (cutin) and/or cutin (cutin)), an outer layer of cell walls of pollen grains, or outer wall of spores, and combinations or pluralities thereof.

In addition, the biological barrier further comprises a carbohydrate layer, a protein layer or any other biological layer, or a combination or plurality thereof. For example, skin is a biological barrier with multiple biological layers. The skin contains an epithelial layer (outer surface), a cortex layer and a hypodermal layer. The epithelial layer contains a multi-layered structure including a basal cell layer, a spinocellular layer (spinocellular layer), a granular cell layer, and a horny layer. Cells in the epithelium are called keratinocytes. The stratum corneum (also called "hornylayer") is the outermost layer of the epithelium, where the cells are flat and shaped like scales (scaly). These cells contain a large amount of keratin and are arranged in layers to impart toughness, oil repellency and water repellency to the skin surface.

ii) methods of diagnosing a condition in a biological system

Another aspect of the invention relates to methods of using the compositions of the invention for diagnosing a condition in a biological system. The method comprises the following steps:

1) administering to a biological subject a composition comprising an antimicrobial agent or an antimicrobial agent-related compound, HPP;

2) detecting the presence, location or amount of the HPP, a functional group of the HPP or a metabolite thereof in the biological subject; and

3) determining a symptom in the biological subject.

In certain embodiments, the HPP (or a substance cleaved from the HPP) aggregates at the site of action where symptoms appear. In certain embodiments, the presence, location, or content of a functional group of the HPP is also detected. In certain embodiments, the occurrence, development, progression, or slowing of the associated symptoms (e.g., infection) is also determined.

In certain embodiments, the HPP is labeled or conjugated to some detectable substance. Alternatively, HPPs are prepared to include radioisotopes for detection. A variety of detectable substances are available, roughly classified into the following categories:

a) radioisotopes, e.g.³⁵S、¹⁴C、¹³C、¹⁵N、¹²⁵I、³H. And¹³¹I. the diagnostic substance may be labelled with a radioisotope by techniques well known in the art, and radioactivity may be measured by scintillation counting; in addition, the diagnostic substance can detect carbon and nitrogen labels by electron paramagnetic resonance with spin labeling.

b) Fluorescent substances such as BODIPY, BODIPY analogs, rare earth chelates (europium chelates), fluorescein and its derivatives, FITC, 5, 6 carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, green fluorescent protein, yellow fluorescent protein, red fluorescent protein, and Texas Red (TexasRed). Fluorescence can be quantified by a fluorometer.

c) Various enzyme-substrate substances, such as luciferases (e.g., firefly luciferase and bacterial luciferases), luciferin, 2, 3-dihydrophthalazinediones (2, 3-dihydrophthalazinediones), malate dehydrogenase, urease, peroxidases such as horseradish peroxidase (HRPO), alkaline phosphatase, β -galactosidase, glucoamylase, lysozyme, polysaccharide oxidases (e.g., glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (e.g., uricase and xanthine oxidase), lactose peroxidase, microperoxidase, and the like. Enzyme-substrate combinations include, for example: (i) horseradish peroxidase (HRPO) with catalase as a substrate, wherein the catalase oxidizes a dye precursor (e.g., o-phenylenediamine (OPD) or 3, 3 ', 5, 5' -tetramethylbenzidine hydrochloride (TMB); (ii) Alkaline Phosphatase (AP) with p-nitrophenyl phosphate as a chromogenic substrate; (iii) β -D-galactosidase (. beta. -D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-. beta. -D-galactoside) or fluorogenic to 4-methylumbelliferyl-. beta. -D-galactoside (4-methylumbelliferyl-. beta. -D-galactoside).

In certain embodiments, the detectable substance need not be conjugated to the diagnostic substance, but the presence of the diagnostic substance can be identified and the diagnostic substance can be detected.

In certain embodiments, the HPPs of the present invention may be provided by means of a kit of parts (kit), i.e., a packaged combination of predetermined amounts of reagents, with instructions for the operation of a diagnostic test. When the HPP is labeled with an enzyme, the kit may include a substrate and cofactors required by the enzyme (e.g., a substrate precursor that provides a detectable chromophore or fluorophore). In addition, other additives such as stabilizers, buffers (e.g., blocking buffers or lysis buffers), and the like may also be included. The relative amounts of the various reagents may be varied over a wide range to provide various concentrations of the reagent solutions that substantially optimize the sensitivity of the assay. In particular, the reagents may be provided in the form of a dry powder, typically obtained by freeze-drying, which may also include excipients to provide a solution of the reagents having a suitable concentration after dissolution.

iii) methods for screening substances for a desired trait (desired characteristics)

Another aspect of the invention relates to a method of screening a substance for a desired characteristic.

In certain embodiments, the method comprises:

1) covalently linking a test functional unit to a transport unit via a linker to form a test composition (or covalently linking a functional unit to a test transport unit via a linker, or covalently linking a functional unit to a transport unit via a test linker);

2) administering the test composition to a biological system; and

3) determining whether the test composition has the desired property or characteristic.

In one embodiment, the desired characteristics may include, for example, 1) the ability of the test functional unit to form a high penetration composition or be convertible back to the parent drug; 2) testing the penetration capacity and/or speed of the composition; 3) testing the efficiency and/or effectiveness of the composition; 4) testing the transport capacity of the transport unit; and 5) testing the scissibility of the linker.

iv) methods for treating a condition in a biological subject

Another aspect of the invention relates to a method of using the composition of the invention for treating a condition of a biological system. The method comprises administering the pharmaceutical composition to the biological system.

The term "treating" as used herein refers to curing, alleviating, inhibiting, or preventing. The term "treating" or "treatment" as used herein refers to curing, alleviating, inhibiting, or preventing. The term "treatment" as used herein refers to curing, alleviating, inhibiting, or preventing.

The terms "biological system," "biological subject" or "subject" as used herein refer to an organ, a group of organs that work together to accomplish a specific task, an organism, or a group of organisms. The term "organism" refers in the present invention to a collection of molecules which function more or less as a whole and which are of a living nature, such as animals, plants, fungi, or microorganisms.

The term "animal" as used herein refers to a eukaryotic organism characterized by active activity. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, reptiles, amphibians, fish, gills, stenocardia (leptocardia)), tunicates (e.g., gobies, urothecas, deepwater ascidians, ascidioides), somites (e.g., entomophytes, polypodas, malacapos, arachnids, harrachnoids, acropoda, crustaceans, and annelids), gehygea (anchloroda), and worms (helminthides) (e.g., rotifers).

The term "plant" refers in the present invention to an organism belonging to the kingdom Plantae. Examples of plants include, but are not limited to, spermatophytes, bryophytes, ferns, and pteridopsis. Examples of seed plants include, but are not limited to, cycads (cycads), ginsengs (ginkgo), conifers (conifers), gnetophylls (gnetophylls), angiosperms. Examples of bryophytes include, but are not limited to, lichen (liverworts), hornworts, and mosses. Examples of ferns include, but are not limited to, the order chrysosporium (ophthalles) (e.g., paradoxus-tongues, agriophyta (grape-ferns)), the family Synechocystidae, and Phyllostachys gracilis (leptospora). Examples of pseudopteridophytes include, but are not limited to, the class of the pinopidae (e.g., lycopodium, selaginella (spikemoses), and leek (quillworts)), the family of the conidioidea (e.g., phylum lycopodium and order conidioidea), and the family of the equisetum (e.g., class equisetum).

The term "fungus" refers in the present invention to a eukaryotic organism which is a member of the kingdom fungi. Examples of fungi include, but are not limited to, Chytridiomycota, Blastocladiomycota, Neocallimastigomycota, zygomycota, Synechomycota, Ascomycota, and Basidiomycota.

The term "microorganism" as used herein refers to microscopic organisms (e.g., on the order of microns in length). Examples of microorganisms include, but are not limited to, bacteria, fungi, archaea, protozoa, and microscopic plants (e.g., green algae) and microscopic animals (e.g., plankton, trichuris, and amoebas).

Some examples of conditions treatable by the present methods include those treatable by prodrugs of HPPs.

v) antimicrobial and antimicrobial-related compounds and methods of use of pharmaceutical compositions thereof in therapy

Another aspect of the invention relates to a method of treating a condition in a biological system using an HPP of an antimicrobial agent or antimicrobial agent related compound, or a pharmaceutical composition thereof, by administering an HPP of an antimicrobial agent or antimicrobial agent related compound, or a pharmaceutical composition thereof, to the biological system or subject.

Antimicrobial agents and antimicrobial-related compounds are useful for the broad regulation of a variety of biological processes in biological systems. These conditions associated with biological processes can be treated by the corresponding antimicrobial agent or antimicrobial related compound, and thus also by HPP or HPC of the antimicrobial agent or antimicrobial related compound, or a pharmaceutical composition thereof.

These symptoms include, but are not limited to, pain, injury, and microbiologically related symptoms. The symptoms associated with microorganisms refer to symptoms caused by microorganisms such as bacteria, fungi, protozoa, and viruses. For example, symptoms caused by bacteria (bacteria-related symptoms), protozoa (protozoa-related symptoms), fungi (fungi-related symptoms), and viruses (virus-related symptoms).

Bacterial-related conditions include, for example, infection (e.g., infection of an organ such as liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gall bladder, duodenum, rectus intestine (rectus tomach), colorectal, intestinal, venous, respiratory system, vascular, anorectal, and anal pruritus, respiratory tract infection, upper respiratory tract infection, urinary tract infection, nosocomial infection, pseudomonas infection, coagulase-positive staphylococcal infection (e.g., skin infection, poisoning, acute infective endocarditis, septicemia, necrotizing pneumonia), infection after implantation of a prosthesis, opportunistic infection with septicemia and pneumonia), plague (e.g., lymphadenitis and pneumonic plague), anthrax (e.g., skin, lung, and gastrointestinal anthrax), Lyme disease, brucellosis, pertussis, acute enteritis, respiratory infection, pertussis, and pertussis, Psittacosis, nongonococcal urethritis, trachoma, neonatal inclusion body conjunctivitis, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, dysentery, neonatal meningitis, hemorrhagic colitis, hemolytic uremic syndrome, tularemia, pneumonia, bronchitis, gastric ulcer, legionnaires 'disease, Pontian fever, leptospirosis, listeriosis, leprosy, tuberculosis, mycoplasmal pneumonia, gonorrhea, neonatal ophthalmia, septic arthritis, successive outbreaks of meningococcal disease, Hua-Freund's syndrome (acute fulminant meningococcal bacteraemia), rocky mountain spotted fever, typhoid salmonella (typhoideflagellosis), salmonellosis with gastroenteritis and colitis, salmonellosis with bacillary dysentery/bacillary dysentery, cystitis, meningitis and septicemia, Endometritis, otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever and cholera.

Protozoan-related symptoms include, for example: malaria, lethargy and toxoplasmosis.

Fungal-related symptoms include, for example: aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioomycosis, sporotrichosis, and zygomycosis.

Virus-related symptoms include, for example: virus-related symptoms include, for example: influenza, yellow fever and AIDS.

In certain embodiments, a method of treating a condition alleviated or treated with an antimicrobial or antimicrobial-related compound in a biological subject comprises administering to the biological subject a therapeutically effective dose of an HPP of an antimicrobial or antimicrobial-related compound, or a pharmaceutical composition thereof.

HPP or a pharmaceutical composition thereof may be administered to a biological system by any route of administration known in the art, including, but not limited to, oral, intestinal, oral, nasal, topical, rectal, vaginal, aerosol, transmucosal, transdermal, epithelial, ocular, pulmonary, subcutaneous, and/or injectable routes of administration. The pharmaceutical composition can be administered in a variety of unit dosage forms depending on the mode of administration.

By injection is meant a route of administration commonly associated with injection, including, but not limited to, intravenous, intramuscular, arterial, intrathoracic, intracapsular (intracapsule), intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, sublingual, sub-cuticular, intraarticular (intraarticular), subcapsular, subarachnoid, intraspinal, and/or intrasternal injection and/or instillation.

The HPP or pharmaceutical composition thereof may be administered to a subject in a formulation or preparation suitable for each route of administration. Formulations useful in the methods of the invention include one or more HPPs, one or more pharmaceutically acceptable carriers, and other therapeutic ingredients. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The active ingredient may be combined with a carrier material to form a single dosage form, the amount of which may vary depending upon the subject being treated and the particular mode of administration. The HPP may be combined with a carrier material to form a pharmaceutically effective dose, typically an amount of HPP that produces a therapeutic effect. Generally, the amount of HPP may vary from about 1% to about 99% HPP, preferably from about 1% to about 20%, based on 100%.

The methods of making these formulations or compositions include the step of associating HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association the HPP with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product.

Dosage forms suitable for oral administration may be capsules, cachets (cachets), pills, tablets, lozenges (using stirred base ingredients, usually sucrose, acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs (elixir) or syrups, or lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or mouthwashes and the like, each containing a predetermined amount of HPP as the active ingredient. The compounds may also be administered by bolus (bolus), electuary (electuary), or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), HPP is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or optionally from: (1) fillers or additives, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution moderators (solutionreducer), such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol (acetyl alcohol) and glyceryl monostearate; (8) absorbents such as kaolin and bentonite (bentonitelay); (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a colorant. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose or milk sugar (milksugars) as well as high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or molding, optionally with the addition of one or more accessory ingredients. Compressed tablets may be prepared by binding agents (for example, gelatin or hydroxypropyl cellulose), lubricating agents, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active agents or dispersing agents. Compression molded tablets may be made by compression molding in a suitable machine a mixture of powdered beta-lactam antibiotic or peptidomimetic moistened with an inert liquid diluent. Tablets, or other solid dosage forms such as dragees, capsules, pills and granules, optionally scored or otherwise prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may also provide sustained or controlled release of HPP by formulation, for example, using hydroxypropylmethylcellulose in various ratios to provide a desired release profile, using other polymer matrices, using liposomes, and/or using microspheres. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents into sterile solid compositions which may be dissolved in sterile water, or other sterile injectable vehicles, immediately prior to use. These compositions may optionally also contain soothing agents (pacifyingants) which may release HPP only, or preferentially, at a particular site in the gastrointestinal tract, optionally by delayed release. Examples of useful embedding compositions include polymeric substances and waxes. The HPPs may also be in the form of microcapsules, where appropriate with one or more of the excipients mentioned above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to HPP, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate (ethyl lcarbonate), ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyethylene glycols and fatty acids of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, which contain, in addition to HPP, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum oxyhydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more HPPs with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, which is solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active substance. Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Formulations which may be used for transdermal or epicutaneous or dermal administration of the HPP composition include powders, sprays, ointments, pastes, creams, lotions (lottations), gels, solutions, patches (patches) and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any desired preservatives, buffers, or propellants (propellants). Ointments, pastes, creams and gels may contain, in addition to the HPP composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to the HPP composition, excipients such as lactose, talc, silicic acid, aluminium hydroxide. Calcium silicate and polyamide, or mixtures of these. Sprays can additionally contain propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane. The best formulations for topical or transdermal administration are pure water, solutions, aqueous solutions, ethanol and water solutions, and isopropanol and water solutions.

The HPP or pharmaceutical composition thereof may alternatively be administered by aerosol. By making an aqueous aerosol, liposome formulation or solid particles containing HPP. Non-aqueous (e.g., fluorocarbon propellant) suspensions may also be used. Ultrasonic atomizers may also be used. Aqueous aerosols may be prepared by co-formulating an aqueous solution or suspension of the drug with conventional pharmaceutically acceptable carriers and stabilizers. The carrier and stabilizer may vary according to the requirements of the particular compound, but may generally include non-dissociating surfactants (tweens, Pluronics, or polyethylene glycols), non-toxic proteins such as serum globulins, sorbitan esters, oleates, lecithins, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols can generally be prepared from isotonic solutions.

Transdermal patches may also be used to deliver HPP compositions to a target site. Such formulations may be prepared by dissolving or dispersing the drug in a suitable vehicle. Pro-absorbant agents may also be used to increase the flux (flux) of the drug across the skin. The flow rate can be controlled by using a rate controlling membrane or by dispersing the drug in a polymer matrix or gel.

Ophthalmic formulations, ocular ointments, powders, solutions, and the like are also included within the scope of the present invention.

Formulations useful for injectable administration comprise HPP and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted with sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended subject, or suspending or thickening agents.

Examples of aqueous and non-aqueous carriers that can be used in formulations suitable for injectable administration include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Formulations for injectable administration may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by the addition of various antibacterial and antifungal substances, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. Isotonic substances, such as sugars, sodium chloride, and the like, may also preferably be included in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the addition of agents delaying absorption, such as aluminum monostearate and gelatin.

Injectable depot formulations (depotforms) can be made by forming microencapsulated matrices of HPP or formed in biodegradable polymers such as polylactic-polyglycolide. The control of the rate of drug release may depend on the ratio of HPP to polymer, as well as the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by encapsulating HPP in liposomes or microemulsions compatible with body tissues.

In certain embodiments, a therapeutically effective dose of an HPP of an antimicrobial agent or antimicrobial agent-related compound, or a pharmaceutical composition thereof, can be delivered to the site of a disease or tumor. It is well known in the pharmacological arts that the precise amount of a pharmaceutically effective dose of HPP, which depends, for example, on the activity, specific properties, metabolic properties, pharmacokinetic properties, and bioavailability of the particular HPP, the physiological condition of the subject (including race, age, sex, body weight, diet, disease type and stage, general physical condition, responsiveness to the particular dose and type of treatment), the nature of the pharmaceutically acceptable carrier in the formulation, the route and frequency of administration, the severity or predisposition of the disease to the pathogenic microorganism of interest, etc., may provide the most effective result in terms of therapeutic efficacy for a particular patient, to name a few. However, the above guidelines may serve as a basis for fine-tuning treatment, e.g., determining the optimal dosage to administer, which does not exceed routine experimentation consisting of monitoring the subject and adjusting the dosage. For reference, Remington: the science and practice of pharmacy (Gennano.20. sup. th edition, Williams & WilkinsPA, USA) (2000).

Advantages of

Antimicrobial agents such as antibiotics and antimicrobial-related compounds are generally relatively hydrophilic and thus difficult to penetrate the skin membrane barrier. Antimicrobial agents and antimicrobial related compounds are inactivated by first pass metabolism when they are administered orally. In the case of injections, the administration of antimicrobial agents can cause pain, and in many cases frequent and costly visits to a physician are required to treat chronic conditions.

In certain embodiments, since the HPP or HPC of the present invention can penetrate one or more biological barriers, the HPP or HPC can be administered topically (e.g., topically or transdermally) to reach the site of symptom development without systemic administration (e.g., oral or injection administration). Local administration and penetration of HPP or HPC such that local concentrations of therapeutic substance (agent) or drug achievable by HPP or HPC are at the same level as when the parent drug or drug is administered systemically, but the amount or dose of HPP or HPC is much lower than the amount of parent drug or drug administered systemically; furthermore, systemic administration may not achieve higher local concentrations or require very high doses of therapeutic substances, if possible. The high local concentration of HPP or HPC or its sheared parent drug renders it more effective in treating a condition or more rapid than systemic administration of the parent drug and renders a new condition treatable or unobserved previously. Local administration of HPP or HPC may reduce the potential suffering of a biological subject from systemic administration, such as side reactions, gastrointestinal reactions or renal reactions associated with systemic exposure to therapeutic substances. In addition, topical administration allows HPP or HPC to pass through various biological barriers and through, for example, the general circulation, to the system, thus eliminating the need for systemic administration (e.g., injection) and avoiding the pain associated with injection administration.

In certain embodiments, the HPP or HPC or pharmaceutical composition of the present invention may be administered systemically (e.g., orally or by injection). HPPs or HPCs or the active therapeutic substances (e.g. drugs or metabolites) of HPPs or HPCs can enter the general circulation and reach the site of action of a condition at a faster rate than the parent drug. Furthermore, HPP or HPC can pass through biological barriers (e.g. blood brain barrier, blood milk barrier) that are not penetrated if the parent drug alone is administered, and thus HPP or HPC can provide a new treatment for previously untreatable or unobserved symptoms.

For example, the High Penetration Compositions (HPCs) of the antimicrobial agents or antimicrobial-related compounds of the present invention exhibit high penetration rates into biological barriers (e.g., at least about 10-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 1000-fold higher than when the antimicrobial agent or antimicrobial-related compound is administered alone). No or little side effects were observed in subjects using the antimicrobial agent HPP or HPC, whereas side effects (such as nausea) were observed in subjects using the antimicrobial agent at the same dose.

With the high use of antimicrobials, pathogens mutate over time making drug resistance a common and serious problem. The High Penetration Compositions (HPCs) of the antimicrobial agents or antimicrobial-related compounds of the present invention are capable of penetrating biological barriers, such as biofilms, bacterial, fungal and other microbial cell walls, at higher rates to overcome resistance problems.

V. examples

The following examples are intended to better illustrate the claimed invention and should not be construed as limiting the invention in any way. All of the specific compositions, materials and methods described below, in whole or in part, are intended to be included within the scope of the present invention. These specific compositions, materials, and methods are not intended to limit the invention, but merely to illustrate specific examples within the scope of the invention. Those skilled in the art may develop equivalent compositions, materials, and methods without the exercise of inventive faculty, and without departing from the scope of the invention. It should be understood that many variations can be made using the methods described herein while still being encompassed within the scope of the invention. Such variations are considered by the inventors to be included within the scope of the invention.

Example 1 Process for making prodrugs from parent drugs

In certain embodiments, a parent drug having the structure of the following structural formula F-C:

HPP which can be converted to a structure having the structure of formula L-1:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein F, L₁、L₂And L₄As defined above;

t is a transport unit for the antimicrobial agent or antimicrobial related compound. For example, T may be selected from the aforementioned W and R₆A set of compositions.

In certain embodiments of the present invention, the HPP of formula L-1 may be prepared by reacting a parent drug or derivative of a parent drug (e.g., an acid chloride or mixed anhydride of the parent drug compound) of formula D:

with a compound of structural formula E (scheme 1):

T-L₂-H

structural formula E

Prepared by organic synthesis. Wherein Wc is selected from the group consisting of OH, halogen, alkoxycarbonyl, and substituted aryloxycarbonyloxy; F. l is₁、L₂、L₄And T is as defined above.

Scheme 1 preparation of HPP from parent drug (I)

In certain embodiments, HPPs having the structural formula L-1 are prepared by scheme 1 below, wherein L₄Is C ═ O.

In certain embodiments, the parent drug having the following structural formula F:

with a compound having the following structural formula G:

to give HPP of formula L:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

F、L₁、L₂、L₄and T_NAs defined above;

t is a transport unit for the antimicrobial agent or antimicrobial related compound. For example, T may be selected from W and R as previously described₆A set of compositions; and

m may be selected from the group consisting of sodium, potassium, or other metals, and may be selected from the group consisting of OH, halogen, alkoxycarbonyl, and substituted aryloxycarbonyloxy (scheme 2).

Scheme 2 preparation of HPP from parent drug (II)

In certain embodiments, HPPs of formula L-1 may be prepared by organic synthesis, wherein unwanted reactive sites such as-C (═ O) OH, -NH, may be attached to the functional unit prior to attachment of the transport unit to the functional unit₂-OH, or-SH. In certain embodiments, the obtained protected HPPs may be further partially or fully deprotected to obtain protected HPPs or unprotected HPPs, respectively.

Preparation of 6-phenoxyacetamidopenicillin acid 2-diethylaminoethyl ester hydrochloride

39g of potassium penicillin V were dissolved in 100ml of acetonitrile. A mixture of 39g of 2-bromo-N, N-diethylethylamine as the hydrobromide salt in ethyl acetate was added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. 39g (0.15 mol) of the hydrogen bromide salt of 2-bromo-N, N' -diethylethylamine and 30g of sodium hydrogencarbonate were added to the reaction mixture. The mixture was stirred at room temperature for another 12 hours. The solid was removed by filtration. 3.5g of hydrochloric acid gas dissolved in 50ml of diethyl ether are added to the mixed solution with stirring. The solid product was collected by filtration. After drying, 38g of hygroscopic product was obtained, yield 78.2%. Elemental analysis: c₂₂H₃₂ClN₃O₅S; molecular weight: 486.0. calcd% C54.37, H: 6.64, N: 8.65, Cl: 7.29, O: 16.46, S: 6.60, measurement% C: 54.32, H: 6.68, N: 8.61, Cl: 7.32, O: 16.51, S: 6.56.

preparation of 6- (2, 6-dimethoxybenzamide) penicillin acid-2-diethylaminoethyl ester hydrochloride

38g6- (2, 6-dimethoxybenzamide) penicillin acid was dissolved in 300ml chloroform. 20.6g of N, N' -dicyclohexylcarbodiimide were added. 11.7g of N, N-dimethylaminoethanol and 2 g of 4-dimethylaminopyridine are added to the reaction mixture. The reaction was stirred at room temperature for 10 hours. The solid was filtered off. The chloroform layer was washed 2 times with 5% sodium bicarbonate solution (2x100ml) and then 3 times with water (3x100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. 3.5g of hydrogen chloride was added to the reaction mixture with stirring, and the solid product was collected by filtration. After drying, 40g of hygroscopic product was obtained, yield 77.5%. Elemental analysis: c₂₃H₃₄ClN₃O₆S; molecular weight: 516.05. calculated% C: 53.53, H: 6.64, N: 8.14, Cl: 6.87, O: 18.60, S: 6.21, measurement% C: 53.49, H: 6.68, N: 8.11, Cl: 6.90, O: 18.64, S: 6.18.

preparation of acetamidophenylacetamidopenicillin acid 2-diethylaminopropyl ester hydrochloride

43g of acetaminophen-acetamidopenicillsodium salt are dissolved in 100ml of acetonitrile. A mixture of 40g 2-bromo-N, N-diethylpropylamine hydrogen bromide in ethyl acetate was added to the reaction

₂₆H₃₃ClN₄O₅S; molecular weight: 541.11. calculated 55.49; h: 6.89; n: 10.35; cl: 6.55; o: 14.78; s: 5.92; measurement value% C: 55.44; h: 6.92; n: 10.32 of; cl: 6.58; o: 14.82; s: 5.92.

preparation of 6- (5-methyl-3-phenyl-2-isoxazoline-4-formylamino) penicillin acid 4-piperidine ethyl ester hydrochloride

50g of 6- (5-methyl-3-phenyl-2-isoxazoline-4-carboxamido) penicillin sodium was dissolved in 100ml of acetonitrile. A mixture of 38g 4-piperidinylethyl bromide in ethyl acetate was added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. 38g of 4-piperidinylethyl bromide hydrogen salt and 30g of sodium hydrogencarbonate were added to the reaction mixture. The mixture was stirred at room temperature for 12 hours. The solid was removed by filtration. 3.5g of hydrochloric acid gas dissolved in 50ml of diethyl ether are added to the mixed solution with stirring. The solid product was collected by filtration. After drying, 30g of hygroscopic product was obtained. Elemental analysis: c₂₆H₃₃ClN₄O₅S; molecular weight: 549.08. calculated% C: 56.88, respectively; h: 6.06; n: 10.20; cl: 6.46; o: 14.57; s: 5.83; measurement value% C: 56.85, respectively; h: 6.08 of; n: 10.19; cl: 6.47; o: 14.59; s: 5.82.

preparation of 3- [ [ (aminocarbonyl) oxy ] methyl ] -7-methoxy-8-one-7- [ (2-thienylacetyl) amino) ] -5-thia-1-azabicyclo- [4.2.0] -oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride

41g of 3- [ [ (aminocarbonyl) oxy ] are taken]Methyl radical]-7-methoxy-8-one-7- [ (2-thienylacetyl) amino)]-5-thia-1-azabicyclo- [4.2.0]Sodium-oct-2-ene-2-carboxylate was dissolved in 100ml of acetonitrile. Mixture of 35g 2-bromo-N, N-diethylethylamine hydrogen bromide in ethyl acetateIs added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. 30g of 2-bromo-N, N' -diethylethylamine hydrogen bromide and 30g of sodium hydrogencarbonate were added to the reaction mixture. The mixture was stirred at room temperature for an additional 12 hours. The solid was removed by filtration. 3.5g of hydrochloric acid gas dissolved in 50ml of diethyl ether are added to the mixed solution with stirring. The solid product was collected by filtration. After drying, 30g of hygroscopic product was obtained. Elemental analysis: c₂₂H₃₁ClN₄O₇S₂(ii) a Molecular weight: 563.08. calculated% C: 46.93; h: 5.55; n: 9.95; cl: 6.30; o: 19.89; s: 11.39; measurement value% C: 46.91, respectively; h: 5.57; n: 9.93; cl: 6.32; o: 19.91; s: 11.36.

HPPs of other antimicrobial agents or antimicrobial-related compounds can also be synthesized by similar methods.

Example 2 HPP of antimicrobial agent or antimicrobial-related Compound penetrates human skin faster in vitro than the parent drug

The penetration of these HPPs into human skin was measured in vitro in a modified Franz cell having two cells, an upper cell being the sample cell and a lower cell being the receiving cell, separated from human skin tissue (360-.

The test substance [2ml, 10% solution in phosphate buffered saline (0.2M) at pH7.4 ] was placed in the cuvette. The receiving cell contained 10ml of phosphate buffered saline (0.2M) at pH 7.4. The receiving solution was stirred at a speed of 600 revolutions per minute. The amount of the test substance passing through the skin is measured by a specific high performance liquid chromatography. The results are shown in fig. 1a1, fig. 1a2, fig. 1a3, fig. 1a4, 1b, and fig. 1c, and the apparent penetration values of the test compounds were calculated from the slopes of fig. 1a1, fig. 1a2, fig. 1a3, and fig. 1a4, and are summarized in table 1a. The apparent penetration values calculated from the slopes of fig. 1b, 1c are summarized in table 1b and table 1c, respectively.

Due to apparent penetration in the processThe lowest detection limit of the value is 1. mu.g/cm²H, so that the apparent penetration value is equal to or less than 1. mu.g/cm²The penetration of skin tissue by the parent drug/h is considered undetectable. For apparent penetration values of less than 1. mu.g/cm²The parent drug (e.g. penicillin V, penicillin O) of/h, whose HPP has a detectable apparent penetration value. For apparent penetration values greater than 1. mu.g/cm²The parent drug of/h, whose HPP has a higher detectable apparent penetration value. Thus HPP of the antimicrobial agent or antimicrobial-related compound exhibits a higher penetration rate (600-fold higher) into skin tissue than the parent drug.

TABLE 1a penetration Rate (I) of HPP of antimicrobial agent in vitro

TABLE 1b penetration rate of HPP of beta-lactamase inhibitors in vitro (II)

TABLE 1c penetration rate of HPP of sulfonamides and quinolones parent drug in vitro (III)

Example 3 penetration rate of HPP through skin and/or blood brain Barrier in vivo

The experiment compared the rate of penetration of the prodrug through the skin and blood brain barrier of live hairless and non-lescent mice. Donors were prepared from 1ml of 20% prodrug solution (6- (2, 6-dimethoxybenzamide) penicilloic acid-2-diethylaminoethyl ester hydrochloride solution, 6- (5-methyl-3-phenyl-2-isoxazoline-4-carboxamido) penicilloic acid-2-diethylaminoethyl ester hydrochloride solution or 6- [3- (o-chlorophenyl) -5-methyl-4-isoxazolecarboxamido]Penicillin acid-2-diethylaminoethyl ester hydrochloride solution). It is applied to 10cm back of hairless mouse²And (4) the part. After 2 hours, the mice were killed. 1g of blood, 1g of liver, 1g of kidney, 1g of muscle and 1g of brain are respectively added with 5ml of methanol, are evenly stirred by a homogenizer, are centrifuged for 5 minutes and are measured by HPLC. The results show that the prodrug can well penetrate the blood brain barrier.

TABLE 2 HPP penetration of beta-lactam antibiotics in vivo against biological barriers

90 cows secreting milk are selected. 500mg of 6-phenoxyacetamidopenicillic acid 2-diethylaminoethyl ester hydrochloride (penicillin V-DEE), 6- (2, 6-dimethoxybenzamide) penicillic acid 2-diethylaminoethyl ester hydrochloride (methicillin-DEE) or 7- [ [ (2-acetamido-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (oxazolidinecefxime-DEE) dissolved in 10ml of a phosphate buffer solution (0.2M) having a pH of 7.4 are sprayed onto the skin of the breast. 1 hour after topical prodrug administration, a sample of cow's milk was taken for analysis. The results are shown in Table 3. And (6) measuring the content of the mother medicine in the cow milk. The results show a high penetration rate of these prodrugs into the blood-milk barrier. The high blood milk barrier penetration rate of these prodrugs abrogates their usefulness for treating brain, breast, prostate and other inflammatory conditions.

TABLE 3 penetration of HPP against the blood-milk barrier in vivo

Example 4 HPPs of antimicrobial or antimicrobial-related Compounds penetrate the cell wall of bacteria faster than the parent drug

0.5 mmol of a test compound (6-p-phenoxyacetamido-penicillic acid 1-piperidine ethyl ester hydrochloride (penicillin V-PEE), penicillin V, 6- (2, 6-dimethoxybenzamide) penicillic acid 2-tetrahydropyrrole methyl ester hydrochloride (methicillin-PME), methicillin, 7- [ [ (2-acetamido-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride (ceftizoxime-DEE) or ceftizoxime) was added to 100ml of E.coli suspension, and the suspension was shaken for 3 minutes. The mixture was centrifuged at 3000rpm, the supernatant was decanted, and the large intestine rod was washed three times with phosphate buffer pH7.4 and pelleted. Finally 10ml of acetonitrile were added to the E.coli precipitate and the suspension was heated at 60 ℃ for 2 minutes. The acetonitrile solution was collected and then evaporated to dryness. The amount of drug was determined by HPLC method. The results are shown in Table 4.

Table 4: antibiotic entering into colibacillus cell and its HPP medicine amount

Example 5 transformation of HPP to parent drug

HPP of an antimicrobial or antimicrobial-related compound can be rapidly converted to the parent antimicrobial or antimicrobial-related compound in human plasma with high yield.

10mg of the antimicrobial-prodrug was dissolved in 0.1ml of phosphate buffered saline (0.2M) at pH 7.4. 1ml of human blood was preheated to 37 ℃ and added to the solution, and the mixture was placed in a 37 ℃ water bath. Every 2 minutes, 0.2ml of sample was removed and 0.4ml of methanol was added to precipitate plasma proteins. After centrifugation for 5 minutes, the cells were analyzed by high performance liquid chromatography. The results show that most of the HPPs of the antimicrobial or antimicrobial-related compound are converted to the parent antimicrobial or antimicrobial-related compound (table 5).

TABLE 5 half-life of HPP in plasma

Example 6 Minimum Inhibitory Concentration (MIC) of HPP for antimicrobial agent or antimicrobial-related Compound

Antimicrobial agents and their novel antimicrobial Minimum Inhibitory Concentrations (MICs) were determined according to literature reported methods (JenniferM. Andrews, journal of antimicrobial chemistry 48, Suppl. S1, 5-16 (2001)). These results (tables 6a-6c) demonstrate that these novel antimicrobial prodrugs are effective in overcoming resistance to methicillin-resistant staphylococcus aureus (MRSA) based on Minimum Inhibitory Concentration (MIC).

Table 6a. Minimum Inhibitory Concentration (MIC) (mg/L) of antimicrobial agents and their prodrugs against methicillin staphylococcus aureus (MRSA).

TABLE 6b minimum inhibitory concentrations MICs (mg/L) for various antibiotics plus beta lactamase inhibitors or their HPPs

TABLE 6c MICs (mg/L) for sulfonamides and quinolones and prodrugs thereof

Example 7 antifungal Effect of antimicrobial Agents or antimicrobial-related Compounds HPP

Antifungal activity of 2-diethylaminoethyl 6-phenoxyacetamipridinate hydrochloride (penicillin V-DEE), 2-diethylaminoethyl 6- (2, 6-dimethoxybenzamide) penicillate hydrochloride (methicillin-DEE) or 2-diethylaminoethyl 7- [ [ (2-acetamido-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride (cefazoloxime-DEE) was determined according to the method reported in roetherw. The results are shown in Table 7:

TABLE 7 minimum inhibitory concentration (mg/L) of β -lactam antibiotic prodrugs against fungi in vitro

Example 8 treatment of clinical mastitis with HPP of beta-lactam antibiotics or antimicrobial-related Compounds

90 cows secreting milk are selected. The term "bacteriological cure" means that no bacteria were detected in the samples taken from the infected cows on days 17 and 22. clinical cure means the disappearance of clinical symptoms (clinical symptoms are 1 day after complete elimination), in other words, the recovery of food intake, rectal temperature < 39.0 ℃, good general symptoms, disappearance of mammary edema, normal milk properties, and normal milk production.

500mg of 2-diethylaminoethyl 6-phenoxyacetamipridate hydrochloride (penicillin V-DEE), 2-diethylaminoethyl 6- (2, 6-dimethoxybenzamide) penicillate hydrochloride (methoxybenzene-DEE) or 2-diethylaminoethyl 7- [ [ (2-acetamido-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride (ceftizoxime-DEE) dissolved in 10ml of a phosphate buffer solution having a pH of 7.4 are sprayed twice daily onto the skin of the breasts. The results are shown in tables 8a and 8 b. The results show that the prodrugs can achieve good clinical cure rate and bacteriological cure rate.

TABLE 8a clinical cure rate for mastitis in cows with topical novel antibiotic prodrugs

Table 8 b: bacteriological cure rate (22 days) for mastitis in cows with topical novel antibiotic prodrugs

Example 9 anti-Mycobacterium tuberculosis Properties of prodrugs of antimicrobial Agents

Female mice six weeks old (BALB/c mice) were infected with 2.21. + -. 0.15X10 by air-borne means³CFU of Mycobacterium tuberculosis H37 Rv. After 20 days, the CFU mean value for the lungs was 8.23. + -. 0.27X10⁷CFU, followed by drug treatment of mice. Group a was blank control (N ═ 20), group B mice were treated with isoniazid/moxifloxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, oral) for 45 days, group C mice were treated with isoniazid/moxifloxacin/pyrazinamide (0.18/0.22/1.2mmol/kg, oral) for 90 days, group D mice were treated with N- (N-methyl-phenylalanine) -N' -isoniazid (prodrug-isoniazid, obtained by reacting N-methyl phenylalanine with isoniazid, transdermal administration)/1-cyclopropyl-7- { S, S-2, 8-diazo-bicyclo [4.3.0]Nonane-8-yl } -6-fluoro-8-methoxy-1, 4-dihydro-4-one-3-quinolinecarboxylic acid butyl ester (moxifloxacin prodrug)/pyrazinoic acid N, N-diethylaminoethyl ester (pyrazinoic acid prodrug 0.18/0.22/1.2mmol/kg, transdermal administration) for 45 days, group E mice were treated with isoniazid prodrug/moxifloxacin prodrug/pyrazinoic acid prodrug (0.18/0.22/1.2mmol/kg, transdermal administration) for 90 days, group F mice were treated with isoniazid prodrug/moxifloxacin prodrug/pyrazinoic acid prodrug (0.06/0.07/0.4mmol/kg, transdermal administration) for 45 days, group G mice were treated with isoniazid prodrug/moxifloxacin prodrug/pyrazinoic acid (0.06/0.07/0.4mmol/kg, transdermal administration) for 90 days. After treatment was stopped, mice were kept on for 90 days (no medication) and then sacrificed before the cure rate was determined (lung-developing negative cultures were cured). The results indicate that the prodrugs are superior to their parent drugs and can be administered transdermally (tables 9a and 9 b).

TABLE 9a CFU count after combination treatment

TABLE 9b cure rate after combination treatment

Example 10 treatment of tuberculosis in adults (children reduced dose).

40mg N- (N-methyl-phenylalanine) isoniazid hydrochloride (isoniazid prodrug)/50 mg 1-cyclopropyl-7- [ - (1S, 6S) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] -6-fluoro-8-methoxy-1, 4-dihydro-4-one-3-quinolinecarboxylic acid butyl ester hydrochloride (moxifloxacin prodrug)/40 mg N, N-diethylaminoethyl pyrazinecarboxylate hydrochloride (pyrazinecarboxylic acid prodrug) were dissolved in 3ml water and applied to the patient' S chest or to the skin anywhere else in the body (near the affected organs) once a day (twice a day), for 90 days or until recovery.

Example 11 treatment of adult leprosy or Hansen's Disease (HD) (reduced dose in children)

30mg 4-dimethylaminobutylaminophenyl-4-aminophenylsulfone hydrochloride (dapsone prodrug)/50 mg 1-cyclopropyl-7- [ - (1S, 6S) -2, 8-diazabicyclo [4.3.0] nonan-8-yl ] -6-fluoro-8-methoxy-1, 4-dihydro-4-one-3-quinolinecarboxylic acid butyl ester hydrochloride (moxifloxacin prodrug)/15 mg mercaptobenzimidazole 4-N, N-dimethylaminobutyric acid thioester hydrochloride (mercaptobenzimidazole prodrug) were dissolved in 3ml water and applied to the chest of the patient or to the skin of any other part of the body (near the affected organs) once a day and night (twice a day) for 6 months or until recovery.

EXAMPLE 12 treatment of ear infections

20mg of 6-phenoxyacetamipridinecarboxylic acid 2-diethylaminoethyl ester hydrochloride was dissolved in 1ml of water and applied to the skin of the patient (near the affected ear) once a day in the morning and at the evening (twice a day) for two weeks or until recovery.

EXAMPLE 13 treatment of lower respiratory tract infections in adults (Children reduced dose)

80mgD- α - [ (imidazolidin-2-one-1-yl) carboxamido ] benzyl penicillin 2-tetrahydropyrrolemethyl ester hydrochloride was dissolved in 3ml of water and applied to the skin of the neck or chest of a patient (near the affected organ) once a day, morning and evening (twice a day), for two weeks or until recovery.

EXAMPLE 14 treatment of adult upper respiratory tract infections (Children reduced dose)

80mg of 6-D (-) - α - (4-ethyl-2, 3-dione-1-piperazinecarboxamido) - α -phenylacetamidopenicillin acid-2-diethylaminoethyl ester hydrochloride was dissolved in 2ml of water and applied to the skin of the neck of the patient (close to the affected organs) once a day, morning and evening (twice a day), for two weeks or until recovery.

Example 15 treatment of upper respiratory tract infections in adults (reduced dose in children)

30mg of 3- [ [ (aminocarbonyl) oxy ] methyl ] -7-methoxy-8-one-7- [ (2-thienylacetyl) amino) ] -5-thia-1-azabicyclo- [4.2.0] -oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride was dissolved in 2ml of distilled water and the drug was sprayed into the mouth or nose of the patient once a day (twice a day) in the morning and evening for two weeks or until reconstitution.

EXAMPLE 16 treatment of meningitis in adults (Children reduced dose)

80mg of 6-D (-) - α - (4-ethyl-2, 3-dione-1-piperazinecarboxamido) - α -phenylacetamidopenicillin acid-2-diethylaminoethyl ester hydrochloride was dissolved in 3ml of distilled water and applied to the neck and head of the patient once a day (twice a day) in the morning and evening for two weeks or until recovery.

EXAMPLE 17 treatment of diarrhea (reduced dose in children)

80mg of 7- (2-thiopheneacetamido) cephalosporanic acid-2-diethylaminoethyl ester hydrochloride was dissolved in 3ml of distilled water and applied to the skin of a patient near the navel once a day (twice a day) in the morning and evening for two weeks or until recovery.

EXAMPLE 18 treatment of Breast infections

50mg of 7- [ (hydroxyphenylacetyl) amino ] -3- [ [ (1-methyl-1H-tetrazol-5-yl) thio ] methyl ] -8-keto-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride was dissolved in 2ml of distilled water and applied to the skin of the patient around the breasts, once a day in the morning and evening (twice a day), for two weeks or until recovery.

EXAMPLE 19 treatment of infections of the Male or female reproductive System (reduced dose in children)

80mg of 3- [ [ (aminocarbonyl) oxy ] methyl ] -7- [ [ 2-furanyl (methoxyimino) acetamido ] -8-one-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2-diethylaminoethyl ester hydrochloride was dissolved in 3ml of water and applied to the affected part of the patient once in the morning and evening (twice a day) for 2 weeks or until recovery.

Claims

1. A high penetration antimicrobial derivative, and pharmaceutically acceptable salts thereof, comprising structural formula I-2, including stereoisomers and pharmaceutically acceptable salts thereof,

wherein:

w is H;

HA is selected from the group consisting of: HCl, HBr, HI, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, acid tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid;

r is selected from the group consisting of: alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms and halogenated hydrocarbon of 1 to 12 carbon atoms;

R₅is of the structural formula W-4

R_11-13Each independently selected from the group consisting of: H. alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms and halogenated hydrocarbon of 1 to 12 carbon atoms;

x is nothing or CH₂；

X₅Is S or O.

2. A high penetration antimicrobial derivative, and pharmaceutically acceptable salts thereof, comprising structural formula I-4, including stereoisomers and pharmaceutically acceptable salts thereof,

wherein:

w is of the formula W-4

x is S or O.

3. A pharmaceutical composition comprising a high penetration antimicrobial derivative according to claim 1 or 2 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable carrier is polar.

5. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable carrier is selected from the group consisting of: alcohols, ketones, esters, water, and aqueous solutions.

6. Use of a high penetration antimicrobial derivative according to claim 1 or 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment of a condition treatable by an antimicrobial agent in a biological subject.

7. The use of claim 6, wherein the antimicrobial treatable condition is selected from the group consisting of pain, injury, and microbiologically-related conditions.

8. The use of claim 7, wherein the microbe-associated condition is selected from the group consisting of a bacteria-associated condition, a protozoan-associated condition, a fungi-associated condition, and a virus-induced condition.

9. The use of claim 8, wherein the bacteria-associated symptoms are selected from the group consisting of: the bacterially-associated symptoms include infection, plague, anthrax, lyme disease, brucellosis, pertussis, acute enteritis, psittacosis, nongonococcal urethritis, trachoma, neonatal inclusion body conjunctivitis, lymphogranuloma venereum, pseudomembranous colitis, gas gangrene, food poisoning, anaerobic cellulitis, diphtheria, dysentery, neonatal meningitis, hemorrhagic colitis, hemolytic uremic syndrome, tularemia, pneumonia, bronchitis, gastric ulcer, legionnaires' disease, Pontian fever, leptospirosis, listeriosis, leprosy, tuberculosis, gonorrhea, neonatal ophthalmia, septic arthritis, successive epidemic meningococcosis, Hua-Friedel-Barre syndrome, rocky fever, typhoid salmonella disease, salmonellosis with gastroenteritis and colitis, cystitis, meningitis, and, Endometritis, otitis media, sinusitis, syphilis, necrotizing fasciitis, streptococcal pharyngitis, scarlet fever, rheumatic fever, impetigo, erysipelas, puerperal fever and cholera.

10. The use of claim 9, wherein the infection comprises a respiratory infection, a urinary tract infection, a nosocomial infection, a pseudomonas infection, a coagulase-positive staphylococcal infection, a skin infection, a toxemia, an acute infective endocarditis, septicemia, necrotizing pneumonia, a post prosthesis implantation infection, an opportunistic infection with septicemia and pneumonia.

11. The use of claim 10, wherein the respiratory infection is an upper respiratory infection.

12. The use as claimed in claim 9, wherein the plague comprises bubonic plague and pneumonic plague.

13. The use of claim 9, wherein said anthrax comprises cutaneous anthrax, pulmonary anthrax, and gastrointestinal anthrax.

14. The use of claim 9, wherein the pneumonia is mycoplasma pneumonia.

15. The use of claim 9, wherein the symptoms of infection are selected from the group consisting of: respiratory infections, urinary tract infections, nosocomial infections, pseudomonas infections, coagulase-positive staphylococcal infections, skin infections, toxemia, acute infective endocarditis, septicemia, necrotizing pneumonia, infections after prosthesis implantation, opportunistic infections with septicemia and pneumonia, and infections of an organ selected from the group consisting of liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, pancreas, gall bladder, gastrointestinal tract, intestine, and blood vessels.

16. The use of claim 15, wherein the blood vessel is a vein.

17. The use of claim 15, wherein the intestine is selected from the group consisting of colon, duodenum, colorectal, and anorectum.

18. The use of claim 15, wherein the respiratory system is the upper respiratory tract.

19. The use of claim 8, wherein the protozoan-related symptom is selected from the group consisting of: dysentery, narcolepsy, and toxoplasmosis.

20. The use of claim 8, wherein the fungus-related symptom is selected from the group consisting of: aspergillosis, blastomycosis, ringworm, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and zygomycosis.

21. The use of claim 8, wherein the virus-associated symptoms are selected from the group consisting of: influenza, yellow fever and AIDS.

22. The use of claim 9, wherein the dysentery comprises bacillary/bacillary dysentery.

23. The use of claim 15, wherein the respiratory infection comprises a respiratory infection.