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WO2006018284A1 - Compounds and compositions useful as cathepsin s inhibitors - Google Patents

Compounds and compositions useful as cathepsin s inhibitors Download PDF

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Publication number
WO2006018284A1
WO2006018284A1 PCT/EP2005/008896 EP2005008896W WO2006018284A1 WO 2006018284 A1 WO2006018284 A1 WO 2006018284A1 EP 2005008896 W EP2005008896 W EP 2005008896W WO 2006018284 A1 WO2006018284 A1 WO 2006018284A1
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WIPO (PCT)
Prior art keywords
alkyl
unsubstituted
substituted
phenyl
formula
Prior art date
Application number
PCT/EP2005/008896
Other languages
French (fr)
Inventor
Terance William Hart
Allan Hallett
Fumiaki Yokokawa
Hajime Hirao
Takeru Ehara
Atsuko Iwasaki
Junichi Sakaki
Keiichi Masuya
Masashi Kishida
Osamu Irie
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to BRPI0514383-7A priority Critical patent/BRPI0514383A/en
Priority to EP05782460A priority patent/EP1781623A1/en
Priority to JP2007526382A priority patent/JP2008509959A/en
Priority to US11/573,451 priority patent/US7704996B2/en
Priority to MX2007001952A priority patent/MX2007001952A/en
Priority to AU2005274319A priority patent/AU2005274319A1/en
Priority to CA002575826A priority patent/CA2575826A1/en
Publication of WO2006018284A1 publication Critical patent/WO2006018284A1/en

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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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel 2-cyano-pyrimidine derivatives, their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such compounds for the manufacture of a pharmaceutical preparation for the treatment of pain and to a method for the treatment of such a disorder in warm-blooded animals, especially in humans.
  • the 2-cyano-pyrimidine derivatives described herein have advantageous pharmacological properties and inhibit, for example, the activity of cathepsin S enzymes.
  • the 2-cyano-pyrimidine derivatives of formula I are hence suitable to be used in the treatment of diseases wherein the inhibition of cathepsin S activity causes a beneficial effect.
  • the 2-cyano-pyrimidihe derivatives of formula I are suitable, in particular, for the treatment and in the prevention of neuropathic pain and other diseases mentioned hereinafter.
  • the present invention relates to 2-cyano-pyrimidines of formula
  • R 1 denotes a radical of formula
  • A, E and G independently of each other represent O, S or CH 2 , under the proviso that at least one of A and E represents CH 2 ; T is O, S or a bond, if G is CH 2 , and T is a bond, if G is O or S;
  • Ra, Rb and Rc independently of each other represent hydrogen or d-C 4 alkyl; s is O 1 1 or 2, t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
  • R 2 denotes halogen, C 1 -C 4 alkyl, unsubstituted or substituted aryl, 5 or 6 membered heterocyclyi, -C(O)NR 4 R 5 , -NHC(O)R 4 or -CH 2 NHC(O)R 4 , wherein
  • R 4 represents
  • Ci-C 7 alky! which is unsubstituted or substituted by halogen; amino, which is mono- or disubstituted by C 3 -C 5 cycloalkyl or C r C 6 aIkyl which in each case are unsubstituted or mono-, di- or trisubstituted by halogen; unsubstituted or substituted C 4 -C 8 -aliphatic heterocyclyi comprising at least one nitrogen atom; unsubstituted or substituted aryl; unsubstituted or substituted hetaryl; unsubstituted or substituted spiro[4.5]decane which comprises 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur; unsubstituted or substituted C 3 -C 6 cycloalkyl; or 1-aza-(C 5 -C ⁇ )bicycloalkyl;
  • R 4 and R 5 together with the nitrogen to which they are attached represent unsubstituted or substituted C 4 -Ca-aliphatic heterocyclyi comprising at least one nitrogen atom; or
  • R 2 denotes -N(R 9 )SO 2 Ri 0 ,
  • R 9 represents hydrogen or C r C 4 aIkyl
  • Rio represents C 1 -C 4 alkyl, which is unsubstituted or substituted by aryl; or
  • R 9 and R 10 together form a radical -(CRR') m -, wherein m is an integer from and including 2 up to and including 5 and R and R' both represent independently of each other hydrogen or
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 or NR 7 R 8 wherein
  • Y represents O, CH 2 , S, SO, SO 2 or NR N , wherein R N denotes hydrogen or CrC 4 alkyl which is unsubstituted or substituted by CrC 4 alkoxy;
  • R 6 represents CrC 6 alkyl, phenyl, five or six-membered nitrogen containing hetaryl-(CH 2 ) q -, wherein q is an integer from O to 4, or five or six-membered aliphatic heterocyclyl-(CH 2 ) n -, wherein n is an integer from O to 4 and the heterocyclyi moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R 7 and R 8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom;
  • X denotes O, HN, C r C 4 alkyl-N, S, SO, SO 2 , 0(CH 2 ) g NH, wherein g is 1 or 2, (CH 2 ),,, wherein h is 1 or 2, or aryl, which is unsubstituted or mono-, di- or trisubstituted by halogen, C 1 -
  • Halogen or halo is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
  • Alkyl is especially alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, C atoms and is linear or branched; preferably, alkyl is methyl, ethyl, propyl, such as n-propyl or isopropyl, butyl, such as n-butyl, sec-butyl, isobutyl or tert- butyl.
  • Alkoxy is especially methoxy, ethoxy or propoxy.
  • Cycloalkyl is especially C 3 -C 6 cycloalkyl, namely cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Aliphatic heterocyclyl comprising at least one nitrogen atom is especially a five or six- membered heterocyclic radical with one ring nitrogen atom and optionally further 1 or 2 ring heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be wholly or partly saturated, preferably imidazolidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, and which radical can be unsubstituted or substituted.
  • aryl is preferably a mono-, bi- or tricyclic aromatic hydro ⁇ carbon group with 6 to 14 ring carbon atoms, especially phenyl, naphthyl or fluorenyl, more preferably phenyl.
  • Hetaryl as used herein is especially thienyl, pyrrolyl, furyl, oxazolyl, isoxazolyl, isothiazolyl, thiazoyl, pyrazolyl, imidazolyl, benzimidazolyl, benzthiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, more preferably thienyl, furyl, pyridinyl and pyrazolyl.
  • unsubstituted or substituted means that the respective radical is unsubstituted or substituted by one or more, preferably up to four, especially one or two substituents, selected from oxo, amino, CrC 4 alkyl amino, di(C r C 4 alky)-amino, hydroxy-C r C 4 alkyl amino, phenyl-C r C 4 alkyl amino, C 3 -C 5 cycloalkyl amino, di(C 3 -C 5 )cycloalkyl amino, N-CrC 4 alkyl-N-C 3 -C 5 cycloalkyl amino, CrC 4 aIkanoyl amino, halogen, hydroxy, CrC 4 alkoxy, unsubstituted or substituted C 3 -C 6 cycloalkyl, C 3 - C 5 cycloalkyloxy, C 1 ⁇ aIkOXy Ci-C 4 alkoxy, di(
  • C 4 -C 8 heterocyclyloxy e.g. tetrahydropyranyloxy, unsubstituted
  • any reference to the free com ⁇ pounds hereinbefore and hereinafter is to be understood as referring also to the correspon ⁇ ding salts, as appropriate and expedient.
  • Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharma ⁇ ceutically acceptable salts.
  • pharmaceutically unacceptable salts for example picrates or perchlorates.
  • only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • the compounds of formula I exhibit valuable pharmacological properties in mammals and are particularly useful as inhibitors of cathepsin S.
  • the cathepsin S inhibitory effects of the compounds of formula I can be demonstrated in vitro by measuring the inhibition of e.g. recombinant human cathepsin S (in vitro cathepsin S assay).
  • the in vitro assay is carried out in clear, flat-bottomed, 96-well microtiter plates (Greiner GmbH, Germany) at ambient temperature using recombinant human cathepsin S.
  • Inhibition of human cathepsin S is assayed at a constant enzyme and various substrate concentrations (substrate is Z-Leu-Leu-4-methylcoumaryl-7-amide (Bachem (Switzerland)) in 100 parts 0.2M sodium phosphate, pH 7.0, containing 2 mM EDTA, 2 parts 1% Triton X-100, 10 parts 20 mM dithiothreitol (DTT) and 58 parts distilled water.
  • the assay is started by adding the enzyme solution (13 times higher concentration of final concentration of recombinant human Cathepsin S) to the reaction mixture containing various concentrations of the corresponding substrate and the compound. Substrate concentrations between 3.4 and 17 ⁇ M are used. The recombinant human Cathepsin S is used at a final concentration of 0.04 nM. Test compounds are used at concentrations between 0.4 and 2 times the determined IC50 of the compound at the enzyme. The relative fluorescence is continuously measured for 30 minutes and the initial velocity is obtained from each progress curve. The inhibition patterns and the Ki values are determined by Dixon plot analysis.
  • Compounds of formula I typically have IC 50 S for inhibition of human cathepsin S of less than about 350 nM down to about 1 nM or less, preferably of about 50 nM or less.
  • compounds of formula I are particularly useful in mammals as agents for the treatment and prophylaxis of diseases and medical conditions involving elevated levels of cathepsin S activity.
  • diseases include chronic neuropathic pain, exemplified by conditions such as diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful diabetic polyneuropathy, post-stroke pain (central pain), postamputation pain, myelopathic or radiculopathic pain (e.g. spinal stenosis, arachnoiditis, root sleeve fibrosis), atypical facial pain and causalgia-like syndromes (complex regional pain syndromes).
  • chronic neuropathic pain exemplified by conditions such as diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful diabetic polyneuropathy, post-stroke pain (central pain), postamputation pain, myelopathic or radiculopathic pain (e.g. spinal stenosis, arachnoidit
  • Cathepsin S is present in antigen presenting cells and plays a key role in events involved in antigen presentation.
  • inhibitors of cathepsin S could be useful agents in the prevention, inhibition or treatment of immune and autoimmune disorders, including, but not ' limited to asthma, rheumatoid arthritis, multiple sclerosis, systemic lupus erythmatosus, psoriasis and Crohn's disease and for the prevention, inhibition or treatment of tissue transplant rejection.
  • cathepsin S can be secreted by some antigen presenting cells and thus play a role in extracellular matrix interactions. Therefore, cathepsin S inhibitors could be useful agents in the prevention, inhibition or treatment of neurodegenerative diseases with a possible inflammatory component, Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), HIV neuropathy, diabetic neuropathies, Guillain - Barre syndrome, CIPD (Chronic inflammatory demyelinating polyradiculoneuropathy), other demyelinating diseases, meningitis, brain/spinal cord trauma, stroke, schizophrenia.
  • neurodegenerative diseases with a possible inflammatory component, Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), HIV neuropathy, diabetic neuropathies, Guillain - Barre syndrome, CIPD (Chronic inflammatory demye
  • Cathepsin S inhibitors could be useful agents in the prevention, inhibition or treatment of a variety of other diseases involving extra-cellular proteolysis such as the development of emphysema in chronic obstructive pulmonary disease, atherosclerosis, restenosis and tumor cell invasion.
  • Cathepsin S is present in inflammatory cells and cathepsin S inhibitors could be useful agents compounds for the treatment of Creutzfeldt-Jakob Disease, interstitial cystitis, inflammatory bowel disease and vasculitic disorders.
  • Beneficial effects are evaluated in in vitro and in vivo pharmacological tests generally known in the art, and as illustrated herein.
  • the above cited properties are demonstrable in in vitro and in vivo tests, using advantageously mammals, e.g. rats, mice, dogs, rabbits, monkeys or isolated organs and tissues, as well as mammalian enzyme preparations, either natural or prepared by e.g. recombinant technology.
  • Compounds of formula I can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions or suspensions, and in vivo either enterally or parenterally, advantageously orally, e.g. as a suspension or in aqueous solution, or as a solid capsule or tablet formulation.
  • the dosage in vitro may range between about 10 "5 molar and 10 '9 molar concentrations.
  • the dosage in vivo may range, depending on the route of administration, between about 0.1 and 100 mg/kg.
  • the efficacy of the compounds of formula I for the treatment of chronic inflammatory or neuropathic pain can be determined using the following In vivo animal models:
  • the intraplantar injection of zymosan -induced mechanical hyperalgesia may be used as a model of chronic inflammatory pain (Meller et al, Neuropharmacology 33:1471-1478, 1994).
  • a male Sprague-Dawley or Wistar rat 200-250 g receives an intraplantar injection of 3 mg/100 ⁇ l zymosan into one hind paw.
  • a marked inflammation occurs in this hind paw.
  • Drugs are generally administered for evaluation of efficacy, 24 hours after the inflammatory insult, when mechanical hyperalgesia is considered fully established.
  • the Chung model involves ligation of the spinal nerve.
  • rats are anesthetized and placed into a prone position and an incision is made to the left of the spine at the L4-S2 level.
  • a deep dissection through the paraspinal muscles and separation of the muscles from the spinal processes at the L4-S2 level will reveal part of the sciatic nerve as it branches to form the L4, L5 and L6 spinal nerves.
  • the L6 transverse process is carefully removed with a small rongeur enabling visualisation of these spinal nerves.
  • the L5 spinal nerve is isolated and tightly ligated with 7-0 silk suture.
  • the wound is closed with a single muscle suture (6-0 silk) and one or two skin closure clips and dusted with antibiotic powder.
  • the L5 nerve is exposed as before but not ligated and the wound closed as before.
  • % reversal — X 100 naive threshold - predose threshold
  • Wistar rats male
  • Rats weigh approximately 120-140 grams at the time of surgery. All surgery is performed under enflurane/O 2 inhalation anaesthesia. In all cases the wound is closed after the procedure and the animal allowed to recover.
  • a marked mechanical and thermal hyperalgesia and allodynia develops in which there is a lowering of pain threshold and an enhanced reflex withdrawal response of the hind-paw to touch, pressure or thermal stimuli. After surgery the animals also exhibit characteristic changes to the affected paw.
  • the efficacy of the compounds of the invention for the treatment of osteoarthritis can be determined using models such as or similar to the rabbit partial lateral meniscectomy model, as described previously (Colombo et al. Arth. Rheum. 1993 26, 875-886).
  • the efficacy of the compounds in the model can be quantified using histological scoring methods, as described previously (O'Byrne et al. lnflamm Res 1995, 44, S117-S118).
  • a compound of formula I can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined admini ⁇ stration of fixed combinations and one or more other therapeutic agents.
  • a combination which comprises a cathepsin S inhibitor as disclosed herein and gabapentin, pregabalin, non steroidal anti-inflammatory drugs, COX-2 inhibitors, steroids, tricyclic antidepressants, other anticonvulsants (e.g carbamazepine, lamotrigine, Trileptal) or an opioid is highly suitable.
  • opioid refers to all drugs, both natural and synthetic, with morphine- like actions.
  • An opioid suitable for the present invention is especially selected from the group comprising alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitaze ⁇ e, codeine, cyclorphan, desomorphine, dextro- moramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, eptazocine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, levo- phenacylmorphan, levorphanol, lofentanil, methylmorphine, morphine, necomorphine, normethadone, normorphine, opium, oxycodone, oxymorphone, pholcodine, profadol
  • alfentanil can be administered, e.g., in the form as marketed, e.g. under the trademark RapifenTM; allylprodine can be administered, e.g., in the form as marketed, e.g. under the trademark AlperidineTM; anileridine can be administered, e.g., in the form as marketed, e.g. under the trademark LeritineTM; benzylmorphine can be administered, e.g., in the form as marketed, e.g. under the trademark PeronineTM; bezitramide can be administered, e.g., in the form as marketed, e.g.
  • buprenorphine can be administered, e.g., in the form as marketed, e.g. under the trademark BuprenexTM; butorphanol can be administered, e.g., in the form as marketed, e.g. under the trademark TorateTM; dextromoramide can be administered, e.g., in the form as marketed, e.g. under the trademark PalfiumTM; dezocine can be administered, e.g., in the form as marketed, e.g. under the trademark DalganTM; dihydrocodeine can be administered, e.g., in the form as marketed, e.g.
  • dihydromorphine can be administered, e.g., in the form as marketed, e.g. under the trademark ParamorphanTM
  • eptazocine can be administered, e.g., in the form as marketed, e.g. under the trademark SedapainTM
  • ethylmorphine can be administered, e.g., in the form as marketed, e.g. under the trademark DioninTM
  • fentanyl can be administered, e.g., in the form as marketed, e.g. under the trademark FentanestTM or LeptanalTM
  • hydrocodone can be administered, e.g., in the form as marketed, e.g.
  • hydromorphone can be administered, e.g., in the form as marketed, e.g. under the trademark NovolaudonTM
  • hydroxypethidine can be administered, e.g., in the form as marketed, e.g. under the trademark BemidoneTM
  • levorphanol can be administered, e.g., in the form as marketed, e.g. under the trademark DromoranTM
  • normethadone can be administered, e.g., in the form as marketed, e.g. under the trademark TicardaTM
  • oxycodone can be administered, e.g., in the form as marketed, e.g.
  • DihydroneTM and oxymorphone can be administered, e.g., in the form as marketed, e.g. under the trademark NumorphanTM.
  • NumorphanTM e.g., a trademark of Numorphan
  • R 1 denotes a radical of formula
  • a and G both represent O or both represent CH 2 , E is CH 2 and T is a bond;
  • Ra, Rb and Rc all represent hydrogen; s is 0 or 1 , t is 1 or 2, more preferably 1 , and p is 1 ;
  • R 2 preferably denotes -C(O)-NR 4 R 5 , -N(Rg)-SO 2 -Ri O , bromo, chloro, C 1 -C 4 alkyl, in particular isopropyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing at least one oxygen atom;
  • R 3 preferably denotes hydrogen, Y-R 6 , NR 7 R 8 or CrC 4 alkyl, more preferably Y-R 6 or NR 7 R 8 ;
  • R 4 preferably represents
  • phenyl which is mono-, di- or trisubstituted by phenyl, C 3 -C 5 cycloalkyloxy, Ci-C 4 alkoxy, Ci-C 4 alkoxy Crdalkoxy, CrC 4 alkoxy phenyl, di(C r C 4 alkyl)-amino CrC 4 alkoxy, N-(C 1 - C 4 alkyl) piperazinyl, N-(C r C 4 alkyl) piperidinyloxy or N-(C r C 4 alkyl) piperidinyl C r C 4 alkoxy;
  • R 9 preferably represents hydrogen or Ci-C 4 alkyl
  • R 10 preferably represents CrC 4 alkyl, which is unsubstituted or substituted by phenyl;
  • X preferably denotes HN, C r C 4 aikyI-N or O;
  • Y preferably represents O or NH.
  • pyridyl is preferably unsubstituted or mono-, di- or trisubstituted by halogen, CrC 4 alkyl or piperazinyl.
  • CVC 7 alkyl preferably is unsubstituted or substituted by amino, which is mono- or disubstituted by C 3 -C 5 cycloalkyl or CrC 6 alkyl which in each case is unsubstituted or mono-, di- or trisubstituted by halogen; C 4 -C 8 -aliphatic heterocyclyl comprising at least one nitrogen atom, which radical is unsubstituted or mono-, di- or trisubstituted by CrC 4 alkyl, halogen, C r C 4 alkoxy, CrC 4 alkoxy Ci-C 4 alkyl, C r C 4 alkyl amino, phenyl, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, morpholinyl, C 4 -C 6 cycloalkyl or C 1 - C 6 alkyl which is mono-, di- or trisubstituted by hydroxy or halogen; or
  • N-(CrC 4 alkyl) piperidinyl is preferably substituted by phenyl;
  • phenyl is preferably mono-, di- or trisubstituted by phenyl, C 3 -C 5 cycloalkyloxy, C 1 - C 4 alkoxy, C r C 4 alkoxy CrGjalkoxy, C r C 4 alkoxy phenyl, di(C r C 4 alkyl)-amino C 1 - C 4 alkoxy, N-(CrC 4 alkyl) piperazinyl, N-(CrC 4 alkyl) piperidinyloxy or N-(Ci -C 4 alkyl) piperidinyl C r C 4 alkoxy;
  • C 3 -C 6 cycloalkyl is preferably unsubstituted
  • isoxazolyl, imidazolyl or pyrazolyl is preferably unsubstituted or mono- or disubstituted by pyridyl or phenyl;
  • N-(C r C 6 aikyl) piperidinyl or N-(C 4 -C 6 cycloalkyl) piperidinyl are preferably substituted by phenyl CrC 4 alkyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted by halogen.
  • R 4 and R 5 together with the nitrogen to which they are attached represent pyrrolidinyl or piperidinyl, such radical is preferably unsubstituted or mono-, di- or trisubstituted by hydroxy, CrC 4 alkoxy or C r C 4 alkyl.
  • CrC 6 alkyl is preferably unsubstituted or mono-, di- or trisubstituted by pyridyl, Cr C 4 alkyl pyridyl, imidazolyl, C-i-C 4 alkyl imidazolyl, phenyl, hydroxy phenyl, hydroxy, C 1 - C 4 alkoxy, C r C 4 alkoxy carbonyl, hydroxy C r C 4 alkyl amino, Ci-C 4 alkyl-amino, di-(C r C 4 alkyl)- amino, C r C 4 alkanoyl-amino, phenyl-C r C 4 alkyl amino, C r C 4 alkylthio, morpholinyl, morpholinyl carbonyl, 2-oxo-imidazolidinyl, 2-oxo-pyrrolidinyI, C 5 -C 7 cycloalkyI-amino, C 3 - C 5 cycl
  • RQ represents (a) CrCealkyl, which is unsubstituted or substituted by di-(C r C 4 alkyl)-amino, N-(CrC 4 aikyl) piperazinyl or hydroxy, or (b) N-(Q)- piperidinyl-(CH 2 )n-, wherein n is an integer from 0 to 4, and Q is hydrogen, d-C 4 alkyl or N- (C r C 4 alkyl) piperidinyl.
  • R 7 and R 8 together with the nitrogen to which they are attached represent piperidinyl, which is unsubstituted or substituted by C r C 4 alkyl, hydroxy, aminocarbonyl, amino C r C 4 alkyl, hydroxy C r C 4 alkyl, or unsubstituted or substituted by C 4 -C 8 aliphatic heterocyclyl, morpholinyl or thiomorpholinyl which is unsubstituted or substituted by C f -C 4 alkyl or oxo; piperazinyl, which is unsubstituted or substituted by CrC 4 alkyl or Ci-C 4 alkoxy CrC ⁇ Ikyl, or pyrrolidinyi, which is unsubstituted or substituted by hydroxy Ci-C 4 alkyl, C r C 4 alkoxy C 1 - C 4 alkyl, formyl, di-C r C 4 alkyl amino, Ci-C 4 alkyl amino,
  • R 7 and R 8 together with the nitrogen to which they are attached represent piperidinyl, such radical is preferably substituted by N-(C 1 -C 4 alkyl) piperazinyl.
  • C r C 4 alkyl is preferably unsubstituted or substituted by phenyl.
  • phenyl is preferably unsubstituted or mono-, di- or trisubstituted by halogen, d-dalkyl or Ci-C 4 alkoxy.
  • the invention relates in particular to 2-cyano-pyrimidines of formula I wherein R 1 denotes a radical of formula
  • A, E and G independently of each other represent O, S or CH 2 , under the proviso that at least one of A and E represents CH 2 ; T is O, S or a bond, if G is CH 2 , and T is a bond, if G is O or S; Ra, Rb and Rc independently of each other represent hydrogen or CrC 4 alkyl; s is O or 1 , t is 1 , 2, 3 or 4 and p is 0, 1 or 2; R 2 denotes halogen, C 1 -C 4 alkyl, unsubstituted or substituted phenyl, 5 or 6 membered heterocyclyl, -C(O)NR 4 R 5 , -NHC(O)R 4 , -CH 2 NHC(O)R 4 or -N(R 9 )SO 2 R 10 , wherein R 4 represents
  • phenyl which is mono-, di- or trisubstituted by phenyl, C 3 -C 5 cycloalkyloxy, C 1 - C 4 alkoxy, C r C 4 alkoxy CrC 4 alkoxy, CrC 4 alkoxy phenyl, di(CrC 4 alkyl)-amino C 1 - C 4 alkoxy, N-(C r C 4 alkyl) piperazinyl, N-(C r C 4 alkyl) piperidinyloxy or N-(C 1 - C 4 alkyl) piperidinyl CrC 4 alkoxy;
  • R 5 represents hydrogen or CrC 4 alkyl
  • R 4 and R 5 together with the nitrogen to which they are attached represent pyrrolidinyl or piperidinyl which is unsubstituted or substituted by hydroxy;
  • R 9 represents hydrogen or Ci-C 4 alkyl;
  • R 10 represents C r C 4 alkyl, which is unsubstituted or substituted by phenyl; or R 9 and R 10 together form a radical -(CRR 1 Jm-, wherein m is an integer from and including 2 up to and including 4 and R and R 1 both represent hydrogen; R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or monosubstituted by halogen or piperazinyl, Y-R 6 or NR 7 R 8 wherein
  • Y represents O, CH 2 , S, SO, SO 2 or NR N , wherein RN denotes hydrogen or C r C 4 alkyl which is unsubstituted or substituted by Ci-C 4 alkoxy;
  • R 6 represents CrC 6 alkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH 2 ) q -, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl-(CH 2 ) n -, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R 7 and R 8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom;
  • X denotes O, HN 1 C r C 4 alkyl-N, S, SO, SO 2 , OCH 2 CH 2 NH, CH 2 or phenyl, which is unsubstituted or monosubustituted by halogen; or
  • A, E and G independently of each other represent O, S or CH 2 , under the proviso that at least one of A and E represents CH 2 ;
  • T is O, S or a bond, if G is CH 2 , and T is a bond, if G is O or S;
  • Ra, Rb and Rc independently of each other represent hydrogen or CrC 4 alkyl;
  • s is O or 1
  • t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
  • R 2 denotes bromo, chloro, C 1 -C 4 alkyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing at least one oxygen atom, -C(O)-NR 4 R 5 or -N(R 9 )-S0 2 -Rio ⁇ wherein R 4 represents
  • phenyl which is mono-, di- or trisubstituted by phenyl, C 3 -C 5 cycloalkyloxy, C r C 4 alkoxy, C r C 4 alkoxy C r C 4 alkoxy, CrC 4 alkoxy phenyl, di(CrC 4 alkyl)-amino C 1 - C 4 alkoxy, N-(C r C 4 alkyl) piperazinyl, N-(C r C 4 alkyl) piperidinyloxy or N-(C 1 - C 4 alkyl) piperidinyl CrC 4 alkoxy;
  • R 5 represents hydrogen or C r C 4 alkyl
  • R 4 and R 5 together with the nitrogen to which they are attached represent pyrrolidinyl
  • R 9 represents hydrogen or C r C 4 alkyl
  • R 10 represents CrC ⁇ lkyl, which is unsubstituted or substituted by phenyl; or
  • R 9 and R 10 together form a radical -(CRR') m -, wherein m is an integer from and including 2 up to and including 4 and R and R' both represent hydrogen; R 3 denotes hydrogen, Y-R 6 or NR 7 R 8 wherein
  • Y represents O or NR N , wherein R N denotes hydrogen or C r C 4 alkyl which is unsubstituted or substituted by CrC 4 alkoxy;
  • R 6 represents CrC 6 alkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH 2 ) q -, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocycIyl-(CH 2 )n ⁇ , wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R 7 and R 8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes HN, C r C 4 alkyl-N or O; and the corresponding salts of such 2-cyano-pyrimidine.
  • A, E and G independently of each other represent O or CH 2 , under the proviso that at least one of A and E represents CH 2 ; T is O or a bond, if G is CH 2 , and T is a bond, if G is O; Ra, Rb and Rc all represent hydrogen; s is O or 1 , t is 1 or 2 and p is 1;
  • R 2 denotes bromo, chloro, isopropyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing two oxygen atoms, -C(O)-NR 4 R 5 or -N(R 9 )-S0 2 -Rio > wherein R 4 represents
  • Ci-C 4 alkyl or Ci-C 4 alkyl amino piperidinyl, which is unsubstituted or mono- or disubstituted by halogen, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C 4 -C 6 )cycloalkyl or Ci-C 6 alkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by C r C 4 alkyI or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or C r C 4 alkoxy; halogen, C 3 -Cscycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- s
  • phenyl which is mono-, di- or trisubstituted by phenyl, C 3 -C 5 cycloalkyloxy, C 1 - C 4 alkoxy, C r C 4 alkoxy d-C 4 alkoxy, C r C 4 alkoxy phenyl, di(Ci-C 4 alkyl)-amino C 1 - C 4 alkoxy, N-(C 1 -C 4 alkyl) piperazinyl, N-(C 1 -C 4 alkyl) piperidinyloxy or N-(C 1 - C 4 alkyl) piperidinyl CrC 4 alkoxy;
  • R 5 represents hydrogen or Ci-C 4 alkyl
  • R 4 and R 5 together with the nitrogen to which they are attached represent pyrrolidinyl
  • Rg represents hydrogen or Crdalkyl
  • R 1 O represents CrC 4 alkyl, which is unsubstituted or substituted by phenyl; or
  • R 9 and R 10 together form a radical -(CRR') m -, wherein m is an integer from and including 2 up to and including 4 and R and R' both represent hydrogen; R 3 denotes hydrogen, Y-R 6 or NR 7 R 8 wherein
  • Y represents O or NR N , wherein R N denotes hydrogen or C r C 4 alkyl which is unsubstituted or substituted by C r C 4 alkoxy;
  • R 6 represents CrC 6 alkyI, phenyl, five or six-membered nitrogen containg hetaryl-
  • the invention provides:
  • a method for the treatment of neuropathic pain or another disease mentioned herein which comprises administering a 2-cyano-pyrimidine of formula I or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in a quantity effective against such disease, to a warm-blooded animal requiring such treatment;
  • a pharmaceutical preparation comprising a 2-cyano-pyrimidine of formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier;
  • a method of selectively inhibiting cathepsin S activity in a mammal which comprises administering to a mammal in need thereof an effective cathepsin S inhibiting amount of a compound of formula I, more specifically this relates to a method of treating chronic inflammatory or neuropathic pain (or another disease mentioned herein) in mammals comprises administering to a mammal in need thereof a correspondingly effective amount of a compound of formula 1.
  • a compound of formula I may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se, especially a process characterized in that a) for the synthesis of a compound of the formula I wherein R 2 represents -C(O)NR 4 R 5 , R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes HN, C r C4alkyl-N, O(CH 2 ) g NH, O or S and the remaining radicals and symbols Ri, R 4 , R 5 , R 6 , R 7 , R 8 and g are as defined for a compound of the formula I 1 the 5-pyrimidyl carboxylic acid of formula Il
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes HN, Ci-C 4 alkyl-N, O(CH 2 ) g NH, O or S, and the remaining radicals and symbols R 1 , R 6 , R 7 , R 8 and g are as defined for a compound of the formula I, is reacted as defined under process variant (a) with an amine of formula III
  • R 2 represents C(O)NR 4 R 5
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes HN, CrC 4 alkyl-N, O(CH 2 ) g NH, O or S and the remaining radicals and symbols R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and g are as defined for a compound of the formula I, the 6-chloro pyrimidine derivative of formula IV
  • R 2 denotes -C(O)NR 4 R 5
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S 1 or NR 7 R 8 , and the remaining radicals R 6 , R 7 and R 8 are as defined for a compound of the formula I, is reacted as defined under process variant (b) with a compound of formula V
  • X denotes HN, CrC 4 alkyl-N, O(CH 2 ) g NH, O or S and Ri has the meaning as defined for a compound of the formula I;
  • R 2 denotes -N(R 9 )SO 2 Ri O
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O 1 NH or S 1 or NR 7 R 8 , X denotes HN, CrC 4 alkyl-N, O(CH 2 ) g NH, O or S and the remaining radicals and symbols Ri, R 6 , R 7 , R 8 , Rg, R 10 and g are as defined for a compound of the formula I, the 5-amino pyrimidine of formula Vl
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes HN, C r C 4 alkyl-N, O(CH 2 ) g NH, O or S and the remaining radicals and symbols R 1 , R 6 , R 7 , R 8 and g are as defined for a compound of the formula I, is reacted as defined under process variant (c) with a sulfonyl halide of formula VII
  • starting materials of formula Il to VII may also be present with functional groups in protected form, if necessary, and/or in the form of salts, provided a salt- forming group is present and the reaction in salt form is possible;
  • an obtainable compound of formula I is converted into another compound of formula I, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.
  • the amination of the carboxylic acid of formula Il can be accomplished by standard procedures known in the art, e.g., by reacting both compounds in a suitable solvent by the addition of a suitable coupling agent, such as POCI 3 , sulfuryl chloride fluoride, P 2 I 4 or, in particular, N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC-HCI) or N.N'-dicyclohexylcarbodiimide (DCC).
  • EDC-HCI N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride
  • DCC N.N'-dicyclohexylcarbodiimide
  • the reaction can be carried out, e.g., in dimethylformamide, at a temperature between about 10 °C and about 35 0 C, e.g. about 20 to 24 0 C, for a period
  • the reaction preferably takes place under standard conditions useful in the nucleophilic re ⁇ placement of leaving groups with amino compounds.
  • the 6-chloro pyrimidine derivative of formula IV can be reacted with the nucleophil of formula V in the presence of a base in a suitable solvent.
  • a base e.g. a nitrogen base, such as triethylamine, or a basic salt, such as an alkali metal carbonate, e.g.
  • potassium carbonate to the starting materials of formula IV and V in a suitable solvent; such as an ether, for example dioxane or tetrahydrofurane, or nitriles, such as acetonitrile, and heating the reaction mixture to about reflux temperature of the solvent for a period of about 6 to 12 hours, especially between 8 hours and 10 hours.
  • a suitable solvent such as an ether, for example dioxane or tetrahydrofurane, or nitriles, such as acetonitrile
  • the sulfonylamide of formula I wherein R 2 denotes -N(R 9 )SO 2 RiO can be prepared by adding the sulfonylhalide of formula VII to a solution of the amine of formula Vl in a suitable solvent such as dichloromethane or chloroform in the presence of an equimolar amount of pyridine or a similar base and, optionally, catalytic amounts of dimethylamino pyridine, at a temperature between about 10 0 C and about 50 0 C, e.g. between about 20 and 25 0 C, for a period of about 1 to 12 hours, e.g. between 2 hours and 6 hours.
  • a suitable solvent such as dichloromethane or chloroform
  • protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
  • the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
  • Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • a salt with two acid mo ⁇ lecules (for example a dihalogenide of a compound of formula I) may also be converted into a salt with one acid molecule per compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 130 to 170°C, one molecule of the acid being ex ⁇ pelled per molecule of a compound of formula I.
  • Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • All process steps described here can be carried out under known reaction conditions, pre ⁇ ferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralisiing agents, for example ion exchangers, typically cation exchangers, for example in the H + form, de ⁇ pending on the type of reaction and/or reactants at reduced, normal, or elevated tempera ⁇ ture, for example in the range from -100 0 C to about 19O 0 C, preferably from about -8O 0 C to about 15O 0 C, for example at -80 to -6O 0 C, at room temperature, at - 20 to 4O 0 C or at the boi- ling point of the solvent used, under atmospheric pressure or in a closed vessel, where ap ⁇ limbate under pressure, and/or in an inert atmosphere, for example under
  • Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
  • the solvents from which those can be selected which are suitable for the reaction in ques ⁇ tion include for example water, esters, typically lower alkyl-lower alkanoates, e.g diethyl acetate, ethers, typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g.
  • tetrahydro- furan liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically metha ⁇ nol, ethanol or 1- or 2-propanol, nitriles, typically acetonitrile, halogenated hydrocarbons, typically dichloromethane, acid amides, typically dimethylformamide, bases, typically hetero ⁇ cyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g.
  • ace ⁇ tic anhydride cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
  • solvent mixtures may also be used in processing, for example through chromatography or distribution.
  • a compound of formula I is prepared according to or in analogy to the processes and process steps defined in the Examples.
  • the dosage of the active ingredient depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the invention relates also to pharmaceutical compositions comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned disorders, of compound of the formula I or a tautomer thereof together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
  • pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
  • diluents for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.
  • Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenterally administrable compositions or in the form of infusion solutions.
  • binders for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone
  • disintegrators for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • excipients for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • the present pharmaceutical compositions which may, if desired, comprise other pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 1% to 95%, especially from approximately 1% to approximately 20%, active ingredient(s).
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes HN, CrC 4 alkyl-N or O(CH 2 ) g NH, and the remaining radicals and symbols R-t, R 6 , R 7 , Rs and g are as defined for a compound of the formula I, can be obtained by reacting the 5-pyrimidyl carboxylic acid halide of the formula VIII
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , and the remaining radicals R 6 , R 7 and R 8 are as defined for a compound of the formula I, in a first step with an alcohol AIkOH, wherein AIk denotes alkyl, preferably CrC 4 alkyl, and in a second step with an amine of the formula V
  • X denotes HN, C r C 4 alkyl-N, 0(CH 2 ) g NH, and R-i is as defined for a compound of the formula I 1 in order to prepare the 2-chloro-pyrimidine of formula IX,
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , AIk denotes alkyl, preferably Ci-C 4 alkyl, X denotes HN, Ci-C 4 alkyl-N, O(CH 2 ) g NH, and g, R 1 , R 6 , R 7 and R 8 are as defined for a compound of the formula I.
  • the reaction of the 5-pyrimidyl carboxylic acid halide of the formula VIII with the alcohol AIkOH can be carried out under customary conditions, e.g., by dissolving the acid halide in a suitable solvent, such as dichloromethane, and adding staggered or simultaneously the alcohol and an equivalent amount of a suitable base, such as a tri(C r C 4 aIkyl)amine, at a temperature between -10 and 25 0 C, preferably at about 0 0 C.
  • a suitable solvent such as dichloromethane
  • the obtained carboxylic acid ester can advantageously be further reacted without intermediate isolation thereof by addition of the amine of formula V and an equivalent amount of a suitable base, such as the same or a different tri(Ci-C 4 alkyl)amine as used above, at a temperature between -10 and + 25 0 C, such as about 0 0 C
  • the 2-chloro-pyrimidine of formula IX wherein R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , AIk denotes alkyl, preferably C r C 4 alkyl, X denotes HN, C 1 - C 4 alkyl-N, O(CH 2 ) g NH and g, R 1 , R 6 , R 7 and R 8 are as defined for a compound of the formula I 1 is then further reacted for a period of 15 to 360 minutes with an alkali metal cyanide, such as potassium cyanide, in a suitable solvent, such as dimethylformamide or dimethylsulfoxide, in the presence of a suitable base, such as 1 ,4-diazabicyclo[2.2.2]octane,
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O 1 NH or S, or NR 7 R 8 , AIk denotes alkyl, preferably CrC 4 alkyl, X denotes HN, C r C 4 alkyl-N, O(CH 2 ) g NH, and g, R 1 , R 6 , R 7 and R 8 are as defined for a compound of the formula I.
  • Said carboxylic acid ester of formula X is then finally subjected to a saponification reaction by addition of a great excess of water under conditions known in the art catalyzed by a suitable base furnishing the 5-pyrimidyl carboxylic acid of formula Il as defined above.
  • a suitable base furnishing the 5-pyrimidyl carboxylic acid of formula Il as defined above.
  • the carboxylic acid ester can be solved in a solvent miscible with water, such a tetrahydrofuran, and a solution of a suitable base, such as lithium hydroxide, in water is added at a temperature between -5 and 20 0 C, preferably at about 0 0 C.
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes O or S, and the remaining radicals R 1 , R 6 , R 7 and R 8 are as defined for a compound of the formula I, can be obtained by reacting the 5-pyrimidyl carboxylic acid halide of the formula VIII wherein R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , and the remaining radicals R 6 , R 7 and R 8 are as defined for a compound of the formula I, in a first step with water, and in
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes O or S, and the remaining radicals R 1 , R 6 , R 7 and R 8 are as defined for a compound of the formula I.
  • the reaction of the 5-pyrimidyl carboxylic acid haiide of the formula VIII with water can be carried out under customary conditions, e.g., by dissolving the acid halide in a suitable solvent which is miscible with water, such as tetrahydrofuran, and adding an excess amount of water, at a temperature between 15 and 35 0 C, preferably at about 20 to 25 0 C.
  • a strong base such as potassium tert-butoxide
  • the alcohol or thiol of the formula V in a suitable solvent, such as tetrahydrofuran, for a period of 30 to 360 minutes at a temperature between -10 and 20 0 C, preferably at about O 0 C.
  • the 2-chloro-pyrimidyl-5-carboxy!ic acid of formula Xl wherein the radicals have the meanings as provided above, is then reacted in a suitable solvent such as dimethyl- formamide at a temperature between 30 and 60 0 C, preferably at about 45 to 55 0 C for a period of 10 to 120 minutes, more preferably 30 to 45 minutes, with an excess amount of an allyl halide, e.g. allylbromide, in the presence of a suitable base, such as potassium carbonate, delivering the carboxyiic allyl ester of formula (XII),
  • a suitable solvent such as dimethyl- formamide
  • the carboxyiic allyl ester of formula (XII), wherein the radicals have the meanings as provided for the compound of formula Xl above, is then reacted for a period of 15 to 360 minutes with an alkali metal cyanide, such as potassium cyanide, in a suitable solvent, such as dimethylformamide or dimethylsulfoxide, in the presence of a suitable base, such as 1 ,A- diazabicyclo[2.2.2]octane, at a temperature between +15 and +35 "C 1 preferably at about 20 to 25 0 C, to furnish the carboxyiic allyl ester of formula (XIII),
  • an alkali metal cyanide such as potassium cyanide
  • a suitable solvent such as dimethylformamide or dimethylsulfoxide
  • a suitable base such as 1 ,A- diazabicyclo[2.2.2]octane
  • the compound of formula Il as defined above is obtained by hydrolysis of said carboxylic allyl ester of formula XIII by addition of a Pd(O) catalyst, e.g. tetrakis(triphenyl- phosphinei)palladium(O), and morpholine to a solution of the allyl ester in a suitable solvent, such as tetrahydrofuran, at a temperature between +15 and +35 0 C, preferably at about 20 to 25 0 C, followed by addition of an aqueous solution of sodium hydrogencarbonate.
  • a Pd(O) catalyst e.g. tetrakis(triphenyl- phosphinei)palladium(O)
  • morpholine e.g. tetrakis(triphenyl- phosphinei)palladium(O)
  • a suitable solvent such as tetrahydrofuran
  • the 5-pyrimidyl carboxylic acid of formula Il wherein R 3 denotes Y-R 6 , wherein Y represents O, NH or S, X denotes HN, C r C 4 alkyl-N or O(CH 2 ) g NH, and the remaining radicals and symbols R 1 , R 6 and g are as defined for a compound of the formula I, can also be obtained by reacting firstly the 2-methylthio-5-pyrimidyl carboxylic acid of the formula XIV
  • R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula I, in the presence of a strong base, such as sodium hydrid, in a suitable solvent such as tetrahydrofuran at a temperature between -10 and 30 C C, preferably at about 20 0 C, and, subsequently, the reaction product is reacted in a suitable solvent such as dimethylformamide at a temperature between 30 and 60 0 C, preferably at about 45 to 55 0 C, for a period of 10 to 120 minutes, more preferably 45 to 75 minutes, with an excess amount of an allyl halide, e.g. allylbromide, in the presence of a suitable base, such as potassium carbonate, delivering the carboxylic allyl ester of formula XVI,
  • R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula I.
  • the methylthio group in the carboxylic allyl ester of formula XVI is subsequently replaced by a cyano group by means of a two step reaction.
  • the carboxylic allyl ester of formula XVI wherein the radicals have the meanings as provided above, is oxidized with a suitable oxidizing agent, preferably with a 3-fold molar excess of meta chloro perbenzoic acid, in a suitable solvent, such as dichloromethane, at a temperature between -10 and +10 0 C, preferably at about 0 0 C.
  • a second step the resulting methyl sulfonyl group is replaced by a cyano group by reaction of the obtained intermediate in a suitable solvent, for instance dichloromethane, with a suitable cyanide, e.g. sodium cyanide, in the presence of a suitable catalyst, such as tetra(alkyl)ammonium bromide, at a temperature between 15 and 30 0 C, preferably at about 20 to 25 0 C 1 furnishing the 2-cyano pyrimidyl-5-carboxylic acid allyl ester of formula XVII,
  • a suitable solvent for instance dichloromethane
  • a suitable cyanide e.g. sodium cyanide
  • a suitable catalyst such as tetra(alkyl)ammonium bromide
  • R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula I.
  • the obtained 2-cyano pyrimidyl-5-carboxylic acid allyl ester of formula XVII wherein R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula I, is finally transferred into the carboxylic acid of formula Il by first reacting 2-cyano pyrimidyl-5-carboxylic acid allyl ester of formula XVII with the amine of formula V and an equivalent amount of a suitable base, such as the same or a different tri(C r C 4 alkyl)amine as used above, at a temperature between -10 and + 25 0 C, such as about 0 0 C, and secondly by hydrolysis of the obtained allyl ester by addition of a Pd(O) catalyst, e.g.
  • a Pd(O) catalyst e.g.
  • tetrakis(triphenyl- phosphine)palladium(O), and morpholine to a solution of the allyl ester in a suitable solvent, such as tetrahydrofuran, at a temperature between +15 and +35 0 C 1 preferably at about 20 to 25 0 C, followed by addition of an aqueous solution of sodium hydrogencarbonate.
  • a suitable solvent such as tetrahydrofuran
  • R 2 denotes -C(O)NR 4 R 5
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R ⁇ , wherein Y represents O, NH or S, or NR 7 R 8 , and the remaining radicals R 6 , R 7 and R 8 are as defined for a compound of the formula I, can be obtained starting from the 2-methylthio-5-pyrimidyl carboxylic acid of the formula XIV
  • R 2 denotes -C(O)NR 4 R 5
  • R3 denotes Y-R 6
  • Y represents O, NH or S
  • R 4 , R 5 and R 6 have the meanings as defined for a compound of formula I above.
  • R 3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R 6 , wherein Y represents O, NH or S, or NR 7 R 8 , X denotes HN, CrC 4 alkyl-N, O(CH 2 ) g NH, O or S and the remaining radicals and symbols R 1 , R 6 , R 7 , R 8 and g are as defined for a compound of the formula I, can be obtained starting from the 2- methylthio-5-pyrimidyl carboxylic acid of the formula XIV
  • the carboxylic acid of the formula XIV is transferred to the corresponding carbamic acid allyl ester of formula XX
  • Such carbamic acid allyl ester of formula XX can be further reacted with the amine, alcohol or thiol of formula XV wherein R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula I 1 in the presence of a strong base, such as sodium hydride or potassium tert-butoxide, in a suitable solvent such as tetrahydrofuran at a temperature between -10 and 30 0 C, preferably at about 20 0 C, furnishing the 2-methylthio- pyrimidine derivative of formula XXI,
  • R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula I.
  • the methylthio group in the 2-methylthio-pyrimidine of formula XXI is subsequently replaced by a cyano group by means of a two step reaction as described for the carboxylic ally! ester of formula XlX above, furnishing the 2-cyano pyrimidyl-5-carbamic acid allyl ester of formula XXII,
  • R 3 denotes Y-R 6 , wherein Y represents O, NH or S and R 6 is as defined for a compound of the formula 1.
  • Said 2-cyano pyrimidyl-5-carbamic acid allyl ester is finally transferred into the 5-amino pyrimidine derivative of formula Vl by first reacting the compound of formula XXII with an amine of formula V as specified hereinabove and subsequent hydrolysis of the carbamic acid function in the obtained intermediate by addition of a Pd(O) catalyst, e.g.
  • tetrakis- (triphenylphosphine)palladium(O), and morpholine to a solution of the carbamic acid allyl ester in a suitable solvent, such as tetrahydrofuran, at a temperature between +15 and +35 0 C, preferably at about 20 to 25 0 C, followed by addition of an aqueous solution of sodium hydrogencarbonate.
  • a suitable solvent such as tetrahydrofuran
  • the spirocyclic starting materials being incorporated in radical R 1 can be prepared in accordance with the procedures described in the Examples or by acetalisation reactions.
  • the diols being used as a starting material for such procedures described in the Examples as well as for acetalisation reactions can be, for instance, be prepared by subjecting in a first step a dicarboxylic acid ester of formula XXIII, (XXIlI)
  • Rn is C r C 4 alkyl and b is an integer selected from 1 , 2 or 3, to a reduction reaction, e.g. to reduction with LiAIH 4 in tetrahydrofuran, to furnish the diol of formula (XXIV) 1
  • b is an integer selected from 1 , 2 or 3.
  • nucelophilic substitution reactions e.g. by reaction with p-tosylchloride in the presence of a suitable base, such as triethylamine, under suitable reaction conditions.
  • nucelophilic substitution reaction is carried out with potassium cyanide in an aprotic solvent, such as dimethylsulfoxide, to deliver the di- (cyanomethyl) cycloalkyl compound of formula XXV
  • di-(cyanomethyl) cycloalkyl compound of formula XXV is then further subjected to alkaline hydrolysis providing the free di-carboxylic acid derivative and finally said di-carboxylic acid derivative is reduced, e.g. by reduction with LiAIH 4 in tetrahydrofuran, to the diol of formula (XXVI),
  • b is an integer selected from 1 , 2 or 3.
  • Step 1.1 (2-Morpholin-4-yl-2-oxo-1-phenylethyl)carbamic acid terf-butyl ester
  • morpholine 4.0 mmol
  • EDCI-H 2 O 4.8 mmol
  • DMAP 0.40 mmol
  • Step 1.2 2-Amino-1-morpholin-4-yl-2-phenylethanone
  • Step 1.4 2-Cyano-4-(cyclohexylmethylamino)-pyrimidine-5-carboxylic acid
  • Step 2.2 4-(2- ⁇ 2-Cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin- 4-y!oxy ⁇ ethyl)piperidine-1-carboxylic acid terf-butyl ester
  • Step 58.2 5-(1-Methylpiperidin-4-yloxy)biphenyl-2-ylamine
  • Step 66.1 4-Amino-4-benzyl-piperidine-1-carboxylic acid terf-butyl ester
  • Step 73.2 2-Chloro-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxyIic acid allyl ester
  • Et 3 N 2.4 mmol
  • a solution of methyl-spiro[2.5]oct-6- ylmethylamine (1.6 mmol) in dioxane (2.0 mL) is added dropwise to the reaction mixture.
  • the reaction mixture is stirred at room temperature for 12 h and the reaction is quenched by the addition of water.
  • Step 73.3 2-Cyano-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxyIic acid allyl ester
  • Step 74.2 2-Chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid
  • Step 74.4 2-Cyano-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester
  • Step 75.1 4-[2-(1 -ferf-Butoxycarbonylpiperidin ⁇ -yOethoxyl- ⁇ -chloro ⁇ -methylthio- pyrimidine-5-carboxylic acid allyl ester
  • Step 75.2 4-[2-(1-fert-Butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methane sul- fonylpyrimidine-5-carboxylic acid ally! ester
  • step 2.1 4-[2-(1-fe/t- butoxycarbonyl piperidin ⁇ -yOethoxyl ⁇ . ⁇ -dichloropyrimidine- ⁇ -carboxylic acid allyl ester (3.0 mmol) is treated with m-CPBA (8.9 mmol) in CH 2 CI 2 (10 mL) at 0 0 C. After usual work-up, the crude material is purified by silica gel chromatography to give 4-[2-(1-ferf- butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methane sulfonylpyrimidine-5-carboxylic acid allyl ester as colorless oil.
  • Step 75.3 4-[2-(1-tert-Butoxycarbonylpiperidin-4-y!)ethoxy]-6-chloro-2-cyano pyrimi- dine-5-carboxylic acid allyl ester
  • Step 75.4 4-[2-(1 -fert-Butoxycarbonylpiperidin-4-yl)ethoxy]2-cyano-6-[(spiro[3.5]non- 7-ylmethyl) amino] pyrimidine-5-carboxylic acid
  • Example 76 2-Cvano-4-r2-(1 -methylpiperidin-4-yl)ethoxy1-6-r(spiror2.51oct- ⁇ -ylmethv ⁇ - aminoipyrimidine-5-carboxylic acid benzyl amide
  • Step 76.1 4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid benzylamide
  • Step 76.2 4-[2-(5-Benzylcarbamoyl-6-chloro-2-methylsulfany[pyrimidin-4-yloxy) ethyl]piperidine-1-carboxylic acid tert-butyl ester
  • Step 76.3 4-[2-(5-Benzylcarbamoyl-6-ch(oro-2-cyanopyrimidin-4-yIoxy)ethyl]- piperidine-1-carboxylic acid ferf-butyl ester
  • 4-[2-(5-benzylcarbamoyl-6-chloro-2-methylsulfanylpyrimidin ⁇ 4- yloxy)ethyl]piperidine-1-carboxylic acid ferf-butyl ester (2.7 mmol) in CH2CI2 (50 rnL) is added m-CPBA (4.1 mmol) at O 0 C.
  • reaction mixture After stirring over night under N2 atmosphere, the reaction mixture is quenched by the addition of Na2S 2 O3 and aq. sat. NaHCO3 at O 0 C.
  • the mixture is extracted twice with CH 2 CI 2 , and the combined organic extracts are washed with aq. sat. NaHC ⁇ 3 and water.
  • Step 76.4 4-(2- ⁇ 5-Benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl)amino]- pyrimidin-4-yloxy ⁇ ethyl)piperidine-1-carboxylic acid tert-butyl ester
  • HPLC conditions Phenomenex Luna reverse phase C18 3 micron 30 x 4.6mm column. Linear gradient from 90% water with 0.08% formic acid : 10% acetonitrile to 100% acetonitrile over 10 min. Detection at 254 nm.
  • Example 165 N-f2-Cvano-4-f2-f1-methylpiperidin-4-yl)ethoxy ⁇ -6-r(spirof3.51non-7- ylmethvOaminoipyrimidin-5-yli-C-phenylmethanesulfonamide
  • Step 165.1 (4,6-Dichloro-2-methylsulfanylpyrimidin-5-yl)carbamic acid allyl ester
  • Step 165.2 4-[2-(5-AIIyloxycarbonylamino-6-chloro-2-methylsulfanylpyrimidin-4- yloxy)ethyl]piperidine-1-carboxylic acid terf-butyl ester
  • step 2.0 (4,6-di chloro ⁇ -methylsulfanylpyrimidin- ⁇ -yOcarbamic acid allyl ester is converted to 4-[2-(5- allyloxycarbonylamino- ⁇ -chloro ⁇ -methylsulfanylpyrimidin ⁇ -yloxyj ethyljpiperidine-i- carboxylic acid ferf-butyl ester.
  • Step 165.3 4-[2-(5-Allyloxycarbonylamino-6-chloro-2-cyano-pyrimidin-4-yloxy)ethyl] piperidine-1 -carboxylic acid tert-butyl ester
  • Step 165.4 4-(2- ⁇ 5-AIIyloxycarbonylamino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)- amino]pyrimidin-4-yloxy ⁇ ethyl)piperidine-1 -carboxylic acid fert-butyl ester
  • step 2.2 for 4- (2- ⁇ 2-cyano-6-[(spiro[3.5]non-7-ylmethyl)-amino]pyrimidin-4-yloxy ⁇ ethyl)piperidine-1- carboxylic acid te/t-butyl ester, 4-[2-(5-Allyloxycarbonylamino-6-chloro-2-cyano-pyrimidin-4- yloxy)ethyl] piperidine-1 -carboxylic acid ferf-butyl ester is converted to 4-(2- ⁇ 5-allyloxy carbonylamino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy ⁇ ethyl)piperidine-1 -carboxylic acid terf-butyl ester.
  • Step 165.5 4-(2- ⁇ 5-Amino-2-cyano-6-[(spiro[3.5]non-7-yImethyI)amino]pyrimidin-4- yloxy ⁇ ethyl)piperidine-1 -carboxylic acid fert-butyl ester
  • Step 165.6 4-(2- ⁇ 2-Cyano-5-phenylmethanesulfonylamino-6-[(spiro[3.5]non-7- ylmethyl)amino]pyrimidin-4-yloxy ⁇ ethyl)piperidine-1-carboxylic acid tert-butyl ester
  • Benzylsulfonylchloride (0.50 mmol) is added to a solution of 4-(2- ⁇ 5-amino-2-cyano-6- [(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy ⁇ ethyl)piperidine-1-carboxylic acid f-butyl ester (167 mg) and pyridine (0.66 mmol) in CH 2 CI 2 (3 imL) are added at 0 0 C. After stirring at room temperature for 1 h, benzylsulfonylchloride (0.50 mmol), pyridine (0.66 mmol) and DMAP (catalytic amount) are added to the reaction mixture again.
  • Preparation process The pulverized active ingredient is suspended in Lauroglykol® (propy ⁇ lene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introdu ⁇ ced into soft gelatin capsules using a capsule-filling machine.
  • Lauroglykol® propy ⁇ lene glycol laurate, Gattefosse S.A., Saint Priest, France

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Abstract

The present invention relates to the use of a 2-cyanopyrimidine compound of the formula (I), wherein R1, R2, R3 and X are as defined in the specification and in the claims, in free form or in salt form, and , where possible, in tautomeric form, as an inhibitor of the activity of cathepsin S.

Description

COMPOUNDS AND COMPOSITIONS USEFUL AS CATHEPSIN S INHIBITORS
The present invention relates to novel 2-cyano-pyrimidine derivatives, their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such compounds for the manufacture of a pharmaceutical preparation for the treatment of pain and to a method for the treatment of such a disorder in warm-blooded animals, especially in humans.
Surprisingly, it has been found that the 2-cyano-pyrimidine derivatives described herein have advantageous pharmacological properties and inhibit, for example, the activity of cathepsin S enzymes. The 2-cyano-pyrimidine derivatives of formula I are hence suitable to be used in the treatment of diseases wherein the inhibition of cathepsin S activity causes a beneficial effect.
The 2-cyano-pyrimidihe derivatives of formula I are suitable, in particular, for the treatment and in the prevention of neuropathic pain and other diseases mentioned hereinafter.
Hence, the present invention relates to 2-cyano-pyrimidines of formula
Figure imgf000002_0001
wherein R1 denotes a radical of formula
Figure imgf000002_0002
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2; T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S;
Ra, Rb and Rc independently of each other represent hydrogen or d-C4alkyl; s is O1 1 or 2, t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
R2 denotes halogen, C1-C4 alkyl, unsubstituted or substituted aryl, 5 or 6 membered heterocyclyi, -C(O)NR4R5, -NHC(O)R4 or -CH2NHC(O)R4, wherein
R4 represents
(a) Ci-C7alky! which is unsubstituted or substituted by halogen; amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6aIkyl which in each case are unsubstituted or mono-, di- or trisubstituted by halogen; unsubstituted or substituted C4-C8-aliphatic heterocyclyi comprising at least one nitrogen atom; unsubstituted or substituted aryl; unsubstituted or substituted hetaryl; unsubstituted or substituted spiro[4.5]decane which comprises 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur; unsubstituted or substituted C3-C6cycloalkyl; or 1-aza-(C5-Cβ)bicycloalkyl;
(b) unsubstituted or substituted N-(CrC4alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl;
(c) unsubstituted or substituted aryl;
(d) unsubstituted or substituted C3-C6cycloalkyl; or
(e) unsubstituted or substituted 5 or 6 membered hetaryl containg one nitrogen atom; and R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent unsubstituted or substituted C4-Ca-aliphatic heterocyclyi comprising at least one nitrogen atom; or
R2 denotes -N(R9)SO2Ri0,
R9 represents hydrogen or CrC4aIkyl; and
Rio represents C1-C4alkyl, which is unsubstituted or substituted by aryl; or
R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 5 and R and R' both represent independently of each other hydrogen or
Ci-C4alkyl;
R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6 or NR7R8 wherein
Y represents O, CH2, S, SO, SO2 or NRN, wherein RN denotes hydrogen or CrC4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents CrC6alkyl, phenyl, five or six-membered nitrogen containing hetaryl-(CH2)q-, wherein q is an integer from O to 4, or five or six-membered aliphatic heterocyclyl-(CH2)n-, wherein n is an integer from O to 4 and the heterocyclyi moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom;
X denotes O, HN, CrC4alkyl-N, S, SO, SO2, 0(CH2)gNH, wherein g is 1 or 2, (CH2),,, wherein h is 1 or 2, or aryl, which is unsubstituted or mono-, di- or trisubstituted by halogen, C1-
C4alkyl or CrC4alkoxy; and to salts and tautomers of such 2-cyano-pyrimidines.
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Halogen or halo is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
Alkyl is especially alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, C atoms and is linear or branched; preferably, alkyl is methyl, ethyl, propyl, such as n-propyl or isopropyl, butyl, such as n-butyl, sec-butyl, isobutyl or tert- butyl.
Alkoxy is especially methoxy, ethoxy or propoxy.
Cycloalkyl is especially C3-C6cycloalkyl, namely cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Aliphatic heterocyclyl comprising at least one nitrogen atom is especially a five or six- membered heterocyclic radical with one ring nitrogen atom and optionally further 1 or 2 ring heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be wholly or partly saturated, preferably imidazolidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, and which radical can be unsubstituted or substituted. In unsubstituted or substituted aryl, aryl is preferably a mono-, bi- or tricyclic aromatic hydro¬ carbon group with 6 to 14 ring carbon atoms, especially phenyl, naphthyl or fluorenyl, more preferably phenyl.
Hetaryl as used herein is especially thienyl, pyrrolyl, furyl, oxazolyl, isoxazolyl, isothiazolyl, thiazoyl, pyrazolyl, imidazolyl, benzimidazolyl, benzthiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, more preferably thienyl, furyl, pyridinyl and pyrazolyl.
Unless otherwise mentioned, the term "unsubstituted or substituted" as used herein means that the respective radical is unsubstituted or substituted by one or more, preferably up to four, especially one or two substituents, selected from oxo, amino, CrC4alkyl amino, di(Cr C4alky)-amino, hydroxy-CrC4alkyl amino, phenyl-CrC4alkyl amino, C3-C5cycloalkyl amino, di(C3-C5)cycloalkyl amino, N-CrC4alkyl-N-C3-C5cycloalkyl amino, CrC4aIkanoyl amino, halogen, hydroxy, CrC4alkoxy, unsubstituted or substituted C3-C6cycloalkyl, C3- C5cycloalkyloxy, C1^aIkOXy Ci-C4alkoxy, di(CrC4alkyl)-amino Cr^alkoxy, carbamoyl, N- CrC4alkyl-carbamoyl, N,N-di(C1-C4alkyl)-carbamoyl, nitro, cyano, carboxy, CrC4alkoxy carbonyl, Ci-C4alkanoyl, CrC4alkanoyloxy, benzoyl, amidino, guanidino, ureido, mercapto, CrC4alkylthio, pyridyl, CrC4alkyl pyridyl, phenyl, unsubstituted or substituted phenyl, phenoxy, CrC4alkoxy phenyl, phenylthio, phenyl-Ci-C4a!kylthio, CrC4a!kylsulfonyl, phenylsulfonyl, Ci-C4alkylphenylsulfonyl, CrC4aIkenyl, unsubstituted or substituted C4- C8heterocyclyl, e.g. C5-C7oxacyloalkyl or Cs-Crdioxacyloalkyl, unsubstituted or substituted C4-C8heterocyclyloxy, e.g. tetrahydropyranyloxy, unsubstituted or substituted C4- C8heterocyclyl CrC4alkoxy, CrC4alkylene dioxy bound at adjacent C-atoms of the ring, and CrC4alkyl, which is unsubstituted or substituted by halogen, hydroxy, CrC4alkoxy, nitro, imino, cyano, carboxy, d-C4alkoxy carbonyl, CrC4alkanoyl, CrC4alkanoyloxy or unsubstituted or substituted C4-C8heterocyclyl.
In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free com¬ pounds hereinbefore and hereinafter is to be understood as referring also to the correspon¬ ding salts, as appropriate and expedient. Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharma¬ ceutically acceptable salts. For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
The compounds of formula I exhibit valuable pharmacological properties in mammals and are particularly useful as inhibitors of cathepsin S. The cathepsin S inhibitory effects of the compounds of formula I can be demonstrated in vitro by measuring the inhibition of e.g. recombinant human cathepsin S (in vitro cathepsin S assay).
The in vitro assay is carried out in clear, flat-bottomed, 96-well microtiter plates (Greiner GmbH, Germany) at ambient temperature using recombinant human cathepsin S. Inhibition of human cathepsin S is assayed at a constant enzyme and various substrate concentrations (substrate is Z-Leu-Leu-4-methylcoumaryl-7-amide (Bachem (Switzerland)) in 100 parts 0.2M sodium phosphate, pH 7.0, containing 2 mM EDTA, 2 parts 1% Triton X-100, 10 parts 20 mM dithiothreitol (DTT) and 58 parts distilled water. The assay is started by adding the enzyme solution (13 times higher concentration of final concentration of recombinant human Cathepsin S) to the reaction mixture containing various concentrations of the corresponding substrate and the compound. Substrate concentrations between 3.4 and 17 μM are used. The recombinant human Cathepsin S is used at a final concentration of 0.04 nM. Test compounds are used at concentrations between 0.4 and 2 times the determined IC50 of the compound at the enzyme. The relative fluorescence is continuously measured for 30 minutes and the initial velocity is obtained from each progress curve. The inhibition patterns and the Ki values are determined by Dixon plot analysis.
Compounds of formula I typically have IC50S for inhibition of human cathepsin S of less than about 350 nM down to about 1 nM or less, preferably of about 50 nM or less.
In view of their activity as inhibitors of cathepsin S, compounds of formula I are particularly useful in mammals as agents for the treatment and prophylaxis of diseases and medical conditions involving elevated levels of cathepsin S activity. Such diseases include chronic neuropathic pain, exemplified by conditions such as diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful diabetic polyneuropathy, post-stroke pain (central pain), postamputation pain, myelopathic or radiculopathic pain (e.g. spinal stenosis, arachnoiditis, root sleeve fibrosis), atypical facial pain and causalgia-like syndromes (complex regional pain syndromes).
Cathepsin S is present in antigen presenting cells and plays a key role in events involved in antigen presentation. In this respect inhibitors of cathepsin S could be useful agents in the prevention, inhibition or treatment of immune and autoimmune disorders, including, but not ' limited to asthma, rheumatoid arthritis, multiple sclerosis, systemic lupus erythmatosus, psoriasis and Crohn's disease and for the prevention, inhibition or treatment of tissue transplant rejection.
Furthermore cathepsin S can be secreted by some antigen presenting cells and thus play a role in extracellular matrix interactions. Therefore, cathepsin S inhibitors could be useful agents in the prevention, inhibition or treatment of neurodegenerative diseases with a possible inflammatory component, Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), HIV neuropathy, diabetic neuropathies, Guillain - Barre syndrome, CIPD (Chronic inflammatory demyelinating polyradiculoneuropathy), other demyelinating diseases, meningitis, brain/spinal cord trauma, stroke, schizophrenia.
Cathepsin S inhibitors could be useful agents in the prevention, inhibition or treatment of a variety of other diseases involving extra-cellular proteolysis such as the development of emphysema in chronic obstructive pulmonary disease, atherosclerosis, restenosis and tumor cell invasion.
Cathepsin S is present in inflammatory cells and cathepsin S inhibitors could be useful agents compounds for the treatment of Creutzfeldt-Jakob Disease, interstitial cystitis, inflammatory bowel disease and vasculitic disorders.
Beneficial effects are evaluated in in vitro and in vivo pharmacological tests generally known in the art, and as illustrated herein. The above cited properties are demonstrable in in vitro and in vivo tests, using advantageously mammals, e.g. rats, mice, dogs, rabbits, monkeys or isolated organs and tissues, as well as mammalian enzyme preparations, either natural or prepared by e.g. recombinant technology. Compounds of formula I can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions or suspensions, and in vivo either enterally or parenterally, advantageously orally, e.g. as a suspension or in aqueous solution, or as a solid capsule or tablet formulation. The dosage in vitro may range between about 10"5 molar and 10'9 molar concentrations. The dosage in vivo may range, depending on the route of administration, between about 0.1 and 100 mg/kg.
The efficacy of the compounds of formula I for the treatment of chronic inflammatory or neuropathic pain can be determined using the following In vivo animal models:
Chronic inflammatory pain model:
The intraplantar injection of zymosan -induced mechanical hyperalgesia may be used as a model of chronic inflammatory pain (Meller et al, Neuropharmacology 33:1471-1478, 1994). In this model, typically a male Sprague-Dawley or Wistar rat (200-250 g) receives an intraplantar injection of 3 mg/100 μl zymosan into one hind paw. A marked inflammation occurs in this hind paw. Drugs are generally administered for evaluation of efficacy, 24 hours after the inflammatory insult, when mechanical hyperalgesia is considered fully established.
Chronic neuropathic pain models:
Two animal models of chronic neuropathic pain may be used that involve some form of peripheral nerve damage. In the Seltzer model (Seltzer et al. (1990) Pain 43: 205-218) rats are anaesthetised and a small incision made mid-way up one thigh (usually the left) to expose the sciatic nerve. The nerve is carefully cleared of surrounding connective tissues at a site near the trochanter just distal to the point at which the posterior biceps semitendinosus nerve branches off the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle, and tightly ligated so that the dorsal 1/3 to 1/2 of the nerve thickness is held within the ligature. The muscle and skin are closed with sutures and clips and the wound dusted with antibiotic powder. In sham animals the sciatic nerve is exposed but not ligated and the wound closed as in nonsham animals.
In the Chronic Constriction Injury (CCI) model (Bennett, GJ. and Xie, Y.K. Pain (1988) 33: 87-107) rats are anaesthetised and a small incision is made mid-way up one thigh (usually the left) to expose the sciatic nerve. The nerve is cleared of surrounding connective tissue and four ligatures of 4/0 chromic gut are tied loosely around the nerve with approximately 1 mm between each, so that the ligatures just barely constrict the surface of the nerve. The wound is closed with sutures and clips as described above. In sham animals the sciatic nerve is exposed but not ligated and the wound closed as in nonsham animals.
In contrast to the Seltzer and CCI models, the Chung model involves ligation of the spinal nerve. (Kim, S.O. and Chung, J.M. Pain (1992): 50:355-363). in this model, rats are anesthetized and placed into a prone position and an incision is made to the left of the spine at the L4-S2 level. A deep dissection through the paraspinal muscles and separation of the muscles from the spinal processes at the L4-S2 level will reveal part of the sciatic nerve as it branches to form the L4, L5 and L6 spinal nerves. The L6 transverse process is carefully removed with a small rongeur enabling visualisation of these spinal nerves. The L5 spinal nerve is isolated and tightly ligated with 7-0 silk suture. The wound is closed with a single muscle suture (6-0 silk) and one or two skin closure clips and dusted with antibiotic powder. In sham animals the L5 nerve is exposed as before but not ligated and the wound closed as before.
Behavioral index
In all chronic pain models (inflammatory and neuropathic) mechanical hyperalgesia is assessed by measuring paw withdrawal thresholds of both hindpaws to an increasing pressure stimulus using an Analgesymeter (Ugo-Basile, Milan). Mechanical allodynia is assessed by measuring withdrawal thresholds to non-noxious mechanical stimuli applied with von Frey hairs to the plantar surface of both hindpaws. Thermal hyperalgesia is assessed by measuring withdrawal latencies to a noxious thermal stimulus applied to the underside of each hindpaw. With all models, mechanical hyperalgesia and allodynia and thermal hyperalgesia develop within 1 - 3 days following surgery and persist for at least 50 days. For the assays described herein, drugs may be applied before and after surgery to assess their effect on the development of hyperalgesia, particularly approximately 14 days following surgery, to determine their ability to reverse established hyperalgesia.
The percentage reversal of hyperalgesia is calculated as follows:
n/ , postdose threshold - predose threshold τ. , __
% reversal = — X 100 naive threshold - predose threshold In the experiments disclosed herein, Wistar rats (male) are employed in the pain models described above. Rats weigh approximately 120-140 grams at the time of surgery. All surgery is performed under enflurane/O2 inhalation anaesthesia. In all cases the wound is closed after the procedure and the animal allowed to recover. In all pain models employed, after a few days in all but the sham operated animals, a marked mechanical and thermal hyperalgesia and allodynia develops in which there is a lowering of pain threshold and an enhanced reflex withdrawal response of the hind-paw to touch, pressure or thermal stimuli. After surgery the animals also exhibit characteristic changes to the affected paw. In the majority of animals the toes of the affected hind paw are held together and the foot turned slightly to one side; in some rats the toes are also curled under. The gait of the ligated rats varies, but limping is uncommon. Some rats are seen to raise the affected hind paw from the cage floor and to demonstrate an unusual rigid extension of the hind limb when held. The rats tend to be very sensitive to touch and may vocalise. Otherwise the general health and condition of the rats is good.
The efficacy of the compounds of the invention for the treatment of osteoarthritis can be determined using models such as or similar to the rabbit partial lateral meniscectomy model, as described previously (Colombo et al. Arth. Rheum. 1993 26, 875-886). The efficacy of the compounds in the model can be quantified using histological scoring methods, as described previously (O'Byrne et al. lnflamm Res 1995, 44, S117-S118).
A compound of formula I can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined admini¬ stration of fixed combinations and one or more other therapeutic agents. For the treatment of pain, in particular a combination which comprises a cathepsin S inhibitor as disclosed herein and gabapentin, pregabalin, non steroidal anti-inflammatory drugs, COX-2 inhibitors, steroids, tricyclic antidepressants, other anticonvulsants (e.g carbamazepine, lamotrigine, Trileptal) or an opioid is highly suitable.
The term "opioid" as used herein refers to all drugs, both natural and synthetic, with morphine- like actions. An opioid suitable for the present invention is especially selected from the group comprising alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazeπe, codeine, cyclorphan, desomorphine, dextro- moramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, eptazocine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, levo- phenacylmorphan, levorphanol, lofentanil, methylmorphine, morphine, necomorphine, normethadone, normorphine, opium, oxycodone, oxymorphone, pholcodine, profadol and sufentanil.
For instance, alfentanil can be administered, e.g., in the form as marketed, e.g. under the trademark Rapifen™; allylprodine can be administered, e.g., in the form as marketed, e.g. under the trademark Alperidine™; anileridine can be administered, e.g., in the form as marketed, e.g. under the trademark Leritine™; benzylmorphine can be administered, e.g., in the form as marketed, e.g. under the trademark Peronine™; bezitramide can be administered, e.g., in the form as marketed, e.g. under the trademark Burgodin™; buprenorphine can be administered, e.g., in the form as marketed, e.g. under the trademark Buprenex™; butorphanol can be administered, e.g., in the form as marketed, e.g. under the trademark Torate™; dextromoramide can be administered, e.g., in the form as marketed, e.g. under the trademark Palfium™; dezocine can be administered, e.g., in the form as marketed, e.g. under the trademark Dalgan™; dihydrocodeine can be administered, e.g., in the form as marketed, e.g. under the trademark Novicodin™; dihydromorphine can be administered, e.g., in the form as marketed, e.g. under the trademark Paramorphan™; eptazocine can be administered, e.g., in the form as marketed, e.g. under the trademark Sedapain™; ethylmorphine can be administered, e.g., in the form as marketed, e.g. under the trademark Dionin™; fentanyl can be administered, e.g., in the form as marketed, e.g. under the trademark Fentanest™ or Leptanal™; hydrocodone can be administered, e.g., in the form as marketed, e.g. under the trademark Bekadid™ or Calmodid™; hydromorphone can be administered, e.g., in the form as marketed, e.g. under the trademark Novolaudon™; hydroxypethidine can be administered, e.g., in the form as marketed, e.g. under the trademark Bemidone™; levorphanol can be administered, e.g., in the form as marketed, e.g. under the trademark Dromoran™; normethadone can be administered, e.g., in the form as marketed, e.g. under the trademark Ticarda™; oxycodone can be administered, e.g., in the form as marketed, e.g. under the trademark Dihydrone™ and oxymorphone can be administered, e.g., in the form as marketed, e.g. under the trademark Numorphan™. In formula I the following significances are preferred independently, collectively or in any combination or sub-combination:
R1 denotes a radical of formula
Figure imgf000012_0001
wherein A and G both represent O or both represent CH2, E is CH2 and T is a bond;
Ra, Rb and Rc all represent hydrogen; s is 0 or 1 , t is 1 or 2, more preferably 1 , and p is 1 ;
R2 preferably denotes -C(O)-NR4R5, -N(Rg)-SO2-RiO, bromo, chloro, C1-C4 alkyl, in particular isopropyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing at least one oxygen atom;
R3 preferably denotes hydrogen, Y-R6, NR7R8 or CrC4alkyl, more preferably Y-R6 or NR7R8;
R4 preferably represents
(a) CrC7alkyl which is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6alkyl which is unsubstituted or trisubstituted by halogen;
1-aza-(C4-C8)cycloalkyl, which is unsubstituted or substituted by d-C4alkyl; pyrrolidinyl, which is unsubstituted or substituted by halogen, CrC4alkoxy, CrC4alkoxy C1-
C4alkyl or CrC4alkyl amino; piperidinyl, which is unsubstituted or mono- or disubstituted by halogen, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C4-C6)cycloalkyl or CrC6alkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by C.i-C4alkyl or phenyl; phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-C5cycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza-spiro[4.5]decane or 1 -aza-(C5-C7)bicycloalkyl;
(b) N-(CrC4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, Ci-C4alkoxy, Ci-C4alkoxy Crdalkoxy, CrC4alkoxy phenyl, di(CrC4alkyl)-amino CrC4alkoxy, N-(C1- C4alkyl) piperazinyl, N-(CrC4alkyl) piperidinyloxy or N-(CrC4alkyl) piperidinyl CrC4alkoxy;
(d) C3-C8cycloalkyl;
(e) pyrazolyl, which is mono- or disubstituted by pyridyl or phenyl; or
(f) N-(CrC6alkyI) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or monosubstituted by halogen;
R9 preferably represents hydrogen or Ci-C4alkyl;
R10 preferably represents CrC4alkyl, which is unsubstituted or substituted by phenyl;
X preferably denotes HN, CrC4aikyI-N or O; and
Y preferably represents O or NH.
In R3, pyridyl is preferably unsubstituted or mono-, di- or trisubstituted by halogen, CrC4alkyl or piperazinyl.
In R4,
• CVC7alkyl preferably is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6alkyl which in each case is unsubstituted or mono-, di- or trisubstituted by halogen; C4-C8-aliphatic heterocyclyl comprising at least one nitrogen atom, which radical is unsubstituted or mono-, di- or trisubstituted by CrC4alkyl, halogen, CrC4alkoxy, CrC4alkoxy Ci-C4alkyl, CrC4alkyl amino, phenyl, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, morpholinyl, C4-C6cycloalkyl or C1- C6alkyl which is mono-, di- or trisubstituted by hydroxy or halogen; or phenyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, CrC4alkoxy, CrC4alkoxy C1- C4alkyl, trifluoromethyl or C4-C8-aliphatic heterocyclyl; hetaryl, which radical is unsubstituted or mono-, di- or trisubstituted by CrC4alkyl, halogen, Ci-C4alkoxy, C1- C4alkoxy CrC4alkyl, CrC4alkyl amino, phenyl, pyrrolidinyl, piperidinyl, di(halo)- piperidinyl, morpholinyl, C4-C6cycloalkyl or d-C6alkyl which is mono-, di- or trisubstituted by hydroxy or halogen; spiro[4.5]decane which comprises 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur; halogen, C3-C6cycloalkyl or 1 -aza-(C5-C8)bicycloa!kyl;
• N-(CrC4alkyl) piperidinyl is preferably substituted by phenyl;
• phenyl is preferably mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, C1- C4alkoxy, CrC4alkoxy CrGjalkoxy, CrC4alkoxy phenyl, di(CrC4alkyl)-amino C1- C4alkoxy, N-(CrC4alkyl) piperazinyl, N-(CrC4alkyl) piperidinyloxy or N-(Ci -C4alkyl) piperidinyl CrC4alkoxy;
• C3-C6cycloalkyl is preferably unsubstituted;
• isoxazolyl, imidazolyl or pyrazolyl is preferably unsubstituted or mono- or disubstituted by pyridyl or phenyl; and
• N-(CrC6aikyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl are preferably substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted by halogen.
If R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl or piperidinyl, such radical is preferably unsubstituted or mono-, di- or trisubstituted by hydroxy, CrC4alkoxy or CrC4alkyl.
In Re, CrC6alkyl is preferably unsubstituted or mono-, di- or trisubstituted by pyridyl, Cr C4alkyl pyridyl, imidazolyl, C-i-C4alkyl imidazolyl, phenyl, hydroxy phenyl, hydroxy, C1- C4alkoxy, CrC4alkoxy carbonyl, hydroxy CrC4alkyl amino, Ci-C4alkyl-amino, di-(CrC4alkyl)- amino, CrC4alkanoyl-amino, phenyl-CrC4alkyl amino, CrC4alkylthio, morpholinyl, morpholinyl carbonyl, 2-oxo-imidazolidinyl, 2-oxo-pyrrolidinyI, C5-C7cycloalkyI-amino, C3- C5cycloalkyl, amino-C4-C7cycloalkyl, hydroxy-C4-C7cycloalkyl, tetrahydropyranyl-oxy, N-(C1- C4alkyl) piperazinyl, oxa-Cs-Cecycloalkyl, dioxa-C5-C7cycloalkyl, or piperidinyl, which is unsubstituted or substituted by halogen, especially fluoro, hydroxy, imino-C1-C4alkylI C1- C4alkyl, CrC4alkanoyl, CrC4alkyl sulfonyi or hydroxy CrC4alkyl.
In one preferred embodiment, RQ represents (a) CrCealkyl, which is unsubstituted or substituted by di-(CrC4alkyl)-amino, N-(CrC4aikyl) piperazinyl or hydroxy, or (b) N-(Q)- piperidinyl-(CH2)n-, wherein n is an integer from 0 to 4, and Q is hydrogen, d-C4alkyl or N- (CrC4alkyl) piperidinyl.
Preferably, R7 and R8 together with the nitrogen to which they are attached represent piperidinyl, which is unsubstituted or substituted by CrC4alkyl, hydroxy, aminocarbonyl, amino CrC4alkyl, hydroxy CrC4alkyl, or unsubstituted or substituted by C4-C8 aliphatic heterocyclyl, morpholinyl or thiomorpholinyl which is unsubstituted or substituted by Cf-C4alkyl or oxo; piperazinyl, which is unsubstituted or substituted by CrC4alkyl or Ci-C4alkoxy CrC^Ikyl, or pyrrolidinyi, which is unsubstituted or substituted by hydroxy Ci-C4alkyl, CrC4alkoxy C1- C4alkyl, formyl, di-CrC4alkyl amino, Ci-C4alkyl amino, amino, CrC4alkanoyl amino or aminocarbonyl.
if R7 and R8 together with the nitrogen to which they are attached represent piperidinyl, such radical is preferably substituted by N-(C1-C4alkyl) piperazinyl.
In R10, CrC4alkyl is preferably unsubstituted or substituted by phenyl.
In X, phenyl is preferably unsubstituted or mono-, di- or trisubstituted by halogen, d-dalkyl or Ci-C4alkoxy.
The invention relates in particular to 2-cyano-pyrimidines of formula I wherein R1 denotes a radical of formula
Figure imgf000015_0001
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2; T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S; Ra, Rb and Rc independently of each other represent hydrogen or CrC4alkyl; s is O or 1 , t is 1 , 2, 3 or 4 and p is 0, 1 or 2; R2 denotes halogen, C1-C4 alkyl, unsubstituted or substituted phenyl, 5 or 6 membered heterocyclyl, -C(O)NR4R5, -NHC(O)R4, -CH2NHC(O)R4 or -N(R9)SO2R10, wherein R4 represents
(a) CrCyalkyl which is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6alkyl which is unsubstituted or trisubstituted by halogen; aza-(C4-C8)cycloalkyl, which is unsubstituted or substituted by halogen, C1-
C4alkoxy, CrC4alkoxy Ci-C4alkyl, CrC4alkyl amino, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C4-C6)cycloalkyl or CrCβalkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by Ci~C4alkyl or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-C5cycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- spiro[4.5]decane or 1-aza-(C5-C7)bicycloalkyl;
(b) N-(CrC4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, C1- C4alkoxy, CrC4alkoxy CrC4alkoxy, CrC4alkoxy phenyl, di(CrC4alkyl)-amino C1- C4alkoxy, N-(CrC4alkyl) piperazinyl, N-(CrC4alkyl) piperidinyloxy or N-(C1- C4alkyl) piperidinyl CrC4alkoxy;
(d) C3-C5cycloalkyl;
(e) isoxazolyl, imidazolyl or pyrazolyl, which in each case is mono- or disubstituted by pyridyl or phenyl; or
(f) N-(C-ι-C6alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or mono- substituted by halogen; and
R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl or piperidinyl which is unsubstituted or substituted by hydroxy; R9 represents hydrogen or Ci-C4alkyl; and
R10 represents CrC4alkyl, which is unsubstituted or substituted by phenyl; or R9 and R10 together form a radical -(CRR1Jm-, wherein m is an integer from and including 2 up to and including 4 and R and R1 both represent hydrogen; R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or monosubstituted by halogen or piperazinyl, Y-R6 or NR7R8 wherein
Y represents O, CH2, S, SO, SO2 or NRN, wherein RN denotes hydrogen or CrC4alkyl which is unsubstituted or substituted by Ci-C4alkoxy;
R6 represents CrC6alkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH2)q-, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl-(CH2)n-, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes O, HN1 CrC4alkyl-N, S, SO, SO2, OCH2CH2NH, CH2 or phenyl, which is unsubstituted or monosubustituted by halogen; or to salts of such 2-cyano-pyrimidines.
In particular compounds of formula I are preferred, wherein Ri denotes a radical of formula
Figure imgf000017_0001
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2; T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S; Ra, Rb and Rc independently of each other represent hydrogen or CrC4alkyl; s is O or 1 , t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
R2 denotes bromo, chloro, C1-C4 alkyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing at least one oxygen atom, -C(O)-NR4R5 or -N(R9)-S02-Rioι wherein R4 represents
(a) Ci-C7alkyl which is unsubstituted or substituted by 5 008896
- 17 -
amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6alky) which is unsubstituted or trisubstituted by halogen; aza-(C4-C8)cycloalkyl, which is unsubstituted or substituted by halogen, C1-
C4alkoxy, CrC4alkoxy CrC4alkyl, CrC4aIkyl amino, pyrrolidinyl, piperidinyl, di(halo)~piperidinyl, (C4-C6)cycloalkyl or CrC6alkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by Ci-C4alkyl or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-C5cycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- spiro[4.5]decane or 1-aza-(C5-C7)bicyc!oalkyl;
(b) N-(CrC4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, Cr C4alkoxy, CrC4alkoxy CrC4alkoxy, CrC4alkoxy phenyl, di(CrC4alkyl)-amino C1- C4alkoxy, N-(CrC4alkyl) piperazinyl, N-(CrC4alkyl) piperidinyloxy or N-(C1- C4alkyl) piperidinyl CrC4alkoxy;
(d) C3-C5cycloalkyl;
(e) pyrazolyl, which is mono- or disubstituted by pyridyl or phenyl; or
(f) N-(CrC6alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or mono- substituted by halogen; and
R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl;
R9 represents hydrogen or CrC4alkyl; and
R10 represents CrC^lkyl, which is unsubstituted or substituted by phenyl; or
R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 4 and R and R' both represent hydrogen; R3 denotes hydrogen, Y-R6 or NR7R8 wherein
Y represents O or NRN, wherein RN denotes hydrogen or CrC4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents CrC6alkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH2)q-, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocycIyl-(CH2)n~, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes HN, CrC4alkyl-N or O; and the corresponding salts of such 2-cyano-pyrimidine.
More preferred are 2-cyano-pyrimidines of formula I1 wherein Ri denotes a radical of formula
Figure imgf000019_0001
wherein A, E and G independently of each other represent O or CH2, under the proviso that at least one of A and E represents CH2; T is O or a bond, if G is CH2, and T is a bond, if G is O; Ra, Rb and Rc all represent hydrogen; s is O or 1 , t is 1 or 2 and p is 1;
R2 denotes bromo, chloro, isopropyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing two oxygen atoms, -C(O)-NR4R5 or -N(R9)-S02-Rio> wherein R4 represents
(a) CrC7alkyl which is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or Ci-C6alkyl which is unsubstituted or trisubstituted by halogen;
1-aza-(C7-C8)cycloalkyl, which is unsubstituted or substituted by CrC4alkyl; 1-aza-(C4)cycloalkyl, which is unsubstituted or substituted by Ci-C4alkyl; pyrrolidinyl, which is unsubstituted or substituted by halogen, Ci-C4alkoxy, Cr
C4alkoxy Ci-C4alkyl or Ci-C4alkyl amino; piperidinyl, which is unsubstituted or mono- or disubstituted by halogen, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C4-C6)cycloalkyl or Ci-C6alkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by CrC4alkyI or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-Cscycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- spiro[4.5]decane or 1-aza-(C5-C7)bicycloalkyl;
(b) N-(Ci-C4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, C1- C4alkoxy, CrC4alkoxy d-C4alkoxy, CrC4alkoxy phenyl, di(Ci-C4alkyl)-amino C1- C4alkoxy, N-(C1 -C4alkyl) piperazinyl, N-(C1 -C4alkyl) piperidinyloxy or N-(C1- C4alkyl) piperidinyl CrC4alkoxy;
(d) C3-C5cycloalkyl;
(e) pyrazolyl, which is mono- or disubstituted by pyridyl or phenyl; or
(f) N-(CrC6alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or mono- substituted by halogen; and
R5 represents hydrogen or Ci-C4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl;
Rg represents hydrogen or Crdalkyl; and
R1O represents CrC4alkyl, which is unsubstituted or substituted by phenyl; or
R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 4 and R and R' both represent hydrogen; R3 denotes hydrogen, Y-R6 or NR7R8 wherein
Y represents O or NRN, wherein RN denotes hydrogen or CrC4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents CrC6alkyI, phenyl, five or six-membered nitrogen containg hetaryl-
(CH2)q-, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl-(CH2)n-, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes HN, CrC4alkyl-N or O; or the salts of such 2-cyano-pyrimidines. Particularly preferred compounds of the invention are the compounds of the Examples.
Accordingly, in further aspects the invention provides:
• 2-cyano-pyrimidines of formula I or tautomers thereof, or a pharmaceutically acceptable salt of such a compound, for use in a method for the treatment of the human or animal body;
• the use of a 2-cyano-pyrimidine of formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound, for the preparation of a pharmaceutical product for the treatment of neuropathic pain or another disease mentioned herein;
• a method for the treatment of neuropathic pain or another disease mentioned herein, which comprises administering a 2-cyano-pyrimidine of formula I or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in a quantity effective against such disease, to a warm-blooded animal requiring such treatment;
• a pharmaceutical preparation, comprising a 2-cyano-pyrimidine of formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier;
• a method of using compounds of formula I and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals for inhibiting cathepsin S, and for the treatment of cathepsin S dependent conditions, such as the cathepsin S dependent conditions described herein, e.g. chronic inflammatory or neuropathic pain; and
• a method of selectively inhibiting cathepsin S activity in a mammal which comprises administering to a mammal in need thereof an effective cathepsin S inhibiting amount of a compound of formula I, more specifically this relates to a method of treating chronic inflammatory or neuropathic pain (or another disease mentioned herein) in mammals comprises administering to a mammal in need thereof a correspondingly effective amount of a compound of formula 1.
A compound of formula I may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se, especially a process characterized in that a) for the synthesis of a compound of the formula I wherein R2 represents -C(O)NR4R5, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols Ri, R4, R5, R6, R7, R8 and g are as defined for a compound of the formula I1 the 5-pyrimidyl carboxylic acid of formula Il
Figure imgf000022_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, Ci-C4alkyl-N, O(CH2)gNH, O or S, and the remaining radicals and symbols R1, R6, R7, R8 and g are as defined for a compound of the formula I, is reacted as defined under process variant (a) with an amine of formula III
R5
R4 (III) wherein the symbols R4 and R5 are as defined for a compound of the formula I;
b) alternatively for the synthesis of a compound of the formula I wherein R2 represents C(O)NR4R5, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols R1, R4, R5, R6, R7, R8 and g are as defined for a compound of the formula I, the 6-chloro pyrimidine derivative of formula IV
Figure imgf000022_0002
(IV) wherein R2 denotes -C(O)NR4R5, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S1 or NR7R8, and the remaining radicals R6, R7 and R8 are as defined for a compound of the formula I, is reacted as defined under process variant (b) with a compound of formula V
R1-X-H (V)
wherein X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and Ri has the meaning as defined for a compound of the formula I;
c) for the synthesis of a compound of the formula I wherein R2 denotes -N(R9)SO2RiO, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O1 NH or S1 or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols Ri, R6, R7, R8, Rg, R10 and g are as defined for a compound of the formula I, the 5-amino pyrimidine of formula Vl
Figure imgf000023_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols R1, R6, R7, R8 and g are as defined for a compound of the formula I, is reacted as defined under process variant (c) with a sulfonyl halide of formula VII
Figure imgf000023_0002
(VII) wherein the radical R10 is as defined for a compound of the formula I and Hal denotes halide, optionally followed by replacing the hydrogen atom in the sulfonamide function of the obtained compound of formula I by the group R9 by means of an alkylation reaction;
wherein in all cases the starting materials of formula Il to VII may also be present with functional groups in protected form, if necessary, and/or in the form of salts, provided a salt- forming group is present and the reaction in salt form is possible;
wherein any protecting groups in a protected derivative of a compound of the formula I are subsequently removed;
and, if so desired, an obtainable compound of formula I is converted into another compound of formula I, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.
Detailed Description of the Process Variants (a), (b) and (c):
Process Variant (a)
The amination of the carboxylic acid of formula Il can be accomplished by standard procedures known in the art, e.g., by reacting both compounds in a suitable solvent by the addition of a suitable coupling agent, such as POCI3, sulfuryl chloride fluoride, P2I4 or, in particular, N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC-HCI) or N.N'-dicyclohexylcarbodiimide (DCC). When using EDC-HCI or DCC the reaction can be carried out, e.g., in dimethylformamide, at a temperature between about 10 °C and about 35 0C, e.g. about 20 to 24 0C, for a period of about 3 to 48 hours, e.g. 24 hours or 36 hours.
Process Variant (b)
The reaction preferably takes place under standard conditions useful in the nucleophilic re¬ placement of leaving groups with amino compounds. The 6-chloro pyrimidine derivative of formula IV can be reacted with the nucleophil of formula V in the presence of a base in a suitable solvent. If, e.g., X denotes NH, CrC4alkyl-N or O(CH2)gNH, the reaction can be carried out by addition of a base, e.g. a nitrogen base, such as triethylamine, or a basic salt, such as an alkali metal carbonate, e.g. potassium carbonate, to the starting materials of formula IV and V in a suitable solvent; such as an ether, for example dioxane or tetrahydrofurane, or nitriles, such as acetonitrile, and heating the reaction mixture to about reflux temperature of the solvent for a period of about 6 to 12 hours, especially between 8 hours and 10 hours.
Process Variant (c)
The sulfonylamide of formula I wherein R2 denotes -N(R9)SO2RiO can be prepared by adding the sulfonylhalide of formula VII to a solution of the amine of formula Vl in a suitable solvent such as dichloromethane or chloroform in the presence of an equimolar amount of pyridine or a similar base and, optionally, catalytic amounts of dimethylamino pyridine, at a temperature between about 10 0C and about 50 0C, e.g. between about 20 and 25 0C, for a period of about 1 to 12 hours, e.g. between 2 hours and 6 hours.
Protecting groups
If one or more other functional groups, for example carboxy, hydroxy, amino, or mercapto, may need to be protected in the starting materials by protecting groups. The protecting groups employed may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" {Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.
Additional process steps
Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. A salt with two acid mo¬ lecules (for example a dihalogenide of a compound of formula I) may also be converted into a salt with one acid molecule per compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 130 to 170°C, one molecule of the acid being ex¬ pelled per molecule of a compound of formula I.
Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
General process conditions
All process steps described here can be carried out under known reaction conditions, pre¬ ferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralisiing agents, for example ion exchangers, typically cation exchangers, for example in the H+ form, de¬ pending on the type of reaction and/or reactants at reduced, normal, or elevated tempera¬ ture, for example in the range from -1000C to about 19O0C, preferably from about -8O0C to about 15O0C, for example at -80 to -6O0C, at room temperature, at - 20 to 4O0C or at the boi- ling point of the solvent used, under atmospheric pressure or in a closed vessel, where ap¬ propriate under pressure, and/or in an inert atmosphere, for example under argon or nitro¬ gen.
Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
The solvents from which those can be selected which are suitable for the reaction in ques¬ tion include for example water, esters, typically lower alkyl-lower alkanoates, e.g diethyl acetate, ethers, typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g. tetrahydro- furan, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically metha¬ nol, ethanol or 1- or 2-propanol, nitriles, typically acetonitrile, halogenated hydrocarbons, typically dichloromethane, acid amides, typically dimethylformamide, bases, typically hetero¬ cyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g. ace¬ tic anhydride, cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process. Such solvent mixtures may also be used in processing, for example through chromatography or distribution.
In the preferred embodiment, a compound of formula I is prepared according to or in analogy to the processes and process steps defined in the Examples.
The dosage of the active ingredient depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. The invention relates also to pharmaceutical compositions comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned disorders, of compound of the formula I or a tautomer thereof together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid. There are used for oral administration especially tablets or gelatin capsules that comprise the active ingredient together. with diluents, for example lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol. Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenterally administrable compositions or in the form of infusion solutions. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical compositions, which may, if desired, comprise other pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 1% to 95%, especially from approximately 1% to approximately 20%, active ingredient(s).
Starting materials
Starting materials of the formula Il to VII are known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art, described in the Examples or, in particular, as desribed hereinbelow.
The 5-pyrimidyl carboxylic acid of formula Il
Figure imgf000028_0001
(H) wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N or O(CH2)gNH, and the remaining radicals and symbols R-t, R6, R7, Rs and g are as defined for a compound of the formula I, can be obtained by reacting the 5-pyrimidyl carboxylic acid halide of the formula VIII
Figure imgf000029_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, and the remaining radicals R6, R7 and R8 are as defined for a compound of the formula I, in a first step with an alcohol AIkOH, wherein AIk denotes alkyl, preferably CrC4alkyl, and in a second step with an amine of the formula V
R1-X-H (V)
wherein X denotes HN, CrC4alkyl-N, 0(CH2)gNH, and R-i is as defined for a compound of the formula I1 in order to prepare the 2-chloro-pyrimidine of formula IX,
Figure imgf000029_0002
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, AIk denotes alkyl, preferably Ci-C4alkyl, X denotes HN, Ci-C4alkyl-N, O(CH2)gNH, and g, R1, R6, R7 and R8 are as defined for a compound of the formula I. The reaction of the 5-pyrimidyl carboxylic acid halide of the formula VIII with the alcohol AIkOH can be carried out under customary conditions, e.g., by dissolving the acid halide in a suitable solvent, such as dichloromethane, and adding staggered or simultaneously the alcohol and an equivalent amount of a suitable base, such as a tri(CrC4aIkyl)amine, at a temperature between -10 and 25 0C, preferably at about 0 0C. The obtained carboxylic acid ester can advantageously be further reacted without intermediate isolation thereof by addition of the amine of formula V and an equivalent amount of a suitable base, such as the same or a different tri(Ci-C4alkyl)amine as used above, at a temperature between -10 and + 25 0C, such as about 0 0C
The 2-chloro-pyrimidine of formula IX, wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, AIk denotes alkyl, preferably CrC4alkyl, X denotes HN, C1- C4alkyl-N, O(CH2)gNH and g, R1, R6, R7 and R8 are as defined for a compound of the formula I1 is then further reacted for a period of 15 to 360 minutes with an alkali metal cyanide, such as potassium cyanide, in a suitable solvent, such as dimethylformamide or dimethylsulfoxide, in the presence of a suitable base, such as 1 ,4-diazabicyclo[2.2.2]octane, at a temperature between +15 and +35 0C, preferably at about 20 to 25 0C, furnishing the 2-cyano-pyrimidine- 5-carboxylic acid ester of formula X
Figure imgf000030_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O1 NH or S, or NR7R8, AIk denotes alkyl, preferably CrC4alkyl, X denotes HN, CrC4alkyl-N, O(CH2)gNH, and g, R1, R6, R7 and R8 are as defined for a compound of the formula I. Said carboxylic acid ester of formula X is then finally subjected to a saponification reaction by addition of a great excess of water under conditions known in the art catalyzed by a suitable base furnishing the 5-pyrimidyl carboxylic acid of formula Il as defined above. For instance, the carboxylic acid ester can be solved in a solvent miscible with water, such a tetrahydrofuran, and a solution of a suitable base, such as lithium hydroxide, in water is added at a temperature between -5 and 20 0C, preferably at about 0 0C.
The 5-pyrimidyl carboxylic acid of formula Il
Figure imgf000031_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes O or S, and the remaining radicals R1, R6, R7 and R8 are as defined for a compound of the formula I, can be obtained by reacting the 5-pyrimidyl carboxylic acid halide of the formula VIII wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, and the remaining radicals R6, R7 and R8 are as defined for a compound of the formula I, in a first step with water, and in a second step with an alcohol or thiol of the formula V, wherein X denotes O or S and Ri is as defined for a compound of the formula I, in order to prepare the 2-chloro-pyrimidyl-5-carboxylic acid of formula Xl,
Figure imgf000031_0002
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes O or S, and the remaining radicals R1, R6, R7 and R8 are as defined for a compound of the formula I.
The reaction of the 5-pyrimidyl carboxylic acid haiide of the formula VIII with water can be carried out under customary conditions, e.g., by dissolving the acid halide in a suitable solvent which is miscible with water, such as tetrahydrofuran, and adding an excess amount of water, at a temperature between 15 and 35 0C, preferably at about 20 to 25 0C. The obtained carboxyiic acid is reacted with a strong base, such as potassium tert-butoxide, and the alcohol or thiol of the formula V in a suitable solvent, such as tetrahydrofuran, for a period of 30 to 360 minutes at a temperature between -10 and 20 0C, preferably at about O 0C.
The 2-chloro-pyrimidyl-5-carboxy!ic acid of formula Xl, wherein the radicals have the meanings as provided above, is then reacted in a suitable solvent such as dimethyl- formamide at a temperature between 30 and 60 0C, preferably at about 45 to 55 0C for a period of 10 to 120 minutes, more preferably 30 to 45 minutes, with an excess amount of an allyl halide, e.g. allylbromide, in the presence of a suitable base, such as potassium carbonate, delivering the carboxyiic allyl ester of formula (XII),
Figure imgf000032_0001
wherein the radicals have the meanings as provided for the compound of formula Xl above.
The carboxyiic allyl ester of formula (XII), wherein the radicals have the meanings as provided for the compound of formula Xl above, is then reacted for a period of 15 to 360 minutes with an alkali metal cyanide, such as potassium cyanide, in a suitable solvent, such as dimethylformamide or dimethylsulfoxide, in the presence of a suitable base, such as 1 ,A- diazabicyclo[2.2.2]octane, at a temperature between +15 and +35 "C1 preferably at about 20 to 25 0C, to furnish the carboxyiic allyl ester of formula (XIII),
Figure imgf000032_0002
(XIII) wherein the radicals have the meanings as provided for the compound of formula Xl above.
Finally, the compound of formula Il as defined above is obtained by hydrolysis of said carboxylic allyl ester of formula XIII by addition of a Pd(O) catalyst, e.g. tetrakis(triphenyl- phosphinei)palladium(O), and morpholine to a solution of the allyl ester in a suitable solvent, such as tetrahydrofuran, at a temperature between +15 and +35 0C, preferably at about 20 to 25 0C, followed by addition of an aqueous solution of sodium hydrogencarbonate.
The 5-pyrimidyl carboxylic acid of formula Il wherein R3 denotes Y-R6, wherein Y represents O, NH or S, X denotes HN, CrC4alkyl-N or O(CH2)gNH, and the remaining radicals and symbols R1, R6 and g are as defined for a compound of the formula I, can also be obtained by reacting firstly the 2-methylthio-5-pyrimidyl carboxylic acid of the formula XIV
Figure imgf000033_0001
with the amine, alcohol or thiol of formula XV
H-R3 (XV)
wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I, in the presence of a strong base, such as sodium hydrid, in a suitable solvent such as tetrahydrofuran at a temperature between -10 and 30 CC, preferably at about 20 0C, and, subsequently, the reaction product is reacted in a suitable solvent such as dimethylformamide at a temperature between 30 and 60 0C, preferably at about 45 to 55 0C, for a period of 10 to 120 minutes, more preferably 45 to 75 minutes, with an excess amount of an allyl halide, e.g. allylbromide, in the presence of a suitable base, such as potassium carbonate, delivering the carboxylic allyl ester of formula XVI,
Figure imgf000034_0001
wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I.
The methylthio group in the carboxylic allyl ester of formula XVI is subsequently replaced by a cyano group by means of a two step reaction. In the first step, the carboxylic allyl ester of formula XVI, wherein the radicals have the meanings as provided above, is oxidized with a suitable oxidizing agent, preferably with a 3-fold molar excess of meta chloro perbenzoic acid, in a suitable solvent, such as dichloromethane, at a temperature between -10 and +10 0C, preferably at about 0 0C. In a second step, the resulting methyl sulfonyl group is replaced by a cyano group by reaction of the obtained intermediate in a suitable solvent, for instance dichloromethane, with a suitable cyanide, e.g. sodium cyanide, in the presence of a suitable catalyst, such as tetra(alkyl)ammonium bromide, at a temperature between 15 and 30 0C, preferably at about 20 to 25 0C1 furnishing the 2-cyano pyrimidyl-5-carboxylic acid allyl ester of formula XVII,
Figure imgf000034_0002
wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I.
The obtained 2-cyano pyrimidyl-5-carboxylic acid allyl ester of formula XVII, wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I, is finally transferred into the carboxylic acid of formula Il by first reacting 2-cyano pyrimidyl-5-carboxylic acid allyl ester of formula XVII with the amine of formula V and an equivalent amount of a suitable base, such as the same or a different tri(CrC4alkyl)amine as used above, at a temperature between -10 and + 25 0C, such as about 0 0C, and secondly by hydrolysis of the obtained allyl ester by addition of a Pd(O) catalyst, e.g. tetrakis(triphenyl- phosphine)palladium(O), and morpholine to a solution of the allyl ester in a suitable solvent, such as tetrahydrofuran, at a temperature between +15 and +35 0C1 preferably at about 20 to 25 0C, followed by addition of an aqueous solution of sodium hydrogencarbonate.
The 6-chIoro pyrimidine derivative of formula IV
Figure imgf000035_0001
wherein R2 denotes -C(O)NR4R5, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-Rβ, wherein Y represents O, NH or S, or NR7R8, and the remaining radicals R6, R7 and R8 are as defined for a compound of the formula I, can be obtained starting from the 2-methylthio-5-pyrimidyl carboxylic acid of the formula XIV
Figure imgf000035_0002
Said carboxylic acid can be reacted as specified in the Examples with oxalyl chloride to furnish the corresponding carboxylic acid chloride, which can be transferred by reaction with the amine of formula III, wherein R4 and R5 have the meanings as defined for a compound of formula I above, into the carboxylic acid amide of formula XVIII,
Figure imgf000035_0003
(XVIII), wherein R2 denotes -C(O)NR4R5 and R4 and R5 have the meanings as defined for a compound of formula I above. Such carboxylic acid amide of formula XVIII can be further reacted with the amine, alcohol or thiol of formula XV wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I, in the presence of a strong base, such as sodium hydride, in a suitable solvent such as tetrahydrofuran at a temperature between -10 and 30 0C, preferably at about 20 0C, furnishing the 2- methylthiopyrimidine derivative of formula XIX,
Figure imgf000036_0001
wherein R2 denotes -C(O)NR4R5, R3 denotes Y-R6, wherein Y represents O, NH or S, and R4, R5 and R6 have the meanings as defined for a compound of formula I above.
The methylthio group in the carboxylic allyl ester of formula XIX is finally replaced by a cyano group by means of a two step reaction as described for the carboxylic allyl ester of formula XVI, to result in the 6-chloro pyrimidine derivative of formula IV as described above.
The 5-amino pyrimidine derivative of formula Vl
Figure imgf000036_0002
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols R1, R6, R7, R8 and g are as defined for a compound of the formula I, can be obtained starting from the 2- methylthio-5-pyrimidyl carboxylic acid of the formula XIV
Figure imgf000037_0001
as follows:
In the first step, the carboxylic acid of the formula XIV is transferred to the corresponding carbamic acid allyl ester of formula XX
Figure imgf000037_0002
as specified in the Examples below.
Such carbamic acid allyl ester of formula XX can be further reacted with the amine, alcohol or thiol of formula XV wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I1 in the presence of a strong base, such as sodium hydride or potassium tert-butoxide, in a suitable solvent such as tetrahydrofuran at a temperature between -10 and 30 0C, preferably at about 20 0C, furnishing the 2-methylthio- pyrimidine derivative of formula XXI,
Figure imgf000037_0003
wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula I. The methylthio group in the 2-methylthio-pyrimidine of formula XXI is subsequently replaced by a cyano group by means of a two step reaction as described for the carboxylic ally! ester of formula XlX above, furnishing the 2-cyano pyrimidyl-5-carbamic acid allyl ester of formula XXII,
Figure imgf000038_0001
wherein R3 denotes Y-R6, wherein Y represents O, NH or S and R6 is as defined for a compound of the formula 1.
Said 2-cyano pyrimidyl-5-carbamic acid allyl ester is finally transferred into the 5-amino pyrimidine derivative of formula Vl by first reacting the compound of formula XXII with an amine of formula V as specified hereinabove and subsequent hydrolysis of the carbamic acid function in the obtained intermediate by addition of a Pd(O) catalyst, e.g. tetrakis- (triphenylphosphine)palladium(O), and morpholine to a solution of the carbamic acid allyl ester in a suitable solvent, such as tetrahydrofuran, at a temperature between +15 and +35 0C, preferably at about 20 to 25 0C, followed by addition of an aqueous solution of sodium hydrogencarbonate.
Starting from the 5-amino pyrimidine derivative of formula Vl wherein the radicals are as defined for a compound of formula I above, the 2-cyano pyrimidines of formula I wherein R2 denotes -NHC(O)R4, wherein R4 is as defined for a compound of formula I above, can be obtained by simple acylation reactions which are known as such in the art.
The spirocyclic starting materials being incorporated in radical R1 can be prepared in accordance with the procedures described in the Examples or by acetalisation reactions. The diols being used as a starting material for such procedures described in the Examples as well as for acetalisation reactions can be, for instance, be prepared by subjecting in a first step a dicarboxylic acid ester of formula XXIII,
Figure imgf000039_0001
(XXIlI)
wherein Rn is CrC4alkyl and b is an integer selected from 1 , 2 or 3, to a reduction reaction, e.g. to reduction with LiAIH4 in tetrahydrofuran, to furnish the diol of formula (XXIV)1
Figure imgf000039_0002
wherein b is an integer selected from 1 , 2 or 3. In a second step the hydroxy groups are transferred into suitable leaving groups for nucelophilic substitution reactions, e.g. by reaction with p-tosylchloride in the presence of a suitable base, such as triethylamine, under suitable reaction conditions. Subsequently, nucelophilic substitution reaction is carried out with potassium cyanide in an aprotic solvent, such as dimethylsulfoxide, to deliver the di- (cyanomethyl) cycloalkyl compound of formula XXV
Figure imgf000039_0003
wherein b is an integer selected from 1 , 2 or 3. The di-(cyanomethyl) cycloalkyl compound of formula XXV is then further subjected to alkaline hydrolysis providing the free di-carboxylic acid derivative and finally said di-carboxylic acid derivative is reduced, e.g. by reduction with LiAIH4 in tetrahydrofuran, to the diol of formula (XXVI),
Figure imgf000039_0004
wherein b is an integer selected from 1 , 2 or 3.
EXAMPLES The Examples which follow serve to illustrate the invention without limiting the scope thereof.
Temperatures are measured in degrees Celsius. Unless indicated otherwise, reactions are carried out at room temperature. The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g. microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR).
Abbreviations
Abbreviations used are those conventional in the art and, in particular, have the meanings provided below.
Ac acetyl aq. Aqueous
Boc tert-butoxycarbonyl cone. concentrated mCPBA meta-chloroperbenzoic acid
DABCO 1 ,4-diazabicyclo[2.2.2]octane
DMAP dimethylaminopyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
Et ethyl
EtOAc ethyl acetate h hour(s) iPr isopropyl
LAH lithium aluminium hydride
LDA lithium diisopropyl amide
Me methyl
MS mass spectrometry
NMR nuclear magnetic resonance
Ph phenyl
RP-HPLC reversed phase high pressure liquid chromatography sat. saturated soln. Solution TBAB tetrabutylammonium bromide
TFA trifluoroacetic acid
THF tetrahydrofurane
Starting Materials
2-Cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid
To a solution of 4-chloro-2-cyano-pyrimidine-5-carbonyl chloride (8.80 mmol) in CH2CI2 (30 ml_) are successively added MeOH (9.60 mmol) and /-Pr2NEt (9.80 mmol) at 0 0C. After stirring at 0 0C for 15 min, to the reaction mixture are successively added C-spiro[2.5]oct-6- yl-methylamine hydrochloride (8.50 mmol) and triethylamine (24.0 mmol) at 0 0C. The reaction mixture is stirred at 0 0C to room temperature for 50 min, and then the bulk of solvent is concentrated in vacuo. After the residue is diluted with AcOEt, the mixture is washed with aq. KHSO4, water, sat. aq. NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The residue is directly used for the next reaction without further purification.
To a solution of the above residue in DMSO (10 ml.) are successively added a solution of KCN (14.2 mmol) in water (2 ml_) and DABCO (2.80 mmol) at room temperature. After stirred at the same temperature, the reaction mixture is diluted with AcOEt. The resulting mixture is washed with water (x 2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography (n-hexane : AcOEt = 5 : 1 ) to afford the cyanopyrimidine, which is directly used for the next reaction without further purification.
To the above cyanopyrimidine in THF (20 mL) is added a solution of LiOH-H2O (19.0 mmol) in water (10 mL) at 0 0C. After stirring at room temperature for 1 h, the reaction is quenched by the addition of aq. KHSO4. The resulting precipitated solid is filtered, washed with water, and triturated with the small amount of CH3CN to afford the title compound; 1H NMR (400 MHz, DMSO), δ 0.22 (2H, dd), 0.32 (2H, dd), 0.95-0.98 (2H, m), 1.15-1.24 (2H, m), 1.68- 1.74 (5H, m), 3.47 (2H1 1), 8.88 (1H, t).
4-(3,3-Difluoro-pyrrolidin-1 -yl)piperidine hydrochloride A mixture of 3,3-difluoro-pyrrolidine hydrochloride (2.02 mmol), 4-oxo-piperidine-i-carboxylic acid terf-butyl ester (2.02 mmol) and Ti(OZPr)4 (2.42 mmol) in THF is stirred at room temperature for 1h. To the resulting mixture are added ethanol (3 mL) and NaBH3CN (1.21 mmol). After stirring for 17h, the reaction is quenched by the addition of sat. aq. NaHCO3 and the resulting precipitate is filtered out. After the filtrate is diluted with AcOEt, the mixture is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-(3,3-difluoro-pyrrolidin-1-yl)-piperidine-1- carboxylic acid ferf-butyl ester; 1H NMR (CDCI)3 δ: 1.34-1.52 (2H, m), 1.45 (9H, s), 1.79 (2H1 bd), 2.19-2.33 (3H, m), 2.78 (2H, dd), 2.83 (2H, dd), 2.95 (2H, dd), 4.00 (2H, bs). 4-(3,3-difluoro-pyrrolidin-1-yl)-piperidine-1-carboxylic acid fert-butyl ester (1.77 mmol) is treated with AN HCI in 1 ,4-dioxane (6 mL) and stirred at room temperature for 1h. The reaction mixture is concentrated in vacuo and the resulting residue is used for the next step without further purification.
4-Phenyl-2-pyridin-2-yl-2H-pyrazol-3-yIamine
To a solution of 3-hydroxy-2-phenylacrylonitrile (3.4 mmol) in EtOH (6.8 mL) is added AcOH (0.66 mL) and 2-hydrazinopyridine (6.8 mmol) at room temperature. After stirred at 80 0C for 5 h, the reaction mixture is cooling and concentrated in vacuo. The residue is diluted with H2O and extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue is triturated with ether to give the title compound; 1H NMR (CDCI3) δ 6.27(br, 2H), 7.11-7.14 (m, 1H), 7.21-7.25 (m, 1H)1 7.40- 7.48 (m, 4H), 7.65 (s, 1H), 7.79-7.84 (m, 1H)1 8.02 (d, 1H)1 8.35-8.37 (m, 1H).
3-Cyclopropyl-2,2-dimethylpropylamine hydrochloride
To a solution of isobutyronitrile (29 mmol) in THF (60 mL) is added LDA (2 M in THF, 35 mmol) at -78 0C. After stirring at -78 0C for 2 h, to this solution is added bromomethyl cyclopropane (32 mmol) at -78 0C. The mixture is stirred at room temperature for 13 h, and then the reaction is quenched by the addition of aq. NH4CI. The mixture is extracted with ether, and the combined organic extracts are washed with H2O and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 3-cyclopropyl-2,2- dimethylpropionitrile, which is directly used for the next reaction without further purification. To a suspension of LAH (87 mmol) in THF (200 mL) is added dropwise cone. H2SO4 (44 mmol) at O 0C. After stirred at O 0C for 0.5 h, to the suspension is added 3-cyclopropyl-2,2- dimethylpropionitrile at 0 0C. The mixture is refluxed for 4.5 h. After cooling down to 0 0C, the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is treated with HCI in 1 ,4-dioxane. The resulting suspension is concentrated in vacuo to give the title compound; 1H NMR (DMSO) δ: 0-0.03 (2 H1 m), 0.39- 0.44 (2 H, m), 0.97 (6 H, s), 1.19 (2 H, d), 2.66 (q, 2 H)1 8.05 (3 H1 br).
2-Cyclopropyl-2-methylpropylamine hydrochloride
To a solution of cyclopropylacetonitrile (25 mmol) in THF (60 mL) is added LDA (2 M in THF1 30 mmol) at -78 0C. After stirring at -78 0C for 2 h, to the solution is added iodomethane (30 mmol) at -78 0C. The reaction mixture is stirred at room temperature for 1 h, and then the reaction is quenched by the addition of aq. NH4CI. After the mixture is extracted with ether, the organic extracts are washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 2-cyclopropylpropionitrile, which is directly used for the next reaction without further purification.
To a solution of the 2-cyclopropylpropionitrile (25 mmol) in THF (60 mL) is added LDA (2 M in THF, 74 mmol) at -78 0C. After stirring at -78 0C for 2.5 h, to the solution is added iodomethane (99 mmol) at -78 0C. The reaction mixture is stirred at room temperature for 11 h, and then the reaction is quenched by the addition of aq. NH4CI. After the mixture is extracted with ether, the organic extracts are washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 2-cyclopropyl-2- methylpropionitrile, which is directly used for the next reaction without further purification. To a suspension of LAH (87 mmol) in THF (200 mL) is added dropwise cone. H2SO4 (44 mmol) at 0 0C. After stirring at 0 0C for 0.5 h, to the suspension is added the 3-cyclopropyl- 2,2-dimethyIpropionitriIe at 0 0C. The reaction mixture is refluxed for 4.5 h. After cooling down to 0 0C1 the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is treated with HCI in 1,4-dioxane. The resulting suspension is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
2-(1 -Methylcyclobutyl)ethylamine hydrochloride
To a solution of cyclobutanecarboxylic acid (50 mmol) in THF (10OmL) is added LDA (2 M in THF, 125mmol) at 0 0C. After stirring at 0 0C for 2 h, to the solution is added iodomethane (125 mmol) at 0 0C. The reaction mixture is stirred at room temperature for 14 h. The reaction is quenched by the addition of water, and then the aqueous layer is separated from THF layer. To this aqueous layer is added aq. NH4CI, and the mixture is acidified to pH < 2 with aq. HCI. After the mixture is extracted with AcOEt, the organic extracts are washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 1-methylcyclobutanecarboxylic acid, which is directly used for the next reaction without further purification.
To a suspension of LAH (200 mmol) in THF (250 mL) is added 1-methylcyclo¬ butanecarboxylic acid (32 mmol) at 0 0C. The reaction mixture is stirred at 60 0C for 6 h. After cooled down to 0 0C, the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo to give the (1-methylcyclobutyl) methanol, which is directly used for the next reaction without further purification.
To a solution of (1-methylcyclobutyl) methanol (32 mmol) in CH2CI2 (100 mL) are added triethylamine (65 mmol), trimethylamine hydrochloride (6 mmol), and a solution of p- toluenesulfonyl chloride (49 mmol) in CH2CI2 (50 mL) at 0 0C, then the mixture is stirred at 0 0C for 0.5 h. The reaction is quenched by the addition of water, and the mixture is extracted with CH2CI2. The combined organic extracts are washed with water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo to give toluene-4-sulfonic acid 1-methylcyclobutylmethyl ester, which is directly used for the next reaction without further purification.
To a solution of the toluene-4-sulfonic acid 1-methylcyclobutylmethyl ester in DMF (60 mL) is added potassium cyanide (60 mmol). The reaction mixture is stirred at 60 °C for 11 h. After cooled to room temperature, the mixture is diluted with water, and then extracted with ether. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to (i-methylcyclobutyOacetonitrile, which is directly used for the next reaction without further purification.
To a suspension of LAH (97 mmol) in THF (200 mL) is added dropwise cone. H2SO4 (49 mmol) at 0 °C. After stirred at 0 0C for 1 h, to the suspension is added (1-methyl- cyclobutyl)acetonitrile at 0 0C. The reaction mixture is refluxed for 4.5 h. After cooled down to 0 0C1 the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is treated with HCI in 1,4-dioxane, and then the suspension is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
2-Phenyl-2-pyrroIidin-1 -ylethylamine dihydrochloride To a suspension of benzaldehyde (9.4 mmol) in H2O (6 mL) are added sodium hydrogensulfate (9.4 mmol) and pyrrolidine (9.4 mmol). After stirring at room temperature for 0.5 h, to the suspension is added sodium cyanide (9.4 mmol), and the resulting mixture is stirred at room temperature for 15 h. The reaction mixture is diluted with sat. aq. NaHCO3, then extracted with AcOEt. The organic extracts are washed with water (x 2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give phenylpyrrolidin-1-ylacetonitrile, which is directly used for the next reaction without further purification. To a solution of LAH (26 mmol) in THF (100 mL) is added dropwise cone. H2SO4 (13 mmol) at O 0C. After stirred at O 0C for 0.5 h, to the solution is added phenylpyrrolidin-1-ylacetonitrile at O 0C, then the mixture is stirred at 60 0C for 3 h. After cooled down to O 0C, the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo. After the residue is diluted with ether, the mixture is treated with HCI in 1,4-dioxane. The precipitate is collected by filtration to give the title compound, which is directly used for the next reaction without further purification; 1H NMR (DMSO) δ: 1.74-1.99 (4 H, m), 2.87 (2 H, br), 3.14 (2 H, br), 3.40-3.78 (4 H, m), 4.64 (1 H, br), 7.50-7.53 (3 H. m), 7.75-7.77 (2 H, m), 8.26 (3H, br).
2-phenyl-3-pyrrolidin«1 -yl propylamine
To a solution of tropic acid (0.12 mmol) and pyrrolidine (0.12 mmol) in DMF (20 mL) are added HOAt (0.18 mmol) and EDCI-HCI (0.18 mmol). The reaction mixture is stirred at room temperature for 14 h. The reaction mixture is diluted with water, then extracted with AcOEt. The organic extracts are successively washed with water, sat. aq, NaHCO3, H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 3-hydroxy-2-phenyl-1~pyrrolidin-1-yl propan-1-one. To a solution of LAH (10 mmol) in THF (50 mL) is added 3-hydroxy-2-phenyl-1-pyrrolidin-1-yl propan-1-one (5 mmol) at 0 0C. The reaction mixture is stirred at 0 0C for 1.5 h. After cooled down to 0 0C1 the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo to give 2-phenyl-3- pyrrolidin-1-yl propan-1-ol, which is directly used for the next reaction without further purification.
To a solution of 2-phenyl-3-pyrrolidin-1-yl propan-1-ol (3.4 mmol) in THF (10 mL) is successively added phthalimide (4.1 mmol), triphenylphosphine (5.1 mmol) and diethyl azodicarboxylate (5.1 mmol) at 0 0C, then the mixture is stirred at 0 0C for 1.5 h. After dilution with water, the mixture is acidified to pH < 3 with aq. KHSO4 then washed with AcOEt. The aqueous layer basified to pH > 11 with sat. aq. NaHCO3 then extracted with AcOEt. The organic extracts are washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is triturated with ether to give 2-(2-phenyl-3- pyrrolidin-1-yl propyl) isoindole-1,3-dione, which is directly used for the next reaction without further purification.
A solution of 2-(2-phenyl-3-pyrrolidin-1-yl propyl)isoindole-1 ,3-dione (3 mmol) and hydrazine monohydrate (6 mmol) in ethanol (10 ml_) is refluxed for 3.5 h. The reaction mixture is cooled and filtered through celite. The filtrate is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
C-[1-(4-methoxybenzyl)-4-phenyl-piperidin-4-yl]-methylamine dihydrochloride
Figure imgf000046_0001
2HCI
To a solution of 4-phenylpiperidine-4-carbonitrile (9.0 mmol) in MeOH (20 mL) is added 4- methoxybenzaldehyde (14 mmol) and sodium triacetoxyborohydride (27 mmol). The reaction mixture is stirred at room temperature for 2.5 h, and then the bulk of solvent is concentrated in vacuo. After dilution with water, and the mixture is extracted with AcOEt. The organic extracts are washed with water, sat. aq. NaHCO3, water and brine, then dried over MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in ether, and then trated with HCI in AcOEt. The precipitate is collected by filtration to give 1-(4-methoxyben∑yl)~4- phenylpiperidine-4-carbonitrile hydrochloride, which is directly used for the next reaction without further purification; 1H NMR (CDCI3) δ: 2.19 (2 H, d), 3.10-3.24 (4 H, m), 3.59 (2 H, d), 3.84 (3 H, s), 4.17 (2 H, d), 6.99 (2 H, d), 7.35-7.45 (3 H, m), 7.57-7.62 (4 H, m), 13.08 (1H, br).
To a solution of LAH (27 mmol) in THF (100 mL) is added dropwise cone. H2SO4 (14 mmol) at 0 0C for 0.5 h, then 1-(4-methoxybenzyl)-4-phenylpiperidine-4-carbonitrile is added at 0 0C, then the reaction mixture is refluxed for 2 h. After cooled down to 0 0C, the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is treated with HCI in 1 ,4-dioxane, then concentrated in vacuo to give the titled compound, which is directly used for the next reaction without further purification. 1 -(4-aminomethyl-4-phenylpiperidin-1 -yl)-ethanone hydrochloride
To a solution of C-[1-(4-methoxybenzyl)-4-phenyl-piperidin-4-yl]-methylannine dihydrochloride (3.9 mmol) in ether (20 mL) and 1 N aq. NaOH (20 mL) is added BoC2O (4.6 mmol) at 0 0C, then the mixture is stirred at room temperature for 18 h. The reaction mixture is acidified to pH < 3 with 10 % aq. KHSO4, then the aqueous layer is separated from the organic layer. The acidic aqueous layer is basified to pH > 12 with aq. NaOH, then the mixture is quickly extracted with AcOEt (x 2). The combined organic extracts are washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated to give [1-(4-Methoxy- benzyl)-4-phenylpiperidin-4-ylmethyl] carbamic acid terf-butyl ester, which is directly used for the next reaction without further purification.
To a solution of [1-(4-methoxy-benzyl)-4-phenylpiperidin-4-ylmethyl]carbamic acid te/f-butyl ester (3.2 mmol) in CH2CI2 is added 1-chloroethyl chloroformate (4.7 mmol), then the mixture is stirred at room temperature for 2.5 h. After the bulk of solvent is concentrated in vacuo, the residue suspended in ether and filtered. After the filtrate is concentrated in vacuo, the residue is suspended in hexane and filtered. The filtrate is concentrated in vacuo to give the 4-(terf-butoxycarbonylaminomethyI)-4-phenylpiperidine-1-carboxylic acid 1-chloroethyl ester, which is directly used for the next reaction without further purification. A mixture of 4-(ferf-butoxycarbonylaminomethyl)-4-phenylpiperidine-1-carboxylic acid 1- chloroethyl ester in MeOH is stirred at 60 0C for 5 h, then the reaction mixture is concentrated in vacuo to give (4-phenylpiperidin-4-ylmethyi) carbamic acid te/f-butyl ester, which is directly used for the next reaction without further purification. To a solution of (4-phenylpiperidin-4-ylmethyl) carbamic acid te/t-butyl ester (2.1 mmol) in CH2CI2 is added acetic anhydride (3.1 mmol) and triethylamine (3.1 mmol) at O 0C. The reaction mixture is stirred at room temperature for 2.5 h then the bulk of solvent is concentrated in vacuo. After the residue is suspended in AcOEt1 the mixture is washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give (1-acetyl-4- phenylpiperidin-4-ylmethyI) carbamic acid te/t-butyl ester, which is directly used for the next reaction without further purification.
To a solution of (1-acetyl-4-phenylpiperidin-4-ylmethyl) carbamic acid te/t-butyl ester in ether is added 4 N HCI in 1,4-dioxane. The reaction mixture is stirred at room temperature for 1 h, and concentrated in vacuo. The resulting solid is washed with ether to give the title compound, which is directly used for the next reaction without further purification. 4-(2-Fluorophenyl)-1-methylpiperidine-4-carbonitrile hydrochloride
To a solution of (2-fluorophenyl)acetonitrile (15 mmol) in THF (20 mL) are successively added bis-(2-chloroethyl)methylamine hydrochloride (16 mmol), tetrabutylammonium hydrogensulfate (1.5 mmol), and 40% aq. NaOH (20 mL), then the mixture is refluxed for 5.5 h. The reaction mixture is cooled at room temperature, diluted with water, then extracted with THF. The organic extracts are washed with water (x 2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is dissolved in ether, then HCI in 1,4-dioxane is added. The precipitate is collected by filtration to give the titled compound, which is directly used for the next reaction without further purification; 1H NMR (DMSO) δ: 2.43-2.60 (4 H, m), 2.86 (3 H, d), 3.20-3.28 (2 H, m), 4.02-4.04 (2 H, m), 7.31-7.40 (2 H, m), 7.48-7.60 (2 H, m), 11.16 (1 H, br).
1,4-diphenyIpiperidine-4-carbonitrile
To a suspension of 4-phenylpiperidine-4-carbonitrile hydrochloride (6.7 mmoi) in toluene (30 mL) are successively added bromobenzene (8.0 mmol), sodium te/f-butoxide (17 mmoi), tri- o-tolylphosphine (1.3 mmol), and tris(dibenzylideneacetone)dipalladium (0.7 mmol), then the mixture is refluxed for 20 h. The reaction mixture is cooled, diluted with water, then extracted with AcOEt. The organic extracts are washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCI3) δ: 2.12-2.20 (2 H, m), 2.23-2.28 (2 H, m), 2.94-3.01 (2 H, m), 3.86 (2 H, d), 6.83 (1 H, t), 7.04 (2 H, d), 7.22-7.28 (2 H, m), 7.36-7.41 (1 H, m), 7.45-7.49 (2 H, m), 7.56-7.59 (2 H, m).
C-(1-methyl-4-phenylpipeπdin-4-yl)methylamine dihydrochloride
To a solution of LAH (7.5 mmol) in THF (10 mL) is added dropwise cone. H2SO4 (3.8 mmoi) at 0 0C. After stirred at 0 0C for 0.5 h, 1-methyl-4-phenylpiperidine-4-carbonitrile hydrochloride (2.5 mmol) is added at 0 0C. The reaction mixture is stirred at 60 0C for 6 h. After cooled down to 0 0C, the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo. The residue is suspended in ether and treated with HCl in 1 ,4-dioxane. The resulting white solid is collected by filtration to give the title compound, which is directly used for the next reaction without further purification.
C-[4-phenyl-1-(2,2,2-trifluoroethyl) piperidin-4-yl]methylaminedihydrochloride
To a solution of 4-phenylpiperidine-4-carbonitrile hydrochloride (6.7 mmol) in pyridine (13 mL) is added trifluoroacetic anhydride (10 mmol) at 0 0C, then the mixture is stirred at 0 0C for 1 h. The reaction mixture is diluted with water, and extracted with AcOEt. The organic extracts are successively washed with water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo to give 4-phenyl-1 -(2,2,2- trifluoroacetyl)piperidine-4-carbonitrile, which is directly used for the next reaction without further purification.
To a solution of LAH (40 mmol) in THF (40 mL) is added dropwise cone. H2SO4 (20 mmol) at 0 0C and the mixture is stirred for 0.5 h. To the solution is added 4-phenyl-1 -(2,2,2- trifluoroacetyl)piperidine-4-carbonitri!e at 0 0C, then the mixture is refluxed for 3 h. The reaction mixture is cooled down at 0 0C and the reaction is quenched by the addition of Na2SO4-IOH2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo. The residue is suspended in ether and treated with HCI in 1,4- dioxane. The white solid is collected by filtration to give the titled compound, which is directly used for the next reaction without further purification.
C-spiro[3.5]non-7-yl-methylamine hydrochloride
To a solution of 1,1-di-(2-hydroxyethyl)-cyclobutane (37.8 g, 262 mmol) and Me3N-HCI (5.136 g, 53.7 mmol) in CH2CI2 (680 mL) is added Et3N (146 mL, 1052 mmol) at 0 0C. After 5 min, p-TsCI (106.4 g, 558 mmol) is added at the same temperature. The reaction mixture is stirred at 0 0C for 2 h, then warmed up to room temperature for 2 h. The resulting mixture is diluted with CH2CI2 (1600 mL), and washed with aq. sat. NaHCO3 (400 mL, pH of the aq. layer - 9), and brine (400 mL). The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (silica gel, /7-hexane : EtOAc = 2:1) to give the desired di-tosylate.
To a suspension of NaH (60 %, 34.3 g, 858 mmol) in THF (890 mL) is added dropwise a solution of diethyl malonate (160 mL) in THF (640 mL) at 0 0C during 30 min. Hydrogen gas is vigorously liberated. After stirring at 0 0C for 10 min the white suspension dissolves to give a colorless solution and a solution of the di-tosylate from the previous reaction (110.9 g, 245 mmol) in THF (660 mL) is added dropwise at 0 0C. After stirring at 0 0C to room temperature for 1 h the reaction mixture (yellow suspension) is refluxed for 20 h. The mixture is cooled to 0 0C, and then sat. aq. NH4CI (800 mL) and water (400 ml) are added at 0 0C. The layers are separated. The aqueous layer is extracted with EtOAc (500 mL x 4). The combined organic layers are washed with brine (500 mL), dried over MgSO4, and concentrated in vacuo. The excess diethyl malonate is removed by distillation to give the desired spiro[3.5]cyclononane-7,7-di-carboxylic acid di-ethyl ester.
To a solution of spiro[3.5]cyclononane-7,7-di-carboxylic acid di-ethyl ester (62.4 g, 233 mmol) in DMSO (620 mL) is added LiCI (19.7 g) and H2O (4.2 mL) at room temperature. The reaction mixture is stirred at 185 0C for 13 h. The mixture is cooled to 0 0C, and poured into water (1600 mL). The resulting mixture is extracted with EtOAc (30OmL x 4). The combined extracts are washed with water (150 ml x 2), dried over MgSO4, and concentrated in vacuo to give spiro[3.5]cyclononane-7-carboxylic acid ethyl ester, which is immediately subjected to the next reaction.
To a suspension of LiAIH4 (15.6 g) in THF (450 mL) is added dropwise a solution of spiro[3.5]cyclononane-7-carboxylic acid ethyl ester in THF (220 mL) at 0 0C during 1 h. The reaction mixture is stirred at 0 0C to room temperature for 14 h and excess LiAIH4 is quenched with Na2SO4-IOH2O at 0 0C. The mixture is stirred at 0 0C for 30 min, and then filtered through a celite pad. The filtrate is concentrated to provide 7-(hydroxymethyl)- spiro[3.5]cyclononane.
To a solution of 7-(hydroxymethyl)-spiro[3.5]cyclononane (11 g, 71.3 mmol) in CH2CI2 (100 mL) are added Et3N (21.8 mL) and Me3N-HCI (682 mg) at 0 0C. A solution of p- toluenesulfonyl chloride (14.28 g) in CH2CI2 (20 ml) is added dropwise to the reaction mixture at 0 0C. The reaction mixture is stirred at 0 0C for 30 min, then the bulk of solvent is removed. After the residue is diluted with EtOAc (300 mL), the mixture is washed with aq. KHSO4 (80 mL x 2), water (80 mL), sat. aq. NaHCO3 (80 mL), water (80 mL), and brine (80 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to give the corresponding tosylate, which is directly used for the next reaction without further purification.
To a solution of the above tosylate in DMF (100 mL) is added NaN3 (27.5 g) at room temperature. The reaction mixture is stirred at 60 0C for 13 h . After dilution with ether (300 mL), the mixture is washed with water (80 mL x 2) and brine (80 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to give 7-azidomethyl-spiro[3.5]cyclononane, which is directly used for the next reaction without further purification.
To a solution of the above azide in THF (100 mL)-H2O (50 mL) is added Ph3P (20 g) at room temperature. The reaction mixture is stirred at the same temperature for 3 h. After dilution with EtOAc (200 mL), the mixture is extracted with 1 N HCI (80 mL x 3). The combined aqueous extracts are washed with CH2CI2 (50 mL), and then basified with 6 N NaOH. The resulting mixture is extracted with ether (100 mL x 3). The combined organic extracts are dried K2CO3, and filtered. To this filtrate 4 N hydrogen chloride in EtOAc is added, and the resulting hydrochloride salt is filtered, washed with ether, and dried at 55 0C under reduced pressure to furnish C-spiro[3.5]non-7-yl-methylarnine hydrochloride.
Reference Example 1 : 2-Cvano-4-(cvclohexylmethylamino)pyrimidine-5-carboxylic acid (2-morpholin-4-yl-1 -phenylethvDamide
Figure imgf000051_0001
To a solution of 2-cyano-4-(cyclohexylmethylamino)-pyrimidine-5-carboxylic acid (0.33 mmol, step 1.4) in DMF (2.0 mL) are added 2-morpholin-4-yl-1-phenylethylamine (69 mg, step 1.3), EDCI-H2O (0.50 mmol) and HOAt (0.50 mmol) at room temperature. After stirring at room temperature for 24 h, the reaction mixture is diluted with AcOEt. The mixture is washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; 1H NMR (DMSO) δ 0.6-1.08 (m, 2H), 1.20- 1.35 (m, 3H), 1.65-1.78 (m, 6H), 2.48-2.53(m, 2H), 2.60-2.62 (m, 2H), 2.87-2.93 (m, 2H), 3.31-3.35 (m, 1H), 3.36-3.44 (M, 1H), 3.60-3.68 (m, 4H), 5.29-5.35 (m, 1H), 7.34-7.36 (m, 1H), 7.43-7.47 (m, 2H), 7.50-7.52 (m-, 2H), 8.86 (s, 1H), 9.00-9.04 (m, 1H), 9.21 (d, 1H).
Step 1.1 : (2-Morpholin-4-yl-2-oxo-1-phenylethyl)carbamic acid terf-butyl ester To a solution of terf-butoxycarbonylaminophenylacetic acid (4.0 mmol) in CH2CI2 (8.0 mL) is added morpholine (4.0 mmol), EDCI-H2O (4.8 mmol) and DMAP (0.40 mmol) at room temperature. After stirring at room temperature for 24 h, the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting solid is triturated with ether-n-hexane to give the title compound; 1H NMR (CDCI3) δ 1.41 (s, 9H)1 3.08-3.12 (m, 1H), 3.20-3.28 (m, 1H), 3.39-3.45 (m, 1H), 3.49-3.60 (m, 3H), 3.66-3.76 (m, 2H), 5.54 (d, 1 H), 6.01 (d, 1 H), 7.29-7.36 (m, 5H).
Step 1.2: 2-Amino-1-morpholin-4-yl-2-phenylethanone
To a solution of (2-morpholin-4-yl-2-oxo-1-phenylethyl)carbamic acid tert-butyl ester (3.0 mmol) in CH2CI2 (6.0 mL) is added TFA (2.0 mL) at 0 0C. After stirring at room temperature for 24h, the reaction mixture is basified to pH 8 with sat. aq NaHCO3. The mixture is extracted with CH2CI2, and then the combined organic extracts are dried over Na2SO4 and concentrated in vacuo to give the title compound; 1H NMR (CDCI3) δ 2.02 (s, 2H), 3.09-3.14 (m, 1 H), 3.20-3.25 (m, 1H), 3.34-3.40 (m, 1 H), 3.46-3.60 (m, 3H), 3.65-3.71 (m, 1H), 3.74- 3.80 (m, 1H), 7.27-7.34 (m, 5H).
Step 1.3: 2-Morpholin-4-yl-1-phenylethyIamine
To a stirred suspension of LAH (6.1 mmol) in THF (25 mL) is added dropwise a solution of 2- amino-1-morpholin-4-yl-2-phenylethanone (670 mmol) in THF (5 mL) at 0 0C. The reaction mixture is refluxed for 2 hr, and then the reaction is quenched by the addition of Na2SO4- 10H2O at 0 0C. After stirring at room temperature for 0.5 h, the resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
Step 1.4: 2-Cyano-4-(cyclohexylmethylamino)-pyrimidine-5-carboxylic acid
To a solution of 2,4-dichloro-pyrimidine-5-carbonyl chloride (8.80 mmol) in CH2CI2 (30 mL) are successively added MeOH (9.60 mmol) and /-Pr2NEt (9.80 mmol) at 0 0C. After stirring at 0 0C for 15 min, to the reaction mixture are successively added cyclohexylmethylamine hydrochloride (8.50 mmol) and triethylamine (24.0 mmol) at 0 0C. The reaction mixture is stirred at 0 0C to room temperature for 50 min, and then the bulk of solvent is concentrated in vacuo. After the residue is diluted with AcOEt, the mixture is washed with aq. KHSO4, water, sat. aq. NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The residue is directly used for the next reaction without further purification.
To a solution of the above residue in DMSO (10 mL) are successively added a solution of KCN (14.2 mmol) in water (2 mL) and DABCO (2.80 mmol) at room temperature. After stirring at the same temperature for 1 h, the reaction mixture is diluted with AcOEt. The resulting mixture is washed with water (x 2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography (/7-hexane : AcOEt = 5 : 1 ) to afford the cyanopyrimidine, which is directly used for the next reaction without further purification.
To the above cyanopyrimidine in THF (20 mL) is added a solution of LiOH-H2O (19.0 mmol) in water (10 mL) at O 0C. After stirring at room temperature for 1 h, the reaction is quenched by the addition of aq. KHSO4. The resulting precipitated solid is filtered, washed with water, and triturated with the small amount of CH3CN to afford the titled compound.
Reference Example 2: 4-r2-(6-Chloro-2-methanesulfonylpyrimidin-4-yloxy)ethvπ- piperidine-i-carboxylic acid fert-butyl ester
To a solution of the crude 4-[2-(6-chloro-2-methylsulfanylpyrimidin-4-yloxy)ethyl]piperidine-1- carboxylic acid ferf-butyl ester (4.7 g, step Ref. Ex. 2.1) in CH2CI2 (100 mL) is added m- CPBA (40 mmol) at 0 0C. After stirring at room temperature for 3 h, the reaction mixture is quenched by 10% Na2SO3 at 0 0C. The separated organic layer is washed twice with sat. NaHCO3 and dried over MgSO4. The organic layer is evaporated in vacuo. The resulting residue is dissolved in n-hexane:AcOEt (1 :1) and silica gel is added to the mixture. After filtration, the filtrate is evaporated in vacuo to give a crude 4-[2-(6-chloro-2-methane- sulfonylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid ferf-butyl ester.
Ref. Example 2, Step 2.0: 4-[2-(6-Chloro-2-methylsulfanylpyrimidin-4-yloxy)- ethyl]piperidine-1-carboxylic acid ferf-butyl ester
NaH (6.4 mmol) is added to a solution of 4-(2-hydroxy-ethyl)piperidine-1-carboxylic acid tert- butyl ester (5.3 mmol) in THF (10 mL) at 0 0C. After stirring at room temperature for 30 min, a solution of 4;6-dichloro-2-methylsulfanyl-pyrimidine (5.3 mmol) in THF (10 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and quenched by H2O. The mixture is extracted with AcOEt. The organic layer is washed with H2O, dried over MgSO4 and evaporated in vacuo to give a crude 4-[2-(6-chloro-2- methylsulfanylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxyIic acid fert-butyl ester. Ref. Example 2, Step 2.1: 4-[2-(6-Chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1- carboxylic acid te/f-butyf ester
To a solution of the crude 4-[2-(6-chloro-2-methanesulfonylpyrimidin-4-yl oxy)ethyl]- piperidine-1-carboxylic acid tert-butyl ester (4.9 g) and NaCN (14 mmol) in CH2CI2:H2O (50 mL, 4:1) is added TBAB (tetrabutylammonium bromide) (0.06mmol) at room temperature. After stirring at the same temperature for 10 h, TBAB (0.19 mml) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 2 h and H2O is added. The organic layer is separated, dried over MgSO4 and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-[2-(6-chloro-2-cyanopyrimidin-4- yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester; 1H-NMR (CDCI3), δ: 1.14 -1.28 (2 H, m), 1.45 (9H, s), 1.56 -1.78 (7H1 m), 2.69 (2H, t), 4.11 (2H1 m), 4.49 (2H, t), 6.93 (1H, s).
Ref. Example 2, Step 2.2: 4-(2-{2-Cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin- 4-y!oxy} ethyl)piperidine-1-carboxylic acid terf-butyl ester
To a solution of 4-[2-(6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (0.82 mmol) and C-spiro[3.5]non-7-ylmethylamine (0.86 mmol) in CH3CN (10 mL) is added K2CO3 (2.2 mmol) at room temperature. After stirring at 80 0C for 12 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed twice with H2O and dried over MgSO4 and evaporated in vacuo to give a crude 4-(2- {2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester.
Examples 2 to 57
By repeating the procedures described above using appropriate starting materials and conditions, the following compounds are obtained.
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Example 58: 2-Cyano-4-r(spiror2.51oct-6-yl methyl) aminolpyrimidine-5-carboxylic acid f5-(1 -methylpiperidin-4-yloxy) biphenyl-2-vnamide
To a solution of 5-(1-methylpiperidin-4-yloxy)biphenyl-2-ylamine (0.27 mnnol, step 58.2) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.33 mmol) in DMF (2 ml.) are added EDCI-HCI (0.54 mmol) and HOAt (0.54 mmol) at 0 0C. After stirring at the ambient temperature overnight, the reaction mixture is purified by RP- HPLC to give the title compound as a white solid; 1H NMR (CDCI3), δ 0.18-0.21 (2 H, m), 0.27-0.30 (2 H, m), 0.90- 0.94 (2 H, m), 1.14-1.25 (2 H, m), 1.58-1.78 (5 H, m), 1.85-1.92 (2 H, m), 2.02-2.06 (2 H1 m), 2.32 (3 H, s), 2.70 (2 H, br s), 3.41-3.44 (2H, t), 4.35 (1H, m), 6.89 (1 H, d), 6.97 (1 H, dd), 7.35-7.37 (2 H, m), 7.45-7.52 (3 H, m), 7.65 (1 H, s), 7.92 (1 H, s), 8.06 (1 H, d), 8.90 (1 H1 s).
Step 58.1 : 5-Fluoro-2-nitrobiphenyl
To a solution of 5-fluoro-2-nitrophenol (10.0 mmol) and triethylamine (12.0 mmol) in CH2CI2 (100 mL) is added trifluoromethanesulfonic acid anhydride (11.0 mmol) at 0 0C. After stirring at the same temperature for 0.5 h under N2, the reaction mixture is diluted with H2O. The mixture is extracted with CH2CI2 and AcOEt1 respectively (x 2). The combined organic extracts are dried over Na2SO4, filtered through a short pad of celite and silica gel, washed with AcOEt. The filtrate is concentrated in vacuo to give trifluoromethanesulfonic acid 5- fluoro-2-nitrophenyl ester as a yellow oil. To a solution of trifluoromethanesulfonic acid 5-fluoro-2-nitrophenyl ester (4.0 mmol) in DME (10 mL) are added phenylboronic acid (4.8 mmol), Pd(PPh3)4 (0.4 mmol), and K3PO4 (3.2 mmol) at room temperature. After stirring at 80 0C for 6 h, the reaction mixture is filtered through celite, and the filter cake is washed with AcOEt. The filtrate is diluted with water and extracted with ether (x 2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n- hexane : AcOEt = 6 :1) to give the title compound; 1H NMR (CDCI3), δ 7.12-7.19 (2 H, m), 7.29-7.32 (2 H, m), 7.42-7.45 (3 H, t), 7.94 (1 H, dd).
Step 58.2: 5-(1-Methylpiperidin-4-yloxy)biphenyl-2-ylamine
To a solution of 5-fluoro-2-nitrobiphenyl (0.86 mmol) in toluene/aq.KOH (2 mL/2 mL) are added 1-methylpiperidin-4-ol (1.1 mmol) and TBAB (0.17 mmol) at room temperature. After stirred at 70 0C overnight, the reaction mixture is diluted with AcOEt and water, and extracted with AcOEt (x 2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (CH2CI2: MeOH=I 0:1) to give 1-methyl-4-(6-nitrobiphenyl-3-yloxy)piperidine as a yellow solid. To a solution of 1-methyl-4-(6-nitrobiphenyl-3-yloxy) piperidine (0.63 mmol) in EtOH (5 mL) is added 5 % palladium on activated carbon (50 mg) under N2 atmosphere. The reaction mixture is vigorously stirred at room temperature for 2.5 h under H2, and then filtered through celite (linsed with AcOEt). The filtrate is concentrated in vacuo to the title compound as a brown oil; 1H NMR (CDCI3), δ 1.79-1.87 (2 H, m), 1.96-2.01 (2 H, m), 2.25- 2.31 (2 H, m), 2.29 (3 H, s), 2.70 (2 H, brs), 3.52 (2H, m), 4.15-4.18 (1 H, m), 6.70 (1 H, d), 6.76-6.80 (2 H, m), 7.32-7.38 (1 H1 m), 7.42-7.45 (4 H1 m).
Examples 59 to 65
By repeating the procedures described above using appropriate starting materials and conditions, the following compounds are obtained.
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000067_0001
Figure imgf000068_0001
Example 66: 2-Cvano-4-r(spiror2.51oct-6-ylmethv[)aminoTpyrimidine-5-carboxylic acid (4-benzyl-1-isopropylpiperidin-4-yl)amide
To a solution of the 4-amino-4-benzylpiperidine-1-carboxylic acid tert-butyl ester (0.38 mmol, step 66.1) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.38 mmol) in DMF (1.3 mL) are added HOAt (0.51 mmol) and EDCI-HCI (0.51 mmol) at 0 0C. After warming to room temperature and stirring for 15 h, the reaction mixture is diluted with AcOEt and washed with 1Λ/ aq. KHSO4, sat. aq. NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)-amino]- pyrimidine-δ-carbonytyarninojpiperidine-i-carboxylic acid tert-butyl ester. To a solution of 4-benzyl-4-({2-cyano-4-[(spiro[2.5}oct-6-ylmethyl)amino]-pyrimidine-5- carbonyl}amino)piperidine-1-carboxyric acid te/f-butyl ester (0.14 mmol) in CH2CI2 (1.5 mL) is added TFA (0.4 mL) at 00C. After stirring at room temperature for 0.5h, the reaction mixture is concentrated in vacuo. The residue is dissolved in DMF (1.5 mL) and treated with K2CO3 (0.35 mmol) and isopropyl iodide (0.28 mmol) at 00C. After stirring at room temperature for 5h, the reaction mixture is diluted with AcOEt and washed with H2O and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by RP-HPLC to give the title compound; 1H NMR (CDCI3), δ: 0.18-0.26 (2H, m), 0.27-0.34 (2H, m), 0.91-0.99 (2H, m), 1.01-1.13 (6H1 s), 1.17-1.33 (2H, m), 1.63-1.97 (7H, m), 2.15-2.40 (4H, m), 2.64-2.90 (3H1 m), 3.15 (2H1 s), 3.46 (2H, dd), 5.28 (1H, s), 7.02-7.10 (2H, m), 7.20- 7.30 (3H, m), 8.05 (1H1 s), 8.70 (1H1 bs).
Step 66.1: 4-Amino-4-benzyl-piperidine-1-carboxylic acid terf-butyl ester
To a solution of 4-benzyl-piperidine-1 ,4-dicarboxylic acid mono-terf-butyl ester (0.65 mmol) in 1,4-dioxane (2 mL) are added Et3N (0.71 mmol) and DPPA (0.71 mmol) at room temperature. After warming to 1000C and stirring for 2h, the reaction mixture is diluted with AcOEt. The organic layer is washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (4 mL) and 6Λ/ aq. NaOH (0.22 mL) is added at room temperature. After stirring for 4h, the reaction mixture is diluted with CH2CI2, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCI3), δ: 1.18 (2H, bs), 1.28-1.37 (2H, m), 1.46 (9H, s), 1.51-1.64 (2H, m), 2.66 (2H, s), 3.20 (2H, dd), 3.74 (2H1 bd), 7.13-7.19 (2H, m), 7.21-7.34 (3H, m).
Examples 67 to 72
By repeating the procedures described above using appropriate starting materials and conditions, the following compounds are obtained.
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000070_0001
Figure imgf000071_0001
Example 73: (R)-2-Cvano-4-(methylspirof2.51oct-6-ylmethylamino)pyrimidine-5- carboxylic acid (2-phenvMs3yrroKdin-1-ylmetrtylethv0arnide
To a solution of the crude 2-cyano-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5- carboxylic acid (82 mg, step 73.4) in DMF (1.5 ml_) are added (f?)-2-phenyl-1-pyrrolidin-1- ylmethylethylamine (0.3 mmol), EDCI-HCI (0.4 mmol), and HOAt (0.4 mmol) at room temperature. The reaction mixture is stirred for 24h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt and the organic extracts are dried over Na2SO4, filtered, concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS(M+1)+ 488, Rf (solvent) 0.13 (CH2CI2: MeOH = 10:1).
Step. 73.1: 2,4-Dichloropyrimldine-5-carboxylic acid ally! ester
To a solution of the 2,4-dich(oropyrimidine-5-carbonyl chlorode (5.1 mmol) in THF (10 ml_) are added allyl alcohol (5.1 mmol) and DIEA (Λ/,/V-diisopropylethylamine) (6.1 mmol) at 0 0C. After stirring at 0 0C for 3.5 h, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCI3) δ 4.87-4.89 (m, 2H), 5.35-5.48 (m, 2H), 5.97-6.08 (M, 1H), 9.05 (s, 1H).
Step 73.2: 2-Chloro-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxyIic acid allyl ester To a solution of the 2,4-dichloropyrimidine-5-carboxylic acid allyl ester (1.6 mmol) in dioxane (6 mL) is added Et3N (2.4 mmol) at room temperature. A solution of methyl-spiro[2.5]oct-6- ylmethylamine (1.6 mmol) in dioxane (2.0 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and the reaction is quenched by the addition of water. The mixture is extracted with CH2CI2. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound (370 mg); 1H NMR (CDCI3) δ 0.15-0.19 (m, 2H), 0.25-0.29 (m, 2H), 0.87-0.91 (m, 2H)1 1.08-1.20 (m, 2H), 1.60-1.85 (m, 5H), 2.95 (s, 3H), 3.59 (d, 2H), 4.77-4.78 (m, 2H), 5.29-6.08 (m, 1 H), 8.48 (s, 1H).
Step 73.3: 2-Cyano-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxyIic acid allyl ester
To a solution of the 2-chloro-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid aliyl ester (1.1 mmol) in DMSO (2.0 mL) are added KCN (1.6 mmol), DABCO (0.3 mmol), and H2O (0.2 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound.
Step 73.4: 2-Cyano-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid
To a solution of a 2-cyamo-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid allyl ester (0.87 mmol) in THF (8.7 mL) are added Pd(PPh3)4 (0.087 mmol) and morphorine (1.7 mmol) at room temperature. The reaction mixture is stirred at room temperature for 0.5h, and the reaction is quenched by the addition of water and sat. aq NaHCO3. The mixture is washed with ether. The aqueous layer is acidified to pH 2 with sat. aq KHSO4. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. Example 74: (R)-2-Cvano-4-(sDiror2.51oct-6-ylmethyl)Dyrimidine-5-carboxylic acid (2- phenyl 1-pyrrolidin-1-ylmethylethvQamide
To a solution of the crude 2-cyano-4-(spiro[2.5]oct-6-ylmethyl)pyrimidine-5-carboxylic acid (22 mg, step 74.5) in DMF (1.5 mL) are added (RJ-2-phenyl-1-pyrrolidin-1- ylmethylethylamine (0.083 mmol), EDCI-H2O (0.11 mmol), and HOAt (0.11 mmol) at room temperature. The reaction mixture is stirred for 24h and the reaction is quenched by the addition of H2O. The mixture is extracted with AcOEt, and the organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS(M+1)+ : 474, Rf (solvent): 0.63 (CH2CI2: MeOH = 10:1 ).
Step 74.1 : 2,4-Dichloroprimidine-5-carboxylic acid
To a solution of the 2,4-dichloropyrimidine-5-carbonyl chloride (24 mmol) in THF (24 mL) is added H2O (0.64 mL) at room temperature. The reaction mixture is stirred at room temperature for 0.83 h and then diluted with H2O. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude titled compound; 1H NMR (CDCI3) δ 6.80 (brs, 1H), 9.18 (s, 1H).
Step 74.2: 2-Chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid
To a solution of a 2,4-dichloroprimidine-5-carboxy!ic acid (440 mg) in THF (4.0 mL) are added /-BuOK (potassium te/ϊ-butoxide) (5.7 mmol) and spiro[2.5]oct-6-ylmethanol (2.3 mmol) in THF (1.0 mL) at O 0C. After stirring at O 0C for 1.5 h, the reaction is quenched by the addition of sat. aq. NaHCO3. The mixture is washed with ether. The aqueous layer is acidified to pH 2 with sat. aq. KHSO4, then extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude title compound.
Step 74.3: 2-Chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid ally! ester
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid (490 mg) in DMF (2.9 mL) are added K2CO3 (4.4 mmol) and allyl bromide (7.4 mmol) at room temperature. After stirring at 50 0C for 0.5 h, the reaction mixture is cooling and diluted with H2O. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give a crude title compound.
Step 74.4: 2-Cyano-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine~5-carboxy!ic acid allyl ester (0.62 mmol) in DMSO (1.0 mL) are added KCN (0.94 mmol), DABCO (0.19 mmol), and H2O (0.10 mL) at room temperature. The reaction mixture is stirred at room temperature for 0.5 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the titled compound; 1H NMR (CDCI3) δ 0.19-0.20 (m, 2H), 0.21-0.33 (m, 2H), 0.91- 0.96 (m, 2H), 1.23-1.33 (m, 3H), 1.72-1.85 (m, 4H), 4.38 (d, 2H), 4.84 (d, 2H), 5.31-5.45 (m, 1H), 9.01 (s, 1 H).
Step 74.5: 2-Cyano-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid
To a solution of a 2-cyano-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester (0.096 mmol) in THF (1.0 mL) are added Pd(PPh3J4 (tetrakis(triphenyl- phosphine)palladium) (0.0096 mmol) and morpholine (0.19 mmol) at room temperature. The reaction mixture is stirred at room temperature for 0.5h and the reaction is quenched by the addition of sat. aq. NaHCO3. The mixture is extracted with ether. The aqueous layer is acidified to pH 2 with sat. aq. KHSO4. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude titled compound.
Example 75: 2-Cyano-4-f2-(1 -methylpiperidin-4-yl)ethoxy|-6-T(spiror3.51non-7-yl- methyl)amino]pyrimidine-5-carboxylic acid methylamide
To a solution of 4 [2-(1-ferf-butoxycarbonylpiperidin-4-yl)ethoxy]-2-cyano-6-[(spiro[3.5]non-7- ylmethyI)amino]pyrimidine-5-carboxylic acid (0.23 mmol, step 75.4) and 2 M methyl amine solution (0.30 mmol) in DMF (1 mL) are added EDCl-HCI (0.34 mmol) and HoAt (0.34 mmol) at 0 0C. The reaction mixture is stirred at room temperature for 1 h. After dilution with AcOEt, the mixture is washed with H2O and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by silicagel column chromatography to give 4-(2- {2-cyano-5-methylcarbamoyl-6-[(spiro[3.5]non-7-ylmethyl)amino]-pyrimidin-4- yloxy}ethyl)piperidine-1-carboxylic acid te/t-butyl ester as a white solid; 1H-NMR (CDCI3), δ: 0.98-1.07 (2H,m), 1.14-1.85 (2OH, m), 146 (9H, s), 2.70 (2H, t), 2.93 (3H, d), 3.33 (2H, t), 4.05-4.15 (2H, m), 4.54 (2H, t), 7.80-7.85 (1H, m), 10.10-10.15 (1 H, m). To a solution of 4-(2-{2-cyano-5-methylcarbamoyl-6-[(spiro[3.5]non-7-yl-methyl)amino]- pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl esterther (0.25 mmol) in CH2Cb (3 mL) is added TFA (0.70 mL) at room temperature. After stirring at the same temperature for 0.5 h, the reaction mixture is evaporated in vacuo, which is directly used for the next reaction. To a solution of the crude product in THF (5 mL) is added aq. HCHO (0.10 mL) at room temperature. After stirring at the same temperature for 0.5 h, 1 M NaBH3CN solution (0.10 mmol) is added to the reaction mixture at 0 0C. The reaction mixture is warmed to room temperature and further stirred for 0.5 h. After dilution with AcOEt, the organic layer is washed twice with H2O and evaporated in vacuo. The residue is purified by RP-HPLC to give a 2-cyano-4-[2-(1-methylpiperidin-4-yl)ethoxy]-6-[(spiro[3.5]non-7-ylmethyl)amino] pyrimi- dine-5-carboxylic acid methylamide (NVP-TAF059) as a white solid, 1H-NMR (CDCI3), δ: 0.97-1.07 (2 H, m), 1.19-1.26 (2 H, m), 1.43-1.88 (18H, m), 2.14-2.17 (2 H, m), 2.42 (3H, S), 2.93 (3H, d), 3.05-3.08 (2H, m), 3.32 (2H, t), 4.54 (2H, t), 7.81 (1H, br d), 10.14 (1H, bit).
Step 75.1 : 4-[2-(1 -ferf-Butoxycarbonylpiperidin^-yOethoxyl-θ-chloro^-methylthio- pyrimidine-5-carboxylic acid allyl ester
To a mixture of NaH (9.0 mmol) and Λ/-BOC-4-piperidine ethanol (4.9 mmol) in dry THF (15 mL) is added dropwise a solution of 4,6-dichIoropyrimidine-2-methylthio-5-carboxylic acid (3.8 mmol) in dry THF at 0 0C and the mixture is stirred at room temperature for 1.5 h. The mixture is diluted with AcOEt, washed with H2O, and brine. The organic layer is dried over MgSO4, filtered, and concentrated to give the adduct product (1.6 g), which is directly used for the next reaction without further purification.
To a solution of the above product (1.5 mmol) in DMF (7 mL) is added allylbromide (7.5 mmol) and K2CO3 (17.4 mmol) at room temperature. After stirred at 50 0C for 1 h, the mixture is diluted with AcOEt. The organic layer is washed with H2O and brine. After drying MgSO4, the mixture is filtered, and concentrated under reduced pressure. The residue is directly used for the next reaction. 1H-NMR (CDCI3), δ: 1.12-1.73 (9H1 m), 1.46 (9H, s), 2.54 (3H1 s), 2.67-2.69 (2H, m), 4.08-4.13 (2H, m), 4.47 (2H, t), 4.80 (2H, dt), 5.30 (1 H, brd), 5.43 (1H, m), 5.98 (1H, ddt)
Step 75.2: 4-[2-(1-fert-Butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methane sul- fonylpyrimidine-5-carboxylic acid ally! ester
Following the synthetic procedure as described in Ref. Example 2, step 2.1, 4-[2-(1-fe/t- butoxycarbonyl piperidin^-yOethoxyl^.β-dichloropyrimidine-δ-carboxylic acid allyl ester (3.0 mmol) is treated with m-CPBA (8.9 mmol) in CH2CI2 (10 mL) at 0 0C. After usual work-up, the crude material is purified by silica gel chromatography to give 4-[2-(1-ferf- butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methane sulfonylpyrimidine-5-carboxylic acid allyl ester as colorless oil. 1H-NMR (CDCI3), δ: 1.12-1.73 (9H, m), 1.46 (9H, s), 2.67-2.69 (2H, m), 3.20 (3H, s), 4.08-4.11 (2H, m), 4.46 (2H, t), 4.87 (2H, dt), 5.33-5.37 (1 H, m), 5.42- 5.47 (1 H, m), 5.98 (1 H, ddt)
Step 75.3: 4-[2-(1-tert-Butoxycarbonylpiperidin-4-y!)ethoxy]-6-chloro-2-cyano pyrimi- dine-5-carboxylic acid allyl ester
Following the synthetic procedure as described in Ref. Example 2, a solution of 4-[2-(1-ferf- butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methanesulfonylpyrimidine-5-carboxylic acid allyl ester (1.8 mmol) in CH2CI2 (5 mL) is treated with a solution of NaCN (2.2 mmol) and tetra-n-butylammonium bromide (0.10 mmol) in water (2 mL) for 0.5 h. After usual work-up, the crude material is purified by silica gel chromatography to give 4-[2-(1-ferf- butoxycarbonylpiperidin-4-yl) ethoxy]-6-chloro-2-cyanopyrimidine-5-carboxylic acid allyl ester as colorless oil; 1H-NMR (CDCI3), δ: 1.12-1.73 (9H, m), 1.48 (9H, s), 2.68 (2H, brt), 4.05-4.09 (2H, m), 4.55 (2H, t), 4.87 (2H, dt), 5.33-5.37 (1H, m), 5.41-5.47 (1H, m), 5.98 (1 H, ddt).
Step 75.4: 4-[2-(1 -fert-Butoxycarbonylpiperidin-4-yl)ethoxy]2-cyano-6-[(spiro[3.5]non- 7-ylmethyl) amino] pyrimidine-5-carboxylic acid
To a solution of 4-[2-(1-fert-butoxycarbonylpiperidin-4-yl)ethoxy]-6-chloro-2-cyanopyrimidine- 5-carboxylic acid allyl ester (1.1 mmol) and C-Spiro[3.5]non-7-yl-methylamine (1.4 mmol) in C2H5CN (10 mL) is added triethylamine (2.8 mmol) at room temperature. After stirring at 80 0C for 1 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed with H2O and aq. KHSO4 and brine. The organic layer is dried over MgSO4 and evaporated in vacuo, which is directly used for the next reaction without further purification. To a solution of the crude 4-[2-(1-fe/f-butoxy carbonylpiperidin-4- yI)ethoxy]-2-cyano-6-[(spiro[3.5]non-7-ylmethyl) amino] pyrimidine-5-carboxylic acid allyl ester (1.1 mmol) in THF (5 mL) are added morpholine (3.4 mmol) and Pd(PPh3)4 (0.06 mmol) successively. After stirring at the same temperature for 0.5 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The residue is purified by silica gel column chromatography to give a 4-[2-(1-tenf- butoxycarbonylpiperidin^-yOethoxy^-cyano-e-KspirotS.δlnon^-ylmethyl) amino]pyrimidine- 5-carboxylic acid as yellow pale solid; 1H-NMR (CDCI3), 5: 0.97-1.08 (2 H, m), 1.15-1.29 (5 H, m), 1.48 (9H1 s), 1.48-1.86 (15H, m), 2.69 (2 H, t), 3.39 (2H, t), 4.11 (2H, m), 4.66 (2H,t), 9.42 (1 H, br t).
Example 76: 2-Cvano-4-r2-(1 -methylpiperidin-4-yl)ethoxy1-6-r(spiror2.51oct-β-ylmethvπ- aminoipyrimidine-5-carboxylic acid benzyl amide
To a solution of 4-(2-{5-benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl) amino]- pyrimidin-4-yloxy}ethyI)piperidine-1-carboxylic acid terf-butyl ester (0.68 mmol) in CH2CI2 (10 mL) is added TFA (2 mL) at 0 0C. After stirring for 2 h at 0 0C under N2 atmosphere, the mixture is concentrated and dried in vacuo to give 2-cyano-4-(2-piperidin-4-yl-ethoxy)-6- [(spiro[2.5]oct-6-yl methyl) amino]pyrimidine-5-carboxylic acid benzyl amide as a yellow solid. 1H-NMR (CDCI3), δ 0.17-0.30 (4 H, m), 0.89-0.93 (2 H, m), 1.00-1.11 (2 H, m), 1.14-1.24 (2 H, m), 1.29-1.38 (1 H, m), 1.51-1.81 (9 H, m), 2.41- 2.48 (2 H, m), 2.99- 3.02 (2 H, m), 3.42 (2 H, t), 4.45 (2 H, t), 4.56 (2 H, d), 7.29-7.39 (5 H1 m), 8.17 (1 H, t), 10.16 (1 H, t).
To a solution of 2-cyano-4-(2-piperidin-4-yl-ethoxy)-6-[(spiro[2.5]oct-6-yl methyl)amino]- pyrimidine-5-carboxylic acid benzylamide (0.19 mmol) in THF (2 mL) is added formaldehyde solution (100 μL), and the resulting solution is stirred for 0.5 h at room temperature. After cooled to 0 0C, 1 M NaBH3CN solution in THF is added dropwise, and the reaction mixture is stirred for 2 h at room temperature. The reaction is quenched by the addition of H2O, and extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and con¬ centrated. The residue is purified by silica gel column to give 2-cyano-4-[2-(1-methyl- piperidin-4-yl)ethoxy]-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid benzylamide as a colorless oil; 1H-NMR (CDCI3), δ 0.17-0.30 (4 H, m), 0.89-0.94 (2 H, m), 1.14-1.29 (3 H, m), 1.40-1.50 (2 H, m), 1.58-1.78 (9 H, m), 1.95 - 2.01 (3 H, m), 2.38 (3 H, S), 2.95- 2.98 (2 H, m), 3.42 (2 H1 1), 4.46 (2 H, t), 4.56 (2 H, d), 7.31-7.39 (5 H1 m), 8.13 (1 H, t), 10.16 (1 H1 1).
Step 76.1: 4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid benzylamide
To a suspension of 4, e-dichloro^-methylsulfanylpyrimidine-δ-carboxyϋc acid (2.1 mmol) in CH2CI2 (20 mL) are added oxalyl chloride (4.2 mmol) and one drop of DMF at 0 0C. After stirred at room temperature for 3 h under N2 atmosphere, the reaction mixture is concentrated and dried in vacuo, to give 4, 6-dichloro-2-methylsulfanylpyrirnidine-5-carbonyl chloride as a yellow crystal.
To a solution of 4, 6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride in THF (15 mL), triethylamine (2.3 mmol) and benzylamine (2.5 mmol) are added at 0 0C. After stirred at room temperature for 2 h, the reaction mixture is diluted with AcOEt and H2O. The mixture is extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to give 4,6- dichloro^-methylsulfanylpyrimidine-δ-carboxylic acid benzylamide as a white solid. 1H-NMR (CDCI3), δ 2.57 (3 H, s), 4.66 (2 H, d), 6.08 (1 H, br s), 7.31-7.35 (2 H, m), 7.36-7.38 (3 H, m).
Step 76.2: 4-[2-(5-Benzylcarbamoyl-6-chloro-2-methylsulfany[pyrimidin-4-yloxy) ethyl]piperidine-1-carboxylic acid tert-butyl ester
To a solution of 4, β-dichioro^-methylsulfanylpyrimidine-δ-carboxylic acid benzylamide (3 mmol) in THF (20 mL) is added KOfBu (3.6 mmol) at 0 0C under N2. After stirred at 0 0C for 20 min, the above mixture is added dropwise to a solution of 4-(2-hydroxyethyl)piperidine-1- carboxylic acid tert-butyl ester (3.3 mmol) in THF (20 mL) at -78 0C. The resulting mixture is gradually warm up to -30 0C over 2.5 h. The reaction is quenched by the addition of H2O. The mixture is extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated to give 4-[2-(5-benzylcarbamoyI-6-chloro-2-methylsulfanylpyrimidin-4- yloxy)ethyl]piperidine-1-carboxylic acid terf-butyl ester as a white solid; 1H-NMR (CDCI3), δ 1.07-1.17 (2 H, m), 1.48 (9 H, s), 1.62-1.70 (2 H, m), 2.54 (3 H, s), 2.64 (2 H, br t), 4.06 (2 H, m), 4.45 (2 H, t), 4.64 (2 H, d), 6.06 (1 H, t), 7.30-7.34 (2 H, m), 7.35-7.36 (3 H, m).
Step 76.3: 4-[2-(5-Benzylcarbamoyl-6-ch(oro-2-cyanopyrimidin-4-yIoxy)ethyl]- piperidine-1-carboxylic acid ferf-butyl ester To a solution of 4-[2-(5-benzylcarbamoyl-6-chloro-2-methylsulfanylpyrimidin~4- yloxy)ethyl]piperidine-1-carboxylic acid ferf-butyl ester (2.7 mmol) in CH2CI2 (50 rnL) is added m-CPBA (4.1 mmol) at O 0C. After stirring over night under N2 atmosphere, the reaction mixture is quenched by the addition of Na2S2O3 and aq. sat. NaHCO3 at O0C. The mixture is extracted twice with CH2CI2, and the combined organic extracts are washed with aq. sat. NaHCθ3 and water. The organic layer is dried over Na2SO4, and concentrated to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-methanesulfonylpyrimidin-4-yloxy)ethyl] piperidine- 1-carboxylic acid terf-butyl ester as a white solid; 1H-NMR (CDCI3), δ 1.08-1.18 (2 H1 m), 1.45 (9 H1 S)1 1.63-1.75 (5 H, m), 2.64 (2 H1 br t), 3.32 (3 H1 s), 4.05-4.08 (2 H1 m), 4.59 (2 H1 1), 4.66 (2 H1 d), 6.20 (1 H, t), 7.31-7.37 (5 H1 m).
To a solution of the above product, 4-[2-(5-benzylcarbamoyl-6-chloro-2-methanesulfonyl- pyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid terf-butyl ester in CH2CI2 / H2O (20 ml_ / 2 ml_) is added NaCN (3.3 mmol) and tetra-n-butylammonium bromide (0.14 mmol) at 0 0C. After warmed up to room temperature, the reaction mixture is vigorously stirred for 1.5 h at room temperature. The mixture is diluted with CH2C12, washed with aq. NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyano- pyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid terf-butyl ester as a white solid. 1H-NMR (CDCI3), δ 1.09-1.19 (2 H1 m), 1.46 (9 H, s), 1.63-1.74 (5 H1 m), 2.66 (2 H, br t), 4.07 (2 H, m), 4.51 (2 H, t), 4.66 (2 H, d), 6.11 (1 H, t), 7.31-7.37 (5 H, m).
Step 76.4: 4-(2-{5-Benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl)amino]- pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester
To a solution of 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyanopyrimidin-4-yloxy) ethyfjpiperidine- 1-carboxylic acid terf-butyl ester (0.23 mmol) in CH3CN (5 ml_), C-spiro [2.5] oct-6-yl- methylamine hydrochloride (0.25 mmol) and K2CO3 (0.7 mmol) are added at room temperature. After warmed up to 70 0C1 the reaction mixture is stirred over night. The mixture is diluted with H2O and AcOEt1 and extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated to give 4-(2-{5-benzylcarbamoyl-2-cyano-6- [(spiro[2.5]oct-6-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid terf-butyl ester as a white solid; 1H-NMR (CDCi3), δ 0.17-0.30 (4 H1 m), 0.89-1.06 (4 H1 m), 1.14-1.38 (3 H1 m), 1.46 (9 H, s), 1.49-1.79 (9 H1 m), 2.51 (2 H1 br t), 3.42 (2 H, t), 4.00 (2 H1 m), 4.45 (2 H1 1), 4.55 (2 H1 d), 7.30-7.39 (5 H, m), 8.12 (1 H1 1), 10.16 (1 H1 1). Examples 77 to 164
By repeating the procedures described above using appropriate starting materials and conditions, the following compounds are obtained.
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
HPLC conditions: Phenomenex Luna reverse phase C18 3 micron 30 x 4.6mm column. Linear gradient from 90% water with 0.08% formic acid : 10% acetonitrile to 100% acetonitrile over 10 min. Detection at 254 nm.
(i) Compound of Example 114: Melting point = 159°C.
Example 165: N-f2-Cvano-4-f2-f1-methylpiperidin-4-yl)ethoxy^-6-r(spirof3.51non-7- ylmethvOaminoipyrimidin-5-yli-C-phenylmethanesulfonamide
Followed by the synthetic procedures for 4-[2-(1-methylpiperidin-4-yl)ethoxy]-6- [(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-2-carbonitrile, 4-(2-{2-cyano-5- phenylmethanesulfonylamino-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4- yloxy}ethyl)piperidine-1-carboxylic acid fe/f-butyl ester is converted to N-{2-cyano-4-[2-(1- methylpiperidin-4-yl)ethoxy]-6-[(spiro[3.5]non-7-ylmethyl)amino] pyrimidin-5-yl}-C- phenylmethanesulfonamide.
Step 165.1 : (4,6-Dichloro-2-methylsulfanylpyrimidin-5-yl)carbamic acid allyl ester
To a solution of 4,6-dichloro-2-methylsu!fanylpyrimidine-5-carboxylic acid (5.5 mmol) in dioxane (10 mL) are added diphenyl phosphoryl azide (6.6 mmol), triethylamine (6.6 mmol) and allyl alcohol (11 mmol) at room temperature under N2 atmosphere. After stirring at . 100 0C for 1 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed twice with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give (4,6-dichloro-2-methylsulfanyl- pyrimidin-5-yl)carbamic acid allyl ester. Step 165.2: 4-[2-(5-AIIyloxycarbonylamino-6-chloro-2-methylsulfanylpyrimidin-4- yloxy)ethyl]piperidine-1-carboxylic acid terf-butyl ester
Followed by the synthetic procedures as desribed in Reference Ex. 2, step 2.0, (4,6-di chloro^-methylsulfanylpyrimidin-δ-yOcarbamic acid allyl ester is converted to 4-[2-(5- allyloxycarbonylamino-θ-chloro^-methylsulfanylpyrimidin^-yloxyj ethyljpiperidine-i- carboxylic acid ferf-butyl ester.
Step 165.3: 4-[2-(5-Allyloxycarbonylamino-6-chloro-2-cyano-pyrimidin-4-yloxy)ethyl] piperidine-1 -carboxylic acid tert-butyl ester
Followed by the synthetic procedures as described in Reference Example 2 for 4-[2-(6- chloro-2-cyanopyrimidin-4-yl oxy)ethyl]piperidine-1 -carboxylic acid ferf-butyl ester, 4-[2-(5- allyloxycarbonyl amino-6-chloro-2-methylsulfanylpyrimidin-4-yloxy)ethyl]piperidine-1- carboxylic acid tert-butyl ester is converted to 4-[2-(5-Allyloxycarbonylamino-6-chloro-2- cyano-pyrimidin-4-yloxy)ethyl]piperidine-1 -carboxylic acid ferf-butyl ester.
Step 165.4: 4-(2-{5-AIIyloxycarbonylamino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)- amino]pyrimidin-4-yloxy}ethyl)piperidine-1 -carboxylic acid fert-butyl ester
Followed by the synthetic procedures as described in Reference Example 2, step 2.2, for 4- (2-{2-cyano-6-[(spiro[3.5]non-7-ylmethyl)-amino]pyrimidin-4-yloxy}ethyl)piperidine-1- carboxylic acid te/t-butyl ester, 4-[2-(5-Allyloxycarbonylamino-6-chloro-2-cyano-pyrimidin-4- yloxy)ethyl] piperidine-1 -carboxylic acid ferf-butyl ester is converted to 4-(2-{5-allyloxy carbonylamino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy} ethyl)piperidine-1 -carboxylic acid terf-butyl ester.
Step 165.5: 4-(2-{5-Amino-2-cyano-6-[(spiro[3.5]non-7-yImethyI)amino]pyrimidin-4- yloxy}ethyl)piperidine-1 -carboxylic acid fert-butyl ester
To a solution of the crude 4-(2-{5-allyloxycarbonylamino-2-cyano-6-[(spiro [3.5]non-7- ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1 -carboxylic acid tert-butyl ester (230 mg) in THF (10 mL) are added trietylamine (1.25 mmol) and Pd(PPh3J4 (catalytic amount) at room temperature under N2 atmosphere. After stirring at the same temperature for 1 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-(2- {δ-Amino^-cyano-θ-KspirotS.δlnon^-ylmethyOaminolpyrimidin^-yloxyJ ethyOpiperidine-i- carboxylic acid ferf-butyl ester; 1H-NMR (CDCI3), §:0.97-1.07 (2H, m), 1.13-1.28 (4H5 m), 1.42-1.88 (25H, m), 2.69 (2H, t), 3.22 (2H1 s), 3.31 (2H, t), 4.04-4.16 (2H, m), 4.40 (2H, t), 4.51 (1H1 1).
Step 165.6: 4-(2-{2-Cyano-5-phenylmethanesulfonylamino-6-[(spiro[3.5]non-7- ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester
Benzylsulfonylchloride (0.50 mmol) is added to a solution of 4-(2-{5-amino-2-cyano-6- [(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid f-butyl ester (167 mg) and pyridine (0.66 mmol) in CH2CI2 (3 imL) are added at 0 0C. After stirring at room temperature for 1 h, benzylsulfonylchloride (0.50 mmol), pyridine (0.66 mmol) and DMAP (catalytic amount) are added to the reaction mixture again. The reaction mixture is stirred at room temperature for 1 h and diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-(2-{2-cyano-5-phenylmethanesulfonylamino-6-[(spiro[3.5]non-7- ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid te/f-butyl ester.
Examples 166 and 167
By repeating the procedures described above using appropriate starting materials and conditions, the following compounds are obtained.
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0003
Example 168 - 173:
By repeating the procedures described above using appropriate starting materials and conditions, the following compounds can be obtained.
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000096_0001
Me = methyl
(ii) Compound of Example 168: Melting point = 1310C; (M+H)+ = 412.
Example 174: Soft Capsules
5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one of the com¬ pounds of formula I mentioned in the preceding Examples, are prepared as follows:
Composition
Active ingredient 250 g
Lauroglycol 2 litres
Preparation process: The pulverized active ingredient is suspended in Lauroglykol® (propy¬ lene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 μm. 0.419 g portions of the mixture are then introdu¬ ced into soft gelatin capsules using a capsule-filling machine.

Claims

Claims
1. A 2-cyanopyrimidine of the formula
Figure imgf000097_0001
wherein
Ri denotes a radical of the formula
Figure imgf000097_0002
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2;
T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S;
Ra, Rb and Rc independently of each other represent hydrogen or CrC4alkyl; s is 0, 1 or 2, t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
R2 denotes halogen, C1-C4 alkyl, unsubstituted or substituted aryl, 5 or 6 membered heterocyclyl, -C(O)NR4R5, -NHC(O)R4 or -CH2NHC(O)R4, wherein
R4 represents
(a) CrC7alkyl which is unsubstituted or substituted by halogen; amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6alkyl which in each case are unsubstituted or mono-, di- or trisubstituted by halogen; unsubstituted or substituted C4-Cβ-aIiphatic heterocyclyl comprising at least one nitrogen atom; unsubstituted or substituted phenyl; unsubstituted or substituted hetaryl; unsubstituted or substituted spiro[4.5]decane which comprises 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur; unsubstituted or substituted C3-C6cycloalkyl; or 1-aza-(C5-C8)bicycIoalkyl; (b) unsubstituted or substituted N-(CrC4alkyl) piperidinyl or N-(C4-C6cycloalkyI) piperidinyl;
(c) unsubstituted or substituted aryl;
(d) unsubstituted or substituted C3-C6cycloalkyl; or
(e) unsubstituted or substituted 5 or 6 membered hetaryl containg one nitrogen atom; and
R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent unsubstituted or substituted C4-C8-aliphatic heterocyclyl comprising at least one nitrogen atom; or R2 denotes -N(R9)SO2RiO,
R9 represents hydrogen or CrC4alkyl; and
Rio represents CrC4alkyl, which is unsubstituted or substituted by aryl; or
R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 5 and R and R' both represent independently of each other hydrogen or C-ι-C4alkyl;
R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-Rβ or NR7Rs wherein
Y represents O, CH2, S, SO, SO2 or NRN, wherein RN denotes hydrogen or CrC4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents Ci-C6alkyl, aryl, five or six-membered nitrogen containing hetaryI-(CH2)q- , wherein q is an integer from O to 4, or five or six-membered aliphatic heterocyclyl- (CH2),,-, wherein n is an integer from O to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom;
X denotes O, HN, CrC4alkyl-N, S1 SO, SO2, O(CH2)gNH, wherein g is 1 or 2, (CH2)h, wherein h is 1 or 2, or phenyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, CV C4alkyl or C1-C4BIkOXy; or a tautomer and/or salt of such 2-cyano-pyrimidine.
2. A 2-cyano-pyrimidine according to claim 1 of the formula I, wherein notes a radical of formula
Figure imgf000099_0001
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2; T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S; Ra, Rb and Rc independently of each other represent hydrogen or CrC4alkyl; s is 0 or 1 , t is 1 , 2, 3 or 4 and p is O1 1 or 2; R2 denotes halogen, C1-C4 alkyl, unsubstituted or substituted phenyl, 5 or 6 membered heterocyclyl, -C(O)NR4R5, -NHC(O)R4, -CH2NHC(O)R4 Or -N(R9)SO2R10, wherein R4 represents
(a) CrC7alkyl which is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or C^Cealkyl which is unsubstituted or trisubstituted by halogen; aza-(C4-C8)cycloalkyl, which is unsubstituted or substituted by halogen, C1-
C4alkoxy, CrC4alkoxy CrC4alkyl, CrC4alkyl amino, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C4-C6)cycloalkyl or CrC6alkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by Ci-C4alkyl or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-C5cycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- spiro[4.5]decane or 1-aza-(C3-C7)bicycloalkyl;
(b) N-(CrC4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, C1- C4alkoxy, CrC4alkoxy C1-C4BIkOXy, CrC4alkoxy phenyl, di(CrC4alkyl)-amino C1- C4alkoxy, N-(CrC4alkyl) piperazinyl, N-(CrC4alkyl) piperidinyloxy or N-(C1- C4alkyl) piperidinyl CrC4alkoxy;
(d) C3-C5cycloalkyl; (e) isoxazolyl, imidazolyl or pyrazolyl, which in each case is mono- or disubstituted by pyridyl or phenyl; or
(f) N-(CrC6alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyI, wherein phenyl is unsubstituted or mono- substituted by halogen; and
R5 represents hydrogen or Ci-C4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl or piperidinyl which is unsubstituted or substituted by hydroxy; R9 represents hydrogen or CrC4alkyl; and
R10 represents CrC4alkyl, which is unsubstituted or substituted by phenyl; or R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 4 and R and R" both represent hydrogen; R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or monosubstituted by halogen or piperazinyl, Y-Re or NR7R8 wherein
Y represents O, CH2, S, SO, SO2 or NRN, wherein RN denotes hydrogen or Ci-C4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents Ci-C6alkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH2Iq-, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl-(CH2)n-, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes O, HN, CrC4alkyl-N, S1 SO, SO2, OCH2CH2NH, CH2 or phenyl, which is unsubstituted or monosubustituted by halogen; or a tautomer and/or salt of such 2-cyano-pyrimidine.
3. A 2-cyano-pyrimidine according to claim 1 of the formula I, wherein Ri denotes a radical of formula
Figure imgf000101_0001
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2; T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S; Ra, Rb and Rc independently of each other represent hydrogen or CrC4alkyl; s is 0 or 1 , t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
R2 denotes bromo, chloro, C1-C4 alkyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing at least one oxygen atom, -C(O)-NR4R5 or -N(Rg)-SO2-Ri0, wherein R4 represents
(a) CrC7alkyl which is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6alkyl which is unsubstituted or trisubstituted by halogen; aza-(C4-C8)cycloalkyl, which is unsubstituted or substituted by halogen, Cr
C4alkoxy, CrC4alkoxy Ci-C4alkyl, CrC4alkyl amino, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C4-C6)cycloalkyl or CrC6alkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by Ci-C4alkyl or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-C5cycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- spiro[4.5]decane or 1-aza-(C5-C7)bicycloalkyl;
(b) N-(CrC4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, C1- C4alkoxy, CrC4alkoxy CrC4alkoxy, CrC4alkoxy phenyl, di(Ci-C4alkyl)-amino C1- C4alkoxy, N-(CrC4alkyl) piperazinyl, N-(CrC4alkyl) piperidinyloxy or N-(C1- C4alkyl) piperidinyi CrC4alkoxy;
(d) C3-C5cycloalkyl;
(e) pyrazolyl, which is mono- or disubstituted by pyridyl or phenyl; or (f) N-(Ci-C6alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or mono- substituted by halogen; and R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl; R9 represents hydrogen or d-C4alkyl; and
R10 represents C1-C4BIkVl, which is unsubstituted or substituted by phenyl; or R9 and Ri0 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 4 and R and R' both represent hydrogen; R3 denotes hydrogen, Y-R6 or NR7R8 wherein
Y represents O or NRN, wherein RN denotes hydrogen or Ci-C4alkyl which is unsubstituted or substituted by CrC4alkoxy;
Re represents CrCβalkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH2)q-, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl-(CH2)n~, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes HN, CrC4alkyl-N or O; or a tautomer and/or salt of such 2-cyano-pyrimidine.
4. A 2-cyano-pyrimidine according to claim 1 of the formula I, wherein Ri denotes a radical of formula
Figure imgf000102_0001
wherein A, E and G independently of each other represent O or CH2, under the proviso that at least one of A and E represents CH2; T is O or a bond, if G is CH2, and T is a bond, if G is O; Ra, Rb and Rc all represent hydrogen; s is 0 or 1 , t is 1 or 2 and p is 1 ;
R2 denotes bromo, chloro, isopropyl, unsubstituted phenyl or a 6 membered heterocyclyl group containing two oxygen atoms, -C(O)-NR4R5 or -N(Rg)-SO2-Ri0, wherein R4 represents
(a) CrC7alkyl which is unsubstituted or substituted by amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrC6a)kyl which is unsubstituted or trisubstituted by halogen;
1-aza-(C7-C8)cycloalkyl, which is unsubstituted or substituted by CrC4alkyl; 1-aza-(C4)cycloalkyl, which is unsubstituted or substituted by Ci-C4alkyl; pyrrolidinyl, which is unsubstituted or substituted by halogen, CrC4alkoxy, C1-
C4alkoxy CrC4alkyl or CrC4alkyl amino; piperidinyl, which is unsubstituted or mono- or disubstituted by halogen, pyrrolidinyl, piperidinyl, di(halo)-piperidinyl, (C4-C6)cycloalkyl or CrCβalkyl which is unsubstituted or mono- or disubstituted by hydroxy or halogen; piperazinyl, which is mono- or disubstituted by CrC4alkyl or phenyl; or phenyl, which is unsubstituted or mono- or disubstituted by halogen, morpholinyl, trifluoromethyl or CrC4alkoxy; halogen, C3-C5cycloalkyl, morpholinyl, thienyl, furyl, pyridyl, 2-oxa-6-aza- spiro[4.5]decane or 1-aza-(C5-C7)bicycloalkyl;
(b) N-(CrC4alkyl) piperidinyl, which is substituted by phenyl;
(c) phenyl, which is mono-, di- or trisubstituted by phenyl, C3-C5cycloalkyloxy, C1- C4alkoxy, C1-C^IkOXy C1-C4BIkOXy, CrC4alkoxy phenyl, di(CrC4alkyl)-amino C1- C4alkoxy, N-(CrC4alkyl) piperazinyl, N-(CrC4alkyI) piperidinyloxy or N-(C1- C4alkyl) piperidinyl Ci-C4alkoxy;
(d) C3-C5cycloalkyl;
(e) pyrazolyl, which is mono- or disubstituted by pyridyl or phenyl; or
(f) N-(C1 -C6alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl which in both cases is substituted by phenyl CrC4alkyl, wherein phenyl is unsubstituted or mono- substituted by halogen; and
R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent pyrrolidinyl;
R9 represents hydrogen or CrC4alkyl; and
R10 represents CrC4alkyl, which is unsubstituted or substituted by phenyl; or R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 4 and R and R' both represent hydrogen; R3 denotes hydrogen, Y-R6 or NR7R8 wherein
Y represents O or NRN, wherein RN denotes hydrogen or CrC4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents CrC6alkyl, phenyl, five or six-membered nitrogen containg hetaryl- (CH2)q-, wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl-(CH2)n-, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted;
R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom; X denotes HN, CrC4alkyl-N or O; or a tautomer and/or salt of such 2-cyano-pyrimidine.
5. A 2-cyano-pyrimidine according to any one of claims 1 to 4 of the formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound or tautomer, for use in a method for the treatment of the human or animal body.
6. Use of a 2-cyano-pyrimidine according to any one of claims 1 to 4 of the formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound or tautomer, for the preparation of a pharmaceutical product for the treatment of neuropathic pain.
7. A method for the treatment of neuropathic pain, which comprises administering a 2-cyano- pyrimidine according to any one of claims 1 to 4 of the formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound or tautomer, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
8. A pharmaceutical preparation, comprising a 2-cyano-pyrimidine according to any one of claims 1 to 4 of the formula I or a tautomer thereof, or a pharmaceutically acceptable salt of such a compound or tautomer, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
9. A process for the preparation of a 2-cyano-pyrimidine of the formula
Figure imgf000105_0001
wherein
R1 denotes a radical of formula
Figure imgf000105_0002
wherein A, E and G independently of each other represent O, S or CH2, under the proviso that at least one of A and E represents CH2; T is O, S or a bond, if G is CH2, and T is a bond, if G is O or S; Ra, Rb and Rc independently of each other represent hydrogen or Ci-C4alkyl; s is 0, 1 or 2, t is 1 , 2, 3 or 4 and p is 0, 1 or 2;
R2 denotes halogen, Ci-C4 alky!, unsubstituted or substituted aryl, 5 or 6 membered heterocyclyl, -C(O)NR4R5, -NHC(O)R4 or -CH2NHC(O)R4, wherein R4 represents
(a) CrC7alkyl which is unsubstituted or substituted by halogen; amino, which is mono- or disubstituted by C3-C5cycloalkyl or CrCδalkyl which in each case are unsubstituted or mono-, di- or trisubstituted by halogen; unsubstituted or substituted C4-Cg-aliphatic heterocyclyl comprising at least one nitrogen atom; unsubstituted or substituted phenyl; unsubstituted or substituted hetaryl; unsubstituted or substituted spiro[4.5]decane which comprises 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur; unsubstituted or substituted C3-C6cycloalkyl; or 1-aza-(C5-C8)bicycloalkyl;
(b) unsubstituted or substituted N-(CrC4alkyl) piperidinyl or N-(C4-C6cycloalkyl) piperidinyl; (c) unsubstituted or substituted aryl;
(d) unsubstituted or substituted C3-C6cycloalkyl; or
(e) unsubstituted or substituted 5 or 6 membered hetaryl containg one nitrogen atom; and
R5 represents hydrogen or CrC4alkyl; or
R4 and R5 together with the nitrogen to which they are attached represent unsubstituted or substituted C4-Cβ-aliphatic heterocyclyl comprising at least one nitrogen atom; or R2 denotes -N(R9)SO2Ri0,
R9 represents hydrogen or CrC4alkyl; and
R10 represents C1-C4BlKyI, which is unsubstituted or substituted by aryl; or
R9 and R10 together form a radical -(CRR')m-, wherein m is an integer from and including 2 up to and including 5 and R and R' both represent independently of each other hydrogen or Ci-C4alkyl;
R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6 or NR7R8 wherein
Y represents O1 CH2, S, SO, SO2 or NRN, wherein RN denotes hydrogen or Ci-C4alkyl which is unsubstituted or substituted by CrC4alkoxy;
R6 represents CrC6alkyl, aryl, five or six-membered nitrogen containing hetaryl-(CH2)q- , wherein q is an integer from 0 to 4, or five or six-membered aliphatic heterocyclyl- (CH2)n-, wherein n is an integer from 0 to 4 and the heterocyclyl moiety comprises at least one ring nitrogen atom, which radicals in each case can be unsubstituted or substituted; R7 and R8 together with the nitrogen to which they are attached represent unsubstituted or substituted five or six-membered aliphatic heterocyclyl, wherein the heterocyclyl moiety comprises at least one nitrogen atom;
X denotes O1 HN1 CrC4alkyl-N, S, SO1 SO2, O(CH2)gNH, wherein g is 1 or 2, (CH2)h, wherein h is 1 or 2, or phenyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, C1- C4alkyl or CrC4alkoxy; characterized in that a) for the synthesis of a compound of the formula I wherein R2 represents -C(O)NR4R5, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O1 NH or S, or NR7R8, X denotes HN, Ci-C4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols R1, R4, R5, R6, R7, Re and g are as defined in claim 1 for a compound of the formula I, the 5-pyrimidyl carboxylic acid of formula Il
Figure imgf000107_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S, and the remaining radicals and symbols R1, R6, R7, R8 and g are as defined in claim 1 for a compound of the formula I, is reacted with an amine of formula III
Figure imgf000107_0002
wherein the symbols R4 and R5 are as defined for a compound of the formula I;
b) for the synthesis of a compound of the formula I wherein R2 represents C(O)NR4R5, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols R1, R4, R5, Rθ> R7, R8 and g are as defined in claim 1 for a compound of the formula I, the 6-chloro pyrimidine derivative of formula IV
Figure imgf000107_0003
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, and the remaining radicals R2, Re, R7 and R8 are as defined in claim 1 for a compound of the formula I, is reacted with a compound of formula V
R1-X-H (V)
wherein X denotes HN, Ci-C4alkyl-N, O(CH2)gNH, O or S and Ri has the meaning as defined in claim 1 for a compound of the formula I;
c) for the synthesis of a compound of the formula I wherein R2 denotes -N(R9)SO2RI0, R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols Ri1 R6, R7, Re. R9. R10 and g are as defined for a compound of the formula I, the 5-amino pyrimidine of formula Vl
Figure imgf000108_0001
wherein R3 denotes hydrogen, halogen, phenyl, pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, Y-R6, wherein Y represents O, NH or S, or NR7R8, X denotes HN, CrC4alkyl-N, O(CH2)gNH, O or S and the remaining radicals and symbols R1, R6, R7, R8 and g are as defined for a compound of the formula I, is reacted with a sulfonyl halide of formula VII
Figure imgf000108_0002
wherein the radical R10 is as defined for a compound of the formula I and Hal denotes halide, optionally followed by replacing the hydrogen atom in the sulfonamide function of the obtained compound of formula I by the group R9 by means of an alkylation reaction; wherein in all cases the starting materials of formula Il to VII may also be present with functional groups in protected form, if necessary, and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible;
wherein any protecting groups in a protected derivative of a compound of the formula I are subsequently removed;
and, if so desired, an obtainable compound of formula I is converted into another compound of formula I, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.
PCT/EP2005/008896 2004-08-17 2005-08-16 Compounds and compositions useful as cathepsin s inhibitors WO2006018284A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2009051112A1 (en) 2007-10-15 2009-04-23 Takeda Pharmaceutical Company Limited Amide compounds and use of the same
US8329691B2 (en) 2007-10-15 2012-12-11 Takeda Pharmaceutical Company Limited Amide compounds and use of the same
JP5441705B2 (en) * 2007-10-15 2014-03-12 武田薬品工業株式会社 Amide compounds and uses thereof
EP2370423A1 (en) * 2008-12-04 2011-10-05 Glaxo Group Limited Method for preparing a spiroindoline and a precursor thereof
EP2370423A4 (en) * 2008-12-04 2012-05-30 Glaxo Group Ltd Method for preparing a spiroindoline and a precursor thereof
WO2020201572A1 (en) 2019-04-05 2020-10-08 Université De Bretagne Occidentale Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning

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