WO1993008211A1 - Derives tripeptidiques utilises comme agents anti-inflammatoires - Google Patents

Derives tripeptidiques utilises comme agents anti-inflammatoires Download PDF

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WO1993008211A1
WO1993008211A1 PCT/US1992/008901 US9208901W WO9308211A1 WO 1993008211 A1 WO1993008211 A1 WO 1993008211A1 US 9208901 W US9208901 W US 9208901W WO 9308211 A1 WO9308211 A1 WO 9308211A1
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carbon atoms
mmol
phe
saturated
alkyl
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PCT/US1992/008901
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John Mcmillan Mciver
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The Procter & Gamble Company
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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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the subject invention relates to novel tripeptide derivatives which are useful as anti-inflammatory agents.
  • n is an integer of from 0 to about 2;
  • -R is selected from straight or branched alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 1 to about 6 carbon atoms; and cyclic alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 3 to about 13 carbon atoms; and the carbon atom to which -R is bonded is in either D or L configuration;
  • -R' is selected from branched alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 3 to about 6 carbon atoms; cyclic alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 3 to about 13 carbon atoms; and arylalkyl, the alkyl portion being saturated and having from 1 to about 3 carbon atoms; and the carbon atom to which -R' is bonded is in L configuration;
  • (e) -Y is hydrogen or trifluoro ethyl ;
  • (g) -V- is selected from -0C(0)-, -N(Q)C(0)-, -N(Q)C(S)-, -C(0)-, -S0 : - and -P(0)(0H)-; when -V- is -0C(0), -Z- is -NH-;
  • -X is selected from cyclic alkyl, branched alkyl having at least two branches, and aryl, each having from 5 to about 20 carbon atoms; and (i) -Q is selected from hydrogen; and straight or branched alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 1 to about 6 carbon atoms; or -Q and -X are covalently linked forming a cyclic moiety which includes the nitrogen to which -Q is bonded and from 5 to about 20 carbon atoms.
  • the subject invention also involves pharmaceutical composi ⁇ tions comprising the above compounds, and methods for treating inflammation or pain using such compounds and compositions.
  • alkyl as used herein, unless otherwise indicated, means carbon-containing chains which may be straight, branched or cyclic; which may be saturated or unsaturated; and which may be unsubstituted or substituted.
  • cyclic alkyl may have all or only a portion of the total number of carbon atoms indicated as being in the alkyl group in the cyclic ring itself. Cyclic alkyl includes monocycloalkyl , bicycloaTkyl and/or tricycloalkyl . Preferred alkyl are as noted in this paragraph unless provided otherwise in particular instances. Preferred alkyl are saturated. Preferred alkyl are unsubstituted.
  • alkyl substituents are selected from halo, amino, hydroxy, alkoxy, cyano, nitro, aryl and trifluoromethyl.
  • alkoxy is -0-alkyl. It is preferred that substituted alkyl be mono-, di- or trisubstituted, especially monosubstituted.
  • aryl means aryl rings which may be unsubstituted or substituted. Pre ⁇ ferred aryl is as noted in this paragraph, unless provided otherwise in particular instances. Preferred aryl are phenyl and naphthyl, especially phenyl. Preferred aryl are mono-, di-, tri- or unsubstituted; more preferred aryl are monosubstituted or unsubstituted, especially unsubstituted. Preferred aryl sub ⁇ stituents include « ⁇ kyl, halo, amino, hydroxy, alkoxy, cyano, nitro and trifluoromethyl.
  • arylalkyl means alkyl sub ⁇ stituted with aryl.
  • a preferred arylalkyl is arylmethyl .
  • amino acids may refer to the amino acid itself, or more often to an amino acid moiety , that is part of a peptide or peptide derivative structure.
  • DIBAL-H Trifluoromethyltrimethyl silane CF j
  • TMS Tetra-n-butylammonium fluoride trihydrate TBAF
  • novel anti-inflammatory compounds of the subject invention are those having the following chemical structure: R R' R"
  • n is an integer of from 0 to about 2; n is preferably 0 or 1.
  • -R is selected from the group consisting of straight or branched alkyl, saturated or unsaturated with 1 or
  • Preferred -R is saturated alkyl.
  • Preferred alkyl are unsubstituted, or are arylalkyl, especially benzyl and naphtha!.
  • Preferred cyclic alkyl are cyclic C 3 -C ⁇ (more preferably C 5 -C 6 ) methyl or adamantylmethyl .
  • Preferred -R is hydrophobic, preferably with the hydrophobicity concentrated close to the carbon atom to which -R is bonded.
  • preferred -R include t-butyl, 1,1-dimethyl- propyl, i-propyl, i-butyl, s-butyl, neo-pentyl , cyclohexyl, cyclohexylmethyl, adamantyl, naphtha!; most preferred -R is t-butyl .
  • the carbon to which -R is bonded is in either D or L, preferably D, configuration.
  • the structure -Z-CH(R)-C(0)- is an amino acid moiety (hereinafter -AA 1 -) when • I- is -NH; preferred amino acid moieties for -AA 1 - include t-Bug, Val, He, Leu, Chg, Cha, Phe, NaT, Trp and Adg; more preferred are t-Bug, Val and He; most preferred -AA 1 - is t-Bug.
  • -R' is selected from branched alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 3 to about 6 carbon atoms; cyclic alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 3 to about 13 carbon atoms; and arylalkyl, the alkyl portion being saturated and having from 1 to about 3 carbon atoms.
  • Preferred branched or cyclic alkyl are saturated.
  • Preferred branched or cyclic alkyl are unsub ⁇ stituted.
  • Preferred branched alkyl have from 3 to 5 carbon atoms; most preferred branched alkyl is i-butyl.
  • Preferred cyclic alkyl have a C 3 -C 7 , more preferably C 5 -C 6 , cyclic ring bonded to a methylene, ethylene or n-propylene (preferably methylene or ethylene, more preferably methylene) which is bonded to the carbon atom in Structure (1) to which -R' is bonded.
  • Preferred arylalkyl are benzyl, p-hydroxybenzyl and naphthal. More preferred -R' is selected from i-propyl, i-butyl, s-butyl, cyclohexylmeth 1 , benzyl and naphthal; most preferred is benzyl.
  • the carbon atom to which -R' is bonded is in L configuration.
  • the structure -NH-CH(R')-C(0)- is an amino acid moiety (hereinafter -AA 2 -); preferred amino acid moieties for -AA 2 - include Phe, Nal , Cha, Leu and He; most preferred -AA 2 - is Phe.
  • -R" is -(CH 2 ) m -A-NH 2 or -(CH 2 ) m -A-B- C(NH 2 ) «NH, wherein is an integer of from 1.
  • -A- is a covalent bond, p-phenyl or p-cyclohexyl
  • -B- is a covalent bond or -NH-.
  • m is preferably 2-5, more preferably 2-4, more preferably still 3 or 4.
  • -A- is p-phenyl or p-cyclohexyT
  • m is preferably 1-4, more preferably 1-3, more preferably still 1.
  • -A- is preferably a covalent bond.
  • -B- is preferably -NH-. More preferred -R" is 3-guanidino-n- propyl or 4-amino-n-butyl.
  • the carbon to which -R" is bonded is in L configuration.
  • the structure -NH-(CH(R")-C(0)- is an amino acid moiety (hereinafter -AA 3 -); preferred amino acid moieties for -AA 3 - include Arg, Lys and p-Gphe; most preferred -AA 3 - is Arg.
  • -Y is hydrogen or trifluoromethyl.
  • -Z- is -0- or -NH-.
  • Preferred -I- is -NH-.
  • -V- is selected from -0C(0)-, -N(Q)C(0)-,
  • -V- is selected from -0C(0)-, -N(Q)C(0)-, -N(Q)C(S)-, and -C(0)-. More preferred -V- is -0C(0)- or -N(Q)C(0)-. Most preferred -V- is
  • -X is selected from cyclic alkyl, branched alkyl having at least 2 branches, and aryl, each having from 5 to about 20 carbon atoms. Preferred -X has from 5 to 15 carbon atoms; more preferred -X has from 8 to 12 carbon atoms. Pre ⁇ ferred alkyl portions of -X are saturated. Preferred -X is unsubstituted or substituted with unsubstituted alkyl or aryl.
  • Preferred cyclic alkyl are monocycloalkyl, bicycloalkyl , and tricycloal yl, more preferred are bicycloalkyl and tricycloalkyl, especially tricycloalkyl .
  • Preferred cycloalkyl have 5 or 6 carbon atoms, worn preferably 6 carbon atoms, in each cyclic ring.
  • a highly preferred -X is adamantyl.
  • Preferred aryl -X are naphthyl and phenyl, unsubstituted or substituted with alkyl. Particularly preferred aryl -X include naphthyl and fluorenyl.
  • n is preferably 1.
  • -V- is -N(Q)C(0)- or -N(Q)C(S)-
  • -Q is selected from hydrogen; straight or branched alkyl, saturated or unsaturated with 1 or 2 double bonds, having from 1 to about 6 carbon atoms; or -Q and -X are covalently linked forming a cyclic moiety which includes the nitrogen to which -Q is bended and from 5 to about 20 carbon atoms.
  • Preferred -Q-X- has from 5 to 15 carbon atoms; more preferred -Q-X- has from 8 to 12 carbon atoms.
  • Preferred -Q-X- is unsubstituted or substituted with unsubstituted alkyl or aryl.
  • - N ⁇ - X is onocyclic, bicyclic or tricyclic; more preferred is monocyclic. Most preferred -Q is hydrogen.
  • preferred X-(CH 2 ) n -V- include Boc, Adoc, Ad, Fmoc, Ada, Adac, Mnoc, Norad, Hadoc, Foe * Imoc, Ipoc, 3,5-Dmadoc, eBroc, Noc and Moc; more preferred X' is Adoc, Ipoc and eBroc; most preferred -X' is Adoc.
  • Preferred anti-inflammatory compounds of the subject invention include pharmaceutically-acceptable salts of the above compounds. Particularly preferred salts include salts of addition formed between a strong acid and the above compounds. Particularly preferred are such salts of addition where -R" is protonated, resulting in a positive charge on the -R" moiety.
  • Preferred compounds of the subject invention are ⁇ ften associated with one or more molecules of water in the form of hydrates.
  • Preferred anti-inflammatory compounds of the subject invention include the following compounds:
  • Ad-D-Phe-Phe-Arg-CF 3 Adoc-D-Val -Phe-Arg-H Adoc-D-t-Bug-2-Nal -Arg-H Ada-D-t-Bug-Phe-Arg-H Adoc-D-Chg-Phe-Arg-H
  • compositions of the subject invention com ⁇ prise a safe and effective amount of a tripeptide derivative as defined hereinabove and a pharmaceutically-acceptable carrier.
  • Such compositions typically comprise from about 0.1% to about 95% by weight of the tripeptide derivative, preferably from about 1% to about 90% and more preferably from about 5% to vabout 75%.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or 'lower animal.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or 'lower animal.
  • compact ⁇ ible means that the components of the pharma ⁇ ceutical compositions are capable of being commingled with the tripeptide derivative of the subject invention, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composi ⁇ tion under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for admini ⁇ stration to the human or lower animal being treated.
  • substances which can s ⁇ rwe as pharma ⁇ ceutically-acceptable carriers are sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxy- methylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatins; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; pyrogen-free water; isotonic saline; phosphate buffer solutions; cocoa butter (suppository base); emulsifiers, such as Tweens ® ; wetting agents and lubricants, such as
  • a pharmaceutically-acceptable carrier to be used in conjunction with the tripeptide derivatives of the subject invention is determined by the way the active is to be administered. Preferred modes of administering the actives of the subject invention are by injection, ingestion, inhalation and topically.
  • the pharmaceutically-acceptable carrier employed in con ⁇ junction with the tripeptide derivative of the subject invention is used at a concentration sufficient to provide a practical size to dosage relationship.
  • the pharmaceutically-acceptable carrier in total, typically comprises from about 5% to about 99.9% by weight of the pharmaceutical compositions of the subject invention, preferably from about 10% to about 99%, and more preferably from about 25% to about 95%.
  • Total single dosages of the tripeptide derivatives of the subject invention in pharmaceutical compositions are generally from about 1 mg to about 1000 mg, preferably from about 50 mg to about 800 mg, more preferably from about 100 mg to about 500 mg.
  • the subject invention also encompasses methods of producing ant -inflammatory activity and/or analgesia in humans or lower animals through administering, to the human or lower animal in need of such treatment, a safe and effective amount of a tri ⁇ peptide derivative of the subject invention.
  • the amount can be given in a single dose or multiple doses repeatedly over the course of the treatment. While dosages higher than those described herein are effective to reduce inflammation and produce analgesia, care must be taken in some individuals to prevent adverse side effects.
  • the tripeptide derivatives and composi ⁇ tions of the subject invention can be used to reduce inflammation . in various disorders at the deeper structures, muscles, tendons, bursa and joints associated with disease and trauma, to treat and prevent pain.
  • the preferred modes of administering the tripeptide derivatives of the subject invention are by injection, ingestion, inhalation and topically.
  • Specific modes of administration include, without limitation, oral ingestion; injection, such as intramuscular, intravenous, intraperitoneal , intradermal and subcutaneous; inhalation; and topically, such as transdermally, orally, mucosally and sublingually.
  • safe and effective amount means an amount of a tripeptide derivative or composition high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement.
  • a safe and effective amount of a tripeptide derivative or com ⁇ position will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific active employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • Preferred daily dosages of the tripeptide derivatives of the subject invention range from about 0.1 mg/kg of body weight to about 500 mg/kg of body weight, more preferably from about
  • Preferred amounts of the tripeptide derivatives administered by injection are from about 0.1 mg/kg/day to about 50 mg/kg/day, more preferably from about 1 mg/kg/day to about 10 mg/kg/day.
  • Preferred amounts - of the tripeptide derivatives administered by oral ingestion are from about 1 mg/kg/day to about 500 mg/kg/day, more preferably from about 5 mg/kg/day to about 100 mg/kg/day.
  • Preferred amounts of the tripeptide derivatives administered by inhalation are from about 0.1 mg/kg/day to about 500 mg/kg/day, more preferably from about 5 mg/kg/day to about 100 mg/kg/day.
  • Preferred amounts of the tripeptide derivatives administered topically are from about 1 mg/kg/day to about 500 mg/kg/day, more preferably from about 50 mg/kg/day to about 250 mg/kg/day.
  • Peptide aldehydes are synthesized according to Schemes A and B hereinbelow.
  • the Z-protected arginine derivative 1 is cyclized utilizing isobutyl chloroformate and an appropriate base in an inert solvent and deblocked with anhydrous HC1 to give the cyclic arginine derivative 2: (Z)-cArg-HCl .
  • This compound can be coupled with a dipeptide unit with a protecting group on the amino terminus utilizing diethyl cyanophosphonate and an appropriate amine base at room temperature to form the tripeptide nucleus 3.
  • the ester 3 can be effectively reduced with lithium aluminum hydride in THF at -20 * C and the protecting group (Z) removed by catalytic hydrogenolysis to yield the target peptide 4-
  • the cyclic arginine derivative 2 is coupled to a Boc-protected amino acid under conditions identical to those utilized for the formation of 3 to form a dipeptide unit 5.
  • the Boc group is then removed with anhydrous HC! in dioxane and the resulting amine salt coupled with another amino acid derivative under the same conditions after exposure to base. This again forms the tripeptide nucleus 3.
  • this compound is converted to 4.
  • Trifluoromethyl ketones are synthesized according to Schemes C and D hereinafter.
  • a diamine 8 is monoprotected as the Boc derivative and the resulting free amine oxidized with warm 3-chloroperoxybenzoic acid in dichloroethylene to give the nitro derivative 9.
  • This compound is condensed with CF 3 CH0 hydrate in THF to afford a nitro alcohol and the nitro reduced to the amine to give 10. Subsequent reaction of this free amine
  • SUBSTITUTESHEET with a dipeptide unit in the presence of diethyl cyanophosphonate and a suitable amine is followed by selective removal of the Boc with anhydrous acid, guanylation of the resulting free amine with 3,5-dimethylpyrazole-carboxamidine nitrate in dry DMF and oxidation with Dess-Martin periodinane (see Dess, D.B. & J.C. Martin, "Readily Accessible 12-1-5 Oxidant for the Conversion of Primary and Secondary Alcohols to Aldehydes and Ketones", Journal of Organic Chemistry. Vol. 48 (1983), pp. 4155-4156) to give the trifluoromethyl ketone 12.
  • Boc-D-Phe-Phe-OBn To a slurry of Boc-D-Phe-OH (1.00 g, 3.77 mmol) and Phe-0Bn-p-TSA salt (1.61 g, 3.77 mmol) in 50 ml dichloromethane under argon is added 1.27 ml (9.05 mmol) TEA followed by the addition of 0.682 ml (4.5 mmol) of diethyl cyanophosphonate (DECP). The mixture is stirred overnight and the solvent is removed. Flash chromotography on silica gel gives 2.01 g of the desired compound.
  • DECP diethyl cyanophosphonate
  • Example 3 N-(Cbz)amidino-2-aminovalerolactam-HCl salt ((Z)-cArg-HCl) : To a solution of 1.35 g (3.45 mmol) N-(Cbz)amidino-2-(Boc)amino- valerolactam (Example 1) in 25 ml dioxane is added 15 ml of 3.38M HCl in dioxane. The solution is, stirred at room temperature for 1.5 h, and the solvent is removed. The residue is triturated with ether and the solids filtered under argon to give 1.05 g of white crystalline product.
  • Example 4 Boc-D-Phe-Phe-OH: To a solution of 0.520 g (1.04 mmol) Boc-D-Phe-Phe-OBn (Example 2) in 10 ml MeOH is added 0.250 g palladium on carbon and 0.5 ml acetic acid. The slurry is hydrogenated on the Paar® apparatus at 45-50 psi overnight. The catalyst is filtered through Celite ® , and the solvent is removed to afford 0.204 g product.
  • Example 5 Boc-D-Phe-Phe-(Z)-cArg: To a solution of Boc-D-Phe-Phe-OH (Example 2) (0.390 g, 0.980 mmol) and (Z)-cArg ⁇ C!
  • Example 3 (0.432 g, 0.980 mmol) in dichloromethane is added 0.30 ml (2.16 mmol) TEA followed by 0.17 ml (1.08 mmol) diethyl cyano ⁇ phosphonate. The mixture is stirred overnight and washed with IN HCl, saturated sodium bicarbonate, and saturated sodium chloride. Flash chro otography on silica gel gives 0.400 g product. Rf- 0.45 (5% ipa/CH 2 Cl 2 ).
  • Example 6
  • Boc-D-Phe-Phe-Arg-H-OAc To a cold (-23'C) solution of Boc-D-Phe-Phe-(Z)-cArg (Example 5) (0.170 g, 0.250 mmol) in 15 ml THF is added 0.019 g (0.500 mmol) of LAH portionwise over a period of 1 min. After stirring for 1 h at this temperature the reaction is quenched with 1 ml of water, warmed to room tempera ⁇ ture and filtered, and the solvent is removed. The residue is dissolved in dichloromethane and washed with brine. The resulting organic phase is dried with magnesium sulfate and filtered, and the solvent is removed.
  • Example 1 Boc-D-Pro-Phe-(Z)-cArg To a solution of Boc-D-Pro-Phe-OH (0.357 g, 0.810 mmol) and (Z)-cArg-HC! in 25 ml dichloromethane is added 0.250 ml (1.78 mmol) TEA dropwise followed by 0.140 ml (0.890 mmol). The solution is stirred overnight, and the solvent is removed. Chromotography on silica gel gives 0.362 g product. Rf - 0.40 (5% ipa/CH 2 Cl 2 ).
  • Boc-D-Pro-Phe-Arg-H-OAc As in Example 6, 0.285 g (0.460 mmol) of Boc-D-Pro-Phe-(Z)-cArg (Example 7) and 0.035 g (0.92 mmol) LAH gives crude product. This product is chromatographed on silica gel to give 0.100 g product, which is then hydrogenated (0.100 g palladium on carbon) to afford 0.088 g of the desired product.
  • Example 9 Boc-D-1-Nal-Phe-OBn: As in Example 2, 0.177 g Boc-D-1-Nal- OH (0.560 mmol) and 0.265g Phe-OBn-p-TSA (0.620 mmol) with 0.100 ml DECP (0.620 mmol) and 0.160 ml (1.12 mmol) gives 0.230 g product. Rf» 0.75 (3% ipa/CH 2 Cl 2 ).
  • Boc-D-1-Nal-Phe-Arg-H-OAc As in Example 6, 0.130 g (0.180 mmol) Boc-D-1-Nal-Phe-(Z)-cArg (Example 10) and 0.014 g LAH
  • Example 12 Boc-D-Phe-Cha-OBn: As in Example 2, 0.223 g (0.840 mmol) Boc-D-Phe-OH and 0.250 g Cha-OBn-HCl (Example 76) (0.840 mmol) with 0.140 ml (0.923 mmol) DECP and 0.234 ml (1.68 mmol) TEA gives 0.262 g product. Rf - 0.51 (25% EtOAc/ pentane).
  • Example 13 Boc-D-Phe-Cha-OH: As in Example 4, 0.262 g (0.515 mmol) Boc-D-Phe-Cha-OBn (Example 12) and 0.110 g palladium on carbon gives 0.212 g product.
  • Example 14 Boc-D-Phe-Cha-OH: As in Example 4, 0.262 g (0.515 mmol) Boc-D-Phe-Cha-OBn (Example 12) and 0.110 g palladium on carbon gives 0.212 g product.
  • Example 14 Boc-D-Phe-Cha-OH: As in Example 4, 0.262 g (0.515 mmol) Boc-D-Phe-Cha-OBn (Example 12) and 0.110 g palladium on carbon gives 0.212 g product.
  • Example 14 Boc-D-Phe-Cha-OH: As in Example 4, 0.262 g (0.515 mmol) Boc-D-Phe-Cha-OBn (Example 12) and 0.110 g
  • Example 16 Adoc-D-Phe-Phe-OBn: Boc-D-Phe-Phe-OBn (Example 2) (0.500 g, 0.995 mmol) is dissolved in 5 ml of ethyl acetate, and 5ml of 5M 1° HCl is added. After 2.5 h the solvent is removed, and the residue is placed on the vacuum pump overnight. The solid obtained (D-Phe-Phe-OBn-HCl) is dissolved in a mixture of 1 ml of dioxane and 0.995 ml of IN NaOH. The solution is cooled to O'C and 0.092 g (1.09 mmol) sodium bicarbonate is added.
  • Example 17 Adoc-D-Phe-Phe-OH: As in Example 4, 0.380 g (0.653 mmol) of Adoc-D-Phe-Phe-OBn (Example 16) and 0.076 g Pd/C gives 0.192 g of the desired product.
  • Example 18 0 Adoc-D-Phe-Phe-(Z)-cArg: As in Example 5, 0.100 g (0.204 mmol) of Adoc-D-Phe-Phe-OH (Example 17) and 0.061 g (0.185 mmol) of (Z)-cArg-HCl (Example 3) with 0.031 ml (0.204) DECP and 0.057 ml (0.408 mmol) TEA gives 0.079 g product. Rf- 0.53 (5% ipa/CH 2 Cl 2 ).
  • Example 19 Adoc-D-Phe-Phe-Arg-H-OAc: As in Example 6, 0.078 g (0.102 mmol) Adoc-D-Phe-Phe-(Z)-cArg (Example 18) and 0.008 g (0.204 mmol) LAH gives 0.064 g product that is hydrogenated and lyophilized to afford 0.059 g product. FAB-MS 631 m/z (MH+).
  • Example 20 Adoc-D-2-Nal-Phe-(Z)-cArg: To 0.046 g (0.062 mmol) of Boc-D-2-Nal-Phe-(Z)-cArg (see Example 10 for preparation method used to make an analogous compound) in 5 ml ethyl acetate is added 1 ml of 5M HCl in ethyl acetate. The solution is stirred for 8 h; the solvent is removed, and the residue is placed on the vacuum pump for several hours. The resulting amine salt (D-2- Nal-Phe-(Z)-cArg-HCl) is dissolved in 0.5 ml of dioxane and 0.5 ml of water.
  • Example 22 Boc-Phe-(Z)-cArg: To a solution of Boc-Phe-OH (1.30 g, 4.90 mmol) and (Z)-cArg.-HCl (Example 3) (1.60 g, 4.90 mmol) in 25 ml dichloromethane under an inert atmosphere is added in succession 1.43 ml (10.3 mmol) TEA and 0.743 ml (4.90 mmol) DECP. After stirring overnight the solvent is removed, and the residue is chromatographed on silica gel to afford 1.44 g product.
  • Example 23 Phe-(Z)-cArg-HCl: Boc-Phe-(Z)-cArg (Example 22) (1.44 g, 2.68 mmol) is dissolved in 20 ml ethyl acetate and 22 ml of a 3M solution of HCl in ethyl acetate is added. The solution is stirred for 4 h, and the resulting solid material is filtered through a Buchner funnel with a continuous stream of argon passing over any exposed solid material. The filter cake is 5 washed with ethyl acetate and placed under vacuum for future use. 1.23 g of white solid is obtained.
  • Boc-D-Trp-Phe-(Z)-cArg To a solution of 0.150 g
  • Example 26 N-Bn-D-Ser-OH: 10.0 g (95.2 mmol) of D-Serine and 4.78 g (76.12 mmol) of sodium cyanoborohydride are suspended in 200 ml methanol, and 10.6 g (104 mmol) benzaldehyde is added dropwise. The slurry is stirred for 48 h and filtered. The filter cake is washed with methanol and placed on the vacuum pump overnight. 10.5 g of a white powder that is a 1:1 mixture of starting material and product is obtained.
  • N-Bn,N-(Z)-D-Ser A 1:1 mixture of N-Bn-D-Ser-OH and D-Serine (Example 26) (5.00 g) is dissolved in 18.3 ml 2N NaOH and 6 ml THF is added. The solution is cooled to O'C, and 7.86 l (55.0 mmol) benzylchloroformate is added. During addi ⁇ tion the pH is maintained between 9.5 and 10.5 by addition of IN NaOH. After 1 h of stirring and continuously maintaining the pH, the solution is acidified to pH - 2.4 with concentrated HCl.
  • Example 29 To a dry flask under argon con ⁇ taining 1.52 g triphenylphosphine (5.77 mmol) in 20 m
  • N-Bn-N-(Z)-D-tBal-0H To a slurry of cuprous bromide/di- methylsulfide complex (0.581 g, 2.83 mmol) in 5 ml THF in a previously dried flask at -78'C under argon is added 2.96 ml t-BuLi (1.7M in pentane, 5.04 mmol) dropwise. The slurry is stirred at this temperature for 0.75 h and 0.3 h at -45'C.
  • Example 30 Boc-D-t-Bal-OH: To a solution of N-Bn-N-(Z)-D-tBal-0H (Example 29) (0.160 g, 0.432 mmol) in water:acetic acid (1:2, 15 ml) is added 0.030 g Pd/C and the slurry hydrogenated on the Paar* apparatus at 45 psi for 16 h. After filtering through Celite*, the solvent is removed, and the residue is placed on the vacuum pump. The deprotected product is dissolved in 0.480 ml IN NaOH and 2 ml dioxane, and 1 ml water is added.
  • Example 32 Boc-D-t-Bal-Phe-Arg-OAc: As in Example 6, 0.055 g (0.083 mmol) Boc-D-t-Bal -Phe-(Z)-cArg (Example 31) and 0.006 g (0.166 mmol) LAH gives 0.027 g product that fs hydrogenated (0.010 g Pd/C) and lyophilized to give 0.035 g product.
  • Example 35 Boc-D-1-Adl-Phe-(Z)-cArg: As in Example 24, 0.047 g (0.145 mmol) Boc-D-I-Adl-OH (Example 34) and 0.069 g (0.145 mmol) Phe-(Z)cArg-HCl (Example 23) with 0.044 ml (0.319 mmol) TEA and 0.022 ml (0.145 mmol) DECP gives 0.067 g product. [ ⁇ ] ⁇ 5 - -15.8 (c - 1, chloroform). Rf - 0.64 (5% ipa/CH 2 Cl 2 ).
  • Example 36 Boc-D-1-Adl-Phe-Arg-H-OAc: As in Example 6, 0.065 g Boc-D- l-Adl-Phe-(Z)-cArg (Example 35) (0.088 mmol) and 0.007 g (0.175 mmol) LAH gives 0.045 product- 0.014 g of this product is hydrogenated (0.002 g Pd/C) and lyophilized to give 0.015 g product. FAB-MS - 611 m/z (MH+), 719 m/z (MH + TG)+.
  • Example 37 ⁇ -N-Boc-e-N-(Z)-D-Orn-Phe-(Z)-cArg: As in Example 24, 0.250 g (0.710 mmol) ⁇ -N-Boc-S-N-(Z)-D-Orn-OH and 0.338 g (0.71 mmol) Phe-(Z)-cArg-HCl (Example 23) with 0.390 ml (2.80 mmol) TEA and 0.120 ml (0.800 mmol) DECP gives 0.310 g product. Rf - 0.52 (5% ipa/CH 2 Cl 2 ).
  • Example 38 ⁇ -N-Adoc-,.-N-(Z)-D-Orn-Phe-(Z)-cArg: To a cold (O'C) solution of 0.300 g (0.420 mmol) of tt-N-Adoc-i-N-(Z)-D-0rn-Phe- (Z)-cArg (Example 37) in 15 ml water and 15 ml dioxane is added 0.134 g (1.60 mmol) sodium bicarbonate followed by 0.099 g (0.500 mmol) adamantyl fluoroformate in 1 ml dioxane dropwise. The cool ng bath is removed ⁇ and the solution is stirred for 1 h.
  • Adoc-D-0rn-Phe-Arg-H-0Ac As in Example 6, 0.165 g (0.190 mmol) ⁇ -N-Adoc- ⁇ $-N-(Z)-D-Orn-Phe-(Z)-cArg (Example 38) and 0.015 g (0.380 mmol) LAH gives 0.035 g product that is hydrogenated and lyophilized to give 0.030 g product.
  • Example 40 Adac-D-t-Bug-Phe-OBn: To a solution of 5 ml of a 15% 5 solution of phosgene in toluene under argon is added 0.140 ml TEA (1.00 mmol). This is followed by the addition of 0.112 g (0.750 mmol) of 1-adamantanamine in 1 ml toluene dropwise via syringe. The resulting slurry is stirred for 0.3 h, and the excess phosgene is removed by purging with argon. The solid is 10 filtered off by suction through a sintered glass funnel, and the solvent is removed.
  • Example 41 Adac-D-t-Bug-Phe-(Z)-cArg: To a mixture of 0.082 g Adac-D- 0 t-Bug-Phe-OH (see Example 4 for preparation method used to make an analogous compound) (0.150 mmol) and (Z)-cArg-HCl (Example 3) (0.080 g, 0.180 mmo! ) in 25 ml dichloromethane under argon is added 0.084 ml (0.600 mmol) TEA followed by 0.030 ml (0.200 mmol) DECP. The mixture is stirred overnight, and the solvent is 5 removed. The residue is chromatographed on silica gel to give 0.085 g product. Rf- 0.35 (3% ipa/CH 2 Cl 2 ).
  • Example 42 Adac-D-t-Bug-Phe-Arg-H: As in Example 6, 0.085 g Adac-D-t- Bug-Phe-(Z)-cArg-H (Example 41) (0.120 mmol) and 0.009 g LAH 0 (0.240 mmol) gives 0.054 g chromatographed product that is hydrogenated and lyophilized to give 0.044 g product. FAB-MS - 596 m/z (MH+).
  • Ada-D-t-Bug-Phe-(Z)-cArg To a solution of Boc-D-t-Bug- 5 Phe-(Z)-cArg (see Example 5 for preparation method used to make an analogous compound) (0.060 g, 0.082 mmol) in 2 ml ethyl acetate is added 1 ml 5 M HCl in ethyl acetate, and the solution is stirred at room temperature for 6 h. An additional 1 ml of HCl in ethyl acetate is added, and the solution is stirred overnight. The solvent is removed, and the residue is placed on the vacuum pump.
  • Ada-D-t-Bug-Phe-Arg-H As in Example 6, 0.013 g
  • Example 46 (3(2R),4R)-3(2-adamantyl-2-azido-l-oxo)-4-(phenylmethyl)-2- oxazol dinone: (4R)-3-(2-adamantyl-l-oxo)-4-(phenylmethyl)-2- oxazolidinone (Example 45) (0.389 g, 1.10 mmol) is dissolved in 15 ml THF and cooled to -78'C. This solution is then added via cannula to a 0.3 M THF solution of 1.27 mmol of KHMDS that is also maintained at -78'C.
  • Example 47 (2R)-2-azido-adamantaneacetic acid: (3(2R),4R)-3(2-ada- mantyl-2-azido-l-oxo)-4-(phenylmethyl)-2-oxazolidinone (Example 46) (0.270 g, 0.690 mmol) is dissolved in 10 ml THF and cooled to O'C. To this solution is added a mixture of 3.63 ml of 0.2 M lithium hydroxide, 0.35 ml of 30% hydrogen peroxide and 4 ml of water dropwise. After 1 h at O'C, 10 equivalents of sodium bisulfite in 2 ml water is added, and the solution is stirred for 15 min.
  • Adoc-D-Adg-Phe-(Z)-cArg As in Example 24, 0.040 g (0.100 mmol) of (R)-Adoc-Adg-OH (Example 48) and 0.049 g
  • Example 50 Adoc-D-Adg-Phe-Arg-H: As in Example 6, 0.030 g Adoc-D-Adg- Phe-(Z)-cArg (Example 49) (0.037 mmol) and LAH (0.003 g, 0.075 mmol) gives 0.010 g chromatographed product that is hydro ⁇ genated with 0.002 g Pd/C and lyophilized to afford 0.009 g product. FAB-MS 675 m/z (MH+).
  • Example 51 Adoc-D-Adg-Phe-Arg-H: As in Example 6, 0.030 g Adoc-D-Adg- Phe-(Z)-cArg (Example 49) (0.037 mmol) and LAH (0.003 g, 0.075 mmol) gives 0.010 g chromatographed product that is hydro ⁇ genated with 0.002 g Pd/C and lyophilized to afford 0.009 g product.
  • Adoc-D-t-Bug-Phe-(Z)-Lys-OMe To a solution of 0.432 g Adoc-D-t-Bug-Phe-OH (see Example 17 for preparation method used to make an analogous compound) (0.946 mmol) and 0.298 g N-e-(Z)- Lys-OHe (0.901 mmol) in 25 ml dichloromethane is added 0.276 ml TEA (1.98 mmol) followed by 0.144 ml DECP (0.946 mmol); the solu ⁇ tion is stirred overnight. The solvent is removed, and the residue is chromatographed on silica gel to give 0.495 g product. Rf - 0.49 (4% MeOH/CH 2 Cl 2 ).
  • Example 52 Adoc-D-t-Bug-Phe-(Z)-Lysinol: Adoc-D-t-Bug-Phe-(Z)-Lys-0Me (Example 51) (0.070 g, 0.096 mmol) is dissolved in 1 ml of ethanol and cooled in an ice/methanol bath. To this solution is added solid anhydrous calcium chloride (0.021 g, 0.191 mmol) and 1 ml THF. Sodium borohydride (0.144 g, 0.382 mmol) is added in one portion and the resulting slurry is allowed to warm to room temperature over a period of 3 h. The reaction is quenched with 1 ml of 1 M citric acid.
  • Example 54 Adoc-D-t-Bug-Phe-Lys-H-TFA: To a solution of 0.009g Adoc-D-t-Bug-Phe-(Z)-Lys-H (Example 53) (0.013 mmol) and 0.006 g of 9.7% HCl in dioxane in 0.900 ml DMF is added 0.005 g Pd black. This slurry is hydrogenated at atmospheric pressure for 0.3 h. The slurry is diluted with 1 ml dioxane and filtered through Celite*. The filter cake is washed with methanol, and the solvent is removed.
  • Example 55 eBroc-D-t-Bug-Phe-(Z)-cArg: To a solution of 0.080 g of (-)endoborneol (0.520 mmol) and 0.041 ml pyridine (0.520 mmol) in 2 ml toluene is added 7 ml of a 12% solution of phosgene in toluene dropwise. After 1 h, argon is bubbled through the solution to purge any remaining phosgene. After 10 min the slurry is filtered, and the solvent is removed.
  • Example 56 eBroc-D-t-Bug-Phe-Arg-H: As in Example 6, 0.090 g (0.120 mmol) of eBroc-D-t-Bug-Phe-(Z)-cArg (Example 55) and 0.009 g LAH (0.240 mmol) gives 0.065 g product after chro atog- raphy. This compound is hydrogenated on the Paar* apparatus for 3 h (AcOH/MeOH - 1/20) to give 0.045 g after lyophilization. FAB-MS - 599 m/z (MH+), 707 m/z (MH + TG)+.
  • Tr-p-Nph-OMe 26.0 g (99.8 mmol) of p-Nph-OMe-HCl is suspended in 500 ml dichloromethane, and 27.8 ml TEA (199.6.mmol) is added dropwise. After the addition is complete, 26.4 g
  • Tr-p-nitrophenylalaninol To a solution of 45.3 g (97.2 mmol) of Tr-p-Nph-OMe (Example 57) in 500 ml THF at O'C under argon is added 200 ml (300 mmol) DIBAL-H at a moderate rate. After 1 h, the solution is transferred to a 2 1 Erlenmeyer ftask and cooled to O'C. To this solution is added 500 ml saturated potassium sodium tartrate solution cautiously. The mixture is extracted with 3 X 1 1 ethyl acetate, and the organic phases are dried. Removal of solvent gives 40 g that is chromatographed on silica gel to give 26.9 g of product.
  • Tr-p-nitrophenylalaninal To a solution of 0.581 ml oxalyl chloride (6.67 mmol) in 50 ml dichloromethane under argon at -78'C is added 0.946 ml DMSO (13.3 mmol) in 2 ml dichloromethane dropwise. After the addition is complete, 2.25 g (5.13 mmol) of Tr-p-nltrophenyTalaninol (Example 58) in 7 ml dichloromethane is added. The solution is stirred for 0.5 h and is then poured into a mixture of ether and water.
  • Example 62 4-p-Aminophenyl -3-t-butyloxycarbonylamino-l,1,1-trifluoro- 2-butanol: To a solution of 3-amino-4-p-aminophenyl-l,l,l-tri- fluoro-2-butanol (Example 61) (5.26 g, 22.5 mmol) in 200 ml THF is added 5.31 g di-t-butyl dicarbonate (23.6 mmol), and the solution is stirred overnight. The solvent is removed, and the residue is chromatographed on silica gel to give 5.70 g product. Rf - 0.48, 0.68 (1 NH 4 0H/1% ipa/98% CH 2 C1 2 ).
  • Example 63 3-t-Butyloxycarbonylamino-4-di-CBz-p-guanidinophenyl-1,1,1- trifluoro-2-butanol : To a solution of 0.020 g (0.060 mmol ) of 4-p-aminophenyl -3-t-butyloxycarbonylamino-1,1,1-trifluoro-2- butanol (Example 62) in 5 ml THF under argon is added 0.027 mg (0.072 mmol) of N,N' ,-di-Cbz-S-methylisothiourea (Example 74) followed by addition of 5.7 mg mercuric acetate.
  • Example 64 3-Amino-4-di-Cbz-p-guanidinophenyl-1,1,1-trif1uoro-2-butanol hydrochloride salt: A solution of 2.8 g (4.34 mmol) of 3-t- butyloxycarbonylamino-4-di-Cbz-p-guanidinophenyl-1,1,1-tri- fluoro-2-butanol (Example 63) in 40 ml dioxane and 15 ml 4M HCl • in dioxane is stirred for 2 h at room temperature. The dioxane is removed in vacuo, and the residue is triturated with ether. The slurry is filtered under argon and is found to weigh 2.4 g.
  • Example 65 3-(Adamantyloxy-D-t-butylglycylphenylalanyl)amino-4-di- Cbz-p-guanidinophenyl-1,1,1-trifluoro-2-butanol : To a solution of 0.750 g 3-amino-4-di-Cbz-p-guanidinophenyl-l,l,l-trifluoro- 2-butanol (Example 64) (1.29 mmol) and 0.647 g Adoc-D-t-Bug- Phe-OH (see Example 17 for preparation method used to make an analogous compound) (1.42 mmol) in 10 ml DMF is added 0.500 ml TEA (3.58 mmol) followed by 0.232 ml DECP (1.42 mmol); the mixture is stirred overnight.
  • Example 66 3-(Adamantyloxy-D-t-butylglycylphenylalanyl)amino-4-di- Cbz-p-guanidinophenyl-l,l,l-trifiuoro-2-butanone: To a solution of 0.452 g Dess-Martin periodinane (1.07 mmol) in 10 ml dichloro ⁇ methane is added 0.352 g 3-(adamantylo ⁇ y-D-t-butylglycylphenyl- alany1)amino-4-di-Cbz-p-guanidinophenyl-1,1,1-trifluoro-2-butanol (Example 65) (0.356 mmol) in 10 ml dichloromethane dropwise.
  • Example 68 4-t-Butyloxycarbonylamino-l-nitrobutane: To a solution of 4.00 g 4-t-butyloxyamino-l-aminobutane (see Stahl , G.L., R. Walter & C.W. Smith, "General Procedure for the Synthesis of Mono-N-acylated 1,6-Diaminohexanes", Journal of Organic Chemistr y . Vol. 43, No. 11 (1978), pp. 2285-2286) ⁇ 21.3 mo! ) in 50 ml dichloroethane is added 14.7 g (85.0 mmol) MCPBA in 1 g portions. The temperature is raised to reflux (83'C) and held there for 3 h.
  • Example 70 3-A ⁇ no-6-Boc-amino-l,l,l-trifluoro-2-hexanol: To a solution of 0.280 g (0.885 mmol) of 6-Boc-amino-3-nitro-l,l,l- trifluoro-2-hexanol (Example 69) in 5 ml methanol is added 5 drops of acetic acid and 0.056 g 10% Pd/C. The slurry is hydrogenated at 45 psi for 20 h and filtered through Celite ® . The solvent is removed, and the residue is chromatographed on silica gel to give two diastereomers (0.072 g and 0.108 g) that are easily separated. Rf- 0.27, 0.45 (1% NH 4 0H/2.5% Me0H/96.5% CH 2 C1 2 ).
  • Example 71 3-(eBroc-D-t-Bug-Phe-amino-6-t-butyloxycarbonylamino-1,1,1- " trifluoro-2-hexanol: To a solution of 3-amino-6-t-Boc-amino- l,l,l-trifluoro-2-hexanol (Example 70) (0.600 g, 1.31 mmol) and eBroc-D-t-Bug-Phe-OH (see Example 17 for preparation method used to make an analogous compound) (0.370 g, 1.31 mmol) in 20 ml dichloromethane under argon is added 0.360 ml TEA (2.62 mmol) followed by the addition of 0.200 ml DECP (1.31 mmol). The mixture is stirred overnight, and the solvent is. removed. The residue is chromatographed on silica gel to afford 0.800 g product. Rf- 0.34 (5% ipa/CH 2 Cl
  • Example 72 3-(eBroc-D-t-Bug-Phe)-amino-6-guanidino-l,l,l-trifluoro-2- hexanol TFA salt: To a solution of 0.800 g 3-(eBroc-D-t-Bug- Phe)-amino-6-Boc-amino-l,l,l-trifluoro-2-hexanol (Example 71) (1.10 mmol) in 20 ml dioxane is added 3 ml 3.2M HCl in dioxane; the mixture is stirred for 2 h. At this time an additional 1 ml HCl is added, and the mixture is stirred for an additional 2.5 h.
  • Example 73 3-(eBroc-D-t-Bug-Phe)-amino-6-guanidino-l,l,l-trifluoro-2- hexanone TFA salt: To a solution of Dess-Martin periodinane (0.400 g, 0.850 mmol) in 10 ml CH 2 C1 2 is added a solution of 3-(eBroc-D-t-Bug-Phe)-amino-6-guanidino-l,l,l-trifluoro-2-hexanol TFA salt (Example 72) (0.190 g, 0.240 mmol) in 10 ml CH 2 C1 2 . The mixture is stirred overnight, and the solvent is removed.
  • N,N'-bis-carbobenzyloxy-S-methyl-isothiourea To a solution of S-methyl-isothiourea sulfate dimer (5.00 g, 18.0 mmol) of cold
  • Example 75 Boc-Cha-OBn: To a slurry of Boc-Cha-OH (1.56 g, 5.75 mmol) and NaHCO j (1.54 g, 18.33 mmol) in 50 ml DMF is added 0.700 ml (6.72 mmol) benzyl bromide. The mixture is stirred for 2 days. The DMF is evaporated, and the solid is dissolved in EtOAc. The slurry is washed with water; the organic phase is dried, and the filtrate is evaporated. 1.91 g product that is homogeneous by TLC is recovered. Rf - 0.70 (25% EtOAc/pet ether).
  • Example 76 Cha-OBn-HCl: To a solution of Boc-Cha-OBn (1.81 g, 5.01 mmol) (Example 75) in dioxane is added 18 ml of 3.34M HCl in dioxane. After 1 h, 10 ml additional 3.34M HCl in dioxane is added. The solvent is removed, and the residue is triturated with EtOAc, filtered and placed on a vacuum .pump. 1.22 g of a white solid is recovered.
  • Methods for Testing Activity of the Com p ounds The following non-limiting procedures are methods for testing the anti-inflammatory and/or analgesic activity of the tripeptide derivatives of the subject invention.
  • enzyme inhibition assays are known to be predictive of anti-inflammatory activity for compounds. Such enzyme assays are useful for measuring the activity of compounds of the subject invention. Such enzyme assays include the following: porcine pancreatic kallikrein (PPK) - see references A, E and F; human urinary kallikrein (HUK) - see references E and F; human plasma kallikrein - see references B and E; human plasmin (HP) - see references B and C; and urokinase (UK) - see reference D.
  • porcine pancreatic kallikrein - see references A, E and F
  • human urinary kallikrein HUK
  • human plasma kallikrein - see references B and E
  • human plasmin HP
  • urokinase UK
  • Another useful assay of activity is based on a method for determination of slow-binding enzyme inhibition disclosed in Imperiali, B. & R.H. Abeles, "Inhibition of Serine Proteases by Peptidyl Fluoromethyl Ketones", Biochemistry. Vol. 25 (1986) pp. 3760-3767. The method is modified as described below in order to study the slow binding inhibition of human plasmin (A*) and kallikrein (pig pancreatic) (B*).
  • reaction mixtures contain 78 mM ' tris-.HCl buffer, pH 7.4, 78 mM NaCl , 0.2 mg/ml bovine serum albumin, 0.2 mM S-2251 (D-Val-Leu-Arg-p-nitroanilide), 0.5 U/ml plasmin (1 ⁇ M), and variable concentrations of the test compound to be studied, in a total volume of 1 ml .
  • the stock solution of plasmin is 1 U/ml in 50% glycerol.
  • the absorbance change due to release of p-nitroaniline on enzymatic cleavage of S-2251 is monitored using an HP-8450 spectrophotometer system, set to measure A 400*410 - A 470 ' 4 * 0 .
  • the temperature is 30'C.
  • in vivo assays are known to be predictive of the anti-inflammatory activity of compounds. Such in vivo assays are useful for measuring the activity of compounds of the subject invention. Such n vivo assays are disclosed in the following references which are hereby incorporated herein by reference: Winter, C.A., E.A. Risley, GN. Nuss, "Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs", Proc. Soc. EXP. Bio!.. N.Y., Vol. Ill (1962), pp. 544-547; Vander Wende, C. & S.
  • Tablets are made by conventional procedures, each having the following composition:
  • One tablet is administered orally four times daily to a patient to aleviate inflammation in joints due to arthritis.
  • Example 78 A lotion is made by conventional procedures, the lotion having the following composition:
  • Example 79 One gram of the lotion is administered topically to the skin in the area of a burn twice daily to reduce inflammation and pain.
  • a solution is made by conventional means, each 2 ml of solution having the following composition:
  • a 2 ml dose of the solution is injected intramuscularly to a patient with arthritis to reduce inflammation and pain.
  • Example 80 A solution is made by conventional means, the solution having the following composition:

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Abstract

Composés anti-inflammatoires ayant la structure (I), dans laquelle: (a) n est un nombre entier compris entre 0 et 2 environ; (b) -R est sélectionné parmi alkyle linéaire ou ramifié et saturé ou insaturé à 1 ou 2 liaisons doubles et à 1 à 6 atomes de carbone environ; et alkyle cyclique saturé ou insaturé à 1 ou 2 liaisons doubles et à 3 à 13 atomes de carbone environ; l'atome de carbone auquel -R est lié présentant une configuration D ou L; (c) -R' est sélectionné parmi alkyle ramifié et saturé ou insaturé à 1 ou 2 liaisons doubles et à 3 à 6 atomes de carbone environ; alkyle cyclique et saturé ou insaturé à 1 ou 2 liaisons doubles et à 3 à 13 atomes de carbone; et arylalkyle, la partie alkyle étant saturée et possédant de 1 à 3 atomes de carbone environ; et l'atome de carbone auquel -R' est lié présentant une configuration L; (d) -R'' représente -(CH2)m-A-NH2 ou -(CH2)m-A-B-C(NH2)=NH, où m est un nombre entier compris entre 1 et 5 environ; -A- représente une liaison covalente, ou p-phényle ou p-cyclohexyle; et -B- représente une liaison covalente ou -NH-; l'atome de carbone auquel -R'' est lié présentant une configuration L; (e) -Y représente hydrogène ou trifluorométhyle; (f) -Z- représente -O- ou -NH-; (g) -V- est sélectionné parmi -OC(O)-, -N(Q)C(O)-, -N(Q)C(S)-, -C(O)-, -SO2- et -P(O)(OH)-; lorsque -V- représente -OC(O)-, -Z- représente -NH-; (h) -X est sélectionné dans le groupe constitué d'alkyle cyclique, d'alkyle ramifié à au moins deux ramifications, et d'aryle, chacun possédant de 5 à 20 atomes de carbone environ; et (i) -Q est sélectionné dans le groupe constitué d'hydrogène; et d'alkyle linéaire ou ramifié et saturé ou insaturé à 1 ou 2 liaisons doubles et à 1 à 6 atomes de carbone environ; ou -Q et -X sont liés de manière covalente de façon à former une fraction cyclique comprenant l'azote auquel -Q est lié, ainsi que de 5 à 20 atomes de carbone environ. On a également prévu des compositions pharmaceutiques composant les composés précités, ainsi que des procédés de traitement des inflammations et des douleurs à l'aide de ces composés et de ces compositions.
PCT/US1992/008901 1991-10-23 1992-10-19 Derives tripeptidiques utilises comme agents anti-inflammatoires WO1993008211A1 (fr)

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US5436229A (en) * 1994-03-04 1995-07-25 Eli Lilly And Company Bisulfite adducts of arginine aldehydes
US5440015A (en) * 1992-07-21 1995-08-08 Glycomed Incorporated Selectin peptide medicaments for treating disease
US5439888A (en) * 1994-03-04 1995-08-08 Eli Lilly And Company Antithrombotic agents
EP0675899A1 (fr) * 1992-12-15 1995-10-11 Corvas International, Inc. NOUVEAUX INHIBITEURS DU FACTEUR Xa
US5484772A (en) * 1994-03-04 1996-01-16 Eli Lilly And Company Antithrombotic agents
US5488037A (en) * 1994-03-04 1996-01-30 Eli Lilly And Company Antithrombotic agents
US5578574A (en) * 1994-03-04 1996-11-26 Eli Lilly And Company Antithrombotic agents
US5599793A (en) * 1994-03-04 1997-02-04 Eli Lilly And Company Antithromobotic 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
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
US5726159A (en) * 1994-03-04 1998-03-10 Eli Lilly And Company Antithrombotic agents
US5885967A (en) * 1994-03-04 1999-03-23 Eli Lilly And Company Antithrombotic agents
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
US6664349B2 (en) 2001-03-29 2003-12-16 Equistar Chemicals, Lp Ethylene polymerization process
US7649000B2 (en) * 2002-03-08 2010-01-19 Vantia Limited Selective dipeptide inhibitors of kallikrein

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EP0313969A2 (fr) * 1987-10-30 1989-05-03 Nitto Boseki Co., Ltd. Dérivés de tripeptide et agents les contenant

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5440015A (en) * 1992-07-21 1995-08-08 Glycomed Incorporated Selectin peptide medicaments for treating disease
EP0675899A4 (fr) * 1992-12-15 1996-01-24 Corvas Int Inc NOUVEAUX INHIBITEURS DU FACTEUR Xa.
US5883077A (en) * 1992-12-15 1999-03-16 Corvas International, Inc. Inhibitors of factor Xa
EP0675899A1 (fr) * 1992-12-15 1995-10-11 Corvas International, Inc. NOUVEAUX INHIBITEURS DU FACTEUR Xa
US5705487A (en) * 1994-03-04 1998-01-06 Eli Lilly And Company Antithrombotic agents
US5726159A (en) * 1994-03-04 1998-03-10 Eli Lilly And Company Antithrombotic agents
US5488037A (en) * 1994-03-04 1996-01-30 Eli Lilly And Company Antithrombotic agents
US5578574A (en) * 1994-03-04 1996-11-26 Eli Lilly And Company Antithrombotic agents
US5599793A (en) * 1994-03-04 1997-02-04 Eli Lilly And Company Antithromobotic agents
US5602101A (en) * 1994-03-04 1997-02-11 Eli Lilly And Company Antithrombotic agents
US5436229A (en) * 1994-03-04 1995-07-25 Eli Lilly And Company Bisulfite adducts of arginine aldehydes
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US6124277A (en) * 1994-03-04 2000-09-26 Eli Lilly And Company Antithrombotic agents
US5484772A (en) * 1994-03-04 1996-01-16 Eli Lilly And Company Antithrombotic agents
US5439888A (en) * 1994-03-04 1995-08-08 Eli Lilly And Company Antithrombotic agents
US5885967A (en) * 1994-03-04 1999-03-23 Eli Lilly And Company Antithrombotic agents
US6090787A (en) * 1994-03-04 2000-07-18 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
US6664349B2 (en) 2001-03-29 2003-12-16 Equistar Chemicals, Lp Ethylene polymerization process
US7649000B2 (en) * 2002-03-08 2010-01-19 Vantia Limited Selective dipeptide inhibitors of kallikrein

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MX9206150A (es) 1993-08-01
PT101001A (pt) 1994-01-31
AU2882792A (en) 1993-05-21
TW240234B (fr) 1995-02-11

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