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WO2004076434A1 - Inhibiteurs de dipeptidyl peptidases - Google Patents

Inhibiteurs de dipeptidyl peptidases Download PDF

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Publication number
WO2004076434A1
WO2004076434A1 PCT/IB2004/000525 IB2004000525W WO2004076434A1 WO 2004076434 A1 WO2004076434 A1 WO 2004076434A1 IB 2004000525 W IB2004000525 W IB 2004000525W WO 2004076434 A1 WO2004076434 A1 WO 2004076434A1
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WIPO (PCT)
Prior art keywords
hef
het
piperidinyl
oxo
butanediamine
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PCT/IB2004/000525
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English (en)
Inventor
Simon Scharpe
Koen Augustyns
Achiel Haemers
Anne-Marie Lambeir
Ingrid De Meester
Kristel Senten
Pieter Van Der Veken
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Aic
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Priority claimed from PCT/IB2003/000792 external-priority patent/WO2004076433A1/fr
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Publication of WO2004076434A1 publication Critical patent/WO2004076434A1/fr

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    • 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
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • 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
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel inhibitors of serine type peptidases in general and of serine type dipeptidyl peptidases in particular.
  • the present invention further relates to the use of the dipeptidyl peptidase inhibitors for selective inhibition of serine type peptidases.
  • the present invention also relates to pharmaceutical compositions comprising these novel dipeptidyl peptidase inhibitors.
  • the present invention further relates to the use of the novel inhibitors in therapy, diagnosis and research.
  • Serine type proteases serve an important role in human physiology by mediating the activation of vital functions. In addition to their normal physiological function, serine proteases have been implicated in a number of pathological conditions in humans. Serine proteases are characterized by a catalytic triad consisting of aspartic acid, histidine and serine at the active site.
  • Serine peptidases like granzymes, mast cell tryptase, elastases, trypsin-like enzymes, prolyl oligopeptidase, and serine type dipeptidyl peptidases such as DPPII, DPPIV, QPP, FAP ⁇ , DPP8 and DPP9 are involved in various processes that take place in the body, such as blood coagulation, inflammation, immune response, and control of peptide hormone metabolism in general.
  • DPPs Dipeptidyl peptidases
  • DPP II EC 3.4.14.2
  • DPP IV EC 3.4.14.5
  • Xaa-Pro- or Xaa-Ala- N-terminal dipeptide moieties
  • DPP IV and DPP II share substrate specificity, they can be functionally and biochemically distinguished.
  • Dipeptidyl peptidase IV is a highly specific exopeptidase with a serine type mechanism of peptidase activity, cleaving off dipeptides from the amino-terminus of peptides with proline or alanine at the penultimate position. In addition the slow release of dipeptides of the type X-Gly or X-Ser is reported for some naturally occurring peptides.
  • DPP IV is constitutively expressed on epithelial and endothelial cells of a variely of different tissues, and is also found in body fluids. In the hematopoietic system, DPP IV was identified as the leukocyte antigen CD26.
  • DPP II DPP II, first identified by McDonald at al. (S. J. Biol. Chem., 1968, 243, 4143-4150), is believed to be involved in the physiological breakdown of some proline-containing oligopeptides and neuropeptides and in the degradation of collagen (Andersen ei al. Renal Physiol. Biochem., 1989, 12, 32-40) together with tripeptidyl peptidase and in lysosomal degradation and protein turnover. DPP II is generally localized in lysosomes and is found in a number of mammalian tissues and body fluids..
  • Dipeptidyl peptidase II and quiescent cell proline dipeptidase QPP have recently been suggested to be identical proteases based on sequence comparison of human quiescent cell proline peptidase and rat DPPII. Additional biochemical evidence is provided by Kau, B. et al. (Biochem. J. 2003, 371 , 525-532).
  • the invention also aims to provide novel inhibitors that have a more specific and selective DPP inhibitory activity than currently available inhibitors.
  • the invention provides compounds according to claim 1 , which are able to inhibit the enzymatic activity of serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • Such compounds according to the present invention induce strong inh bition of dipeptidyl peptidase enzyme activity.
  • the present novel dipeptidyl peptidase nhibitors are therefore very suitable for use in all kinds of research, therapeutic and d agnostic applications as described below.
  • the present invention further relates in another aspect to the use of said compounds as a medicament.
  • the invention concerns the use of said compounds in the treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase, or in diagnostic and research methods.
  • the present invention further relates to the use of the compounds in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase and in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
  • the present invention also relates to the use of the compounds in diagnostic and research methods.
  • the present invention also relates to pharmaceutical compositions and kits comprising tie compounds according to the invention.
  • the present invention relates to methods for inhibiting the activity of a serine type dipeptidyl peptidase in vitro, ex vivo and in vivo.
  • the present invention also relates to method for purifying and synthesizing the present compounds.
  • Figure 1 illustrates the synthesis of compounds having formulas IV, IX, XI, XII, XIII, XIV, XV, XVI and XXI as illustrated in example 2, Table B.
  • Figure 2 illustrates the synthesis of compounds having formulas XVIII, XVII, XX as illustrated in example 2, Table B.
  • Figure 3 illustrates the synthesis of compounds having formulas V, VI, VII, VIII, X, XIX as illustrated in example 2, Table B.
  • Figure 4 illustrates the synthesis of compounds having formulas XXII, XXlll, XXIV, XXV,
  • Figure 5 illustrates the synthesis of compounds having formulas XXXV and XXXVI as illustrated in example 2, Table B.
  • Figure 6 illustrates the synthesis of compounds having formulas XXXVll to XXXXI as illustrated in example 2, Table B.
  • Figure 7 illustrates the synthesis of compounds having formulas XXXXI I to XXXXVII as illustrated in example 2, Table B.
  • Figure 8 illustrates the synthesis of compounds having formulas 1-18, 19, 23, 24 and 25- 26 as illustrated in example 6, Table C.
  • Figure 9 illustrates the synthesis of compounds having formulas 20 and 3 as illustrated in example 6, Table C.
  • Figure 10 illustrates the synthesis of compounds having formulas 21 , 22, and 27-36 as illustrated in example 6, Table C.
  • Figure 11 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the relative DPPII activity in plasma in rabbits after intravenous administration.
  • Figure 12 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the relative DPPII activity in plasma in rats after oral administration.
  • Figure 13 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the specific activity of DPPII, DPPIV in several organs in rats.
  • the present invention relates to novel inhibitors of serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • serine type dipeptidyl peptidases or "dipeptidyl peptidases” or “DPP” are used as synonyms and refer to serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • modulator inhibitor
  • compound inhibiting compound
  • modulating compound refers to compounds according to the invention having an modulating activity on DPP, which may mostly comprise inhibiting properties in various degrees going from very inhibiting to weakly inhibiting. Although the compounds will mostly have inhibiting properties, it is also within the scope of the invention that the present compounds may have in some situations enhancing properties.
  • the present invention relates a compound having a modulating activity on a serine type dipeptidyl peptidase, having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, formula I wherein 1 is selected from the group comprising -CH 2 -, oxa, thia and imino, or wherein Ft 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R 3 , R 4 and R 6 are selected from the group comprising hydrogen, oxyalkyl alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl, alkoxycarbonyl alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyi, cycloalkyl cycloalkylalkylalkyl, cyclo
  • alkylaminocarbonylaminoakyl arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxy
  • Het aralkanoyl Het 1 aroyl, Het 1 arylcarbonyl, Het 1 aryloxycarbonyl, Het 1 arylthiocarbonyi
  • Het aralkylaminocarbonylarrinoalkyl Het 1 alkylaminoaryl, Hefarylaminoaryl
  • Het aralkylaminoaryl Het 1 alkanoylaminoaryl, Het 1 aroylaminoaryl
  • Het arylaminocarbonylarrinoaralkyl Het alkylaminocarbonylaminoaralkyl.Het 2 , Het 2 oxy Het 2 alkyl, Het ⁇ oxyalkyl, Hef ⁇ cycloalkyl, He alkoxycarbonyl, Het ⁇ sxycarbonyl Het 2 alkanoyl, He alkyloxyalkyi, Hel ⁇ oxyalkylcarbonyl, Het 2 alkyloxyalkylcarbonyl Het 2 aminocarbonyl, Hefcarbonyloxyalkyl, He alkylcarbonyloxyalkyl, Hef ⁇ ryl Het 2 arylaminoalkoxy, Het 2 arylamino, Het 2 arylaminoalkyl, Hefarylaminoalkylamino Het 2 aryloxy, Hefaryloxyalkoxy, Het 2 aryloxyalkyl, Het 2 aryloxyalkylamino, Hefaralkyl Het 2 a
  • Het 2 aralkylaminoaryl He ⁇ alkanoylaminoaryl, Hef ⁇ roylaminoaryl Het 2 aralkanoylaminoaryl, He alkyloxycarbonylaminoaryl, Hef ⁇ ryloxycarbonylam ' noaryl Het 2 aralkoxycarbonylaminoaryl, Het 2 alkylaminocarbonylarrinoaryl
  • the highly specific and potent inhibitors of serine type dipeptidyl peptidases can advantageously be used to unravel of the physiological functions of the serine type dipeptidyl peptidase enzyme and are also very useful to differentiate between different serine type dipeptidyl peptidases activity in biological systems.
  • alkyl alone or in combination, means straight and branched chained saturated hydrocarbon radicals containing from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms.
  • examples of such radicals include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2- methylbutyl, pentyl, iso-amyl, hexyl, 3-methylpentyl, octyl and the like.
  • cycloalkyl alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or polycyclic alkyl radical wherein each cyclic moiety contains from about 3 to about 8 carbon atoms, more preferably from about 3 to about 7 carbon atoms.
  • monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, and the like.
  • cycloalkylalkyl means an alkyl radical as defined herein, in which at least one hydrogen atom on the alkyl radical is replaced by a cycloalkyl radical as defined herein.
  • examples of such cycloalkylalkyl radicals include cyclopropylmethyi, cyclobutylmethyl, cyclopentylmethyl, cyclohexyl methyl, 1-cyclopentylett ⁇ yl, 1-cyclohexyielhyl, 2- cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl,3-cyclopentylbutyl, cyclohexylbuty! and the like.
  • alkoxy or "alkyloxy”, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, hexanoxy and the like.
  • alkanoyl or "alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
  • alkylamino alone or in combination, means an alkyl amine radical (i.e. RNH-), wherein the term “alkyl” is defined as above.
  • alkylamino radicals include methylamino (NHCH 3 ), ethylamino (NHCH 2 CH 3 ), n-propylamino, isopropylamino, n- butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-hexylamino, and the like.
  • aminoalkyl alone or in combination, means an amine alkyl radical (i.e. NH 2 R-), wherein the term “alkyl” is defined as above.
  • aminoalkanoyl means an acyl group derived from an amino-substituted alkylcarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • aminocarbonyl alone or in combination, means an amino-substituted carbonyl (carbamoyl) group wherein the amino group can be a primary, secondary ortertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • aryl alone or in combination, is meant to include phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, Het 1 , amido, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsultbnyl, and phenyl optionally substituted with one or more substituents selected from C
  • aryl includes phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3- methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3- acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl ⁇ 3- aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl, 2,4-dimethyl-3- aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, 3- amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6 ⁇ dimethoxy-2- naphthyl and the like.
  • halogen as a group or part of a group is generic for fluoro, chloro, bromo or iodo.
  • haloalkyl alone or in combination, means an alkyl radical having the meaning as defined above wherein one or more hydrogens are replacedwith a halogen, preferably, chloro or fluoro atoms, more preferably fluoro atoms.
  • haloalkyl radicals include chloromeihyl, 1-bromoethyl, fluoromethyl, difluoromettiyl, trifluoromethyl, 1 ,1 ,1- trifluoroethyi and the like.
  • Het 1 alone or in combination, is defined as a saturated or partially unsaturated monocyclic, bicyclic or polycyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino
  • Het 2 as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het 1 , Het 1 alkyl
  • arylamino alone or in combination means an aryl amine radical, wherein the term “aryl” is defined as above.
  • aralkyl alone or in combination, means an alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkyl radicals include benzyl, phenethyl, di benzyl methyl, methylphenylmethyl, 3- (2-naphthyl)-butyl, and the like.
  • aralkanoyl means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropfonyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4- methoxyhydrocinnamoyl.and the like.
  • aralkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkoxy radicals include 2- phenyletinoxy, 2-phenyM-propoxy, and the like.
  • aralkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkylamino radicals include 2-phenethylamino, 4-phenyl-n-butylamino, and the like.
  • aroyl means an acyl radical derived from an arylcarboxylic acid, ayl having the meaning given above.
  • arylcarboxylic acid radicals include substituted and unsubstituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4- carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2- naphthoyl, 3-(benzyloxyformamidol-2-naphthoyl, and the like.
  • arylaminoakoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • alkoxy radicals include 2- (phenylamino)-ethoxy, 2- (2- naphthylamino)-1-butoxy, and the like.
  • arylaminoalkyl means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • arylaminoakyl radicals include phenylaminoethyl, 4- (3-methoxyphenylarrino)- 1 -butyl, and the like.
  • arylaminoalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • Examples of (arylamino) alkylamino radicals include 3- (naphthylamino)-propylamino, 4- (phenylamino)-l- butylamino, and the like.
  • aryloxy means a radical of the formula aryl-O-in which the term aryl has the significance given above.
  • aryloxyalkanoyl means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.
  • aryloxyalkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkoxy radicals include 2-phenoxyethoxy, A- (3-aminophenoxy)-1- butoxy, and the like.
  • aryloxyalkyl means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • aryloxyalkyl radicals include phenoxyethyl, 4- (3-aminophenoxy)-l-butyl, and the like.
  • aryloxyalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • alkylamino radicals include 3-phenoxy-npropylamino, 4-ph ⁇ noxybutylamino, and the like.
  • arylthioalkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkoxy radicals include 2- (phenylthio)-ethoxy, and the like.
  • alkylthio means an alkyl thioether radical, wherein the term “alkyl” is defined as above.
  • alkylthio radicals include methylthio (SCH 3 ), ethylthio (SCH 2 CH 3 ), n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio, and the like.
  • aralkoxycarbonyl alone or in combination, means a radical of the formula aralkyl-O-C(O)- in which the term “aralkyl” has the significance given above.
  • aralkoxycarbonyl radical examples are benzyloxycarbonyl and 4- methoxyphenylmethoxycarbonyl.
  • aralkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkylthio radicals include 3- phenyl-2-propylthio, 2- (2-naphthyl)-ethylthio, and the like.
  • arylaminoalkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • Examples of (arylamino) alkylthio radicals include 2- (phenylamino)- ethylthio, 3- (2-naphlhylamino)-n-propylthio, and the like.
  • aryloxyalkyithio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • Examples of (aryloxy) alkylthio radicals include 3-phenoxypropylthio, 4 (2-fluorophenoxy)-butylthio, and the like.
  • arylthioalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkylamino radicals include 2- (phenylthio)- ethylamino, and the like.
  • arylthioalkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkylthio radicals include 2- (naphthylthio)- ethylthio, 3- (phenyllhio)-propylthio, and the like.
  • cycloalkylalkoxycarbonyl means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl hasthe meaning given above.
  • cycloalkylcarbonyl means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino, amido, mono and dialkyl substituted amino, mono and dialkyl substituted amido and the like, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1 ,2,3,4-tetrahydro-2-naphthoyl.
  • He ⁇ alkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • He alkoxy radicals include 2- pyridylmethoxy, 4- (l-imidazolyl)-butoxy, and the like.
  • Het 2 alkyl means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • Het 2 alkyl radicals include 2- pyridylmethyl, 3- (4-thiazolyl)-propyl, and the like.
  • Hefalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • Het 2 alkylamino radicals include 4-pyridylmethylamino, 3 (2-furanyl)-propylamino, and the like.
  • He ⁇ alkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • Examples of Het 2 alkylthio radicals include 3-pyridylmethylthio, 3 (4-thiazolyl)-propylthio, and the like.
  • Hefamino means Het 2 as defined herein, wherein a hydrogen atom on the Het 2 ring is replaced by a nitrogen.
  • Het 2 amino radicals include, for example, 4- thiazolylamino, 2-pyridylamino, and the like.
  • Het 2 oxy means Het 2 as defined herein, wherein a hydrogen atom on the Het 2 ring is replaced by an oxygen.
  • Het 2 oxy radicals include, for example, 4-pyridyloxy, 5- quinolyloxy, and the like.
  • He oxycarbonyl means an acyl radical derived from a carbonic acid represented by Het 2 -O-COOH wherein Het 2 has the meaning given above.
  • Het 1 alkanoyl is an acyl radical derived from a Het 1 -substituted alkylcarboxylic acid wherein Het 1 has the meaning given above.
  • Het 1 alkoxycarbonyl means an acyl group derived from Het 1 -O-COOH wherein Het 1 is as defined above.
  • oxa refers to the group -O-.
  • thia refers to the group -S-.
  • amino refers to the group -NH-.
  • cyano refers to the group -CN.
  • nitro refers to the group -NO 2 .
  • substituted is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • the term “one or more” covers the possibility of all the available C- atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable, e.g. halogen or alkyl, occurs more than one time in any constituent, each definition is independent.
  • the term "compound(s) of the invention” or a similar term is meant to include the compounds of general formula I or formula II and any subgroup thereof. This term also refers to the compounds as depicted in Table A and B and their N- oxides, salts, stereoisomeric forms, racemic mixtures, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues.
  • the ⁇ /-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • the compounds according to the invention may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the compounds as described herein, are intended to be included within the scope of the present invention.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as purified enantiomers/diasteromers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds per se, as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • pro-drug means the pharmacological ⁇ acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug.
  • the reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated.
  • Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component.
  • pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference.
  • Pro-drugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • the “salts” of the compounds according to the invention are those wherein the counterion is pharmaceulically or physiologically acceptable.
  • the pharmaceutically acceptable salts of the analogues according to the invention i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate aspartate, benzoate, benzenesulfonafe, bisulfate, butyrate, citrate, camphorate camphorsulfonaie, cyclopentanepropiorate, digluconate, dodecylsulfete, ethanesulfonate fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate persulfate, 3-phenylpropbnate, picrate, pivalate, propionate, succinate, tartrate thiocyanate, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylarrine salts, N-methyl-D- glucamine, and salts with amino acids such a sarginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • esters refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred.
  • alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred.
  • other esters such as pheny alkyl may be employed if desired.
  • solvate refers to a complex of variable stoichiometry formed by a solute or a salt or pharmaceutical functional derivative thereof and a solvent.
  • solvents for the purpose of the invention should not interfere with the biological activity of the solute.
  • solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutical acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
  • pharmaceutically functional derivative refers to any pharmaceutical acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation.
  • the compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism. All polymorphic forms (“polymorphs”) are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure, or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics that are known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the invention relates to a compound having the general formula l, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, thia and imino, or wherein R 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyt alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylaminamino,
  • Hefalkyloxyalkylcarbonyl Het 1 aminocarbonyl, Het 1 carbonyloxyalkyl
  • Het 1 aralkylaminoalkyl Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
  • Het 1 alkylaminocarbonylaminoalkyl Het 1 arylaminocarbonyiaminoalkyl
  • Het 1 aralkylaminocarbonylarrinoalkyl Het 1 alkylaminoaryl, Hefarylaminoaryl
  • Het 1 aralkylaminoaryl Hefalkanoylaminoaryl, Het 1 aroylaminoaryl
  • Het 1 aralkanoylaminoaryl Het 1 alkyloxycarbonylaminoaryl, Het 1 aryloxycarbonylarrinoaryl Het 1 aralkoxycarbonylaminoaryl, Het 1 alkylaminocarbonylarrinoaryl
  • Het 2 aralkylaminoalkyl Hefalkanoylaminoalkyl, He ⁇ aroylaminoall Het 2 aralkanoylaminoalkyl, Het 2 alkyloxycarbonylarninoalkyl
  • Het 2 aralkylaminoaryl Hel ⁇ alkanoylaminoaryl, Hef ⁇ roylaminoaryl Het aralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, He ⁇ aryloxycarbonylarrinoaryl Het 2 aralkoxycarbonylaminoaryl, Het 2 alkylaminocarbonylarrinoaryl
  • the invention provides a compound having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, and thia, or wherein R 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyl alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aral
  • Hefaralkanoylaminoalkyl Het 1 alkyloxycarbonyiaminoalkyl
  • Hefaralkylaminocarbonylarrinoalkyl Hefalkylaminoaryl, Hefarylaminoaryl Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
  • Hefaralkanoylaminoaryl Hefalkyloxycarbonylaminoaryl, Hefaryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hefalkylaminocarbonylarrinoaryl
  • Hefalkyloxycarbonylaminoarakyl Hefaryloxycarbonylarrinoaralkyl Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
  • Hefarylaminocarbonylarrinoaralkyl Hefaralkylaminocarbonylaminoaralkyl.Het 2 , Het 2 oxy Het 2 alkyl, Het ⁇ oxyalkyl, He ⁇ cycloalkyl, Hefalkoxycarbonyl, He oxycarbonyl Het 2 alkanoyl, Hefalkyloxyalkyi, Het 2 oxyalkylcarbonyl, Het 2 alkyloxyalkylcarbonyJ Het 2 aminocarbonyl, Hefcarbonyloxyalkyl, He ⁇ alkylcarbonyloxyalkyl, Hefaryl Het 2 arylaminoalkoxy, He arylamino, Het 2 arylaminoalkyl, Hefarylaminoalkylamino Het 2 aryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Het 2 aryloxyalkoxy, Hefaryloxyalkyl, Het 2 aryloxyal
  • Het 2 aralkylaminoalkyl Het ⁇ alkanoylaminoalkyl, Hef ⁇ roylaminoalkyl
  • Het 2 aralkanoylaminoalkyl Het 2 alkyloxycarbonylaminoalkyl Het 2 aryloxycarbonylaminoakyl, Het 2 aralkoxycarbonylaminoalkyl
  • Het 2 aralkanoylaminoaryl He ⁇ alkyloxycarbonylaminoaryl, He ⁇ aryloxycarbonylaminoaryl Het 2 aralkoxycarbonylaminoaryl, Het 2 alkylaminocarbonyIarrinoaryl
  • a compound having the general formula I or pharmaceulically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, and thia or wherein R 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, methyl and cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl, aryl cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl alkylaminocarbonyl, alkylaminoalkyl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl arylaminoalkyl, arylaminoalkylamino, aryloxyalkylamino, aralkylamino, aryla
  • a compound according to the invention is a compound having the general formula I or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, thia wherein R 2 is selected from the group comprising hydrogen, methyl and cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl, amidinoalkyl
  • a compound according to the invention is a compound having the general formula I or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, thia wherein R 2 is selected from the group comprising hydrogen, methyl and cyano, wherein R 3 is hydrogen and R 4 is selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoakyl, amidinoalkyl,
  • the compounds of the invention have general formula II as represented below,
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 have the same meaning as indicated herein, wherein R 4' , R 8 , R 9 , R 10 are selected from the group comprising nitrogen hydrogen, oxyalkyl, alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl alkoxycarbonyl, alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyl cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyl cycloalkylalkoxycarbonyl, cycloalkylalkoxytiiocarbonyl, cycloalkyllhioalkyl alkylcarbonyloxyalkyl, cycloalkylcarbonyl
  • Hefarylaminocarbonylarrinoaralkyl Hefaralkylaminocarbonylaminoaralkyl.Het 2 , Het 2 oxy Het 2 alkyl, Hefoxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl, Het 2 oxycarbonyl Het 2 alkanoyl, Hefalkyloxyalkyl, Het 2 oxyalkylcarbonyl, Het 2 alkyloxyalkylcarbonyl Hefaminocarbonyl, Hefcarbonyloxyalkyl, Hefalkylcarbonyloxyalkyl, Hefaryl Hefarylaminoalkoxy, Hefarylamino, Hefarylaminoalkyl, Hefarylaminoalkylamino Hefaryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkoxy, Hefaryloxy
  • Hefarylalkylthiocarbonyl Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl
  • Hefaralkylaminoalkyl Hefalkanoylaminoalkyl, Hefaroylam noalkyl
  • Hefaralkylaminoaryl Hefalkanoylaminoaryl, Hefaroylaminoaryl Hefaralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl
  • Hefalkylaminoaralkyl He arylaminoarakyl, Hefaralkylaminoaralkyl Hefalkanoylaminoaralkyl, Het 2 aroylaminoaralkyl, Hefaralkanoylaminoaralkyl
  • substituents independently selected from the group comprising hydrogen, amino, hydroxy,
  • a compound is provided being N 1 -benzyl-4-oxo-4-(1- piperidinyl 1 ,3(S)-butanediamine as indicated with formula IV according to the specification given below.
  • This particular compound corresponding to formula IV as represented below is also referred to as KS IV.7.
  • the potency of the compounds to inhibit serine type dipeptidyl peptidases accordingto the present invention are expressed as IC 50 value.
  • the "IC 50 value” is defined as the concentration of a compound, which causes the enzyme activity to decrease with 50 % under assay conditions.
  • a compound selected from the group comprising N 1 -benzyl-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1 -piperidinyl)- 1 ,3(R)-butanediarnine, A-(A- morpholinyl)-4 -oxo-1 ,3(S)-butanediamine, 4-oxo-4-(1-piperazinyl)-1 ,3(S)-butanediamine, benzyl 3-amino-1(S)-(1-piperidinylearbonyl)propyJcarbamate, benzyl 3-atnino-4-o ⁇ o-4- (1 piperidinyl)butyicarbamate, N 1 -benzyl-2(S)-(1-piperidinylcarbonyl>
  • a compound is provided selected from the group comprising /V-(2-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -(3- chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -(4-chlorobenzyl)-4-oxo-4- (1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -[2-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)- 1 ,3(S)-butanediamine, ⁇ / 1 -[4-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -[4-(benzyloxy)benzy
  • the compounds according to the present invention all preferably inhibit DPP activity, exhibiting relatively high activity at relatively low concentrations, as indicated by low IC 50 values.
  • the IC 50 values of the compounds according to the present invention are lower than 100 ⁇ M, more preferred lower than 10 ⁇ M, even more preferred lower than 0.1 ⁇ M.
  • some of the presented compounds are very useful to differentiate between DPP II and DPP IV activity in biological systems, since some of these compounds are highly specific and selective for DPPII inhibitory activity than currently available inhibitors.
  • DPP II and DPP IV both preferentially release N- terminal dipeptide moieties (Xaa-Pro- or Xaa-Ala-) from some oligopeptides or proteins.
  • DPP IV and DPP II share substrate specificity, and differentiating between these acitivites is generally a challenging and difficult task.
  • the compound KS IV.7 as defined above is a particularly active and selective DPPII inhibitor.
  • This compound has an IC 50 value of 0.00203 ⁇ M for DPPII.
  • the IC 50 value of this compound towards DPP IV comprises 247 ⁇ M.
  • This compound thus has a particularly high selectivity of for DPPII, and is particularly suitable for in applications wherein a differentiation is required between DPP II and DPP IV activity.
  • the invention thus relates to compounds for use as a medicament.
  • the compounds according to the present invention can be used in the treatment of pathological states associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
  • said compounds according to the invention can be used in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPIV.
  • said compounds according to the invention can be used in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPII.
  • the invention also relates to the use of the compounds according to the invention in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for inhibiting the activity of DPPIV.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for inhibiting the activity of DPPII.
  • the invention also relates to the use of the compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPIV.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPII.
  • Such medicaments are then specifically intended for treatment and prophylaxis of the conditions listed below.
  • the compounds of the present invention are believed useful for the treatment of a variety of metabolic, neuroendocrine, gastrointestinal, viral, and inflammatory diseases, including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, (auto)immune disorders such as encephalomyelitis, complement mediated disorders such as glomerulonepritis, lipodyslrophy, and tissue damage, psychosomatic, depressive, and neuropsychiairic disease such as anxiety, depress on, insomnia, schizophrenia, epilepsy, spasm, and chronic pain, HIV infection, allerg es, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart fa lure, tumors, and stress-induced abortions.
  • metabolic, neuroendocrine, gastrointestinal, viral, and inflammatory diseases including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, (auto)imm
  • the invention also relates to the diagnostic use of the compounds.
  • the compounds according to the present invention can be used in diagnostic and research methods such as fluorescence, purification and radio-assays, imaging, in situ histochemical and cytochemical staining.
  • the present invention relates to the use of a compound according to the invention in purification procedures of serine type peptidases and preferably of dipeptidyl peptidases.
  • the said compounds can be immobilized to a suitable matrix or used as a competitor to elute bound enzyme from a matrix containing an immobilized compound.
  • the present invention also includes compounds, which have been modified without abolishing the reactivity with the active site.
  • modifications are the incorporation of radioactive labels such as Iodine 125 , or non-radioactive labels such as biotin or a fluorophore.
  • the incorporation of a (radioactive) label is useful in diagnostic methods using the modulating compounds.
  • Labelled compounds can be used essentially in the same type of appli cations as labelled monoclonal antibodies, e.g. fluorescence and radioassays, cytofluorimetry, fluorenscence activated cell sorting, etc ... The principles of such techniques are well known to the person skilled in the art.
  • DPP inhibitors described above which form complexes with dipeptidyl peptidases are therefore suitable for diagnostic applications such as imaging and histochemical staining of DPP.
  • Formulations of the compounds to be used in diagnostic applications are also part of this invention.
  • DPP activities can interfere with certain assays by cleaving the substrate used in the test and thereby giving either false positive (when a chromogenic substrate is cleaved) orfalse negative results (when a peptide is degraded).
  • the inhibitors of this invention can be used to inactivate a contaminating DPP activity before carrying on with the analysis.
  • DPP target protease
  • the label can be fluorescent for fluorescence microscopy, radioactive for autoradiography, or electron dense for electron microscopy.
  • the target structures can be whole cells, cells fixed onto slides or sections through solid tissue.
  • a useful modification of these techniques is to use an indirect (“sandwich") assay employing the specific high affinity interaction between biotin and avidin (reviewed in Methods in Enzymology, vol. 184, 1990).
  • inhibitors labeled with a suitable isotope e.g. I 125 or I 131
  • a suitable isotope e.g. I 125 or I 131
  • the compounds of the invention which form a stable adduct with DPP may be used as a tool for diagnosing of the above cited disease states.
  • compositions prepared for storage and subsequent administration which have a therapeutically effective amount of one or more compounds of the invention and a pharmaceutically acceptable excipient, carrier or diluent.
  • Such pharmaceutical preparations are intended for the treatment and prophylaxis of the above conditions.
  • terapéuticaally effective amount means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • Preservatives, stabilizers, dyes and flavoring agents may be provided in the pharmaceutical compositions.
  • Preservatives, stabilizers, dyes and flavoring agents may be provided in the pharmaceutical compositions.
  • sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • compositions of this invention may be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions or suspensions for injectable administration; aerosols; unguents for topical administration.
  • absorption enhancing preparations e.g. liposomes
  • the amount of the active substances(s) in a dosage unit may vary between 0.01 mg and 1 g.
  • Formulations of the present invention include those especially formulated for oral, buccal, parental, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • oral administration typically is preferred.
  • tablets, capsules, and caplets may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, and/or wetting agents.
  • binding agents include syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, or polyvinylpyrrolidone (PVP).
  • fillers include, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol.
  • lubricants include, for example, magnesium sterate, stearic acid, talc, polyethylene glycol or silica.
  • disintegrants include, for example, potato starch or sodium starch glycollate.
  • a non-limiting example of a wetting agent includes sodium lauryl sulfate.
  • the tablets additionally may be coated according to methods known in the art.
  • the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs.
  • formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Liquid preparations may contain conventional additives.
  • Non-limiting examples of such additives include suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum sterate gel or hydrogenated edible fats.
  • emulsifying agents such as lecithin, sorbitan mono-oleate or acacia
  • non-aqueous vehicles which may include edible oils
  • preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid, may be incorporated into the preparation.
  • Such preparations may also be formulated as suppositories, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
  • formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
  • the formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation, for example, subcutaneously or intramuscularly, or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials, such as an emulsion in an acceptable oil, ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt.
  • the compounds of the present invention may be used in combination with one or more other therapeutic or diagnostic agents in the treatment, prevention, suppression, amelioration, or diagnosing of diseases or conditions for which compounds of the invention or the other agents may have utility, where the combination of the drugs together are safer or more effective than either agent alone.
  • Such other agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition in unit dosage form containing such other agents and the compound of the invention is preferred.
  • the combination therapy may also include therapies in which the compound of the invention, and one or more other agents are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • Examples of other active ingredients that may be administered in combination with a compound of the present invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to other dipeptidyl peptidase inhibitors.
  • certain compounds of the invention can be combined with each other such that synergetic inhibiting effects are obtained.
  • combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other agents that are used in the treatment/prevention/suppression or amelioration of diseases or conditions for which compounds of the present invention are useful.
  • the weight ratio of a compound of the present invention to a second active ingredent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication.
  • the pharmaceutical compositions of this invention can be administered to humans in dosage ranges specific for each compound comprised in said compositions.
  • the dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain certain amounts of a compound of the present invention depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Examples of such amounts include the formulation containing about 0.1 to about 99.9% active ingredient.
  • Preferred unit dosage formulations are those containing a predetermined dose, such as a daily dose, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • the invention in another embodiment, relates to a method of treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention.
  • a pharmaceutical composition according to the invention.
  • the term "individual,” as used herein refers to an animal, preferably a mammal, and most preferably a human, who has been the object of treatment, observation or experiment
  • said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment.
  • the present invention relates to a method for inhibiting the activity of a serine type dipeptidyl peptidase by administering a compound according to the present invention.
  • the present invention relates to a method for in vitro inhibition of the activity of a serine type dipeptidyl peptidase by means of administering a suitable concentration of a compound of the invention.
  • Such method is in particular useful when a DPP enzyme inactivates a peptide prior to measurement thereof in a peptide assay.
  • the compounds of the invention can be used to inhibit the degradation of the peptide substrate by the enzyme in such assay.
  • the compounds of the invention are also useful in a method for ex vivo inhibition of the activity of a serine type dipeptidyl peptidase, such as the treatment outside the body of cells and organs for transplantation in order to avoid rejection thereof by the recipient body.
  • the method comprises administering a suitable concentration of a compound according to the invention.
  • the compounds of the invention can be used in a method for in vivo inhibiting of the activity of a serine type dipeptidyl peptidase by means of administering to a living organism a suitable amount of a compound of the invention.
  • the present invention relates to kits comprising a compound according to the invention.
  • the invention further provides for assay kits for assaying the inhibition of the activity of a serine type dipeptidyl peptidase comprising a compound according to the invention and means to detect said inhibition.
  • Example 1 Non-limiting examples of compounds according to the invention
  • Non-limiting examples of compounds according to the invention and having general formula II are listed in Table A, wherein reference is made to R 1 , R 2 , R 3 , R 4' , R 5 , R 6 , R 7 , R 8 ,
  • Example 2 Specific examples of compounds ac ⁇ rding to the invention
  • the present example illustrates some specific examples of compounds according to the invention (Table B). Also indicated are the IC 50 values of the indicated compounds for DPPII and DPPIV.
  • the compounds according to the invention strongly inhibit DPPII activity, as indicated by the low IC 50 values of the illustrated compounds for DPPII.
  • most of the compounds in the following examples have an activity in inhibiting DPPII generally lower than 100 ⁇ M and in some cases lower than 10 ⁇ M and even lower than 1 ⁇ M. Such results are indicative of the intrinsic activity of the compounds in use as inhibitors of DPPII enzyme activity.
  • the compound with formula IV is a particularly active and selective DPPII inhibitor.
  • This compound has an IC 50 value of 0.00203 ⁇ M for DPPII.
  • the IC 50 value of this compound towards DPP IV comprises 247 ⁇ M.
  • This compound thus has a particularly high selectivity of for DPPII, and is particularly suitable for in applications wherein a differentiation is required between DPP II and DPP IV activity.
  • the present compounds may be active, i.e. have a strong inhibitory activity on DPP II.
  • the present compounds as claimed in claim 1 may show a high selectivity for DPPII.
  • the presented compounds are very useful to be applied in all kinds of research, therapeutic and diagnostic applications for inhibiting the activity of a serine type dipeptidyl peptidase.
  • the present example illustrates the synthesis of compounds as illustrated in Table B of example 2, according to different synthesis schemes.
  • Procedure E Deprotection of the benzyloxycarbonyl (Z) group was done by hydrogenolysis: to a mixture of compound obtained from previous step in methanol (50 ml) was added Pd/C (20%) and acetic acid (1 ml). A flow of nitrogen-gass was carried over the solution for 10 minutes, followed by a flow of H 2 -gas. The reaction was monitored by TLC. After completion, again a flow of nitrogen was carried over the solution for 10 minutes. The mixture was filtered over a celite and the methanol was removed in vacuo. The compound obtained was used as such in the next step.
  • N-Boc protected title compound was obtained by submitting N-Boc-N- cyclohexylglycine b procedure A (81%)
  • the title compound was obtained by sequentially applying procedures H, N, O, A and B to benzylamine.
  • the title compound was obtained by sequentially applying procedures M and B to N-Boc- ⁇ /-benzyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
  • the title compound was obtained by sequentially applying procedures M and B to /V-Boc- ⁇ /-piperonyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
  • Example 4 Use of a compound of the invention as affinity ligand during the purifica ⁇ on of DPPII
  • This example illustrates the use of a compound (formula XXII) according to the present invention as affinity ligand during the purification of DPPII.
  • NHS-activated Sepharose 4 fast flow gel (Amersham) was used as matrix.
  • An appropriate amount of the gel was washed on a sintered glass filter with 1 mM HCI.
  • An excess of Lys- Pip (formula XXII) was solubilized in isopropanol (1 column volume) and allowed to react with the matrix during 24 h at room temperature in an end over end mixer. Afterwards the gel was washed with an excess isopropanol, followed by water.
  • the low pH buffer consisted of 100 mM acetate pH 4.0 containing 500 mM NaCI.
  • the high pH buffer consisted of 50 mM Tris base with 500 mM NaCI.
  • the Lys-Pip affinity matrix was stored in 100 mM cacodylate at 4-8°C.
  • a biological sample containing DPPII was applied onto the Lys-Pip affinity matrix in Na- acetate buffer, 50 mM pH 5.5. Unbound protein was removed by washing with 100 mM cacodylate pH 5.5. Elution was performed with 100 mM cacodylate pH 5.5 containing 500 mM NaCI.
  • the present example is a further illustration of the present invention.
  • the invention relates to the development of highly specific and potent inhibitors of DPP II, which will contribute to the unravelling of the physiological fundions of this enzyme and will be helpfull to differentiate between DPP II and DPP IV in biological systems.
  • the resembling substrate specificity and catalytic mechanism can complicate this challenging task.
  • DPPs Dipeptidyl peptidases
  • DPP II is generally localized in lysosomes and is found in a number of mammalian tissues and body fluids. Recently it is reported to be identical to human quiescent cell proline dipeptidase (QPP), based on the significant sequence homology (79.4%) found between human QPP and rat DPP II (Araki et al. J.
  • DPP IV has been studied extensively over the last three decades and a broad array of diverse functional properties in the immune, nerve and endocrine system is suggested Augustyns et al. Curr. Med. Chem., 1999, 6, 311-327; Villhaueret al. Annual Reports in Medicinal Chemistry, Academic Press, 2001 , Vol 36, pp 191-200).
  • DPP IV is bound to the cell membrane and expressed quite ubiquitously in mammalian tissues. In the hematopoietic system it was identified as the leukocyte antigen CD26. Inhibition of DPP IV can be valuable in the treatment of type 2 diabetes and some important DPP IV inhibitors are currently under evaluation in this field (Villhaueret al.
  • DPP IV inhibitors resemble often the dipeptide cleavage product with a proline mimic at the Pi-site.
  • Amino acyl pyrrolidides (1) and thiazolidides (2) are known as potent, competitive inhibitors of DPP IV ( see below). Substituting the pyrrolidine ring with 6- or 7-membered rings or acyclic amines results in loss of potency (Auguslyns et al. Eur. J. Med. Chem., 1997, 32, 301-309).
  • Cha cyclohexylalanine
  • IC 50 3 ⁇ M
  • the expected increase of DPP IV inhibition that occurs in general with the replacement of pyrrolidine by thiazolidine is notseen for this compound.
  • Replacing the pyrrolidine ring by piperidine in 8.3 and 8.4 we can observe a 2 to 6-fold improvement of the DPP II inhibition.
  • this introduction of a 6-membered ring gives a serious decrease in potency for DPP IV inhibitors.
  • Lys-Pip (8.4) came out as the most potent DPP ll-inhibitor in this series exhibiting an IC 50 of 1.6 ⁇ M. This compound is also the most selective towards DPP IV with a selectivity index of 156.
  • b Cha cyclohexylalanine
  • c Dab 2,4-diaminobutyric acid
  • d Dap 2,3-diaminopropionic acid
  • Abu 2-aminobutyric acid
  • f Nva norvaline
  • b Dab 2,4-diaminobutyric acid
  • c Cha cyclohexylalanine
  • Selectivity is also declined although a selectivity index of more than 4000 can still be considered high.
  • b Cha cyclohexylalanine
  • Dab 2,4-diaminobutyric acid
  • Dab-Pip (10.7) As the most potent and selective inhibitor, some analogues were prepared by replacing the piperidine ring with respectively morfoline (12) and piperazine (13) (Table 8).
  • Aminoacylpyrrolidide-2-nitriles are slow-binding, reversible inhibitors of DPP IV with approximately a 1000-fold increase in potency compared to the parent amino acyl pyrrolidides (low nM Kj) and a more than 500-fold selectivity against DPP II (Li et al. Arch. Biochem. Biophys., 1995, 323, 1 , 148-154).
  • DPP II Low nM Kj
  • the formulas for synthesised dipeptide nitriles (14, 15, 16) are provided below.
  • the selectivity could be reversed by replacing the pyrrolidine ring with piperidine.
  • Lys-Pip-2-CN (16.1) only slightly affect the DPP II inhibition while inhibitory activity of DPP IV declined with a factor 160.
  • Compound 16.1 is therefore a more selective DPP II inhibitor compared to the cyanopyrrolidide analogue (15).
  • Lys-Pip (8.4) no improvement in DPP II inhibitory potency is observed and is toweried by a 4-fold decrease in selectivity. It must be noticed that for this compound a mixture of diastereomers was tested: the inactive L-Lys-Pip-2(R)-CN and biological active -Lys-Pip- 2(S)-CN isomer.
  • b The compound tested was -Lys-Pip-2(R,S)-CN.
  • Reverse phase HPLC was run on a Gilson instrument (Viliers-le-bel, France) equipped with an Ultrasphere ODS column (4.6 x 250 mm, 5 ⁇ m, Beckman, Fullerton, CA, USA) and a uv-detector (10-100% ACN, 35 min, 214 nm, 1 ml/min).
  • Preparative TLC was performed on Silicagel 60PF 254 containing gypsum.
  • DPP IV was purified from human seminal plasma as described previously (De Meester et al. J. Immunol. Methods 1996, 189, 99 105).
  • DPP II was isolated from the same source using techniques described previously for purification of the enzyme from porcine seminal plasma (Huang et al. Biochim. Biophys. Acta 1996, 1290, 149 156), supplemented with adenosine deaminase affinity chromatography to eliminate contaminating DPP IV(De Meester et al. J. Immunol. Methods 1996, 189, 99 105).
  • Enzyme activity was measured kinetically with the chromogenic substrates Gly-Pro-p-nitroanilide at pH 8.3 and Lys-Ala-p- nitroanilide at pH 5.5 for DPP IV and DPP II respectively.
  • Test compounds were dissolved and diluted in DMSO (final concentration DMSO during assay 5% v/v). Highest concentration of compounds tested is 1 mM.
  • IC 50 value was defined as the inhibitor concentration, which caused a 50% decrease of the activity under assay conditions.
  • the protected amino acids amides (respectively 2 and 10) were prepared by parallel synthesis using the PASP-protocol. Thioxylation of these compounds was performed according to the following procedure: To a solution of the Boc-protected amino acid amides (2 eq) in 5 ml of toluene was added 2,4-bis(p-methoxyphenyl)-1 ,3- dithiadiphosphatane 2,4-disulfide (Lawesson's reagent) (1 eq). The reaction mixture was stirred for 2 h at 80°C. The solvent was removed by evaporation and the crude compound was purified by preparative TLC (EtOAc/hexane, 40:60). Pure compounds were deprotected according to the general procedure. Lys ⁇ fCS-NJ-Thia (4.1).
  • 3-Substituted pyrrolidide analogues were synthesised from 1-rN-(tert-butyloxycarbonyl)-L- lysyll-3(R,S)-hydroxy-pyrrolidine.
  • Example 6 specific examples of compounds according to the invention
  • Table C illustrates some specific examples of compounds according to the invention (Table C). Also indicated are the IC 50 values of the indicated compounds for DPPII and DPPIV.
  • the compounds of formula 1 to 36 specifically relates to the structures as illustrated in Table C and are distinct and different from the compounds described in example 5, and are not to be confused therewith. Table C
  • the compounds according to the invention strongly inhibit DPPII activity, as indicated by the low IC 50 values of the illustrated compounds for DPPII, and are active in the nanomolar range.
  • the present invention encompasses all the compounds as described in Tables A, B and C.
  • Example 7 Synthesis of the compounds according to the invention The present example illustrates the synthesis of compounds as illustrated in Table C of example 6, according to different synthesis schemes illustrated in Figures 8, 9 and 10.
  • the procedures A to M described in this example and in Figures 8 to 10 for the synthesis of compounds listed in Table C are distinct and different from the procedures described in example 3, and are not to be confused therewith.
  • LC-MS were recorded on an Agilent 1100 Series HPLC system using a Discovery Cyano column (2.1 x 50 mm, 5 ⁇ m, Supelco, Sigma-Aldrich) coupled with a Bruker Esquire 3000 plus mass spectrometer (0-80% ACN, 22 min, 0.2 ml/min).
  • Reversed phase HPLC was run on a Gilson instrument (Viliers-le-bel, France) equipped with an Ultrasphere ODS column (4.6 x 250 mm, 5 ⁇ m, Beckman, Fullerton, CA, USA) and a uv-detection (10-100% ACN, 35 min, 214 nm, 1 ml/min).
  • Serum levels of DPPII were measured using the chromogenic substrate Lys-Ala-p- nitroanilide at pH 5.5 in an assay with a final % dilution of the serum.
  • the DPP II activity in tissues was determined after homogenizing parts of the organs using n-octylglycoside as a detergent using the same substrate and buffer. Final dilution of extract in the assay was 1/20.
  • Tissue DPPIV activity was measured using Gly-Pro-p-nitroanilide as the substrate in Tris-HCI buffer pH 8.3.
  • Figure 11 shows the influence of intravenous administration of Compound 3 on the DPPII activity in serum of rabbits. Blood samples were taken at different timepoints after the injection of compound or vehicle (control animal). The 3 panels show 3 separate experiments in the same animals. The relative activity of serum DPPPII is given with the pretest value of each animal considered as 100
  • Figure 12 gives the influence of oral administration (gavage) of Compound 3 on the DPPII activity in serum of rats. After the administration of compound or vehicle (control animals) blood samples were taken from the tail at the timepoints indicated. In a first experiment (upper panel), the same dose was given to the 2 experimental animals. Very comparable and significant inhibition of serum DPPII activity was seen 1 hour after oral administration of compound. In a second experiment (lower panel), 2 different doses were compared. From this preliminar experiment a dose-dependency of the effect is expected.
  • Figure 13 details the influence of compound 3 on the specific activity of DPPII and DPPIV in several organs. Euthanasia of the animals was carried out 2 hours after compound administration. The measurements were carried out in a final dilution of 1/20 so the results underestimate the in vivo inhibition level obtained after oral administration of compound 3.
  • the upper panel depicts the DPPII specific activity and the lower panel represents the DPPIV activity. The preliminar results predict a dose dependent inhibition of DPPII but not DPPIV in the peripheral organsof the rat.

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Abstract

L'invention concerne de nouveaux inhibiteurs de peptidases de type sérine en général et de dipeptidyl peptidases de type sérine en particulier. L'invention concerne également l'utilisation des inhibiteurs de dipeptidyl peptidases dans l'inhibition sélective de dipeptidyl peptidases. L'invention concerne en outre des compositions pharmaceutiques comportant ces nouveaux inhibiteurs de dipeptidyl peptidases. Par ailleurs, la présente invention se rapporte à l'utilisation de ces nouveaux inhibiteurs dans les domaines thérapeutique, diagnostique et de recherche.
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WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
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WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
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EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP4000630A1 (fr) 2014-09-03 2022-05-25 Invex Therapeutics Ltd Traitement de la pression intracrânienne élevée
WO2022232573A1 (fr) * 2021-04-29 2022-11-03 Insmed Incorporated Certains n-(1-cyano-2-phényléthyl)-1,4-oxazépane-2-carboxamides pour le traitement de la fibrose kystique
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US12059424B2 (en) 2018-03-01 2024-08-13 Astrazeneca Ab Pharmaceutical compositions comprising (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

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US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
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WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
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WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013050721A1 (fr) * 2011-10-07 2013-04-11 Pharmamens Composés piégeurs d'alpha-oxoaldéhydes et d'aldéhydes alpha, béta-insaturés, compositions les contenant et leurs utilisations dans des traitements de maladies liées à l'accumulation des age et ale
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US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
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US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
CN108164506A (zh) * 2018-02-02 2018-06-15 上海交通大学 一种dpp-4酶抑制剂及其制备和应用
CN108164506B (zh) * 2018-02-02 2021-03-16 上海交通大学 一种dpp-4酶抑制剂及其制备和应用
US12059424B2 (en) 2018-03-01 2024-08-13 Astrazeneca Ab Pharmaceutical compositions comprising (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
US11998553B2 (en) 2018-07-17 2024-06-04 Insmed Incorporated Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating lupus nephritis
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