EP0632808A1 - Peptides antiviraux - Google Patents

Peptides antiviraux

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Publication number
EP0632808A1
EP0632808A1 EP93906535A EP93906535A EP0632808A1 EP 0632808 A1 EP0632808 A1 EP 0632808A1 EP 93906535 A EP93906535 A EP 93906535A EP 93906535 A EP93906535 A EP 93906535A EP 0632808 A1 EP0632808 A1 EP 0632808A1
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EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
compound
group
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP93906535A
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German (de)
English (en)
Inventor
Colin William Greengrass
Stephen Derek Albert Street
Peter John Whittle
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Pfizer Ltd
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Pfizer Ltd
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Priority claimed from GB929206462A external-priority patent/GB9206462D0/en
Priority claimed from GB939301638A external-priority patent/GB9301638D0/en
Application filed by Pfizer Ltd filed Critical Pfizer Ltd
Publication of EP0632808A1 publication Critical patent/EP0632808A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to certain peptide derivatives containing a heterocyclic group which are useful in the treatment or prophylaxis of human retroviral infections.
  • HIV human immunodeficiency virus
  • AIDS Abrered Immunodeficiency Syndrome
  • ARC AIDS-Related Complex
  • HIV Infection with HIV is characterised by progressive breakdown of the immune system and CNS dysfunction. Severely immune deficient patients suffer from a wide range of opportunistic infections (e.g. pneumocystis carinii, human cytomegalovirus, or Candida) , and cancers such as Kaposi's sarcoma. Loss of cells, particularly CD4 lymphocytes, following infection with HIV is an important factor in the progressive impairment of immune function. The infection of cells of monocyte/macrophage lineage with HIV also contributes to the observed pathology. Thus, successful infection of CD4 cells by HIV is a key step in the disease process.
  • HIV is a retrovirus; it encodes its genetic information in RNA, which is converted into DNA after the virus enters the host cell.
  • An essential step in the retroviral replication cycle is the processing of an initial polypeptide precursor into mature structural and replicative proteins. This processing is carried out by a virus-coded protease and, in the absence of this enzyme activity, viral replication is blocked.
  • R 1 is C ! -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl, heterocyclyl or CONR 9 R 10 ;
  • R 2 is Ci-Cg alkyl, C 3 -C 8 cycloalkyl(Cj-C 4 )alkyl, aryl(Cj-Q t )alkyl or heterocyclyl(C ⁇ C 4 )alkyl;
  • R 3 is C x -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C,-C 4 )alkyl, aryl(C,-C 4 )alkyl, aryl(C 2 -C 4 )- alkenyl, heterocyclyl(C x -C 4 )alkyl or heterocyclyl(Cj-d)- alkenyl;
  • R 4 is C ! -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl or heterocyclyl; each of R 5 , R 6 , R 7 and R 8 is independently H, 0,-Cg alkyl or C 3 -C 8 cycloalkyl; or R 5 and R 6 , or R 7 and R 8 may be joined together to form a 3 to 8 membered carbocyclic ring;
  • X is a 4-10 membered mono- or bicyclic heterocyclic group containing carbon ring atoms and one ring nitrogen atom through which the group is attached to the adjacent carbonyl group; the group may be saturated or partially unsaturated and, in addition to the -(CR 7 R 8 ) m -Het substituent, it may be substituted by up to 4 further substituents each independently chosen from F, C,-C 6 alkyl, C 3 -C 8 cycloalkyl, OR 11 or NR 9 R 10 ;
  • Het is an imidazolyl or triazolyl group either of which may optionally be substituted by C,-C 6 alkyl, C 3 -C 8 cycloalkyl, NR 9 R 10 or CONR'R 10 , each of R 9 and R 10 is independently H, C,-C 6 alkyl or C 3 -C 8 cycloalkyl,or R 9 and R 10 may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered nitrogen- containing heterocyclic group,
  • R n is H, C,-C 6 alkyl or C 3 -C 8 cycloalkyl; and n and m are each independently O, 1 or 2; wherein any alkyl or cycloalkyl group included in the aforementioned definitions may optionally be fully or partially substituted by fluorine.
  • heterocyclyl means a 4 to 6 membered heterocyclic group containing as heteroatoms up to four nitrogen atoms, or an oxygen or sulphur atom optionally with one or two nitrogen atoms.
  • the ring may be aromatic, or fully or partially saturated and may optionally be benzo-fused or substituted by C j -C,; alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkanoyl, C ⁇ C 4 alkoxy, halo, hydroxy, oxo or aryl.
  • Preferred heterocyclyl groups are pyridyl, pyrimidinyl, thienyl, isoquinolyl and tetrazolyl.
  • aryl means phenyl optionally substituted with from 1 to 3 substituents each independently selected from C,-C 6 alkyl, C 3 -C 8 cycloalkyl, C,-C 4 alkoxy, C 2 -C 5 alkanoyl, hydroxy, halo, C,-C 4 alkyl fully or partially substituted by fluorine, Cj-C 4 alkoxy fully or partially substituted by fluorine, phenyl, phenoxy, benzyl, benzoyl, phenylS0 2 -, pyridyl, tetrazolyl, phenyltetrazolyl, NR 9 R 10 or CONR ⁇ 10 ; wherein R 9 and R 10 are as previously defined.
  • Halo means fluoro, chloro, bromo or iodo.
  • the imidazolyl or triazolyl group, Het may be linked either by a ring carbon or ring nitrogen atom and may be unsubstituted or mono-, di or or tri- substituted.
  • Triazolyl includes both 1,2,3 and 1,2,4- triazolyl groups.
  • Alkyl and alkoxy groups containing 3 or more carbon atoms may be branched or straight-chain. Any alkyl, alkoxy or cycloalkyl group included in the above definitions may optionally be fully or partially substituted by fluorine.
  • bioprecursor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a compound of the formula (I) .
  • examples include ester derivatives formed between the free hydroxy group in the compound of formula (I) and, for example, an amino acid (such as L- valine) .
  • aryl is preferably phenyl and heterocyclyl is preferably oxetan-3-yl or 1,1- dioxothietan-3-yl.
  • R 1 is preferably t-butyl, isopropyl, oxetan-3-yl or 1,l-dioxothietan-3-yl and (CR 5 R 6 ) n is absent; or R 1 is phenyl and (CR 5 R 6 ) n is CH 2 ; or R 1 is H 2 NCO-, CH 3 NHCO- or (CH 3 ) 2 NCO- and (CR 5 R 6 ) n is CH 2 or CH(CH 3 ) .
  • Particularly preferred are compounds wherein R 1 is t-butyl, isopropyl or oxetan-3-yl and n is 0, most particularly where R ⁇ CR ⁇ 6 ),,- is t-butyl.
  • aryl is preferably phenyl and heterocyclyl is for example pyridyl, pyrimidinyl or thienyl.
  • R 2 is preferably aryl(C j -C 4 )alkyl; benzyl is particularly preferred.
  • aryl is preferably phenyl and heterocyclyl is preferably pyridyl, pyrimidinyl or thienyl.
  • R 4 is preferably C j -C,; alkyl; particularly preferred are isopropyl and sec-butyl (valine or isoleucine derivatives) .
  • the heterocyclic group X is preferably a 4-6 membered saturated or monounsaturated group and is most preferably an azetidine, pyrrolidine, tetrahydropyridine or piperidine group; piperidine being particularly preferred.
  • R 7 and R 8 are preferably H and is preferably O or 1.
  • aryl is phenyl, unsubstituted or substituted as defined in the term aryl above, and heterocyclyl is for example pyridyl, pyrimidinyl, isoquinolyl or thienyl.
  • R 3 is preferably aryl(C,-C 4 )alkyl or aryl(C 2 -C 4 )alkenyl; R 3 is most preferably benzyl optionally substituted in the phenyl ring by fluoro, chloro, iodo, methyl, trifluoromethyl or trifluoromethox , or R 3 is 3-phenyl-prop-2-enyl or 3-phenylpropyl.
  • Particular and preferred individual compounds include: l-[N-((R)-2-benzyl-(S)-5-(t-butoxycarbonylamino)-(S)-4- hydroxy-6-phenylhexanoyl)-(S)-valyl]-3-(imidazol-1- yl)azetidine,
  • a compound of formula (I) for use as a medicament, especially for use in the treatment or prophylaxis of human retroviral infections, in particular HIV infections.
  • the invention also includes the use of a compound of the formula (I) , or of a pharmaceutically acceptable salt thereof or bioprecursor therefor, for the manufacture of a medicament for use in the prophylaxis or treatment of retroviral infections.
  • the invention further includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) , or a pharmaceutically acceptable salt thereof or bioprecursor therefor, and a pharmaceutically acceptable diluent or carrier.
  • the antiviral activity of the compounds of general formula (I) is established using in vitro assay systems.
  • the compounds of formula (I) are able to completely protect human T-cell line H9 for 7 days from the progressive effects of HIV infection.
  • Untreated virus-infected cells display typical cytopathic effects such as formation of syncytia and cell death.
  • virus particles produced from virus-infected cells treated with a compound of formula (I) are non-infectious.
  • infections which may be treated or prevented by the compounds of formula (I) include those caused by human or animal retroviruses, especially HIV- 1.
  • Clinical conditions which may therefore be treated or prevented include AIDS, ARC, and HIV related dementia.
  • the compounds may also be used to block disease progression in symptomless infected individuals.
  • the compounds of formula (I) can be prepared using the coupling and protection techniques which are familiar to those skilled in the art of peptide chemistry.
  • intermediate (IX) can be produced by coupling of the intermediate (X) with the intermediate (VI) .
  • the intermediate (X) can be prepared from intermediate (IV) by reaction with a carboxyl protected amino acid H 2 NCH(R 4 )C0 2 R and subsequent basic hydrolysis.
  • Amide coupling reagents - e.g., l-(3-dimethylaminopropyl)-3-ethyIcarbodiimide
  • Protecting groups:- P; t-butoxycarbonyl or benzylox carbonyl are preferred
  • X is either H or a protecting group, e.g., t-butyldimethylsilyl.
  • Y is a group which is susceptible to nucleophilic displacement - succinimidooxy is preferred.
  • the starting materials of formula (V) required for the procedure described above are in some cases literature compounds or they can be prepared by routine synthetic procedures from readily available starting materials. Thus for example reaction of l(N-t- butoxycarbonyl)-3-hydroxy-azetidine with methanesulphonyl chloride followed by reaction with a compound of formula Het-H in the presence of a base gives the required compounds of formula (V) wherein X is an azetidine ring.
  • 1- (N-benzyloxycarbonyl)-4-ketopiperidine is converted to the 4-amino derivative by reaction with sodium cyanoborohydride in the presence of ammonium acetate. Subsequent reaction with dimethylformamide azine gives the 4-(l,2,4-triazol-4-yl) derivative.
  • the intermediates of formula (V) in Scheme B where does not equal 0 can be prepared by standard transformations from the appropriate precursors using, for example, nucleophilic opening of an epoxide group to introduce the Het group.
  • reaction of l-(N-t-butoxycarbonyl)-4-ketopiperidine with trimethylsulphonium iodide in the presence of a base gives the 4-spiro-2'-oxirane.
  • Reaction of this product with imidazole followed by elimination of the 4-hydroxy group gives l-(N-t-butoxycarbonyl)-4-(imidazol-l- yl)methyl-l,2,5,6-tetrahydropyridine; reduction gives the corresponding piperidine derivative.
  • N-t-butoxycarbonyl (BOC-) derivatives of the naturally occurring amino acids used in the synthesis of the compounds of the formula (VII) are commercially available as are their hydroxysuccinimido esters.
  • the corresponding intermediates derived from unnatural amino acids can be prepared by standard procedures (see, for example, . J. O'Donnell et aJL, J. Amer. Chem. Soc. , 1989, 111, 2353).
  • the compounds of formula (II) can be prepared from the corresponding t- butyloxycarbonyl-protected amino-aldehydes (see D. H. Rich et aJL, J. Org. Chem.. 1978, 4_3_, 3624 and Y.
  • Amino protecting groups having varying levels of lability can be used. Such groups are known in the art and attention is directed to the reviews by Bodansky et al., "Peptide Synthesis", 2nd Ed., John Wiley & Sons, N.Y. (1976) ; Greene, “Protective Groups in Organic Synthesis”, John Wiley & Sons, N.Y. (1981); McOmie, “Protective Groups in Organic Chemistry", Plenum Press, N.Y. (1973) ; and to Sheppard in “Comprehensive Organic Chemistry, The Synthesis and Reactions of Organic Compounds", Pergamon Press, N.Y. (1979), edited by E. Hasla , Part 23.6, pages 321-339.
  • Representative amino- ⁇ rotecting groups include, but are not limited to, ar -xycarbonyl such as benzyloxycarbonyl; sub ⁇ .tuted or unsubstituted aralkyl such as benzyl, trityl f oenzhydryl and 4-nitrobenzyl; benzylidene; arylthio such as phenylthio, nitro- phenylthio and trichloro- phenylthio; phosphoryl derivatives such as dimethylphosphoryl and 0,0- dibenzylphosphoryl; trialkylsilyl derivatives such as trimethylsilyl; and others as are described in U.S. Pat. No. 4,322,341.
  • the preferred amino protecting group for use in the above sequence is t-butoxy ⁇ carbonyl.
  • Procedures for substituting said group on a given amino group are well known. In general they comprise acylating the appropriate amino compound with the corresponding carbonyl chloride or anhydride in a reaction inert solvent, e.g. water, methylene chloride or tetrahydrofuran, in the presence of a base (acid acceptor) e.g., sodium or potassium hydroxide when water is solvent; and, when an organic solvent is used, in the presence of a tertiary amine such as a triethylamine or pyridine.
  • a reaction inert solvent e.g. water, methylene chloride or tetrahydrofuran
  • a base e.g., sodium or potassium hydroxide when water is solvent
  • a tertiary amine such as a triethylamine or pyridine.
  • pH of the reaction is typically held at about pH 8
  • hydroxy-protecting groups are also known and are described in the literative sources already cited above.
  • a preferred hydroxy protecting group is t-butyldimethylsilyl. This is introduced as previously described and is readily removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature.
  • Activation of carboxy groups as a means of expediting a given acylation reaction is also methodology known to those skilled in the art.
  • Especially useful in the herein described reaction sequence are the use of anhydrides and activated esters, particularly those esters derived from N- hydroxyphthalimide, N-hydroxysuccinimide or 1- hydroxybenzotriazole, all of which are used in peptide syntheses.
  • a dehydrative coupling agent is used to form the activated ester.
  • Such coupling agents are l-cyclohexyl-3-(2-morpholinoethyl)- carbodiimide, N,N , dicyclohexylcarbodiimide, N,N'- carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide, ethoxyacetylene, diphenylketene and N-ethyl-5-phenylisoxazoline-3' ⁇ sulfonate.
  • the reaction conditions for using such coupling agents are well described in the literature.
  • the various protecting groups can be removed by the appropriate techniques previously discussed, and the compounds of the formula (I) isolated and purified using conventional procedures such as recrystallisation or column chromatography.
  • the invention includes a process for preparing a compound of the formula (I) which comprises removing the protecting group from a compound of the formula:
  • X 1 is a selectively removable hydroxy- protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically acceptable salt thereof.
  • the preferred protecting group for X 1 is t- butyldimethylsilyl; this is removed by treatment with tetra-n-butylammonium fluoride in an organic solvent, preferably tetrahydrofuran.
  • Examples of pharmaceutically acceptable salts of the compounds (I) are acid-addition salts, e.g. sulfates, bisulfates, phosphates, lactates, esylates, fumarates, citrates, succinates and gluconates.
  • acid-addition salts e.g. sulfates, bisulfates, phosphates, lactates, esylates, fumarates, citrates, succinates and gluconates.
  • the compounds (I) will be administered by any suitable route, e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, intramuscular, or intradermal) , rectal, nasal, topical (including buccal and sublingual) or vaginal routes.
  • parenteral e.g. subcutaneous, intravenous, intramuscular, or intradermal
  • nasal including buccal and sublingual
  • vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, intramuscular, or intradermal)
  • nasal e.g. subcutaneous, intravenous, intramuscular, or intradermal
  • topical including buccal and sublingual
  • vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, intramuscular, or intradermal)
  • nasal including buccal and sublingual
  • vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, intra
  • Rectal formulations will be in suppository form, and vaginal formulations as, for example, tampons, creams or foams.
  • Parenteral formulations will be in sterile form, e.g. as vials for injection containing aqueous or non- aqueous diluents, buffers and antioxidants so that the formulation will be isotonic with blood.
  • the appropriate dose of the anti-retroviral agents of the formula (I) will be from 1-50 mg/kg/day, preferably 1-25 mg/kg/day given in up to six divided doses per day. There may be of course instances where higher or lower dosages are merited according to the age, weight, degree of illness and response of the patient, and appropriate therapy will be as determined by the medical practitioner.
  • the compounds of formula (I) may be used in combination with other drugs, some of which may potentiate their activity.
  • drugs include the following:-
  • Reverse transcriptase inhibitors such as AZT, ddl, ddC, foscarnet, TIBO compounds, dipyrido- diazepinones or 6-substituted acyclopyrimidine (HEPT) derivatives;
  • gpl20-CD4 blockers such as dextran sulphate and soluble CD4, including its combination with toxic agents such as pseudomonas toxin;
  • tat antagonists such as D-penicillamine
  • biological response modifiers including interferons, interleukins or colony stimulating factors, e.g. GM-CSF.
  • the compounds of the invention were evaluated for antiviral activity by dissolving the test compound in 50 ⁇ l of DMSO and diluting in RPMI 1640, a complex salts solution with a pH of 7.2, to 1 mg/ml. Testing was performed at 0.001, 0.01, 0.1, 1 and 10 ⁇ g/ml against HIV 1 (strain IIIB) in a human T-cell line (H9) . Untreated control infections were initiated at the same time.
  • N.M.R. (CDC1 3 ) ⁇ 1.30-1.39 (m, 3H) ; 1.43 (s, 9H) ; 2.90-3.11 (m, 2H) ; 3.37-3.38 and 4.16-4.19 (2x brm, IH) ; 3.93-4.04 (m, IH) ; 4.22-4.33 (m, 2H) ; 4.51-4.56 (m, IH) ; 4.77-4.79 and 4.87-4.90 (2 x br , IH) ; 7.24- 7.35 (m, 5H) .
  • N.M.R. (CDC1 3 ) S 1.24-1.33 (m, 3H) ; 1.39 and 1.42 (2 X s, 9H) ; 1.72-1.95 (m, 2H) ; 2.38-2.62 (m,2H); 2.77- 2.98 (m,2H); 3.02-3.04 and 3.40-3.42 (2 x m, IH exch. D 2 0) ; 3.59-3.91 (m, 2H) ; 4.08-4.22 (m, 2H) ; 4.58-4.61 and 4.86-4.89 (2 x m, IH) ; 7.22-7.37 (m, 5H) .
  • PREPARATIONS 5-13 The following compounds of formula (IV) were prepared by the procedure described in Preparation 2 but using the appropriate substituted benzyl bromide or bromomethylisoquinoline to alkylate the gamma- butyrolactone in step (a) followed by ring opening and reaction with t-butyldimethylsilylchloride as described in step (b) .
  • PREPARATIONS 19-25 The following compounds of formula (V) were prepared following the procedure described in Preparation 18 above but using the appropriate starting material from Preparations 14 to 17 and reacting with the appropriate substituted or unsubstituted imidazole or triazole. PREPARATION 26
  • the reaction mixture was stirred with hydrochloric acid (50 ml, 0.1N) for 15 minutes, ethyl acetate (50 ml) was then added and the resulting mixture stirred for 5 minutes.
  • the organic layer was separated and the aqueous layer extracted with ethyl acetate (1 x 50 ml) .
  • the combined organic extracts were washed with saturated sodium bicarbonate solution (1 x 50 ml) , then with saturated sodium chloride solution.
  • the organic layer was then dried (MgS0 4 ) and evaporated to a yellow oil, 8.0 g.
  • step (b) A stirred solution of imidazole (1.91 g) in dry acetonitrile (30 ml) under nitrogen was treated with an 80% oil dispersion of sodium hydride (0.84 g) and the resulting mixture heated to 60°C until solution occurred. After 15 minutes the product from step (a) (2.0 g) was added and the reaction maintained for 5 hours. After allowing the reaction to stand at room temperature overnight, the solvent was evaporated under vacuum and the oily residue partitioned between methylene chloride (40 ml) and water (20 ml) . The organic phase was separated and washed with water, dried (MgS0 4 ) and evaporated under vacuum.
  • step (c) A stirred solution of the product from step (b) (2.0 g) and triethylamine (5.44 ml) in dry methylene chloride (80 ml) at 0 to 5°C was treated with a solution of methanesulphonyl chloride (2.20 ml) in dry methylene chloride (10 ml) and the resulting mixture allowed to warm to room temperature and maintained for 14 hours. The reaction mixture was then washed with water, dried (MgS0 4 ) and evaporated under vacuum.
  • N.M.R. (CDC1 3 ) ⁇ 1.45 (s, 9H) ; 1.97 (m, 2H) ; 3.50 (t, 2H) ; 3.90 (s, 2H) ; 4.50 (s, 2H) ; 5.50 (s, IH) ; 6.90 (s, IH) ; 7.10 (s, IH) ; 7.55 (s, IH) .
  • N.M.R. (CDCI 3 ) ⁇ 1.15 (m, 2H) ; 1.45 (s, 9H) ; 1.58 (m, 2H) ; 1.85 (m, IH) ; 2.65 (t, 2H) ; 3.80 (d, 2H) ; 4.10 (m, 2H) ; 6.90 (s, IH) ; 7.10 (s, IH) ; 7.45 (s, IH) .
  • Imidazole (8.20 g) was stirred in dry methylene chloride (30 ml) at -10°C and thionyl chloride (4.8 ml) in dry methylene chloride (30 ml) added. The resulting slurry was allowed to warm to room temperature and after 2 hours a solution of l-(N-t-butoxycarbonyl)-4- keto-piperidine (6.0 g) in dry methylene chloride (50 ml) was added dropwise. The reaction mixture was stirred overnight and then evaporated under vacuum. Potassium carbonate (6.0 g) in water (30 ml) was added to the oily residue and the product extracted with methylene chloride (2 x 60 ml) .
  • N.M.R. (DMSO-d 6 ) ⁇ 1.82 (m, 2H) ; 2.01 (m, 2H) ; 2.83- 3.09 (m, 2H) ; 4.12 ( , 2H) ; 4.40 (m, IH) ; 5.11 (s, 2H) ; 7.28-7.45 (m, 5H) ; 8.65 (s, 2H) .
  • N.M.R. (DMSO-d ⁇ ) ⁇ 0.89 (m, 6H) ; 1.38 (s, 9H) ; 1.90 (m, IH) : 3.61-3.78 (m, IH) ; 3.92-4.10 (m, IH) ; 4.24- 4.80 (m, 3H) ; 5.19 ( , IH) ; 6.98 (s, IH) ; 7.06 (dd, IH) ; 7.38 (s, IH) ; 7.77 (s IH) .
  • PREPARATIONS 34-43 The following compounds of formula (VII) where R 4 is (S)- isopropyl and R 7 and R 8 are hydrogen were prepared following the procedure of Preparation 33 using the appropriate intermediate from Preparations 18 to 32 and coupling to N-t-butoxycarbonyl-(S)-valine N- hydroxysuccinimide ester.
  • Oxetan-3-ol (2.0 g) and N,N-diisopropylethylamine (7.76 g) were dissolved in methylene chloride (50 ml) and the solution was added dropwise to a solution of bis-trichloromethyl carbonate (2.69 g) in methylene chloride (100 ml) maintained at -20°C over a period of 15 minutes under an atmosphere of nitrogen. The solution was then stirred for a further 15 minutes at - 20 * C and N-hydroxy-succinimide (3.45 g) was added in one portion.
  • step (a) The product from step (a) (1.19 g) was dissolved in tetrahydrofuran and treated with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature. After 48 hours the solvent was removed under vacuum, the product taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate and water, dried over MgS0 4 and the solvent evaporated under vacuum.
  • Examples 14-37 The following compounds were prepared following the procedure described in Example 13 but using the appropriate protected carboxylic acid intermediate of formula (IV) and the appropriate valine or isoleucine derivative of formula (VIII) in the coupling step (a) followed by removal of the t-butyldimethylsilyl protecting group as described in step (b) .
  • the benzyloxycarbonyl protecting group was removed from 1-(N-benzyloxycarbonyl)-4-(1,2,4-triazol-4-yl)- piperidine (Preparation 32) by catalytic hydrogenation and the resulting amine product coupled to N-((R)-2- benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t- butyldimethylsilyloxy)-6-phenylhexanoyl)-(S)-valine following the procedure described for Example 1 step (a), to give l-[N-((R)-2-benzyl-(S)-5-(t-butoxy ⁇ carbonylamino)-(S)-4-(t-butyldimethylsilyloxy)-6- phenylhexanoyl)-(S)-valyl]-4-(1,2,4-triazol-4- yl)piperidine, m/e 761 (MH + ) .
  • Example 1(b) gave the title product, free base. This was dissolved in absolute ethanol and treated with a solution of 1-tartaric acid (0.14 g) in absolute ethanol. Addition of ether gave a precipitate which was filtered and dried to give the 1-tartrate salt as a colourless solid, m.p. 92-152°C (0.61 g) . Found: C,
  • step c) The product from step b) above (404 mg) and 1- isocyano-3-methyl-l-(p-toluenesulphonyl)-but-1-ene, (from Preparation 51, 150 mg) were stirred together in methanol (15 ml) with diisopropylethylamme (100 mg) for 16 hours.
  • Example 16 The product from Example 16 (4.0 g) was dissolved in methylene chloride (40 ml) and cooled in an ice bath. Trifluoroacetic acid (10 ml) was added dropwise over a period of 5 minutes and the solution stirred at 0°C for 1.5 hours. The solvent was evaporated under vacuum and the residue taken up in ethyl acetate (250 ml) and washed with 1M sodium hydroxide (50 ml) and brine (50 ml) . The organic solution was dried (MgS0 4 ) , filtered and the solvent was evaporated under vacuum.
  • step b) The product from step a) (0.818 g) was dissolved in methylene chloride (30 ml) . 3-Oxetanylcarbonyloxy- succinimide (0.344 g) was added and the solution stirred at room temperature for one hour. The solution was then washed with 0.5M sodium hydroxide (15 ml) and brine (15 ml) , dried (MgS0 4 ) , filtered and evaporated under vacuum. The resulting solid was recrystallised from ethyl acetate to give the title compound as a white solid, m.p. 201-203°C. Found: C,60.32; H,6.22;
  • EXAMPLE 36 1-TN-(S)-4-Hvdroxy-(S) -5-(isopropyloxycarbonylamino) -6- phenyl-(R)-2-(3-phenylprop-2-enyl)hexanoyl) -(S) - isoleucyl]-4-(imidazol-1-yl) iperidine; tartrate
  • the title compound was prepared by the procedure described above for Example 35, except that isopropylchloroformate was used for reaction with the amine intermediate. Purification by chromatography on silica gel eluting with methylene chloride-methanol- concentrated aqueous ammonia (97:2:1 to 95:4:1) gave the product as a colourless powder, which was recrystallised from ethyl acetate-hexane. The free base was dissolved in ethanol and treated with a solution of 1-tartaric acid. Addition of diethyl ether gave the tartrate salt as a colourless powder, m.p. 156-157°C.
  • EXAMPLE 37 1-TN-(S)-5-(t-Butoxycarbonylamino)-6-phenyl-(R)-2-(4- trifluoromethoxybenzyl)-4-((S)-valyloxy)hexanoyl)-(S)- valyll-4-(imidazol-1-yl) iperidine: tartrate a) N-Benzyloxycarbonyl-L-valine (1.03 g) and dicyclohexylcarbodiimide (0.51 g) were dissolved in dichloromethane (25 ml) and the mixture was stirred for 3 hours. The precipitated dicyclohexylurea was removed by filtration and the filtrate /aporated to a white foam.
  • This white foam was com, -led with the product of Example 16 in N,N-dimethylfo_rn_- _.de (20 ml) and 4- dimethylaminopyridine (0.025 g. added. After stirring at room temperature fcr five days the fixture was partitioned between ethyl acetate and water.
  • N.M.R. (DMSO-d 6 ) ⁇ 0.8-0.95 (m, 12H) ; 1.2 (s, 11H) ; 1.35-1.77 (m, 2H) ; 1.8-2.15 (m, 4H) ; 2.4-3.2 ( , 8H) ; 3.51 (m, IH) ; 3.8 (m, IH) ; 4.1 (m, IH) ; 4.3 ( , IH) ; 4.4-4.65 (m, 2H) ; 4.81 (m, IH) ; 6.83 (s, IH) ; 7.0-7.32 (m, 12H) ; 7.66 (d, IH) ; 7.73-8.0 (m, IH) .

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Abstract

Composés répondant à la formule (I), leurs sels pharmaceutiquement acceptables, et leurs précurseurs biologiques. Dans ladite formule (I), R1 représente alkyle C¿1-6?, cycloalkyle C3-8, aryle, hétérocyclyle ou CONR?9R10; R2¿ représente alkyle C¿1-6?, cycloalkyl(C1-4)alkyle C3-8, aryl(C1-4)alkyle ou hétérocyclyl(C1-4)alkyle; R?3¿ représente alkyle C¿1-6?, cycloalkyle C3-8, cycloalkyl(C1-4)alkyle C3-8, aryl(C1-4)alkyle, aryl(C2-4)alcényle, hétérocyclyl(C1-4)alkyle ou hétérocyclyl(C2-4)alcényle; R?4¿ représente alkyle C¿1-6?, cycloalkyle C3-8, aryle ou hétérocyclyle; R?5, R6, R7 et R8¿, chacun indépendamment des autres, représentent H, alkyle C¿1-6?, ou cycloalkyle C3-8; ou R?5 et R6, ou R7 et R8¿ sont liés l'un à l'autre et forment un carbocyle de 3 à 8 chaînons; X représente un groupe hétérocyclique mono- ou bicyclique de 4 à 10 chaînons, contenant des atomes de cycle de carbone et un atome d'azote de cycle par l'intermédiaire duquel le groupe est rattaché au groupe carbonyle voisin; le groupe peut être saturé ou partiellement insaturé et, en plus du substituant -(CR7R8)m-Het, il peut être substitué par jusqu'à 4 substituants supplémentaires sélectionnés indépendamment parmi F, alkyle C¿1-6?, cycloalkyle C3-8, OR?11 ou NR9R10¿; Het représente un groupe imidazolyle ou triazolyle dont l'un ou l'autre est éventuellement substitué par alkyle C¿1-6?, cycloalkyle C3-7, NR?9R10¿ ou CONR?9R10; R9 et R10¿, indépendamment l'un de l'autre, représentent H, alkyle C¿1-6? ou cycloalkyle C3-8, ou R?9 et R10¿ sont liés l'un à l'autre de manière à former, conjointement avec l'azote auquel ils sont liés, un groupe hétérocyclique de 4 à 8 chaînons contenant de l'azote; R11 représente H, alkyle C¿1-6? ou cycloalkyle C3-8; n et m, indépendamment l'un de l'autre, sont 0, 1 ou 2; l'un quelconque des groupes alkyle ou cycloalkyle compris dans les notations précitées étant éventuellement substitué entièrement ou partiellement par fluor. Lesdits composés sont des inhibiteurs de protéases rétrovirales utilisables dans le traitement et la prévention des infections rétrovirales chez l'homme.
EP93906535A 1992-03-25 1993-03-13 Peptides antiviraux Withdrawn EP0632808A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9206462 1992-03-25
GB929206462A GB9206462D0 (en) 1992-03-25 1992-03-25 Antiviral peptides
GB939301638A GB9301638D0 (en) 1993-01-27 1993-01-27 Antiviral peptides
GB9301638 1993-01-27
PCT/EP1993/000597 WO1993019059A1 (fr) 1992-03-25 1993-03-13 Peptides antiviraux

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CA (1) CA2131154A1 (fr)
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CA2098020C (fr) * 1991-01-02 2003-10-21 Daniel Schirlin Composes antiviraux
ES2152982T3 (es) * 1993-07-08 2001-02-16 Merrell Pharma Inc Analogos de la difluoroestatona.
ES2133573T3 (es) * 1993-09-09 1999-09-16 Merrell Pharma Inc Analogos antiviricos de difluoro estatone.
US6114380A (en) * 1995-12-18 2000-09-05 Merrell Pharmaceuticals Inc. Difluoro statone analogs
GB9601680D0 (en) 1996-01-27 1996-03-27 Pfizer Ltd Therapeutic agents
US6436960B1 (en) * 1998-02-02 2002-08-20 Lg Chemical Ltd. Farnesyl transferase inhibitors having a piperidine structure and process for preparation thereof
US6809200B2 (en) 2000-07-28 2004-10-26 Pfizer Inc. Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof
US7462639B2 (en) 2005-04-14 2008-12-09 Hoffmann-La Roche Inc. Aminopyrazole derivatives

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IL91780A (en) * 1988-10-04 1995-08-31 Abbott Lab History of the amine of the xenon-preventing xanine acid, the process for their preparation and the pharmaceutical preparations containing them
IL92011A0 (en) * 1988-10-19 1990-07-12 Abbott Lab Heterocyclic peptide renin inhibitors
CA2010531A1 (fr) * 1989-03-06 1990-09-06 Werner Neidhart Derives d'acides amines
AU5407190A (en) * 1989-04-18 1990-11-16 Upjohn Company, The Peptides having novel polar n-terminal groups
DE4001236A1 (de) * 1990-01-18 1991-07-25 Bayer Ag Neue peptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel, insbesondere als arzneimittel gegen retroviren

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NO943540L (no) 1994-11-21
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AU3748393A (en) 1993-10-21
CZ229594A3 (en) 1995-04-12
HU9402744D0 (en) 1994-12-28
RU94041225A (ru) 1996-07-20
FI944428A (fi) 1994-09-23
NO943540D0 (no) 1994-09-23
CA2131154A1 (fr) 1993-09-30
FI944428A0 (fi) 1994-09-23
SK114094A3 (en) 1995-04-12
WO1993019059A1 (fr) 1993-09-30
BR9306138A (pt) 1998-06-23

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