EP0724446A1 - Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine - Google Patents

Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine

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Publication number
EP0724446A1
EP0724446A1 EP94930595A EP94930595A EP0724446A1 EP 0724446 A1 EP0724446 A1 EP 0724446A1 EP 94930595 A EP94930595 A EP 94930595A EP 94930595 A EP94930595 A EP 94930595A EP 0724446 A1 EP0724446 A1 EP 0724446A1
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EP
European Patent Office
Prior art keywords
gly
hcl
borolys
hydrocinnamoyl
phenethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94930595A
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German (de)
English (en)
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EP0724446A4 (fr
Inventor
Robert Anthony Galemmo, Jr.
Matthew Mark Apartment 3312 ABELMAN
Eugene Cruz Amparo
John Matthew Fevig
Robert Madara Knabb
William Henry Miller
Gregory James Pacofsky
Patricia Carol Weber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
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Publication of EP0724446A1 publication Critical patent/EP0724446A1/fr
Publication of EP0724446A4 publication Critical patent/EP0724446A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates generally to electrophilic peptide analogs as inhibitors of trypsin-like serine
  • proteases 15 proteases. These compounds are dipeptides in which an electrophilic derivative of an ⁇ -amino acid is conjugated with an N, N-disubstituted ⁇ -amino acid.
  • the N, N- disubstituted ⁇ -amino acid conjugates of the electrophilic amino acid analog are derivatives of an amino acid where
  • the ⁇ -amino group is alkylated and acylated or diacylated to give alicyclic or cyclic substituents.
  • the electrophilic functional groups used to derivatize these peptide analogs are: boronic acids and their esters, ⁇ - ono- and ⁇ -perhaloketones, aldehydes, vicinal di- and
  • Electrophilic tripeptide analogs 30 containing the ( (D-phenylalanyl)prolyl) - arginyl- sequence are well known as effective inhibitors of the trypsin-like i serine protease thrombin.
  • H-(D)Phe-Pro-ArgCH 2 Cl was first reported by Kettner and Shaw ⁇ Thromb . Res . 14, 969 (1979)) to be a selective but irreversible inhibitor of human 35 thrombin.
  • a number of studies looking for alternatives to the electrophilic Pi argininechloromethylketones that would yield a reversible protease inhibitor have been reported. Bajuez et al . ⁇ Folia Haematol . 109, s.
  • Patent disclosures in this area have centered around suitably protected peptides composed of natural and unnatural amino acids.
  • U.S. Patent No. 5,187,157 DuPont Merck has disclosed peptides comprised of C-terminal boronic acid derivatives of lysine, ornithine and arginine as reversible inhibitors of trypsin-like serine proteases, as well as a series of boropeptides active as elastase inhibitors in U.S. Patent No. 4,499,082.
  • the present invention concerns dipeptides which contain an electrophilic derivative of an ⁇ -amino acid at P conjugated with an N, N-disubstituted ⁇ -amino acid at P 2 .
  • the electrophilic functional groups used to derivatize the Pi amino acid analog are: boronic acids and their esters, ⁇ -mono- and ⁇ -perhaloketones, vicinal di- and tricarbonyl compounds, and ⁇ . ⁇ -dihalo- ⁇ ketoesters .
  • N, N- disubstituted ⁇ -amino acids are derivatives of an amino acid other than proline where the ⁇ -amino group is alkylated and acylated or diacylated to give alicyclic or cyclic substituents.
  • these compounds are found to have the advantage of an improved toxicological profile as well as the selectivity and inhibition activity for thrombin required for a useful therapeutic agent.
  • R 1 is a) -(C1-C12 alkyl)-X, b) -(C 1 -C 12 alkenyl)-X, or c)
  • R 2 IS a) hydrogen, or b) C1-C4 alkyl
  • R 4 and R ⁇ are independently selected at each occurrence from the group consisitng of: a) hydrogen, b) C 1 -C4 alkyl, c) - (C 1 -C 4 alkyl) -aryl, or d) C 5 -C 7 cycloalkyl;
  • R 6 , R 7 , R 8 and R 9 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C 1 -C 4 alkyl, c) C 1 -C 4 alkoxy, d) aryl, e) -(C 1 -C 4 alkyl) -aryl, f) -(C 1 -C 4 alkyl) -heterocycle, g) -O-aryl, h) -(CH2)p-C0 R 4 , i) R ⁇ and R 7 can be taken together to form a (C 2 -C 7 ) alkyl, or j) R 8 and R 9 can be taken together to form a (C 2 -C 7 ) alkyl;
  • phenyl wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 7 - C 15 alkylaryl, C 7 -C 15 alkoxyaryl, methylenedioxy,
  • R 11 ' is independently selected at each occurrence from the group consisting of: a) hydrogen; b) C 1 -C 4 alkyl
  • R 13 is independently selected at each occurrence from the group consisting of: a) hydrogen b) halogen, c) C 1 -C 4 alkyl, d) C 1 -C 4 alkoxy, e) methylenedioxy, f) -NO2, g) -CF3, h) -SH, i) -S(0) r -(C ⁇ -C 4 alkyl) , j) -CN, k) -OH,
  • R---' nd R-- ⁇ are independently selected at each occurrence from the group consisting of: a) hydroge , b) C 1 -C 4 alkyl, c) -(C 1 -C 4 alkyl) -aryl, where aryl is defined above, d) C 5 -C 7 cycloalkyl, or e) phenyl, unsubstituted or substituted by R 13 , f) C1-C4 alkoxy; R 15 and R 16 taken together to form a ring can also include: a)
  • R 17 is : a) hydrogen, b) C 1 -C 4 alkyl , c) aryl, wherein aryl is defined above, d) -(C 1 -C 4 alkyl) -aryl, wherein aryl is defined above, or e) C 5 -C 7 cycloalkyl;
  • R 18 is: a) hydrogen, b) -(C 1 -C 5 ) alkyl, or c) -(C 1 -C 5 ) haloalkyl, d) -(C1-C5) alkoxy;
  • R-- 1S a) hydrogen, b) -(C 1 -C 5 ) alkyl, c) halo, or d) -(C 1 -C 5 ) haloalkyl, e) -NO2, f) -NR 4 R 5 ' g) -CN, h) -(C1-C5) alkoxy;
  • R 20 is a) hydrogen; or b) -N 2 with amine protecting;
  • Ci-Cs alkoxy or when taken together Y ⁇ and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or
  • a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or
  • Y 3 and Y 4 are a) -OH or b) -F;
  • n 0 or 1 p is 0 to 3 q is 0 to 4, r is 0 to 2, t is 1 to 3. u is 1 to 4, v is 1 to 17
  • Specifically preferred compounds of this invention include:
  • CioHie [N-(-C (0) Ph-3-CH 2 Ph) -N-(CH 3 ) ]Gly-boroOrn (N-methylamidino) -
  • CioHie [N-(-C(0)Ph-3-CH 2 Ph-2-CF 3 ) -N-(CH 3 ) ]Gly-boroOrn (N- methylamidino) -C 10 H 16 [N-(-C (0) (CH 2 ) 2 h) -N-(C 2 H 5 ) ]Gly-boroOrn (N-methylamidino) -
  • CioHie [N-(-C (0) (CH 2 ) 2 h) -N-(C 6 H 12 ) ]Gly-boroOrn (N-methylamidino) -
  • CioHie N-(-C(0) (CH2)2Ph) -N-(OH) ] Gly-boroOrn (N-methylamidino) -
  • CioHie [N-(-C(0) (CH 2 )2Ph) -N-( ⁇ H 2 ) ] Gly-boroOrn (N-methylamidino) - 10H16 [N-(-C(0) (CH 2 )2Ph)-N-( ⁇ (CH 3 ) 2 ) ]Gly-boroOrn (N- methylamidino) -C 1 0H16 [N-(-C (0) (CH2)2Ph) -N-( ⁇ HBoc) ] Gly-boroOrn (N-methylamidino) -
  • CioHie [N-(-C (0) Ph) -N-(CH 3 ) ]Gly-boroOrn (N-methylamidino) -C 10 H 16 [N-(-C(0) (CH 2 )2Ph)-N-CH 2 Ph) ] Gly-boroOrn (N-methylamidino) -
  • CioHie [N- -C(O) (CH 2 ) 2 Ph) -N- ( i-C 3 H 7 ) ]Gly-boroOrn(formamidino) -
  • compositions comprising one or more of the foregoing compounds and methods of using such compositions in the treatment of aberrant proteolysis such as thrombosis in mammals .
  • Trp L-tryptophan
  • the "D” prefix for the foregoing abbreviations indicates the amino acid is in the D-configuration.
  • “D,L” indicates the amino is present in mixture of the D- and the -configuration.
  • the prefix "boro” indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if R-'- is isopropyl and ⁇ l and Y 2 are OH, the C-terminal residue is abbreviated "boroVal-OH” where "-OH” indicates the boronic acid is in the form of the free acid.
  • pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "- Cl ⁇ Hi6" and "-C6H 2", respectively.
  • Examples of other useful diols for esterification with the boronic acids are 1, 2-ethanediol, 1, 3-propanediol, 1, 2-propanediol, 2,3- butanediol, 1, 2-diisopropylethanediol, 5, 6-decanediol, and 1, 2-dicyclohexylethanediol .
  • the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties.
  • the present invention comprises all of the stereoisomers or mixtures thereof. If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard techniques, including chiral chromatography and recrystalization of diastereomeric salts.
  • amine-blocking group refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substituents on these groups maybe either alkyl, aryl, alkaryl which may contain the heteroatoms, 0, S, and N as a substituent or as inchain component. A number of amine-blocking groups are recognized by those skilled in the art of organic synthesis.
  • suitable groups include for yl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl or adamantyloxycarbonyl.
  • aromatic urethane protecting groups such as, benzyloxycarbonyl
  • aliphatic urethane protecting groups such as t-butoxycarbonyl or adamantyloxycarbonyl.
  • amino acid residues refers to natural or unnatural amino acids of either D- or L- configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose. "Amino acids residues” also refers to various amino acids where ⁇ idechain functional groups are coupled with appropriate protecting groups known to those skilled in the art.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Cycloalkyl is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth.
  • Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
  • Halo or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo.
  • aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents.
  • heteroaryl is meant to include 5-, 6-, 9-, or 10-membered mono- or bicyclic aromatic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of 0, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents.
  • heteroaryl include the following: 2- , or 3-, or 4-pyridyl; 2-or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b] thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3- pyrrolyl; 1- or 2- or 3- indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ; 2- or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5- pyrimidinyl; 2-pyrazinyl; 2-triaziny
  • heterocycle is meant to include 5-, 6-, 9-, or 10-membered mono- or bicyclic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of N, 0, or S, with the proviso that proline is excluded from this group; said ring(s) may be unsubstituted or include optional substitution with one to three substituents.
  • group heterocycle include tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine. Particularly preferred are 1-, 3-, or 4-tetrahdroisoquinolinyl .
  • stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I) .
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds .
  • Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy1, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like.
  • compositions of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed.,
  • the compounds of Formula (I) can be prepared using the reactions and techniques described below, in addition to synthetic procedures described in Applicant's Assignee's commonly assigned patent applications U ⁇ SN 08/010,731 (filed January 29, 1993), USSN 08/036,378 (filed March 24, 1993), and USSN 08/052,835 (filed April 27, 1993), all of which are hereby incorporated by reference.
  • the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed.
  • M is a carboxylic acid protecting group
  • N, N-disubstituted amino acid subunit can be accomplished by the sequence outlined in Scheme 1.
  • a variety of methods for the asymmetric synthesis of the amino acids required for the amino acid ester substrate (II) is reviewed by Morrison and Mosher (Asymmetri c Organic Reactions , American Chemical Society, 297-334 (1976) and references there in) .
  • the appropriate ester (II) where M is the ester residue, can be conjugated to give the N-substituted intermediate (III) by N-monoalkylation with an alkyl halide related to R 11 .
  • Typical conditions for N-monoalkylation include the admixture of an excess of (II), the required alkyl bromide or iodide and a base in an anhydrous polar aprotic solvent, such as acetone, acetonitrile, N, N-dimethylformamide or methyl sulfoxide.
  • anhydrous polar aprotic solvent such as acetone, acetonitrile, N, N-dimethylformamide or methyl sulfoxide.
  • the base added is chosen so that it will not interfere with the ester functionality of (II) ; among those recommended are non-nucleophilic bases such as sodium hydride or potassium carbonate.
  • Another general route for the preparation of compounds of this type is the reductive amination of (II) with a selected aldehyde related to R 11 .
  • a mixture of (II) and the aldehyde are heated in an anhydrous non polar solvent, such as benzene, toluene or xylene, with continuous removal of evolved water by drying agents or azeotropic distillation.
  • This process causes condensation of the aldehyde with amine (II) .
  • the condensation product is reduced to monoalkylated (III) by treatment with a selective hydride reducing agent such as sodium cyanoborohydride or sodium borohydride, according to the method of Getson et . al . , J.
  • the second method is the mixed anhydride procedure of Anderson et al . reported in J. Am. Chem . Soc . 89, 5012 (1967) .
  • the alkyl mixed anhydride is generated by dissolving a selected carboxylic acid related to R 3 in non-polar anhydrous solvent, such as tetrahydrofuran or dichloromethane, and adding one equivalent of a trialkylamine base.
  • the solution is stirred at -78°C or higher and one equivalent of an alkylchloroformate is added.
  • a solution of one equivalent each of intermediate (III) and a trialkylamine base is added dropwise. The mixture is stirred with or without cooling until the reaction is complete.
  • the third method preferred for amide formation is the hydroxybenzotriazole / dialkylcarbodiimide method of Koing and Geiger in Chem. Ber. 103, 788 (1970) .
  • a selected carboxylic acid related to R 3 dissolved in an aprotic solvent like N, N-dimethylformamide, dichloromethane or tetrahydrofuran, at -78°C or higher, is added dialkylcarbodiimide, hydroxybenzotriazole and a trialkylamine base. If necessary, the stirred solution is allowed to thaw to ambient temperature over several hours .
  • N, N-disubstituted amino acids uses ⁇ -halo- or ⁇ -sulfonate acylesters such as (V) of Scheme 2.
  • Compound (V) can be treated with a primary amine related to R 11 in.the presence of a variety of bases like potassium carbonate, triethyl amine or sodium hydride and in solvents such as ethyl ether, acetone or dimethylformamide at temperatures ranging from -78° C to the reflux point of the solvent selected.
  • N-alkyl aminoacid ester (III) of Scheme 1 From this reaction can be isolated the N-alkyl aminoacid ester (III) of Scheme 1; the N-alkyl -N-acylamino acid ester (IV) can be prepared from compound (III) by any of the methods outlined in Scheme 1 and the related discussion hereafter.
  • the alkali metal salt of the required cyclic amide or phthalimide is generated by adding one equivalent of a strong non-nucleophilic base such as sodium or potassium hydride, a lithium dialkylamine, or lithium trimethyl- or lithium triphenylmethane to a solution of the amide or phthalimide in an anhydrous inert solvent, such as tetrahydrofuran or 1, 2-dimethoxyethane, at -78° C or higher.
  • anhydrous inert solvent such as tetrahydrofuran or 1, 2-dimethoxyethane, at -78° C or higher.
  • the solvent is removed by distillation and replaced by the appropriate polar aprotic solvent such as acetonitrile, N, N- dimethylformamide or methylsulfoxide.
  • the appropriate ⁇ - chloro- or ⁇ -bromoester is introduced and the mixture stirred at room temperature or with heating until the haloester is consumed.
  • Scheme 3 illustrates the coupling of the acid derivatives of (IV) or (VI) with boropeptide synthons (VII) or (VIII) to give intermediates (IX) or (X) .
  • a process for the preparation of the boropeptide thrombin inhibitors of this invention from intermediates (IX) and (X) is disclosed in Scheme 4.
  • Compound (IX) serves as a starting point for isothiouronium thrombin inhibitors (XI) and (XII) .
  • the boronic ester (XI) is prepared by stirring a solution of (IX) and thiourea in an inert polar solvent, such as an alcohol or N, N- dimethylformamide, at temperatures ranging from ambient to the reflux temperature of the selected solvent.
  • a boronic acid ester like compound (XI) is an effective thrombin inhibitor, however, it may be transformed to the corresponding free boronic acid (XII) without a loss of biological activity.
  • Compound (XII) is derived from the boron ester (XI) by transesterification under equilibrium conditions.
  • Thrombin inhibitors (XIII) to (XVI) are obtained by reduction of an azide intermediate prepared from (IX) or (X) .
  • the azide intermediate is prepared by heating either (IX) or (X) with an inorganic azide, such as sodium or potassium azide, in an anhydrous polar aprotic
  • phase transfer conditions may be employed to prepare the azide intermediate from (IX) or (X) .
  • a tetraalkylammonium azide in a non-polar aprotic solvent, such as tetrahydrofuran or toluene, or a crown ether and inorganic azide in biphasic mixtures of water and an immiscible solvent, such as benzene, toluene or xylene can be stirred at room temperature or heated up to the reflux point of the selected solvent .
  • the primary amines (XIII) and (XIV) are most conveniently obtained from the catalytic hydrogenation of the azide in an inert solvent, such as an alcohol, ethyl acetate or tetrahydrofuran with a transition metal catalyst such as platinum or palladium on carbon under an atmosphere of hydrogen gas .
  • an inert solvent such as an alcohol, ethyl acetate or tetrahydrofuran with a transition metal catalyst such as platinum or palladium on carbon under an atmosphere of hydrogen gas .
  • the acid salt of the resulting amines (XIII) and (XIV) may be formed by the addition of one equivalent of the desired acid to the hydrogenation mixture.
  • Phenylboric acid mediated hydrolysis of esters (XIII) and (XIV) gives the free boronic acid thrombin inhibitors (XV) and (XVI) , compounds of formula (I) of the invention.
  • guanidine boronic acid esters (XVII) can be deesterified to give the corresponding boronic acid (XVIII) by the phenylboric acid procedure described above.
  • Effective methods include the use of potassium or sodium cyanides in polar aprotic solvents, such as N,N- dimethy1formamide, methylsulfoxide, acetone or ethylmethyl ketone, at temperatures ranging from ambient up to the reflux point of the selected solvent. More useful, however, are conditions employing phase transfer agents such as tetrabutylammonium cyanide in a nonpolar aprotic solvent such as tetrahydrofuran or toluene, or a biphasic mixture of a crown ether and an inorganic cyanide in water with an immiscible solvent like benzene, toluene or xylene.
  • phase transfer agents such as tetrabutylammonium cyanide in a nonpolar aprotic solvent such as tetrahydrofuran or toluene, or a biphasic mixture of a crown ether and an inorganic cyanide in water with an immiscible
  • An amidine like (XX) is prepared by first treating nitrile (XIX) with a saturated solution of a mineral acid such as hydrogen chloride in an alcohol solvent at room temperature or lower.
  • a mineral acid such as hydrogen chloride
  • the intermediate O-alkylimidate can be exposed to ammonia, or a primary or secondary amine under anhydrous conditions with or without an inert solvent.
  • compound (XX) is produced by treating the O-alkylimidate formed from (XIX) with neat anhydrous ammonia at reflux.
  • the free boronic acid (XXI) is obtained by transesterification of (XX) with phenylboric acid in a mixture of water and diethyl ether.
  • the formamidine substituted boronic acid (XXIII) is prepared from alkylamine (XV) as shown in Scheme 6.
  • Compounds of (XV) can be stirred with an O-alkyl or O-aryl formimidate from 0°C or up to the reflux temperature of an inert anhydrous solvent such as tetrahydrofuran or N, N- dimethylformamide to give formamidine (XXII) .
  • Free boronic acid (XXIII) is produced from (XXII) by the phenylboric acid transesterification protocol.
  • the N-cyanoguanidine substituted boronic acid (XXVI) can be prepared by the reaction of (XV) with an N-cyanoisourylation agent such as £,_?-dimethyl N-cyanoiminodithiocarbonate or 0, O-diphenyl N-cyanodiimino- carbonate.
  • N-cyanoisourylation agent such as £,_?-dimethyl N-cyanoiminodithiocarbonate or 0, O-diphenyl N-cyanodiimino- carbonate.
  • compounds of Formula (XV) are combined with a selected iminocarbonate in an inert, anhydrous solvent like tetrahydrofuran or N, N- dimethylformamide.
  • ammonia or more generally, an alkylamine or an arylamine with or without an inert solvent like water, tetrahydrofuran or an alcohol at temperatures ranging from 0°C to reflux to give the aminolysis product (XXV) .
  • Treatment of (XXV) as described above with phenylboric acid can provide (XXVI) .
  • N-hydroxyguanidino inhibitors are prepared by treating amine (XV) with cyanogen bromide or cyanogen chloride followed by hydroxylamine in an inert• solvent to yield (XXVII) according to ⁇ akahara et. al., Tetrahedron 33, 1591 (1977); and Belzecki et al., J. Chem. Soc . Chem . Commun . p. 806 (1970) . Transesterification of (XXVII) by the phenylboric acid method can provide (XXVIII) .
  • the a-aminoboronic acid, (XXX) can be obtained by treating (XXIX) with the sodium or lithium salt of hexamethyldisilizane in a polar aprotic solvent like acetone, N, N-dimethylformamide or methyl sulfoxide with heating at temperature up to the reflux point of the selected solvent, if necessary.
  • a polar aprotic solvent like acetone, N, N-dimethylformamide or methyl sulfoxide
  • compound (XXXIa) is a versatile intermediate that can be hydrogenated to yield the aminomethyl derivative (XXXIIIa) under a variety of conditions (Hudlicky, (1984), pp 173).
  • Catalysts recommended for this transformation include transition metals like rhodium, Raney nickel, nickel boride, nickel, platinum or palladium; these reductions occur readily under atmospheres of hydrogen or ammonia at pressures ranging from 1 to 300 atmospheres, at room temperature or higher, and in inert solvents such as water, an alcohol, ethyl acetate or tetrahydrofuran.
  • Aromatic boronic acid inhibitors (XLIa.b) , with the guanidine functionality substituted directly on the aromatic nucleus, can be prepared from precursor (XXXVIII) according to Scheme 11. Nitration of the aromatic ring of (XXXVIII) according to the method of Olah and Kuhn, J. Amer. Chem. Soc.
  • 84, 3684 (1962) can occur readily with agents such as acetyl nitrate, nitrosonium tetrafluoroborate (N ⁇ 2 + BF 4 ⁇ ) and nitrosonium hexafluorophosphate (N ⁇ 2 + PF 6 ⁇ ) in inert solvents like tetrahydrofuran or dichloromethane at -78°C or higher.
  • agents such as acetyl nitrate, nitrosonium tetrafluoroborate (N ⁇ 2 + BF 4 ⁇ ) and nitrosonium hexafluorophosphate (N ⁇ 2 + PF 6 ⁇ ) in inert solvents like tetrahydrofuran or dichloromethane at -78°C or higher.
  • the products of formula (XXXIX) can be reduced to the aniline derivative (LX) by catalytic hydrogenation.
  • the catalysts recommended for this procedure include iron, zinc, platinum oxide, rhodium
  • the aniline (LX) can be converted to the phenylguanidine (LXIa) by the procedure described for (XVII) in Scheme 4.
  • the transformation of (LXIa) to the free boronic acid (LXIb) is effected as in Scheme 4.
  • the several types of inhibitors disclosed in this invention can be broadly classified by their electrophilic functional group _ ⁇ , as defined in Formula -(I) .
  • the compounds described below unlike the boron containing peptides, utilize a highly electrophilic carbon atom at A to interact with the active site serine of thrombin.
  • the precursor for the electrophilic carbon inhibitors is the appropriately protected amino acid (LXII) of Scheme 12.
  • M alkyl or benzyl
  • the acid can be transformed to the mixed anhydride by condensation of the trialkylammonium salt of the acid with an alkyl- or arylchloroformate in an inert non-polar solvent such as tetrahydrofuran, 1,2-dimethoxyethane or toluene at-78°C to
  • the peptidyl alcohol can be oxidized to aldehyde (LII) without over oxidation by a variety of procedures, as detailed by Hudlicky in Oxidations in Organic Chemistry, American Chemical Society, p. 114 (1991) ; the preferred methods
  • a metallated trifluoromethyl anion is generated from an excess of trifluoromethyliodide or -bromide and an active metal such as zinc, magnesium, lithium or cadmium in inert, anhydrous solvents like tetrahydrofuran or N,N-dimethyIformamide at temperatures of -100°C up to the reflux point of the solvent.
  • an active metal such as zinc, magnesium, lithium or cadmium in inert, anhydrous solvents like tetrahydrofuran or N,N-dimethyIformamide
  • the metalated trifluoromethyl anion may be generated by the transmetallation of trifluoromethyliodide or -bromide with an organometallic compound such as a Grignard reagent or alkyllithium compound in an inert solvent like tetrahydrofuran, hexane or ether at temperatures ranging from -78°C up to the reflux point of the selected solvent.
  • an organometallic compound such as a Grignard reagent or alkyllithium compound in an inert solvent like tetrahydrofuran, hexane or ether at temperatures ranging from -78°C up to the reflux point of the selected solvent.
  • Aldehyde (LII) can be added to the solution of the metalated trifluoromethyl anion to form the trifluoroethanol derivative at temperatures of -100°C or higher.
  • Trihalomethyl analogs of (LIII) where J is fluoro can also be prepared from aldehyde (LII) by a different method.
  • the trihalomethyl ketones are prepared by treating aldehyde (LII) with either the trimethylsilyl trihaloacetate or the potassium or sodium trihaloacetate in a polar solvent such as an alcohol, N, N-dimethylformamide or methylsulfoxide with or without a base such as a trialkyl amine, potassium carbonate or sodium hydroxide at temperatures of -78°C or higher according to the method of Beaulieu, Tetrahedron Lett . 32, 1031 (1991); Shell Int. Res., European Patent Application EP 16504 ) .
  • the resulting a,a,a-trihaloethanol is oxidized and group X can be deprotected as above to give the thrombin inhibitors or formulae (LIII) .
  • the a-ketoester thrombin inhibitors exemplified by (LV) , are prepared according to a route disclosed by Iwanowicz et. al. in Bioorgan . Med. Chem. Let t . 12, 1607 (1992) .
  • the tris (ethylthio)methyl anion is added to the peptidyl aldehyde (LII) in a solvent such as tetrahydrofuran, 1, 2-dimethoxyethane or toluene at -100°C or higher to give the alcohol (LIV) .
  • the a-hydroxyl ester is generated from (LIV) by treatment with a mixture of mercuric salts, such as mercuric chloride and mercuric oxide, in an alcohol or water. Swern or Pfitzner-Moffat oxidation of the a-hydroxyl ester followed by the deprotection of substituent X protecting group provides thrombin inhibitors of formula (LV) .
  • This alkoxyolefin product may then be transformed to (LV) by oxidative cleavage with reagents such as ozone or periodate in an inert solvent such as a halohydrocarbon, lower alkyl ketone, an alcohol or water at temperatures ranging from -100 °C to ambient temperature, followed by oxidation of the intervening a-hydroxyester and deprotection as described above.
  • reagents such as ozone or periodate in an inert solvent such as a halohydrocarbon, lower alkyl ketone, an alcohol or water at temperatures ranging from -100 °C to ambient temperature, followed by oxidation of the intervening a-hydroxyester and deprotection as described above.
  • reagents such as ozone or periodate in an inert solvent such as a halohydrocarbon, lower alkyl ketone, an alcohol or water at temperatures ranging from -100 °C to ambient temperature
  • the a,a-dihalomethylketone (LVII), where J is fluoro can be prepared from the aldehyde (LII) by selective reaction of the aldehyde with the anion of the corresponding dihalomethane.
  • the metalated dihalomethane anion is generated from one equivalent each of a strong hindered base, such as lithium tetramethylpiperidide or tertbutyllithium, and the selected dihalomethane in an anhydrous, inerfsolvent like tetrahydrofuran or 1,2- dimethoxyethane at -100°C or higher according to the method of Taguchi et. al. Bull . Chem. Soc. Jpn . , 50, 1588 (1977).
  • the metalated dihalomethane anion can be added to the aldehyde (LII) at -100°C or higher.
  • the dihalomethane anion is generated from a dihalomethyl (trimethyl)silane and an anhydrous fluoride ion source such as tris (diethylamino)sulfonium difluoromethyl silicate in an inert solvent like benzene, acetonitrile or tetrahydrofuran at -78°C or higher, then (LII) can be added to give dihaloethanol (LVI) according to the method of Fujita and Hiyama, J. Am . Chem . Soc . 107, 4085 (1985) .
  • a-Halomethylketone thrombin inhibitors can be prepared by the process illustrated in Scheme 17.
  • the acid chloride (LVIII) can be prepared from acid (LI), wherein M is hydrogen or its trialkylammonium, sodium or potassium salt with a chlorinating agent such as thionyl chloride, oxalyl chloride or dichloromethylmethyl ether in a solvent like tetrahydrofuran or dichloromethane with or without a catalytic amount of N. N-dimethylformamide at -78°C or higher.
  • a chlorinating agent such as thionyl chloride, oxalyl chloride or dichloromethylmethyl ether in a solvent like tetrahydrofuran or dichloromethane with or without a catalytic amount of N. N-dimethylformamide at -78°C or higher.
  • the mixed anhydride of (LI) may be prepared as described for (LI) in Scheme 15.
  • Compound (LVIII) or the mixed anhydride of (LI) can be treated with an ether solution of diazomethane and either anhydrous hydrogen fluoride or hydrogen chloride gas according to that described by McPhee and Klingsbury, Org. Synth . Coll . Ill, 119 (1955); or hydrogen bromide according to the method Miescher and Kaji, Helv. Chim . Acta . 24, 1471 (1941) .
  • the preparative routes for the synthesis of the a- mono- and a,a-dihalo-b-ketoester -amide and ketone thrombin inhibitors of this invention are summarized in Scheme 19.
  • the exemplified jb-ketoester (LXII) is available from the acid derivative (LI) .
  • the acid (LI) can be treated with carbonyl diimidazole in an inert solvent such as tetrahydrofuran or dichloromethane at 0°C or higher to form the acyl imidazole.
  • This acyl imidazole, or the mixed anhydride of (LI) can be further reacted with lithioethylacetate in solvents such as 1, 2-dimethoxyethane or tetrahydrofuran/hexane at temperatures ranging from
  • Reagents such as N- fluorobis [ (trifluoromethyl) sulfonyl] imide are useful for the preparation of mono- and difluoro analogs (LXIII) and (LXIV) by reacting the appropriate stoichiometry of this reagent with (LXII) in a halogenated solvent at temperatures of -78°C or higher according to the method of Resnati and DesMarteau, J. Org . Chem. 56, 4925 (1991). Deprotection of substituent X of the halogenation products (LXIII) and (LXIV) can provide the corresponding thrombin inhibitors.
  • the decarboxylation of these halogenation products, (LXIII) and (LXIV) can be effected by saponification of the ester with mild aqueous base such as potassium carbonate or sodium hydroxide in water miscible solvents like an alcohol, tetrahydrofuran or N. N-dimethyIformamide, followed by adjusting the pH to a range of 4 to 6.
  • This mixture can be either stirred at ambient temperatures or heated at various temperatures up to the reflux point of the solvent chosen until the formation of (LVII) or (LIX) is complete and is similar to that reported in Matsuda et. al., Tetrahedron Lett . 30, 4259 (1989). Removal of protecting group(s) can provide thrombin inhibitors corresponding to (LVII) or (LIX) .
  • Inhibitors which contain a substituted phenethyl group as R 11 are easily prepared according to Scheme 26.
  • the appropriate phenylacetate (XCIV) is readily dialkylated with an excess of a small, unbranched alkyl halide (R 18 -X) and a suitable base such as .potassium tert-butoxide to form an a,a-bisalkylated ester (XCVa) .
  • Reduction of XCVa to the primary alcohol may accomplished with many hydride reducing agents, a preferred agent being lithium aluminum hydride. Oxidation of the alcohol under Swern conditions or with pyridinium chlorochromate affords the aldehyde (XCV) .
  • XCV is best coupled to the appropriate glycine derivative by reductive amination, a preferred procedure being reduction with sodium cyanoborohydride.
  • the resulting amine (XCVI) is then coupled with R 3 by any of several standard amide bond forming reactions familiar to those skilled in the art.
  • a preferred method involves treating the amine with the appropriate acid chloride in the presence of a tertiary amine base, such as N- methylmorpholine or triethylamine. Saponifica ion of the ester affords the carboxylic acid (XCVII) .
  • the acid (XCVII) is then coupled to (LXXXVI) and elaborated to the inhibitors of the present invention by following the procedures outlined in Schemes 3, 4, and 5.
  • Inhibitors which contain a 1 , w-alkanediyl substituted phenethyl group (XCVb) as R 11 are easily prepared according to Scheme 27 .
  • This procedure is similar to that of Scheme 26 , except that a l , w-bifunctional alkylating agent (X-R 18 - X) instead of a monofunctional alkylating agent (R 18 -X) .
  • inhibitors of the present invention with the general formula (XCVII lb ) may be prepared .
  • Inhibitors in which R- is an acylalkyl terminated by a carboxylic acid or ester are prepared by the general route described in Scheme 28. Reaction of a suitably substituted cyclic anhydride (C) with an alkoxide such as sodium benzyl oxide affords a mono-protected diacid (C .
  • ester groups should allow for selective deprotection of the glycine carboxylate.
  • Preferred ester groups are methyl or ethyl on the glycine carboxylate and benzyl on the acylalkyl chain, so that saponification gives the acid (CII) .
  • (CII) is then converted to the final products (CIII) following methods described in previous schemes.
  • Part A To hydrocinnamic acid (10.0 g, 66.7 mmol) and 4- methylmorpholine (6.74 g, 66.7 mmol) in tetrahydrofuran (THF, 200 inL) at 0°C was added n-butylchloroformate. The reaction was maintained at 0°C for 15 minutes, and the hydrochloride salt of sarcosine ethyl ester (10.23 g, 66.7 mmol) followed by triethylamine (Et 3 ⁇ , 16.84 g, 166.8 mmol) was added. The reaction was allowed to thaw to ambient temperature and stirred for 18 hours.
  • THF tetrahydrofuran
  • Part B To a solution of ethyl N-methyl-N- [ (3- phenyl)propionyl]glycine (11.81 g, 47.4 mmol) in ethanol (300 mL) was added aqueous sodium hydroxide ( ⁇ aOH, 1 ⁇ , 94.8 mL, 94.8 mmol). The reaction was stirred at ambient temperature for 18 hour, afterwhich the solvent was removed by distillation in vacuo . The residue was dissolved in HCl (1 ⁇ , 100 mL) and the solution extracted with methylene chloride (CH 2 CI 2 . 2 x 100 mL) .
  • aqueous sodium hydroxide ⁇ aOH, 1 ⁇ , 94.8 mL, 94.8 mmol
  • Part A A mixture of Intermediate 1 (0.31 g, 1.5 mmol), pinanediol l-amino-5-bromopentaneboronate (0.57 g, 1.85 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), 4- methylmorpholine (0.17 mL, 1.5 mmol), and 1,3- dicyclohexylcarbodiimide (DCC, 0.33 g,1.5 mmol) were stirred in dry CH 2 CI 2 at 0°C for 1 hour. The reaction was thawed to ambient temperature and stirred an additional 18 hour. After this time, the reaction mixture was diluted with CH 2 CI 2 (25 mL) and filtered.
  • DCC 1,3- dicyclohexylcarbodiimide
  • Part B The intermediate from Part A (0.75 g, 1.4 mmol) was heated with sodium azide ( ⁇ a ⁇ 3 , 0.15 g, 2.3 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 100°C for 2 hours. The reaction mixture was partitioned between water (H 2 O) and EtOAc (25 mL each) , and the EtOAc layer was washed with additional H 2 0 (6 x 15 mL) .
  • H 2 O water
  • EtOAc 25 mL each
  • Part C The azide from Part B (0.48 g, 0.9 mmol) was dissolved in methanol (MeOH, 15 mL) with benzenesulfonic acid (0.15 g, 0.9 mmol) and Pearlman's catalyst (palladium hydroxide on carbon, 0.05 g) . This mixture was shaken under an atmosphere of 50 psi of hydrogen for 18 hours at ambient temperature. The reaction mixture was purged with nitrogen and the catalyst was removed by filtration through, a pad of diatomaceous earth.
  • Part A A mixture of benzyl glycinate, p-toluenesulfonic acid salt (2.68 g, 7.94 mmol), (2-phenyl)bromoethane (0.98 g, 5.29 mmol), and solid ⁇ aHC0 3 (1.56 g, 18.5 mmol) in acetonitrile (25 mL) were heated at reflux for 18 hour. The reaction was concentrated and diluted with EtOAc (25 mL) . The organic solution was washed with H 2 O (25 mL) and brine (25 mL) , dried (Na 2 ⁇ 4 ) and concentrated in vacuo.
  • Part B A mixture of intermediate from Part A (0.82 g, 3.04 mmol) and 4-methylmorpholine (0.62 g, 6.08 mmol) in THF (15 mL) at 0°C was added hydrocinnamoyl chloride (0.51 g, 3.04 mmol). The reaction was thawed to ambient temperature and stirred for 1 hour. The reaction mixture was diluted with EtOAc (50 mL) , washed with HCl (10%, 25 mL) and ⁇ aHC0 3 (saturated, 25 mL) , dried (MgS ⁇ 4 ) and evaporated.
  • Part B The intermediate pinanediol N- ⁇ N- [ (2 - phenyl)ethyl] -N- [ (3-phenyl)propionyl]glycyl ⁇ -1-amido-
  • Part A By substituting pinanediol l-amino-4- bromobutaneboronate for pinanediol l-amino-5- bromopentaneboronate and coupling with Intermediate 3 according to the procedure in Example 21.1.3, Parts A-C, the amino intermediate was prepared.
  • Part A The intermediate from Example 50, Part A hydrochloride salt (1.0 g, 2 mmol), formamidine sulfonic acid (0.496 g, 4 mmol) and DMAP (0.488 g, 4 mmol) in ethanol (50 mL) were heated at reflux for 3 hours. The reaction was cooled to ambient temperature, filtered through a pad of Celite, rinsed with chloroform (CHC1 3 ) and evaporated. The residue was dissolved in CHCI 3 and washed with HCl (0.1 ⁇ ) and brine, dried and evaporated. The title compound was obtained as a white solid. HRMS calcd for C 26 H 39 B ⁇ 5 ⁇ 4 Cl 2 :582.247216 + ; found: 566.247905.
  • Part B To a solution of hexamethyldisilazane (0.21 mL, 0.98 mmol) in THF (2 mL) at -78°C was added n-butyllithium (1.45 M, 0.67 mL, 0.98 mmol) . The solution was allowed to slowly warm to room temperature to ensure the anion generation was complete and recooled to -78°C, upon which a solution of product from Part A (0.33 g, 0.98 mmol) in THF (2 mL) was added. The mixture was allowed to warm to room temperature and to stir overnight . The volatiles were evaporated and hexane (8 mL) was added to give a suspension.
  • Pinanediol N- ⁇ N-methyl -N- [ (3- phenyl)propionyl]glycyl ⁇ -l-amido-4-aminobutylboronate, hydrochloride salt was prepared by the method outlined for Example 21.1.3, wherein pinanediol l-amino-4- bromobutylboronate hydrochloride was used instead of pinanediol l-amino-5-bromopentane-boronate hydrochloride.
  • Part B To a solution of the product from Part A (0.45 g, 0.89 mmol) in ethanol (10 mL) was added DMAP (0.22 g, 1.78 mmol) . After 15 minutes at room temperature, ⁇ - methylaminoiminomethanesulfonic acid (0.25 g, 1.78 mmol) was added and the resulting suspension stirred at reflux for 5 hours. The reaction was cooled to room temperature, filtered, the precipitate washed with CHCI 3 and the combined filtrate concentrated under vacuum. The resulting oil was dissolved in CHCI 3 (40 mL) and the organic solution washed with ice cold HCl (0.1 M, 1x10 mL) , ice cold H 2 O
  • Part A Boc- (D)Phe-OH (6.9 g, 26 mmoles) as dissolved in THF (50 mL) and 4-methylmorpholine (2.86 mL, 26 mmoles) was added. The solution was cooled to -20°C and isobutylchlorofor ate (3.38 ml, 26 mmoles) was added. After stirring 5 minutes at -20°C, the mixture was added to a cold solution of H-Sar-Bzl»toluenesulfonic acid dissolved in CHC1 3 (50 mL) , followed by E 3 (3.6 mL, 26 mmoles).
  • Part B The product from Part A (10.4 g) was dissolved in MeOH (100 mL) and the sample was hydrogenated for 2 hour on a Parr apparatus in the presence of palladium on carbon (10%, 0.5 g) . The catalysis was removed by filtration and solvent was evaporated to yield Boc- (D) Phe-Sar-OH as a foam (7.8 g) .
  • Part C The mixed anhydride of product from Part B (4.42 g, 13.1 mmoles) was prepared as previously described and coupled to NH2-CH[ (CH2)4Br]B02CioHi6 «HCl (5.0 g, 13.1 mmoles) using the procedure described in Part A.
  • the crude product (7.7 g) was purified by chromatography of a 4.2 g portion on a 2.5 x 100 cm column of Sephedex LH-20 using MeOH as a solvent to give Boc- (D) Phe-Sar-NH-CH[ (CH2) 4- Br]B02CiQHi6.
  • Part D The product from Part C (3.5 g, 5.8 mmoles) was dissolved in anhydrous HCl in dioxane (4.1 N, 50 mL) and was stirred for 1 hour at room temperature. Solvent and excess HCl were removed by evaporation. The residue was triturated with hexane to yield H- (D) Phe-Sar-NH-CH[ (CH2) 4- Br]BO2Cl0Hi6»HCl (2.9 g) .
  • Part E The product from Part D (2.9 g, 4.8 mmoles) was dissolved in 30 mL of a 50% (v/v) solution of dioxane: water and acetic anhydride (0.92 ml, 9.7 mmoles) was added. NaHC03 (0.81 g, 9.7 mmoles) was added and the solution was allowed to stir 45 minutes at room temperature. Acetic acid (3 ml) was added and solution was concentrated approximately 50% by evaporation. It was diluted to 100 mL with EtOAc and was washed with NaHC03 (5%), HCl (0.2 N) , and brine.
  • Part F The product from Part E (2.5 g, 4.1 mmoles) and a 3 (0.54 g, 8.3 mmoles) were dissolved in DMF (5 mL) and heated at 100°C for 1 hour. The reaction was allowed to cool and was diluted with EtOAc (100 mL) . The organic phase was washed with H2O and saturated brine, dried over a2S04, filtered, and evaporated to yield Ac- (D)Phe-Sar-NH- CH[ (CH2)4- 3]B02CioHi6 as a white foam (2.2 g) .
  • Part G The product from Part F (2.0 g, 3.5 mmoles) was dissolved in MeOH (100 mL) and was hydrogenated on a Parr apparatus in the presence of HCl in dioxane (4.1 N, 1.3 ml, 5.3 mmoles) and palladium on carbon (10%, 0.5 g) . The catalysis was removed by filtration and solvent was removed by evaporation.
  • Part H The product from Part G (1.5 g, 2.5 mmoles) and phenyl boronic acid (1.5 g, 12 mmoles) was dissolved in H2O and Et 2 ⁇ (15 ml each) . The mixture was stoppered and allowed to stir for 3 hour at room temperature. The phases were separated and the aqueous phase was washed extensively with Et 2 0. The aqueous phase was evaporated, dried in vacuo., and triturated with Et 2 ⁇ to yield the title compound (0.98 g) . An analytical sample was prepared as the pinacol ester by treating 4 mg of the boronic acid with 2 equivalents of pinacol in 1.4 ml of MeOH for 5 minutes and evaporating solvent. HRMS calcd for the pinacol ester C25H41N4O5B (M+H) : 489.3248. found: 489.3242.
  • Part B To the hydrochloride salt prepared above (1.0 g, 5.97 mmol) and hydrocinnamic acid (0.9 g, 5.97 mmol) in DMF (20 mL) was added 0-benzotriazole-N, N, N ', N'- tetramethyluronium hexafluorophosphate (2.26 g, 5.97 mmol) followed by N, ⁇ -diisopropylethylamine (1.69 g, 13.1 mmol) . The reaction was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with 1:1 EtOAc:hexane and washed with H 2 0 (2 x) , HCl (10%) , saturated ⁇ aHC0 3 and brine.
  • Part A A mixture of 2- (methylphenyl)benzoic acid (3.09 g, 14.55 mmol), sarcosine ethyl ester hydrochloride salt (2.23 g, 14.55 mmol), DCC (3.0 g, 14.55 mmol), HOBT (1.97 g, 14.55 mmol) and Et 3 ⁇ (1.47 g, 14.55 mmol) in THF (50 mL) were stirred at ambient temperature for 48 hours. The reaction was evaporated and the residue dissolved in EtOAc. The EtOAc solution was washed with HCl (10%), saturated NaHC ⁇ 3 and brine, and dried (MgS0 4 > .
  • Pinanediol N- ⁇ N- methyl-N-[2- (methylphenyl)benzoyl]glycyl ⁇ -1-amido-5- bromopentaneboronate was reacted withe a 3 by under the conditions detailed above to give pinanediol N- ⁇ N-methyl-N- [2- (methylphenyl)benzoyl]glycyl ⁇ -1-amido-
  • Trimethylsilyl cyanide (5.80 mL, 44.0 mmol) was added dropwise to a solution of benzaldehyde (3.10 g, 29.0 mmol) and zinc iodide (280 mg, 8.80 mmol) at 0 °C.
  • the reaction mixture was warmed to room temperature over 18 h then treated with saturated aqueous NaHC03 (ca. 100 mL) .
  • the layers were separated and the aqueous was extracted with EtOAc (2 x 75 mL) .
  • Lithium aluminum hydride (2.10 g, 55.0 mmol) was added in portions over 15 min to a solution of [2 - (trimethylsilyl)oxy] -phenylacetonitrile (3.75 g, 18.3 mmol) in anhydrous THF (75 mL) at 0 °C.
  • the reaction was quenched by the sequential addition of H 2 0 (2.10 mL) , 10% aqueous NaOH (2.10 mL) , and H 2 0 (6.30 mL) then dried (Na 2 S0 4 ) and filtered through a pad of Celite using EtOAc (ca. 75 mL) .
  • Part B Phosgene (6.0 mL of a 1.93 M solution in toluene (PhCH 3 ), 12.0 mmol) was added to a solution of 2-hydroxy-l- phenethylamine (1.18 g, 8.60 mmol) in PhCH 3 (100 mL) at 0 °C followed by the dropwise additon of Et 3 N (1.80 mL, 13.0 mmol) .
  • the reaction mixture was warmed to room temperature over 48 h and poured into EtOAc (ca. 200 mL) . The layers were separated and the aqueous was extracted with EtOAc (1 x 50 mL) .
  • Part C A solution of 5-phenyl-2-oxazolidinone (500 mg, 3.1 mmol) in anhydrous THF was added dropwise to a suspension of NaH (91 mg, 3.7 mmol) in anhydrous THF at 0 °C. The reaction mixture was warmed to room temperature over 30 min then heated at reflux for 15 min. Methyl bromoacetate (0.32 mL, 3.4 mmol) was added and the ixtue was heated at reflux for 2h. The reaction mixture was cooled to room temperature and quenched with H 0 (ca. 20 mL) . The aqueous was extracted with EtOAc (2 x 75 mL) .
  • Part D A solution of 2- [3- (5-phenyl-2- oxazolidino) ]acetic acid, methyl ester (540 mg, 2.30 mmol) in MeOH (10 mL) and H 2 0 (10 mL) was treated with NaOH (138 mg, 3.40 mmol) and heated at reflux for 15 min. The reaction mixture was cooled to room temperature, acidified to pH 2 with 2M aqueous HCl, and extracted with EtOAc (3 x 50 mL) .
  • Part F A solution of ( 2R) -2- [ [3- (5-phenyl-2- oxazolidino) ] -acetamido] -4-bromo-l-aminobutane-l-boronic acid, (+) -pinanediol ester (770 mg, 1.45 mmol) and thiourea (220 mg, 2.90 mmol) in EtOH (15 mL) was heated at reflux for 36 hours then_ cooled to room temperature and diluted with Et 2 0 (ca. 100 mL) which was decanted. The residue was purified by size exclusion chromatography on Sephadex LH - 20, elution* with MeOH, to give a foam.
  • N- ( 1 , 8- napthyldiimido)glycine would be to react the sodium salt of 1, 8-napthalic phthalimide with ethyl bromoacetate in dimethylformamide at 60°C. The resulting ester can then be hydrolyzed with IN sodium hydroxide in ethanol solution to give the title compound.
  • Part B _V,W-(l,8- ⁇ apthyldiimido)glycine (0.56 g, 2.1 mmol) and N-methylmorpholine (0.53 mL, 4.82 mmol) were dissolved in THF (10 mL) and DMF (1 mL) then cooled to -20 °C. Isobutylchloroformate (0.31 mL, 2.32 mmol) was added to the cold solution and the reaction was stirred at -20 °C for 20 min.
  • Part D To a solution of pinanediol N- [N, N- ( l , 8- napthyldiimido)glycyl] -l-amido-4-bromobutaneboronate (1.21g, 2.13 mmol) in DMF (10 mL) was added ⁇ a ⁇ 3 (0.28 g, 4.27 mmol) . The reaction mixture was heated at 65 °C for 8 h, then it was allowed to cool to room temperature and partitioned between H2O (15 mL) and EtOAc (20 mL) . The layers were separated and the organic phase was washed with H 2 O (3x20 mL) and brine (20 mL) .
  • Part E To a solution of pinanediol N- [N, N- ( 1 , 8 - napthyldiimido)glycyl] -l-amido-4-aminobutaneboronate (0.51 g, 1.01 mmol) in pyridine (10 mL) was added aminoiminomethanesulfonic acid (0.13 g, 1.01 mmol).
  • N- (3-methylphenethyl) -Gly-OMe (3.15 g, 15.2 mmol) in THF at 0° C was added N-methylmorpholine (3.34 mL, 30.4 mmol) and hydrocinnamoyl chloride (2.26 mL, 15.2 mmol). The mixture was allowed to stir with warming to 25° C for 6 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with 10% aq HCl, sat' aq NaHC ⁇ 3 and brine. The organic layer was dried (MgS04) and concentrated to afford 4.4 g (86%) of the title compound. MS (CD : m/z 340 (M+H) +.
  • reaction mixture was allowed to stir while slowly warming to 25° C. After 1 h the reaction was quenched by addition of saturated aq NH4CI, diluted with ethyl acetate and washed with brine. The organics were dried (MgS ⁇ 4) and concentrated to afford 1.1 g (92%) of the title compound.
  • N- (2, 2-dimethyl) - phenethyl-Gly-OEt 2.4 g, 10.1 mmol
  • N- methylmorpholine 2.22 mL, 20.2 mmol
  • hydrocinnamoyl chloride 1.50 mL, 10.1 mmol
  • the resulting solution was allowed to warm to 25° C and was stirred for 3h.
  • the THF was removed in vacuo and ' the residue was taken up in ethyl acetate and washed with 10% aq HCl, satd. aq. NaHC03 and brine.
  • the organics were dried (MgS04) and concentrated.
  • Example 24.59.1 Pinanediol N- ⁇ N-phenyl-N- [N ' -methyl-N'- methylphenyl)aminocarbonyl]glycyl ⁇ -l-amido-4- isothiouroniumbutylboronate ; HRMS (M+H) + calcd: 606.338533, found: 606.329421.
  • Example 30 Pinanediol N- ⁇ N- [ (naphth-2-yl)methyl] -N- [ (3- phenyl)propionyl]glycyl ⁇ -l-amido-4- isothiouroniumbutylboronate; HRMS (M+H) + calcd: 655.348934, found: 655.347870.
  • Example 50 1.3 Hydrocinnamoyl-[N-(N(CH3)2) -Gly] -boroLys-Cl0H16 HCl; MS (NH 3 -CI) (M+H) + 513.5.
  • Part B Preparation of Part A: Na-t-boc-Ne-Cbz-lysinal
  • Hydrocinnamic acid was added to 100 ml of anhydrous CH 2 CI 2 followed by the addition of N-methylmorpholine (44.0 ml, 400.0 ml), and cooled to -78°c.
  • N-methylmorpholine 44.0 ml, 400.0 ml
  • isobutylchloroformate 17.3 ml, 133.17 mmol
  • the sarcosine ethyl ester hydrochloride (20.00 gr, 133.17 mmol) was added and the solution stirred for and additional hr at -78°c and allowed to warm to rt.
  • Hydrocinnamoyl-Sar-OH (690 mg, 3.10 mmol), NE-Cbz lysine[C(OH)C0 2 CH 3 ] TFA salt (1.36 gr, 3.10 mmol), N-Methyl morpholine (1.0 ml, 9.3 mmol), HOBT (420 mg, 3.10 mmol) and 1- (3-Dimethyl amino propyl)-3 ethyl carbodiimide (600 mg, 3.10 mmol) were dissolved in 50 ml of anhydrous DMF and stirred overnight at r . The resulting solution was diluted with 300 ml of EtOAc and washed repeatedly with brine. The organic were dried over MgS0 4, filtered through a pad of silica gel, and the volatiles dried in vacuo to an oil (1.08 gr) . MS: CI m/z 528.4 (M+H)+.
  • Example 60.4.1 Hydrocinnamoyl- ⁇ N- [2- (3, 5-dimethylphenyl) -ethyl] -Gly ⁇ - boroOrn-ClOHl ⁇ HCl; MS (ESI) (M+H) + 588.3
  • Example 60.4.2 Hydrocinnamoyl- [N- (Cyclopropyl) -Gly] -boroOrn-ClOHl ⁇ HCl; MS (NH 3 CD (M+H) + 496.3
  • Part B Preparation of 2-bromo-3 ' -chloro diphenyl methane 2-bromo-3 ' -chloro diphenyl methanol (38.8 gr, 130.35 mmol) and triethylsilane (31.23 ml, 195.53 mmol) were combined in 200 ml of TFA and stirred overnight at rt . The volatiles were removed in vacuo and the residue purified by flash chromatography (33.32 grams) MS: CI m/z 283.0 (M+H)+.
  • Part C Preparation of 3-chlorobenzylbenzoic acid
  • Example 65.1.3 N- ⁇ N-methyl-N- [2- (pyrrol-1-ylmethyl) -Benzyl]glycyl ⁇ -1- amido-5-a ⁇ .inopentaneboronic acid, hydrochloride salt; MS: ESI m/z 601.3 (M+H) +

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Abstract

L'invention concerne des analogues dipeptidiques électrophiles, conjugués à un acide α-aminé N,N-disubstitué, qui servent d'inhibiteurs aux enzymes sérines protéases apparentées à la trypsine.
EP94930595A 1993-10-07 1994-10-06 Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine Withdrawn EP0724446A4 (fr)

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US13325193A 1993-10-07 1993-10-07
US133251 1993-10-07
US13944593A 1993-10-20 1993-10-20
US139445 1993-10-20
PCT/US1994/011280 WO1995009634A1 (fr) 1993-10-07 1994-10-06 Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine

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CA2174314C (fr) 2000-04-11
AU7966494A (en) 1995-05-01
WO1995009634A1 (fr) 1995-04-13
IL111175A0 (en) 1994-12-29

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