WO2002076968A1 - Malonates en tant qu'inhibiteurs de la famille ice/ced-3 des cysteines proteases - Google Patents

Malonates en tant qu'inhibiteurs de la famille ice/ced-3 des cysteines proteases Download PDF

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Publication number
WO2002076968A1
WO2002076968A1 PCT/EP2002/003194 EP0203194W WO02076968A1 WO 2002076968 A1 WO2002076968 A1 WO 2002076968A1 EP 0203194 W EP0203194 W EP 0203194W WO 02076968 A1 WO02076968 A1 WO 02076968A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
phenoxy
mmol
oxo
phenylcarbamoyl
Prior art date
Application number
PCT/EP2002/003194
Other languages
English (en)
Inventor
Silvio Roggo
Samuel Hintermann
Vittorio Rasetti
Ulrike Von Krosigk
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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 Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2002076968A1 publication Critical patent/WO2002076968A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/46—Phosphinous acids [R2POH], [R2P(= O)H]: Thiophosphinous acids including[R2PSH]; [R2P(=S)H]; Aminophosphines [R2PNH2]; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel malonate derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • Q is hydrogen, fluoromethyl, diphenylphosphinyloxymethyl, mono-, di-, tri-, tetra- or penta- Hal-phenyl-oxy(or thio)methyl or mono-, di-, tri-, tetra- or penta-Hal-phenyl-carbonylo ⁇ y(or thio)methyl,
  • R is hydrogen or (C ⁇ alkyl
  • S is (C 1 - )alkyl, phenyl or phenyl(C ⁇ . )alkyl and
  • T is hydrogen or
  • U is hydrogen, carboxy(C ⁇ )alkyl or (C t . )alkyl
  • V is hydrogen, carboxy(C ⁇ . 4 )alkyl, hydroxy(C 1 . 4 )alkyl, (C ⁇ . )alkoxycarbonyl(C 1 ⁇ )alkyl, (C ⁇ )alkoxy(C ⁇ . 4 )alkyl, phenyl or phenyl(C 1 . 4 )alkyl optionally mono- or disubstituted in the phenyl ring by (C ⁇ )alkoxy or Hal, (Cm)alkylsulfonyl(C 1 . 4 )alkyl, cyano(C 1 . 4 )alkyl, (C . 7 )cycloalkyl(C ⁇ .
  • X is hydrogen or (C 1 ⁇ )alkyl, or forms with Y a -COCH 2 CH 2 -bridge, or forms with Y and the nitrogen atom on which X and Y are located a morpholino group
  • Y is (C ⁇ )alkyl, phenyI(C ⁇ . 4 )alkyl, (C ⁇ _ 4 )alkoxy(C 1 . 4 )alkyl, diphenylmethyl, (C M )alkylphenyl, (C ⁇ )alkoxyphenyl, morpholino, morpholino(C-
  • Hal is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
  • the invention provides a process for the production of the compounds of formula I and their salts, whereby
  • oxidation and deprotection reactions under a) and b) can be effected according to conventional methods, e.g. as described in the examples.
  • the starting materials of formulae II and III may be produced according to one of the following schemes, wherein R-t, S, T, U, ⁇ , X and Y are as defined above, A and B are conventional protecting or activating groups and W is a group of formula
  • agents of the invention exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
  • agents of the invention are inhibitors of interleukin-1 ⁇ converting enzyme and related proteases ("ICE/ced-3 family of cysteine proteases").
  • Interleukin 1 is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. J. H. Oppenheim et al., Immunology Today, 7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. B. S. Mosely et al., Proc. Nat. Acad. Sci. , 84:4572-4576 (1987); G. Lonnemann et al., Eur. J. Immunol. , 19:1531-1536 (1989).
  • IL-1 ⁇ is synthesized as a biologically inactive precursor, prolL-1 ⁇ .
  • ProlL-1 ⁇ is cleaved by a cysteine protease called interleukin-1 ⁇ converting enzyme ("ICE") between Asp-116 and Ala- 117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid.
  • ICE interleukin-1 ⁇ converting enzyme
  • ICE is a cysteine protease localized primarily in monocytes.
  • ICE In addition to promoting the pro- inflammatory and immunoregulatory properties of IL-1 ⁇ , ICE, and particulary its homologues, also appear to be involved in the regulation of cell death or apoptosis. J. Yuan et al., Cell, 75:641-652 (1993); M. Miura et al., Cell, 75:653-660 (1993); M. A. Nett-Giordalisi et al., J. Cell Biochem., 17B:117 (1993).
  • ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer's and Parkinson's disease. J. Marx and M. Baringa, Science, 259:760-762 (1993); V. Gagliardini et al., Science, 263:826-828 (1994).
  • disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; certain neurodegenerative diseases such as Alzheimer's and Parkinson's disease; and ophthalmic diseases such as glaucoma and myopia.
  • infectious diseases such as meningitis and salpingitis
  • inflammatory conditions such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury
  • ischemic diseases
  • the agents of the invention inhibit the ICE/ced-3 family of cysteine proteases, as determined in the assay according to J.C. Wu and LC. Fritz [Methods, 17(4): 320-8 (1999)] or in the assay according to M. Garcia - Calvo et al. [J. Biol. Chem., 273(49): 32608-13 (1998)] in which the agents of the invention exhibit Kj values of from about 0.1 to about 5000 nanoMolar.
  • the agents of the invention are therefore useful in the treatment of the above-listed disease states, more particularly in the treatment of inflammatory diseases, autoimmune diseases and neurodegenerative diseases, and for inhibiting unwanted apoptosis involved in ischemic injury, such as ischemic injury to the heart (e.g. myocardial infraction), brain (e.g. stroke), and kidney (e.g. ischemic kidney disease).
  • ischemic injury to the heart (e.g. myocardial infraction), brain (e.g. stroke), and kidney (e.g. ischemic kidney disease).
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.05 to about 150, preferably from about 0.1 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 0.5 to about 5000, preferably from about 1 to about 500mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • the agent of the invention may be administered by any conventional route, in particular enteraliy, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
  • the present invention also provides an agent of the invention, for use as pharmaceutical, e.g. for the treatment of any condition indicated above.
  • the present invention furthermore provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms contain, for example, from about 0.1 to about 2500, preferably from 0.1 to about 250 mg of a compound according to the invention.
  • the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above. ln still a further aspect the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
  • This deprotection step is also applied to other aspartyl precursors mentioned in this document.
  • This intermediate is dissolved in a mixture of 3 ml of acetonitrile and 0.8 ml of water and 0.3 ml of acetic acid and 0.3 ml of aqueous formaldehyde (35%) are added. After stirring 15 hours at rt. the reaction mixture is concentrated and purified (RP18- chromatography, 0-100% acetonitrile/water) yielding 9 mg (13%) of the desired product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Rheumatology (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle Q, R, S, T, U, V, X et Y sont tels que définis dans la description, ainsi que la préparation de ces composés. Ces composés représentés par la formule (I) sont utiles en tant que produits pharmaceutiques.
PCT/EP2002/003194 2001-03-23 2002-03-21 Malonates en tant qu'inhibiteurs de la famille ice/ced-3 des cysteines proteases WO2002076968A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0107365.9A GB0107365D0 (en) 2001-03-23 2001-03-23 Organic compounds
GB0107365.9 2001-03-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045580A1 (fr) * 2008-10-17 2010-04-22 Exelixis, Inc. Antagonistes des récepteurs de sphingosine-1-phosphate
WO2015095227A2 (fr) 2013-12-16 2015-06-25 Genentech, Inc. Composés peptidomimétiques et conjugués anticorps-médicament de ceux-ci
WO2016205176A1 (fr) 2015-06-15 2016-12-22 Genentech, Inc. Anticorps et immunoconjugués
JP2016216433A (ja) * 2015-05-15 2016-12-22 Dic株式会社 カルボン酸化合物、その製造方法、その化合物を使用した液晶組成物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GARCIA-CALVO M ET AL: "INHIBITION OF HUMAN CASPASES BY PEPTIDE-BASED AND MACROMOLECULAR INHIBITORS", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 273, no. 49, 4 December 1998 (1998-12-04), pages 32608 - 32613, XP002928863, ISSN: 0021-9258 *
WU J C ET AL: "IRREVERSIBLE CASPASE INHIBITORS: TOOLS FOR STUDYING APOPTOSIS", METHODS: A COMPANION TO METHODS IN ENZYMOLOGY, ACADEMIC PRESS INC., NEW YORK, NY, US, vol. 17, no. 4, 1999, pages 320 - 328, XP001000619, ISSN: 1046-2023 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045580A1 (fr) * 2008-10-17 2010-04-22 Exelixis, Inc. Antagonistes des récepteurs de sphingosine-1-phosphate
US20110288076A1 (en) * 2008-10-17 2011-11-24 Exelixis, Inc. Sphingosine-1-Phosphate Receptor Antagonists
JP2012505920A (ja) * 2008-10-17 2012-03-08 エグゼリクシス， インコーポレイテッド スフィンゴシン１リン酸塩受容体拮抗薬
US8791102B2 (en) 2008-10-17 2014-07-29 Exelixis, Inc. Acetanilide sphingosine-1-phosphate receptor antagonists
WO2015095227A2 (fr) 2013-12-16 2015-06-25 Genentech, Inc. Composés peptidomimétiques et conjugués anticorps-médicament de ceux-ci
JP2017504606A (ja) * 2013-12-16 2017-02-09 ジェネンテック， インコーポレイテッド ペプチド模倣化合物及びその抗体−薬物コンジュゲート
US10632210B2 (en) 2013-12-16 2020-04-28 Genentech, Inc. Peptidomimetic compounds and antibody-drug conjugates thereof
JP2016216433A (ja) * 2015-05-15 2016-12-22 Dic株式会社 カルボン酸化合物、その製造方法、その化合物を使用した液晶組成物
WO2016205176A1 (fr) 2015-06-15 2016-12-22 Genentech, Inc. Anticorps et immunoconjugués

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