MXPA01009885A - Viral treatment - Google Patents

Viral treatment

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Publication number
MXPA01009885A
MXPA01009885A MXPA/A/2001/009885A MXPA01009885A MXPA01009885A MX PA01009885 A MXPA01009885 A MX PA01009885A MX PA01009885 A MXPA01009885 A MX PA01009885A MX PA01009885 A MXPA01009885 A MX PA01009885A
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MX
Mexico
Prior art keywords
group
hydrogen
carbamic acid
composition according
hiv
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MXPA/A/2001/009885A
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Spanish (es)
Inventor
James Berger Camden
Joseph Herman Gardner
David Thomas Stanton
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The Procter & Gamble Company
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Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Publication of MXPA01009885A publication Critical patent/MXPA01009885A/en

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Abstract

A pharmaceutical composition that inhibits or slows the growth of viruses in animals, particularly in mammals, is disclosed. This same composition can be used to treat viral infections, particularly HIV. The composition comprises from about 10 mg to about 10000 mg of a carbamic acid ester derivative of formula (I) wherein X is independently oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, R1 is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, wherein R2 is independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chloro, fluoro, bromo, hydroxy, oxychloro and sulfhydryl or pharmaceutical addition salt or prodrug thereof. The most preferred compound is (4-chlorophenyl)-carbamic acid, 3-(hexahydro-3-ethyl-1-methyl-2-oxo-1H-azepin-3-yl) 2 phenyl ester.

Description

VIRAL TREATMENT TECHNICAL FIELD This invention relates to certain esters of carbamic acid which are effective against viruses and can be used to treat viral infections in -amals. The preferred compound is (-chlorophenyl) carbamic acid, 3- (hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) 2-phenyl ester. The composition may contain one or more of the carbamic acid esters, its pharmaceutical drug addition salt thereof.
BACKGROUND OF THE INVENTION HIV and other viral infections such as, for example, hepatitis are among the few causes that lead to death. It is known that HIV. It is the virus that causes the acquired immunodeficiency syndrome (AIDS) in humans. HIV is a disease in which a virus replicates in the body or in host cells. The virus attacks the body's immune system Several drugs have been approved for the treatment of this devastating disease, including azidovudine (AZT), didanosine (dideoxyinosine, ddl), d4T, zalcitabine (dideoxycytosine, ddC), nevirapine, lamivudine. (epivir, 3TC), saquinavir (Invirase), ritonavir (Norvir), indinavir (Crixivan), and delavirdine (Rescriptor). See M. I. Johnston & D. F. Hoth, Science, 260 (5112), 1286-1293 (1993) and D. D. Richman, Science, 272 (5270), 1886-1888 (1996). A vaccine for AIDS (Salk vaccine) has been tried and it has been discovered that various proteins that are chemokines from CD8 act as suppressors of HIV. In addition to the above nucleoside analogs, proteins and antibodies, it has been found that various plants and substances derived therefrom have anti-HIV activity in vitro. However, HIV is not easily destroyed nor is there a good mechanism to prevent host cells from replicating the virus. In this way, medical professionals continue to search for drugs that can prevent HIV infections, treat HIV carriers to prevent their disease from progressing to fully developed deadly AIDS, and to treat the patient with AIDS. Herpes simplex virus (HSV) types 1 and 2 are persistent viruses that commonly infect humans; they cause a variety of diseases that afflict the human being. HSV type 1 causes "febrile vesicles", oral (recurrent cold sores), and HSV type 2 causes genital herpes, which has been seen to be the main venereal disease in many parts of the world. Currently there is no completely satisfactory treatment for genital herpes. In addition, although it is rare, HSV can also cause encephalitis, a life-threatening infection of the brain. (The Merck Manual, Holvey, Ed., 1972, hitley, Herpes Simplex Virus, In: Virology, 2nd Ed., Raven Press (1990)). A more serious disorder caused by HSV is dendritic keratitis, an ocular infection that produces a branched injury to the cornea, which in turn can lead to permanent scarring and loss of vision. Eye infections with HSV are a leading cause of blindness. The HSV is also difficult, if not impossible to cure. Hepatitis is a disease of the human liver. It is manifested by inflammation of the liver and is usually caused by viral infections and sometimes from toxic agents. Hepatitis can progress to liver cirrhosis, liver cancer, and eventually death. It is known that various viruses such as, for example, hepatitis A, B, C, D, E and G cause various types of viral hepatitis. Among them, HBV and HCV are the most serious. HBV is a DNA virus with a virion size of 42 nm. HCV is an RNA virus with a virion size of 30-60 nm. See D. S. Chen, J. Forays Med. Assoc., 95 (1), 6-12 (1996). Hepatitis C infects 4 to 5 times the number of people infected with it. HIV Hepatitis C is difficult to treat and it is estimated that there are 500 million people infected with it worldwide (approximately 15 times of those infected with HIV). Currently no effective immunization is available, and hepatitis C can only be controlled by other preventive measures such as, for example, improving hygiene and sanitary conditions and interrupting the route of transmission. Currently, the only acceptable treatment for chronic hepatitis C is interferon that requires at least six (6) months of treatment and / or ribavaren that can inhibit viral replication in infected cells and also improve liver function in some people . Treatment with interferon, however, has a limited long-term efficacy with a response rate of approximately 25%. Infection with the hepatitis B virus can lead to a broad spectrum of liver damage. In addition, chronic hepatitis 3 infection has been linked to the subsequent development of hepa tocellular carcinoma, a leading cause of death. The current prevention of HBV infection is a vaccination against hepatitis B that is safe and effective. However, vaccination is not effective in treating those who are already infected (ie, carriers and patients). Many drugs have been used to treat chronic hepatitis B and none has proven effective, except interferon. The treatment of HCV and HBV with interferon has limited success and has often been associated with adverse side effects such as, for example, fatigue, fever, chills, headache, prialgia, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid malfunction. Because interferon therapy has limited efficacy and frequent adverse effects, a more effective regimen is necessary.
In the present invention it has been discovered that the compounds described above are useful for the treatment of hepatitis C virus, hepatitis B virus, herpes simplex and the treatment of HIV infection and other viral infections.
BRIEF DESCRIPTION OF THE INVENTION A pharmaceutical composition for the treatment of animals and in particular, warm-blooded animals, including humans, is disclosed, comprising a pharmaceutical carrier and an effective amount of an arylcarbamic acid ester which has the following formula: wherein X independently is oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, Ri is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms , wherein R2 is independently selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy, and sulfhydryl or a halo; of pharmaceutical addition or a pro-drug thereof. The preferred compound is (4-chlorophenyl) -carbamic acid, 3- (hexahydro-3-ethyl-1-methyl-2-oxo-l-azepin-3-yl) 2-phenyl ester; wherein X is oxygen, Y is chlorine, R is hydrogen, R2 is ethyl and Ri is methyl.
The compositions can be used in a method for treating HIV, in particular chronic HIV, and other viral infections. The drug can be administered daily in one or more doses and 1 to 4 times a week. The compositions may be used in conjunction with other treatments for viral infections.
DETAILED DESCRIPTION OF THE INVENTION A. Definitions: In the sense in which it is used in the present "alkyl" includes straight chain, branched and cyclic alkanes. In the sense in which it is used in the present "aryl" it includes phenyl or phenyl derivatives, for example, chlorophenyl, fluorophenyl or methylphyl. In the sense in which it is used herein, the term "safe and effective amount" refers to the amount of a component that is sufficient to provide a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) in proportion to a reasonable benefit / risk ratio when used in the manner of this invention. In the sense in which it is used herein, the term "therapeutically effective amount" means an amount of a compound of the present invention effective to provide the desired therapeutic response. For example, to inhibit HIV infection or treat the symptoms of infection in a host or an effective amount to treat hepatitis. The specific and therapeutically effective safe and effective amount will vary, obviously, according to factors such as the particular condition that will be treated, the physical condition of the patient, the mammal or animal tlpc to be treated, the duration of the treatment, the nature of the concurrent therapy (in its case) and the specific formulations used and the structure of the compounds or their derivatives. As used herein, a "pharmaceutical addition salt" is a salt of the arylcarbamic acid ester derivative that is modified by producing an acid or basic salt of the compounds. Examples of pharmaceutical addition salts include, but are not limited to: mineral or organic acid salts of basic waste such as, for example,, amines, alkaline or organic salts of acidic residues such as, for example, carboxylic acids. Preferably, the salts are produced using an organic or inorganic acid. These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the anti-viral agent to the animal or human. "The carrier can be liquid or solid and is selected with the intended administration form in mind, as used herein, the term "anti-viral compound" means an arylcarbamic acid ester or the pharmaceutically acceptable salt thereof or a prodrug thereof. Carbamic acid ester In the sense in which it is used herein, the term "ester derivative of carbamic acid" or "ester of aryl carbamic acid" are compounds having the formula: in donate X independently is oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, Ri is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms , wherein R2 is independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy, oxychlor and sulfhydryl or a pharmaceutical addition salt or a prodrug thereof. "Pro drugs" are considered any covalently attached carriers that release the active precursor drug according to the formula of derivatives described above when this pro-drug is administered to a mammalian subject or patient. The aryl carbamic acid ester drugs are prepared by modifying the functional groups present in the compounds in such a way that the modifications adhere, either in routine or in vivo manipulation, to the precursor compounds. The pro-drugs include compounds wherein the hydroxyl, sulfhydryl, or amine groups are attached to any group which, when administered to a mammalian subject, adheres to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of drug prodrugs include, but are not limited to: acetate, formate, or alcohol benzoate derivatives and amine functional groups in the carbamic acid ester derivatives; phosphate esters, dimet il glycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboalkyl alcohol esters and phenol functional groups in the ester derivatives of carbamic acid; and the like. In the sense in which it is used herein, "viruses" include viruses that infect animals or mammals, including humans, viruses include retroviruses, HIV, influenza, poliovirus, herpes simplex, hepatitis B, hepatitis C, and others. viral strains of hepatitis, Kaposi's sarcoma, rhinovirus, and the like In the sense in which it is used herein "combination therapy" means that the patient in need of the drug is treated or given another drug for the disease This combination therapy can be a sequential therapy where the patient is treated first with one drug and then the other, or the two drugs are administered simultaneously, in the sense in which it is used in combination with the carbamic acid ester derivatives. herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation and rejection). allergic response) in proportion to a reasonable benefit / risk ratio. In the sense in which it is used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the anti-viral agent to the animal or human. The ported can be liquid or solid and is selected with the planned form of administration in mind. In the sense in which it is used herein, "anti-viral compounds" are the carbamic acid ester derivatives described above.
B. THE ANT-VIRAL COMPOUNDS The aryl carbamic acid ester has the following formula: wherein X independently is oxygen or sulfur, R is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, "Ri is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms. carbon, wherein R2 is independently selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy, oxychlor and sulfhydryl or a pharmaceutical addition salt or a prodrug thereof The preferred compound is (4-chlorophenyl) -carbamic acid, 3- (hexahydro-3-ethyl-1-methyl-2-oxo-lH-azepin-3) -il) 2-phenyl ester, where X is oxygen, Y is chlorine, R is hydrogen, R2 is ethyl and Ri is methyl, its formula is: The pharmaceutically acceptable salts of the carbamic acid ester derivatives include the conventional non-toxic salts or the quaternary ammonium salts of the carbamic acid ester derivatives formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as, for example, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroximic, phenolic, glutamic, benzoic, salicylic, sulphanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from carbamic acid ester derivatives containing a basic or acid entity by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or the basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; in general, non-aqueous media similar to ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th. ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure thereof is incorporated herein by reference. The disclosures of all references cited herein are incorporated herein by reference in their entirety.
C. SYNTHESIS Ester derivatives of carbamic acid can be prepared in several of the ways well known to one skilled in the art of organic synthesis. Carbamic acid ester derivatives can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. The relevant portions of each of the references cited below are incorporated herein by reference. The preferred compound, carbamic acid (4-chlorophenyl), 3- (hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) 2-phenyl ester, can be prepared as follows: A in acetonitrile, lithium bromide, copper bromide at 25 ° C for 16 hours gives B B + [CH 3) 2CH] 2NLi + CH 3 CH 2 I in tetrahydrofuran at 10 ° C for 15 min and then at 65 ° C for six hours provides C.
First, 3-me t-oxycyclohexenone (see Shepherd, et al., J. Chem Soc. Perkin Trans I, 2153 (1987), for a synthetic method to produce 3-me toxiciclohexenone of 1,3-cyclohexanedione and orthoformiate trimethyl) is reacted with N-methyl caprolactam in the presence of an organolithium compound, preferably lithium diisopropylamide, (see for example, US 4,197,241). The resulting product is treated with lithium bromide and copper bromide in acetonitrile to convert the unsaturated ketone to the corresponding aromatic compound which is then treated with ethyl iodide in the presence of a lithium catalyst (lithium diisopropylamide) to prepare the ethyl intermediate. . Reaction with para-chlorophenylisocyanate in pyridine using dibutyltin dilaurate as a catalyst results in 3-hexahydro-3-yl-1-yl-yl-2-oxo-lH-a-zepin-3-yl) phenyl ester of (4-chlorophenyl) -carbamic acid. Similar routes can be used to produce the other derivatives of arylcarbamic acid esters of the type described herein.
D. DOSAGE AND FORMS OF DOSING SUPPLY The compounds in general are safe. The compounds can be administered orally and are not very soluble, preferably they are provided in tablet form or as an oral or intravenous suspension. Any suitable dosage can be provided in the method of the invention. The type of compound and the carrier and the amount will vary depending on the species of animal or human of warm blood, body weight, and the virus that will be treated. Of course, the dosage administered will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and / or weight of the recipient; to the nature and degree of the symptoms; the type of concurrent treatment; the frequency of treatment; and the desired effect. The ester of carbamic acid is preferably micronized or pulverized in such a way that it is dispersed and solubilized more easily by the body. Processes for grinding or spraying the drugs are well known in the art. For example, grinding by hammer or similar grinding device. The preferred particle size is less than about lOOμ and preferably less than 50μ .. As a general guide, a dosage as small as approximately 1 milligram (mg) per kilogram (kg) of body weight and preferably as small as 10 mg / kg and up to approximately 10,000 mg per kg of body weight is adequate. Preferably, 10 mg / kg and 5000 mg / kg body weight are used. More preferably, the doses are between about 250 mg / kg and 5000 mg / kg. Intravenously, the most preferred dose may vary from about 1 to 10 mg / kg / minute during an infusion at a constant rate. The ester compounds of carbamic acid can be administered in divided doses of two, three, or four times daily. Carbamic acid ester derivatives can be administered in one or more doses on a daily basis or one to three times a week. Dosing is preferred two times a week for a period of at least several weeks and antiviral compounds will often be administered for prolonged periods of time and may be administered during the patient's lifetime. Carbamic acid ester derivatives can also be administered in intranasal form by topical use of intranasal vehicles, or by transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, of course, administration will be continuous rather than intermittent throughout the dosage regimen. In general, the dosage in man will be lower than for small warm-blooded mammals such as mice. A dosage unit may comprise a single compound or mixtures thereof with other compounds or other compounds for viral inhibition. The dosage unit may also comprise diluents, extenders, carriers and the like. The unit may be in the form of a solid or gel such as, for example, pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection in or around to the virus. The carbamic acid ester derivatives are usually mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid and the type in general is selected based on the type of administration that will be used. The active agent can be coadministered in the form of a tablet or capsule, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. The capsule or tlabletas can be prepared easily and can be easily produced for swallowing or chewing; other solid forms include aggregates and powders. The tablets may contain suitable binders, "lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents Examples of suitable liquid dosage forms include pharmaceutically acceptable solutions or suspensions in water, fats and oils. , alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.Oral dosage forms optionally contain flavors and coloring agents. intravenous They could also include minerals and other materials to produce them that are compatible with the type of injection or delivery system selected.
EXAMPLES OF FORMULATION The ester derivatives to the carbamic acid of this invention can be administered as a treatment for viral infections by any means that produces contact of the active agent with the site of action of the agent in the body. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. • They can be administered alone, although in general they are administered with a pharmaceutical carrier selected on the basis of the selected administration route and standard pharmaceutical practice. The carbamic acid ester can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or time delay formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Carbamic acid ester derivatives can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using well-known dosage forms for those with normal experience in pharmaceutical techniques. In the methods of the present invention, the compounds of the present invention described in detail can form the active ingredient and are typically administered in a mixture with suitable diluents, excipients or carrier carriers (collectively referred to as a carrier or pharmaceutically acceptable carrier materials) appropriately selected with respect to the intended form of administration, ie, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the unit dosage form of a tablet or capsule, the active drug component can be combined with an inert carrier, pharmaceutically acceptable, non-toxic, oral, such as lactose, starch, sucrose, glucose, ti lcelulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
For oral administration in liquid dosage form, the oral drug components can be combined with any inert, pharmaceutically acceptable, non-toxic, oral carrier, such as ethanol, glyceroi, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate *, carboxymethylcellulose, polyethylene glycol, waxes and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium venzoate, sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. The ester derivatives of carbamic acid can also be administered in the form of systems for delivery of liposomes, such as, for example, small unilamellar vesicles, large vesicles, etc. unilamellar and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as for example, cholesterol, teari lamina, or phosphat idylcholine. Carbamic acid esters can also be packed with soluble polymers as carriers of the white drug. These polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug., for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoes, polyacetals, polyhydrodynamines, poly cyanoacrylates, and block copolymers of crosslinked or amphipathic hydrogels. The dosage forms (compositions suitable for administration) contain between about 1 milligram and 1000 milligrams of the active ingredient per dosage unit. From 2.9 Preferably, the dosage forms will contain between about 10 mg and 500 mg. In these pharmaceutical compositions the active ingredient will normally be present in an amount of between about 0.5 and 95% by weight based on the total weight of the unit dose. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally in liquid dosage forms including liposomes. The gelatin capsules may contain the active ingredient and powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to produce compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide a continuous release of the drug over a period of hours. The compressed tablets may be coated with sugar or a coated film to mask the unpleasant taste and protect the tablet from the atmosphere, or with enteric coating for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavors to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient or a liposome, suitable stabilizing agents, and if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and disodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-parabeni and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The pharmaceutical dosage forms useful for the administration of the compounds of this invention are illustrated as follows: Capsules Many unit capsules are prepared by filling standard two-piece hard gelatin capsules, each containing 100 milligrams of the powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.
Soft gelatin capsules A mixture of the active ingredient is prepared in a digestible oil such as, for example, soybean oil, cottonseed oil or olive oil and is injected by means of a gelatin positive displacement pump to form the capsules of soft gelatin containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets Many tablets are prepared by conventional procedures in such a way that the dosage unit is 100 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Suitable coatings can be applied to increase palatability or delay absorption.
Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension An aqueous suspension is prepared for oral administration in such a way that every 5 ml contains 100 mg of the finely divided active ingredient., 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin. The present invention also includes pharmaceutical kits useful, for example, for the treatment of HIV infection, comprising one or more containers containing a pharmaceutical composition comprising a compound of the formula (I). These kits may also include, if desired, one or more of the various components of the conventional pharmaceutical equipment, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. The technique. Printed instructions, either as inserts or as labels, indicating the quantities of components to be administered, directions for administration, and / or directions for mixing the components can also be included in the kit. In the present disclosure it should be understood that specific materials and conditions are important for practicing the invention although non-specific materials and conditions are not excluded as long as they do not prevent the benefits of the invention from being carried out.
F. TREATMENT METHOD The method of treatment can be any suitable method that is effective in the treatment of the particular virus. The above formulations can be used for treatment. The treatment can be by oral, rectal, topical, parenteral or intravenous administration and the like. The method for administering an effective amount also varies depending on the virus that will be treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the aryl carbamate ester compounds, is prepared with a suitable carrier, an additional compound or compounds for viral inhibition or a diluent to facilitate the application will be the preferred method for administering the compounds to mammals or warm-blooded animals. The actual duration of treatment and dosage will depend on the virus that will be treated and the desired blood levels. Carbamic acid ester derivatives can also be used as an antifungal treatment and are administered as the antiviral treatment or they can also be applied topically in a cream, gel or liquid form. They can also be prepared as a suppository.
G. COMBINATION THERAPY One or more of the carbamic acid ester derivatives may be combined with other antiviral agents or enhancers. Potentiators are materials that affect the body's response to the antiviral agent. In the case of HIV, combination therapy with AZT, TC-3 or protease inhibitors is effective. In the case of hepatitis, cyclovir, famcíclovir or valaciclovir, Ribavirin, interferon or combinations of Ribavirin and Inferior or beta globulins are administered as a combination therapy. For herpes, a recombinant alpha interferon can be used as a combination therapy. In some embodiments, the aryl carbamate ester compound is used in combination with one or more enhancers and / or antiviral agents for the treatment of viral infections. An exemplary enhancer is triprolidine or its cis-isomer which are used in combination with chemotherapeutic agents and the aryl carbamate ester compound. Triprolidine is described in US 5,114,951 (1992). Another enhancer is procodazole, lH-benzimidazole-2-propanoic acid; L- (2-benzimidazole) propionic acid; 2- (2-carboxyethyl) benzimidazole; propazole]. Procodazole is a non-specific immunoprotective agent against viral and bacterial infections which is used with the compositions claimed herein. This is effective with the aryl carbamate ester compound to treat viral infections. The procodazole can also combine the carbamate ester compound. Procodazole can also be combined with the carbamate ester compound and other anti viral agents. Other enhancers that can be used as aryl carbamate ester compounds include monensin, an anti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, an immunotixin receptor for anti-trans fer brain, me toclopramide, 7-thia -8-oxoguanosine, N-solanesyl-N, N'-bis (3,4-dime toxibenci 1) ethylenediamine, leucovorin, heparin, N- [4- [(4-fluorophenyl) sulfonyl] phenyl] acetamide, heparin sulfate , cimetidine, a radiosensitizer, a hypoxic cell cytotoxic agent, muramyl dipeptide, vitamin A, 2'-deoxy cof ormicin, a bis-diketopiperazine derivative and dimethyl sulfoxide. In some embodiments of the invention, an aryl carbamate ester compound is used in combination with one or more other therapeutic agents, such as, for example, anti-inflammatory, anti-viral, anti-vaginal, amoebicidal, ricominoidal, analgesic, antineoplastic, ant i-hypertensive, ant i-microbial and / or steroidal, to treat viral infections. In some preferred embodiments, patients with viral infections are treated with a combination of one or more aryl carbamate ester compounds with one or more of the "antibiotics be ta-lact ama"., tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, nor rofurazone, nalidixic acid, cortisone, hydrocort isone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac, acyclovir, amantadine, rimantadine, soluble CD4 (rsCD4) recombinant, anti-i-receptor antibodies (for rhinoviruses), nevirapine, cidofovir (Vistide ™), trisodium phosphonoformate (Foscarnet ™), famciclovir, penciclovir, valaciclovir, nucleic acid / replication inhibitors, interferon, zidovudine (AZT, Retrovir didanosine (dideoxy inosine, ddl VidexMR), stavudine (d4T, ZeritMR), zalcitabine (dideoxycytosine, ddC, VihidMR), nevirapine (ViramuneMR), lamivudine (EpivirMR, 3TC), protease inhibitors, saquinavir (InviraseMR, Fortovase R), ritonavir (NorvirMR), nelfinavir (ViraceptMR), efavirenz (SustivaMR), abacavir (ZiageriMR), amprenavir (Agenerase ™) indinavir (Crixivan ™), ganciclovir, AzDU, delavirdine (Rescriptor ™), rifampin, t iromycin, er 11 ropoyet ina, colony stimulating factors (G-CSF and GM-CSF), nucleoside reverse transcriptase inhibitors, nucleoside inhibitors, adriamycin, f luorouracil, methotrexate, asparaginase and combinations thereof. The combination therapy can be sequential, that is, the treatment with a first agent and then the second agent, or it can be the treatment with the agents at the same time. Sequential therapy may be within a reasonable time after completing the first therapy before starting the second therapy. Treatment with both agents at the same time can be in the same dose daily or in separate doses. For example, treatment with one agent on day 1 and the other on day 2. The exact regimen will depend on the disease that will be treated, the severity of the infection and the response to treatment.
MECHANISM The mechanism of action of esters of carbamic acid is not known. The aryl carbamic acid ester shows no activity as a protease inhibitor when selected using a fluorometric method or as an integrase inhibitor. These results are summarized below: Protease inhibition analysis Protease inhibition is evaluated using a fluorometric method. The enzyme (Bachem) is diluted to μgm / ml in 50mM NaOAC, 5mM DTT, 2mM EDTA, 10% glycerol (pH 5.0) and stored as 10μl samples at -20 ° C, the protease substratum I HIV (molecular probes) is diluted to a working concentration of 0.32 nmoles / μl. The enzyme (20 μl) and the drug (20 μl) are added to each well of a microtiter plate as appropriate. The positive and negative control are evaluated in parallel. Fluorescence is quantified in Labsystems Fluroskan II using 355 nm / 460 nm at 37 ° C at time zero and at 30 minute intervals for 2 hours. In cases where autofluorescence avoids the use of flucometric HIV-1 protease analysis or confirmation of a result is required, an HPLC-based protease assay can also be used.
Analysis of Integrase Inhibition An analysis of biochemical integrase is described by Craigie et al (HIV, vol.2: A practical Approach) Biochemistry, Molecular Biology and Drug Discovery, Ed. J. Karn 1995) to select agents for their ability to inhibit the integrase of HIV-1. In this system, an oligonucleotide subjected to kinase treatment serves as the target of 3 'processing and the subsequent filament transfer reaction. The 3 'processing reaction includes the removal of 2 nucleotides from the 3' ends of the substrate and this is followed by the filament transfer reaction in which the ends 31 'are bound to the exposed 5' ends. The 20 μl reaction mixture contains 25 mM MOPS (pH 7.2), 100 g / ml BSA, 10 mM β-mercaptoethanol, 10% glycerol, 25 nM 7.5 mM MnCl2, (7 ng) substrate (Oligo's Etc., ilsonville, OR) and integrase 200 nM (128 ng) (NIAID AIDS Research and Reference Reagent Program, Bethesda, MD). The reaction proceeds at 37 ° C for 1-2 hours and is terminated by the addition of 20 μl of disruption solution by sequencing (USB Amersham, Ariington Heights, IL). The reaction products are visualized by autoradiography after electrophoresis in Urea 6M gel of 15% polyacrylamide. The substrate migrates as a 30 mer, the 3 'processing product migrates as an N-2 band and the filament transfer products migrate more slowly to various sizes larger than the substrate.
INHIBITION OF PROTEASE 3-HEXAHIDRQ-3-ETHYL-1-METHYL-2-QXQ-1H-AZEPIN-3-IL) PHENYL ESTER CARBAMIC 4-CHLOROPHENYL ACID The EC50 value is > 100 μg / ml for (4-chlorophenyl) -carbamic acid, 3- (hexahydro-3-yl-l-methyl-2-oxo-lH-azepin-3-yl) 2-phenyl ester and 0.699 μM / ml for 654021.
INHIBITION OF INTEGRASA HIV-1 ACID (4-CHLOROPHENYL) -CARBÁMICO, 3 - (HEXAHIDRQ- 3 -ETIL- 1 -METIL- The IC50 (μg / ml) is greater than 100 for this compound Inhibition of HIV-1 integrase by 654021F a control drug The IC50 (nM) is 699.01 The compounds in general are safe. The LD50 is clearly higher and there are no special handling requirements. The compounds can be administered orally and as they are not very soluble, they are preferably administered in tablet form or as a suspension or liposome.
Preparation of the virus: An aliquot of the virus (-80 ° C) is removed from the frozen and left to thaw slowly at room temperature in a biological safety cabinet. The virus is resuspended and diluted in tissue culture medium such that the amount of virus added to each cavity in a volume of 50μl will be the amount determined to provide total cell killing at 6 days after infection . In general, virus collections produced with HIV IIIB isolate required the addition of 5μl of virus per cavity. The RF virus collections were 5 to 10 times more potent requiring 0.5-] μl of the virus per cavity. The calculation of TCID50 by final titration in CEM-SS cells indicated that the infection rate of these analyzes varied from 0.005 to 2.5.
Plate format: The format of the test plate has been standardized. Each plate contains cavities for cell control (cells only), cavities for virus control (cells plus viruses), cavities for toxicity control (cells plus drug only), cavities for calorimetric control of the drug (only drug) as well as cavities experimental (drug plus cells plus virus).
XTT staining of the selection plates: After 6 days (or the experimental period) of incubation at 37 ° C in a 5% carbon dioxide incubator, the test plates were analyzed by staining with the tetrazolium pigment, XTT .
The XTT-tetrazolium is metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product, allowing rapid quantitative analysis of the inhibition of cell death "induced by HIV through an anti-HIV test substance. After infection, the plates were removed from the incubator and observed.The use of round bottom microtiter plates allows a rapid macroscopic analysis of the active of a test compound determined by the evaluation of the granule size. macroscopic observations were confirmed and intensified by additional microscopic analysis.The XTT solutions are prepared daily as a 1 mg / ml concentrate in PBS.The phenazine methosulphate solution (PMS) is prepared at 15 mg / ml in PBS and stored in the dark at 20 ° C. The XTT / PMS concentrate is prepared immediately before ut Isolate by diluting the PMS in 1: 100 in PBS and add 40 μl per ml of XTT solution. Fifty microtitre XTT / PMS were added to each well of the plate and the plate was re-incubated for 4 hours at 37 ° C. Adhesive sealants for plates were used in place of the lids and the sealed plate was inverted several times to mix the soluble formazan product. Plating on plates was read spectroscopically at 450 nm with a Molecular Devices Vmax plate reader. The reduction in cell percentage, the viability of the cell percentage, IC25 / 50 and 95 can then be calculated.
Analysis of reverse transcriptase activity: A reverse transcriptase (RT) reaction is used based on microtitre (Buckheit et al (1991) AIDS Research and Human _Re troviruses 7: 295-302). The titrated thymidine triphosphate (NEN) (TTP) is resuspended in distilled water at 5 ° Ci / ml. Poly rA and oligo dT are prepared as a concentrated solution maintained at -20 ° C. The reaction buffer RT is prepared fresh on a daily basis and consists of 125 μl of EGTA 1M, 125 μl of water, 125 μl of Triton X-100, 50 μl of Tris (pH 7.4), 50 μl of I MDDT, and 40 μl of 1M MgCl 2. These three solutions are mixed together in a ratio of 1 part TTP, 2.5 parts poly. rA: oligo dT, 2.5 parts of reaction buffer and 4 parts of distilled water. Ten microliters of this reaction are placed in a round bottom microtiter and 15 μl of the supernatant containing the virus are added and mixed. The plate is incubated at 37 ° C and incubated for 60 minutes. After the reaction, the reaction volume is stained on filter mats, washed 6 times for 5 minutes each time in a 5% sodium phosphate burner, 2 times for 1 minute each in distilled water, 2 times during 1 minute. minute each in 70% ethanol, and then dried. The filter mat is placed in a plastic sample bag, the Betaplate scintillation fluid is added and the bag is heat sealed. The incorporated radioactivity is quantified using a Wallac Microbeta scintillation counter. Acute infection of most human cell lines established with HIV-1 results in the eventual establishment of a chronically infected cell line that produces constitutive viruses. The cells are passed through for prolonged periods of time in culture without loss of virus production. These cells can be used to evaluate the effects of anti-HIV compounds on zinc formation or to evaluate the effects of anti-HIV compounds on the levels of virus production from these cells.
Chronically infected cell lines exhibit little or no CD4 cell surface and can not be super-infected with other HIV-1 isolates. Each of the cells contains an integrated HIV genome or provirus. The chronically infected CEM, H9 and U937 cell lines were prepared and cultured by the Southern Research Institute, Frederick MD and are available therefrom. CEM-SS cells chronically infected with the HIV isolate, for example SKI (CEM-SKI) are cultured in RPMI1640 tissue culture medium supplemented with 10% fetal bovine serum and antibiotics. The selection is made by culturing the cells in the presence of the compound that will be tested in T25 flasks. CEM-SKI or other infected cells without adding drugs are used as control cells. The cells are allowed to develop at a density of about 1 x 10 6 cells / ml and then passed at a 1:10 dilution. After a period of time, usually at one-week intervals of treatment with the drug, the cells were evaluated to determine whether the inhibitory activity of the compound was affected by treatment of the cells with any of the compounds. The concentration of the drug in the flask was then increased twice and the cells were maintained as above. Cell populations contain integrated copies of the HIV genome and produce constitutively HIV at relatively high levels or are latently infected and produce only virus after stimulation with phorbol esters, tumor necrosis factor or IL6 (IU and ACH2). Reductions in virus products were observed when the reverse transcriptase activity of the supernatant was quantified. The toxicity values by XTT and the activity of the compound in the tests were measured by an Inverse Transcriptase analysis.
EXAMPLE 1 HIV-1 A long-term in vi t ro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-a zepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against HIV-1 cell line, CEMSKI, was conducted at three different levels. The results with CEMSKI cells are reported at weekly intervals. The reverse transcriptase data is summarized below.
CEMSKI CELLULAR LINE This test was run for 222 days and the data remained consistent. The CEMSKI cell line is a viral strain of the CEMSS cell line.
EXAMPLE 3 CEMRF A long-term in vi t ro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against an HIV cell line -1, CEMRF, was conducted to three different levels. The results with CEMRF cells are reported at weekly intervals. The reverse transcriptase data is summarized below. CEMRF is a chronic HIV cell line.
This test was run for 222 days and the data remained consistent.
EXAMPLE 4 CEMIIIB A long-term in vi t ro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against an HIV cell line -1, CEMIIIB, was conducted at three different levels. The results with CEMIIIB cells are reported at weekly intervals. The reverse transcriptase data is summarized below.
CEMIIIB is a viral strain of the CEMSS cell line and is a chronic HIV cell line.
This test was run for 22 days and the data remained consistent.
EXAMPLE 5 CEMROD A long-term in vi tro study of 3-hexahyd o-3-ethyl-1-met il-2-oxo-lH-a zepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against a line Cellular HIV-2, CEMROD, was conducted at three different levels. The results with CEMROD cells are reported at weekly intervals. The reverse transcriptase data showed similar decreases as the previous ones.
EXAMPLE 6 U937IIIB A long-term in vitro study of 3-hexahydro-3-ethyl-1-methyl-yl-2-oxo-l-azepin-3-yl) phenyl ester with 4-chlorophenyl carbamic acid against an HIV cell line -1, U937IIIB, was conducted to three different levels. The results with cells U937IIIB are reported at weekly intervals. The data of reverse transcriptase was similar to the data reported previously.
EXAMPLE 7 U937RF A long-term in vitro study of 3-hexahydro-3-ethyl-l-methyl-2-oxo-lH-azepin-3-yl) phenyl ester of 4-chlorophenyl carbamic acid against a U937RF cell line, a Protease-resistant strain, was conducted at three different levels. The results with U937RF cells are reported at weekly intervals. The reverse transcriptase data were similar to those reported previously. Similar results were obtained with U937KN1272, a strain resistant to the protease.

Claims (10)

  1. CLAIMS 1. The use of a pharmaceutical composition for producing a medicament for treating a viral infection wherein the composition comprises a safe and effective amount of a carbamic acid ester having the formula: wherein X independently is oxygen or sulfur; R is selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms; Ri is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, wherein R 2 is independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, and wherein Y is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, hydroxy and sulfhydryl or a pharmaceutical addition salt or a prodrug thereof.
  2. 2. The use according to claim 1, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and from 1 mg to 6000 mg of a carbamic acid ester or pharmaceutically acceptable acidic, organic or inorganic addition salt thereof.
  3. 3. The use of a pharmaceutical composition according to claim 1 or 2, wherein X is oxygen, Y is chlorine, R is hydrogen, Ri is methyl and R2 is ethyl.
  4. 4. The use of a composition according to claim 1, 2 or 3, comprising from 10 mg to 6000 mg of the carbamic acid ester having the formula: or the pharmaceutically acceptable salt thereof
  5. 5. The use of a composition according to claim 1, 2, 3 or 4, wherein the pharmaceutical addition salt is selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates and ascorbates.
  6. 6. The use of a composition according to claim 1, 2, 3, 4 or 5, wherein the pharmaceutical composition is a solid form comprising a carrier selected from the group consisting of lactose, sucrose, gelatin and agar.
  7. 7. The use of a composition according to claim 1, 2, 3, 4 or 5, wherein the pharmaceutical composition is in a liquid dosage form comprising a carrier selected from the group consisting of an aqueous solution, an emulsion, a solution of suspension yua reconstituted suspension from non-effervescent or effervescent preparations.
  8. 8. The use of a composition according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the viral infection is caused by a virus selected from the group consisting of HIV, influenza, hepatitis and rhinovirus.
  9. 9. The use of a composition according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the pharmaceutical composition further comprises an antiviral agent or an enhancer.
  10. 10. The use of a composition according to claim 9, wherein the viral infection is caused by HIV virus and the antiviral agent is selected from the group consisting of AZT, TC-3 and protease inhibitors.
MXPA/A/2001/009885A 1999-03-31 2001-10-01 Viral treatment MXPA01009885A (en)

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