WO2006040300A1 - Derives de 4-cycloalkyl-pyrimidine-2-carbonitrile - Google Patents

Derives de 4-cycloalkyl-pyrimidine-2-carbonitrile Download PDF

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Publication number
WO2006040300A1
WO2006040300A1 PCT/EP2005/055091 EP2005055091W WO2006040300A1 WO 2006040300 A1 WO2006040300 A1 WO 2006040300A1 EP 2005055091 W EP2005055091 W EP 2005055091W WO 2006040300 A1 WO2006040300 A1 WO 2006040300A1
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Prior art keywords
pyrimidine
alkyl
carbonitrile
cycloalkyl
propyl
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PCT/EP2005/055091
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English (en)
Inventor
Jiaqiang Cai
Zoran Rankovic
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N.V. Organon
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Publication of WO2006040300A1 publication Critical patent/WO2006040300A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links

Definitions

  • the invention relates to 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives, to pharmaceutical compositions comprising the same, as well as to the use of these derivatives for the preparation of a medicament for the treatment of cathepsin K related diseases such as osteoporosis and atherosclerosis.
  • Cysteine proteases represent a class of peptidases characterised by the presence of a cysteine residue in the catalytic site of the enzyme, and these proteases are associated with the normal degradation and processing of proteins. Many pathological disorders or diseases are the results of abnormal activity of cysteine proteases such as over expression or enhanced activation.
  • the cysteine cathepsins e.g. cathepsin B, K, L, S 1 V, F, are a class of lysosomal enzymes which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors, coronary disease, atherosclerosis, autoimmune diseases and infectious diseases.
  • Cathepsin K has strong collagenolytic, elastase and gelatinase activities (Bromme et al., J. Biol, Chem, 271, 2126-2132, 1996) and is predominantly expressed in osteoclasts (Bromme and Okamoto, Biol. Chem. Hopp-Seyler, 376, 379-384, 1995). It cleaves key bone matrix proteins, including collagen type I and Il (Kaffienah et al., Biochem. J. 331., 727-732, 1998), gelatine, osteopontin and osteonectin, and as such is involved in extracellular matrix metabolism necessary for normal bone growth and remodelling (Bossard et al., J. Biol. Chem.
  • Cathepsin K inhibitors may therefore represent new therapeutic agents for the treatment of disease states in man such as osteoporosis.
  • Inhibition of cathepsins K and/or S at sites of plaques prone to rupture may thus represent an effective way of preventing such events.
  • 4-Amino-pyrimidine-2-carbonitrile derivatives have been disclosed as inhibitors of cathepsins K in the International Patent Application WO 03/020278 (Novartis Pharma GMBH) and WO04/020441 (Novartis Pharma GMBH), while structurally related 4- amino-pyrimidine-2 carbonitrile derivatives were recently disclosed in WO04/000819 (ASTRAZENECA AB) as Cathepsin S inhibitors.
  • R 2 is (Ci -6 )alkyl, optionally substituted with one or more halogens, OH, (d -4 )alkyloxy or NR 3 R 4 ;
  • R 3 and R 4 are independently H, (Ci -4 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(Ci -4 )alkyl, (C 6- io)aryl, (C 6- i 0 )aryl(Ci -4 )alkyl, (C 2-9 )heteroaryl, (C 2-9 )heteroaryl(Ci -4 )alkyl or (Ci -4 )- alkyl substituted with a 4-8 membered saturated heterocyclic ring comprising 1-3 heteroatoms selected from O, S and NR 5 ; or
  • R 3 and R 4 together with the nitrogen to which they are bound form a 4-8 membered saturated heterocyclic ring, which ring optionally comprises NR 5 , and which ring is optionally substituted with (C 6- io)aryl, (C 6- io)aryloxy, (C 6- io)aryl(Ci -4 )alkyloxy, (C 2-9 )- heteroaryl, NR 61 R 7 , CONR 6 R 7 or NR 6 COR 7 ;
  • R 5 is H, (Ci -4 )alkyl, (C 6- i 0 )aryl, (C 6- i 0 )aryl(Ci -4 )alkyl, (C 2-5 )heteroaryl or (C 2-5 )- heteroaryl(Ci -4 )alkyl;
  • R 6 and R 7 are independently H or (Ci -4 )alkyl; or a pharmaceutically acceptable salt thereof; are inhibitors of cathepsin K and can therefor be used for the preparation of a medicament for the treatment of osteoporosis, atherosclerosis and related Cathepsin K dependent disorders.
  • the term (d -6 )alkyl as used in the definition of formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, pentyl, 3-methyl-butyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
  • a preferred (Ci -6 )alkyl, as used in the definition of R 2 in formula I, is n-propyl.
  • the term (Ci -4 )alkyl means a branched or unbranched alkyl group having 1-4 carbon atoms, like butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
  • (C 3-8 )cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, such as cyclooctyl, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl
  • (C 6- io)aryl means a radical derived from an aromatic group having 6-10 carbon atoms like for example phenyl and naphthyl.
  • (C 6- io)aryl(Ci -4 )alkyl means a (Ci -4 )alkyl group which is substituted with a (C 6- io)aryl group, like for example the benzyl group.
  • (C 2-9 )heteroaryl means a 5 or 6-membered cyclic aromatic group having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzo-group.
  • Examples of (C 2-9 )heteroaryl groups are pyridyl, imidazolyl, furanyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thienyl, oxadiazolyl, quinolyl, isoquinolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, and the like.
  • Preferred heteroaryl groups are 2-pyridyl and 3-pyridyl.
  • the term (C 2-9 )heteroaryl(Ci -4 )alkyl means a (Ci -4 )alkyl group which is substituted with a (C 2-9 )heteroaryl group, like for example a pyridin-4-ylmethyl group.
  • (C 2-5 )heteroaryl means a 5 or 6-membered cyclic aromatic group having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Examples of such (C 2-5 )heteroaryl groups are pyridyl, imidazolyl, furanyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thienyl and oxadizolyl.
  • R 3 and R 4 can form together with the nitrogen to which they are bound a 4-8 membered saturated heterocyclic ring, such as an azetidine, a pyrrolidine, a piperidine, or a 1 H-azepine ring.
  • Such rings may contain 1 or more additional heteroatoms selected from O, S or NR 5 to form rings such as a morpholine, a thiomorpholine, a hexahydro-1 ,4-oxazepine, a piperazine, a homo- piperazine, an imidazolidine or a tetrahydrothiazole ring.
  • halogen means F, Cl, Br, or I.
  • F is preferred.
  • a preferred halogen substituted alkyl group is trifluoromethyl.
  • Preferred in the invention are those 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives according to formula I wherein R 1 is H and R 2 is (Ci -6 )alkyl substituted with OH, one or more halogens, (Ci -4 )alkyloxy or NR 3 R 4 . Further preferred are the compounds wherein R 2 is n-propyl substituted at the 3- position with NR 3 R 4 .
  • compositions comprising a
  • the 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives of general Formula I may be prepared by, as depicted in Scheme 1, by condensation of a methyl ketone derivative having formula (II), wherein R represents a (C 5-8 )cycloalkyl group, with an ester of formula R'-OC(O)R 2 , wherein R' represents a (Ci -6 )alkyl group and R 2 is as previously defined, to form a 1 ,3-dione derivative of formula (III).
  • R' and R 2 can also be part of 5-8 membered rings formed together with the ester function to which they bound.
  • the group Ri can be introduced by alkylation of the 1 ,3-dione derivative in the presence of a base, e.g. potassium carbonate, and a suitable solvent, e.g. THF or acetone with heating, to provide a 2-alkyl-1,3-dione derivative having formula (IV).
  • a base e.g. potassium carbonate
  • a suitable solvent e.g. THF or acetone with heating
  • Cyclisation of the 1 ,3-dione (IV) with urea in the presence of an acid, e.g. concentrated aqueous hydrochloride in a suitable solvent, e.g. ethanol with heating produces the 2-hydroxy-4-cycloalkyl-pyrimidine derivative of formula (V).
  • a 1 ,3-dione derivative of formula (IV) is treated with S-methyl isothiourinium iodide neat or in a suitable solvent, e.g. isopropanol, and a suitable base, e.g. triethyl amine, to give a 2-methylsulfanyl-4- cycloalkyl-pyrimidine derivative of formula (VIII).
  • a suitable solvent e.g. isopropanol
  • a suitable base e.g. triethyl amine
  • the 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives of general Formula I, wherein R 2 represents a (d -6 )alkyl group substituted with NR 3 R 4 , can advantageously be prepared starting from the corresponding alcohol derivative as depicted in scheme 4 for compounds of the invention in which R 2 represent a 3-OH-propyl substituent.
  • Oxidation of the pertinent alcohol derivative of fomula (I) with Dess-Martin periodinane, or using an alternative oxidation procedure provides the corresponding aldehyde derivative according to formula (X), which is subsequently condensed with an amine of formula HNR 3 R 4 under reductive amination conditions to produce said 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives of the invention.
  • the compounds of the invention which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid,
  • Compounds of the invention may exist in solvated as well as in unsolvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Compounds of the present invention may exist as amorphous forms, but also multiple crystalline forms may be possible. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of this invention.
  • the 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives of the invention and their salts may contain a centre of chirality in one or more of the side chains R 1 -R 5 , and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers.
  • Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction or starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers or enantiomers using chromatography on chiral media. Such methods are for example described in Chirality in Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley).
  • the compounds of the inventioin were found to be inhibitors of human Cathepsin K and can therefore in a further aspect of the invention be used in therapy, and especially for the preparation of a medicament for the treatment of osteoporosis, atherosclerosis and related Cathepsin K dependent disorders.
  • the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg per kg body weight.
  • a daily dosage of 0.001-100 mg per kg body weight preferably 0.01-10 mg per kg body weight.
  • the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • Example 4 The procedure described in Example 4 was further applied, using the appropriate amine derivatives, to prepare the compounds of Examples 5-30:
  • the inhibitory activity of the compounds of the invention was demonstrated in vitro by measuring the inhibition of recombinant human Cathepsin K as follows: To a 384 well microtitre plate is added 5 ⁇ l of a 100 ⁇ M solution of test compound in assay buffer (10OmM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol) with 10% dimethylsulfoxide (DMSO), plus 10 ⁇ l of 100 ⁇ M solution of the substratre Z-Phe- Arg-AMC (Bachem; 7-amido-coumarine derivative of the dipeptide N-benzyloxy- carbonyl-Phe-Arg-OH) in assay buffer and 25 ⁇ l of assay buffer.
  • assay buffer 10OmM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol
  • DMSO dimethylsulfoxide
  • Compounds of the invention typically have a plC 50 (negative logarithm of the IC 50 concentration) for inhibition of human cathepsin K of more than 6, preferably more than 7 such as for the compounds of Examples ⁇ _, 3, 4, 5, 6, 7, 8, 9, ⁇ 7_, 23, and most preferably a plC 50 of more than 8, such as for the compounds of Examples 12, 15, 25, and 30.
  • a plC 50 negative logarithm of the IC 50 concentration

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  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des dérivés de 4-cycloalkyl-pyrimidine-2-carbonitrile représentés par la formule générale (I), dans laquelle n est 0, 1, 2 ou 3, R1 est H ou (C1-6)alkyle, R2 est (C2-6)alkyle éventuellement substitué par un ou plusieurs halogènes, OH, (C1-4)alkyloxy ou NR3R4, R3 et R4 sont indépendamment H, (C1-4)alkyle, (C3-8)cycloalkyle, (C3-8)cycloalkyl(C1-4)alkyle, (C6-10)aryle, (C6-10)aryl(C1-4)alkyle, (C2-9)hétéroaryle, (C2-9)hétéroaryl(C1-4)alkyle ou (C1-4)alkyle substitué par un noyau hétérocyclique saturé à 4 à 8 éléments comprenant entre 1 et 3 hétéroatomes choisis parmi O, S et NR5, ou R3 et R4, conjointement avec l'azote auquel ils sont liés, forment un noyau hétérocyclique saturé à 4 à 8 éléments, ce noyau comprenant éventuellement NR5, ledit noyau étant éventuellement substitué par (C6-10)aryle, (C6-10)aryloxy, (C6-10)aryl(C1-4)alkyloxy, (C2-9)hétéroaryle, NR6R7, CONR6R7 ou NR6COR7, R5 est H, (C1-4)alkyle, (C6-10)aryle, (C6-10)aryl(C1-4)alkyle, (C2-5)hétéroaryle or (C2-5)hétéroaryl(C1-4)alkyle, et R6 et R7 sont indépendamment H ou (C1-4)alkyle, ou un sel pharmaceutiquement acceptable correspondant. L'invention concerne également des compositions pharmaceutiques comprenant ces composés ainsi que leur utilisation dans le traitement de l'ostéoporose, de l'athérosclérose et de troubles associés.
PCT/EP2005/055091 2004-10-12 2005-10-07 Derives de 4-cycloalkyl-pyrimidine-2-carbonitrile WO2006040300A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7439240B2 (en) 2002-06-24 2008-10-21 Astrazeneca Ab Purine-or pyrrolol[2,3-d]pyrimidine-2-carbonitiles for treating diseases associated with cysteine protease activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020278A1 (fr) * 2001-08-30 2003-03-13 Novartis Ag Inhibiteurs de cysteine protease ayant une structure de 2-cyano-4-amino-pyrimidine et une activite d'inhibition de cathepsine k, pour traiter les inflammations et autres troubles
WO2004000819A1 (fr) * 2002-06-24 2003-12-31 Astrazeneca Ab Nouvelle utilisation de pyrimidine - ou triazine- 2-carbonitiles destines au traitement de maladies liees a l'activite de protease a cysteine et nouveaux derives de pyrimidine-2-carbonitile
WO2004020441A1 (fr) * 2002-08-30 2004-03-11 Novartis Ag Derives d'hetereoaryle nitrile

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020278A1 (fr) * 2001-08-30 2003-03-13 Novartis Ag Inhibiteurs de cysteine protease ayant une structure de 2-cyano-4-amino-pyrimidine et une activite d'inhibition de cathepsine k, pour traiter les inflammations et autres troubles
WO2004000819A1 (fr) * 2002-06-24 2003-12-31 Astrazeneca Ab Nouvelle utilisation de pyrimidine - ou triazine- 2-carbonitiles destines au traitement de maladies liees a l'activite de protease a cysteine et nouveaux derives de pyrimidine-2-carbonitile
WO2004020441A1 (fr) * 2002-08-30 2004-03-11 Novartis Ag Derives d'hetereoaryle nitrile

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7439240B2 (en) 2002-06-24 2008-10-21 Astrazeneca Ab Purine-or pyrrolol[2,3-d]pyrimidine-2-carbonitiles for treating diseases associated with cysteine protease activity

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