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WO1995006031A1 - Inhibitors of tnf-alpha secretion - Google Patents

Inhibitors of tnf-alpha secretion Download PDF

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Publication number
WO1995006031A1
WO1995006031A1 PCT/US1994/009343 US9409343W WO9506031A1 WO 1995006031 A1 WO1995006031 A1 WO 1995006031A1 US 9409343 W US9409343 W US 9409343W WO 9506031 A1 WO9506031 A1 WO 9506031A1
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Prior art keywords
compound
alkyl
tnf
compound according
hydrogen
Prior art date
Application number
PCT/US1994/009343
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English (en)
French (fr)
Inventor
Roy A. Black
Jeffrey N. Fitzner
Paul R. Sleath
Original Assignee
Immunex Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Immunex Corporation filed Critical Immunex Corporation
Priority to CA002170158A priority Critical patent/CA2170158A1/en
Priority to AU75694/94A priority patent/AU687436B2/en
Priority to EP94925940A priority patent/EP0715619A4/en
Priority to NZ271893A priority patent/NZ271893A/en
Priority to JP7507668A priority patent/JPH09503201A/ja
Publication of WO1995006031A1 publication Critical patent/WO1995006031A1/en
Priority to FI960803A priority patent/FI960803L/fi
Priority to NO960723A priority patent/NO960723L/no

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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
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C07K5/06095—Arg-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic 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
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • 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
    • C07K5/0606—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • TNF- ⁇ is a principal mediator of the host response to gram-negative bacteria.
  • Lipopolysaccharide LPS, also called endotoxin
  • endotoxin derived from the cell wall of gram-negative bacteria
  • TNF- ⁇ secreted has only been recently elucidated. Kriegler et al. Cell, 53, 45-53, (1988) conjectured that TNF- ⁇ "secretion" is due to the cleaving of the 26 kD membrane-bound molecule by a proteolytic enzyme or protease. Scuderi et. al., J. Immunology, 143, 168-173 (1989), suggested that the release of TNF- ⁇ from human leukocyte cells is dependent on one or more serine proteases, e.g., a leukocyte elastase or trypsin.
  • serine proteases e.g., a leukocyte elastase or trypsin.
  • protease which causes the cleavage of the TNF- ⁇ molecule into the 17 kD protein is, in fact, a metalloprotease which is believed to reside in the plasma membrane of cells producing TNF- ⁇ .
  • the physicochemical characteristics of the enzyme have not been published.
  • Cardiovascular Disease which includes:
  • Neurologic which includes:
  • Metabolic/Idiopathic which includes:
  • Inhibitors of TACE would prevent the cleavage of cell-bound TNF- ⁇ thereby reducing the level of TNF- ⁇ in serum and tissues. Such inhibitors would be of significant clinical utility and could be potential therapeutics for treating the above TNF- ⁇ -related disorders.
  • the invention relates to compounds of formula I:
  • n 0, 1 or 2;
  • B is unsubstituted or substituted C 2 to C 8 alkylene
  • R 1 , R 2 and R 3 each independent of the other is hydrogen, alkylene(cycloalkyl), OR 4 , SR 4 , N(R 4 )(R 5 ), halogen, substituted or unsubstituted C 1 to C 8 alkyl, C 1 to
  • n 0, 1 or 2;
  • Y is hydrogen, unsubstituted or substituted C 1 to C 8 alkyl, alkylene(cycloalkyl), the group -R 8 -COOR 9 or the group -R 10 N(R 1 1 )(R 12 ); wherein R 8 is C 1 to C 8 alkylene; R 9 is hydrogen or C 1 to C 8 alkyl; R 10 is unsubstituted or substituted C 1 to C 8 alkylene; and R 11 and R 12 are each, independent of the other, hydrogen or C 1 to C 8 alkyl;
  • A is a protected or an unprotected ⁇ -amino acid radical
  • A is the same or different protected or unprotected ⁇ -amino acid radical; and the pharmaceutically acceptable salts thereof;
  • the compound is capable of reducing serum TNF- ⁇ levels by at least 80% when administered at 25mg/kg in a murine model of LPS-induced sepsis syndrome; and a pharmaceutically acceptable carrier.
  • the invention is directed to a compound of formula I:
  • X is hydroxamic acid, thiol, phosphoryl or carboxyl
  • n 0, 1 or 2;
  • R 1 , R 2 and R 3 each independent of the other is hydrogen, alkylene(cycloalkyl), OR 4 , SR 4 , N(R 4 )(R 5 ), halogen, substituted or unsubstituted C 1 to C 8 alkyl, C 1 to
  • A is a protected or an unprotected ⁇ -amino acid radical; provided that when n is 1 , A is a protected or an unprotected ⁇ -amino acid radical; when n is 2, A is the same or different protected or unprotected ⁇ -amino acid radical;
  • B is unsubstituted or substituted C 2 to C 8 alkylene
  • the compounds of formula I are useful as inhibitors of TNF- ⁇ secretion, and particularly useful as inhibitors of the TNF- ⁇ converting enzyme (TACE).
  • TACE TNF- ⁇ converting enzyme
  • the invention also relates to a method for treating a mammal having a condition or a disease characterized by overproduction or unregulated production of TNF- ⁇ , comprising administering to the mammal a composition comprising an effective amount of a biologically active compound of formula II:
  • X is hydroxamic acid, thiol, phosphoryl or carboxyl
  • n 0, 1 or 2;
  • Y is hydrogen, unsubstituted or substituted C 1 to C 8 alkyl, alkylene(cycloalkyl), the group -R 8 -COOR 9 or the group -R 10 N(R 1 1 )(R 12 ); wherein R 8 is C 1 to C 8 alkylene; R 9 is hydrogen or C 1 to C 8 alkyl; R 10 is unsubstituted or substituted C 1 to
  • R 11 and R 12 are each, independent of the other, hydrogen or C 1 to
  • A is a protected or an unprotected ⁇ -amino acid radical; and when n is 2, A is the same or different protected or unprotected ⁇ -amino acid radical; and the pharmaceutically acceptable salts thereof;
  • the compound is capable of reducing serum TNF levels by at least 80% when administered at 25mg/kg in a murine model of LPS-induced sepsis syndrome; and a pharmaceutically acceptable carrier.
  • the invention includes pharmaceutical compositions containing a compound according to formula I as the active component.
  • pharmaceutical compositions comprising a compound according to formula II and a protein which binds TNF are described.
  • An example of a protein which binds TNF is an anti-TNF antibody or a soluble TNF receptor which is described in EPA 0418014, assigned to the assignee of the instant application. The disclosure of EPA 0418014 is incorporated herein by reference.
  • Alkyl means a straight or branched, univalent, saturated or unsaturated hydrocarbon group of 1 to 8 carbon atoms. Alkyl groups include the straight-chain groups methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl as well as the branched isomers thereof. "Substituted alkyl” means an alkyl group substituted with one or more of hydroxy, amino, halogen, or thiol.
  • Alkylene means a bivalent alkyl group as defined above.
  • substituted alkylene means an alkylene group substituted with one or more of hydroxy, amino, halogen or thiol groups.
  • Aryl means an aromatic or heteroaromatic group, including for example, phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl and the like, optionally substituted with one or more of C 1 to C 8 alkyl, hydroxy, amino, halogen, thiol or alkyl groups.
  • Alkylene(cycloalkyl) refers to groups of the structure -R 13 -R 14 wherein R 13 is an alkylene as defined above, and R 14 is a univalent cyclic alkane radical, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Alkylenearyl means the group -R 15 -R 16 , wherein R 15 is a substituted or unsubstituted alkylene group as defined above, and R 16 is a substituted or unsubstituted aryl group as defined above.
  • Biologically active as used in defining certain compounds of formula II, designates a compound capable of (a) inhibiting secretion of TNF- ⁇ ; (b) preventing cleavage of membrane-bound TNF- ⁇ by TACE; or (c) reducing serum TNF levels by at least 80% when administered at 25 mg/kg in a standard murine model of LPS-induced sepsis syndrome.
  • preferred radicals for X are hydroxamic acid, thiol and phosphoryl. More preferred X radicals are hydroxamic acid and thiol, while the most preferred radical is hydroxamic acid.
  • the preferred value for m is 1.
  • R 1 or R 2 radicals are hydrogen, C 1 to C 8 alkyl and C 1 to C 8 alkylenearyl.
  • R 1 or R 2 is alkyl, preferred is C 1 to C 6 alkyl and most preferred is C 1 to C 4 alkyl.
  • R 1 or R 2 is alkylenearyl, preferred alkylene groups are C 1 to C 6 alkylene, and more preferred is C 1 to C 4 alkylene; and preferred aryl groups are phenyl and substituted phenyl.
  • the most preferred alkylenearyl group for R 1 or R 2 is C 1 to C 4 alkylenephenyl.
  • the most preferred group for R 1 is hydrogen and the most preferred group for R 2 is isobutyl.
  • R 3 radicals are substituted and unsubstituted C 1 to C 8 alkyl and C 1 to C 8 alkylenearyl.
  • R 3 is alkyl, preferred is C 1 to C 6 alkyl and more preferred is C 1 to C 4 alkyl, with t- butyl being most preferred.
  • R 3 is C 1 to C 8 alkylenearyl
  • preferred alkylene groups are C 1 to C 6 alkylene, and more preferred is C 1 to C4 alkylene
  • preferred aryl groups are phenyl, naphthyl, and thienyl, each optionally substituted with hydroxy, amino, halogen, thiol or alkyl groups.
  • R 3 Preferred groups for R 3 are therefore C 1 to C 4 alkylenephenyl, C 1 to C 4 alkylenenaphthyl, and C 1 to C 4 alkylenethienyl. More preferred is C 1 to C 4 alkylenenaphthyl, with methylenenaphthyl being most preferred.
  • R 3 is a protected or unprotected side chain of a naturally occurring ⁇ -amino acid
  • R 3 preferably is an arginine, lysine, tryptophan or tyrosine side chain.
  • the most preferred radicals for R 3 are t-buyl, methylene(cyclohexyl) and methylene-(2'naphthyl).
  • Y is preferably hydrogen, unsubstituted or substituted C 1 to C 8 alkyl or the group -R 10 N(R 1 1 )(R 1 2 ).
  • R 10 preferably being unsubstituted or substituted C 1 to C 6 alkylene
  • R 1 1 and R 12 preferably are each independently hydrogen or C 1 to C 6 alkyl.
  • More preferred R 10 radicals are unsubstituted or substituted C 1 to C 4 alkylene, with dimethylene being most preferred.
  • More preferred radicals for R 10 and R 11 are hydrogen or C 1 to C 4 alkyl, with hydrogen being most preferred.
  • a hydroxylamine reagent described above can be hydroxylamine or alternatively, it can be an O-protected hydroxylamine such as commercially available O-trimethylsilyl hydroxylamine, O-tert-butylhydroxylamine, or O-benzylhydroxylamine.
  • precursor compound (Io) may be carried out by condensing the dicarboxylate compound (Ie), with the amine (In), wherein R" is an activating group
  • the benzyl ester compound (lb) is treated with a Wittig reagent, typically methyl or tert-butyl triphenylphosphoranylidene acetate, to form the alkene (Ic), as a mixture of E- and Z- isomers.
  • a Wittig reagent typically methyl or tert-butyl triphenylphosphoranylidene acetate
  • Reduction of the alkene compound (Ic) is carried out with hydrogen, in the presence of an appropriate catalyst (typically palladium on activated charcoal), to both hydrogenate the double bond and to remove the benzyl ester, giving the mono-ester compound (Id) as a enantiomeric mixture.
  • Compound (Ie) is obtained by treating the mono-ester compound (Id) using any of a variety of conventional carboxylate activation procedures.
  • the preparation of the amine compound (In) is achieved by condensing the compound (II) with the amine compound (Ik), wherein P' is an amine protective group other than P, and R" is an activating group such as an active ester, anhydride or other group that causes condensation with the amine terminus of (Ik) to occur with formation of a peptide bond, to give compound (Im). Removal of P is accomplished under appropriate conditions (Bodanszky, M.; Bodanszky, A., "The Practice of Peptide Synthesis”; Springer-Verlag: Berlin, 1984; Chapter III) to produce compound (In), either as corresponding amine or the amine salt.
  • compound (If) is available commercially and others can be easily synthesized by classical methods.
  • the amine-nitrile (If) is protected with an appropriate protective group reagent to produce the protected amine-nitrile (Ig).
  • P is typically CBZ, BOC or FMOC groups, but can be any other suitable group.
  • the protected amine-nitrile (Ig) undergoes reduction with a reagent such as borane-methyl sulfide complex or sodium borohydride/cobalt (II) chloride, to give the mono-protected diamine (Ih) which can be isolated as its amine salt.
  • the compounds of formula II may be administered orally, parenterally, via inhalation, transdermally, intra-nasally, intra-ocularlly, mucosally, rectally and topically. Such administration may be in dosage unit formulations containing conventional adjuvants and carrier materials.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intracisternal injection or infusion techniques.
  • the diastereomers of (A) were separated and purified by reverse phase HPLC using a C 1 8 column, eluting with water containing 0.1% trifluoracetic acid with a gradient of acetonitrile (0-60% in 30 minutes) and also containing 0.1% trifluoroacetic acid, ("Method A"), to give a purified early eluting diastereomer and a purified late eluting diastereomer, which had retention times of 21 and 23 minutes respectively.
  • TLC Rf 0.13 (chloroform-methanol 9:l)
  • N-CBZ-aminoacetonitrile (1e) was dissolved in anhydrous tetrahydrofuran (32 ml).
  • the solution was stirred and 64 ml of borane-methylsulfide complex (2M in tetrahydrofuran) was added via syringe.
  • the mixture was heated to reflux and stirred overnight.
  • the mixture was cooled with an ice bath as 5 ml of water was added slowly, with vigorous stirring. The stirring was continued for ca. 5 minutes, then 75 ml of 6M HCl was slowly added.
  • the non- homogeneous solution was transferred to a flask containing 100 ml of absolute ethanol, and heated until it became homogeneous.
  • the hot solution was dried over a small amount of anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a solid.
  • the solid was triturated with cold 1 :3 ethyl acetatehexane and collected by filtration to give 1.46g (71% yield) of L-3-(2'-naphthyl)alanyl-L-alanine, 2-(benzyloxy-carbonyl-amino)-ethyl amide (lj) as a white solid.
  • the diastereomers of (1) were separated by reverse phase HPLC using a C 1 8 column and eluting with water containing 0.1% trifluoroacetic acid with a gradient of acetonitrile (0-60% in 30 minutes) also containing 0.1% trifluoroacetic acid (hereinafter "Method A”).
  • the purified diastereomers (1n) and (1o) had retention times of 20 and 22 minutes, respectively.
  • Diastereomer (1n) showed the following NMR data.
  • 4-methylpentanoyl chloride 12(b) was prepared by adding dropwise with stirring, 38ml (0.52 mol) of thionyl chloride to 50g (0.43 mol) of 4-methylvaleric acid over 30 minutes. The mixture was heated during the addition, leading to vigorous HCl gas evolution. When the thionyl chloride addition was completed, the reaction mixture was refluxed for 1 hour. The reaction mixture was distilled, with collection of the distillate between 135 and 148 °C.
  • reaction mixture was cooled to -78 °C and 34.6ml (0.25 mol) of 12(b) was added over 10 minutes. Stirring was continued at -78 °C for one hour, then the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was removed in vacuo by rotary evaporation to produce an orange residue.
  • reaction mixture was stirred at -5 °C for 20 minutes, then a solution of 25.0g (0.0934 mol) of 12(d) dissolved in 380 ml of anhydrous tetrahydrofuran (pre-cooled to -5°C) was added.
  • the reaction was stirred at -5 °C for 2 hours, then water (50ml) was added.
  • the reaction was allowed to warm to room temperature.
  • the tetrahydrofuran was removed by rotary evaporation to produce a residue.
  • the residue was dissolved in ethyl acetate (250ml) and washed with water (125ml) and brine (125ml).
  • the reaction was filtered to remove the solid, using 500ml of dichloromethane and 250ml of water to rinse the solid collected.
  • the filtrate was tranferred to a separatory funnel and the layers were separated.
  • the lower(dichloromethane) layer was filtered and concentrated in vacuo by rotary evaporation to produce a dark oil.
  • the oil was purified with two successive flash chromatography columns [each column: 500 grams of silica gel 60, eluted with 1900ml of 1:4 ethyl acetate: hexane, and 1000 ml of ethyl acetate] to produce 26.6 (65% yield) of 12(f) as a viscous oil.
  • the diastereomers (2) and (3) can be made from L-3-(2'-naphthyl)alanine amide hydrochloride (8b) and compound (2d), using the sequence of reactions used to prepare Compound (1) from Compounds (1j) and (1d).
  • Compounds (2) and (3) were separated by reverse phase HPLC as described above.
  • Compound (5b) was prepared from Compound (5a) in 87% yield, by the method used to prepare Compound (lj).
  • TLC Rf 0.11 (chloroform-isopropanol 9:1); 1 H NMR (CDCl 3 ) ⁇ 1.28(d,3H), 1.43(m,1H), 1.70(m,4H), 3.30(m,6H), 3.91(m,2H) 4.34(m,1H), 5.03(s,2H), 5.11(s,2H), 5.22(s,2H), 5.50(m,1H) , 7.01(m,1H) , 7.33(bmJ5H), 7.76(d,1H), 9.25(m,1H), 9.41(m,1H); 13 C NMR (CDCl 3 ) ⁇ 17.7, 24.5, 31.1, 40.3, 40.6, 44.1, 48.6, 54.1, 66.7, 66.9, 68.9, 127.9, 128.0, 128.1, 128.
  • Hydroxamate (5d) was prepared from Compound (5c) in 78% yield as a mixture of diastereomers.
  • Compound (6b) was prepared from Compounds (6a) and (1d) in 69% yield using the method previously described to prepare Compound (A 2 ).
  • TLC Rf 0.21 and 0.29 (chloroform-isopropanol 9: 1);
  • 1 H NMR (d 6 -DMSO; mixture of diastereomers) ⁇ 0.81(m,3H), 0.88(m,3H), 1.17 & 1.23(d,3H), 1.40(bm,8H), 2.46(m,3H), 2.78(m,1H), 2.98(m,2H), 3.54 & 3.56(s, 3H), 4.08(m,1H), 4.16(m,1H), 5.00(s,2H), 7.04(m,1H), 7.23(t,1H), 7.34(m,6H), 7.58 & 7.68(d,1H), 8.10 & 8.42(d,1H).
  • Compound (7c) was prepared from Compound (7b) in 48% yield with the method used to prepare Compound (6c). A single diastereomer of Compound (7c) was isolated by
  • the dicyclohexylurea by-product was removed by filtration, and the filtrate was transferred to a flask containing 1.5 ml (0.022 mol) of concentrated NH4OH. After the mixture had stirred at room temperature for 1 hour, the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate (350 ml) and washed with water (100 ml), 1M HCL (100 ml), water (100 ml), saturated sodium bicarbonate solution (100 ml) and finally with brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to produce a solid.
  • the diastereomers (8) and (9) can be made from L-3-(2'-naphthyl)alanine amide hydrochloride (8b) and (1d), using the sequence of reactions used to prepare Compound (1) from Compounds (1j) and (1d).
  • N-BOC-L-3-(2'-naphthyl)alanyl-L-(O-benzyl)serine amide (10a) was prepared from N-BOC-L-3-(2'-naphthyl)alanine and L-(O-benzyl)serine amide in 80% yield with the method used to prepare (7a).
  • Compound (10d) was prepared from Compound (10c) in 74% yield with the method used to prepare Compound (lm). TLC: Rf 0.12 (chloroform-isopropanol 9:1).
  • Compound (10) was prepared from Compound (10d) in 84% yield with the method used to prepare Compound (1n). HPLC retention times: 25.2 and 27.1 minutes (method A).
  • Compound (11b) was prepared from Compounds (11a) and (1d), in 86% yield using the method previously described to prepare Compound (A 2 ).
  • the following example demonstrates the selective in vitro inhibition of T-cell TNF- ⁇ secretion, as compared to TNF-ß and IFN- ⁇ secretion, by Compound 1.
  • Human peripheral blood T-cells were purified from peripheral blood mononuclear cells by rosetting with 2-aminoethylisothiouronium bromide hydrobromide-treated sheep erythrocytes. After hypotonic lysis of sheep erythrocytes, monocytes were depleted by plastic adherence for one hour at 37 °C.
  • the peripheral blood T-cells were stimulated with anti-CD3 antibody (OKT3) which was immobilized on the culture wells at 10 ⁇ g/ml in PBS plus 10 ng/ml of the phorbol ester, PMA.
  • Culture medium comprised RPMI 1640 medium containing 10% fetal bovine serum, 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin. The stimulation was performed in the presence or absence of the inhibitor Compound 1 (200 ⁇ M), and TNF- ⁇ in the medium was assayed by ELISA. Results are shown in Table I.
  • Compound 1 inhibited TNF- ⁇ release by 72% and 63%, respectively, while there was no inhibitory effect on the release of TNF- ⁇ or interferon- ⁇ .
  • Compound 1 clearly demonstrates selective inhibition of TNF- ⁇ secretion and has no effect on either
  • TNF- ⁇ or interferon- ⁇ secretion are TNF- ⁇ or interferon- ⁇ secretion.
  • T-cells which have been stimulated by PMA and ionomycin.
  • the alloreactive human T-cell clone, PL-1 does not express cell surface TNF- ⁇ in the absence of stimulation.
  • cell surface TNF- ⁇ as well as the ligands for CD40 and 41 BB, are rapidly induced on the cell surface.
  • Detection of cell surface TNF- ⁇ was performed by staining with an Fc fusion protein consisting of an Fc portion of a human IgG1 molecule (1gGFc) coupled with an extracellular domain of TNF receptor (p80).
  • Detection of cell surface ligands for 41BB and CD40 was performed by staining with analogous Fc fusion proteins consisting of IgGFc and extracellular domains of 41BB and CD40, respectively.
  • a fusion molecule consisting of IgGFc and the extracellular portion of the IL-4 receptor (IL-4R:Fc) was utilized as a negative control for staining, since PL-1 cells do not express cell-surface IL-4 in response to PMA stimulation.
  • IL-4R:Fc IL-4 receptor
  • mice Female Balb/c mice (18-20g) were injected i.v. with 400 ⁇ g of LPS. Simultaneously, the mice were injected subcutaneously with 500 ⁇ g of Compound A or Compound 1 in 0.5 ml of saline containing 0.02% DMSO. Control mice received LPS intravenously and saline/DMSO subcutaneously. Two hours following the LPS injection, serum was obtained and pooled from two mice in each treatment group. TNF- ⁇ levels were determined by ELISA and are shown in the following Table III.
  • Compound 1 inhibits the secretion of TNF- ⁇ at least by 80%, and essentially by 100%, as the TNF- ⁇ levels were undetectable. Comparatively, Compound A reduced serum TNF- ⁇ levels by approximately 60% as compared to the saline/DMSO control.
  • mice were injected i.v. with
  • mice were injected subcutaneously with 500 ⁇ g
  • Compound 1 As compared to mice that received LPS + saline, Compound 1 reduced serum TNF- ⁇ levels by 84%. Overall, Compound 1 reduced serum TNF- ⁇ levels by 85.4 ⁇ 2.98% as compared to TNF- ⁇ levels in mice that received LPS only. From Tables III and IV, Compound 1 effectively reduces serum TNF- ⁇ levels by at least 80% when administered at 25 mg/kg in a murine model of LPS-induced sepsis syndrome. 250 ⁇ g Compound A versus Compound 1 versus control
  • mice Female Balb/c mice (18-20g) were injected i.v. with 450 ⁇ g of LPS. Simultaneously, the mice were injected subcutaneously with 250 ⁇ g of Compound A or Compound 1 in 0.25 ml of saline containing 0.02% DMSO. Control mice received LPS intravenously and saline/DMSO subcutaneously. Two hours following the LPS injection, serum was obtained from three mice in each treatment group. TNF- ⁇ levels were determined by ELISA. The results are expressed as the mean optical density (OD) obtained in the ELISA from each treatment group, and are shown in Table V. The background OD of the control sample was 0.162 ⁇ 0.003. TABLE V
  • Table V illustrates the effect of Compound 1 and Compound A on inhibiting serum
  • TNF- ⁇ release in LPS -stimulated mice Compound 1 reduced serum TNF- ⁇ levels to those of the control, thereby indicating a complete inhibition of TNF- ⁇ secretion at 250 ⁇ g/ml.
  • Each of Compound 1 and Compound A was diluted to 50 ⁇ M in normal mouse serum and incubated at 37°C. At various times, aliquots were withdrawn, diluted 100-fold into ice-cold PBS, and tested for inhibitory efficacy against purified TACE. After 40 minutes, Compound A showed a decrease in inhibitory effect corresponding to a 3-4 fold loss in concentration of the compound, and Compound 1 showed no decrease in inhibitory effect.

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PCT/US1994/009343 1993-08-23 1994-08-19 Inhibitors of tnf-alpha secretion WO1995006031A1 (en)

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CA002170158A CA2170158A1 (en) 1993-08-23 1994-08-19 Inhibitors of tnf-alpha secretion
AU75694/94A AU687436B2 (en) 1993-08-23 1994-08-19 Inhibitors of TNF-alpha secretion
EP94925940A EP0715619A4 (en) 1993-08-23 1994-08-19 Inhibitors of tnf-alpha secretion
NZ271893A NZ271893A (en) 1993-08-23 1994-08-19 Inhibitors of tnf-alpha secretion
JP7507668A JPH09503201A (ja) 1993-08-23 1994-08-19 Ｔｎｆ−アルファ分泌の阻害剤
FI960803A FI960803L (fi) 1993-08-23 1996-02-22 TNF-alfa-sekreetion inhibiittoreita
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WO1996035711A1 (en) * 1995-05-10 1996-11-14 Chiroscience Limited Peptide compounds which inhibit metalloproteinase and tnf liberation, and their therapeutic use
WO1996035714A1 (en) * 1995-05-10 1996-11-14 Chiroscience Limited Peptide compounds which inhibit metalloproteinase and tnf liberation and their therapeutic uses
WO1996035712A1 (en) * 1995-05-10 1996-11-14 Chiroscience Limited Peptidyl compounds which inhibit metalloproteinase and tnf liberation and their therapeutic use
WO1997012902A1 (en) * 1995-10-05 1997-04-10 Darwin Discovery Limited Thio-substituted peptides as inhibitors for metalloproteinases and tnf liberation
WO1997019053A1 (en) 1995-11-23 1997-05-29 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US5665777A (en) * 1995-11-14 1997-09-09 Abbott Laboratories Biphenyl hydroxamate inhibitors of matrix metalloproteinases
WO1997038007A1 (en) * 1996-04-04 1997-10-16 Darwin Discovery Limited Peptidyl compounds having mmp and tnf- liberation inhibitory activity
WO1998030541A1 (en) * 1997-01-07 1998-07-16 Abbott Laboratories C-terminal ketone hydroxamic acid inhibitors of matrix metalloproteinases and tnfa secretion
WO1998057657A1 (en) * 1997-06-18 1998-12-23 The Rockefeller University Methods for identifying antibodies and peptides useful in the treatment of septic shock and experimental arthritis and uses thereof
US5883241A (en) * 1995-09-05 1999-03-16 Celltech Therapeutics Limited DNA sequences coding for a human metalloproteinase and variants thereof
WO1999018942A1 (en) * 1997-10-10 1999-04-22 Imperial College Innovations Ltd. Use of csaidtm compounds for the management of uterine contractions
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
US5990293A (en) * 1996-09-05 1999-11-23 Celltech Therapeutics Limited Human metalloproteinase, variants thereof and DNA sequence coding therefor
WO1999059568A1 (en) * 1998-05-16 1999-11-25 British Biotech Pharmaceuticals Limited Hydroxamic acid derivatives as antibacterials
US5994312A (en) * 1994-10-05 1999-11-30 Darwin Discovery, Ltd. Peptidyl compounds
WO2000018358A2 (en) * 1998-09-30 2000-04-06 The Procter & Gamble Company Method of treating hair loss using ketoamides
WO2000018361A2 (en) * 1998-09-30 2000-04-06 The Procter & Gamble Company Method of treating hair loss using sulfonamides
WO2000041473A2 (de) * 1999-01-13 2000-07-20 Jomaa Pharmaka Gmbh Verwendung von 3-isoxazolidinonen und hydroxylaminsäuren zur behandlung von infektionen
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US6172064B1 (en) 1998-08-26 2001-01-09 Glaxo Wellcome Inc. Formamides as therapeutic agents
US6191150B1 (en) 1998-08-26 2001-02-20 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
WO2001022952A2 (en) * 1999-09-25 2001-04-05 Smithkline Beecham P.L.C. Use of tace inhibitors
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US6329550B1 (en) 1998-12-31 2001-12-11 Aventis Pharmaceuticals Inc. Amidomalonamides useful as inhibitors of MMP of matrix metalloproteinase
US6329400B1 (en) 1998-08-26 2001-12-11 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
WO2002006227A1 (fr) * 2000-07-18 2002-01-24 Chugai Seiyaku Kabushiki Kaisha Inhibiteurs de la metalloprotease matricielle
WO2002028829A2 (en) * 2000-09-25 2002-04-11 Questcor Pharmaceuticals, Inc. Peptide deformylase inhibitors
US6406901B1 (en) 1995-06-08 2002-06-18 Immunex Corporation TNF-a converting enzyme
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7915225B2 (en) 1999-04-19 2011-03-29 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

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US6180611B1 (en) 1994-10-05 2001-01-30 Darwin Discovery, Ltd. Peptidyl compounds
US5994312A (en) * 1994-10-05 1999-11-30 Darwin Discovery, Ltd. Peptidyl compounds
US6110896A (en) * 1995-05-10 2000-08-29 Darwin Discovery, Ltd. Peptidyl compounds and their therapeutic use
US5981491A (en) * 1995-05-10 1999-11-09 Darwin Discovery Limited Peptidyl compounds and their therapeutic use
WO1996035712A1 (en) * 1995-05-10 1996-11-14 Chiroscience Limited Peptidyl compounds which inhibit metalloproteinase and tnf liberation and their therapeutic use
US5994293A (en) * 1995-05-10 1999-11-30 Darwin Discovery Ltd. Peptidyl compounds and their therapeutic use
WO1996035714A1 (en) * 1995-05-10 1996-11-14 Chiroscience Limited Peptide compounds which inhibit metalloproteinase and tnf liberation and their therapeutic uses
WO1996035711A1 (en) * 1995-05-10 1996-11-14 Chiroscience Limited Peptide compounds which inhibit metalloproteinase and tnf liberation, and their therapeutic use
AU710502B2 (en) * 1995-05-10 1999-09-23 Darwin Discovery Limited Peptidyl compounds which inhibit metalloproteinase and TNF liberation and their therapeutic use
US7695948B2 (en) 1995-06-08 2010-04-13 Immunex Corporation Antibodies that bind TNF-α converting enzyme
US7199224B2 (en) 1995-06-08 2007-04-03 Immunex Corporation Antibodies that bind TNF-α converting enzyme
US6406901B1 (en) 1995-06-08 2002-06-18 Immunex Corporation TNF-a converting enzyme
US6406877B2 (en) 1995-06-08 2002-06-18 Immunex Corporation TNF-α converting enzyme
US6555354B2 (en) 1995-06-08 2003-04-29 Immunex Corporation TNF-α converting enzyme
US5883241A (en) * 1995-09-05 1999-03-16 Celltech Therapeutics Limited DNA sequences coding for a human metalloproteinase and variants thereof
US5981490A (en) * 1995-10-05 1999-11-09 Darwin Discovery, Ltd. Peptidyl compounds
WO1997012902A1 (en) * 1995-10-05 1997-04-10 Darwin Discovery Limited Thio-substituted peptides as inhibitors for metalloproteinases and tnf liberation
US5665777A (en) * 1995-11-14 1997-09-09 Abbott Laboratories Biphenyl hydroxamate inhibitors of matrix metalloproteinases
WO1997019053A1 (en) 1995-11-23 1997-05-29 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
AU720239B2 (en) * 1996-04-04 2000-05-25 Darwin Discovery Limited Peptidyl compounds having MMP and TNF- liberation inhibitory activity
US5872146A (en) * 1996-04-04 1999-02-16 Chiroscience Limited Mercapto alkyl peptidyl compounds having MMP and TNF inhibitory activity
WO1997038007A1 (en) * 1996-04-04 1997-10-16 Darwin Discovery Limited Peptidyl compounds having mmp and tnf- liberation inhibitory activity
US5990293A (en) * 1996-09-05 1999-11-23 Celltech Therapeutics Limited Human metalloproteinase, variants thereof and DNA sequence coding therefor
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
WO1998030541A1 (en) * 1997-01-07 1998-07-16 Abbott Laboratories C-terminal ketone hydroxamic acid inhibitors of matrix metalloproteinases and tnfa secretion
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
AU730308B2 (en) * 1997-06-18 2001-03-01 Rockefeller University, The Methods for identifying antibodies and peptides useful in the treatment of septic shock and experimental arthritis and uses thereof
WO1998057657A1 (en) * 1997-06-18 1998-12-23 The Rockefeller University Methods for identifying antibodies and peptides useful in the treatment of septic shock and experimental arthritis and uses thereof
WO1999018942A1 (en) * 1997-10-10 1999-04-22 Imperial College Innovations Ltd. Use of csaidtm compounds for the management of uterine contractions
US6992190B2 (en) 1998-05-16 2006-01-31 British Biotech Pharmaceuticals Ltd. Hydroxamic acid derivatives as antibacterials
WO1999059568A1 (en) * 1998-05-16 1999-11-25 British Biotech Pharmaceuticals Limited Hydroxamic acid derivatives as antibacterials
GB2353708A (en) * 1998-05-16 2001-03-07 British Biotech Pharm Hydroxamic acid derivatives as antibacterials
US7323563B2 (en) 1998-05-16 2008-01-29 British Biotech Pharmaceuticals Ltd. Hydroxamic acid derivatives as antibacterials
EP1754477A3 (en) * 1998-05-16 2007-03-14 Vernalis (Oxford) Limited Hydroxamic acid derivatives as antibacterials
EP1754477A2 (en) * 1998-05-16 2007-02-21 Vernalis (Oxford) Limited Hydroxamic acid derivatives as antibacterials
US6441042B1 (en) 1998-05-16 2002-08-27 British Biotech Pharmaceuticals Limited Hydroxamic acid derivatives as antibacterials
US6172064B1 (en) 1998-08-26 2001-01-09 Glaxo Wellcome Inc. Formamides as therapeutic agents
US6329400B1 (en) 1998-08-26 2001-12-11 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
US6191150B1 (en) 1998-08-26 2001-02-20 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
WO2000018361A2 (en) * 1998-09-30 2000-04-06 The Procter & Gamble Company Method of treating hair loss using sulfonamides
WO2000018358A3 (en) * 1998-09-30 2000-07-27 Procter & Gamble Method of treating hair loss using ketoamides
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
WO2000018361A3 (en) * 1998-09-30 2000-05-25 Procter & Gamble Method of treating hair loss using sulfonamides
WO2000018358A2 (en) * 1998-09-30 2000-04-06 The Procter & Gamble Company Method of treating hair loss using ketoamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
US6329550B1 (en) 1998-12-31 2001-12-11 Aventis Pharmaceuticals Inc. Amidomalonamides useful as inhibitors of MMP of matrix metalloproteinase
WO2000041473A3 (de) * 1999-01-13 2001-11-29 Jomaa Pharmaka Gmbh Verwendung von 3-isoxazolidinonen und hydroxylaminsäuren zur behandlung von infektionen
WO2000041473A2 (de) * 1999-01-13 2000-07-20 Jomaa Pharmaka Gmbh Verwendung von 3-isoxazolidinonen und hydroxylaminsäuren zur behandlung von infektionen
US7915225B2 (en) 1999-04-19 2011-03-29 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
US8119605B2 (en) 1999-04-19 2012-02-21 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
WO2001022952A3 (en) * 1999-09-25 2003-02-20 Smithkline Beecham Plc Use of tace inhibitors
WO2001022952A2 (en) * 1999-09-25 2001-04-05 Smithkline Beecham P.L.C. Use of tace inhibitors
WO2002006227A1 (fr) * 2000-07-18 2002-01-24 Chugai Seiyaku Kabushiki Kaisha Inhibiteurs de la metalloprotease matricielle
WO2002028829A2 (en) * 2000-09-25 2002-04-11 Questcor Pharmaceuticals, Inc. Peptide deformylase inhibitors
WO2002028829A3 (en) * 2000-09-25 2003-12-24 Questcor Pharmaceuticals Inc Peptide deformylase inhibitors
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7034057B2 (en) 2001-12-20 2006-04-25 Schering Corporation Compounds for the treatment of inflammatory disorders
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

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AU5030298A (en) 1998-03-05
CA2170158A1 (en) 1995-03-02
FI960803L (fi) 1996-04-22
EP0715619A4 (en) 1997-03-19
EP0715619A1 (en) 1996-06-12

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