EP1301512A2 - Derives d'hydantoine bicycliques et bibliotheques combinatoires de ces derniers - Google Patents

Derives d'hydantoine bicycliques et bibliotheques combinatoires de ces derniers

Info

Publication number
EP1301512A2
EP1301512A2 EP01960516A EP01960516A EP1301512A2 EP 1301512 A2 EP1301512 A2 EP 1301512A2 EP 01960516 A EP01960516 A EP 01960516A EP 01960516 A EP01960516 A EP 01960516A EP 1301512 A2 EP1301512 A2 EP 1301512A2
Authority
EP
European Patent Office
Prior art keywords
substituted
group
phenyl
formula
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01960516A
Other languages
German (de)
English (en)
Inventor
Shao-Po Lu
R. Normand Hebert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sygnis Pharma AG
Original Assignee
Lion Bioscience AG
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 Lion Bioscience AG filed Critical Lion Bioscience AG
Publication of EP1301512A2 publication Critical patent/EP1301512A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • n 0, 1 or 2;
  • R 6 is the formula -L-M, wherein -L- is -C(O)-, -C(0)0- or -S(0) 2 - and M is a hydrogen atom, C x to C 12 alkyl, C ⁇ to C 12 substituted alkyl, C 2 to C 12 alkenyl, C 2 to C 12 substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 7 to C 13 phenylalkyl, C 7 to C 18 substituted phenylalkyl, C__ to C 12 heterocyclicalkyl, C, to C 12 substituted heterocyclicalkyl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; R 7 is the formula -D-W-E-, wherein at least one of D, W and E is present and the other two are optionally present or absent, and wherein:
  • C x to C 12 alkyl denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, amyl; tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • Preferred “C__ to C 12 alkyl” groups are methyl, ethyl, iso-butyl, sec-butyl and iso-propyl.
  • C l to C 12 alkylene denotes radicals of 1 to 12 carbons connected to two other parts in the compound.
  • the substituted alkyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents .
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C- L to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 acyl, C X to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • (monosubstituted) amino refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, C x to C 12 alkyl, C x to C 12 substituted alkyl, C x to C 12 acyl, C x to C 12 substituted acyl, C 2 to C 12 alkenyl, C 2 to C 12 substituted alkenyl, C 2 to C 12 alkynyl, C 2 to C 12 substituted alkynyl, C 7 to C 18 phenylalkyl, C to C 18 substituted phenylalkyl, heterocyclic ring, substituted heterocyclic ring, C x to C 12 heterocycloalkyl and C x to C 12 substituted heterocycloalkyl.
  • the (monosubstituted) amino can additionally have an amino-protecting group as encompassed by the term "protected (monosubstituted) amino.
  • amino-protecting groups are Boc, Cbz and Fmoc. Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis,” 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapter 7, M.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • carboxylic acid protecting groups include t-butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3, 4-dimethoxybenzyl, 2, 4-dimethoxybenzyl, 2,4, 6-trimethoxybenzyl, 2,4, 6-trimethylbenzyl, pentamethylbenzyl, 3, 4-methylenedioxybenzyl, benzhydryl, 4, 4 '-dimethoxytrityl, 4 , 4 ' , 4 "-trimethoxytrityl,
  • C x to C 10 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n- butylsulfonyl, t-butylsulfonyl and the like. It should also be understood that the above thio, sulfoxide or sulfonyl groups can be at any point on the alkyl chain (e.g., 2-methylmercaptoethyl) .
  • a ring nitrogen compound with a group containing -C (0) -0- attached (and directly attached to the carbonyl carbon) to a position adjacent to the ring nitrogen can be coupled with an isocyanate derivative of the formula variable-NCO to form a ring nitrogen compound with the group -C (0) -NH-variable directly attached to the ring nitrogen (see step c of Figure 3) .
  • the resulting compound can be cyclized in the presence of a base, for example, tetramethylguanidine or barium hydroxide, to form a bicyclic hydantoin derivative (see step c of ⁇ ? 4
  • the nonsupport-bound combinatorial libraries can be screened as single compounds.
  • the nonsupport-bound combinatorial libraries can be screened as mixtures in solution in assays such as radio-receptor inhibition assays, anti-bacterial assays, anti-fungal assays, calmodulin-dependent phosphodiesterase (CaMPDE) assays and phosphodiesterase (PDE) assays, as described in detail below.
  • Deconvolution of highly active mixtures can then be carried out by iterative or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the combinatorial libraries of the present invention using any one of the below-described assays or others well known in the art.
  • a new sub-library with the first two variable positions defined is reacted again with all the other possibilities at the remaining undefined variable position.
  • the identity of the third variable position in the sub-library having the highest activity is determined. If more variables exist, this process is repeated for all variables, yielding the compound with each variable contributing to the highest desired activity in the screening process. Promising compounds from this process can then be synthesized on larger scale in traditional single-compound synthetic methods for further biological investigation.
  • Assays which can be used to test the biological activity of the instant compounds include antimicrobial assays, a competitive enzyme-linked immunoabsorbent assay and radio-receptor assays, as described below.
  • the melanocortin (MC) receptors are a group of cell surface proteins that mediate a variety of physiological effects, including regulation of adrenal gland function such as production of the glucocorticoids cortisol and aldosterone; control of melanocyte growth and pigment production; thermoregulation; immunomodulation; and analgesia.
  • bicyclic hydantoin derivative compounds of the invention bind to one or more MC receptors.
  • bicyclic hydantoin derivative compounds of the invention can exhibit a range of affinities and specificity for various MC receptors.
  • the invention provides MC receptor ligands that can bind to several MC receptors with similar affinity.
  • the invention also provides MC receptor ligands that can be selective for one or more MC receptors.
  • selective means that the affinity of a MC receptor ligand differs between one MC receptor and another by about 10-fold, generally about 20- to 50-fold, and particularly about 100-fold.
  • a MC receptor ligand having broad specificity is desired.
  • MCR-1 ligands are particularly useful for treating pain and inflammation, whereas MCR-4 ' ligands are useful for treating obesity.
  • the binding characteristics and specificity of a given MC receptor ligand can be selected based on the particular disease or physiological effect that is desired to be altered.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés dérivés d'hydantoïne bicycliques de formule (I) suivante : dans laquelle R1 à R5 et n sont tels que définis dans la description. L'invention concerne, en outre, des bibliothèques combinatoires contenant deux ou plusieurs de ces composés, ainsi que des procédés de préparation des composés dérivés d'hydantoïne bicycliques.
EP01960516A 2000-07-21 2001-07-18 Derives d'hydantoine bicycliques et bibliotheques combinatoires de ces derniers Withdrawn EP1301512A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US62117700A 2000-07-21 2000-07-21
US621177 2000-07-21
PCT/EP2001/008322 WO2002008227A2 (fr) 2000-07-21 2001-07-18 Derives d'hydantoine bicycliques et bibliotheques combinatoires de ces derniers

Publications (1)

Publication Number Publication Date
EP1301512A2 true EP1301512A2 (fr) 2003-04-16

Family

ID=24489060

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01960516A Withdrawn EP1301512A2 (fr) 2000-07-21 2001-07-18 Derives d'hydantoine bicycliques et bibliotheques combinatoires de ces derniers

Country Status (4)

Country Link
EP (1) EP1301512A2 (fr)
AU (1) AU2001281995A1 (fr)
CA (1) CA2416654A1 (fr)
WO (1) WO2002008227A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044181A1 (fr) * 2000-12-01 2002-06-06 Bristol-Myers Squibb Company Composes d'hydantoine utiles en tant qu'agents anti-inflammatoires
US7199149B2 (en) 2003-10-01 2007-04-03 Bristol Myers Squibb Company Monocyclic and bicyclic lactams as factor Xa inhibitors
EP1939184B1 (fr) * 2005-09-02 2013-06-05 Nippoh Chemicals Co., Ltd Compose 1,3-diiodohydantoine et son procede de fabrication
ES2618315T3 (es) 2007-05-25 2017-06-21 Ipsen Pharma S.A.S. Ligandos del receptor de melanocortina modificados con hidantoína
EP2937338B1 (fr) 2012-12-19 2019-07-10 Nippoh Chemicals Co., Ltd Procédé et dispositif de production d'un composé d'halohydrantoïne, système réutilisable, et composé d'halohydrantoïne
JP6470045B2 (ja) 2012-12-19 2019-02-13 日宝化学株式会社 ハロヒダントイン化合物の製造方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4198423A (en) * 1979-03-20 1980-04-15 Basf Aktiengesellschaft 1,3-Bis-(trihalomethylsulfenyl)-imidazoline-2,4-diones
HUT62296A (en) * 1990-12-18 1993-04-28 Sandoz Ag Herbicidal composition comprising hydantoin derivative as active ingredient and process for producing the active ingredient
AU2115595A (en) * 1994-03-01 1995-09-18 Degussa A.G. Herbicidal bicyclic hydantoins
WO1997047626A1 (fr) * 1996-06-14 1997-12-18 Sagami Chemical Research Center Derives d'hydantoine bicycliques, produits intermediaires destines a leur fabrication, procede de preparation de ces derives et herbicides les contenant en qualite d'ingredient actif
WO1998008813A1 (fr) * 1996-08-26 1998-03-05 Eli Lilly And Company Procede combinatoire de preparation d'echantillotheques de pyrrolidine substituee
JPH1087663A (ja) * 1996-09-12 1998-04-07 Sagami Chem Res Center 双環性ヒダントイン誘導体、それらの製造方法およびそれらを有効成分とする除草剤
US5859190A (en) * 1997-02-04 1999-01-12 Trega Biosciences, Inc. Combinatorial libraries of hydantoin and thiohydantoin derivatives, methods of making the libraries and compounds therein
DE60034571T2 (de) * 1999-06-15 2007-12-27 Aventis Pharmaceuticals Inc. Festphasensynthese von n,n-disubstituierten diazacycloalkylcarboxy-derivaten
PT1307455E (pt) * 1999-10-20 2005-06-30 Tanabe Seiyaku Co Inibidores de adesao celular mediada por (alfa)l (beta)2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0208227A3 *

Also Published As

Publication number Publication date
CA2416654A1 (fr) 2002-01-31
AU2001281995A1 (en) 2002-02-05
WO2002008227A3 (fr) 2002-08-29
WO2002008227A2 (fr) 2002-01-31

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