WO2006066747A1 - 4-aminopiperidine derivatives - Google Patents

4-aminopiperidine derivatives Download PDF

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Publication number
WO2006066747A1
WO2006066747A1 PCT/EP2005/013292 EP2005013292W WO2006066747A1 WO 2006066747 A1 WO2006066747 A1 WO 2006066747A1 EP 2005013292 W EP2005013292 W EP 2005013292W WO 2006066747 A1 WO2006066747 A1 WO 2006066747A1
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Prior art keywords
phenyl
piperidine
butyl
amine
amine hydrochloride
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PCT/EP2005/013292
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French (fr)
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WO2006066747A8 (en
Inventor
Markus Boehringer
Daniel Hunziker
Bernd Kuhn
Bernd Michael Loeffler
Thomas Luebbers
Fabienne Ricklin
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F. Hoffmann-La Roche Ag
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Priority to JP2007547255A priority Critical patent/JP2008524276A/en
Priority to BRPI0519585-3A priority patent/BRPI0519585A2/en
Priority to EP05815325A priority patent/EP1831165A1/en
Priority to MX2007007434A priority patent/MX2007007434A/en
Priority to AU2005318597A priority patent/AU2005318597A1/en
Priority to CA002590957A priority patent/CA2590957A1/en
Publication of WO2006066747A1 publication Critical patent/WO2006066747A1/en
Publication of WO2006066747A8 publication Critical patent/WO2006066747A8/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56Nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56Nitrogen atoms
    • C07D211/58Nitrogen atoms attached in position 4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4468Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/45Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to novel 4-aminopiperidine derivatives, their manufacture and their use as medicaments.
  • the invention relates to compounds of the formula (I)
  • R 1 is selected from the group consisting of
  • phenyl unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, lower alkoxy, phenyl, phenoxy, halogen, or lower halogenalkyl;
  • naphthyl unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • m is 1, 2, or 3 and phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy, and wherein R 3 is independently selected from hydrogen, lower alkyl or phenyl;
  • n 1, 2 or 3;
  • n 1, 2, 3 and heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy; -C(O)-CH 2 -phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
  • R" is selected from the group consisting of
  • phenyl unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
  • naphthyl unsubstituted-or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
  • heteroaryl unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
  • R 4 and R 5 are lower alkyl or together with the nitrogen atom to which they are attached form a 4-, 5-or 6- membered heterocycle which may contain a further heteroatom selected from O, N or S,
  • the enzyme dipeptidyl peptidase IV EC.3.4.14.5 (EC is the abbreviation for "Enzyme Committee" of the International Union of biochemistry this enzyme is abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones.
  • DPP-IV is degrading efficiently and rapidly glucagon like peptide 1 (GLP-I), which is one of the most potent stimulator of insulin production and secretion. Inhibiting DPP-IV would potentate the effect of endogenous GLP-I, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycemia and accordingly reduce the risk of tissue damage.
  • DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes mellitus (e.g. Villhauer, WO98/19998).
  • Other related state of the art can be found in WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, US 6110949, WO 00/34241 and US6011155.
  • the compounds of the present invention are useful for the treatment and/ or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit.
  • the compounds of the present invention can also be used in the treatment and/ or prophylaxis of obesity, metabolic syndrome, ⁇ -cell protection, autoimmune diseases such as inflammatory bowel disease, encephalitis periaxialis scleroticans and rheumatoid arthritis, Colitis Ulcerrosa, Morbus Crohn, psoriasis, lichen planus and/or benign prostate hypertrophy.
  • autoimmune diseases such as inflammatory bowel disease, encephalitis periaxialis scleroticans and rheumatoid arthritis, Colitis Ulcerrosa, Morbus Crohn, psoriasis, lichen planus and/or benign prostate hypertrophy.
  • the compounds may also be useful for the prevention of AIDS (acquired immunodeficiency syndrome) or for the preventing metastasis, particularly preventing metastasis of breast and prostate cancer to lung.
  • the compounds of the present invention can be used as diuretic agent and for the treatment and/or prophylaxis of hypertension.
  • the compounds of the present invention exhibit improved therapeutic and pharmacological properties compared to other DPP-IV inhibitors known in the art, such as e.g. in context of pharmacokinetics and bioavailability.
  • Objects of the present invention are compounds of formula I and their production, as well as the use of the compounds of formula I in accordance with the invention in the control and prevention of illnesses of the aforementioned kind, and respectively, for the production of corresponding medicaments.
  • lower is used to mean a group consisting of one to six, preferably of one to four carbon atom(s).
  • halogen refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred. Most preferred halogen is chlorine.
  • alkyl refers to a branched or straight- chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.
  • This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n- pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.
  • Preferable lower alkyl residues are methyl ethyl, n-propyl and n-butyl, with methyl being especially preferred.
  • lower halogenalkyl refers to a lower alkyl group wherein at least one of the hydrogens of the lower alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro.
  • a halogen atom preferably fluoro or chloro, most preferably fluoro.
  • preferred lower halogenalkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially preferred.
  • alkoxy refers to the group R'-O-, wherein R' is alkyl.
  • lower alkoxy refers to the group R'-O-, wherein R 1 is lower-alkyl.
  • Examples of lower alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being especially preferred.
  • cycloalkyl or "Cs-y-cycloalkyl” refers to a monovalent carbocyclic radical of three to seven carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with cyclopropyl and cyclohexyl being preferred.
  • heteroaryl refers to an aromatic 5- or 6-membered ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/ or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl.
  • heteroaryl further refers to bicyclic aromatic groups comprising two 5- or 6- membered rings, in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl.
  • Preferred heteroaryl groups are thienyl, pyridyl and indolyl, which can optionally be substituted as described above, preferably with lower alkyl or halogen.
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle which may contain an additional heteroatom selected from O, N or S means that R 4 and R 5 together with the nitrogen atom form a ring such as pyrrolidinyl, dihydropyrrolyl (pyrrolinyl), piperidyl, imidazolidinyl, morpholinyl, piperazinyl, thiazolidinyl, thiomorpholinyl, with thiazolidinyl and dihydropyrrolyl being especially preferred.
  • salts embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, salicylic acid, p- toluenesulphonic acid and the like, which are non toxic to living organisms.
  • Preferred salts with acids are formates, maleates, citrates, hydrochlorides, hydrobromides and methanesulfonic acid salts, with hydrochlorides being especially preferred.
  • the invention relates to compounds of the formula (I)
  • R 1 is selected from the group consisting of
  • phenyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, lower alkoxy, phenyl, phenoxy, halogen or lower halogenalkyl;
  • naphthyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower allcyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • R 3 is independently selected from hydrogen, lower alkyl or phenyl
  • n 1, 2 or 3;
  • n 1, 2, 3 and heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy; -C(O)-CH 2 -phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • R 2 is selected from the group consisting of
  • phenyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • naphthyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • heteroaryl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • R 4 and R 5 are lower alkyl or together with the nitrogen atom to which they are attached form a 4-, 5-or 6- membered heterocycle which may contain a further heteroatom selected from O, N or S,
  • R 1 is selected from the group consisting of
  • phenyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • naphthyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • n 1 or 2 and with heteroaryl mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • One group of preferred compounds of formula I according to the present invention are those compounds, wherein R 1 is selected from the group consisting of
  • phenyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • naphthyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
  • R 1 is phenyl di- or trisubstituted by lower alkoxy, with R 1 being 3,4-dimethoxyphenyl or 2,3,4-trimethoxyphenyl being most preferred.
  • a further group of preferred compounds of formula I are those, wherein R 1 is
  • n 1 or 2; or -(CH 2 ) n -heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
  • Preferred heteroaryl is indolyl or pyridyl.
  • n 2 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 + (0.05 * (1 +
  • phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; or
  • R 2 is selected from the group consisting of
  • phenyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • heteroaryl unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
  • phenyl unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
  • R 2 is phenyl or phenyl mono-, di-, or trisubstituted, independently, by lower alkyl or halogen.
  • heteroaryl unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy, with compounds, wherein heteroaryl is pyridyl or thienyl being especially preferred.
  • Preferred compounds of formula I are selected from:
  • the compounds of formula I have two asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of diastereomers, racemates, or mixtures of diasteroisomeric racemates.
  • the invention embraces all of these forms.
  • R 2 and the amino group of the piperidine structure are in trans-configuration, i.e.
  • R 2 and the amino group of the piperidine structure are in ris-configuration, i.e.
  • the invention comprises a process for the manufacture of compounds of formula I, which process comprises
  • R 1 and R 2 are as defined before,
  • R and R are as defined before, and further reducing the oxime of formula III by catalytic hydrogenation or alternatively by a reduction with a metal hydride into the compound of formula I
  • R and R 2 are as defined before and R is an amino protecting group.
  • R p is a suitable amino protecting group such as benzyloxycarbonyl (Z or Cbz), allyloxycarbonyl (Aloe), 9-fluorenylmethoxycarbonyl (Fmoc), and preferably, tert- butoxycarbonyl (Boc).
  • the compounds of formula I can be manufactured by the methods given below, by the methods shown in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are commercially available or can be prepared by methods analogous to the method given below or in the examples or by methods known in the art.
  • N-protection can easily be achieved with a benzyl group (Bz).
  • Bz benzyl group
  • the N-protection is removed e.g.
  • R 1 having the meaning of unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl, tetrahydronaphthyl or C 3 .
  • 7 -cycloalkyl and R 2 being lower alkyl can be prepared following scheme 2:
  • a 4-oxo-piperidinium iodide can be formed from a suitably N- benzyl protected 3-alkyl-4-oxo-piperidine per reaction with methyl iodide in a suitable solvent.
  • R 1 can be inserted by reaction of the 4-oxo-piperidinium iodide with the respective aniline R 1 NH 2 thereby forming the respective 3-alkyl-l-aryl-4-oxo-piperidine.
  • Transformation of this intermediate into the desired 4-aminopiperidine can then take place via an oxime formation with hydroxylamine followed by a reduction for example by catalytic hydrogenation in the presence of a common hydrogenation catalyst such as Raney Nickel or palladium/charcoal in a suitable solvent.
  • a common hydrogenation catalyst such as Raney Nickel or palladium/charcoal in a suitable solvent.
  • an acrylic acid ester is reacted with the respective arylalkylamine R 1 NH 2 to form the respective arylalkylamino propionic acid ester which is then converted with the respective arylacetic acid or aryl acetic acid halogenide R 2 COOH or R 2 COHaI into an R 2 acetyl amino propionic acid ester.
  • Subsequent ring formation with e.g. an alkalibutylate or with sodium hydride leads to a piperidine-2,4- dione which is then transformed with hydroxylamine to the piperidine-2,4dione-4- oxime.
  • This intermediate can finally be reduced for example with LLAIH 4 (LAH) in a suitable solvent to the desired 4-aminopiperidine.
  • LAH LLAIH 4
  • 4-aminopiperidines of the formula I with R 1 having the meaning of unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di-, or trisubstituted naphthyl, tetrahydronaphthyl or C 3 - 7 -cycloalkyl and R 2 being unsubstituted or mono-, di-, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl or unsubstituted or mono-, di, or trisubstituted heteroaryl can be prepared following scheme 4:
  • l-aryl-3-aryl ⁇ 4-amino piperidines can either be performed following scheme 2 via an N-benzyl-protected 3-aryl-4-oxo-piperidinium iodide which is treated with the aniline R 1 NH 2 to give the respective 3-aryl-l-aryl-4-oxo-piperidine.
  • Treatment of this compound with hydroxylamine will give the corresponding oxime that can be reduced subsequently to give the desired 4-amino-piperidine.
  • an N-benzyl-protected 4-oxo-piperidinium iodide can be reacted in a first step with aryl aniline R 1 NH 2 to give the l-aryl-4-oxo-piperidine.
  • the aryl-group in position 3 can then be introduced with an aryl halogenide R Hal in the presence of Pd-acetate, sodium tert-butoxide and P(tBu) 3 .
  • the resulting 3-aryl-l-aryl-4-oxo- piperidine can then be transformed to the desired 4-amino piperidine as outlined above.
  • a first step the amino group of a 4-amino-piperidine-l,3-dicarboxylic acid di- ester is protected with a benzyloxycarbonyl group.
  • the ester group in position 3 can then be hydrolyzed, followed by formation of the amide using the corresponding amine
  • the BOC protecting group at position 1 can be removed for example by treatment with trifluoroacetic acid and then the aryiakyl group can be introduced at Nl by treatment with the respective aryl alkyl halogenide R 1 Hal. Finally the desired 4-aminopiperidine can be obtained by removal of the benzyloxycarbonyl protecting group in the presence of HBr.
  • 4-aminopiperidines of the formula I with R 1 having the meaning of unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di-, or trisubstituted naphthyl, tetrahydronaphthyl or C 3-7 -cycloalkyl and R 2 being unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl or unsubstituted or mono-, di, or trisubstituted heteroaryl can be prepared following scheme 6:
  • a l-benzyl-4-oxo-piperidine-3-carboxylic acid ester is first reacted with ammonia to give the respective tetrahydropyridine which can then be reduced for example with sodium borohydride to give the 4-amino piperidine carboxylic acid ester.
  • BOC protection of the amino group in 4-position and subsequent removal of the benzyl group by e.g. catalytic hydrogenation in the presence of a hydrogenation catalyst then affords 4- N-BOC protected piperidine-3-carboxylic acid ester.
  • arylamine R 1 is reacted with an acrylic acid ester in the presence of CuCl and acetic acid to form the respective l-aryl-4-oxo-piperidine-3- carboxylic acid ester.
  • Treatment of this intermediate with ammonium acetate and sodium cyano borohydride gives the l-aryl-4- amino piperidine-3 ⁇ carboxylic acid ester.
  • BOC protection of the free amino group in 4-position and subsequent ester hydrolysis provides the free carboxylic acid which can then used for coupling with amine R 4 R 5 NH.
  • the desired 4-aminopiperidine can then be obtained by removal of the BOC protecting group with e.g. trifluoro acetic acid.
  • the invention further relates to compounds of formula I as defined above, when manufactured according to a process as defined above.
  • the invention also relates to compounds of formula I as defined above for use as therapeutic active substances for the treatment and / or prophylaxis of diseases which are associated with DPP-IV.
  • Such diseases which are associated with DPP-IV are diabetes, particularly non- insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit.
  • the compounds of the present invention can also be used in the treatment and/ or prophylaxis of obesity, metabolic syndrome, ⁇ - cell protection autoimmune diseases such as inflammatory bowel disease, encephalitis periaxialis scleroticans and rheumatoid arthritis, Colitis Ulcerrosa, Morbus Crohn, psoriasis, lichen planus and/ or benign prostate hypertrophy.
  • the compounds may also be useful for the prevention of AIDS (acquired immunodeficiency syndrome) or for the preventing metastasis, particularly preventing metastasis of breast and prostate cancer to lung.
  • AIDS immunodeficiency syndrome
  • the compounds of the present invention can be used as diuretic agent and for the treatment and/or prophylaxis of hypertension.
  • the compounds of formula I of the present invention can be used as medicaments for the treatment and/or prophylaxis of such diseases which are associated with DPP-IV as defined above.
  • the invention therefore also relates to pharmaceutical compositions comprising a compound formula I of the present invention and a pharmaceutically acceptable carrier and/or adjuvant.
  • the invention relates to compounds of formula I of the present invention for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of the diseases which are associated with DPP-IV as defined above.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV as defined above, which method comprises administering a compound of formula I to a human being or animal.
  • the invention further relates to the use of compounds formula I of the present invention for the treatment and/ or prophylaxis of diseases which are associated with DPP-IV as defined above.
  • the following diseases relate to a preferred embodiment: diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity, and/or metabolic syndrome or ⁇ -cell protection, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance.
  • DPP-IV inhibitors Activity of DPP-IV inhibitors are tested with natural human DPP-IV derived from a human plasma pool or with recombinant human DPP-IV.
  • Human citrate plasma from different donors is pooled, filtered through a 0.2 micron membrane under sterile conditions and aliquots of 1 ml are shock frozen and stored at -12O 0 C.
  • colorimetric DPP-IV assay 5 to 10 ⁇ l human plasma and in the fluorometric assay 1.0 ⁇ l of human plasma in a total assay volume of 100 ⁇ l is used as an enzyme source.
  • Human DPP- IV is expressed and purified from the culture medium using conventional column chromatography including size exclusion and anion and cation chromatography. The final enzyme preparation was observed on SDS-page stained with Coomassie blue and shown a purity of > 95%.
  • 20 ng rec.h DPP-IV and in the fluorometric assay 2 ng rec-h DPP-IV in a total assay volume of 100 ⁇ l is used as enzyme source.
  • Ala-Pro-7-amido-4-trifluoromethylcoumarin (Calbiochem No 125510) is used as a substrate.
  • a 20 mM stock solution in 10 % DMF/H 2 O is stored at -20 0 C until use.
  • IC 50 determinations a final substrate concentration of 50 ⁇ M is used.
  • assays to determine kinetic parameters as K m , V max , Ki the substrate concentration is varied between 10 ⁇ M and 500 ⁇ M.
  • H-Ala-Pro-pNA ⁇ Cl (Bachem L-1115) is used as a substrate.
  • a 10 mM stock solution in 10% MeOH/H 2 O is stored at -2O 0 C until use.
  • IC 50 determinations a final substrate concentration of 200 ⁇ M is used.
  • assays to determine kinetic parameters as K n ,, Y max , K; the substrate concentration is varied between 100 ⁇ M and 2000 ⁇ M.
  • Fluorescence is detected in a Perkin Elmer Luminescence Spectrometer LS 5OB at an excitation wavelength of 400 nm and an emission wavelength of 505 nm continuously every 15 seconds for 10 to 30 minutes. Initial rate constants are calculated by best fit linear regression.
  • DPP-IV activity assays are performed in 96 well plates at 37°C in a total assay volume of 100 ⁇ l.
  • the assay buffer consists of 50 mM Tris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl.
  • Test compounds are solved in 100 % DMSO, diluted to the desired concentration in 10% DMSO/H 2 O. The final DMSO concentration in the assay is 1 % (v/v). At this concentration enzyme inactivation by DMSO is ⁇ 5%.
  • Compounds are with (10 minutes at 37 0 C) and without pre-incubation with the enzyme. Enzyme reactions are started with substrate application followed by immediate mixing.
  • IC 50 determinations of test compounds are calculated by non-linear best fit regression of the DPP-IV inhibition of at least 5 different compound concentrations.
  • Kinetic parameters of the enzyme reaction are calculated at least 5 different substrate concentrations and at least 5 different test compound concentrations.
  • the compounds of the present invention exhibit IC 50 values of 0.1 ⁇ M to lOO ⁇ M, more preferably of 0.1 ⁇ M to 10 ⁇ M, as shown in the following table:
  • the compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
  • the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/ or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency- improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
  • the pharmaceutical preparations conveniently contain about 1-500 mg, preferably
  • DCM dichloromethane
  • HOAc acetic acid
  • AcOEt ethyl acetate
  • DMF dimethylformamide
  • DIPEA diisopropylethylamine (Huenig's base)
  • THF tetrahydrofuran
  • LAH lithium aluminium hydride
  • CDI carbonyldiimidazole
  • TFA trifluoro acetic acid
  • EDCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl
  • HOBt 1-hydroxybenzotriazole.
  • Step A] l-Benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide
  • the ketone (460 mg) was dissolved in ethanol (60 ml). Hydroxylamine hydrochloride (109 mg) and sodium acetate (129 mg) were added and the solution was stirred at room temperature for one hour. After TLC control, Raney-Nickel was added (Nr 313 Degussa B 1132) and the reaction was stirred at room temperature under an atmosphere of hydrogen over night. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel (DCM/ MeOH/ 25% aqueous NH 4 OH solution 95:5:1). The separated products were dissolved in ethanol and 1 ml of saturated ethanolic hydrogen chloride solution was added. The solutions were evaporated to yield the cis- (150 mg) and the fr ⁇ ns-diastereomers (160 mg) as light yellow solids. MS (ESI): 323.4 (MH + ).
  • This compound was synthesized in analogy to example 5 using Steps B] and C] from l-benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide and 4-phenoxy-aniline with the exception that Step C] was replaced by a different method.
  • Step C 3-Butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine hydrochloride
  • the compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 5-amino-tetraline to yield a mixture of as- and trans- diastereomers as a white solid. Separation of the diastereomers (as the free amines) using flash chromatography was not possible. MS (ESI): 287.3 (MH + ).
  • the compound was synthesized in analogy to example 6 from 1 -benzyl- 3 -butyl- 1- methyl-4-oxo-piperidinium iodide and 1-naphthylamine to yield a 1/2-mixture of the cis/trans-diastereomers as a white solid. Separation of the diastereomers (as the free amines) using flash chromatography was not possible. MS (ESI): 283.2 (MH + ).
  • This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 6-methoxy-biphenyl-3-ylamine to yield the cis- and the trans- diastereomers as white solids.
  • Step A] 3-Phenethylamino-propionic acid ethyl ester
  • Step C] 1 -Phenethyl-3-phenyl-piperidine ⁇ 2,4-dione
  • Step E] l-Phenethyl-3-phenyl-piperidine-4-yl amine
  • This compound was made according to example 20, Step A] to E] from phenethylamine and ethyl acrylate but with a modified coupling step B] where (4- methyl-pyridin-2-yl)-acetic acid was used instead of the corresponding acid chloride.
  • Step B 3- ⁇ [2-(4-Methyl-pyridin-2-yl)-acetyl] -phenethyl-amino ⁇ -propionic acid ethyl ester:
  • Step A] l-Benzyl-l-methyl-4-oxo-3-o-tolyl-piperidinium iodide
  • step B the aryl bromide and tri(tert- butyl)phosphine were added as a solution in tetrahydrofuran and the reaction was run at 70 0 C for 5 hours. Separation of the diastereomers (free bases) could not be achieved by flash chromatography. MS (ESI): 327.3 (MH + ).
  • Step A] (3R, 4S) -4-Benzyloxycarbonylamino-piperidine-l,3-dicarboxylic acid
  • Step C] (3R,4S)-4-Benzyloxycarbonylamino-3-(thiazolidine-3-carbonyl)- piperidine-1-carboxylic acid tert-butyl ester
  • Step E] (3R- 4S) [l-Phenethyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl] - carbamic acid benzyl ester
  • Step A] 4-Amino-l-benzyl-l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester
  • rac-l-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester 25 g was suspended in 100 ml ammonium hydroxide 25 % and heated at 50 0 C during 18 h. The mixture was cooled with ice and then, NaBH 4 (1 g) was added in several portions. Stirring was continued for 18 h at ambient temperature and the mixture was diluted with water/ice, with cooling, and extracted with AcOEt. The organic extract was washed with brine and dried over sodium sulfate.
  • Step B] rac-4- Amino- l-benzyl-piperidine-3-carboxylic acid ethyl ester
  • Step D] (3R,4R) and (3S,4S)-4-tert-Butoxycarbonylamino-l-[2-(3,4-dimethoxy- phenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester
  • Step F (3R,4R) and (3S,4S)-4-Amino-l-[2-(3,4-dimethoxy-phenyl)-ethyl]- piperidine-3-carboxylic acid
  • the suspension was stirred 2h at 140 0 C, cooled, diluted with AcOEt and washed with water and brine.
  • the aqueous phases were extracted twice with AcOEt, the organic layers were dried over MgSO 4 , filtered, evaporated and chromatographied (silica gel, AcOEt/heptane, 1/3) to obtain the title compound as a white solid (13.53 g, 68 %).
  • Step C] rac-4-tert-Butoxycarbonylamino-l-(3,4-dimethoxy-phenyl)-piperidine-3- carboxylic acid ethyl ester
  • This material was prepared in analogy to example 40, steps E and F, using 2,5- dihydro-pyrrole.
  • This material was prepared in analogy to example 40, steps E and F, using 2,5- dihydro-pyrrole.
  • Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water.
  • the granulate is mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively.
  • the kernels are lacquered with an aq. solution / suspension of the ab ove mentioned film co at.
  • Example B
  • Capsules containing the following ingredients can be manufactured in a conventional manner:
  • the components are sieved and mixed and filled into capsules of size 2.
  • Injection solutions can have the following composition:
  • the active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part).
  • the pH is adjusted to 5.0 by acetic acid.
  • the volume is adjusted to 1.0 ml by addition of the residual amount of water.
  • the solution is filtered, filled into vials using an appropriate overage and sterilized.
  • Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size.
  • the filled soft gelatin capsules are treated according to the usual procedures.
  • Sachets containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water.
  • the granulate is mixed with magnesium stearate and the flavouring additives and filled into sachets.

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Abstract

The present invention relates to compounds of the formula (I), wherein R1 and R2 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/ or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, obesity, and/or metabolic syndrome or ß-cell protection.

Description

4-Aminopiperidine Derivatives
The present invention relates to novel 4-aminopiperidine derivatives, their manufacture and their use as medicaments.
In particular, the invention relates to compounds of the formula (I)
Figure imgf000002_0001
wherein
R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, lower alkoxy, phenyl, phenoxy, halogen, or lower halogenalkyl;
naphthyl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
tetrahydronaphthyl;
C3-7-cycloalkyl;
-(CHR3)m-phenyl, wherein m is 1, 2, or 3 and phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy, and wherein R3 is independently selected from hydrogen, lower alkyl or phenyl;
-(CH2)n-heteroaryl, wherein n is 1, 2 or 3;
-(CH2)n-heteroaryl, wherein n is 1, 2, 3 and heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy; -C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
-C(O)-CH2-heteroaryl; and
-C(O)-CH2-heteroaryl, wherein heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy; and
R" is selected from the group consisting of
lower alkyl, lower halogenalkyl;
phenyl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
naphthyl, unsubstituted-or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
heteroaryl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy;
-COOH; -
-C(O)-NR4R5; wherein
R4 and R5 are lower alkyl or together with the nitrogen atom to which they are attached form a 4-, 5-or 6- membered heterocycle which may contain a further heteroatom selected from O, N or S,
and pharmaceutically acceptable salts thereof.
The enzyme dipeptidyl peptidase IV EC.3.4.14.5 (EC is the abbreviation for "Enzyme Committee" of the International Union of biochemistry this enzyme is abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones. In particular DPP-IV is degrading efficiently and rapidly glucagon like peptide 1 (GLP-I), which is one of the most potent stimulator of insulin production and secretion. Inhibiting DPP-IV would potentate the effect of endogenous GLP-I, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycemia and accordingly reduce the risk of tissue damage. Consequently, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes mellitus (e.g. Villhauer, WO98/19998). Other related state of the art can be found in WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, US 6110949, WO 00/34241 and US6011155.
We have found novel DPP-IV inhibitors that very efficiently lower plasma glucose levels. Consequently, the compounds of the present invention are useful for the treatment and/ or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit. In addition, the compounds of the present invention can also be used in the treatment and/ or prophylaxis of obesity, metabolic syndrome, β-cell protection, autoimmune diseases such as inflammatory bowel disease, encephalitis periaxialis scleroticans and rheumatoid arthritis, Colitis Ulcerrosa, Morbus Crohn, psoriasis, lichen planus and/or benign prostate hypertrophy. The compounds may also be useful for the prevention of AIDS (acquired immunodeficiency syndrome) or for the preventing metastasis, particularly preventing metastasis of breast and prostate cancer to lung.
Furthermore, the compounds of the present invention can be used as diuretic agent and for the treatment and/or prophylaxis of hypertension.
Unexpectedly, the compounds of the present invention exhibit improved therapeutic and pharmacological properties compared to other DPP-IV inhibitors known in the art, such as e.g. in context of pharmacokinetics and bioavailability.
Objects of the present invention are compounds of formula I and their production, as well as the use of the compounds of formula I in accordance with the invention in the control and prevention of illnesses of the aforementioned kind, and respectively, for the production of corresponding medicaments.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term "lower" is used to mean a group consisting of one to six, preferably of one to four carbon atom(s).
The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred. Most preferred halogen is chlorine.
The term "alkyl", alone or in combination with other groups, refers to a branched or straight- chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. The term "lower alkyl" or "Ci-6-alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n- pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like. Preferable lower alkyl residues are methyl ethyl, n-propyl and n-butyl, with methyl being especially preferred.
The term "lower halogenalkyl" refers to a lower alkyl group wherein at least one of the hydrogens of the lower alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro. Among the preferred lower halogenalkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially preferred.
The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term "lower alkoxy" refers to the group R'-O-, wherein R1 is lower-alkyl. Examples of lower alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being especially preferred.
The term "cycloalkyl" or "Cs-y-cycloalkyl" refers to a monovalent carbocyclic radical of three to seven carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with cyclopropyl and cyclohexyl being preferred.
The term "heteroaryl" refers to an aromatic 5- or 6-membered ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/ or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term "heteroaryl" further refers to bicyclic aromatic groups comprising two 5- or 6- membered rings, in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl. Preferred heteroaryl groups are thienyl, pyridyl and indolyl, which can optionally be substituted as described above, preferably with lower alkyl or halogen.
The term "R4 and R5 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle which may contain an additional heteroatom selected from O, N or S" means that R4 and R5 together with the nitrogen atom form a ring such as pyrrolidinyl, dihydropyrrolyl (pyrrolinyl), piperidyl, imidazolidinyl, morpholinyl, piperazinyl, thiazolidinyl, thiomorpholinyl, with thiazolidinyl and dihydropyrrolyl being especially preferred. The term "pharmaceutically acceptable salts" embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, salicylic acid, p- toluenesulphonic acid and the like, which are non toxic to living organisms. Preferred salts with acids are formates, maleates, citrates, hydrochlorides, hydrobromides and methanesulfonic acid salts, with hydrochlorides being especially preferred.
The invention relates to compounds of the formula (I)
Figure imgf000006_0001
wherein
R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, lower alkoxy, phenyl, phenoxy, halogen or lower halogenalkyl;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower allcyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
tetrahydronaphthyl;
C3.7-cycloalkyl;
-(CHR3)m-phenyl, wherein m is 1, 2, or 3 and phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein
R3 is independently selected from hydrogen, lower alkyl or phenyl;
-(CH2)n-heteroaryl, wherein n is 1, 2 or 3;
-(CH2)n-heteroaryl, wherein n is 1, 2, 3 and heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl or lower alkoxy; -C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
-C(O)-CH2-heteroaryl; and
-C(O)-CH2-heteroaryl, wherein heteroaryl is mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; and
R2 is selected from the group consisting of
lower alkyl, lower halogenalkyl;
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
heteroaryl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
-COOH;
-C(O)-NR4R5; wherein
R4 and R5 are lower alkyl or together with the nitrogen atom to which they are attached form a 4-, 5-or 6- membered heterocycle which may contain a further heteroatom selected from O, N or S,
and pharmaceutically acceptable salts thereof.
In preferred compounds of the present invention, R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
-(CHR3)m-phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein R3 is hydrogen; -(CH2)n-heteroaryl, wherein n is 1 or 2;
-(CH2)n-heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
-C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
-C(O)-CH2-heteroaryl; and
-C(O)-CH2-heteroaryl, with heteroaryl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
One group of preferred compounds of formula I according to the present invention are those compounds, wherein R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; and
-(CHR3)m-phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di, or trisubstituted by lower alkoxy and wherein R3 is hydrogen.
Especially preferred are compounds of formula I, wherein R1 is
phenyl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy.
More preferably R1 is phenyl di- or trisubstituted by lower alkoxy, with R1 being 3,4-dimethoxyphenyl or 2,3,4-trimethoxyphenyl being most preferred.
A further group of preferred compounds of formula I are those, wherein R1 is
-(CH2)n-heteroaryl, wherein n is 1 or 2; or -(CH2)n-heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
Preferred heteroaryl is indolyl or pyridyl.
Preferred meaning of n is 2.
Also preferred are compounds of formula I, wherein R1 is
-C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; or
-C(O)-CH2-heteroaryl.
Especially preferred are -C(O)-CH2-phenyl and C(O)-CH2-thienyl.
In preferred compounds of the present invention, R2 is selected from the group consisting of
lower alkyl;
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
heteroaryl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; and
-C(O)-NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a 5-membered heterocycle which may contain a further heteroatom selected from O, N or S.
Especially preferred are compounds of formula I, wherein R2 is lower alkyl, with n-butyl being most preferred.
Another group of preferred compounds of formula I are those, wherein R2 is
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy. Especially preferred are those compounds of formula I, wherein R2 is phenyl or phenyl mono-, di-, or trisubstituted, independently, by lower alkyl or halogen.
Also preferred are compounds of formula I, wherein R2 is
heteroaryl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy, with compounds, wherein heteroaryl is pyridyl or thienyl being especially preferred.
Further preferred are compounds of formula I, wherein R2 is
-C(O)-NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a 5-membered heterocycle which may contain a further heteroatom selected from O, N or S.
Especially preferred are compounds of formula I, wherein R2 is
-C(O)-thiazolidinyl or -C(O)-dihydropyrrolyl.
Examples of compounds of the formula I of the present invention are the following:
(as) -3-butyl- 1 -phenethyl-piperidine-4-yl-amine,
(trans)-3-butyl- 1 -phenethyl-piperidine-4-yl-amine,
's)-3-butyl-l-benzyl-piperidine-4-yl-amine
ffrαπsJ-3-butyl-l-benzyl-piperidine-4-yl-amine
fαsJ-3-bu1yl-l-[2-(lH-indol-3-yl)-ethyl]-piperidine-4-ylamine, (
ftransJ-3-butyl-l-[2-(lH-indol-3-yl)-ethyl]-piperidine-4-ylamine,
fdsj-3-butyl-l-[2-(3,4-dimethoxy-phenyl-lyl)-ethyl] piperidine-4-ylamine,
(trans)-3-butyl- 1 - [2- (3,4-dimethoxy-phenyl- lyl)-ethyl] piperidine-4-ylamine,
CcisJ-3-butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
ffrαnsJ-3-butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
fdsJ-3-butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine, (YrattsJ-3-butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine,
(cis/trans) -3 -butyl- 1 - ( 5,6,7,8-tetrahydro-naphthalen- IyI) -piperidine-4-yl-amine hydrochloride,
(czs)-3-butyl-l-(3, 4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(trans)-3-butyl-l-(3, 4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(cis) -3-butyl- 1 -naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,
('transJ-3-butyl-l-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,
(cis/trans) -3 -butyl- l-naphthalen-l-yl-piperidine-4-yl-amine hydrochloride,
fαsj-3-butyl-l-(3, 4-dichloro-phenyl) -piperidine-4-yl-amine hydrochloride,
('αs/)-3-butyl-l-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
fα5J-3-butyl-l-p-tolyl-piperidine-4-yl-amine hydrochloride,
(trans)-3-butγl- l-p-tolyl-piperidine-4-yl-amine hydrochloride,
fcJ5/)-3-butyl-l-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
('cisΛrfln5/)-3-butyl-l-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
fαs)-3-butyl-4-methyl-l-phenyl-piperidine-4-yl-amine hydrochloride,
ffrfl«5/)-3-butyl-4-methyl-l-phenyl-piperidine-4-yl-amine hydrochloride,
fdsJ-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
(ds/trαπs>)-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
('α'sΛransJ-3-butyl-l-cyclohexyl-piperidine-4-yl-amine hydrochloride,
('ds/irαnsJ-3-butyl-l-(3,5-bis-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
CcisJ-S-butyl-l-Cβ-methoxy-biphenyl-S-y^-piperidine^-yl-amine hydrochloride, ( trans) -3 -butyl- 1 - (6-methoxy-biphenyl-3 -yl) -piperidine-4-yl-amine hydrochloride,
fαs/fraπsj-3-butyl-l-benzhydryl-4-yl-piperidine-4-yl-amine hydrochloride,
f dsj-3-phenyi- 1 -phenethyl-piperidine-4-yl-amine,
ftraπsj-3-phenyl-l-phenethyl-piperidine-4-yl-amine,
(dsJ-3-phenyl- 1 -benzyl-piperidine-4-yl-amine,
ffrflπsJ-3-phenyl-l-benz7l-piperidine-4-yl-amine,
fαs/trαnsJ-methyl-r-phenethyl-r,2',3',4τ,5',6'-hexahydro-[2,3']bipyridinyl-4'-yl-amine,
('dsJ-3-(3-chloro-phenyl)-l-phenethyl-piperidine-4-yl-amine,
Ccfs/fraπsJ-3-(3-chloro-phenyl)-l-ben2yl-piperidine-4-yl-amine,
fds/iταπ5J-3-(3-methyl-phenyl)-l-benzyl-piperidine-4-yl-amine,
fcisJ-3-(3-chloro-phenyl)- 1- [2-(3)4-dimethoxy-phenyl)-ethyl] -piperidine-4-yl-amine,
ftraπsJ-l-benzyl-3-thiophen-2-yl-piperidine-4-yl amine
(cz\)-3-o-tolyl-l-(3, 4, 5-trimethox7-phenyl)-piperidine-4-yl-amine hydrochloride,
(ϊrαns,)-3-o-tolyl-l-(3, 4, 5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(cis/trans)-3-o-tόlγ\-l-(3, 4, 5-trimethoxy"-phenyl)-piperidine-4-yl-amine hydrochloride,
fds/trαπsJ-l-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,
fds/frαπsj-l-(3,4-dimethox7-phenyl)-3-p-tolyl-piperidine-4-yl-amine hydrochloride,
('ds//rαnsj-l-(3,4-dimethoxy-phenyl)-3-(3> 4-dimethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
(cis/trans) - 1 - ( 3 ,4- dimethoxy-phenyl) -3 - ( 3 -methoxy-phenyl) -piperidine-4-yl-amine hydrochloride,
('ds/irfln5j-r-(3,4-dimethox7-phenyl)-r,2',3'J4',5',6'-hexahydro-[2,3']bipyridinyl-4'-yl- amine,
((3R,4S)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
((3S,4R)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone, [(3S,4R)-4-amino-l-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidine-3-yl- methanone,
1-[(3S, 4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-phenyl-et±ιanone,
l-[(3S-4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-thiophen-2-yl- ethanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-[2(3,4-dimethoxy-phenyl)-ethyl]-piperidine-3- carboxylic acid,
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidme-3-yl]- thiazolidin-3-yl-methanone
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethox7-phenyl)-piperidine-3-yl]-(2,5- dihydropyrrol-l-yl)-3-yl-methanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-(3,4-dimethox7-phenyl)-piperidine-3-yl]-(2,5- dihydropyrrol- 1 -yl) -3-yl-methanone, and
pharmaceutically acceptable salts thereof.
Preferred compounds of formula I are selected from:
fcis)-3-butyl-l-phenethyl-piperidine-4-yl-amine,
(cisJ-3-butyl- 1- [2-( lH-indol-3-yl)-ethyl] -piperidine-4-ylamine,
fci5J-3-butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(as) - 3 -butyl- 1 - (4-phenoxy-phenyl) -piperidine-4-yl- amine,
Cdsj-3-butyl-l-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(as) -3 -butyl- 1 -naphthalen-2-yl-piperidine~4-yl-amine hydrochloride,
('trøπsj-3-butyl-l-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,
Ccis/frαπsj-3-butyl-l-naphthalen-l-yl-piperidine-4-yl-amine hydrochloride,
fdsJ-3-butyl-l-(3,4-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
('dsj-3-buτyl-l-(4-chloro-3-trifiuoromethyl-ρhenyl)-piperidine-4-yl-amine hydrochloride, (czsJ-3-butyl-l-p-tolyl-piperidine-4-yl-amine hydrochloride,
('cis/)-3-butyl-l-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
fds/trαπsj-3-butyl-l-(3,5-dichloro-pheπyl)-piperidine-4-yl-amine hydrochloride,
fdsJ-3-butyl-4-methyl-l-phenyl-piperidine-4-yl-amme hydrochloride,
fcisJ-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
's/trαπsj-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piρeridine-4-yl-amine hydrochloride,
fdsj-3-butyl-l-(6-methoxy-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride,
(ris)-3-phenyl-l-phenethyl-piperidine-4-yl-amine,
fαs/traπs>methyl-r-phenethyl-r,2',3',4'>5',6'-hexahydro-[2,3']bipyridinyl-4'-yl-amine,
'5J-3-(3-chloro-phenyl)-l-phenethyl-piperidine-4-yl-amine,
(cis/trans)-3- ( 3 -chloro-phenyl) - 1 -benzyl-piperidine-4-yl-amine,
fdsΛm«5j-3-(3-methyl-phenyl)-l-benzyl-piperidine-4-yl-amine,
fci-5j-3-(3-chloro-phenyl)-l- [2-(3,4-dimethoxy-phenyl)-ethyl] -piperidine-4-yl-amine,
(Yrα«s,)-3-o-tolyl-l-(3, 4, 5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(cis/trans)-3-o-tolγl-l-(3, 4, 5-trimethox7-phenyl)-piperidine-4-yl-amine hydrochloride,
(cis/trans) - 1 - ( 3 ,4-dimethoxy-phenyl) -3-m-tolyl-piperidine-4-yl-amine hydrochloride,
fds/frflns>r-(3,4-dimethoxy-phenyl)-r,2',3',4',5',6'-hexahydro-[2,3']bipyridinyl-4'-yl- amine,
((3R,4S)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
((3S,4R)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
[(3S,4R)-4-amino-l-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidine-3-yl- methanone,
l-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-phenyl-ethanone, l-[(3S,4R)-4-ammo-3-(tiiiazolidine-3-carbonyl)-piperidme-l-yl]-2-thiophen-2-yl- ethanone,
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]- thiazolidin- 3 -yl-methanone
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5- dihydropyrrol-l-yl)-3-yl-methanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5- dihydropyrrol-l-yl)-3-yl-methanone, and
pharmaceutically acceptable salts thereof.
Most preferred compounds are selected from
3-(3-chloro-phenyl)-l-phenethyl-piperidine-4-yl-amine,
3-(3-chloro-phenyl)-l-benzyl-piperidine-4-ylamine,
3-(3-chloro-phenyl)-l-[2-(3,4-dimethox7-phenyl)-ethyl]-piperidine-4-ylamine,
l-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl amine hydrochlorid,
((3S,4R)-4-amino-l-phenethyl-piρeridine-3-yl)-thiazolidine-3-yl-methanone,
[(3S,4R)-4-amino-l-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidine-3-yl- methanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]- thiazolidine-3-yl-methanone,
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]- thiazolidine-3-yl-methanone, and
pharmaceutically acceptable salts thereof.
The compounds of formula I have two asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of diastereomers, racemates, or mixtures of diasteroisomeric racemates. The invention embraces all of these forms.
In a preferred embodiment, R2 and the amino group of the piperidine structure are in trans-configuration, i.e.
Figure imgf000016_0001
In a further preferable embodiment, R2 and the amino group of the piperidine structure are in ris-configuration, i.e.
In a further embodiment the invention comprises a process for the manufacture of compounds of formula I, which process comprises
either
a) converting a compound of the formula
Figure imgf000016_0003
wherein R1 and R2 are as defined before,
with hydroxylamine or a salt thereof into an oxime of the formula
Figure imgf000016_0004
wherein R and R are as defined before, and further reducing the oxime of formula III by catalytic hydrogenation or alternatively by a reduction with a metal hydride into the compound of formula I
or
b) deprotecting an 4-aminopiperidine derivative of the formula
Figure imgf000017_0001
wherein R and R2 are as defined before and R is an amino protecting group.
Rp is a suitable amino protecting group such as benzyloxycarbonyl (Z or Cbz), allyloxycarbonyl (Aloe), 9-fluorenylmethoxycarbonyl (Fmoc), and preferably, tert- butoxycarbonyl (Boc).
In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods shown in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are commercially available or can be prepared by methods analogous to the method given below or in the examples or by methods known in the art.
The compounds of formula I of the present invention can be prepared as indicated in schemes 1 to 6 below:
4-Aminopiperidines of the formula I with R1 having the meaning of -(CHR3)m- phenyl and -(CH2)n-heteroaryl, wherein R3, n and m are as defined above and R2 being lower alkyl can be prepared following scheme 1: Scheme 1
Figure imgf000018_0001
R1Br
DIPEA, DMF
Figure imgf000018_0002
In a first step, R2 with the meaning of lower alkyl is inserted in 3 -position via a transformation of a N-protected 4-oxo-piperidine carboxylic acid alkyl ester (AIk = lower alkyl) with a suitable alkyl iodide. N-protection can easily be achieved with a benzyl group (Bz). In a second step, the N-protection is removed e.g. by a catalytic hydrogenation, and subsequently in a third step, an R^halogenide with R1 having the meaning of -(CHR3)m-phenyl and -(CH2)n-heteroaryl is reacted with the deprotected piperidine to the respective 3-alkyl-l-aryl-4-oxo-piperidine. In case R1 is benzyl, these two last steps can be omitted. Transformation of the 3-alkyl-l-aryl-4-oxo-piperidine into the desired 4-aminopiperidine can then take place via an oxime formation with hydroxylamine followed by a reduction for example by LLAIH4 (LAH) in a suitable solvent.
4-Aminopiperidines of the formula I with R1 having the meaning of unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl, tetrahydronaphthyl or C3.7-cycloalkyl and R2 being lower alkyl can be prepared following scheme 2:
Scheme 2
Figure imgf000019_0001
Ra/Ni, H2
Figure imgf000019_0002
Figure imgf000019_0003
In a first step, a 4-oxo-piperidinium iodide can be formed from a suitably N- benzyl protected 3-alkyl-4-oxo-piperidine per reaction with methyl iodide in a suitable solvent. R1 can be inserted by reaction of the 4-oxo-piperidinium iodide with the respective aniline R1NH2 thereby forming the respective 3-alkyl-l-aryl-4-oxo-piperidine. Transformation of this intermediate into the desired 4-aminopiperidine can then take place via an oxime formation with hydroxylamine followed by a reduction for example by catalytic hydrogenation in the presence of a common hydrogenation catalyst such as Raney Nickel or palladium/charcoal in a suitable solvent.
4-Aminopiperidines of the formula I with R1 having the meaning of-(CHR3)m- phenyl and -(CH2)n-heteroaryl, wherein R3, n and m are as above and R being unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl or unsubstituted or mono-, di, or trisubstituted heteroaryl can be prepared following scheme 3:
Scheme 3
Figure imgf000019_0004
LAH, ether
Figure imgf000019_0005
Figure imgf000019_0006
In a first reaction sequence an acrylic acid ester is reacted with the respective arylalkylamine R1NH2 to form the respective arylalkylamino propionic acid ester which is then converted with the respective arylacetic acid or aryl acetic acid halogenide R2COOH or R2COHaI into an R2 acetyl amino propionic acid ester. Subsequent ring formation with e.g. an alkalibutylate or with sodium hydride leads to a piperidine-2,4- dione which is then transformed with hydroxylamine to the piperidine-2,4dione-4- oxime. This intermediate can finally be reduced for example with LLAIH4 (LAH) in a suitable solvent to the desired 4-aminopiperidine.
4-aminopiperidines of the formula I with R1 having the meaning of unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di-, or trisubstituted naphthyl, tetrahydronaphthyl or C3-7-cycloalkyl and R2 being unsubstituted or mono-, di-, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl or unsubstituted or mono-, di, or trisubstituted heteroaryl can be prepared following scheme 4:
Scheme 4
Figure imgf000020_0001
Figure imgf000020_0002
The synthesis of l-aryl-3-aryl~4-amino piperidines can either be performed following scheme 2 via an N-benzyl-protected 3-aryl-4-oxo-piperidinium iodide which is treated with the aniline R1NH2 to give the respective 3-aryl-l-aryl-4-oxo-piperidine. Treatment of this compound with hydroxylamine will give the corresponding oxime that can be reduced subsequently to give the desired 4-amino-piperidine.
As an alternative an N-benzyl-protected 4-oxo-piperidinium iodide can be reacted in a first step with aryl aniline R1NH2 to give the l-aryl-4-oxo-piperidine. The aryl-group in position 3 can then be introduced with an aryl halogenide R Hal in the presence of Pd-acetate, sodium tert-butoxide and P(tBu)3. The resulting 3-aryl-l-aryl-4-oxo- piperidine can then be transformed to the desired 4-amino piperidine as outlined above.
4-aminopiperidines of the formula I with R1 having the meaning of-(CHR3)m- phenyl and -(CH2)n-heteroaryl, wherein R3, n and m are as above and R2 being -C(O)- NR4R5, wherein R4 and R5 are as above can be prepared following scheme 5:
Scheme 5
Figure imgf000021_0001
D HBr, HOAc
Figure imgf000021_0002
Figure imgf000021_0003
In a first step the amino group of a 4-amino-piperidine-l,3-dicarboxylic acid di- ester is protected with a benzyloxycarbonyl group. The ester group in position 3 can then be hydrolyzed, followed by formation of the amide using the corresponding amine
HNR4R5 under standard peptide coupling conditions. In the subsequent steps, the BOC protecting group at position 1 can be removed for example by treatment with trifluoroacetic acid and then the aryiakyl group can be introduced at Nl by treatment with the respective aryl alkyl halogenide R1 Hal. Finally the desired 4-aminopiperidine can be obtained by removal of the benzyloxycarbonyl protecting group in the presence of HBr.
4-aminopiperidines of the formula I with R1 having the meaning of unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di-, or trisubstituted naphthyl, tetrahydronaphthyl or C3-7-cycloalkyl and R2 being unsubstituted or mono-, di, or trisubstituted phenyl, unsubstituted or mono-, di, or trisubstituted naphthyl or unsubstituted or mono-, di, or trisubstituted heteroaryl can be prepared following scheme 6:
Scheme 6
Figure imgf000022_0001
A l-benzyl-4-oxo-piperidine-3-carboxylic acid ester is first reacted with ammonia to give the respective tetrahydropyridine which can then be reduced for example with sodium borohydride to give the 4-amino piperidine carboxylic acid ester. BOC protection of the amino group in 4-position and subsequent removal of the benzyl group by e.g. catalytic hydrogenation in the presence of a hydrogenation catalyst then affords 4- N-BOC protected piperidine-3-carboxylic acid ester. The arylalkyl group R1 can be inserted using the respective aldehyde R1CH=O followed by reduction. Removal of the BOC protecting group and ester hydrolysis with a suitable alkali hydroxide leads to the desired l-arylalkyl-4-amino piperidine-3-carboxylic acid.
4-aminopiperidines of the formula I with R1 having the meaning of-(CHR3)m- phenyl and -(CH2)n-heteroaryl, wherein R3, n and m are as above and R2 being -C(O)- NR4R5, wherein R4 and R5 are as above can be prepared following scheme 7: Scheme 7
Figure imgf000023_0001
In a first reaction sequence an arylamine R1 is reacted with an acrylic acid ester in the presence of CuCl and acetic acid to form the respective l-aryl-4-oxo-piperidine-3- carboxylic acid ester. Treatment of this intermediate with ammonium acetate and sodium cyano borohydride gives the l-aryl-4- amino piperidine-3~carboxylic acid ester. BOC protection of the free amino group in 4-position and subsequent ester hydrolysis provides the free carboxylic acid which can then used for coupling with amine R4R5NH. The desired 4-aminopiperidine can then be obtained by removal of the BOC protecting group with e.g. trifluoro acetic acid.
The invention further relates to compounds of formula I as defined above, when manufactured according to a process as defined above.
The invention also relates to compounds of formula I as defined above for use as therapeutic active substances for the treatment and / or prophylaxis of diseases which are associated with DPP-IV.
Such diseases which are associated with DPP-IV are diabetes, particularly non- insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit. In addition, the compounds of the present invention can also be used in the treatment and/ or prophylaxis of obesity, metabolic syndrome, β- cell protection autoimmune diseases such as inflammatory bowel disease, encephalitis periaxialis scleroticans and rheumatoid arthritis, Colitis Ulcerrosa, Morbus Crohn, psoriasis, lichen planus and/ or benign prostate hypertrophy. The compounds may also be useful for the prevention of AIDS (acquired immunodeficiency syndrome) or for the preventing metastasis, particularly preventing metastasis of breast and prostate cancer to lung. Furthermore, the compounds of the present invention can be used as diuretic agent and for the treatment and/or prophylaxis of hypertension.
As described above, the compounds of formula I of the present invention can be used as medicaments for the treatment and/or prophylaxis of such diseases which are associated with DPP-IV as defined above.
The invention therefore also relates to pharmaceutical compositions comprising a compound formula I of the present invention and a pharmaceutically acceptable carrier and/or adjuvant.
Further the invention relates to compounds of formula I of the present invention for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of the diseases which are associated with DPP-IV as defined above.
In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV as defined above, which method comprises administering a compound of formula I to a human being or animal.
The invention further relates to the use of compounds formula I of the present invention for the treatment and/ or prophylaxis of diseases which are associated with DPP-IV as defined above.
In context with the methods and uses defined above, the following diseases relate to a preferred embodiment: diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance.
The following tests were carried out in order to determine the activity of the compound of formula I.
Activity of DPP-IV inhibitors are tested with natural human DPP-IV derived from a human plasma pool or with recombinant human DPP-IV. Human citrate plasma from different donors is pooled, filtered through a 0.2 micron membrane under sterile conditions and aliquots of 1 ml are shock frozen and stored at -12O0C. In the colorimetric DPP-IV assay 5 to 10 μl human plasma and in the fluorometric assay 1.0 μl of human plasma in a total assay volume of 100 μl is used as an enzyme source. The cDNA of the human DPP-IV sequence of amino acid 31 -to 766, restricted for the N- terminus and the transmembrane domain, is cloned into Pichia pastoris. Human DPP- IV is expressed and purified from the culture medium using conventional column chromatography including size exclusion and anion and cation chromatography. The final enzyme preparation was observed on SDS-page stained with Coomassie blue and shown a purity of > 95%. In the colorimetric DPP-IV assay 20 ng rec.h DPP-IV and in the fluorometric assay 2 ng rec-h DPP-IV in a total assay volume of 100 μl is used as enzyme source.
In the fluorogenic assay Ala-Pro-7-amido-4-trifluoromethylcoumarin (Calbiochem No 125510) is used as a substrate. A 20 mM stock solution in 10 % DMF/H2O is stored at -200C until use. In IC50 determinations a final substrate concentration of 50 μM is used. In assays to determine kinetic parameters as Km, Vmax, Ki, the substrate concentration is varied between 10 μM and 500 μM.
In the colorimetric assay H-Ala-Pro-pNAΗCl (Bachem L-1115) is used as a substrate. A 10 mM stock solution in 10% MeOH/H2O is stored at -2O0C until use. In IC50 determinations a final substrate concentration of 200 μM is used. In assays to determine kinetic parameters as Kn,, Ymax, K;, the substrate concentration is varied between 100 μM and 2000 μM.
Fluorescence is detected in a Perkin Elmer Luminescence Spectrometer LS 5OB at an excitation wavelength of 400 nm and an emission wavelength of 505 nm continuously every 15 seconds for 10 to 30 minutes. Initial rate constants are calculated by best fit linear regression.
The absorption of pNA liberated from the colorimetric substrate is detected in a Packard Spectra Count at 405 nm continuously every 2 minutes for 30 to 120 minutes. Initial rate constants are calculated by best fit linear regression.
DPP-IV activity assays are performed in 96 well plates at 37°C in a total assay volume of 100 μl. The assay buffer consists of 50 mM Tris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl. Test compounds are solved in 100 % DMSO, diluted to the desired concentration in 10% DMSO/H2O. The final DMSO concentration in the assay is 1 % (v/v). At this concentration enzyme inactivation by DMSO is < 5%. Compounds are with (10 minutes at 370C) and without pre-incubation with the enzyme. Enzyme reactions are started with substrate application followed by immediate mixing.
IC50 determinations of test compounds are calculated by non-linear best fit regression of the DPP-IV inhibition of at least 5 different compound concentrations. Kinetic parameters of the enzyme reaction are calculated at least 5 different substrate concentrations and at least 5 different test compound concentrations. The compounds of the present invention exhibit IC50 values of 0.1 μM to lOOμM, more preferably of 0.1 μM to 10 μM, as shown in the following table:
Figure imgf000026_0001
The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/ or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency- improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably
1-100 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.
Examples
Abbreviations used:
DCM: dichloromethane; HOAc: acetic acid; AcOEt: ethyl acetate; DMF: dimethylformamide; DIPEA: diisopropylethylamine (Huenig's base); THF: tetrahydrofuran; LAH: lithium aluminium hydride; CDI: carbonyldiimidazole; TFA: trifluoro acetic acid; EDCl: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl; HOBt: 1-hydroxybenzotriazole.
RT: room temperature; HV: high vacuum. TLC: thin layer chromatography. Example 1
3-Butyl-l-phenethyl-piperidine-4-yl-amine
Step A]: l-Benzyl-3-butyl-piperidine-4-one
To a suspension of anhydrous potassium carbonate (22.8g) and l-benzyl-4-oxo- piperidine-3-carboxylic acid ethyl ester (1Og) in acetone (125 ml) was added a solution of butyl iodide (13.4g, 8.3 ml) in acetone (50 ml) under argon over a period of 30 minutes. The resulting suspension was stirred at RT for 30 min and then refluxed for 12 hours. The suspension was cooled, filtered and concentrated in vacuo. The residue was dissolved in DCM and the solution was washed with water and brine, dried over Na2SCU and evaporated. To the residue was added aqueous HCl (20%, 100 ml) and the solution was refluxed for 24 hours. The solution was evaporated and the residue was dissolved in DCM, washed with 10% aq. Na2CO3 solution and brine, dried and evaporated. The crude product was purified by flash chromatography (ethyl acetate/hexanes 1:2) to give the product as a slightly yellow oil (6.4 g). MS (ESI): 246.4 (MH+).
Step B]: 3-Butyl-piperidine-4-one
To a solution of l-benzyl-3-butyl-piperidine-4-one (1.3 g) in HOAc/water 3:1 (25 ml) was added 10% Pd on charcoal (130 mg). A hydrogen atmosphere was introduced by repeated evacuation/gas introduction. The suspension was vigorously stirred for 5 hours. The catalyst was removed by filtration through dicalite and the filtrate was concentrated in vacuo. The oily residue was treated with 10% aq. Na2CO3 and then extracted into DCM. The organic layer was separated, dried over Na2SO4, filtered and evaporated to give the crude product as slightly yellow oil (680 mg) which was used without further purification. MS (ESI): 156.2 (MH+).
Step C]: 3-Butyl-l-phenethyl-piperidine-4-one
To a solution of 3-Butyl-piperidine-4-one (250 mg) in DMF (5 ml) was added
DIPEA (468 mg) and then a solution of (2-bromoethyl) -benzene (373 mg) in DMF (5 ml) over a period of 45 min. The resulting mixture was stirred at RT for 1 hour and then heated to 60 0C for 6 hours. The reaction mixture was cooled, diluted with ether and the organic solution was washed with 10% aq. Na2CC>3 solution twice and brine. The organic layer was dried over MgSO4 , filtered and evaporated to give a residue which was purified by flash chromatography (ethyl acetate/hexanes 1:3) to give the product as a colorless liquid (355 mg). MS (ESI): 260.4 (MH+). Step D] : 3-Butyl-l-phenethyl-piperidine-4-one oxime
3-Butyl-l-phenethyl-piperidine-4-one (300 mg), NaOAc (878 mg) and hydroxylamine hydrochloride (708 mg) were suspended in ethanol/water (1:1, 10 ml) and the mixture was heated to reflux for 5 hours. The clear solution that resulted from this treatment was cooled, diluted with water and basified with 10% aq. Na2CO3 to pH 10. The suspension was extracted with DCM and the organic layer was washed with brine, dried (MgSO/i) and evaporated. The product was sufficiently pure for the next step. Yellowish glass, mixture of cis and trans diastereomers (332 mg). MS (ESI): 261.4 (MH+).
Step E] 3-Butyl-l-phenethyl-piperidine-4-ylamine
3-Butyl-l-phenethyl-piperidine-4-one oxime (218 mg) was dissolved in THF (10 ml) and LAH (261 mg) was added in one portion. The suspension was then allowed to stir at RT for 24 hours. The reaction mixture was carefully pipetted onto 5% aq. NaHCO3 solution and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried (MgSO^) and evaporated to give a colorless oil. This was purified by flash chromatography (gradient of MeOH in DCM containing 1% NH4OH) to give the product as cis and trans diastereomers (cis: 127 mg; trans: 36 mg). MS (ESI): 261.4 (MH+).
Example 2
3-Butyl-l-benzyl-piperidine-4-yl-amine
This compound was synthesized in analogy to example 1, with the exception that Steps B] and C] were omitted altogether and the benzyl group was carried through the whole synthesis. Cis and trans diastereomers as colorless oils. MS (ESI): 247.4 (MH+).
Example 3
3-Butyl-l-[2-(lH-indol-3-yl)-ethyl]-piperidine-4-yiamine
This compound was synthesized as described in example 1 from l-benzyl-4-oxo- piperidine-3-carboxylic acid ethyl ester and 3-(2-bromo-ethyl)-IH-indole as the alkylating agent in Step C]. Cis and trans diastereomers as colorless oils. MS (ESI): 300.5 (MH+). Example 4
3-Butyl-l-[2-(3,4-dimethoxy-phenyl-l-yl)-ethyl]-piperidine-4-ylamine
This compound was synthesized as described in example 1 from l-benzyl-4-oxo- piperidine-3-carboxylic acid ethyl ester and (2-bromoethyl)-3,4-dimethoxybenzene as the alkylating agent used in Step C]. Cis and trans diastereomers as colorless oils. MS (ESI): 321.4 (MH+).
Example 5
3-Butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride
Step A] : l-Benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide
To a solution of 3-butyl-l-benzyl-piperidine-4-one (9080 mg) in acetone (40 ml) was slowly added methyl iodide (6303 mg) at room temperature. The solution was stirred at room temperature for three hours. A white solid precipitated and was filtered off. The solid was washed four times with 50 ml of acetone and dried under reduced pressure. The filtrate was evaporated and the residue was stirred with ethyl acetate. The white solid was filtered, washed with ethyl acetate and dried under vacuum. The two solids were combined to yield l-benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide as a white powder (11200 mg). MS (ESI): 204.2 (M-I').
Step B]: 3-Butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4~one
A slurry of l-benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide (306 mg) in water (2 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (929 mg) and anhydrous potassium carbonate (33 mg) in ethanol (4 ml). The dark solution was heated to reflux for three hours. Water was added and the reaction was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a dark oil, which was purified by flash chromatography (ethyl acetate/hexanes 1:1) to give the product as a colorless oil (520 mg). MS (ESI): 322.4 (MH+).
Step C]: 3-Butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride
The ketone (460 mg) was dissolved in ethanol (60 ml). Hydroxylamine hydrochloride (109 mg) and sodium acetate (129 mg) were added and the solution was stirred at room temperature for one hour. After TLC control, Raney-Nickel was added (Nr 313 Degussa B 1132) and the reaction was stirred at room temperature under an atmosphere of hydrogen over night. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel (DCM/ MeOH/ 25% aqueous NH4OH solution 95:5:1). The separated products were dissolved in ethanol and 1 ml of saturated ethanolic hydrogen chloride solution was added. The solutions were evaporated to yield the cis- (150 mg) and the frøns-diastereomers (160 mg) as light yellow solids. MS (ESI): 323.4 (MH+).
Example 6
3-Butyl- l-(4-phenoxy-phenyl)-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 5 using Steps B] and C] from l-benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide and 4-phenoxy-aniline with the exception that Step C] was replaced by a different method.
Step C (modified version)]: 3-Butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine hydrochloride
3-Butyl-l-(4-phenoxy-phenyl)-piperidine-4-one (320 mg) was dissolved in ethanol (8 ml). Hydroxylamine hydrochloride (76 mg) and sodium acetate (89 mg) were added. The reaction turned yellow and the solution was stirred at room temperature for two hours. TLC control indicated the formation of the E/Z-oximes. Water (8 ml) was added. A suspension was obtained to which Al-Ni-alloy (300 mg) was added. 32 % aqueous sodium hydroxide solution (1.4 ml) was added slowly. The reaction turned warm. After complete addition, the reaction was stirred for two hours at room temperature and the solid was filtered off. The precipitate was washed with DCM. The aqueous solution was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (DCM/MeOH/aq. sat. NH4OH solution 100:5:1). The separated products were dissolved in ethanol and 1 ml of saturated ethanolic hydrogen chloride solution was added. The solutions were evaporated to yield the cis- (117 mg) and the frαns-diastereomer (52 mg) as light yellow solids. MS (ESI): 325.5 (MH+) trans and cis.
Example 7
3-Butyl-l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-piperidine-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 5-amino-tetraline to yield a mixture of as- and trans- diastereomers as a white solid. Separation of the diastereomers (as the free amines) using flash chromatography was not possible. MS (ESI): 287.3 (MH+).
Example 8
3-Butyl-l-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 3,4-dimethoxy-aniline to yield the cis- and the fmo5-diastereomers as white solids. MS (ESI): 293.4 (MH+) cis- and trans-diastereomer.
Example 9
3-Butyl-l-naphthalen-2-yl-piperidine-4-yl- amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 2-naphthyl-amine to yield a 5/2-mixture of the cz's- and trans- diastereomers and the pure ϊrαns-diastereomer as white solids. MS (ESI): 283.2 (MH+) cis- and trαπs-diastereomer.
Example 10
3-Butyl-l-naphthalen-l-yl-piperidine-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 6 from 1 -benzyl- 3 -butyl- 1- methyl-4-oxo-piperidinium iodide and 1-naphthylamine to yield a 1/2-mixture of the cis/trans-diastereomers as a white solid. Separation of the diastereomers (as the free amines) using flash chromatography was not possible. MS (ESI): 283.2 (MH+).
Example 11
3-Butyl-l-(3,4-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 3,4-dichloro-aniline to yield the cis- diastereomer as a white solid. MS (ESI): 301.3 (MH+).
Example 12
3-Butyl-l-(4-chloro-3-trifiuoromethyl-phenyl)-piperidme-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from 1 -benzyl- 3 -butyl- 1- methyl-4-oxo-piperidinium iodide and 4-chloro-3-trifluoromethyl-aniline to yield the czs-diastereomer and a 1/1 -mixture of the cis- and trαπs-diastereomers as white solids. MS (ESI): 335.3 (MH+) cis- and trans-diastereomer.
Example 13
3-Butyl-l-p-tolyl-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 4-methyl-aniline to yield the cis- and trans- diastereomers as white solids. MS (ESI): 247.4 (MH+).
Example 14
3-Butyl-l-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride and 3-butyl-l- phenyl-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 3,5-dichloro-4-methyl-aniline to yield the cis- and a 1/1-mixture of the cis- and trans- diastereomers as white solids. MS (ESI): 301.3 (MH+).
Overreduction led to the formation of the dehalogenated cis- and trans-phenyl derivatives, which were separated as the amines during flash chromatography. The hydrochlorides of the αs-and trαns-diastereomers were isolated as white solids. MS (ESI): 233.3 (MH+).
Example 15
3-Butyl-l-(3-methox7-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidmium iodide and 3-methoxy-5-trifluoromethyl-aniline to yield a mixture of cis- and trøns-diastereomers and the cis-diastereomer as white solids. MS (ESI): 331.4 (MH+).
Example 16
3-Butyl-l~cyclohexyl-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and cyclohexyl amine to yield a mixture of cis- and irans-diastereomers as a white solid. 1H NMR (DMSO): δ 2.81 - 2.65 (m, 2H), 2.60 - 2.00 (m, 5H), 1.74 - 1.60 (m, 5H), 1.60 - 1.40 (m, 3H), 1.40 - 1.00 (10 H), 0.87 (t, 3H). Example 17
l-(3,5-Bis-trifluoromethyl-phenyl)-3-butyl-piperidme-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 6 from 1 -benzyl- 3 -butyl- 1- methyl-4-oxo-piperidinium iodide and 3,5-bis (trifluoromethyl)-aniline to yield a mixture of as- and trørcs-diastereomers as a white solid. MS (ESI): 369.3 (MH+).
Example 18
3-Butyl-l-(6-methoxy-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride
This compound was synthesized in analogy to example 6 from l-benzyl-3-butyl-l- methyl-4-oxo-piperidinium iodide and 6-methoxy-biphenyl-3-ylamine to yield the cis- and the trans- diastereomers as white solids. 1H NMR (DMSO, α's-diastereomer): δ 7.47 (d, 2H), 7.38 (t, 2H), 7.32 (t, IH), 6.97 (d, IH), 6.89 (d, IH), 6.82 (s, IH), 3.67 (s, 3H), 3.07 (dd, 2H), 2.98 (m, 2H), 2.86 (dd, IH), 1.62 (m, 3H), 1.29 (m, 6H), 0.88 (t, 3H). 1H NMR (DMSO, trans-diastereomer): 67.47 - 7.20 (m, 8H), 3.62 (s, 3H), 3.54 (br d, 2H), 2.64 (m, 2H), 2.36 (m, IH), 1.79 (m, 3H), 1.33 (m, 6H), 0.88 (t, 3H).
Example 19
l-Benzhydryl-3-butyl-piperidine-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 6 from (rac)-l-benzyl-3- butyl-l-methyl-4-oxo-piperidinium iodide and diphenyl methyl amine to yield a 1/1- mixture of cis/trans-diastereomers as a white solid. 1H NMR (DMSO): 6 7.37 (m, 4H), 7.27 (m, 4H), 7.16 (t, 2H), 4.26 & 4.22 (2s, IH), 2.81 - 2.73 (m, 3H), 2.48 - 2.08 (m, 3H), 1.56 - 1.05 (m, 8H), 0.84 & 0.77 (2t, 3H).
Example 20
3-Phenyl- 1 -phenethyl-piperidine-4-yl-amine]
Step A] : 3-Phenethylamino-propionic acid ethyl ester
Phenylethyl amine (10 g) was dissolved in EtOH (50 ml) and then treated with acrylic acid ethyl ester (8.3 g) dropwise under argon at RT. The resulting mixture was allowed to stir over night and was evaporated and dried in vacuo. The residue (18.9 g) was used without further purification. Colorless liquid, MS (ESI): 222.3 (MH+). Step B] : 3-(Phenethyl-phenylacetyl-amino)-propionic acid ethyl ester
3-Phenethylamino-propionic acid ethyl ester (8.0 g) was dissolved in absolute pyridine (12 ml) and cooled to 0 0C by means of an ice bath. Phenylacetic acid chloride (1.5 ml) was then added dropwise over a period of 10 min; a yellow suspension was obtained. The mixture was then heated to 60 0C for 2.5 hours, cooled to RT and then allowed to stir over night. The mixture was poured into ice/water containing 25% HCl and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 1:4) to give the product as a yellow oil (3.9 g). MS (ESI): 340.4 (MH+).
Step C] : 1 -Phenethyl-3-phenyl-piperidine~2,4-dione
Sodium hydride (1.1 g, 50% in mineral oil) was suspended in ether (40 ml) under argon at RT. 3-(Phenethyl-phenylacetyl-amino)-propionic acid ethyl ester (2.5 g) was added in portions followed by addition of abs. EtOH (0.5 ml). The resulting mixture was refluxed for 2 hours, cooled and poured into water/ice/ 1 N HCl. The aqueous layer was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SC>4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 1:1 and then DCM/MeOH 95:5) to give the desired product as a light yellow foam (801 mg). MS (ESI: 294.4 (MH+).
Step D]: l-Phenethyl-3-phenyl-piperidine-2,4-dione 4-oxime
l-Phenethyl-3-phenyl-piperidine-2,4-dione (781 mg), sodium acetate (1.15 g) and hydroxylamine hydrochloride (925 mg) were suspended in EtOH/water 1:1 (25 ml) and the mixture was refluxed for 4 hours. The mixture was then poured into ice/water/ IN NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give the crude product that was purified by flash chromatography (DCM/MeOH/NH4OH 98:2:0.25) to give the compound as a white foam (489 mg). MS (ESI): 309.4 (MH+).
Step E] : l-Phenethyl-3-phenyl-piperidine-4-yl amine
l-Phenethyl-3-phenyl-piperidine-2,4-dione 4-oxime (480 mg) was dissolved in abs. ether (30 ml) under argon. LAH (473 mg) was added in one portion and the resulting suspension was refluxed over night. The mixture was carefully poured into IM aqueous sodium potassium tartrate solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography (gradient of MeOH in DCM containing 0.25% NH4OH and then DCM/MeOH/NH4OH 85/15/0.25) to give the compound as the cis diastereomer (95 mg) and trans diastereomer (101 mg) as colorless oils. MS (ESI): 281.4 (MH+).
Example 21
3-Phenyl-l-benzyl~piperidine-4-yl-amine]
This compound was made according to example 20, Step B] to E] from 3- benzylamino-propionic acid ethyl ester and phenylacetic acid chloride. Cis and trans diastereomers as yellow oils. MS (ESI): 326.4 (MH+).
Example 22
4-Methyl-r-phenethyl-r,2',3')4',5',6'-hexahydro-[2,3']bipyridinyl-4'-ylamine
This compound was made according to example 20, Step A] to E] from phenethylamine and ethyl acrylate but with a modified coupling step B] where (4- methyl-pyridin-2-yl)-acetic acid was used instead of the corresponding acid chloride.
Step A] (4-Methyl-pyridin-2-yl)-acetic acid
(4-Methyl-pyridin-2-yl) -acetic acid ethyl ester (1.0 g) - prepared according to
Chem. Parm. Bull 32 (12), 1984, 4866-4872 - was dissolved in ethanol (30 ml) and treated with a IM ethanolic NaOH solution (5.83 ml). The mixture was refluxed for 4 hours, cooled and evaporated in vacuo. The residue was dissolved in water (50 ml) and the pH was adjusted to 3.0 with IM HCl. The solvent was evaporated and the residue was suspended in ethanol (150 ml) and filtered. The clear filtrate was evaporated to dryness and the residue was dried in vacuo to give a light yellow solid (1.0 g). NMR (DMSO-iό)-' 8.65 (d, IH); 7.72 (s, IH), 7.68 (d, IH), 4.04 (s, 2H), 2.49 (s, 3H).
Step B] 3-{ [2-(4-Methyl-pyridin-2-yl)-acetyl] -phenethyl-amino}-propionic acid ethyl ester:
(4-Methyl-pyridin-2-yl) -acetic acid (1.0 g), carbonyldiimidazole (CDI, 1.07 g) and
DIPEA (0.856 g) were added to THF (15 ml) and the light brown suspension was allowed to stir at RT for 1 hour. To the mixture was added 3-phenethylamino-propionic acid ethyl ester (0.898 g) dropwise and the resulting mixture was stirred at 55° over night. The mixture was poured into ice/water and the pH was adjusted to 5.0. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na24, filtered and evaporated. The residue was purified by flash chromatography ( ethyl acetate/hexanes 2:1) to give the desired product as a light brown liquid (0.462 g). MS (ESI): 355.0 (MH+).
The final product of this reaction sequence was obtained as a mixture of as and trans diastereomers, yellow oil. MS (ESI): 296.4 (MH+).
Example 23
3-(3-Chloro-phenyl)-l-phenethyl-piperidine-4-ylamine
This compound was made according to example 22 from phenethylamine, ethyl acrylate and (3-chloro-phenyl) acetic acid. The desired compound was obtained as the αs-diastereomer as a yellow oil. MS (ESI): 315.1 (MH+).
Example 24
3-(3-Chloro-phenyl)-l-benzyl-piperidine-4-ylamine
This compound was made according to example 20, steps B] to E] from 3- benzylamino-propionic acid ethyl ester and (3-chloro-phenyl) acetic acid chloride. The desired compound was obtained as a mixture of as- and irαns-diastereomer as a yellow oil. MS (ESI): 301.2 (MH+).
Example 25
3-(3-Methyl-phenyl)-l-benzyl-piperidine-4-ylamine
This compound was made according to example 20, steps B] to E] from 3- benzylamino-propionic acid ethyl ester and (3-methyl-phenyl) acetic acid chloride. The desired compound was obtained as a mixture of cis and frαns-diastereomers as a yellow oil. MS (ESI): 281.3 (MH+).
Example 26
3-(3-Chloro-phenyl)-l-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-ylamine
This compound was made according to example 20 from ethyl acrylate, 2-(3,4- dimethoxy-phenyl)-ethylamine and (3-chloro-phenyl) acetic acid chloride. The desired compound was obtained as the ris-diastereomer as a yellow oil. MS (ESI): 375.2 (MH+). Example 27
l-Ben2yl-3-thiophen-2-yl-piperidine-4-ylamine
This compound was made in analogy to example 20, steps B] to E] from 3- benzylamino -propionic acid ethyl ester and thiophene-2-acetylchloride. The desired compound was obtained as the frαns-diastereomer as a yellow oil. MS (ESI): 273.2 (MH+).
Example 28
3-o-Tolyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride
Step A] : l-Benzyl-l-methyl-4-oxo-3-o-tolyl-piperidinium iodide
To a solution of l-benzyl-3-o-tolyl-piperidine-4-one (5165 mg) in acetone (25 ml) was slowly added methyl iodide (3048 mg) at room temperature. The solution was stirred at room temperature over night. A white solid precipitated and was filtered off. The solid was washed four times with 50 ml of acetone and dried under reduced vacuum. The filtrate was evaporated and the residue was stirred with ethyl acetate. The white solid was filtered, washed with ethyl acetate and dried under vacuum. The two solids were combined to yield l-benzyl-3-butyl-l-methyl-4-oxo-piperidinium iodide as a yellowish solid (4400 mg). MS (ESI): 294.3 (M-I").
Step B]: 3-o-Tolyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-one
A slurry of l-benzyl-l-methyl-4-oxo-3-o-tolyl-piperidinium iodide (1000 mg) in water (5 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (395 mg) and anhydrous potassium carbonate (37 mg) in ethanol (10 ml). The reaction was heated to reflux over night. Water was added and the reaction was extracted four times with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a red-brown oil, which was purified by flash chromatography (diethyl ether) to give the product as a yellow oil (600 mg). MS (ESI): 356.2 (MH+).
Step C] : 3-o-Tolyl-l-(3,4,5-trimethoxy-phenyl)-piperidme-4-yl-amine hydrochloride
3-o-Tolyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-one (300 mg) was dissolved in ethanol (8 ml). Hydroxylamine hydrochloride (64 mg) and sodium acetate {76 mg) were added. The solution turned from yellow to a brown suspension. After 3 hours stirring at room temperature water (8 ml) was added. A suspension was obtained to which Al-Ni-alloy (300 mg) was added. 32 % aqueous sodium hydroxide solution (1.4 ml) was added slowly; warming of the reaction mixture was observed. After complete addition, the reaction was stirred for two days at room temperature and the solid was filtered off. The precipitate was washed with DCM. The aqueous solution was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (DCM/MeOH/aq. sat MH solution 100:5:1). The separated products were dissolved in ethanol and 1 ml of saturated ethanolic hydrogen chloride solution was added. The solutions were evaporated to yield the cis-diastereomer (76 mg), a mixture of cis- and frαns-diastereomers (170 mg) and the trans-diastereomer (40 mg) as white solids. MS (ESI): 357.3 (MH+).
Example 29
l-(3,4-Dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl amine hydrochloride
Step A]: l-(3,4-Dimethoxy-phenyl)-piperidine-4-one
A slurry of 1 -benzyl- l-methyl-4-oxo-ρiperidinium iodide (9270 mg), 3,4- dimethoxy aniline (3900 mg) and anhydrous potassium carbonate (437 mg) in ethanol (90 ml) / water (45 ml) were heated to reflux for 6 hours. Additional potassium carbonate (200 mg) was added and the reaction was heated to 100 0C over night. Water (50 ml) was added to the reaction mixture, which was extracted three times with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to leave the crude product as a dark oil. The residue was purified by column chromatography (ethyl acetate / hexanes = 1:1) to yield the product as a yellow solid (3700 mg). MS (ESI): 236.1 (MH+).
Step B]: l-(3,4-Dimethoxy-phenyl)-3-m-tolyl-piperidine-4-one
Palladium acetate (23.8 mg), sodium tert-butoxide (306 mg) and l-(3,4- dimethoxy-phenyl)-piperidine-4-one were dissolved in oxygen free tetrahydrofuran (3 ml) under argon. The mixture was immediately degassed. After addition of 3- bromotoluene (363 mg) and tri(tert-butyl)phosphine (25.8 mg) the mixture was stirred at 5O0C over night. There was still some starting material left. The reaction was therefore heated to 700C for 2 hours. After cooling the mixture was diluted with ethyl acetate. It was washed with IN aqueous hydrochloride solution, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (hexanes / ethyl acetate = 2:1) to yield the product as a yellow oil (186 mg). MS (ESI): 326.3 (MH+). Step C]: l-(3,4-Dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl amine hydrochloride
l-(3,4-Dimethoxy-phenyl)-3-m-tolyl-piperidine-4-one (169 mg) was dissolved in ethanol (4 ml). Hydroxylamine hydrochloride (40 mg) and sodium acetate (47 mg) were added. The clear yellow solution turned to a suspension. After 3 hours stirring at room temperature water (4 ml) was added. A suspension was obtained to which Al-Ni-alloy (150 mg) was added. 32 % aqueous sodium hydroxide solution (0.7 ml) was added slowly; warming of the reaction mixture was observed. After complete addition, the reaction was stirred for two days at room temperature and the solid was filtered off. The precipitate was washed with DCM. The aqueous solution was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (DCM/MeOH/aq. sat NH3 solution 100:5:1). The separated products were dissolved in ethanol and 1 ml of saturated ethanolic hydrogen chloride solution was added. The solutions were evaporated to yield the cis- diastereomer (15 mg), a mixture of the trans- and α's-diastereomers (144 mg) and the frαns-diastereomer (6 mg) as white solids. MS (ESI): 327.3 (MH+).
Example 30
l-(3,4-Dimethoxy-phenyl)-3-p-tolyl-piperidine-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 29, steps B] andCl from 1-
(3,4-dimethoxy-phenyl)-piperidine-4-one and 4-bromo-toluene to yield a mixture of CZS- and trø7-zs-diastereomers as a white solid. In step B] the aryl bromide and tri(tert- butyl)phosphine were added as a solution in tetrahydrofuran and the reaction was run at 70 0C for 5 hours. Separation of the diastereomers (free bases) could not be achieved by flash chromatography. MS (ESI): 327.3 (MH+).
Example 31
l-(3,4-Dimethox7-phenyl)-3-(3,4-dimethyl-phenyl)-piperidine-4-yl amine hydrochloride
The compound was synthesized in analogy to example 30 from l-(3, 4-dimethoxy- phenyl)-piperidine-4-one and 4-bromo-o-xylene to yield a mixture of cis/trans- diastereomers as a white solid. Separation of the diastereomers (free bases) could not be achieved by flash chromatography. MS (ESI): 341.3 (MH+). Example 32
1 - (3 ,4-Dimethoxy-phenyl) -3 -( 3-methoxy-phenyl) -piperidine-4-yl-amine hydrochloride
The compound was synthesized in analogy to example 30 from l-(3,4-dimethoxy- phenyl)-piperidine-4-one and 4-bromo-anisole to yield a mixture of cis/trans- diastereomers as a white solid. Separation of the diastereomers (free bases) could not be achieved by flash chromatography. MS (ESI): 343.3 (MH+).
Example 33
r-(3,4-Dimethoxy-phenyl)-r)2',3',4',5',6'-hexahydro-[2,3']bipyridinyl-4'-ylamine
The compound was synthesized in analogy to example 30 from l-(3,4-dimethoxy- phenyl) -piperidine-4-one and 2-bromo-pyridine to yield a mixture of cis/trans- diastereomers as a white solid. Separation of the diastereomers could not be achieved by flash chromatography. MS (ESI): 314.3 (MH+).
Example 34
( (3R, 4S)-4-Amino-l-phenethyl-piperidine-3-yl)-thiazolidin-3-yl-methanone
Step A] : (3R, 4S) -4-Benzyloxycarbonylamino-piperidine-l,3-dicarboxylic acid
1-tert-butyl ester 3-methyl ester
(3£,4S)-4-Amino-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (540 mg, synthesized according to Duan, Jingwu et al, PCT Int. Appl. (2001), WO 2001070673 A2) and WO 2002002525) was dissolved in abs. DCM and NEt3 (0.39 ml) was added. Benzylchloroformiate (0.33 ml) was added and the mixture was allowed to stir at RT over night. The reaction mixture was poured into ice/brine und the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give a residue that was purified by flash chromatography (gradient of ethyl acetate in heptane) to give a colorless gum (598 mg). MS (ESI): 393.2 (MH+).
Step B]: (3R, 4S)-4-Methoxycarbonylamino-piperidinee-l,3-dicarboxylic acid
1-tert-butyl ester
(3R, 4S)-4-Benzyloxycarbonylammo-ρiperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (580 mg) was dissolved in THF (20 ml) and a 1 M aqueous solution of LiOH was added (3.0 ml). The mixture was allowed to stir at RT for 20 hours. The solution was poured into ice /brine containing 2 M HCl (2.5 ml). The aqueous layer was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried (Na2SO4) and evaporated. The residue was dried in high vacuum to furnish a colorless foam (558 mg). MS (ESI): 377.3 (MH+).
Step C] : (3R,4S)-4-Benzyloxycarbonylamino-3-(thiazolidine-3-carbonyl)- piperidine-1-carboxylic acid tert-butyl ester
(3JR,4S)-4-Methoxycarbonylamino-piperidine-l,3-dicarbox7lic acid 1-tert-butyl ester (557 mg) was dissolved in abs. DCM (20 ml). To this solution were added subsequently benzotriazol-l-yloxy)-tripyrrolidinophosphonium-hexafluorophosphate (919 mg), triethylamine (0.47 ml) and - after 5 minutes - thiazolidine (151 mg). The mixture was allowed to stir for 5 hours at RT. The mixture was poured into ice/brine and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (gradient of ethyl acetate in heptane) to give the product as a white foam (403 mg). MS (ESI): 450.3 (MH+).
Step D]: (3i?,4S)-[3-(Thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid benzyl ester
(3R, 4S)-4-Benzyloxycarbonylamino-3-(thiazolidine-3-carbonyl)-piperidine-l- carboxylic acid tert-butyl ester (325 mg) was dissolved in abs. DCM (12 ml) and TFA (0.44 ml) was added dropwise. The resulting mixture was then allowed to stir at RT over night and was then evaporated. The residue was transferred into ice/brine, basified to pH 10 with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to give a residue that was purified by flash chromatography to give the desired product as a white foam (260 mg). MS (ESI): 350.1 MH+).
Step E] : (3R- 4S) [l-Phenethyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl] - carbamic acid benzyl ester
(3jR,4S)-3-(Thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid benzyl ester (255 mg) was dissolved in DMF (5 ml) and DIPEA (0.28 ml) was added. After 20 minutes, a solution of 2- (bromoethyl) -benzene (169 mg) in DMF (4 ml) was added over a period of 15 minutes. The mixture was stirred at RT over night. The reaction mixture was poured into ice/water/sat. Na2CO3 solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography to give the desired product as a light yellow oil (308 mg). MS (ESI): 454.2 (MH+). Step F] : (3R, 4S) - ( 4- Amino - 1 -phenethyl-piperidine-3 -yl) -thiazolidin- 3 -yl- methanone
(3R, 4S)- [l-Phenethyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid benzyl ester (216 mg) was treated with 33% HBr in acetic acid (2.5 ml) for 2 hours at RT under argon. Ether (15 ml) was added and the resulting suspension was cooled to -10° C and stirred for 1 hour. The solvent was then decanted and the solid washed with a small amount of EtOH. The residue was then dissolved in water (pH was adjusted to 10 with cone. NH4OH) and the aqueous layer was saturated with NaCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SC^) and evaporated to give a residue that was purified by flash chromatography (gradient of MeOH in DCM containing 0.5% NH4OH) to furnish the desired product as a light yellow oil (92 mg). MS (ESI): 320.1 MH+).
Example 35
((3S, 4i?)-4-Amino-l-phenethyl-piperidine-3-yl)-thiazolidin-3-yl-methanone
This material was obtained as described in example 34 from the opposite enantiomer (3S, 4i?)-4-amino-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3- methyl ester, thiazolidine and 2- (bromoethyl) -benzene. Yellow oil. MS (ESI): 320.4 (MH+).
Example 36
[((35, 4iR)-4-Amino-l-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidin-3-yl- methanone
This material was obtained as described in example 34 from the opposite enantiomer (3S, 4£)-4-arnino-piperidine-l,3-dicarboxylic acid 1-tert-butyl ester 3- methyl ester, thiazolidine and 2-(2-bromo-ethyl)-pyridine (synthesized according to Synthesis, 5, 1987, 452-455). Yellow oil. MS (ESI): 321.4 (MH+).
Example 37
1-[(3S, 4JR)-4-Amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-phenyl-ethanone ]
This material was obtained according to example 34, but with modified Steps E] and F] : Step E]: [l-Phenylacetyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid methyl ester
3-(Thiazolidine-3-carbonyl)-pipeπdine-4-yl]-carbamic acid benzyl ester (250 mg) was dissolved in abs. DCM (8 ml) and DIPEA (0.184 ml) was added. The mixture was allowed to stir at -15 0C (ice/salt bath) for 20 min and then phenylacetlychlorid (0.104 ml) was added dropwise. The mixture was warmed to 0 0C and stirred for 30 min. The reaction mixture was poured into ice/water/sat. NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography to give the desired product [ l-phenylacetyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl] -carbamic acid methyl ester (304 mg) as a white foam. MS (ESI): 468.1 (MH+).
Step F]: 1-[(3S, 4i?)-4-Amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2- phenyl-ethanone
The reaction was performed as described in example 34, Step F] from [1- phenylacetyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid methyl ester (295 mg) and HBr in HOAc (3 ml) but with a modified purification step: The product was purified by preparative HPLC (RPC18, gradient OfCH3CN in water containing 0.05% formic acid). The appropriate fractions were evaporated to give the desired product as the formic acid salt as a white solid (12 mg). MS (ESI): 334.4 (MH+, free base).
Example 38
l-[(3S-4i?)-4-Amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-thiophen-2-yl- ethanone
This material was obtained according to example 37 with the appropriate reagents: Colorless gum: MS (ESI): 340.4 (MH+, free base).
Example 39
3 [ (3S,4R) and (3R,4S) -4- Amino- 1 -(3,4-dimethoxy-phenyl)~piperidine-3-yl] -thiazolidin-
3-yl-methanone
Step A] : 4-Amino-l-benzyl-l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester
rac-l-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (25 g) was suspended in 100 ml ammonium hydroxide 25 % and heated at 50 0C during 18 h. The mixture was cooled with ice and then, NaBH4 (1 g) was added in several portions. Stirring was continued for 18 h at ambient temperature and the mixture was diluted with water/ice, with cooling, and extracted with AcOEt. The organic extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, heptane/ AcO Et, 1/1) and precipitated (AcOEt/heptane) to give 12.1 g (56 %) of the title compound as white solid and 6 g (25 %) of the title compound as its borane salt.
4-Amino-l-benzyl-l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester : MS: 247.2 (M+H)+ NMR: (DMSO, IH, 400 MHz, δ, TMS): 2.28 (t, 2H), 2.46 (t, 2H), 2.99 (s, 2H), 3.49 (s, 3H), 3.53 (s, 2H), 7.22-7.34 (m, 5H), 6.90 and 7.80 (2 s. large, 2H).
4-Amino-l-benzyl-l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; BH3 salt: MS: 247.2 (M+H)+
NMR: (DMSO, IH, 400 MHz, δ, TMS) 2.45-2.60 (m, 2H), 2.80-2.90 (m, IH), 2.92-3.02 (m, IH), 3.30-3.45 (2d, 2H), 3.53 (s, 3H), 3.80-4.00 (2d, 2H), 7.31-7.40 (m, 5H), 6.90 and 7.80 (2 s. large, 2H).
Step B] : rac-4- Amino- l-benzyl-piperidine-3-carboxylic acid ethyl ester
4-Amino-l -benzyl- l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester BH3 salt was heated in ethanol with NaOH 25 %. After 72 h at 50 0C the mixture was cooled, washed with water/ice and extracted with AcOEt. The extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an yellow oil. To a suspension of 4-amino-l-benzyl-l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester (21 g) in 200 ml THF was added 50 ml TFA at 10 0C under an argon atmosphere. After stirring for 15 min at 00C, NaBH4 (6.43 g) was added over a period of 75 min at 1O0C. The mixture was stirred for additional 90 min at 0 0C. After adding 100 ml NH4Cl saturated, the solution was extracted two times with CH2Cl2. The combined extracts were washed with water/ice and brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil of the title compound which was taken for the next step without purification
Step C]: (3S,4R) and (3R,4S)-l-Benzyl-4-tert-butoxycarbonylamino- piperidine-3-carboxylic acid ethyl ester and (3S,4S) and (3R,4R)-l-Benzyl-4-tert- butoxycarbonylamino-piperidine-3-carboxylic acid ethyl ester
Rac-4-Amino-l-benzyl-piperidine-3-carboxylic acid ethyl ester (80.7 mMol, 21 g) and BOC2O (20.5 g) in 200 ml CH2Cl2 were stirred 17h at ambient temperature. The solution was evaporated and chromatographied (silica gel, AcOEt/heptane, 1/1) to give 7.05 g of the racemic trans isomer, 1.88 g of the racemic cis isomer and 13.87 g of the racemic mixture of the diastereomers.
(3S,4R) and (3R,4S)-l-Benzyl-4-tert-butoxycarbonylamino-piperidine-3-carboxylic add ethyl ester: MS: 363.3 (M+H)+
NMR: (DMSO, IH, 400 MHz, δ, TMS) 1.11 (t, 3H), 1.36 (s, 9H), 1.65-1.71 (m, 2H), 2.30-2.37 (m, 2H), 2.49-2.55 (m, IH), 2.63-2.80 (m, 2H), 3.38 (d, IH), 3.51 (d, IH), 3.80-3.92 (m, IH), 4.02 (q, 2H), 6.60 (s large, IH), 7.21-7.32 (m, 5H).
(3S,4S) and (3R,4R)-l-Benzyl-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acid ethyl ester:
MS: 363.3 (MH-H)+
NMR: (DMSO, IH, 400 MHz, δ, TMS) 1.13 (t, 3H), 1.35 (s, 9H), 1.40-1.50 (m, IH), 1.62-1.71 (m, IH), 1.97-2.11 (m, 2H), 2.43-2.50 (m, 2H), 2.74-2.83 (m, 2H), 3.45 (s, 2H), 3.95-4.04 (m, 2H), 6.85 (d, IH), 7.22-7.33 (m, 5H).
Step D] : (3R,4R) and (3S,4S)-4-tert-Butoxycarbonylamino-l-[2-(3,4-dimethoxy- phenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester
A suspension of (3S,4S) and (3R,4R)-l~benzyl-4-tert-butoxycarbonylamino- piperidine-3-carboxylic acid ethyl ester (700 mg) and 200 mg of Pd/C (10%) in 10 ml of EtOH and 1 ml of Hunig's base was hydrogenated at 22 °C/lbar overnight. The suspension was filtered, the filtrate evaporated and the residue purified by column chromatography (silica gel, AcOEt) to give a pale yellow solid (538 mg). To a solution of the above product (272 mg) and 3,4-dimethoxybenzeneacetaldehyde (CAS 5703-21-9, 191 mg) in ethanol at 0 0C, was added a solution 8M of pyridine-borane-complex (0.5 ml). After 2 h stirring at 0 0C and 3 h at ambient temperature, the mixture was diluted with water/ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography (silica gel, AcOEt) to give 196 mg (45 %) of the title compound as an yellow oil.
MS: 437.4 (M+H)+
NMR: (DMSO, IH, 400 MHz, δ, TMS) 1.14-1.23 (m, 3H), 1.36 (s, 9H), 1.40-1.52 (m, IH), 1.65-1.71 (m, IH), 2.02 (ddd, IH), 2.12 (ddd. IH), 2.42-2.50 (m, 2H), 2.58-2.69 (m, 2H), 2.85 (d, IH), 2.98 (d, IH), 3.45-3.57 (m, IH), 3.62-3.72 (m, IH), 3.70 (s, 3H), 3.72 (s, 3H), 4.02 (q, 2H), 6.70 (dd, IH), 6.81-6.86 (m, 3H). Step E]: (3R,4R) and (3S,4S)-4-Ammo-l-[2-(3,4-dimethox7-phenyl)-ethyl]- piperidine-3-carboxylic acid ethyl ester
A solution of (3R,4R) and (3S,4S)-4-tert-butoxycarbonylamino-l-[2-(3,4- dimethoxy-phenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (24 mg) in 1 ml TFA was stirred 1 h at 0 0C. The mixture was poured onto NaOH IM/ ice and extracted with AcOEt. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography (Isolute SPE Flash NH2 10 g, AcOEt/heptane, 1/2) to give 9 mg (50 %) of the title compound.
MS: 337.4 (M+H)+
Step F]: (3R,4R) and (3S,4S)-4-Amino-l-[2-(3,4-dimethoxy-phenyl)-ethyl]- piperidine-3-carboxylic acid
(3R,4R) and (3S,4S)-4-Amino-l-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-3- carboxylic acid ethyl ester (262 mg) and lithium hydroxide (166 mg) in 5 ml THF, 5 ml MeOH and 1 ml H2O were stirred for 24 h at ambient temperature. The mixture was diluted with buffer pH 7 and extracted with AcOEt. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography (Isolute SPE Flash NH2, AcOEt) and precipitated (AcOEt/heptane) to give 90 mg (37 %) of the title compound as a white solid.
MS: 309.2 (MHhH)+
NMR: (DMSO, IH, 400 MHz, δ, TMS) 1.92-2.02 (m, IH), 2.10-2.20 (m, IH), 2.75-3.10 (2m, 6H), 3.35-3.48 (m, 2H), 3.55-3.62 (m, IH), 3.70-3.80 (m, IH), 3.71 (s, 3H), 3.75 (s, 3H), 6.76 (dd, IH), 6.85-6.90 (m, 2H), 8.3-8.7 (s.broad, 3H).
Example 40
3[(3S,4R) and (3R,4S)-4-Amino-l-(3,4-dimethox7-phenyl)-piperidme-3-yl]-thiazolidm-
3-yl-methanone
Step A]: rac-l-(3, 4-DimeUioxy~phenyl)-4-oxo-piperidine-3-carboxylic acid ethyl ester
A mixture of 3,4-dimethoxyaniline (12g), copper (I) chloride (1.7 g), acetic acid (9 ml) and ethyl acrylic acid (26 ml) was heated 17 hours at 140 °C, cooled with ice, diluted with CH2Cl2 and washed successively with water, ammonium hydroxide 10%, water and brine. The organic layers were dried over MgSCU, filtered and evaporated. Chromatography (silica gel, AcOEt/heptane, 1/1) delivered a yellow oil (22.8 g) which was dissolved in 50 ml xylene and sodium ethoxide (4.42g) was added . Then, the suspension was stirred 2h at 140 0C, cooled, diluted with AcOEt and washed with water and brine. The aqueous phases were extracted twice with AcOEt, the organic layers were dried over MgSO4, filtered, evaporated and chromatographied (silica gel, AcOEt/heptane, 1/3) to obtain the title compound as a white solid (13.53 g, 68 %).
MS: 308.2 (M+H)+
Step B]: rac-4-Amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-carbox7lic acid ethyl ester
A suspension of rac-l-(3,4-dimethoxy-phenyl)-4-oxo-piperidine-3-carboxylic acid ethyl ester (640 mg) and ammonium acetate (3g) in 10 ml methanol was stirred 18h at RT., then sodium cyanoborohydride (2g) was added. After 18h at RT, the mixture was diluted with AcOEt, washed twice with water and brine. The organic layers were dried over MgSO4, filtered, evaporated and chromatographied (silica gel, AcOEt/heptane, 1/1) to give the title compound (450 mg, 70 %).
Step C] : rac-4-tert-Butoxycarbonylamino-l-(3,4-dimethoxy-phenyl)-piperidine-3- carboxylic acid ethyl ester
A solution of rac-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-carboxylic acid ethyl ester (6.47 g) and Boc2O (5.02g) in 50 ml CH2Cl2 was stirred 24 h at RT, then diluted with AcOEt, washed with water and brine. The organic layers were dried over MgSO4, filtered, evaporated and chromatographied (silica gel, AcOEt/heptane, 1/1) to leave the title compound as a mixture of czs-and fr«7?5-diastereomers (4.50 g, 53 %).
MS: 409.4 (M+H)+
Step D]: rac-4-tert-Butoxycarbonylamino-l-(3,4-dimethoxy-phenyl)-piperidine-
3-carboxylic acid
To a solution of rac-4~tert-butoxycarbonylamino-l-(3,4-dimethoxy-phenyl)- piperidine-3-carboxylic acid ethyl ester (170 mg) in 2 ml THF, were added 1 ml NaOH IM and lithium hydroxide (100 mg). The suspension was stirred 22h at RT., diluted with water and extracted twice with tert-butylmethylether. The aqueous layer was acidified to pH 4, saturated with NaCl and then the product was extracted with 3 portions of AcOEt. The organic layers were dried over MgSO4, filtered, evaporated and chromatographed (silica gel, AcOEt) to provide the title compound (38 mg, 55 %). MS: 381.3 (MH-H)+
Step E]: [(3S,4R) and (3R,4S)-l-(3,4-Dimethoxy-phenyl)-3-(thiazolidine-3- carbonyl)-piperidine-4-yl]-carbamic acid tert-butyl ester and [(3S,4S) and (3R,4R)-1- (3,4-Dimethoxy-phenyl)-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid tert-butyl ester
To a solution of rac-4-tert-butoxycarbonylamino-l-(3,4-dimethoxy-phenyl)- piperidine-3-carboxylic acid (200 mg) in acetonitrile (5 ml) under ice cooling was added Hunig's base (0.5 ml), EDCI (191 mg), HOBT (135 mg) and thiazolidine (0.3 ml). The reaction mixture was stirred 3h at 0 0C and kept at RT for 24h, diluted with AcOEt, washed with 5% NaHCO3 and brine, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel using AcOEt to give [(3S,4R) and (3R,4S)-l-(3>4-dimethoxy-phenyl)-3-(thiazolidine-3-carbonyl)-piperidine- 4-yl]-carbamic acid tert-butyl ester (73 mg) and [(3S,4S) and (3R,4R)-l-(3,4-dimethoxy- phenyl)-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid tert-butyl ester (81 mg).
MS: (MHhH)+ 452.4.
Step F]:[(3S,4R) and (3R,4S)-4-Amino-l-(3,4-dimethoxy-phenyl)-piperidine-3- yl] -thiazolidin-3-yl-methanone
[(3S,4R) and (3R,4S)-l-(3)4-Dimethox7-ρhenyl)-3-(thiazolidine-3-carbonyl)- piperidine-4-yl]-carbamic acid tert-butyl ester (50 mg) was treated with 2 ml TFA for one hour at 0 0C. The reaction mixture was diluted with AcOEt, washed with NaOH IM and brine, the organic layers were dried over MgSO/t, filtered, evaporated and chromatographed (Isolute Flash SPE NH2, AcOEt) to give [(3S,4R) and (3R,4S)-4- Amino- 1 - (3 ,4-dimethoxy-phenyl) -piperidine-3 -yl] -thiazolidin-3-yl-methanone (23 mg).
MS: 352.1 (M+H)+
NMR: (DMSO, IH, 400 MHz, 8, TMS, HO0C) 1.70-1.78 (m, IH), 1.80-1.90 (m, IH), 2.98-3.04 (m, 3H), 3.12-3.20 (m, 3H), 3.27-3.36 (m, 2H), 3.68 (s, 3H), 3.76 (s,. 3H), 3.74-3.80 (m, 2H), 4.55 (d, 2H), 6.42 (dd, IH), 6.55 (d, IH), 6.79 (d, IH). Example 41
3[(3S,4S) and (3R,4R)-4-Amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-thiazolidin-
3-yl-methanone
This material was obtained from the racemic ϊrαns-isomer, isolated in example 40, step E, using the same procedure as in example 40, step F, to give 28 mg of the title compound.
MS: 352.1 (M+H)+
NMR: (DMSO, IH, 400 MHz, δ, TMS, 1100C) 1.40-1.55 (m, IH), 1.78-1.86 (m, IH), 2.55-2.90 (m, 4H), 2.90-3.01 (m, IH), 3.03 (t, 2H), 3.50-3.60 (m, 2H), 3.68 (s, 3H), 3.76 (s,. 3H), 3.74-3.90 (2m, 2H), 4.59-4.65 (m, 2H), 6.42 (dd, IH), 6.56 (d, IH), 6.79 (d, IH).
Example 42
3[(3S,4S) and (3R,4R)-4-Ajmino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2>5- dihydropyrrol- 1 -yl) -3 -yl-methanone
This material was prepared in analogy to example 40, steps E and F, using 2,5- dihydro-pyrrole.
MS: 332.2 (M+H)+
Example 43
3[(3S,4R) and (3R,4S)-4-Amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5- dihydropyrrol-l-yl)-3-yl-methanone
This material was prepared in analogy to example 40, steps E and F, using 2,5- dihydro-pyrrole.
MS: 332.2 (M+H)+ Galenical Examples
Example A
Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
Figure imgf000051_0001
The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the ab ove mentioned film co at. Example B
Capsules containing the following ingredients can be manufactured in a conventional manner:
Figure imgf000052_0001
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Figure imgf000052_0002
The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized. Example D
Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
Figure imgf000053_0001
Figure imgf000053_0002
The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a conventional manner:
Figure imgf000054_0001
The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavouring additives and filled into sachets.

Claims

Claims
1. Compounds of the formula I
Figure imgf000055_0001
wherein
R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, lower alkoxy, phenyl, phenoxy, halogen, or lower halogenalkyl;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
tetrahydronaphthyl;
Cs.y-cycloalkyl;
-(CHR3)m-phenyl, wherein m is 1, 2, or 3 and phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein R3 is independently selected from hydrogen, lower alkyl or phenyl;
-(CH2)π-heteroaryl, wherein n is 1, 2 or 3;
-(CH2)n-heteroaryl, wherein n is 1, 2, 3 and heteroaryl is mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
-C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
-C(O)-CH2-heteroaryl; and -C(O)-CH2-heteroaryl, wherein heteroaryl is mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
R2 is selected from the group consisting of
lower alkyl, lower halogenalkyl;
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
heteroaryl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
-COOH;
-C(O)-NR4R5; wherein
R4 and R5 are lower alkyl or together with the nitrogen atom to which they are attached form a 4-, 5-or 6- membered heterocycle which may contain a further heteroatom selected from O, N or S;
and pharmaceutically acceptable salts thereof.
2. Compounds of formula I according to claim 1, wherein R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
~(CHR3)m-phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein
R3 is hydrogen;
-(CH2)n-heteroaryl, wherein n is 1 or 2; -(CH2)π-heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy,
-C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
-C(O)-CH2-heteroaryl; and
~C(O)-CH2-heteroaryl, with heteroaryl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
3. Compounds of formula I according to claims 1 or 2, wherein R1 is selected from the group consisting of
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; and
-(CHR3)m-phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di-, or trisubstituted by lower alkoxy and wherein R3 is hydrogen.
4. Compounds of formula I according to any of claims 1 to 3, wherein R1 is
phenyl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy.
5. Compounds of formula I according to claims 1 or 2, wherein R1 is
-(CH2)n-heteroaryl, wherein n is 1 or 2; or
-(CH2)n-heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
6. Compounds of formula I according to claim 1 or 2, wherein R1 is
-C(O)-CH2-phenyl, with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; or
-C(O)-CH2-heteroaryl.
7. Compounds of formula I according to any of claims 1 to 6, wherein R2 is selected from the group consisting of
lower alkyl;
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;
heteroaryl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; and
-C(O)-NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a 5-membered heterocycle which may contain a further heteroatom selected from O, N or S.
8. Compounds of formula I according to any of claims 1 to 7, wherein R2 is n-butyl.
9. Compounds of formula I according to any of claims 1 to 7, wherein R2 is
phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, halogenalkyl, or lower alkoxy.
10. Compounds of formula I according to any of claims 1 to 7, wherein R2 is
pyridyl or thienyl, wherein pyridyl and thienyl are unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.
11. Compounds of formula I according to any of claims 1 to 7, wherein R2 is -C(O)-NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a 5-membered heterocycle which may contain a further heteroatom selected from O, N or S.
12. Compounds of formula I according to claims 1 to 11, selected from
(ris)-3-butyl-l-phenethyl-piperidine-4-yl-amine,
(trans)~3-buty\- 1 -phenethyl-piperidine-4-yl-amine,
(ris>)-3-butyl-l-benzyl-piperidine-4-yl-amine,
(trans)-3-buty\- 1 -benzyl-piperidine-4-yl-amine,
fds>)-3-butyl-l-[2-(lH-indol-3-yl)-ethyl]-piperidine-4-ylamine,
(trαπsj-3-butyl-l-[2-(lH-indol-3-yl)-ethyl]-piperidine-4-ylamine,
"5J-3-butyl- 1 - [2- (3,4-dimethoxy-phenyl- lyl)-ethyl] piperidine-4-ylamine,
ftrαnsJ-3-butyl-l-[2-(3,4-dimethoxy-phenyl-lyl)-ethyl] piperidine-4-ylamine,
Cα5j-3-butyl-l-(3,4,5-trimethox7-phenyl)-piperidine-4-yl-amine hydrochloride,
Ctrαπ5J-3-butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
Cd5^-3-butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine,
ftmnsJ-3-butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine,
fα5Λratt5J-3-butyl-l-(5,6,7,8-tetrahydro-naphthalen-l7l)-piperidine-4-yl-amine hydrochloride,
Cdsj-3-butyl-l-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(trαπsJ-3-butyl- l-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
CαsJ-3-butyl-l-naphthalene-2-yl-piperidine-4-yl-amine hydrochloride,
(trans) -3 -butyl- 1 -naphthalene-2-yl-piperidine-4-yl-amine hydrochloride,
('αVfrønsj-3-butyl-l-naphthalene-l-yl-piperidine-4-yl-amine hydrochloride,
fcis/)-3-butyl-l-(3,4-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride, ('αsJ-3-butyl-l-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
(αsJ-3-butyl- l-p-tolyl-piperidine-4-yl-amine hydrochloride,
(trans)-3-butγl- l-p-tolyl-piρeridine-4-yl-amine hydrochloride,
fci5)-3-butyl-l-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
(O'5Amn5J-3-butyl-l-(3,5-dichloro-phenyl)-piperidine-4-yl-amiπe hydrochloride,
(α5)-3-butyl-4-methyl- 1 -phenyl-piperidine-4-yl-amine hydrochloride,
ftrαπ5/)-3-butyl-4-methyl- 1 -phenyl-piperidine-4-yl-amine hydrochloride,
fα5J-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
(cis/trans) -3 -butyl- 1 - (3-methoxy-5-trifluoromethyl-phenyl) -piperidine-4-yl-amine hydrochloride,
'5/trflnsj-3-butyl-l-cyclohexyl-piperidine-4-yl-amine hydrochloride,
('α'5/trøπsJ-3-butyl-l-(3,5-bis-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
'5j-3-butyl-l-(6-methoxy'-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride,
(tmπs)-3-butyl- 1 - (6-methoxy-biphenyl-3-yl) -piperidine-4-yl-amine hydrochloride,
(cis/trans)-3-butyl- 1 -benzhydryl^-yl-piperidine^-yl- amine hydrochloride,
(dsj-3-phenyl-l-phenethyl-piperidine-4-yl-amine,
(Yrøns)-3-phenyl- l-ρhenethyl-piperidine-4-yl-amine,
'5J-3-phenyl- 1 -benzyl-piperidine-4-yl-amine,
(frøns)-3-phenyl-l-ben2yl-piperidine-4-yl-amine,
(cis/trans) -methyl- l'-phenethyl- r,2',3',4',5',6'-hexahydro- [2,3']bipyridinyl-4'-yl-amine,
(cis)-3- (3-chloro-phenyl) - 1 -phenethyl-piperidine-4-yl-amine,
fcz5/frflm^-3-(3-chloro-phenyl)-l-benzyl-piperidine-4-7l-amine, (d5/traπsj-3-(3-methyl-phenyl)-l-benzyl-piperidine-4-yl-amine,
fd5J-3-(3-chloro-phenyl)-l-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine,
(trans)- l-benzyl-3-thiophen-2-yl-piperidine-4-yl amine
's)-3-o-tolyl- 1 - (3,4,5-trimethoxy- phenyl) -piperidine-4-yl-amine hydrochloride,
(rfrøπsj-3-o-tolyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
fds/transJ-3-o-tolyl-l-(3,4>5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
Cd5/fran5j-l-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,
(cis/trans)-l - (3,4-dimethoxy-phenyl)-3-p-tolyl-piperidine-4-yl-amine hydrochloride,
(«5/£røπ5j-l-(3,4-dimethoxy-phenyl)-3-(3, 4-dimethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
CdsΛmπ5J-l-(3,4-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
fdsΛraπsj-l'-(3,4-dimethoxy-phenyl)-l',2',3',4',5',6'-hexahydro-[2,3']bipyridinyl-4'-yl- amine,
( (3R,4S)-4-amino-l -phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
((3S,4R)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
[(3S,4R)-4-amino-l-(2-pyridin-2-yl-ethyl)-piρeridine-3-yl]-thiazolidin-3-yl- methanone,
l-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-pipeπdine-l-yl]-2-phenyl-ethanone,
l-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-thiophen-2-yl- ethanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-[2(3,4-dimethox7-phenyl)-ethyl]-piperidine-3- carboxylic acid,
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethox7-phenyl)-piperidine-3-yl]- thiazolidine-3-yl-methanone
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidme-3-yl]-(2,5- dihydropyrrol-l-yl)-3-yl-methanone, 3-[(3S,4R) and (3R,4S)-4-amino-l-(3)4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5- dihydropyrrol- 1 -yl) - 3 -yl- methanone,
and pharmaceutically acceptable salts thereof.
13. Compounds of formula I according to claims 1 to 12, selected from
(VϊsJ-3-butyl-l-ρhenethyl-piperidine-4-yl-amine,
fa's) -3 -butyl- 1- [2-( lH-indol-3-yl)-ethyl] -piperidinee-4-ylamine,
('a5j-3-butyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(αs)-3~butyl-l-(4-phenoxy-phenyl)-piperidine-4-yl-amine,
fd5j-3-butyl-l-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
(αs)-3-butyl-l-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,
(trans)-3-butγ\- 1 -naphthaleπ-2-yl-piperidiπe-4-yl-amine hydrochloride,
fds/trøπsj-3-butyl-l-naphthalen-l-yl-piperidine-4-yl-amine hydrochloride,
fdsJ-3-butyl-l-(3,4-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
's)-3-butyl-l-(4-chloro-3-triiluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
fds)-3-butyl-l-p-tolyl-piperidine-4-yl-amine hydrochloride,
(cis)-3-butγl-l-(3, 5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
(αs/trøπ5J-3-butyl-l-(3, 5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,
fcz5)-3-butyl-4-methyl-l-phenyl-piperidine-4-yl-amine hydrochloride,
'sj-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
fdsΛrønsJ-3-butyl-l-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,
fdsJ-3-butyl-l-(6-methoxy-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride,
(ris)-3-phenyl-l-phenethyl-piperidine-4-yl-amine, rαVtrαnsj-methyl-r-phenethyl-r,2l,3I,4',5',6'-hexahydro-[2,3']biρyridinyl-4'-yl-amine,
Cα5j-3-(3-chloro-phenyl)-l-phenethyl-piperidine-4-yl-amine,
fd5/trønsJ-3-(3-chloro-phenyl)-l-benzyl-piperidine-4-yl-amine,
(cis/trans)-3- (3-methyl-phenyl) - 1 -benzyl-piperidine-4-yl-amine,
fd5J-3-(3-chloro-phenyl)-l-[2-(3,4-dimethoxy-phenyl)-ethyl]-piρeridine-4-yl-amine,
Ctmnsj-3-o-tolyl-l-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,
('d5/frø«5J-3-o-tolyl-l-(3)4,5-trimethoxy"-phenyl)-piperidine-4-yl-amine hydrochloride,
Cα-5/tran5J-l-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,
(cis/trans)-l '-(3,4-dimethoxy-ρhenyl)- 1 ',2',3',4',5',6'-hexahydro- [2,3']bipyridinyl-4'-yl- amine,
((3R,4S)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
((3S>4R)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone>
[(3S,4R)-4-amino-l-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidine-3-yl- methanone,
l-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-phenyl-ethanone,
l-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-l-yl]-2-thiophen-2-yl- ethanone,
3-[(3S,4S) and (3R,4R)-4-amino-l-(3J4-dimethoxy-phenyl)-piperidine-3-yl]- thiazolidin-3-yl-methanone
3- [(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl] -(2,5- dihydropyrrol-l-yl)-3-yl-methanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-(3,4-dimethoxy-ρhenyl)-piperidme-3-yl]-(2,5- dihydropyrrol-l-yl)-3-yl-methanone,
and pharmaceutically acceptable salts thereof.
14. Compounds of formula I according to claims 1 to 13, selected from (άs) -3 - ( 3 - chlor o-phenyl) - 1 -phenethyl-piperidine-4-yl- amine,
CcfsΛrαnsj-3-(3-chloro-phenyl)-l-benzyl-piperidine-4-yl-amine,
'5/fmnsJ-3-(3-chloro-phenyI)-l-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl- amine,
fd5)-l-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,
((3S,4R)-4-amino-l-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,
((3S,4R)-4-amino-l-(2-pyridin-2-yl-ethyl)-piperidine-3-yl)-thiazolidine-3-yl- methanone,
3-[(3S,4R) and (3R,4S)-4-amino-l-(3,4-dimethoxy-phenyl)-piperidine-3-yl] - thiazolidine-3-yl-methanone,
3-[(3S,4S) and (3R,4R)-4-amino-l-(3,4-dimethoxy-ρhenyl)-piperidine-3-yl]- thiazolidin-3-yl-methanone,
and pharmaceutically acceptable salts thereof.
15. A process for the manufacture of compounds of formula I according to any of claims 1 to 14, which process comprises either
a) converting a compound of the formula
Figure imgf000064_0001
wherein R1 and R2 are as defined in claim 1, with hydroxylamine or a salt thereof into an oxime of the formula
Figure imgf000065_0001
wherein R1 and R2 are as defined in claim 1,
and further reducing the oxime of formula III by catalytic hydrogenation or alternatively by a reduction with a metal hydride into the compound of formula I; or
b) deprotecting an 4-aminopiperidine derivative of the formula
Figure imgf000065_0002
wherein R1 and R2 are as defined before and Rp is an amino protecting group.
16. Compounds of formula I according to any of claims 1 to 14 when manufactured by a process according to claim 15.
17. Pharmaceutical compositions comprising a compound according to any of claims 1 to 14 and a pharmaceutically acceptable carrier and/or adjuvant.
18. Compounds according to any of claims 1 to 14 for use as therapeutic active substances.
19. Compounds according to any of claims 1 to 14 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.
20. Compounds according to any of claims 1 to 14 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, non-insulin dependent diabetes mellitus and / or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection.
21. A method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, non-insulin dependent diabetes mellitus and / or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection, which method comprises administering a compound according to any of claims 1 to 14 to a human being or animal.
22. The use of compounds according to any of claims 1 to 14 for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.
23. The use according to claim 22 for the treatment and/ or prophylaxis of diabetes, non-insulin dependent diabetes mellitus and / or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection.
24. The use of compounds according to any of claims 1 to 14 for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.
25. The use of compounds according to any of claims 1 to 14 for the preparation of medicaments for the treatment and/or prophylaxis of diabetes, non-insulin dependent diabetes mellitus and / or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection.
26. The novel compounds, processes and methods as well as the use of such compounds substantially as described hereinbefore.
X-X-*
PCT/EP2005/013292 2004-12-20 2005-12-12 4-aminopiperidine derivatives WO2006066747A1 (en)

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WO2010122580A2 (en) 2009-04-24 2010-10-28 Cadila Healthcare Limited Novel compounds as inhibitors of renin
US7884104B2 (en) 2004-10-01 2011-02-08 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US8143289B2 (en) 2008-11-13 2012-03-27 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
US8455533B2 (en) 2009-09-02 2013-06-04 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2013084241A1 (en) 2011-12-09 2013-06-13 Cadila Healthcare Limited Compounds as inhibitors of renin
US8716482B2 (en) 2009-09-25 2014-05-06 Merck Sharp & Dohme Corp. Substituted aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
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US7625888B2 (en) 2004-08-23 2009-12-01 Merck & Co., Inc. Fused triazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US7884104B2 (en) 2004-10-01 2011-02-08 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
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WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
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US8415297B2 (en) 2008-11-13 2013-04-09 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US8772328B2 (en) 2008-11-13 2014-07-08 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2010122580A2 (en) 2009-04-24 2010-10-28 Cadila Healthcare Limited Novel compounds as inhibitors of renin
US8455533B2 (en) 2009-09-02 2013-06-04 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
US8716482B2 (en) 2009-09-25 2014-05-06 Merck Sharp & Dohme Corp. Substituted aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2013084241A1 (en) 2011-12-09 2013-06-13 Cadila Healthcare Limited Compounds as inhibitors of renin
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase

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