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

• 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 discovered, HTLV-III, now referred to as HIV, was found to cause cell death after infection of T-lymphocytes and has been identified as the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex .(ARC) .
• AIDS acquired immune deficiency syndrome
• ARC AIDS related complex .
• Retroviruses are a class of ribonucleic acid (RNA) containing viruses that replicate by using a reverse transcriptase activity to form a strand of complementary DNA (cDNA) from which a double stranded, proviral DNA is produced. 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.
• RNA ribonucleic acid
• cDNA complementary DNA
• 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.
• the retroviral proteases also show certain commonality by their inhibition by aspartyl protease-specific inhibitors, Iyoko, et al. Nature 329, 654-67. Similarly, amino acid sequencing of the retroviral proteases show they possess sequence homology. Because of their mutual structural and functional characteristics and their obligate function, 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 intervention.
• 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 effectively inhibit HIV activities, and therefore, can be used in the prophylaxis or treatment of viral infections, particularly infections caused by HIV.
• R, Ri and R are independently hydrogen
• naphthalenecarbonyl optionally substituted by methyl or halogen
• cinnamoyl pyridinecarbonyl optionally substituted by methyl or halogen
• dihydropyridine carbonyl optionally substituted by C ⁇ _ ⁇ o alkyl
• thiophenecarbonyl optionally substituted by methyl or halogen
• furancarbonyl optionally substituted by methyl or halogen
• Y is hydrogen, C 1 - 4 alkyl, C 1 - 4 alkoxy, halogen, trifluoromethyl, C 1 -.
• 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, isobutyryl, and hexanoyl.
• the C 1 - 4 alkyl groups referred to above 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, isonicotinoyl, N-methyl-dihydro-pyridine-3-carbonyl , thiophene-2-carbonyl , thiophene-3-carbonyl , furan-2- carbonyl and furan-3-carbonyl.
• the naphthalene, pyridine, thiophene and furan groups can be optionally further substituted as indicated above.
• Preferred compounds of the present invention are those wherein R, Ri and R 2 are 1 or 2 alkanoyl, alkenoyl, or benzoyl groups with the benzoyl substituted by Y, Y' and Y" as described above, especially a C 1 -. 4 alkanoyl or a benzoyl optionally substituted with an alkyl or halogen.
• Ri is a C ⁇ _ 8 alkanoyl, C ⁇ _ 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 castanospermine ester of Claim 1 which is [lS-(l ⁇ ,6 ⁇ ,7 ⁇ ,8 ⁇ ,8a ⁇ ) ]-octahydro-1,6,7,8- indolizinetetrol 6-butanoate:
• Certain compounds are preferred. Amongst the preferred compounds of formula I is [1S- (l ⁇ ,6 ⁇ ,7 ⁇ ,8 ⁇ ,8a ⁇ ) ]-octahydro-1,6,7,8-indolizinetetrol 6- butanoate.
• i zero or one, is Q, or B, B being d with the proviso that B is other than p-hydroxy- benzyl or p-alkoxybenzyl, a is zero, or 1, 2 or 3, b is zero or 1, c is zero or 1, 2, 3, 4 or 5, d is 1 or 2, e is zero, 1 or 2,
• R is hydrogen, -CH 2 CHO, hydroxy C 1-6 alkylene, C _ 6 alkoxy C 1 _ 6 alkylene, C ⁇ _ 6 alkyl, phenyl, _T " ⁇ -(R 3 ) d or Q,
• R j ⁇ is benzyloxy, C 1-6 alkoxy, C 1-6 alkyl, phenyl, benzyl, phenethyl, fluorenylmethylenoxy, 2-isoquinolinyl, PDL, I I
• R 3 is C- j ⁇ . g allenyl C- ⁇ g alkoxy, C 1-6 alkoxy C 1 _ 6 alkylene, hydroxy C- ⁇ g alkylene, C 1 _ alkyl, H, or OH,
• R 4 is H, C- ⁇ g alkyl, phenyl or benzyl,
• R 5 is H, C ⁇ g alkyl, OH, C 1 . 6 alkoxy,-(CH 2 ) d _Q-(V) e , V being OR 4 or hydroxy C 1-6 alkylene, CH 2 Si(CH 3 ) 2 (R 3 ) , -(CH 2 ) d -Q, PDL, - alkylene-)-OR 4 or -CH(Y)(Z), Y being hydroxy C.. 5 alkylene, C- ⁇ g alkyl, oi (CH 2 -)—C 6 H 4 —tV) e , and Z being CHO, C0 2 R 4 , C0 2 NHR 4 oi (CH 2 -)—OR 4 ,
• R g is as defined for R 5 with the proviso that R 6 is other than H when R g 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 5 4-hydroxybutyl
• the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intra ⁇ muscular, transdermal, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing convention non-toxic pharma ⁇ ceutically acceptable carriers, adjuvants and vehicles.
• these compositions When administered orally as a suspension, these 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 sweetener/flavoring agents known in the art.
• 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.
• 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,
• 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.
• Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
• Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
• these compositions When rectally administered in the form of suppositories, these 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.
• 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, tartaric acid, methanesulfonic acid, p-toluenesulphonic acid.
• an inorganic acid or example a hydrobromic acid, sulfphuric acid, nitric acid, phosphoric acid etc.
• organic acid such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid, p-toluenesulphonic acid.
• 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 inhibitor of formula II.
• the present invention includes the use of a glycoprotein processing inhibitor of formula I and a aspartyl protease specific inhibitor of formula II and for the preparation of a pharmaceutical formulation for simultaneous, separate or sequential use for treating an HIV infection wherein the said compounds of formula 1 are
• Ri is a C ⁇ -8 alkanoyl, C ⁇ - ⁇ o alkenoyl, ⁇ -- alkoxyacetyl, or benzoyl optionally substituted with an alkyl or halogen group; or a pharmaceutically acceptable salt thereof and said compound of formula II is
• the compounds of this invention may be assayed for their inhibition of HIV replication using the following published techniques.
• the MTT cell viability assay (Pauwels et al., J. Virol. Methods, 1988, 20, 309-321) was used.
• Various drug combinations were achieved by creating chequerboards with one compound being titrated horizontally with the second compound being titrated vertically across a 96 well microtitre plate using multichannel pipettes.
• the use of six microtiter plates was required for each assay (only inner 60 wells) with quadruplicate wells for each drug combination. Doubling dilutions or half log dilutions, with the end rows left drug free, were usually made.
• 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 ]-(0- benzyl)-D-valinol .
• MDL28574 (Bucast) [ IS-( l ⁇ ,6 ⁇ ,7 ⁇ ,8 ⁇ ,8a ⁇ ) ]-octahydro-

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• 1993
  • 1993-02-22 GB GB939303518A patent/GB9303518D0/en active Pending
• 1994
  • 1994-01-18 AU AU60918/94A patent/AU679497B2/en not_active Ceased
  • 1994-01-18 EP EP94907268A patent/EP0684836A1/en not_active Withdrawn
  • 1994-01-18 JP JP6518971A patent/JPH08509469A/ja not_active Ceased
  • 1994-01-18 HU HU9502451A patent/HUT72493A/hu unknown
  • 1994-01-18 CA CA002155129A patent/CA2155129C/en not_active Expired - Fee Related
  • 1994-01-18 WO PCT/US1994/000710 patent/WO1994019008A1/en not_active Application Discontinuation
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• 1995
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