WO1992000750A1 - Retroviral protease inhibitors - Google Patents

Retroviral protease inhibitors Download PDF

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Publication number
WO1992000750A1
WO1992000750A1 PCT/US1991/004757 US9104757W WO9200750A1 WO 1992000750 A1 WO1992000750 A1 WO 1992000750A1 US 9104757 W US9104757 W US 9104757W WO 9200750 A1 WO9200750 A1 WO 9200750A1
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substituted
compound
alkyl
hydroxyl
unsubstituted
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PCT/US1991/004757
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English (en)
French (fr)
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Geoffrey Bainbridge Dreyer
Jeffrey Charles Boehm
Balan Chenera
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Smithkline Beecham Corporation
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Priority to JP91512663A priority Critical patent/JPH05508855A/ja
Publication of WO1992000750A1 publication Critical patent/WO1992000750A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/18—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with hydroxy groups and at least two amino groups bound to the carbon skeleton
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1782—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings
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    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1787—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings and having unsaturation outside the aromatic rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to compounds which are inhibitors of aspartic proteases, particularly of retroviruses.
  • Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals.
  • Rous sarcoma virus (RSV), murine leukemia virus (MLV), mouse mammary tumor virus (MMTV), feline leukemia virus (FeLV), bovine leukemia virus (BLV), Mason-Pfizer monkey virus (MPMV), simian sarcoma virus (SSV), simian acquired immunodeficiency syndrome (SAIDS), human Tlymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2), which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related complexes, and many others.
  • RSV Rous sarcoma virus
  • MMV murine leukemia virus
  • MMTV mouse mammary tumor virus
  • FeLV feline leukemia virus
  • BLV bovine leukemia virus
  • MPMV Mason-Pfizer monkey virus
  • SSV simian sarcoma virus
  • SAIDS simian acquired immunodefici
  • HIV-1 protease has been classified as an aspartic acid protease (Meek et al., Proc. Natl. Acad. Sci. USA. 88, 1841 (1989)).
  • the proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus.
  • retroviruses which lack the protease or contain a mutated form of it, lack infectivity. See Katoh et al., Virology. 145, 280-92(1985), Crawford, et al., J. Virol.. 53, 899-907(1985), Debouck, et al., Proc. Natl. Acad. Sci. USA. 84, 8903-6(1987). Inhibition of retroviral protease, therefore, presents a method of therapy for retroviral disease.
  • Inhibitors of recombinant HTV protease have been reported (Dreyer et al., Proc. Natl. Acad. Sci. USA. 86, 9752-56 (1989); Tomasselli et al. supra: Roberts et al., Science. 248. 358 (1990); Rich et al., J. Med. Chem..21 1285-88 (1990); Sigal et al., Eur. Pat. Appl. No. 337714; Dreyer et al. Eur. Pat. Appl. No. 352000).
  • the present invention relates to a new inhibitors of retroviral and aspartic proteases. Unlike previously described inhibitors , the
  • compounds of this invention are not analogues of peptide substrates possessing a scissile dipeptide mimetic. They also deviate substantially from peptide substrate-like structure in that they do not possess a conventional amino-to-carboxyl terminus orientation.
  • This invention comprises compounds having the structures particularly pointed out in the claims and described hereinafter which bind to retroviral proteases.
  • compounds are inhibitors of viral protease and are useful for treating disease related to infection by viruses.
  • This invention is also a pharmaceutical composition, which comprises an
  • This invention further constitutes a method for treating viral diseases, which comprises administering to a mammal in need thereof an effective amount of an
  • the compounds of this invention have the structure I or II:
  • B is, independently, an ⁇ -amino acid chosen from the group: Ala, Asn, Cys, Tip, Gly, Gln, lie, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A or the carboxy group of the adjacent residue B, whichever is appropriate, and the carboxy group of B is bonded to the amino group of the adjacent residue B or I or II, whichever is appropriate; and
  • R 4 is:
  • halogen is F, Cl, Br or I, iii) hydroxyl
  • R 10 is, independently, H or C 1 -C 4 alkyl; d) a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl: 5) phthaloyl wherein the aromatic ring is unsubstituted or substituted with one or more substitutents R 4
  • R 5 (R 6 R 7 C) m -CO- wherein m 1-3 and R 5 , R 6 , and R 7 are independently: a) hydrogen,
  • R 5 , R 6 , and R 7 may be independently joined to form a monocyclic, bicyclic, or tricyclic ring system each ring of which is C 3 -C 6 cycloalkyl;
  • R 5 (R 6 R 7 C) m W- wherein m 1-3 and W is OCO or SO 2 and R 5 , R 6 , and R 7 are as defined above, except R 5 , R 6 , and R 7 are not chlorine, fluorine or hydroxyl if they are adjacent to W;
  • R 8 -W- wherein R 8 is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazoyl;
  • R 9 -W- wherein R 9 is phenyl or naphthyl unsubstituted or substituted with one or more substituents R 4 ;
  • R 1 and R 2 are the same or different and are:
  • N-Benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R 4 ;
  • R 1 and R 2 are C 1 - C 6 alkyl.
  • R 1 and R 2 are benzyl.
  • XI and X2 are AlaAla, Val, Cbz-Val, Cbz or hydrogen.
  • X 1 and X 2 are Cbz-Val.
  • the compounds of this invention are useful in the manufacture of a medicament, in particular, for a medicament for treating infection by retroviruses.
  • C 2 symmetric peptide compounds wherein R 1 and R 2 are C 1 - C 6 alkyl or aralkyl and ⁇ 1 and X 2 are single amino acids or mono- or dipeptides; these groups may be terminally substituted by common acyl groups or blocking groups commonly used in peptide synthesis, such as t-Boc or Cbz, are also preferred.
  • pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention are considered to be any covalently bonded carriers which release the parent drug.
  • alkyl refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2-2-dimethylpropyl, n-hexyl, and the like; "alkoxy” represents an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom; "cycloalkyl” is intended to include staurated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; "alkenyl” is meant to include either straight or branched hydrocarbon chains containing one or more carboncarbon double
  • heterocycle represents a stable 5- to 7-membered mono- or bicyclic heterocyclic ring, which is either satureated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, I and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic rings may be attached to any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements including piperidinyl, piperazinyl, 2-oxopinerazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, prydiazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazoyly, furyl, tetrahydrofuryl, tetrahydrophyranyl, thienyl, thiamorpholinyl sulfoxide,
  • any variable e.g., A, B, R 1 , R 2 , R 3 , ..., R 17 , heterocycle, substituted phenyl, etc.
  • its definition on each occurence is independent of its definition at every other occurence.
  • combination of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a geminal diol for example when R6 and R7 are simultaneiously hydrowyl, is meant to be equivalent with a carbon-oxygen double bond.
  • Other abbreviations and symbols commonly used in the art used herein to describe the peptides include the following:
  • Glutamine or Glutamic Acid Glx In accordance with conventional representation, the amino terminus is on the left and the carboxy terminus is on the right. All chiral amino acids (AA) can occur as racemates, racemic mixtures, or individual enantiomers or diasteriomers, with all isomeric forms being included in the present invention.
  • ⁇ -Ala refers to 3-amino propanoic acid.
  • Boc refers to the t-butyloxycarbonyl radical
  • Cbz refers to the carbobenzyloxy radical
  • i-Bu refers to isobutyl
  • Ac refers to the acetyl
  • Ph refers to phenyl
  • DCC refers to
  • DMAP refers to dimethylaminopyridine
  • HOBT refers to 1-hydroxybenzotriazole
  • NMM is N-methylmorpholine
  • DTT is dithiothreitol
  • EDTA is ethylenediamine tetraacetic acid
  • DIE A is diisopropyl ethylamine
  • DBU is 1, 8 diazobicyclo [5.4.0] undec-7-ene
  • DMSO is dimethylsulfoxide
  • DMF is dimethyl formamide
  • THF is tetrahydrofuran.
  • HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.
  • peptide moieties denoted by X 1 and X 2 are generally dipeptides or smaller. However, longer peptides which encompass the residues defined herein are also believed to be active and are considered within the scope of this invention.
  • residues or end groups may be used to confer favorable
  • hydrophilic residues may be used to confer desirable solubility properties or D-amino acids at the carboxy terminus may be used to confer resistance to exopeptidases.
  • the diepoxide 10 can then be reacted with NaN 3 in DMF to provide the resulting dihydroxy terminal diazide, which is convened to the protected diaziridine, 1.2:4,5-Di-(N-benzyloxycarbonylimino)-3-(O-benzyl)pentanol, by dimesylation of the dihydroxy terminal diazide followed by reduction with LiAIH 4 with concommitant diaziridine formation followed by reaction with benzylchloroformate.
  • the resulting diaziridine is reacted with appropriate nucleophiles such as (CH 3 ) 2 CuLi, to introduce the side-chain groups R 1 (Scheme 1).
  • cuprate reagents R 12
  • CuLi or alkynylaluminum reagents to introduce the side-chain groups R 1 (Scheme 2).
  • the resulting diol product is converted to the corresponding diamine with inversion of configuration at the alcohol carbons.
  • Compound I in which R 12 is NH-A can be prepared from the diepoxide 10 by reaction with NaN 3 in DMF to provide the resulting dihydroxy terminal diazide, which is convened to the corresponding tetraazide with inversion of configuration at the alcohol carbons as described above, and subsequently to the corresponding tetraamine.
  • groups R 1 R 2 in compounds I in which R 1 is N(R 10 ) 2 , NR 15 R 16 , R 5 -(R 6 R 7 C) m V- or
  • R 5 (R 6 R 7 C) m -S(O) n - can be introduced by reaction of diepoxide 10 with the appropriate oxygen, nitrogen, or thiol nucleophile, with subsequent thiol oxidation as necessary;
  • compounds represented by I can be prepared from protected alpha-amino aldehydes P 2 NHCH(R 1 )CHO.
  • the required N-protected alpha-amino aldehydes are readily prepared from the respective N-protected alpha-amino acids P 2 NHCH(R 1 )CO 2 H, for example by reduction of the corresponiding esters with diisobutyl aluminum hydride, by reduction of the derived N-methyl, N-methoxy amides P 2 NHCH(R 1 )CONme(OMe) with LiAlH 4 (Fehrentz and Castro, Synthesis 676 (1983)), or by reduction to the N-protected alpha-amino alcohol followed by oxidation with DMSO-(COCl) 2 or SO 3 -pyridine (Review: Jurczak and Golebiowski, Chem Rev.
  • the amino protecting group, P 2 is t-Boc-, Cbz-, p-toluenesulfonyl or another standard protecting group chosen as well known in the peptide art.
  • the synthesis of I proceeds via preparation of an intermediate P 2 NH(R 1 )CH(OH)CH(R 2 )COQ by aldol condensation with an acyl derivative, R 2 CH 2 COQ, under the conditions of Evans et al. (Evans, Ennis and Mathre, L
  • Synthesis of compounds represented by formula II is achieved by oxidation of the central hydroxyl group within the corresponding compounds I, as is well known in the art.
  • Useful oxidation reagents include, but are not limited to, Jones Reagent, (COCl) 2 -DMSO, pyridinium dichromate, and pyridinium chlorochromate.
  • Either enantiomer of compounds of structures I and II can be prepared from the respective enantiomer of arabitol by the procedures shown in Schemes 1-2.
  • this invention is a process for preparing a compound of the formula:
  • N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R 4 ;
  • R" is a hydroxyl protecting group
  • R"' and R'v are hydrogen, an amino-protecting group or taken together are N 2 , which comprises
  • Hydroxyl protecting groups are those groups which are commonly used in the a mask the reactivity of the hydroxyl group, while also capable of being selectively removed to regenerate the hydroxyl group. Typically, the oxygen-hydrogen bond is replaced by oxygen-carbon bond.
  • Useful hydroxyl protecting groups rre described in Greene, T.W. Protective Groups in Organic Synthesis. John Wiley & Sons, New York (1981), but many others are well known in the an.
  • the arylmethyl ethers, substituted or unsubstituted, are one particularly useful class of groups for protecting the hydroxyl group.
  • the benzyl protecting group optionally with substituents upon the aryl ring, is useful.
  • Z is hydrogen, an alkali metal, such as Li, Na or K, or an earth metal such as magnesium, or a transition metal, such as copper, aluminum, titanium, zinc or cadmium, or a species derived therefrom.
  • R'-Z are optionally substituted alkyl, aryl or heteroaryl lithium, alkyl, aryl or heteroaryl magnesium halides (eg. Grignard reagents), lithium dialkyl cuprate, lithium diaryl cuprate, or the alkali metal salts of optionally substituted alkyl alcohols, phenols or benzyl alcohols. Lithium diphenyl cuprate is especially useful.
  • the hydroxyls are converted to suitable displaceable groups, such as mesylate, tosylate, brosylate, benzoate, acetate and halide, by methods common in the art.
  • suitable displaceable groups such as mesylate, tosylate, brosylate, benzoate, acetate and halide.
  • the tosyl group is especially suitable and is formed by reacting the hydroxyl groups with tosyl chloride, for instance.
  • Suitable nitrogen nucleophiles are those which are able to react with a displaceble group.
  • Unhindered organic amines or heterocyles, metal salts of amines, heterocycles or azide are useful.
  • an nitrogen containing group of the formula R'"R'vN-Z, wherein Z is as defined above and R'" and R'v are hydrogen, an amino-protecting group or taken together are N 2 (eg. azide) are useful.
  • a metal azide such as sodium or potassium azide, is preferable. Subsequent reduction of the azido groups provides amino groups.
  • Particularly useful intermediate compounds of this invention are:
  • R' and R" are as defined above.
  • the compounds of this invention are prepared by the solid phase technique of Merrifield (J. Am. Chem. Soc.85 2149 (1964), or preferably by solution methods known to the art.
  • a combination of solid phase and solution synthesis may be used, as in a convergent synthesis in which di-, tri-, or tetra-peptide fragments may be prepared by solid phase synthesis and either coupled or further modified by solution synthesis.
  • the methods of peptide synthesis generally set forth in J. M. Stewart and J. D. Young, "Solid Phase Peptide Synthesis”. Pierce Chemical Company, Rockford, 11 (1984) or M. Bodonsky, Y.A. Klauser and M. A. Ondetti, "Peptide Synthesis” .
  • Each amino acid or peptide is suitably protected as known in the peptide art.
  • the Boc- or carbobenzyloxy-group is preferred for protection of the amino group, especially at the ⁇ position.
  • a benzyl group or suitable substituted benzyl group is used to protect the mercapto group of cysteine, or other thiol containing amino acids; or the hydroxyl of serine or threonine.
  • the tosyl or nitro group may be used for protection of the guanidine of Arg or the imidazole of His, and a suitably substituted carbobenzyloxy group or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or the ⁇ -amino group of lysine.
  • Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group.
  • Cysteine and other sulfur-containing amino acids may also be protected by formation of a disulfide with a thioalkyl or thioaryl group.
  • the protective groups are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment as known in the art.
  • the peptide is built up sequentially starting from the carboxy terminus and working toward the amino terminus of the peptide.
  • Solid phase synthesis is begun by covalently attaching the C terminus of a protected amino acid to a suitable resin, such as a benzhydrylamine resin (BHA), methylbenzhydrylamine resin (MBHA) or chloromethyl resin (CMR), as is generally set forth in U.S. Patent No.
  • a BHA or MBHA support resin is used for the carboxy terminus of the product peptide is to be a carboxamide.
  • a CMR support is generally used for the carboxy terminus if the produced peptide is to be a carboxyl group, although this may also be used to produce a carboxamide or ester.
  • Modification of the terminal amino group of the peptide is accomplished by alkylation or acetylation as is generally known in the art. These modifications may be ca ⁇ ied out upon the amino acid prior to incorporation into the peptide, or upon the peptide after it has been synthesized and the terminal amino group liberated, but before the protecting groups have been removed.
  • acetylation is carried out upon the free amino group using the acyl halide, anhydride or activated ester, of the corresponding alkyl acid, in the presence of a tertiary amine.
  • Mono-alkylation is carried out most conveniently by reductive alkylation of the amino group with an appropriate aliphatic aldehyde or ketone in the presence of a mild reducing agent, such as lithium or sodium cyanoborohydride.
  • Dialkylation as well as quatemization may be carried by treating the amino group with an excess of an alkyl halide in the presence of a base.
  • Solution synthesis of peptides is accomplished using conventional methods used to form amide bonds.
  • a protected Boc-amino acid which has a free carboxyl group is coupled to a protected amino acid which has a free amino group using a suitable carbodiimide coupling agent, such as N, N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP).
  • a suitable carbodiimide coupling agent such as N, N' dicyclohexyl carbodiimide (DCC)
  • catalysts such as 1-hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP).
  • HOBT 1-hydroxybenzotriazole
  • DMAP dimethylamino pyridine
  • a protected Boc-amino acid or peptide is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran (THF), in the presence of a base, such as N-methyl morpholine, or a trialkyl amine, with isobutyl chloroformate to form the mixed anhydride, which is subsequently reacted with the free amine of a second protected amino acid or peptide.
  • anhydrous solvent such as methylene chloride or tetrahydrofuran (THF)
  • a base such as N-methyl morpholine, or a trialkyl amine
  • the peptide formed by these methods may be deprotected selectively, using conventional techniques, at the amino or carboxy terminus and coupled to other peptides or amino acids using similar techniques.
  • the protecting groups may be removed as hereinbefore described, such as by hydrogenation in the presence of a palladium or platinum catalyst, treatment with sodium in liquid ammonia, hydrofluoric acid, trifluoroacetic acid or alkali.
  • Esters are often used to protect the terminal carboxyl group of peptides in solution synthesis. They may be converted to carboxylic acids by treatment with an alkali metal hydroxide or carbonate, such as potassium hydroxide or sodium carbonate, in an aqueous alcoholic solution. The acids may be converted to other esters via an activated acyl intermediate as previously described.
  • the amides and substituted amides of this invention are prepared from carboxylic acids of the peptides in much the same manner.
  • ammonia or a substituted amine may be reacted with an activated acyl intermediate of an amino-protected ⁇ -amino acid or oligopeptide to produce the amide.
  • Use of coupling reagents, such as DCC, is convenient for forming substituted amides from the carboxylic acid itself and a suitable amine.
  • the methyl esters of this invention may be converted to the amides, or substituted-amides, directly by treatment with ammonia, or a substituted amine, in methanol solution.
  • a methanol solution of the methyl ester of the peptide is saturated with ammonia and stirred in a pressurized reactor to yield the simple carboxamide of the peptides.
  • compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipient such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • a preferred composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier.
  • the liposome may be formed by dispersion of the compounds in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization.
  • a suitable method of making such compositions is more fully disclosed in copending Application Serial No. 06/763,484 and is incorporated herein by reference.
  • Such a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus.
  • CD-4 T-cell glycoprotein or a derivative thereof, such as sCD-4 (soluble CD-4), which is reactive with the glycoprotein coat of the human immunodeficiency virus (HIV).
  • sCD-4 soluble CD-4
  • HAV human immunodeficiency virus
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup or oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glycerol monostearate or glycerol distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • a pulverized powder of the compounds of this invention may be combined with excipient such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipient such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
  • This invention is also a method for treating viral infection, particularly infection by retroviruses, which comprises administering a compound of formula I to a patient infected with a susceptible virus.
  • the method is particularly applicable to infection by the Human Immunodeficiency Virus, type 1.
  • the method of treatment comprises the administration orally, parenterally, bucally, trans-dermally, intravenously, intramuscularly, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical cairier.
  • Dosage units of the active ingredient are selected from the range of 0.05 to 50 mg/kg of body weight Dosage units will typically be from 50 to 1000 mg. These dosage units may be administered one to ten times daily for acute or chronic infection. The dosage will be readily deterimined by one skilled in the art and will depend upon the age, weight and condition of the patient, and the route of administration. Combination therapy as described in Eur. Pat. Appl. No. 337714 at pages 42-47 are included herein.
  • Benzyl trichloroacetimidate (29.1 mL, 201 mmol) was added to a solution of D-(+)-arabitol (13.9 g, 91.4 mmol; azeotropically dried with toluene) in dry acetonitrile (200 mL) under Ar, and the mixture was stirred overnight.
  • the solution was concentrated by rotary evaportion, dissolved in ethyl acetate (500 mL), washed with 5% NaHCO 3 (2 ⁇ 30 mL) and brine (30 mL), dired over Na 2 SO 4 and concentrated.
  • step (f) is stirred with 20% Pd(OH) 2 on carbon (50% by weight) in
  • step (k) (87 mg, 0.37 mmol) in 6 mL DMF was added 221 mg (0.75 mmol) carbobenzyloxyalanylalanine, 115 mg (0.75 mmol) HOBT, and 154 mg (0.75 mmol) DCC. The mixture was stirred overnight, then was concentrated, taken up in ethyl acetate, filtered, washed with water and brine and dired (MgSO4). Removal of solvent followed by MPLC (silica; 2% methanol in CH2CI 2 ) provided the titled compound (109 mg).
  • step (a) To the product 19 of step (a) (4.5 mg) in 1 mL DMF was added 10 mg to 20% Pd(OH) 2 on carbon. The mixture was stined under 1 atmosphere of H 2 for 6 hr, then was filtered and concentrated to provide the titled compound 2 (3 mg) wherein X 1 and X 2 are AlaAla and R 1 and R 2 are ethyl.
  • step (a) To the product 21 of step (a) (105 mg, 0.38 mmol) in CH2CI 2 (1 mL) was added 55 mg Ir(COD)Py(PCy)3PF 6 (Crabtree catalyst). The mixture was stirred for 6 hr under 1 atmosphere H 2 , then was filtered and concentrated to provide the titled compound 22 (110 mg, 100% yield).
  • 1 HNMR (CDCI 3 ): ⁇ 7.3(5H, m), 4.6(1H, dd; J 12 Hz), 4.0(2H, m), 3.1(1H, br s), 2.7(2H, br s), 2.0-l.l(6H, m), 1.0-0.8(12H, m).
  • step (c) To the product 23 of step (c) (210 mg) in 2 mL DMF was added 870 mg ( 15 mmol)
  • step (d) To the product 24 of step (d) (52 mg, 0.15 mmol) in THF (3 mL) was added 80 mg LiAlH 4 (2 mmol) at 0 °C. The mixture was stirred at 25 °C overnight, then was quenched with IN NaOH and diluted with ether (50 mL). Filtration and concentration provided the titled compound 25 (44 mg) as a colorless oil.
  • 1 HNMR (CDCI 3 ): ⁇ 7.3(5H, m), 4.6(2H, dd; J 12 Hz), 3.1(1H, m), 3.05-2.95(2H, m), 1.9-1.1(6H, m), 1.0-0.8(12H, m).
  • step (e) (44 mg, 0.15 mmol) in 2 mL DMF was added 110 mg Cbz-AlaAla (0.375 mmol), 58 mg (0.375 mmol HOBT, and 72 mg (0.375 mmol) DCC. The mixture was stirred for 48 hr at 25 °C, then was diluted with 20 mL ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by MPLC (gradient, 0-5% methanol in CH 2 CI 2 ) to provide the titled compound 26 (24 mg).
  • MPLC gradient, 0-5% methanol in CH 2 CI 2
  • step (a) To the product 26 of step (a) (12 mg) in 2 mL DMF was added 50 mg of 20% Pd(OH)2 on carbon. The mixture was stirred under 1 atmosphere of H2 for 10 hr, tiien was diluted with methanol, filtered and concentrated to provide the tided compound 6 (7.5 mg) wherein X 1 and X 2 are AlaAla and R 1 and R 2 are isobutyl.
  • the residual oil was filtered thro silica gel (first eluted with hexane to remove unreacted benzyl bromide and then ethyl acetate Hexane ,1:4) to yield 9.0 g of the bisepoxide as a slight oil. Further purification was acheived by flash chromatography (silica, ethyl acetate,hexane 1:10) to give 6.10 g of the diepoxide 33.
  • the tided product was prepared by the mixed anhydride method from 37 mg (0.107 mmol) of the diamine hydrochloride, 150 mg of Cbz-Val, 98 ⁇ L of N-methyl morpholine and 80 ⁇ L of isobutyl chloroformate 68 mg of a white solid.
  • Analytical samples were prepared by flash column chromatography ( silica, 10% MeOH/CH 2 Cl 2 ).
  • Methanesulfonyl chloride (0.3 mL) was added dropwise to diol 45 (93 mg) in pyridine (1 mL) at 0°C. The mixture was allowed to warm to 25°C. After 12 hr the mixture was diluted with cold 6N HCl (10 mL) and extracted with CH 2 CI 2 . The organic extract was washed with 3% NaHCO 3 , dried over MgSO 4 , and concentrated. The residue was purified by flash chromatography to provide die tided compound (83 mg, 56% yield).
  • MENDT buffer 50 mM Mes (pH 6.0; 2-(N- morpholino) ethanesulfonic acid), 1 m
  • reaction mixtures 37°C were quenched after 10-20 minutes with an equal volume of cold 0.6 N trichloroacetic acid, and, following centrifugation to remove precipitated material, peptidolysis products were analyzed by reverse phase HPLC (Beckman Ultrasphere ODS, 4.5 mm ⁇ 25 mm; mobile phase; 5-20% acetonitrile/H 2 O - .1% TFA 915 min.), 20% acetonitrile/H 2 O - .1% TFA (5 min) at 1.5 mL/min, detection at 220 nm.
  • reverse phase HPLC Beckman Ultrasphere ODS, 4.5 mm ⁇ 25 mm; mobile phase; 5-20% acetonitrile/H 2 O - .1% TFA 915 min.
  • 20% acetonitrile/H 2 O - .1% TFA 5 min at 1.5 mL/min, detection at 220 nm.
  • the compounds of mis invention prefferably have Ki values less than 50 ⁇ M, preferably less than 10 ⁇ M and more preferably less than 1 ⁇ M.

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IE912380A1 (en) 1992-01-15
AU8233491A (en) 1992-02-04
EP0538366A1 (en) 1993-04-28
CA2086414A1 (en) 1992-01-07
ZA915269B (en) 1992-08-26
MX9100119A (es) 1992-02-28
JPH05508855A (ja) 1993-12-09
EP0538366A4 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1994-04-20

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