AU8233491A - Retroviral protease inhibitors - Google Patents

Retroviral protease inhibitors

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Publication number
AU8233491A
AU8233491A AU82334/91A AU8233491A AU8233491A AU 8233491 A AU8233491 A AU 8233491A AU 82334/91 A AU82334/91 A AU 82334/91A AU 8233491 A AU8233491 A AU 8233491A AU 8233491 A AU8233491 A AU 8233491A
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Prior art keywords
substituted
compound
alkyl
hydroxyl
unsubstituted
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AU82334/91A
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Jeffrey Charles Boehm
Balan Chenera
Geoffrey Bainbridge Dreyer
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • 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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    • C07C233/35—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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    • C07C233/35—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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    • C07C237/02—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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    • C07C237/22—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
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    • 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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    • C07C271/10—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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    • C07C311/15—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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    • 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
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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 System
    • 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, i.e. RP(=X)(XH)2 (X = S, 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
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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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    • 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
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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

Description

TITLE RETROVIRAL PROTEASE INHIBITORS
BACKGROUND OF THE INVENTION
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. They are believed to be the causative agents in pathological states associated with infection by 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. Although the pathogens have, in many of these cases, been isolated, no satisfactory method for treating this type of infection has been developed. Among these viruses, the HTLV and HIV have been especially well characterized.
Critical to the replication of retroviruses is the production of functional viral proteins. Protein synthesis is accomplished by translation of the open reading frames into polyprotein constructs, corresponding to the gag, pol and env reading frames. The gag and pol precursor proteins, are processed by a viral protease into the functional proteins. The 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. In fact, it has been demonstrated that 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.
Methods to express retroviral proteases in E. coli have been disclosed (Debouck, et al., Proc. Natl. Acad. Sci. USA. 8903-06(1987) and Tomasselli et al., Biochemistry. 29, 264-9 (1990) and refs. therein).
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). Moreover, certain of these inhibitors have been shown to be potent inhibitors of viral proteolytic processing in cultures of HlV-1 infected T-lymphocytes (Meek et al., Nature (Londonl. 343.90 (1990) and by Roberts et al. supra ).
The limitations of current strategies for aspartic protease inhibition include (1) oral bioavailability; (2) plasma clearance lifetimes (e.g., through biliary excretion or
degradation); (3) selectivity of inhibition; and (4) in the case of intracellular targets, membrane permeability or cellular uptake. 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.
SUMMARY OF THE INVENTION
This invention comprises compounds having the structures particularly pointed out in the claims and described hereinafter which bind to retroviral proteases. These
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
aforementioned compound and a pharmaceutically acceptable carrier therefor.
This invention further constitutes a method for treating viral diseases, which comprises administering to a mammal in need thereof an effective amount of an
aforementioned inhibitor compound. DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention have the structure I or II:
wherein X1 and χ2 are the same or different and are A-(B)n- where n = 0-2; and
B is, independently, an α-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
A is covalently attached to the amine group of the adjacent residue B or to the amine group of I or II if n=0, and is:
1) trityl,
2) hydrogen,
3) C1-C6 alkyl,
4) R3-CO- wherein R3 is:
a) hydrogen,
b) C1 - C6 alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms,
c) phenyl or naphthyl unsubstituted or substituted with one or more substituents R4, wherein R4 is:
i) C1 - C4 alkyl,
ii) halogen, whrein halogen is F, Cl, Br or I, iii) hydroxyl,
iv) nitro,
v) C1 - C3 alkoxy, or
i) -CO-N(R10)2 wherein R10 is, independently, H or C1-C4 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 R4
6) R5(R6R7C)m-CO- wherein m = 1-3 and R5, R6, and R7 are independently: a) hydrogen,
b) chlorine or fluorine,
c) C1 - C3 alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl,
e) phenyl or naphthyl unsubstituted or substituted with one or more substitutents R4,
f) C1 - C4 alkoxy,
g) a 5-7 member heterocycle,
h) R5, R6, and R7 may be independently joined to form a monocyclic, bicyclic, or tricyclic ring system each ring of which is C3-C6 cycloalkyl;
7) R5(R6R7C)mW- wherein m = 1-3 and W is OCO or SO2 and R5, R6, and R7 are as defined above, except R5, R6, and R7 are not chlorine, fluorine or hydroxyl if they are adjacent to W;
8) R8-W- wherein R8 is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazoyl;
9) R9-W- wherein R9 is phenyl or naphthyl unsubstituted or substituted with one or more substituents R4;
10) R5-(R6R7C)m -P(O)(OR11)- wherein R11 is C1 - C4 alkyl or phenyl;
11) R8-P(O)(OR11)-; or
12) R9-P(O)(OR11)-;
R1 and R2 are the same or different and are:
1) -CH2R12 wherein R12 is
a) NH-A wherein A is defined as above;
b) R5-(R6R7C)m-;
c) R5-(R6R7C)mV- wherein V is O or NH, except R5, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to V,
d) R5-(R6R7C)m-S(O)n- wherein m = 1-3 and n = 0-2 and R5, R6, and R7 are as defined above except R5, R6, and R7 are not hydroxyl, chlorine or fluorine if they are adjacen to sulfur,
e) R8-S(O)n-,
f) R9-S(O)n-,
g) (R13O)P(O)(OR14)- wherein R13 and R14 are, independently: i) C1 - C6 alkyl,
ii) C3 - C6 cycloalkyl,
iϋ) H,
iv) R9
v) R8,
h) R13P(O)(OR14)-,
i) N(R10)2, j) NR15R16 wherein R15 and R16 are joined to form a 4-6 membered saturated nitrogenous heterocycle including:
i) azetidinyl,
ii) pyrrolidinyl,
iii) piperidinyl,
iv) morpholinyl,
k) R17OCH2θ wherein R17 is:
i) C1 - C6 alkyl,
ϋ) R9,
iii) CH2Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle,
l) R17OCH2CH2OCH2,
m) N-imidazolyl where the imidazole ring is unsubstituted or substituted by a substituent R4,
n) N-Benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R4;
o) C2 - C6 alkynyl, optionally substituted with one or more groups R9; or
p) C2 - C6 alkenyl, optinally substituted with one or more gropus R9; 2) hydrogen,
3) C1 - C6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups,
4) C3 - C7 cycloalkyl; and pharmaceutically acceptable salts thereof.
Peptide compounds of the foregoing description are prefeired which are C2 symmetric wherein X1=X2, and R1=R2.
Suitably the compound has structure I and R1 - R2 and X1 = X2.
Suitably R1 and R2 are C1 - C6 alkyl. Preferably R1 and R2 are benzyl.
Suitably XI and X2 are AlaAla, Val, Cbz-Val, Cbz or hydrogen. Preferably X1 and X2 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.
C2 symmetric peptide compounds wherein R1 and R2 are C1 - C6 alkyl or aralkyl and χ1 and X2 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. Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the parent drug.
As used herein except where noted, the term "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 bonds which may occur at any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, 2-methyl propenyl, and the like; "alkynyl" refers to either a straight or branched hydrocarbon chain or the indicated number of carbon atoms which contains a carbon-carbon triple bond which may occur at any stable piont along the chain, such as ethylyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-methyl-3-propynyl, and the like.
As used herein except where noted, the term "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. Examples of such 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, thiamorpholinyl sufone, and oxadiazolyl.
When any variable (e.g., A, B, R1, R2, R3, ..., R17, heterocycle, substituted phenyl, etc.) occurs more than one time in any constituent or in formula I or II, its definition on each occurence is independent of its definition at every other occurence. Also, combination of substituents and/or variables are permissible only if such combinations result in stable compounds. By convention used herein, 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:
Amino acid three letter code Amino acid three letter code Alanine Ala Leucine Leu
Arginine Arg Lysine Lys
Asparagine Asn Methionine Met
Aspartic Acid Asp Phenylalanine Phe
Cysteine Cys Proline Pro
Glutamine Gin Serine Ser
Glutaminic Acid Glu Threonine Thr
Glycine Gly Tryptophan Tip
Histidine His Tyrosine Tyr
Isoleucine Ile Valine Val
Asparagine or Aspartic Acid Asx
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. β-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
dicyclohexylcarbodiimide, 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 and THF is tetrahydrofuran. HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.
The peptide moieties denoted by X1 and X2 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.
The selection of residues or end groups may be used to confer favorable
biochemical or physico-chemical properties to the compound. The use of 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.
Synthesis of componds I in which R1 = R12CH2, R1 = R2, and X1 = X2 isachieved from D-(+)-arabitol (Schemes 1-2). Thus, D-(+)-arabitol is convened to 1,2:4,5- Dianhydro-3-(O-benzyl)-D-(+)-arabitol (10) as described by S.L. Schreiber, T. Samnakia and D.E. Uehling, J. Org. Chem. 54, 15-16 (1989). The diepoxide 10 can then be reacted with NaN3 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 LiAIH4 with concommitant diaziridine formation followed by reaction with benzylchloroformate. The resulting diaziridine is reacted with appropriate nucleophiles such as (CH3)2CuLi, to introduce the side-chain groups R1 (Scheme 1). This procedure is especially suited to the preparation of compound I where R1 = CH2R12 where R12 is hydrogen or is a group that foπns a stable and reactive cuprate reagent, such as methyl, butyl, isopropyl, or other alkyl, alkenyl or aryl which is optionally substituted, for example with fluorine or alkoxy or protected hydroxyl.
Alternatively, compounds represented by formula I in which R1 = R12CH2, R1 =
R2, and X1 = X2 can be prepared from the diepoxide 10 by reaction with appropriate carbon nucleophiles such as cuprate reagents (R12)2 CuLi or alkynylaluminum reagents to introduce the side-chain groups R1 (Scheme 2). This procedure is also especially suited to the preparation of compound I where R1 = CH2R12 where R12 is a group that forms a stable and reactive cuprate reagent, as described above. The resulting diol product is converted to the corresponding diamine with inversion of configuration at the alcohol carbons. One way in which this is accomplished is via conversion of the diol to the dimesylate, by reaction with methanesulfonyl chloride and triethylamine, followed by displacement with NaN3 in DMF to provide the substituted 2,4-diazido-3-benzyloxypentane; conversion to the 2,4-diamino derivative follows by reduction with a hydride reagent such as LiAIH4 or by catalytic hydrogenation with a catalyst such as Pd(O) or Raney-Ni to provide the core structure I (Scheme 2). Introduction of the groups X1 = X2 is accomplished by standard condensation reactions as are well known in the an.
Compound I in which R12 is NH-A can be prepared from the diepoxide 10 by reaction with NaN3 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. Selective reaction of the terminal amines with groups A or with protecting groups such as Boc or Cbz is then followed by introdution of the groups χ1 = X2. In a related fashion, groups R1 = R2 in compounds I in which R1 is N(R10)2, NR15R16, R5-(R6R7C)mV- or
R5(R6R7C)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;
reaction of diepoxide 10 with the appropriate phosphorus nucleophile in an Arbuzov or Michaelis-Arbuzov reaction allows introduction of gropus R1 = R2 which are
(R13O)P(O)(OR14)- or R13P(O)(OR14)-.
Alternatively, compounds represented by I can be prepared from protected alpha-amino aldehydes P2NHCH(R1)CHO. The required N-protected alpha-amino aldehydes are readily prepared from the respective N-protected alpha-amino acids P2NHCH(R1)CO2H, for example by reduction of the corresponiding esters with diisobutyl aluminum hydride, by reduction of the derived N-methyl, N-methoxy amides P2NHCH(R1)CONme(OMe) with LiAlH4 (Fehrentz and Castro, Synthesis 676 (1983)), or by reduction to the N-protected alpha-amino alcohol followed by oxidation with DMSO-(COCl)2 or SO3-pyridine (Review: Jurczak and Golebiowski, Chem Rev. 89. 149 (1989)). Generally the amino protecting group, P2, 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 P2NH(R1)CH(OH)CH(R2)COQ by aldol condensation with an acyl derivative, R2CH2COQ, under the conditions of Evans et al. (Evans, Ennis and Mathre, L
Am. Chem. Soc. 104, 1737-39 (1982); Review: Evans, Nelson and Taber, in Topics in Stereochemistry. Vol. 13; Allinger, Eliel, Wilen, eds.; Wiley, 1982; pp 1-114.), where Q is a chiral auxiliary used to direct the stereochemical outcome of the aldol reaction and is often the oxazolidinone derived from valinol, norephedrine, orphenylalanol. Hydroxyl protection with a protecting group P1 such as TBDMS or benzyl and subsequent hydrolytic removal of the group Q yields the intermediate P2NH(R1)CH(OP1)CH(R2)CO2H, which is subjected to Curtius rearrangement (Reviews: Banthoipe, in Patai, "The Chemistry of the Azido Group." pp. 397-405, Interscience Publishers, NY, 1971; Smith, Org. React. 3, 337-449 (1946)) to provide the compound P2NH(R1)CH(OP1)CH(R2)NH2 which is an unsymmetrically protected fσim of I. This route is versatile in that it allows access to all steroisomers of compounds I and to unsymmetrical compounds I, in which R1, R2 aredifferent and X1, X2 are different.
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.
Accordingly, in another aspect, this invention is a process for preparing a compound of the formula:
wherein R' is
1) a) NH-A wherein A, R5- R10 and m are as defined for formula I;
b) R5-(R6R7C)m-;
c) R5-(R6R7C)m V- wherein V is O or NH, except R5, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to V,
d) R5-(R6R7C)m-S- wherein m = 1-3, and R5, R6, and R7 are as defined above except R5, R6, and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to sulfur,
e) R8-S-,
f) R9-S-,
g) (R13O)P(O)(OR14)- wherein R13 and R14 are, independently:
i) C1-C6 alkyl,
ii) C3-C6 cycloalkyl,
iϋ) H,
iv) R9, or
v) R8,
h) R13P(O)(OR14)-,
i) N(R10)2,
j) NR15R16 wherein R15 and R16 are joined to form a 4-6 membered saturated nitrogens heterocycle including:
i) azetidinyl,
ii) pyrrolidinyl,
iii) piperidinyl, or
iv) morpholinyl,
k) R17OCH2O wherein R17 is:
i) C1-C6 alkyl,
ii) R9, or
iii) CH2Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle,
1) R17OCH2CH2OCH2, , m) N-imidazolyl where the imidazole ring is unsubstituted or substitute a substituent R4,
n) N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R4;
o) C2-C6 alkynyl, optionally substituted with one or more groups R9; p) C2-C6 alkenyl, optionally substituted with one or more groups R9;
2) hydrogen,
3) C1-C6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or
4) C3-C7 cycloalkyl,
R" is a hydroxyl protecting group, and
R"' and R'v are hydrogen, an amino-protecting group or taken together are N2, which comprises
1) reacting a compound of the formula:
with a compound R'-Z, wherein Z is a moiety which renders R' nucleophilic, and R" is hydroxyl protecting group,
2) converting the resulting hydroxy groups to displaceable groups,
3) reacting the displaceable groups with a nitrogen nucleophile.
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.
Typically 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. Representative of 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. 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. Generally 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 N2 (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:
wherein 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" . John Wiley & Sons, Inc., New York, N.Y. (1976), or "The Peptides" gross and Meienhoffer, eds.; Acad. Press, 1979, Vols I-III, may be used to produce the peptides of this invention and are incorporated herein by reference.
Each amino acid or peptide is suitably protected as known in the peptide art. For example, the Boc- or carbobenzyloxy-group is preferred for protection of the amino group, especially at the α 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 ε-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. Except for the Boc 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.
If solid phase methods are used, 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.
4,244,946. 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 caπied 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.
Typically, 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. Typically, 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). Other methods, such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a protected Boc-amino acid, and subsequent reaction with the free amine of a protected amino acid, optionally in the presence of a base, are also suitable. For example, 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. 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. After the peptide has been completed, 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. Thus, ammonia or a substituted amine may be reacted with an activated acyl intermediate of an amino-protected α-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.
In addition, 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.
Procedures for the determination of the inhibition constant (Ki) by Dixon analysis are described in the art, e.g., in Dreyer, et al. Proc. Natl. Acad. Sci. U.S.A.. 86, 9752-9756 (1989). A peptidolytic assay is employed using the substrate Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH2 and recombinant HIV protease as in Strieker, et al., Proteins.6,
134-154 (1989). The lower Ki value indicates a higher binding affinity.
Pharmaceutical compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral
administration. 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. Examples of 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. An example of such a protein is the 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). Such proteins are disclosed in copending Application Serial No. 07/160,463, which is incorporated herein by reference. Similar targeting proteins could be devised, by methods known to the art, for other viruses and are considered within the scope of this invention.
Alternatively, 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. 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.
For rectal administration, 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. 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. When the compounds of this invention are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment, 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.
The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention.
In the Examples, all temperatures are in degrees Celsius. Amino acid analyses were performed upon a Dionex Autoion 100. Analysis for peptide content is based upon Amino Acid Analysis. FAB mass spectra were performed upon a VG Aab mass spectrometer using fast atom bombardment. NMR spectra were recorded at 250 MHz using a Bruker Am 250 spectrometer. Multiplicities indicated are: s=singlet, d-doublet, t-triplet, q-quartet, m-multiplet and br indicates a broad signal.
Purification of Recombinant HIV Protease
Methods for expressing recombinant HIV protease in E.coli have bee described by Debouck, et al., Proc. Natl. Acad. Sci. USA, 84, 8903-6 (1987). The enzyme used to assay the compounds of this invention was produced in this manner and purified from the cell pellet as previously described by Stickler et al. Proteins. 6, 139-154 (1989).
EXAMPLES
Example 1
Preparation of (3S. 5S)-3.5-diamino-4-hvdroxyheptane 1
Preparation by the Procedure of Scheme 1 : a) 1.2:4.5-dianhvdro-D-(+)-arabitol 9
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% NaHCO3 (2×30 mL) and brine (30 mL), dired over Na2SO4 and concentrated. The residue was dissolved in dry THF (500 mL) and colled to -10°C, and solid sodium methylate (11.1 g, 205 mmol) was added with mechanical stirring under Ar. After 20 min the mixture was poured into ether (2.51), filtered through glass fiber filter paper to remove sodium methylate, and
concentrated by rotary evaporation at 30°C. The residue was purified by flash
chromatography (silica gel, 3:2 etheπpentane) to provide the titled compound 9 (3.96 g, 34.1 mmol, 37% yield). b) 1.2:4.5-dianhvdro-3-(O-benzyl)-D-(+)-arabitol 10
Benzyl bromide (8.92 mL, 75 mmol) was added to a sluπy of NaH (1.8 g. 75 mmol) in THF (9 mL). The mixture was cooled to -10°C under Ar, and compound 9 (3.90 g, 34 mmol) in THF (9 mL) was added dropwise with stirring. The ice bath was removed, and the mixture was allowed to warm briefly to 40°C, then was recooled. The mixture was diluted with 1% acetic acid (100 mL), and extracted with ethyl acetate (2×250 mL). The organic extracts were washed with 5% NaHCO3 (75 mL) and brine (75 mL), dried over Na2Sθ4, and concentrated. Flash chromatography of the residue (gradient, 0¬
4% ethyl acetate in pentane) provided the titled compound 10 (3.88 g, 17.2 mmol, 55% yield). 1HNMR (CDCI3): δ 7.4-7.1(5H, m) 4.75(1H, d; J = 12 Hz), 4.65(1H, d; J = 12
Hz), 3.2(1H, m), 3.05(1H, m), 2.9(1H, t; J = 7 Hz), 2.8(2H, m), 2.65(2H, m). c) (2S.4S)-1.5-Diazido-2.4-dihydroxy-3-benzyloxypentane 11
To 1.65 g (8.0 mmol) of compound 10 in 50 mL water and 50 mL dioxane was added 6.5 g (100 mmol) NaN3 and 340 mg (1 mmol) tetra-n-butylammonium bisulfate. The reaction mixture was heated under reflex for 4 hr, cooled, and concentrated to ca. 50 mL volume by rotary evaporation, and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried (Na2SO4) and concentrated to an oil, which was combined with etheπhexane (1:1) and allowed to crystallize at 4°C to provie 1.76 g of titled compound 11 (69% yield). 1HNMR (CDCI3): δ 7.5-7.3(5H, m), 4.6(2H, dd; J = 12 Hz),
4.0(2H, m), 3.6-3.0(6H, m). d) (2S.4S)1.5-diazido-2.4-di-(methanesulfonyloxy)-3-benzyloxypentane 12
To 630 mg (2.15 mmol) of bisazide diol 11 in 6.0 mL of pyridine was added 350 μL (4.5 mmol) methanesulfonyl chloride at 0°C. The reaction mixture was allowed to warn to 25°C and stirred for 20 hr, then was diluted with 12 mL 6 N HCl, and extracted with 100 mL methylene chloride. The organic layer was washed with 3% NaHCO3, dried (Na2SO4) and concentrated. Flash chromatography of the residue (95:5 CH2C12:ether) provided 867 mg (90% yield) of the titled compound 12. 1HNMR (CDCI3): δ 7.4-7.2(5H, m), 5.0- 4.7(4H, m), 4.02(2H dd, J = 3 Hz), 3.9-3.5(4H, m), 3.15(3H, s), 3.10(3H, s). e) (2S.4S)-1.2:4.5-di-(N-carbonbenzyloxyimino)-3-benzyloxypentane 13
To 310 mg (0.69 mmol) of the compound 12 of step (d) in 2 mL dry THF at 0°C was added 1.5 mL (1.5 mmol) 1 M LiAIH4 in THF. The mixture was allowed to warm to
25°C and stirred overnight. Water (0.1 mL) was added, followed by 0.1 mL 15% NaOh and 0.4 mL water. The mixture was stirred vigorously with 10 mL ether and filtered. Concentration of the ether layer provided teh crude bisaziridine, which was dissolved in 5 mL CH2CI2 and combined with 200 μL (1.4 mmol) triethylamine and 200 μL (1.4 mmol) of benzyl chloroformate. The mixture was stirred at 25°C for 3 hr, then filtered. The filtrate was concentrated and the residue was purified by flash chromatography (ethyl acetate:hexanes 1:5) to provide 89 mg (28% yield) of the titled compound 13. -1HNMR (400 MHz; CDCI3): δ 7.4-7.2(15H, m), 5.0(1H, d; J = 12 Hz), 4.93(1H, d; J = 12 Hz),
4.88(1H, d; J = 12 Hz), 4.84(1H, d; J = 12 Hz), 4.74(1H, d; J = 12 Hz), 4.39(1H, d; J = 12 Hz), 2.82(1H, t; J = 6 Hz), 2.6(1H, m), 2.45(1H, m), 2.25(1H, d; J = 6 Hz),
2.15(1H, d; J = 6 Hz), 2.04(1H, d; J = 3 Hz), 2.02(1H, d; J = 3 Hz). MS (DCI, NH3): m/z 473.1(M+). f) (3A.5S)-3.5-di-(carbonbenzyloxyam ino)-4-benzyloxyheptane 14
To a suspension of Cul (72 mg, 0.375 mmol) in 1.5 mL ether at -25°C was added 0.5 mL 1.5 M CH3Li in ether. The resulting colorless solution was cooled to -45°C and a solution of bisaziridine 13 (10 mg, 0.02 mmol) in 0.5 mL ether was added. After stirring at -45°C for 1 hr, the mixture was allowed to warm to 10°C over a period of 6 hr, then was stirred for an additional 2 hr. The mixture was diulted with 2 mL saturated aqueous NH4CI and 1 mL saturated aqueous NH3, then was extracted with ether. The organic layer was washed with brine, dried (Na2SO4) and concentrated to provide the titled compound 14 (10 mg). 1HNMR (CDCI3): δ 7.2(15H, m), 5.2-4.9(4H, m), 4.93(1H, d; J = 12 Hz), 4.88(1H, d; J = 12 Hz), 4.84(1H, d; J = 12 Hz), 4.7/2H, d; J = 12 Hz), 4.4(2H, d; J = 12 Hz), 3.7(2H, m), 3.4(1H, d; J = 2 Hz), 1.6(4H, m), 1.0(3H, t; J = 7 Hz), 0.9(3H, t; J = 7 Hz). g) (3S.5S)-3.5-diamino-4-hydroxyheptane 1
The product of step (f) is stirred with 20% Pd(OH)2 on carbon (50% by weight) in
0.1 N methanolic HCl under an atmosphere of hydrogen for 24 hr. Filtration and removal of solvents provides the titled compound 1, as the dihydrochloride salt wherein χ1 and X2 are hydrogen and R1 and R2 are ethyl.
Preparation by the Procedure of Scheme 2:
a) (3R.5R)-3.5-dihydroxy-4-benzyloxyheptane 15
To a suspension of Cul (143 mg, 0.75 mmol) in 3 mL ether at -35°C was added methyllithium (1 mL, 1.5 M in ether, 1.5 mmol). The resulting colorless solution was stirred at -30°C for 30 min, then cooled to -78°C. A solution of bisepoxide 10 (78 mg, 0.37 mmol) in 2 mL ether was added. The reaction was allowed to warm to 25°C over 4 hr, the saturated aqueous NH4CI and concentrated aquaous NH3 were added. The mixture was extracted with ether, the organic layer was dried over Na2SO4 and the solvent was removed to furnish the titled compound (93 mg, 100% yield). 1HNMR (CDCI3): δ 7.4-7.1(5H, m), 4.7(1H, d; J = 12 Hz), 4.55(1H, d; J = 12 Hz), 3.9-3.7(2H, m), 3.2(1H, dd), 2.5(2H, b), 1.6-1.4(4H, m), 1.0(3H, t; J = 7 Hz), 0.9(3H, t; J = 7 Hz). b). (3R.5R)-3.5-methanesulfonyloxy-4-benzyloxyheptane 16
Methanesulfonyl chloride (0.3 mL) was added dropwise to diol 15 (93mg) in pyridine (1mL) at 0°C. The mixture was allowed to warm to 25°C. After 12 hr the mixture was diluted with cold 6N HCI (10 mL) and extracted with CH2Cl2. The organic extract was washed with 3% NaHCO3, dried over MgS04, and concentrated. The residue was purified by flash chromatography to provide the titled compound (83 mg, 56% yield). 1HNMR (CDCI3): δ 7.4-7.2(5H, m), 4.75 (1H, m), 4.7(1H, d; J = 12 Hz), 4.6(1H, d; J =
12 Hz), 4.58(1H, m), 3.9(1H, dd; J = 2.6 Hz), 3.0(3H, s), 2.9(3H, s), 2.1-1.5(4H, m),
1.05(3H, t; J = 7 Hz), 1.0(3H, t; J = 7 Hz). c). (3S. 5SV3.5-diazido-4-benzyloxyheptane 17
A mixture of bismesylate 16 (83 mg. 0.21 mmol) and sodium azide (0.5 g 7.7 mmol) in 1.5 mL dimethylformamide was heated to 70°C for 12 hr. After cooling, ethyl acetate (20 mL) was added and the mixture was filtered and concentrated. Flash chromatography of the residue provided the titled compound (54 mg, 90% yield). 1HNMR
(CDCI3): δ 7.4-7.2(5H, m), 4.65 (2H, s), 3.5-3.2(3H, m), 2.0-1.5(4H, m), 1.1 (3H, t; J
= 6 Hz), 1.05(3H, t; J = 6 Hz). d). (3S. 5S)-3.5-diamino-4-benzyloxyheptane 18
To 328 mg ( 1.14 mmol) bisazide 17 in 5 mL THF at 0°C was added 200 mg
LiAIH4. The mixture was allowed to warm to 25°C and was stirred for 5 hr. The reaction was quenched by addition of 0.5 mL 15% NaOH, stirred for 15 min, diluted with 150 mL ether and filtered. Concentration of the filtrate provided the titled compound (278 mg, 100% yield). 1HNMR (CDCI3): δ 7.26(5H, m), 4.5 (2H, dd; J = 12Hz), 3.1 (1H, dd; J = 4.6
Hz), 2.9(1H, m), 2.75(1H, m), 1.8-1.0(10H, m), 0.9(3H, t; J = 7 Hz), 0.85(3H, t; J = Hz). e) (3S. 5S)-3.5-diamino-4-hvdroxvheptane 1
To the diamine product 18 (52 mg) in 4 mL methanol was added 50 mg 20% Pd(OH)2 on carbon and 2 drops concentrated aqueous HCl. The mixture was stirred under an atmosphere of H2 for 16 hr, then was filtered and concentrated to provide the titled compound 1 (53 mg) as the dihydrochloride salt. 1HNMR (CD3OD): δ 3.75(1H, dd; J = 4.7 Hz), 3.2-3.0(2H, m), 1.8-1.4(4H, m), 0.9(6H, t; J = 7 Hz).
Example 2
Preparation of (3S. 5S)-3.5-di-(alanylalanyl)amino-4-hvdroxyheptane 2. a) (3S.5SV3.5-di-(carbobenzyloxyalanylalanyl)amino-4- benzyloxyheptane 19
To the diamine product 18 of Example 1, 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 CH2CI2) provided the titled compound (109 mg). 1HNMR (DMSO-dό): δ 8.0-7.2(21H, m), 5.0(4H, bs), 4.6(2H, dd; J = 12 Hz), 4.2(2H, m), 4.0(2H, m), 3.8(1H, m), 3.7(1H, m), 3.5(1H, dd; J = 4.7 Hz), 1.7-1.3(4H, m), 1.1(12H, m), 0.75(6H, t). b) (3S.5SV3.5-di-(alanylalanyl)amino-4-hydroxyheptane 2
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 H2 for 6 hr, then was filtered and concentrated to provide the titled compound 2 (3 mg) wherein X1 and X2 are AlaAla and R1 and R2 are ethyl. 1HNMR (CD3OD): δ 4.3QH, m), 3.8(2H, m), 3.7(1H, m), 3.5(1H, m), 1.8-1.2(16H, m), 0.8(6H, dt).
Example 3
Preparation of (3S.5S)-3.5-di-(carbobenzyloxyvalyl)amino-4-hvdroxyheptane 3.
To 133 mg (0.5 mmol) Cbz-Val in 2 mL THF at -40°C was added 65 μL (0.5 mmol)of isobutylchloroformate. After stirring for 10 min a solution of 25 mg (0.17 mmol) diamine hydrochloride 1 and 50 μL NMM in 1 mL DMF was added. The mixture was slowly warmed to 20° C and stirred overnight, then was diluted with ethyl acetate, washed witii 5% HC1, 5% NaHCO3, and brine and the organic layer was concentrated. The residue was purified by flash chromatography (ethyl acetate:hexanes) to provide the titled compound 3 (18 mg) wherein X1 and X2 are Cbz-Val and R1 and R2 are ethyl. 1HNMR (CDCI3): δ 7.5-7.3(10H, m), 6.9(1H,br d), 6.35QH, br d), 5.5(H, br d), 5.25(1H, br d),
5.1(4H, br s), 4.0-3.1(6H, m), 2.4-2.1(2H, m), 2.0-1.4(4H, m), 1.0-0.8(18H, m). MS (FAB): m/z 613.2(M+H)+.
Example 4
Preparation of (2S. 4S)-2.4-di-(alanylalanyl)amino-3-hvdroxy-1.5-diphenylpentane 4. a). (2R.4R)-2.4-dihvdroxy-3-benzyloxy-1.5-diphenylpentane 20
To a suspension of Cul (191 mg, 1 mmol) in ether (5 mL) at -60°C was added phenyllithium (4.0 mL, 2.0 mmol; 0.5 M in ether; freshly prepared from bromobenzene and lithium wire). The mixture was warmed to -50°C, then recooled to -78°C. A solution of bisepoxide 10 (40 mg, 0.19 mmol) in ether (1 mL) was added. The mixture was allowed to warm to 25°C over 6 hr with stirring. After an additional 12 hr, the mixture was diluted with ether and washed with 20 mL of 1:1 concentrated aqueous ammonia:saturated
NH4CL. The organic layer was dried over MgSO4 and concentrated. The residue was purified by medium-pressure liquid chromatography (1 :4 ethyl acetate:hexanes) to provide the titled compound 20 (22 mg, 30% yield) as a colorless solid. 1HNMR (CDCL3): δ 7.5- 7.0)15H,m), 4.75(1H, d; J=12 Hz), 4.55(1H, d; J=12 Hx), 4.2(2H, m), 3.3(1H, m), 3.0-2.7(6H, m). b) (2S.4S)-2.4-di-(alanylalanyl)amino-3-hydroxy- 1 ,5-diphenylpentane 4
The titled compound 4 wherein X1 and X2 are AlaAla and R1 and R2 are PhCH2 is prepared from compound 20 by the procedures of Example 2.
Example 5
Preparation of (4R.6R)-4,6-diamino-5-hydroxy-2.8-dimethyl-1.8-nonane' 5. a). (4R.6R)-4.6-dihvdroxy-5-benzyloxy-2.8-dimethyl- 1.8-nondiene 21
To a suspension fo Cul (192 mg, 1.0 mmol) in ether (2 mL) at -60°C was added isopropenyllithium (5.2 mL, 2.0 mmol; 0.38 M in ether, freshly prepared from 2-bromopropene and lithium wire). The mixture was warmed to -45°C, then recooled to 78°C. A solution of bisepoxide 10 (60 mg, 0129 mmol) in ether (5 mL) was added. The mixture was allowed to warm to 0°C over 2 hr with stirring. The mixture was diluted with ether and washed with 5 mL of 1:1 concentrated aqueous ammonia:saturated NH4CI. The organic layer was dried over MgSθ4 and concentrated to provide the titled compound 21 (81 mg, 96% yield) as a colorless solid. 1HNMR (CDCL3): δ 7.3(5H, m), 4.9(1H, bs), 4.85(1H, bs), 4.80(1H, bs), 4.65(1H, d; J=12 Hz), 4.58(1H, d; J=12 Hz), 4.0(2H, m), 3.3(1H, dd; J=2.5 Hz), 2.55(1H, d; J=6 Hz), 2.55(1H, d; J=4 Hz), 2.5-2.1(4H, m), 1.7(1H, s). b) (4R.6R)-4.6-dihydroxy-5-benxyloxy-2.8-dimethylnonane 22
To the product 21 of step (a) (105 mg, 0.38 mmol) in CH2CI2 (1 mL) was added 55 mg Ir(COD)Py(PCy)3PF6 (Crabtree catalyst). The mixture was stirred for 6 hr under 1 atmosphere H2, then was filtered and concentrated to provide the titled compound 22 (110 mg, 100% yield). 1HNMR (CDCI3): δ 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). c) (4R.6R)-4.6-di-fmethanesulfonvloxv,)-5-benxvloxv-2.8-dimethvlnonane 23
Methanesulfonyl chloride (0.25 mL) was added dropwise to diol 22 (93 mg) in pyridine (1 mL) at 0°C. The mixture was allowed to warm to 25°C. After 10 hr the mixture was diluted with cold 6N HCl (10 mL) and extracted with CH2CI2. The organic extract was washed with 3% NaHC03, dried over MgSO4, and concentrated. The residue was purified by flash chromatography to provide the tided compound 23 (210 mg). 1HNMR (CDCI3): δ 7.4(5H, m), 5.0(1H, d; J=12 Hz). 4.7(1H, m), 4.6(1H, d; J=12 Hz),
3.85(lHx dd; J-4.7 Hx), 3.0(3H, s), 2.0(3H, s), 2.0-1.1(6H, m), 1.0-0.9(12H, m). d) (4R.6RV4.6-diazido-5-benzvIoxy-2.8-dimethylnonane 24
To the product 23 of step (c) (210 mg) in 2 mL DMF was added 870 mg ( 15 mmol)
NaN3. The mixture was heated to 70°C for 7 hr, then was cooled and diluted with ethyl acetate. The filtrate was concentrated and the residue was purified by MPLC (ethyl acetate:hexanes 1:20) to provide the tided compound 24 (52 mg). 1HNMR (CDCI3): δ
7.3(5H, m), 4.55(2H, dd; J-12 Hz), 3.4-3.15(3H, m), 2.0-1.1(6H, m), 1.0-0.75(12H, m). e). (4S.6SV4.6-diamino-5-benzyloxy-2.8-dimethylnonane 25
To the product 24 of step (d) (52 mg, 0.15 mmol) in THF (3 mL) was added 80 mg LiAlH4 (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. 1HNMR (CDCI3): δ 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). f) (4R.6R)-4.6-diamino-5-hvdroxy-2.8-dimethyl-1.8-nonane diahvdrochloride 5
To 165 mg of diamine 25 from step (e) in 10 mL methanol containing 5 drops of cone. HCI was added 100 mg 20% Pd(OH)2 on carbon. The mixture was stirred overnight under 1 atm H2, tiien was filtered and concentrated to provide die tided compounds 5 (75 mg) wherein X1 and X2 are hydrogen and R1 and R2 are isobutyl. 1HNMR (CD3OD): δ 3.7(1H, m), 3.2(1H, m), 1.8-1.0(6H, m), 0.99-0.8(12H, m).
Example 6
Preparation of (4R.6R)-4.6-di-(alanylalanyl)amino-5-hvdroxy-2.8-dimethyl-1.8-nonane 6 a) (4R.6R)-4.6-di-(carbobenzyloxyalanylaIanyl)amino-5-benzyloxy-2.8-dimethyl- 1.8-nonane 26
To the product 25 of Example 5, 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 CH2CI2) to provide the titled compound 26 (24 mg).
1HNMR (CD3OD): δ 8.0-7.2 (21H, m), 5.0 (4H, overlapping dd), 4.2 (2H, m), 4.0 (4H, m), 3.5 (1H, br s), 1.7-1.15( 18H, m), 0.9-0.7Q2H, br t).
(b) (4R. 6R)-4.6-Di-(alanylalanyl)amino-5-hydroxy-2.8-dimethyl -1.8-nonane 6
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 X1 and X2 are AlaAla and R1 and R2 are isobutyl. 1HNMR (CD3OD): δ
4.25 (2H, m), 3.8 (1H, m), 3.65 (2H, m), 3.1 (1H, br d), 1.6-1.1 18H, m), 0.7 (12H, br d).
Example 7
Preparation of (4R.6R)-4.6-di-carbobenzylozv)amino-5-hydroxy-2.8-dimethyl- 1 ,8-nonane
7.
To 6.0 mg of the bis-amine hydrochloride product 5 in 0.5 mL CH2CI2 at 20°C were added 5 mL triethylamine and 10 mL benzyl chloroformate. After 3 hr stirring, the mixture was applied to a silica column and eluted with CH2CI2 followed by ether to provide the tided compound 7 (4.6 mg) wherein X1 and X2 are Cbz and R1 and R2 are isobutyl. 1HNMR (CDCI3): δ 7.3 (10H, bs), 5.1-4.9(6H, m), 3.9-3.7(2H, m), 3.5- 3.35(2H, m; IH exchangeable with D2O), 1.7-1.5(4H, m), 1.3-1.2(2H, m), 1.1-0.8(12H, m).
Example 8
Preparation of (4R.6R)-4.6-di-(carbobenzyloxwalyl)amino-5-hydroxy-2.8-dimethyl-1.8-nonane 8
The tided compound 8 wherein X1 and X2 are Cbz-Val and R1 and R2 are isobutyl was prepared by the procedure of Example 3, except using compound 5 in place of compound 1. 1NMR (250 MHz,CDC_3) 7.5-7.28 (m, 10H), 6.8 (br s, 1H), 6.3 (br d, 1H), 5.6 (br s, 1H), 5.25 (br d, 1H), 5.1 (br s, 4H), 4.5-3.5 (m, 6H), 1.5-2.5 (m, 6H), 0.6-1.0 (m, 24 H).
Example 9
Preparation of (2S.4S)- 1.5-diphenvl.3-hvdroxv-2.4-bis(benzvloxvcarbonvlaminovalinvlamino)pentane 40. a) 2R,4R)-l,2,4,5-dianhydro-3-benzyloxyarabitol 33
To a solution of 15.2 g (100 mmol) of D(+)-arabitol in 350 mL of pyridine cooled in an ice bath was added 38.8 g (203.5 mmol) of p-toluenesulfonyl chloride in small portions.
Stirred for 3 h, warmed to room temperature, poured to 500 mL of ether. Ether layer separated, aqueous layer extracted with 800 mL of ether. The combined organic layers were washed with 400 mL of 3% sodium bicarbonate, dried over anhydrous magnesium sulfate and solvents removed in vacuo to give 34.17g (74%) of die ditosylate 32. 1HNMR (CD3COCD3) δ 7.75 (d, 4 H, J= 7 Hz), 7.25 (d, 4 H, J= 7 Hz), 4.4-3.5 (m, 7 H), 3.2 (b, 3 H), 2.5 (s, 6H).
To 10 g (55-60% in oil, 230 mmol ) of sodium hydride in 300 mL of THF was added at 0° a solution of die bistosylate 32 in 200 mL of THF and stirred vigorously for 1 h. The reaction mixture was treated with dropwise addition of 12 mL of benzyl bromide in 10 mL of THF and stirred at 0° for 1 h. Allowed to warm to room temperature and stirred overnight. Quenched with 50 mL of water. dropwise at 0°. Extracted with ether, washed with water, dried over anhydrous sodium sulfate and solvents removed in vacuo. 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. 1HNMR (CDCI3, 250 MHz) δ 7.4-7.1 (m, 5H), 4.75 (d, 1H, J= 12 Hz), 4.65 (d, 1 H, J= 12 Hz), 3.2 (m, 1H), 3.05 (m, 1 H), 2.9 (t, 1 H, J= 7 Hz), 2.8 (m, 2 H), 2. 65 (m, 2 H). b) (2R,4R)-1,5-diphenyl,3-benzyIoxy-2,4-dihydroxypentane 34
To a suspension of 2.99 g (15.5 mmol) of of copper(l) iodide in 30 mL of THF was added 18 mL of 1.8 M Phenyl lithium in cyclohexane ( (freshly opened botde). The reaction mixture was warmed to -50° and recooled to -78° and a solution of 1.01g (4.9 mmol) of the bisepoxide 33 in 10 mL of THF was added and allowed to warm to room temperature and stirred overnight. Processed as usual to give 1.75 g of of the diol 34 as an oil. Trituration with ether/hexane gave 1.45 g (82 %) of a colorless solid. Anal Calcd for C24H26O3: C(79.53), H(7.23); Found: C(79.25), H(7.18); MS(DCI, NH3) (M+H)+ 364.5; 1HNMR (CDCI3, 250 MHz) δ 7.4-6.8 (m, 15 H), 4.62 (d, 1 H, J= 12 Hz), 4.5 (d, 1 H, J= 12 Hz), 4.2 (m, 2 H), 3.3 (dd, 1 H, J= ), 2.8 (m, 4 H). c) (2R,4R)-1,5-diphenyl-3-benzyloxy-2,4-bis(methanesulfonyloxy)pentane 35 and (2S,4S)-1,5-diphenyl-3-benzyloxy-2,4-diazidopentane 36
To 400 mg of the diol in 5 mL of pyridine at 0° was added 1 mL of methane sulfonyl chloride and stirred for 18 h at room temperature. Poured into 20 mL of ice cold3 N hydrochloric acid extracted with 50 mL of methylene chloride, washed with 3 % sodium bicarbonate dried over anhydrous sodium sulfate and solvents removed in vacuo to give 1.20 g of 35 as an oil.
The above crude product was dissolved in 5 mL of DMSO and added 1.05 g (16 mmol) of sodium azide. The reaction mixture was heated at 80° for 6 h and then at 100° for an additional 8 h. The reaction was cooled, diluted with ether and unreacted sodium azide was filtered off. The combined solvents were removed in vacu and subjected to flash chromatography to give 285 mg of an inseparable mixture of monoazide 36, (2S,4S)-1,5-diphenyl-3-benzyloxy-4-azido-pent-l-ene, and bisazide 37 in the ratio 70: 30 as caclulated from 1HNMR d) (2S,4S)-1,5-diphenyl,3-benzyloxy-2,4-diaminopentane 38
To 279 mg of the mixture of azide products (36+37) obtained above in 10 mL of diethyl ether at 0° was added 3 mL of a 1 M solution of lithium aluminium hydride in THF over 10 min. Stirred at 0° for 30 min warmed to room temperature and stirred for 3 h. Cooled in an ice bath and quenched with 1 mL of 10% sodium hydroxide, diluted with ether and stirred for 2 h. The precipitate was filtered off tiirough celite and washed with ether. Removal of solvents followed by chromatography on 10 g florisil (hexane, ethy acetate:hexane 1:4, then metfiano) gave 112 mg of pure diamine 38. 1HNMR (CDCI3, 250 MHz) δ 7.2 (m, 15 H), 4.7(d, 21 H, J= 12 Hz), 4.5 (d, 21H, J= 1 H), 4.1(m, 1H), 2.3-3.2 (m, 6 H). e) (2S,4S)-1,5-diphenyl-3-hydroxy-2,4-diaminopentane 39
62 mg of the diamino compound was subjected to hydrogenation in 10 mL of methanol containing 75 mg of cone, hydrochloric acid over 25 mg of Pd/C. Stirred for 8 h, catalyst was filtered off and washed with methanol. Removal of solvents gave 68 mg of a solid which on trituration with hexane ether provided 48 mg of the pure diamine as the hydrochloride. 1HNMR (CD3OD, 250 MHz) δ 7.4-6.9 (m, 10 H), 4.1 (bd, 1H, J= 6 Hz), 3.5-3.7 (m, 2 H), 2.5-3.4 (m, 4 H). f) (2S,4S)-1 ,5-diphenyl,3-hydroxy-2,4-bis(benzyloxycarbonylaminovalinylamino)pentane 40
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 μL of N-methyl morpholine and 80 μL of isobutyl chloroformate 68 mg of a white solid. Analytical samples were prepared by flash column chromatography ( silica, 10% MeOH/CH2Cl2). MS(ES/MS) (M-H)+ 735; 1HNMR (CDCI3, 250 MHz) δ 7.4-7.0 ( m, 20 H), 6.1 (d, 1H, J= 7 Hz), 5.5 (d, 1H, J= 7 Hz), 5.0 (m, 8 H), 4.0 (m, 2 H), 3.6 (m, 2 H), 2.8-3.4 (m, 4 H), 2.2 (m, 1H), 1.85 (m, IH), 0.9 (d, 3 H, J= 7 Hz), 0.86 (d, 3 H, J= 7 Hz), 0.7 (d, 3 H, J= 7 Hz), 0.55 (d, 3 H, J= 7 Hz).
Example 10
Preparation of (3S. 5S)-3.5-di-fcarbobenzyloxyalanylalanyl)amino-4-hydroxyheptane 50. a) (2R,4R)-1,5-diazido-2,4-dihydroxy-3-benzyloxypentane 41
To 1.65 g (8.0 mmol) of bisepoxide 33 in 50 mL water and 50 mL dioxane was added 6.5 g (100 mmol) NaN3 and 340 mg (1 mmol) tetra-n-butylammonium bisulfate. The reaction mixture was heated under reflux for 4 hr, cooled, and concentrated to ca. 50 mL volume by rotary evaporation, and extracted witii ethyl acetate (3x50 mL). The combined organic extracts were dried (Na2SO4) and concentrated to an oil, which was combined with with etheπhexane (1:1) and allowed to crystallize at 4°C to provide 1.76 g of the titled compound (69 % yield). 1HNMR (CDCI3): δ 7.5-7.3(5H, m), 4.6(2H, dd; J = 12 Hz), 4.0(2H, m), 3.6-3.0(6H, m). b) (2R,4R)- 1 ,5-diazido-2,4-di-(methanesulfonyloxy)-3-benzyloxypentane 42
To 630 mg (2.15 mmol) of bisazido diol 41 in 6.0 mL of pyridine was added 350 μL (4.5 mmol) methanesulfonyl chloride at 0°C. The reaction mixture was allowed to warm to 25°C and stirred for 20 hr, then was diluted with 12 mL 6 N HCl, and extracted with 100 mL methylene chloride. The organic layer was washed with 3% NaHCO3, dried (Na2SO4) and concentrated. Rash chromatography of the residue (95:5 CH2Cl2:ether) provided 867 mg (90% yield) of the tided compound. 1HNMR (CDCI3): δ 7.4-7.2(5H, m), 5.0-4.7(4H, m), 4.02(2H, dd, J = 3 Hz), 3.9-3.5(4H, m), 3.15(3H, s), 3.10(3H, s). c) (2S,4S)-1,2:4,5-di-(N-carbobenzyloxyimino)-3-benzyloxypentane 43
To 310 mg (0.69 mmol) of the compound 42 in 2 mL dry THF at 0°C was added 1.5 mL (1.5 mmol) 1 M LiAIH4 in THF. The mixture was allowed to warm to 25°C and stirred overnight. Water (0.1 mL) was added, followed by 0.1 mL 15% NaOH and 0.4 mL water. The mixture was stirred vigorously with 10 mL ether and filtered. Concentration of the ether layer provided die crude bisaziridine, which was dissolved in 5 mL CH2CI2 and combined with 200 μL (1.4 mmol) triethylamine and 200 μL (1.4 mmol) of benzyl chloroformate. The mixture was stirred at 25°C for 3 hr, then filtered. The filtrate was concentrated and the residue was purified by flash chromatography (ethyl acetate:hexanes 1:5) to provide 89 mg (28% yield) of the titled compound. 1HNMR (400 MHz; CDCI3): δ 7.4-7.2(15H, m), 5.0(1H, d; J = 12 Hz), 4.93(1H, d; J = 12 Hz), 4.88(1H, d; J = 12 Hz), 4.84(1H, d; J = 12 Hz), 4.74(1H, d; J = 12 Hz), 4.39(1H, d; J = 12 Hz), 2.82(1H, t; J = 6 Hz), 2.6(1H, m), 2.45(1H, m), 2.25(1H, d; J = 6 Hz), 2.15(1H, d; J = 6 Hz), 2.04(1H, d; J = 3 Hz), 2.02(1H, d; J = 3 Hz). MS (DCI, NH3): m/z 473.1(M+). d) (3S, 5S)-3,5-di-(carbobenzyloxyamino)-4-benzyloxyheptane 44
To a suspension of Cul (72 mg, 0.375 mmol) in 1.5 mL ether at -25°C was added 0.5 mL 1.5 M CH3Li in ether. The resulting colorless solution was cooled to -45°C and a solution of bisaziridine 43 (10 mg„ 0.02 mmol) in 0.5 mL ether was added. After stirring at -45°C for 1 hr, the mixture was allowed to warm to 10°C over a period of 6 hr, them was stirred for an additional 2 hr. The mixture was diluted with 2 mL saturated aqueous NH4CI and 1 mL saturated aqueous NH3, then was extracted with etiier. The organic layer was washed witii brine, dried (Na2SO4) and concentrated to provide the tided compound (10 mg). 1HNMR (CDCI3): δ 7.2(15H, m), 5.2-4.9(4H, m), 4.93(1H, d; J = 12 Hz), 4.88(1H, d; J = 12 Hz), 4.84(1H, d; J = 12 Hz), 4.7QH, d; J = 12 Hz), 4.4(2H, d; J = 12 Hz), 3.7(2H, m), 3.4(1H, d; J = 2 Hz), 1.6(4H, m), 1.0(3H, t; J = 7 Hz), 0.9(3H, t; J = 7 Hz). MS(DCI,NH3)
(M+H)+ 505.1 e) (3R, 5R)-3,5-dihydroxy-4-benzyloxyheptane 45
To a suspension of Cul (143 mg, 0.75 mmol) in 3 mL ether at -35°C was added methyllithium (1 mL, 1.5 M in ether; 1.5 mmol). The resulting colorless solution was stirred at -30°C for 30 min, then cooled to -78°C. A solution of bisepoxide 33 (78 mg, 0.37 mmol) in 2 mL ether was added. The reaction was allowed to warm to 25°C over 4 hr, the saturated aqueous NH4CI and concentrated aqueous NH3 were added. The mixture was extracted with ether, the organic layer was dried obver Na2Sθ4 and the solvent was removed furnish the tided compound (93 mg, 100% yield). 1HNMR (CDCI3): δ 7.4-7.1(5H, m), 4.7(1H, d; J = 12 Hz), 4.55(1H, d; J = 12 Hz), 3.9-3.7(2H, m), 3.2(1H, dd), 2.5(2H, b), 1.6-1.4(4H, m), 1.0(3H, t; J = 7 Hz), 0.9(3H, t; J = 7 Hz);
MS(DCI,NH3) (M+H)+ 239.2 f) (3R, 5R)-3,5-Methanesulfonyloxy-4-benzyloxyheptane 46
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 CH2CI2. The organic extract was washed with 3% NaHCO3, dried over MgSO4, and concentrated. The residue was purified by flash chromatography to provide die tided compound (83 mg, 56% yield). 1HNMR (CDCI3): δ 7.4-7.2(5H, m), 4.75 (IH, m), 4.7(1H, d; J = 12 Hz), 4.6(1H, d; J = 12 Hz), 4.58(1H, m), 3.9(1H, dd; J = 2.6 Hz), 3.0(3H, s), 2.9(3H, s), 2.1-1.5(4H, m), 1.05(3H, t; J = 7 Hz), 1.0(3H, t; J = 7 Hz). g) (3S, 5S)-3,5-diazido-4-benzyloxyheptane 47
A mixture of bismesylate 46 (83 mg, 0.21 mmol) and sodium azide (0.50 g, 7.7 mmol) in 1.5 mL dimethylformamide was heated to 70°C for 12 hr. After cooling, ethyl acetate (20 mL) was added and die mixture was filtered and concentrated. Flash
chromatography of the residue provided the tided compound (54 mg, 90% yield). 1HNMR (CDCI3): δ 7.4-7.2(5H, m), 4.65 (2H, s), 3.5-3.2(3H, m), 2.0-1.5(4H, m), 1.1(3H, t: J = 6 Hz), 1.05(3H, t; J = 6 Hz). h) (3S, 5S)-3,5-diamino-4-benzyloxyheptane 48
To 328 mg (1.14 mmol) bisazide 47 from step (j) in 5 mL THF at 0°C was added 200 mg LiAlH4 The mixture was allowed to warm to 25°C and was stirred for 5 hr. The reaction was quenched by addition of 0.5 mL 15% NaOH, stirred for 15 min, diluted with 150 mL ether and filtered. Concentration of the filtrate provided the tided compound (278 mg, 100% yield). 1HNMR (CDCI3): δ 7.26(5H, m), 4.5 (2H, dd; J = 12Hz), 3.1(1H, dd; J = 4.6 Hz), 2.9(1H, m), 2.75(1H, m), 1.8-1.0(10H, m), 0.9(3H, t; J = 7 Hz), 0.85(3H, t; J = 7 Hz). i) (3S, 5S)-3,5-diamino-4-hydroxyheptane 49
52 mg of the diamine product 48 in 4 mL methanol was added 50 mg 20% Pd(OH)2 on carbon and 2 drops concentrated aqueous HCl. The mixture was stirred under an atmosphere of H2 for 16 hr, then was filtered and concentrated to provide the tided compound (53 mg) as the dihydrochloride salt. 1HNMR (CD3OD): δ 3.75QH, dd; J = 4.7 Hz), 3.2-3.0(2H, m), 1.8-1.4(4H, m), 0.9(6H, t; J = 7 Hz). j) (3S, 5S)-3,5-di-(carbobenzyloxyalanylalanyl)amino-4-hydroxyheptane 50
To the diamine product 49 (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 dried (MgSO4). Removal of solvent followed by MPLC (silica; 2% methanol in CH2CI2) provided the tided compound (109 mg). 1HNMR (DMSO-d6): δ 8.0-7.2(21H, m), 5.0(4H, bs), 4.6(2H, dd; J = 12 Hz), 4.2(2H, m), 4.0(2H, m), 3.8(1H, m), 3.7(1H, m), 3.5(1H, dd; J = 4.7 Hz), 1.7-1.3(4H, m), 1.1(12H, m), 0.75(6H, t). MS(FAB) (M+H)+ 789.3
Example 11
Preparation of (3S. 5S)3.5-di-(alanylalanyl)amino-4-hydroxyheptane 51.
To the product 19 (4.5 mg) in 1 mL DMF was added 10 mg of 20% Pd(OH)2 on carbon. The mixture was stirred under 1 atmosphere of H2 for 6 hr, then was filtered and concentrated to provide the tided compound (3 mg). 1HNMR (CD3OD): δ 4.3 (2H, m), 3.8(2H, m), 3.7(1H, m), 3.5(1H, m), 1.8-1.2(16H, m), 0.8(6H, dt). Example 12
Preparation of (3S. 5S)-3.5-di-(carbobenzyloxyvalyI)amino-4-hydroxyheptane 52.
To 133 mg (0.5 mmol) Cbz-Val in 2 mL THF at -40°C was added 65 μL (0.5 mmol) of NMM and 65 μL (0.5 mmol)of isobutylchloroformate. After stirring for 10 min a solution of 25 mg (0.17 mmol) diamine hydrochloride 1 and 50 μL NMM in 1 mL DMF was added. The mixture was slowly warmed to 20°C and stirred overnight, then was diluted with ethyl acetate, washed witii 5% HCl, 5% NaHCO3, and brine and the organic layer was concentrated. The residue was purified by flash chromatography (ethyl acetate:hexanes) to provide the tided compound (18 mg). 1HNMR (CDCI3): δ 7.5-7.3(10H, m), 6.9(1H, bd), 6.35(1H, bd), 5.5(1H, bd), 5.25(1H, bd), 5.1(4H, bs), 4.03.1(6H, m), 2.4-2.1(2H, m), 2.0-1.4(4H, m), 1.0-0.8(18H, m). MS (FAB): m/z 613.2(M+H)+. Example 13
Preparation of (4S. 6S)-4.6-diamino-5-hydroxy-2.8-dimethyl-1.8-nonane dihydrochloride 58.
a) (4R, 6R)-4,6-dihydroxy-5-benzyloxy-2,8-dimethyl-1,8-nondiene 53
To a suspension of Cul (192 mg, 1.0 mmol) in ether (2 mL) at -60°C was added isopropenyllidiium (5.2 mL, 2.0 mmol; 0.38 M in ether; freshly prepared from 2- bromopropene and lithium wire). The mixture was warmed to -45°C, then recooled to 78°C. A solution of bisepoxide 33 (60 mg, 0.29 mmol) in ether (5 mL) was added. The mixture was allowed to warm to 0°C over 2 hr with stirring. The mixture was diluted with ether and washed with 5 mL of 1: 1 concentrated aqueous ammonia:saturated NH4CI. The organic layer was dried over MgSO4 and concentrated to provide the titled compound (81 mg, 96% yield) as a colorless solid. 1HNMR (CDCI3): δ 7.3(5H, m), 4.9(1H, bs), 4.85(1H, bs), 4.80(1H, bs), 4.75(1H, bs), 4.65(1H, d; J = 12 Hz), 4.58(1H, d; J = 12 Hz), 4.0(2H, m), 3.3(1H, dd; J = 2.5 Hz), 2.55(1H, d; J = 6 Hz), 2.55(1H, d; J = 4 Hz), 2.5-2.1(4H, m), 1.7(1H, s). MS(DCI,NH3) (M+H)+ 291.4 b) (4R, 6R)-4,6-dihydroxy-5-benzyloxy-2,8-dimethylnonane 54
To the product 53 (105 mg, 0.38 mmol) in CH2CI2 (1mL) was added 55 mg Ir(COD)Py(PCy)3PF6 (Crabtree catalyst). The mixture was stirred for 6 hr under 1 atmosphere H2, then was filtered and concentrated to provide the titled compound (110 mg, 100% yield). 1HNMR (CDCI3): δ 7.3(5H, m), 4.6(1H, dd; J = 12 Hz), 4.0(2H, m), 3.1(1H, bs), 2.7(2H, bs), 2.0-1.1(6H, m), 1.0-0.8(12H, m).
MS(DCI,NH3) (M+H)+ 295.4. c) (4R, 6R)-4,6-Di-(methanesulfonyloxy)-5-benzyloxy-2,8-dimethylnonane 55
Methanesulfonyl chloride (0.25 mL) was added dropwise to diol 54 (93 mg) in pyridine (1 mL) at 0°C. The mixture was allowed to warm to 25°C. After 10 hr the mixture was diluted with cold 6N HC1 (10 mL) and extracted with CH2CI2. The organic extract was washed with 3% NaHCO3, dried over MgSO4, and concentrated. The residue wasPurified by flash chromatography to provide the titled compound (210 mg). 1HNMR
(CDCI3): δ 7.4(5H, m), 5.0(1H, m), 4.8(1H, d; J = 12 Hz), 4.7(1H, m), 4.6(1H, d; J = 12 Hz), 3.85(1H, dd; J = 4.7 Hz), 3.0(3H, s), 2.9(3H, s), 2.0-1.1(6H, m), 1.0-0.9(12H, m). d) (4R, 6R)-4,6-diazido-5-benzyloxy-2,8-dimethylnonane 56
To the product 55 (210 mg) in 2 mL DMF was added 870 mg (15 mmol) NaN3. The mixture was heated to 70°C for 7 hr, then was cooled and diluted with ethyl acetate. The filtrate was concentrated and the residue was purified by MPLC (ethyl acetate:hexanes 1:20) to provide the tided compound (52 mg). 1HNMR (COCI3): δ 7.3(5H, m),
4.55(2H, dd; J = 12 Hz), 3.4-3.15(3H, m), 2.0-l.l(6H, m), 1.0-0.75(12H, m). e) (4S, 6S)-4,6-diamino-5-benzyloxy-2,8-dimethylnonane 57
To the product 56 (52 mg, 0.15 mmol) in THF (3 mL) was added 80 mg LiAlH4 (2 mmol) at 0°C. The mixture was stirred at 25°C overnight, then was quenched with 1N NaOH and diluted with ether (50 mL). Filtration and concentration provided the tided compound (44 mg) as a colorless oil. 1HNMR (CDCI3): δ 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). f) (4S, 6S)-4,6-diamino-5-hydroxy-2,8-dimethyl-1,8-nonane dihydrochloride 58
To 165 mg of diamine 57 in 10 mL methanol containing 5 drops of cone. HCl was added 100 mg 20% Pd(OH)2 on carbon. The mixture was stirred overnight under 1 atm H2, men was filtered and concentrated to provide the titled compound (75 mg). 1HNMR (CD3OD): δ 3.7(1H, m), 3.35(1H, m), 3.2(1H, m), 1.8-1.0(6H, m), 0.99-0.8(12H,m). MS(DCI, NH3) (M+H)+ 203.2.
Example 14
Preparation of (4S,6S)-4,6-di-(carbobenzyloxyalanylalanyl)amino-5-hydroxy-2,8-dimethyl-1,8-nonane 59
To the product 58 (44 mg, 0.15 mmol) in 2 mL DMF was added 110 mg CbzAlaAla (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 witii 20 mL ethyl acetate and filtered. The filtrate was concentrated and die residue was purified by MPLC (gradient, 0-5% methanol in CH2CI2) to provide the tided compound (24 mg). 1HNMR (CD3OD): δ 8.0-7.2(21H, m), 5.0(4H, overlapping dd), 4.2(2H, m), 4.0(4H, m), 3.5 (IH, br s), 1.7-1.15(18H, m), 0.9-0.7(12H, br t).
Example 15
Preparation of (4S.6S)-4.6-di-(alanylalanyl)amino-5-hydroxy-2.8-dimethyl-1.8-nonane 60.
To the product 59 (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, then was diluted with methanol, filtered and concentrated to provide the tided compound (7.5 mg). 1HNMR (CD3OD): δ 4.25(2H, m), 3.8(1H, m), 3.65(2H, m), 3.1(1H, bd), 1.6-1.1(18H, m), 0.7(12H, bd). MS(FAB) (M+H)+ 487. Example 16
Preparation of (4S. 6S)-4.6-di-(carbobenzyloxy)amino-5-hydroxy-2.8-dimethyl-1.8- nonane 61.
To 6.0 mg of the bis-amine hydrochloride product 58 in 0.5 mL CH2CI2 at 20°C were added 5 mL triethylamine and 10 mL benzyl chloroformate. After 3 hr stirring, the mixture was applied to a silica column and eluted with CH2CI2 followed by ether to provide the tided compound (4.6 mg). 1HNMR (CDCI3): δ 7.3(10H, bs), 5.1-4.9 (6H, m), 3.9-3.7(2H, m), 3.5-3.35(2H, m; IH exchangeable with D2O), 1.7-1.5 (4H, m), 1.3-1.2 (2H, m), 1.1-0.8 (12H, m).
Example 17
Preparation of (2S.4S)-2.4-di-(p-toluenesulfonyl)amino-3-hydroxy-1.5-diphenylpentane 62.
The tided product was prepared by sulfonylation of compound 40 (Example 9) with p-toluenesulfonyl chloride in methylene chloride and triethylamine. 1HNMR (250 MHz, CDCl3) 8.0-6.8 (m, 18H), 5.5 (d, 1H, J=7Hz), 5.2 (d, 1H, J=7Hz), 3.2-3.7 D(m, 4H), 2,4-2.7 (m, 4H), 2.5 (s, 3H), 2,45 (s, 3H).
Enzyme Inhibition
Inhibition of HIV protease activity
The inhibition assay has been previously described in Dreyer et al. Proc. Natl. Acad. Sci. USA.86, 9752-9756 (1989) and Moore et al. Bioch. Bioph. Res. Com.. 159.420 (1989). A typical assay contained 10 mL MENDT buffer (50 mM Mes (pH 6.0; 2-(N- morpholino) ethanesulfonic acid), 1 mM EDTA, ImM dithiodireitol, 200 mM NaCl, 0.1% Triton X-100); 2, 3, or 6 mM N-acetyl-L-arginyl-L-alanyl-L-seryl-L-glutaminyl-L-asparaginyl-L-tyrosyl-L-prolyl-L-valyl-L-valinamide (Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH2; Km = 7 mM); and micromolar and submicromolar concentrations of syndietic compounds. Following incubation at 37°C for several minutes, the reaction was initiated widi 0.001-0. lOmg purified HIV protease. 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/H2O - .1% TFA 915 min.), 20% acetonitrile/H2O - .1% TFA (5 min) at 1.5 mL/min, detection at 220 nm. The elution positions of Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH2 (17-18 min) and Ac-Arg-Ala-Ser-Gln-Asn-Tyr (10-11 min) were confirmed with authentic material. Initial rates of Ac-Arg-Ala-Ser-Gln-Asn-Tyr formation were determined from integration of these peaks, and typically, die inhibitory properties of die synthetic compounds were determined from slope/intercept analysis of a plot of 1/v vs. [inhibitor] (Dixon analysis). Ki values resulting from this type of primary analysis are accurate for competitive inhibitors only, and under conditions in which die Michaelis constant of the substrate used is well-determined.
It is desirable for the compounds of mis invention to have Ki values less than 50 μM, preferably less than 10 μM and more preferably less than 1 μM.
Following the procedures set forth herein and die teachings of the foregoing examples the compounds set forth in the following Table can be prepared having the structure and die substituent groups as designated tiierein.
Inhibition of rHIV-1 Protease
Compound IC50
3 50
6 80
8 80
40 0.123
52 50
60 80
62 1,000

Claims (14)

Claims:
1. A compound of die formula I or II:
wherein X1 and X2 are the same or different and are A-(B)n- where n = 0-2; and
B is, independendy, an α-amino acid chosen from the group: Ala, Asn, Cys, Tip, Gly, Gin, lie, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A or die carboxy group of the adjacent residue B, whichever is appropriate, and die carboxy group of B is bonded to die amino group of the adjacent residue B or I or π, whichever is appropriate; and
A is covalendy attached to the amine group of die adjacent residue B or to die amine group of I or II if n=0, and is:
1) trityl,
2) hydrogen,
3) C1-C6 alkyl,
4) R3-CO- wherein R3 is:
a) hydrogen,
b) C1-C6 alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms,
c) phenyl or naphthyl unsubstituted or substituted with one or more substituents R4, wherein R4 is:
i) C1-C4 alkyl,
ii) halogen, whrein halogen is F, CI, Br or I, iii) hydroxyl,
iv) nitro,
v) C1-C3 alkoxy, or
vi) -CO-N(R10)2 wherein R10 is, independently, H or C1-C4 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 R4,
6) R5(R6R7C)m-CO- wherein m = 1-3 and R5, R6, and R7 are independently: a) hydrogen,
b) chlorine or fluorine, c) C1-C3 alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups,
d) hydroxyl,
e) phenyl or naphthyl unsubstituted or substituted with one or more substitutents R4,
f) C1-C4 alkoxy,
g) a 5-7 member heterocycle,
h) R5, R6, and R7 may be independendy joined to form a monocyclic, bicyclic, or tricyclic ring system each ring of which is C3-C6 cycloalkyl;
7) R5(R6R7C)mW- wherein m = 1-3 and W is OCO or SO2 and R5, R6, and
R7 are as defined above, except R5, R6, and R7 are not chlorine, fluorine or hydroxyl if they are adjacent to W;
8) R8-W- wherein R8 is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazoyl;
9) R9-W- wherein R9 is phenyl or naphthyl unsubstituted or substituted with one or more substituents R4;
10) R5-(R6R7C)m-P(O)(OR1 1)- wherein R1 1 is C1-C4 alkyl or phenyl;
11) R8-P(O)(OR11)-; or
12) R9.P(O)(OR11)-;
R1 and R2 are the same or different and are:
1) -CH2R12 wherein R12 is
a) NH-A wherein A is defined as above;
b) R5-(R6R7C)m.;
c) R5-(R6R7C)mV- wherein V is O or NH, except R5, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to V,
d) R5-(R6R7C)m-S(O)n- wherein m = 1-3 and n = 0-2 and R5, R6 and R7 are as defined above except R5, R6, and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to sulfur,
e) R8-S(O)n-,
f) R9-S(O)n-,
g) (R13O)P(O)(OR14)- wherein R13 and R14 are, independently: i) C1-C6 alkyl,
ii) C3 - Cg cycloalkyl,
iii) H,
iv) R9,
v) R8,
h) R13P(O)(OR14)-, i) N(R10)2,
j) NR15R16 wherein R15 and R16 are joined to form a 4-6 membered saturated nitrogenous heterocycle including:
i) azetidinyl,
ii) pyrrolidinyl,
iii) piperidinyl,
iv) morpholinyl,
k) R17OCH2O wherein R17 is:
i) C1-C6 alkyl,
ii) R9,
iii) CH2Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle,
1) R17OCH2CH2OCH2,
m) N-imidazolyl where the imidazole ring is unsubstituted or substituted by a substituent R4,
n) N-Benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R4;
o) C2-C6 alkynyl, optionally substituted witii one or more groups R9; or
p) C2-C6 alkenyl, optinally substituted widi one or more gropus R9;
2) hydrogen,
3) C1-C6 alkyl, unsubstituted or substituted witii one or more chlorine or fluorine atoms or hydroxyl groups,
4) C3-C7 cycloalkyl; and pharmaceutically acceptable salts thereof.
2. A compound as defined in claim 1 wherein the compound has the structure I and wherein R1 = R2 and X1 = X2.
3. A compound as defined in claim 2 wherein R^ and R2 are C1-C6alkyl.
4. A compound as defined in claim 2 wherein Rl and R2 are benzyl.
5. A compound as defined in claims 1-4 wherein X1 and X2 are selected from AlaAla, Val, Cbz-Val, Cbz or hydrogen.
6. A compound of claim 1 wherein the protease activity inhibitor constant Ki is less than about 10 μM.
7. A compound according to claim 1 for use in a medicament
8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmacetically acceptable carrier.
9. A method of treating infection by a retrovirus which comprises administering a compound according to claim 1.
10. A method according to claim 9 wherein the retrovirus is the Human
Immunodeficiency Virus type 1.
11. A process for preparing a compound of the formula:
wherein R' is
1) a) NH-A wherein A, R5- R10 and m are as defined in claim 1;
b) R5-(R6R7C)m-;
c) R5-(R6R7C)m V- wherein V is O or NH, except R5, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to V,
d) R5-(R6R7C)m-S- wherein m = 1-3, and R5, R6, and R7 are as defined above except R5, R6, and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to sulfur,
e) R8-S-,
f) R9-S-,
g) (R13O)P(O)(OR14)- wherein R13 and R14 are, independently:
i) C1-C6 alkyl,
ii) C3-C6 cycloalkyl,
iii) H,
iv) R9, or
v) R8,
h) R13P(O)(OR14)-,
i) N(R10)2, j) NR15R16 wherein R15 and R16 are joined to form a 4-6 membered saturated nitrogens heterocycle including:
i) azetidinyl,
ii) pyrrolidinyl,
iii) piperidinyl, or
iv) morpholinyl,
k) R17OCH2O wherein R17 is:
i) C1-C6 alkyl,
ii) R9, or
iii) CH2Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle,
1) R17OCH2CH2OCH2,
m) N-imidazolyl where the imidazole ring is unsubstituted or substituted by a substituent R4,
n) N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R4;
o) C2-C6 alkynyl, optionally substituted with one or more groups R9; or p) C2-C6 alkenyl, optionally substituted with one or more groups R9;
2) hydrogen,
3) C1-C6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or
4) C3-C6 cycloalkyl;
R" is a hydroxyl protecting group, R'" and R'v are hydrogen, an amino-protecting group or taken together are N2,
which comprises
1) reacting a compound of the formula:
with a compound R'-Z, wherein Z is a moiety which renders R' nucleophilic,
2) converting die resulting hydroxy groups to displaceable groups, and
3) reacting the displaceable groups with a nitrogen nucleophile.
12. A compound of the formula:
wherein R' is:
1) a) NH-A wherein A, R5 - R10 and m are as defined in claim 1;
b) R5-(R6R7C)m-;
c) R5-(R6R7C)m V- wherein V is O or NH, except R5, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to V,
d) R5-(R6R7C)m-S- wherein m = 1-3, and R5, R6, and R7 are as defined above except R5, R6, and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to sulfur,
e) R8-S-,
f) R9-S-,
g) (R13O)P(O)(OR14)- wherein R13 and R14 are, independendy:
i) C1-C6 alkyl,
ii) C3-C6 cycloalkyl,
iii) H,
iv) R9, or
v) R8,
h) R13P(O)(OR14)-,
i) N(R10)2,
j) NR15R16 wherein R15 and R16 are joined to form a 4-6 membered saturated nitrogens heterocycle including:
i) azetidinyl,
ii) pyrrolidinyl,
iii) piperidinyl, or
iv) morpholinyl,
k) R17OCH2O wherein R17 is:
i) C1-C6 alkyl,
ii) R9, or
iii) CH2Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle,
1) R17OCH2CH2OCH2, m) N-imidazolyl where the imidazole ring is unsubstituted or substituted b a substituent R4,
n) N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R4;
o) C2-C6 alkynyl, optionally substituted with one or more groups R9; or p) C2-C6 alkenyl, optionally substituted with one or more groups R9;
2) hydrogen,
3) C1-C6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or
4) C3-C7 cycloalkyl; and
R" is a hydroxyl protecting group.
13. A compound of the formula:
wherein R' and R" are as defined in claim 12.
14. A compound of the formula:
wherein R" is a hydroxyl protecting group.
AU82334/91A 1990-07-06 1991-07-03 Retroviral protease inhibitors Abandoned AU8233491A (en)

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Cited By (4)

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Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5482947A (en) 1990-11-19 1996-01-09 Talley; John J. Retroviral protease inhibitors
AU667376B2 (en) 1992-05-21 1996-03-21 Monsanto Company Retroviral protease inhibitors
US5364961A (en) 1992-06-15 1994-11-15 Monsanto Company Process for making optically active α-amino ketones
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
DE69321845T2 (en) 1992-08-25 1999-04-29 Searle & Co HYDROXYETHYLAMINOSULPHONAMIDES USED AS INHIBITORS OF RETROVIRAL PROTEASES
US5968942A (en) 1992-08-25 1999-10-19 G. D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6022994A (en) 1992-08-25 2000-02-08 G. D. Searle &. Co. Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US7141609B2 (en) 1992-08-25 2006-11-28 G.D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
EP0666842B1 (en) 1992-10-30 1998-06-24 G.D. Searle & Co. Hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US6337398B1 (en) 1992-10-30 2002-01-08 G.D. Searle & Co. Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US5578606A (en) 1992-10-30 1996-11-26 G. D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US5514801A (en) 1992-12-29 1996-05-07 Monsanto Company Cyclic sulfone containing retroviral protease inhibitors
WO1994017096A1 (en) * 1993-01-17 1994-08-04 Schering Corporation Peptides having anti-hiv activity
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US5831117A (en) 1995-01-20 1998-11-03 G. D. Searle & Co. Method of preparing retroviral protease inhibitor intermediates
US6143747A (en) 1995-01-20 2000-11-07 G. D. Searle & Co. Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors
US6407134B1 (en) 1995-03-10 2002-06-18 G. D. Searle & Co. Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US7339078B2 (en) 1995-03-10 2008-03-04 G.D. Searle Llc Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6667307B2 (en) 1997-12-19 2003-12-23 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6861539B1 (en) 1995-03-10 2005-03-01 G. D. Searle & Co. Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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US7141593B1 (en) 1999-06-04 2006-11-28 Abbott Laboratories Pharmaceutical formulations
EP1666452A2 (en) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
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US6562848B1 (en) 2001-09-18 2003-05-13 Bristol-Myers Squibb Company Bis-amino acid sulfonamides as HIV protease inhibitors
JP2011518188A (en) 2008-04-18 2011-06-23 ユニバーシティ オブ コネチカット Compounds for lysosome regulation and methods of use

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5142056A (en) * 1989-05-23 1992-08-25 Abbott Laboratories Retroviral protease inhibiting compounds
US4661473A (en) * 1984-03-27 1987-04-28 Merck & Co., Inc. Renin inhibitors containing peptide isosteres
IL89900A0 (en) * 1988-04-12 1989-12-15 Merck & Co Inc Hiv protease inhibitors useful for the treatment of aids and pharmaceutical compositions containing them
EP0357332A3 (en) * 1988-08-24 1991-07-31 Merck & Co. Inc. Renin inhibitors useful for the treatment of aids by inhibition of hiv protease
IL91780A (en) * 1988-10-04 1995-08-31 Abbott Lab Renin inhibiting hexanoic acid amide derivatives, process for their preparation and pharmaceutical compositions containing them
DE59009945D1 (en) * 1989-02-10 1996-01-18 Wolfgang Prof Dr Schramm AGENT FOR INHIBITING HIV PROTEASES.

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5679688A (en) * 1992-03-11 1997-10-21 Narhex Limited Quinaldoyl-amine derivatives of oxo-and hydroxy-substituted hydrocarbons
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
US5942504A (en) * 1992-03-11 1999-08-24 Narhex Limited Amine derivatives of oxo- and hydroxy- substituted hydrocarbons
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
US6258806B1 (en) 1992-03-11 2001-07-10 Narhex Limited Amine derivatives of oxo- and hydroxy- substituted hydrocarbons

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EP0538366A4 (en) 1994-04-20
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JPH05508855A (en) 1993-12-09
ZA915269B (en) 1992-08-26

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