EP0722449A1 - Inhibiteurs boropeptidiques de la thrombine contenant un noyau de pyrrolidine substitue - Google Patents

Inhibiteurs boropeptidiques de la thrombine contenant un noyau de pyrrolidine substitue

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Publication number
EP0722449A1
EP0722449A1 EP94929943A EP94929943A EP0722449A1 EP 0722449 A1 EP0722449 A1 EP 0722449A1 EP 94929943 A EP94929943 A EP 94929943A EP 94929943 A EP94929943 A EP 94929943A EP 0722449 A1 EP0722449 A1 EP 0722449A1
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Prior art keywords
compound
formula
methyl
group
independently selected
Prior art date
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EP94929943A
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German (de)
English (en)
Inventor
Gregory James Pacofsky
James Russell Pruitt
Patricia Carol Weber
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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Publication of EP0722449A1 publication Critical patent/EP0722449A1/fr
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    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • 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 System
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • 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 to the discovery of novel and useful ⁇ -amino acid analogs, and the pharmaceutically acceptable salts or prodrugs thereof, as inhibitors of thrombin.
  • These compounds contain a disubstituted- pyrrolidine ring conjugated to an ⁇ -amino acid functionalized with an electrophilic group such as boronic acids and their esters, ⁇ -perhaloketones and aldehydes.
  • Thrombin plays several critical roles in hemostasis, the normal physiological process by which bleeding from an injured blood vessel is arrested. Thrombin cleaves soluble fibrinogen to form insoluble fibrin in the. last proteolytic step of both the extrinsic and intrinsic pathways of the coagulation cascade. Fibrin may be further insolubilized through crosslinking by the thrombin-activated enzyme, factor Xllla. In addition, thrombin-induced activation of platelets leads to their aggregation and the secretion of additional factors that further accelerate creation of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII.
  • thrombin inhibitors A number of naturally occurring thrombin inhibitors have been isolated. These include the marine sponge natural products Theonella sp . occidentalamide A, a linear tetrapeptide reported by Fusetani et al . , Tetrahedron Let t . 32, 7073-4 (1991); Theonel la sp . cyclotheonamides A and B reported by Fusenati et al., J. Am . Chem . Soc .
  • Hirudin a 65 amino acid polypeptide, is responsible for the anticoagulant activity of the medicinal leech, Hirudo medi cinalis .
  • Peptide analogs of thrombin substrates and reaction intermediates also inhibit thrombin.
  • these include the tripeptide aldehyde (D) -Phe-Pro-Arg-H, disclosed by Bajusz et al . , Int . J. Peptide Protein Res . 12, 217-221 (1978) ; a chloromethyl ketone analog (Ac- (D) -Phe-Pro-ArgCH2Cl, disclosed by Kettner and Shaw, Thromb . Res . 14, 969-73 (1979); polyfluorinated analogs such as (D)-Phe-Pro-Arg-CF2 ⁇ CF3 disclosed by Kolb et al . , AU-B-52881/86; Neises and Ganzhorn, European Patent Application EP 503 203 Al;
  • Representative examples of these compounds include t-butyloxycarbonyl- (D)-trimethylsilylalanine-Pro- boroArg-pinanediol, disclosed in Metternich, European Patent Application EP 471 651 A2; Ac-(D)-3- napthylalanine-Pro-boroArg pinanediol ester, disclosed in Kakkar et al., PCT Application WO 92/07869; N- ( t- butyloxycarbonyl) - (D)-phenylglycyl- (L)-prolyl- (L)- arginine aldehyde, disclosed in Gesellchen and Shuman, European Patent Application EP 0 479 489 A2 and J. Med .
  • thrombin inhibitors many of which incorporate an arginine or arginine mimic, have also been disclosed. These include arylsulfonylarginine amides such as ( 2R, 4J) -1- [N 2 - (3-ethyl-l, 2, 3, 4- tetrahydro-8-quinolinesulfonyl) -(L)-arginyl]-4-methy1-2- piperidinecarboxylate, disclosed by Okamoto et al . , U.S. Patent No. 4,258,192; Okamoto et al . , Biochem . Biophys . Res . Commun . 101, 440-446 (1981); Kikumoto et al .
  • arylsulfonylarginine amides such as ( 2R, 4J) -1- [N 2 - (3-ethyl-l, 2, 3, 4- tetrahydro-8-quinolinesulfonyl) -(L)-
  • amidinophenylalanine derivatives such as (2-naphthylsulfonylglycyl) -4- amidino-phenylalanyl piperidine disclosed in Stuber and Dickneite, European Patent Application EP 508 220; amino phenylalanine derivatives, disclosed in Okamoto et al . , U.S. Patent No.
  • Isoquinolinyl guanidino benzoate derivatives disclosed by Takeshita et al., European Patent Application EP 435 235 Al; and 2-[3-(4- amidinophenyl) Jpropionic acid derivatives, disclosed by Mack et al . , PCT Application WO 93/01208 also act as thrombin inhibitors.
  • thrombin inhibitors contain a 5-membered pyrrolidine ring.
  • the pyrrolidine ring is incorporated into the inhibitor as an integral component of the amino acid proline, a 2- substituted pyrrolidine, which in turn is bonded to the remaining atoms of the inhibitor via amide linkages. None of the cited references describe or suggest the new thrombin-inhibiting compounds of the present invention.
  • the novel compounds described in the present invention are substituted at the 4-position of the pyrrolidine ring.
  • R 3 and R 10 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) halogen,' c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 , d) (CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl, e) (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl, f) (CR 6 R 7 ) t W (CR 8 R 9 ) u -heterocycle, g ) (CR 6 R 7 ) t W(CR 8 R 9 ) u -adamantyl, h) (CR 6 R 7 ) t W(CR 8 R 9 ) u (C 5 -C 7 ) cycloalkyl, i)
  • R 3 and R 10 when taken together form a ring such as : a) - (CR 6 R 7 ) t (CR 8 R 9 ) U -W- (CR 8 R 9 ) u (CR 6 R 7 ) t ; b) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl-(CR 8 R 9 ) u W(CR 6 R 7 ) t -; c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl- (CR 8 R 9 ) U W(CR 6 R 7 ) t -; d) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -heterocycle-(CR 8 R 9 ) u W(CR 6 R 7 ) t -; e) - (CR 6 R 7 ) t (CR 8 R 9 ) u -W- (CR 8 R 9 )
  • R 4 and R 5 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C3 . -C4 alkyl, c) C1-C4 alkoxy, d) C5-C 7 cycloalkyl, e) phenyl, f) benzyl;
  • R 11 is a) hydrogen, b) C 1 -C 4 alkyl, c) C 1 -C 4 thioalkyl, d) - (CR 6 R ) t W(CR 8 R 9 ) u -aryl, e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl, f ) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heterocycle; g) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 ;
  • Y 1 and Y 2 are a) -OH, b) -F,
  • Y 1 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 O, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) 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 0;
  • n can be 0 to 4.
  • 5 n can be 0 to 4.
  • p can be 0 to 2
  • 0 q can be 0 to 4.
  • r, s, t, u, and v are independently selected at each occurrence from 0 to 6,
  • 5 w and x are independently selected at each occurence from 0 to 4.
  • Preferred compounds of formula (I) are those compounds wherein :
  • R 1 is (C3-C 4 alkyl) ;
  • R 2 is hydrogen or C 1 -C 4 alkyl.
  • More prefe rred compounds of f ormu la ( I ) are compounds of formula ( Ia ) :
  • R 1 is (C 3 -C 4 alkyl) ;
  • R 2 is hydrogen or C 1 -C 4 alkyl
  • R 3 and R 10 are independently selected at each occ rrence from the group consisting of: a) hydrogen, b) halogen, c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 d) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl;
  • R 4 and R 5 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C 1 -C 4 alkyl,
  • Y 1 and Y 2 are a) -OH, b) -F, c) -NR R 5 -, d) -Ci-C ⁇ alkoxy, or; when taken together Y 1 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 0, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) 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 0;
  • p can be 0 or 2;
  • r can be independently selected at each occurrence from 0 to 3;
  • s can be independently selected at each occurrence from 0 to 3;
  • t can be independently selected at each occurrence from 0 to 2;
  • u can be independently selected at each occurrence from
  • w can be independently selected at each occurrence from
  • x can be independently selected at each occurrence from 0 to 3; with the following provisos: (a) when V is (CH 2 ) X , x cannot be 0 when R 3 is hydrogen;
  • R 1 is (C 3 -C4 alkyl) ;
  • X is from the ' group consisting of
  • R 2 is hydrogen or C 1 -C 4 alkyl
  • R 3 is independently selected from the group consisting of: benzyl, phenyl, phenethyl, (3-phenyl)prop-1-yl, (2- methyl-1-phenyl)prop-2-yl, (2-methy1-2-phenyl)prop- 1-yl, 1, 1-diphenylmethyl, phenoxymethyl, phenylsulfonylmethyl, 2- ( ⁇ n-fluorophenyl) ethyl, 2- (3-pyridyl) ethyl, (/n-aminophenyl)methyl, (m- methylphenyl) methyl, (p-methylphenyl) methyl, 1- naphthylmethyl;
  • .10 is independently selected from the group consisting of: methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl -N-t- butoxycarbonylaminomethyl, iV-methylaminomethyl, (m- methyl) phenethyl, (m-fluoro) phenoxymethyl, (m- methyl) phenoxymethyl, (3-pyridyl) ethyl
  • R 11 is hydrogen
  • Y 1 and Y 2 are a) -OH, b) -F, c) - ⁇ R R 5 -, d) -Ci-Ce alkoxy, or; when taken together Y 1 and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbcn atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) 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 0;
  • Specifically preferred compounds of formula (I) are those compounds of formula (lb) :
  • (D) indicates the amino acid is in the (D)-configuration .
  • “D, " indicates the amino acid is present as a mixture of the (D)- and the (L)-configuration.
  • the prefix "bore” indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if R 1 is isopropyl and Y- and Y- are OH, the C- terminal residue is abbreviated "boroVal-OH” or "jboroValine” 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 "-C10H16" and "-C6H12", 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 .
  • CBZ or Z benzyloxycarbonyl
  • BSA benzenesulfonic acid
  • THF tetrahydrofuran
  • Boc- t- butoxycarbonyl-
  • Ac- acetyl
  • pNA p-nitroaniline
  • DMAP 4-dimethylaminopyridine
  • HOBT 1-hydroxybenzotriazole and hydrate thereof
  • DCC 1, 3-dicyclohexylcarbodimide
  • Tris Tris (hydrqxymethyl)aminomethane
  • MS mass spectrometry
  • FAB/MS fast atom bombardment mass spectrometry.
  • HRMS are low and high resolutior. mass spectrometry, respectively, using ammonia (NH 3 -CI) or methane (CH 4 -CI) as an ion source.
  • 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 recrystallization of diastereomeric salts.
  • any variable for example, R- through R ⁇ -0, m, n, W, Z, etc.
  • its definition on each occurrence is independent of its definition at every -other occurrence.
  • R 3 is - (CR 6 R 7 ) t -W- (CR 8 R 9 ) u -aryl, and u is 0 it is the same as : - (CR 6 R ) t -W-aryl .
  • R 6 and R 7 are taken to for a double bond, and R 8 and R 9 taken to be a triple bond would be:
  • amine-blocking group or "amine- protecting group” as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substituents on these groups may include either alkyl, aryl and alkaryl which may contain the heteroatoms, 0, S, and N as a substituent or as an inchain component. A number of amine-blocking groups are recognized by those skilled in the art of organic synthesis.
  • suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t- butoxycarbonyl (also referred to as t-butyloxycarbonyl) or adamantyloxycarbonyl .
  • aromatic urethane protecting groups such as benzyloxycarbonyl
  • aliphatic urethane protecting groups such as t- butoxycarbonyl (also referred to as t-butyloxycarbonyl) or adamantyloxycarbonyl .
  • amino acid residues refers to natural or unnatural amino acid of either (D)- or (L)- configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys,
  • amino acid residue also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art.
  • the Peptides Vol 3, 3-88 (1981) describes numerous suitable protecting groups and is incorporated herein by reference for that purpose.
  • 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- and polycyclic 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- or 10-rnernbered 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 5-, 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-triazinyl; 3-
  • 2c cinnolinyl 1-phthalazinyl; 2- or 4-quinazolinyl; or 2- quinoxalinyl ring.
  • Particularly preferred are 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl.
  • heterocycle is meant to include 5-, 6- or 10-membered mono- or bicyclic 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. Included in the definition of the group heterocycle, but not limited to, 2- or 3- pyrrolidinyl, a 2-, 3-, or 4-piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4- tetrahydroquinolinyl, 2- or 3-tetrahydrofuranyl, 2- or
  • 3-tetrahydrothiophene 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino.
  • Particularly preferred are 1-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3- pyrrolidinyl, and 2-, 3- or 4-piperidinyl.
  • 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) .
  • Examples of 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 .
  • 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, methanol, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vi vo 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 hydroxyl, 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) .
  • (L) -4-hydroxyproline benzyl ester hydrochloride which is commercially available, or any other suitably protected hydroxyproline, can be treated with a trialkylamine base, typically 4-methylmorpholine, and an acid chloride (R 10 C C1) to afford acylation product (II) selectively.
  • the hydroxyl group can be converted to a corresponding ester by treatment with a second acid chloride (R 3 COCl) in the presence of a trialkylamine or heterocyclic amine base, such as pyridine, and ' a suitable catalyst, such as but not limited to DMAP to generate (III) .
  • the carboxylic acid of the proline moiety can be liberated by hydrogenation using conditions reported by Hartney and Simonoff, Org . React . VII, 263 (1953) wherein an alcohol solution of the compound (III) may be affected under an atmosphere of hydrogen gas using a suitable catalyst, preferably platinum or palladium on carbon catalyst, to provide (IV) .
  • a suitable catalyst preferably platinum or palladium on carbon catalyst
  • the DCC/DMAP esterification procedure reported by Hassner, and Alexanian, Tetrahedron Let t . 19, 4475 (1978) has proved useful for performing the second acylation reaction.
  • ester other than benzyl which might be removed hydrolytically or photilytically, such as photlytic deprotection.
  • a methyl ester of (II) treatment of an alcoholic solution of the compound with a solution of sodium hydroxide so as to deliver 1 equivalent amount of NaOH followed by acidification should provide the carboxylic acid.
  • N-acyl-4- (alkoxy)proline intermediates can prepared as shown in Scheme 2.
  • the hydroxyl function of an N-protected 4-hydroxyproline (V) can be alkylated according to the method of Smith et al., JV Med . Chem . 31, 875 (1988), by treatment with an alkali metal hydride, such as but not limited to sodium hydride and an alkyl halide (R 3 X) to give (VI) .
  • an alkali metal hydride such as but not limited to sodium hydride and an alkyl halide (R 3 X) to give (VI) .
  • benzyl urethane is also viable where hydrogenation over palladium catalyst deliveres the free amine (VII) .
  • Acydlation by one of the methods discussed previously can provide (VIII) .
  • the 4-amino and 4-mercaptoproline intermediates useful for the synthesis of compounds of the formula (I), wherein V is S, NH or derivatives thereof, can be prepared according to Scheme 3.
  • the hydroxyproline ester (IX) wherein the amine is protected as the BOC or CBZ, can be reacted with carbon tetrachloride/ triphenylphosphine according to the method of Webb and Eigenbrot, J. Org . Chem .
  • the chloride- (X) with inversion of stereochemistry.
  • the chloride can be displaced by a sulfur nucleophile, again with inversion of sterochemistry in a manner similar to that reported by Smith et al . (1988) to provide the displacement product (Xllb) , sulfur-containing prolines.
  • the chloride can be displaced by sodium azide, which is reduced to the primary amine and converted by reductive amination to provide the displacement products (Xlla), nitrogen-containing prolines.
  • the R 3 group in (XII) used in the displacement reaction need not be the ultimate R 3 of formula (I); methods for their removal are well known to those skilled in the art of organic synthesis . Methods for the attachment cf preferred R 3 are described herein.
  • thrombin inhibitors of the present invention requires the coupling of either of the aforementioned intermediates, (IV), (VIII), or (XII) with a boron-containing fragment followed by manipulation of the pendant functionalities, as shown in Scheme 4.
  • jborolysine-containing thrombin inhibitors begins with the coupling of amine hydrochloride (XIII) , disclosed by Kettner and Shenvi U.S. Patent No. 5.187.147, to provide amide (XIV) .
  • XIII amine hydrochloride
  • One method calls for the combination of (XIII) and the acid chloride derived from (IV), (VIII) or (XII) in the presence of an amine base, such as but not limited to pyridine.
  • the mixed anhydride method which involves mixing the acid to be coupled with an alkylchloroformate and an tertiary amine base, such as, but not limited to, i-butyl chloroformate and 4-methylmorpholine, followed by addition of the amine discussed previously, to prepare (XIV) from (IV), (VIII) or (XII) ; additionally the DCC/HOBT method may be used to access amines XIV and/or XII Conversion of the bromide to the X group in R 1 of formula (I) can be accomplished by first reaction of bromide (X) with an inorganic azide, such as sodium or potassium azide, in an anhydrous polar aprotic solvent, such as acetone, N, ⁇ -dimethylformamide or methyl sulfoxide at temperatures ranging from ambient to 130°C; typically reaction with sodium azide in N,JV- dimethylforma ide at 65-70 °C for several hours provides (XV)
  • Subsequent reduction of the azide function to the amine (XVI) is effected by catalytic hydrogenation of the azide in a solvent, such as an alcohol or ethyl acetate using a suitable transition metal catalyst under an atmosphere of hydrogen gas.
  • Reduction of the azide (XX) in the presence of sulfur-containing prolines (XV, where V is S) can be done according to the method of Knowles et al . , Tetrahedron Lett . , p. 3663 (1978) to provide the amines (XXI) .
  • a variety of alternative methods can be found in the monograph by Hudlicky, Reductions In ' Organi c Synthesis, John Wiley and Sons, pp. 134 (1984) .
  • the amine (XVI) can be isolated as the free base or a salt, typically, but not exclusively hydrochloride or benzenesulfonate; other salts which impart improved physical properties may be preferred.
  • guanidinium analogs can be prepared in a similar manner starting from amine hydrochloride (XVIII) .
  • Amide bond formation using one of the methods previously described provides (XIX) , which can be converted to the azide (XX) by nucleophilic displacement of the bromide. Reduction of the azide using conditions already described can provide the amine (XXI) .
  • Preparation of formamidine (XXII) can be accomplished by reaction of amine (XXI) with ethyl formimidate hydrochloride in the presence of DMAP according to the method of Ohme and Schmitz, Angew, Chem mt . Ed 6,566 (1967) .
  • the organic layer was washed with saturated aqueous sodium bicarbonate (NaHC0 3 , 1 30 mL) , water (H 2 0, 1 x 30 mL) , saturated aqueous sodium chloride (NaCl, 1 >: 30 mL) , dried over sodium sulfate (Na 2 S0 4 ) and concentrated 5 under reduced pressure.
  • the resulting oil (1.94 g, l l yield) solidified on standing at room temperature.
  • Part B To a solution of the product from Part A (370 mg, 1.41 mmol) and pyridine (0.17 mL, 2.10 mmol) in CH 2 C1 2 (14 mL) at 0 °C was added 3-phenylpropionyl
  • Part C A solution of the product from Part E (340 mg, 0.86 mmol) together with palladium on charcoal (50 mg) in methanol (MeOH, 9 mL) was stirred under hydrogen (1 5 at ) for 2 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give (4.R) -N-acetyl-4- (3-phenylpropionyl) oxy- (L)- proline (245 mg) as a foam in 93% yield.
  • Part D To a solution of the product from Part C (240 mg, 0.79 mmol) and 4-methylmorpholine (0.26 mL, 2.36 mmol) in tetrahydrofuran (THF, 6 mL) at -20 °C was added i-butyl chloroformate (0.11 mL, 0.87 mmol) after which the reaction mixture was stirred for 2 minutes.
  • Part E A mixture of the product from Part D (470 mg, 0.75 mmol) and sodium azide (Na 3 , 97 mg, 1.50 mmol) in DMF (8 mL) was heated at 65-70 °C for 4 hours. The mixture was poured into EtOAc (ca. 75 mL) . and washed with H 2 0 (3 x -20 mL) , sat. aq.
  • Part F A solution of the product from Part E (388 mg, 0.65 mmol) in MeOH (7 mL) together with palladium hydroxide on charcoal (35 mg) was stirred under hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give 320 mg of the title compound as a foam in 86' ⁇ yield.
  • Example 303 To a mixture of Example 303 (1.95 g, 2.52 mmol) in H 2 0 (10 mL) , Et 2 0 (15 mL) , and sufficient MeOH (ca. 1.5 mL) to maintain a clear, biphasic system was added phenylboric acid (1.54 g, 12.6 mmol) . The mixture was stirred for 14 hours, the layers were separated and the aqueous phase was extracted with Et 0 (5 x 20 mL) . The aqueous layer was concentrated under reduced pressure to give the title compound (1.20 g) as an amorphous powder in 75% yield. LRMS 482 (M+H), 464 (base); HRMS Calcd for C 28 H 39 BN 3 0 5 (ethylene gycol ester) : 508.2983. Found:
  • Part A The commercially available starting material, (4.R) -N-BOC-4-hydroxy- (L)-proline methyl ester was dissolved in CH C1 2 (140 mL) and carbon tetrachloride (140 mL) and triphenylphosphine (42.56 g, 162.2 mmol) was added. The mixture was allowed to stir for 2 hours, ethanol (15 mL) was added and stirring was continued for an additional 16 hours. The mixture was concentrated under reduced pressure to 100 mL, cooled to -20 °C and Et 2 0 (200 mL) was added. The resulting precipitate was suction filtered ' and washed with Et 0.
  • Part B A solution of the product from Part A (17.03 g, 64.5 mmol) in trifluoroacetic acid (20 mL) and CH 2 C1 2 (20 mL) was stirred 18 hours. The reaction mixture was concentrated under reduced pressure to give (4S)-4- chloro-(L)-proline methyl ester (18.05 g) as an oil in quanitative yield.
  • -H NMR 300 MHz, CDCI 3 ) ⁇ 4.75 (comp,
  • Part C A solution of the product from Part B (30.28 g, 109 mmol) in CH 2 C1 2 (50 mL) was cooled to 0 °C and E 3 N (45.6 mL, 327 mmol) followed by hydrocinnamoyl chloride (17.8 mL, 120 mmol) were added slowly in order to maintain an internal temperature less than 10 °C . After stirring six hours, H 0 (50 mL) was added to the reaction mixture. The resulting solution was extracted with CH 2 C1 2 (3 x 50 mL) .
  • Part D EtOH (50 mL) was cooled to 0 °C and sodium (0.78 g, 33.8 mmol) was added. After the hydrogen evolution ceased, thiophenol (3.72 g, 33.8 mmol) was added and the reaction mixture stirred for 15 minutes at 0 °C, and the product from Part C (5 g, 16.9 mmol) was added. The stirring was continued for an additional 16 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and acidified with IN HCI to pH . The aqueous solution was extracted with EtOAc (3 x 30 mL) , the organics dried with Na 2 S0 4 and concentrated under reduced pressure.
  • Part E Using the method described above for the preparation of Example 78, Part D, ( 1R) -5-bromo- [ (4R) -N- 0 (3-phenylpropionyl)-4- (phenyl)thio- (L)- prolyl]aminopentane-l-boronic acid, (+) -pinanediol ester was isolated (2.43 g) as an oil in 85% yield. LRMS 681.2 683.2 (M+H, base) .
  • Part F Using the method described above for Example 5 78, Part E, the intermediate ( 1R) -5-azido- [ (4.R) -N- (3- phenylpropionyl) -4- (phenyl) thio- ( )-prolyl] aminopentane- 1-boronic acid, (+) -pinanediol ester was isolated (2.42 g) as an oil in quantitative yield.
  • Part G A solution of the product from Part F (2.42 g, C 3.76 mmol) in 1, 3-propanedithiol (1.62 g, 15 mmol), triethylamine (1.52 g, 15 mmol) and methanol (20 mL) was stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduce pressure and purified by flash chromatography through florosil, eluting with 1:9 5 MeOH-CH Cl 2 . The concentrated residue was dissolved in diethyl ether (10 mL) , acidified with 1 equivalent of IN HCI in Et 2 0 and concentrated to give the title compound
  • Part A A solution of the commercially available starting material, (4.R) -N-BOC-4- (benzyl) oxy- ( )-proline, previously reported by Smith et al., J. Med . Chem . 31, 875 (1988); (2.11 g, 6.57 mmol), in CH 2 C1 2 (27 mL) was treated with anhydrous hydrogen chloride in dioxanes (4 M, 6.60 mL) . The reaction mixture was stirred for 18 hours, during which time a white precipitate formed. The reaction was diluted with diethyl ether (Et 2 0, ca .
  • Part B A suspension of the product from Part A (1.5C g, 5.83 mmol) in CH 2 C1 2 (58 mL) at 0 °C was treated with
  • Part C Using the method described above for the preparation of Example 78, Part D, (1R) -5-bromo- [ ( R) -N- (3-phenylpropionyl) -4- (benzyl) oxy- (L)- prolyl]aminopentane-1-boronic acid (+) -pinanediol ester was isolated (2.80 g) as an oil in 90% yield. LRMS 679, 681 (M+H, base) .
  • Part E A solution of product from Part D (2.24 g, 3.50 mmol) in ' MeOH (35 mL) together with palladium on charcoal (225 mg) was stirred under hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 30 mL) and the filtrate was concentrated under reduced pressure to give a foam which contained a small amount of unreacted azide. This material was resubjected to the hydrogenation conditions described above to afford the title compound (2.00 g) as a white foam in 93% yield. LRMS 616 (M+H, base) .
  • Example 303 A solution of Example 303 (2.00 g, 3.25 mmol) in methanol (25 mL) was treated with a solution of benzenesulfonic acid (0.514 g, 3.25 mmol) in methanol (8 mL) . The mixture was allowed to stand at room temperature for 15 minutes and concentrated under reduced pressure to give a foam. The residue was washed with Et 2 0 (2 x 25 mL) , which was decanted, then dissolved in EtOAc (ca. 20 mL) and triturated with Et 2 0
  • Part A A mixture of the product from Example 302, Part C (3.00g, 10.1 mmol) and NaN 3 (3.30 g, 5C.7 mmol) in DMF (15 mL) was heated to 75 °C for 18 hours. Tne reaction mixture was dissolved in H 2 0 (25 mL) . The aqueous solution was extracted with Et 2 0 (3 x 25 mL) , dried with MgS0 4 and concentrated to give (4 ⁇ )-N-(3- phenylpropionyl) -4-azido- (L)-proline methyl ester (2.13 g) as an oil in 83% yield. -H NMR (300 MHz, CDC1 3 ) ⁇
  • Part B Using the method described above for the preparation of Example 78, Part F, ( 4 ⁇ ) -N- ( 3- phenylpropionyl) -4-amino-(L)-proline methyl ester was isolated (2.43 g) as an oil in 85% yield. --R ⁇ MR (300 5 MHz, CDCI3) ⁇ 7.24 (comp, 5H) , 4.58 (m, IH) , 3.74
  • Part C A_mixture of the product from Part B (1.51 g, 5.46 mmol), benzaldehyde (0.58 g, 5.46 mmol), potassium 0 acetate (0.54 g, 5.46 mmol) and 5% palladium on charcoal (0.21 g) was stirred in MeOH (25 mL) under hydrogen (3 atm) for 5 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate concentrated under reduced pressure to 5 give (4.R) - ⁇ - (3-phenylpropionyl) -4- (benzyl) amino- (L)- proline methyl ester (2.00 g) as an oil in quantitative yield. 1 H ⁇ MR (300 MHz, CDCI3) ⁇ 7.27 (comp, 10H) , 4.58
  • Part D A solution of the product from Part C (2.00 g, 5.46 mmol) methanol (15 mL) and IN sodium hydroxide (9 mL) was stirred for 24 hours. The pH of the solution was adjusted to 6 with IN HCI and a white precipitate 5 formed. The solid material was collected by suction filtration to give (4R) - ⁇ - (3-phenylpropionyl) -4- (benzyl) amino-( )-proline (1.31 g) as a white powder in 68% yield. LRMS 353.2 (M+H, base) .
  • Part E Using the method described above for the 0 preparation of Example 78, Part D, ( 1R) -5-bromo- [ (4J ) - ⁇ - (3-phenylpropionyl) -4- (benzyl) amino- (L)- prolyl]aminopen v tane-l-boronic acid, (+) -pinanediol ester was isolated (0.71 g) as an oil in 49% yield. LRMS 678.3 680.3 (M+H, base) .
  • Part F Using the method described above for Example 78, Part E, the intermediate (li?) -5-azido- [ (4i?) -N- (3- phenylpropionyl) -4- (benzyl) amino- (L)-prolyl] aminopentane- 1-boronic acid, (+)-pinanediol ester was isolated (0.45 g) as an oil in 67% yield.
  • Part G A solution of the product from Part F (0.45 g, 0.70 mmol) in MeOH (5 mL) together with 20% palladium hydroxide on charcoal (0.04 g) was stirred under hydrogen (1 atm) for 4 hours.
  • the reaction mixture was filtered through a pad of Celite with EtOAc (ca. 10 L) .
  • the filtrate was concentrated under reduced pressure and purified by flash chromatography through florosil, eluting with 1:9 MeOH-CH 2 Cl 2 .
  • the concentrated residue was dissolved in Et 0 (10 mL) , acidified with 2 equivalents of IN HCI in Et 0 and concentrated to give the title compound (0.27 g) as a oil in 56% yield.
  • Part B A mixture of the product from Part A (365 mg, 0.55 mmol) and thiourea (83 mg, 1.10 mmol) in ethanol (EtOH, 10 mL) was heated at reflux for 16 hours and cooled to room temperature. The reaction was poured into Et 2 0 (ca. 120 mL) and concentrated under reduced
  • the compounds of formula (I) are useful as inhibitors of serine proteases and notably human thrombin, plasma allikrein and plas in . Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes .
  • Inhibition constants were determined by the method described by Kettner et al . in J. Bi ol . Chem . 265, 18289-18297 (1990), herein incorporated by reference.
  • thrombin-mediated hydrolysis cf the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX)- was monitored spectrophotometrically . Addition of an inhibitor to the assay mixture results n decreased absorbance and is indicative of thrombin inhibition.
  • Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% polyethylene glycol 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Bur .
  • Bovine thrombin was obtained from Sigma and diluted to 24 NIH units/mL. Plasma ( 0.2 mL) and buffer (0.05 mL, 0.10 M Tris [hydroxymethyl]-aminomethane hydrochloride, pH 7.4, 0.9% (w/v) sodium chloride, and 2.5 mg/mL bovine serum albumin) containing inhibitor were incubated 3 min at 37 °C in a fibrameter. Reactions were initiated by adding thrombin (0.05 mL) to achieve a final concentration of 4 NIH units/mL.
  • the compounds of formula (I) have anti- thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for the control of the coagulation of the fibrinolysis system in mammals or they may be added to blood for the purpose of preventing coagulation of the blood due to contact with blood collecting or distribution containers, tubing or apparatus. Generally, these compounds may be administered orally, parenterally or intravenously to a host to obtain an anti-thrombogenic effect.
  • the dosage of the active compound depends on the mammalian species, body weight, age, and mode of administration as determined by one skilled in the art.
  • the compounds may be administered alone or in combination with pharmaceutical carriers or diluents at a dose of from 0.02 to 15 mg/kg to obtain the anti-thrombogenic effect, and may be given as a single dose or in divided doses or as a sustained release formulation.
  • Pharmaceutical carriers or diluents are well known and include sugars, starches and water, which may be used tc make tablets, capsules, injectable solutions or the like which can serve as suitable dosage forms for administration of the compounds of this invention.
  • Remington's Pharmaceutical Sciences. A. Osol is a standard reference text which discloses suitable pharmaceutical carriers and dosage forms. The disclosure of this text is hereby incorporated by reference for a more complete teaching of suitable dosage forms "for administration of the compounds of this invention .

Abstract

L'invention concerne la découverte de nouveaux analogues d'α-aminoacide, ainsi que leurs sels et promédicaments acceptables pharmaceutiquement, contenant un noyau de pyrrolidine disubstitué conjugué à un α-aminoacide, qui sont efficaces en tant qu'inhibiteurs de la thrombine.
EP94929943A 1993-10-07 1994-10-06 Inhibiteurs boropeptidiques de la thrombine contenant un noyau de pyrrolidine substitue Withdrawn EP0722449A1 (fr)

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PCT/US1994/011049 WO1995009859A1 (fr) 1993-10-07 1994-10-06 Inhibiteurs boropeptidiques de la thrombine contenant un noyau de pyrrolidine substitue
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US5885967A (en) * 1994-03-04 1999-03-23 Eli Lilly And Company Antithrombotic agents
ZA951618B (en) * 1994-03-04 1996-08-27 Lilly Co Eli Antithrombotic agents
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
CA2143533A1 (fr) * 1994-03-04 1995-09-05 Kenneth D. Kurz Agents antithrombotiques
US5726159A (en) * 1994-03-04 1998-03-10 Eli Lilly And Company Antithrombotic agents
US5602101A (en) * 1994-03-04 1997-02-11 Eli Lilly And Company Antithrombotic agents
US5705487A (en) * 1994-03-04 1998-01-06 Eli Lilly And Company Antithrombotic agents
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
CA2413418A1 (fr) 2000-06-21 2001-12-27 Joseph B. Santella Amides de piperidine utilises comme modulateurs de l'activite des recepteurs des chimiokines
SI1400245T1 (sl) 2002-09-09 2006-10-31 Trigen Ltd Soli boronske kisline, uporabne v parenteralnih formulacijah za selektivno inhibiranje trombina
US20050288253A1 (en) 2002-09-09 2005-12-29 Trigen Limited Boronic acid salts
ES2802251T3 (es) * 2012-01-06 2021-01-18 Novartis Ag Compuestos heterocíclicos y métodos para su uso
WO2014058538A1 (fr) * 2012-08-27 2014-04-17 Merck Sharp & Dohme Corp. Inhibiteurs de thrombine pyrrolidine substituée
US10590084B2 (en) 2016-03-09 2020-03-17 Blade Therapeutics, Inc. Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof
US11292801B2 (en) 2016-07-05 2022-04-05 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
MX2019003425A (es) 2016-09-28 2019-08-16 Blade Therapeutics Inc Moduladores de calpainas y usos terapeuticos de los mismos.

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US5187157A (en) * 1987-06-05 1993-02-16 Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
GB9017694D0 (en) * 1990-08-13 1990-09-26 Sandoz Ltd Improvements in or relating to organic chemistry
GB9024129D0 (en) * 1990-11-06 1990-12-19 Thrombosis Research Trust Inhibitors and substrates of thrombin
EP0503203A1 (fr) * 1991-03-15 1992-09-16 Merrell Dow Pharmaceuticals Inc. Nouveaux inhibiteurs de la thrombine

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