Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/55—Protease inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

• This invention relates to novel combinations of
• retroviral infections particularly in the treatment of acquired, immune deficiency syndrome(AIDS) and related human immunodeficiency viral (HIV) infections.
• AIDS acquired, immune deficiency syndrome
• HAV human immunodeficiency viral
• the AIDS virus belongs to a general class of viruses known as retroviruses. As a class, many of the known retroviruses are also oncogenic or tumor causing. Indeed the first two human retroviruses discovered, denoted human T-cell leukemia virus type I and type II or HTLV-I and II, were found to cause rare leukemias in humans after infection of T-lymphocytes. The third such human virus to be
• HIV acquired immune deficiency syndrome
• ARC AIDS related complex
• Retroviruses are a class of ribonucleic acid (RNA) containing viruses that replicate by using a reverse RNA
• transcriptase activity to form a strand of complementary DNA (cDNA) from which a double stranded, proviral DNA is
• This proviral DNA is then incorporated into the chromosomal DNA of the host cell making possible viral replication by transcription of this integrated DNA and translation of viral messenger RNA into proteins.
• Replication of the virus occurs by synthesis of viral genomic RNA and its assembly with glycosytated and non- glycosylated viral proteins to form new viral particles.
• Maturation of virions at the cell surface results in the release of infectious virus progeny.
• Retroviral proteins are generally synthesized as
• polyproteins and virus encoded proteases are required to cleave the precursor polyproteins to form the viral enzymes and structural proteins.
• the gag and gag-pol precursor polyproteins of retroviruses are synthesized as precursors of viral encoded enzymes and non-glycosylated structural proteins.
• the envelope protein of HIV is a 160 kDa highly glycosylated precursor glycoprotein.
• the envelope proteins are cleaved by a host-cell protease to give a 120 kDa external glycoprotein (gp 120) and a
• the gp 120 protein contains a high affinity binding site that recognizes the CD4 ligand on CD4-positive human T-helper cells, the known receptor for this virus.
• the retroviral proteases also show certain commonality by their inhibition by aspartyl protease-specific
• the aspartyl proteases serve as a potentially interesting therapeutic target for intervention.
• the correctly processed envelope glycoproteins of the retroviruses play an important role in the virus life cycle, which also offers a possible target for clinical
• the envelope glycoproteins serve a role in both the initial interaction of the virion and the target host-cell and in the subsequent fusion of the viral envelope and host-cell membranes during penetration.
• Certain esters of castanospermine are useful in interfering with the processing of the viral envelope glycoproteins and thereby in preventing the initial virus-host cell interaction and subsequent fusion.
• compositions consist of the
• glucosidase inhibitor of formula I and a viral aspartyl protease inhibitor of formula II.
• compositions of formula 1 and formula II, and their pharmaceutically acceptable addition salts are novel and possess valuable pharmacological properties. Often these compositions can act synergistically to
• compositions of formula I and II are the compositions of formula I and II, and their aforementioned salts, for use as therapeutically active substances, medicaments containing said compounds and salts, their manufacture, and the use of said compositions and salts in the control or prevention of illnesses, especially in the treatment or prophylaxis of HIV infections.
• R, R 1 and R 2 are independently hydrogen
• naphthalenecarbonyl optionally substituted by methyl or halogen
• phenyl(C 2-6 alkanoyl) wherein the phenyl is optionally substituted by methyl or halogen
• cinnamoyl pyridinecarbonyl optionally substituted by methyl or halogen
• dihydropyridine carbonyl optionally
• furancarbonyl optionally substituted by methyl or halogen
• Y is hydrogen, C 1-4 alkyl, C 1-4 alkoxy,
• halogen trifluoromethyl, C 1-4 alkylsulfonyl, C 1-4 alkylmercapto, cyano or dimethylamino
• Y' is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen or it is combined with Y to give 3,4-methylenedioxy
• Y" is hydrogen, C 1-4 alkyl, C 1-4 alkoxy or halogen; with R, R 1 and R 2 being selected in such a way that at least one of them, but not more than two of them, is hydrogen; or a pharmaceutically acceptable salt of these compounds.
• the C 1-14 alkanoyl groups referred to above can be straight- or branched-chain or cyclic and can be exemplified by formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopropanecarbonyl, hexanoyl, octanoyl and decanoyl.
• the C 1-14 alkenoyl groups referred to above can be straight- or branched-chain or cyclic but have at least one carbon-carbon double bond as
• the C 1-6 alkoxyacetyl referred to above can be methoxy-acetyl, ethoxyacetyl and butoxyacetyl.
• the halogens referred to above can be exemplified by fluorine, chlorine, bromine or iodine.
• the C 2-6 alkanoyl groups referred to above can be exemplified by acetyl, propionyl, butyryl,
• the C 1-4 alkyl groups referred to above, whether alone or as part of an alkoxy, an alkylsulfonyl or an alkylmercapto group, can be straight- or branched-chain alkyl groups containing up to 4 carbon atoms. Examples of various such groups are methyl, ethyl, propyl, butyl, methoxy, ethoxy, butoxy, methylsulfonyl, ethylsulfonyl, methylmercapto and ethylmercapto.
• the phenyl (C 2-6 alkanoyl) groups referred to above can be exemplified by benzeneacetyl and benzenepropionyl.
• the various naphthalenecarbonyl, pyridinecarbonyl, thiophenecarbonyl and furancarbonyl groups referred to above include the various position isomers and these can be exemplified by naphthalene-1- carbonyl, naphthalene-2-carbonyl, nicotinoyl,
• R, R 1 and R 2 are alkanoyl or benzoyl, especially a C 1-8 alkanoyl, C 1-8 alkenoyl, or a benzoyl optionally substituted with an alkyl or halogen, and the others are hydrogens.
• one of R, R 1 and R 2 is a C 1-8 alkanoyl, C 1-8 alkenoyl, or a benzoyl optionally substituted with an alkyl or halogen
• an alkyl or halogen especially a methyl, bromo, chloro, or fluoro group, and the others are hydrogens.
• R 1 is a C 1-8 alkanoyl, C 1-8 alkenoyl, or benzoyl optionally substituted with an alkyl or halogen, especially a methyl, bromo, chloro, or fluoro group, most especially a methyl, bromo, chloro, or fluoro group at the para position, and wherein R and R 2 are each a hydrogen.
• a most especially preferred grouping can be any one especially preferred grouping.
• a castanospermine ester of Claim 1 which is [lS-(1 ⁇ ,6 ⁇ ,7 ⁇ ,8 ⁇ ,8a ⁇ )]-octahydro-1,6,7,8- indolizinetetrol 6-butanoate:
• Certain compounds are preferred. Amongst the preferred compounds of formula I is [lS- (1 ⁇ ,6 ⁇ ,7 ⁇ ,8 ⁇ ,8a ⁇ )]-octahydro-1,6,7,8-indolizinetetrol 6- butanoate.
• a is zero, or 1, 2 or 3,
• b is zero or 1
• c is zero or 1, 2, 3, 4 or 5,
• d 1 or 2
• e is zero, 1 or 2
• P 2 is C 1- 6 alkyl, cyclopentyl, cyclohexyl, hydroxy C 1- 6 alkylene, with T being H or C(O)R 4 ,
• R is hydrogen, -CH 2 CHO, hydroxy C 1-6 alkylene, C 1- 6 alkoxy C 1- 6 alkylene, C 1- 6 alkyl, phenyl, (R 3 ) d or Q,
• R 1 is benzyloxy, C 1-6 alkoxy, C 1-6 alkyl, phenyl, benzyl, phenethyl, fluorenylmethylenoxy, 2-isoquinolinyl, PDL,
• N(R 4 )(PDL) N(R 4 )(PDL), with PDL being -(CH 2 ) a -2-,3-, or
• R 3 is C 1- 6 allenyl C 1- 6 alkoxy, C 1-6 alkoxy C 1- 6 alkylene, hydroxy C 1- 6 alkylene, C 1- 6 alkyl, H, or OH,
• R 4 is H, C 1- 6 alkyl, phenyl or benzyl,
• R 5 is H, C 1- 6 alkyl, OH, C 1- 6 alkoxy,-(CH 2 ) d -(V) e , V
• R 6 is as defined for R 5 with the proviso that R 6 is other than H when R 5 is H, and when R 5 and R 6 are taken together with nitrogen atom to which they are attached form a heterocyclic moiety of the formulae:
• R 7 is CH 2 OR 4 or C(O)NHR 4
• R 1 is benzyl, benzyloxy, 4-alkoxybenzyloxy, morpholyl.
• P 2 is methylamid, isopropyl, cyclopentyl,
• P 1 is piperonyl, 4-(benzyloxy)benzyl,
• R 6 is benzyl, piperonyl, CH 2 -pyridyl,
• Y is isopropyl, preferably in the D configuration, or phenyl and when Z is benzyloxymethylene, CHO, COOH, alkoxy or COOR 4 .
• R 5 is other than H it is preferred that R 5 be methyl, 4-hydroxybutyl or 3-hydroxypropyl and that R 6 be benzoxy or benzyl, and when R 5 and R 6 form a heterocyclic moiety with the nitrogen attached thereto, the heterocycle is a perhydroisoquinoline of (f),
• compositions compounds of formula I and II may occur with asymmetric centers or may occur as racemates, racemic mixtures and as individual diastereomers, with all isomeric forms of the compounds being included in the present invention.
• the preferred compounds of formula I and formula II may be selected in any combination from one group select from formula I and one group selected from formula II. It is recognized that such combinations would include, for instance, a pharmaceutical composition comprising a
• R 1 is a C 1-8 alkanoyl, C 1-10 alkenoyl, C 1-8
• R 1 is benzyl oxy, SO 2 HN, (3-pyridyl)ethyl, isoquinolyl, 4-aikoxy- benzyloxy, or morpholyl
• P 2 is isopropyl, cyclopentyl
• R 5 be methyl, 4-hydroxybutyl or 3-hydroxy- propyl and that R 5 be benzoxy or benzyl, and when R 5 and R 6 form a heterocyclic moiety with the
• HIV human immunodeficiency virus
• AIDS acquired immunodeficiency syndrome
• Treating AIDS is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and
• compositions of this invention are useful in preventing infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion,
• the compounds of the present invention may be administered orally, parenterally
• a method of treating and a pharmaceutical composition for treating HIV infection and AIDS involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compounds of formula I and II of the present invention, or a pharmaceutically acceptable salt thereof.
• compositions may be in the form of orally-administerable suspensions or tablets? nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or
• suppositories or they may be administered transdermally.
• compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and
• these compositions may contain
• microcrystalline cellulose dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
• compositions of formula l can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions.
• the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example,
• the compounds of this invention can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
• conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin
• disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch,
• Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent, or emulsifying agent.
• diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent, or emulsifying agent.
• compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solublizing or dispersing agents known in the art.
• compositions including formula 1 and 2 may also be administered parenterally, that is, subcutaneously,
• a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-l,3-dioxolane-4- methanol, ethers such as poly (ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an
• oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil.
• Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
• Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
• Suitable soaps include fatty alkali metal, ammonium, and
• triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
• nonionic detergents for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers
• amphoteric detergents for example, alkyl-beta-aminopropionates, and 2- alkylimidazoline quarternary ammonium salts, as well as mixtures.
• compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidize and/or dissolve in the rectal cavity to release the drug.
• a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidize and/or dissolve in the rectal cavity to release the drug.
• the pharmaceutically acceptable addition salts are those salts that are not
• composition of formula I and II may independently or jointly be formulated as addition salts.
• cation salts include those of alkali metals, as for example, sodium and potassium; alkaline earth metals, such as calcium and magnesium; light metals of Group IIIA including aluminum; and organic primary, secondary and tertiary amines, as for example, trialkylamines, including triethylamine, procaine, dibenzylamine, 1-ethenamine, N,N'-dibenzylethylenediamine, dihydroabiethylamine, N-(lower)alkylpiperidine, and any other suitable amine.
• Sodium salts are preferred.
• An acceptable acid addition salt may be carried out by treating such compounds in a conventional manner with an inorganic acid or example a hydrobromic acid, sulfphuric acid, nitric acid, phosphoric acid etc., or with an organic acid such as acetic acid, citric acid, maleic acid, fumaric acid,
• Dosage levels of the order of 0.02 to 5.0 or 10.0 grams per day of the composition are useful in the treatment or prevention of the above-indicated conditions, with oral doses two to five times higher.
• infection by HIV is effectively treated by the administration of from 10 to 50 milligrams of the compound per kilogram of body weight from one to three times per day. It will be
• the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compounds employed, the metabolic stability and length of action of compounds in combination with each other, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination the severity of the particular condition, and the host undergoing therapy.
• the present invention is also directed to combinations of the HIV protease-inhibitory compounds with one or more agents useful in the treatment of AIDS, such as, for example, with known antiviral agents suitable for treating HIV 1 and HIV 2 viral infections, e.g., a ester of castanospermine of formula I with a viral protease
• glycoprotein processing inhibitor of formula I and a aspartyl protease specific inhibitor of formula II and for the preparation of a
• R 1 is a C 1-8 alkanoyl, C 1-10 alkenoyl, C 1 - 8
• R 1 is benzyl oxy, SO 2 HN, (3-pyridyl)ethyl, isoquinolyl, 4-alkoxy-
• P 2 is isopropyl, cyclopentyl,
• R 5 be methyl, 4-hydroxybutyl or 3-hydroxy- propyl and that R 6 be benzoxy or benzyl, and when R 5 and R 6 form a heterocyclic moiety with the
• compositions containing the compounds of formula I and II are those compositions which contain at least 10% of the compounds of formula I or those
• compositions that contain at least 10% of the compounds of formula II.
• the compounds of this invention may be assayed for their inhibition of HIV replication using the following published techniques.
• MT-4 cells infected with 100 TCID 50 of HIV-1 RF per 5 x 10 4 cells were added to each well at a concentration of 5 x 10 4 cells per well and after incubation at 37°C of six days, 10ul of acidified isopropanol was added and the plates read at 540nm using a Multiscan MCC/340 spectrophotometer (Flow Laboratories). The raw plate data were captured onto floppy disc using Ultroterm (LKB). Subsequent data reduction was performed using Excel (Microsoft). This enabled the mean O.D. values for each drug combination to be calculated and a series of 19 dose response curves, i.e. the dose response of each drug at a fixed concentration of the other to be generated with minimal user intervention.
• the table provides ED50 values computed from dose response lines for each compound in the presence of a fixed concentration of the other compound.
• MDL73669 [1(S)-[[3,3-difluoro-2,4,-dioxo-l-[[4-
• MDL74538 N-[4-(N-benzyloxycarbonyl-L-valyl)amino-2,2- difluoro-1,3,-dioxo-5-(4-benzyloxy)phenyl-pentyl]-(O- benzyl)-D-valinol.
• MDL28574 (Bucast)[IS-(1 ⁇ ,6 ⁇ ,7 ⁇ ,8 ⁇ ,8a ⁇ )]-octahydro-

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