US20100120864A1 - 2-aminooxazolines as taar1 ligands - Google Patents

2-aminooxazolines as taar1 ligands Download PDF

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US20100120864A1
US20100120864A1 US12/639,076 US63907609A US2010120864A1 US 20100120864 A1 US20100120864 A1 US 20100120864A1 US 63907609 A US63907609 A US 63907609A US 2010120864 A1 US2010120864 A1 US 2010120864A1
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dihydro
oxazol
ylamine
phenyl
chloro
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Guido Galley
Katrin Groebke Zbinden
Roger Norcross
Henri Stalder
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • 2-Aminooxazolines are described in the literature as hypertensive agents with good affinity to the adrenergic receptor or as intermediates in processes for preparation of pharmaceutical active agents, for example in EP 0 167 459, U.S. Pat. No. 4,311,840, DE 2,253,555, Tetrahedron (2001), 57(1), 195-200 or in Bioorganic and Medicinal Chemistry Letters (2004), 14(2), 313-316.
  • Some of the physiological effects i.e. cardiovascular effects, hypotension, induction of sedation
  • cardiovascular effects i.e. cardiovascular effects, hypotension, induction of sedation
  • WO02/076950, WO97/12874 or EP 0717 037 may be considered to be undesirable side effects in the case of medicaments aimed at treating diseases of the central nervous system as described above. Therefore it is desirable to obtain medicaments having selectivity for the TAAR1 receptor vs adrenergic receptors.
  • Objects of the present invention show selectivity for TAAR1 receptor over adrenergic receptors, in particular good selectivity vs the human and rat alpha1 and alpha2 adrenergic receptors.
  • biogenic amines The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system [1]. Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions [2-5].
  • a second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlap with the classical biogenic amines regarding structure, metabolism and subcellular localization.
  • the TAs include p-tyramine, ⁇ -phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines [6].
  • TA-specific receptors had only been hypothesized based on anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10,11]. Accordingly, the pharmacological effects of TAs were believed to be mediated through the well known machinery of classical biogenic amines, by either triggering their release, inhibiting their reuptake or by “crossreacting” with their receptor systems [9,12,13]. This view changed significantly with the recent identification of several members of a novel family of GPCRs, the trace amine associated receptors (TAARs) [7,14]. There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene).
  • TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located next to each other on the same chromosomal segment.
  • TAAR1 is in the first subclass of four genes (TAAR1-4) highly conserved between human and rodents. TAs activate TAAR1 via G ⁇ s.
  • Dysregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and therefore TAAR1 ligands have a high potential for the treatment of these diseases.
  • the invention provides compounds of formula I
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. In addition, all tautomeric forms of compounds of formula I are also encompassed by the present invention.
  • the invention also provides pharmaceutical compositions containing one or more compound of the invention and a pharmaceutically acceptable carrier.
  • the invention further provides methods for the manufacture of the compounds and compositions of the invention.
  • Compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1.
  • the invention provides a method for the treatment of diseases related to the biological function of trace amino associated receptors.
  • Such diseases include depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
  • ADHD attention deficit hyperactivity disorder
  • psychotic disorders such as schizophrenia
  • neurological diseases such as Parkinson's disease
  • neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension
  • substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
  • the preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
  • lower alkyl denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
  • Preferred alkyl groups are groups with 1-4 carbon atoms.
  • lower alkoxy denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.
  • lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 and the like.
  • lower alkoxy substituted by halogen denotes an alkoxy group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 and the like.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl is an alkylene ring, containing from 3 to 6 carbon ring atoms.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • Preferred compounds of formula I are those, wherein X is a bond.
  • Preferred compounds of this group of formula I are those, wherein Y is phenyl, substituted by one or more halogen atoms:
  • Y is phenyl substituted by halogen and CF 3 , halogen and CH 3 , halogen and cycloalkyl or by halogen and OCH 3 ,
  • Preferred compounds of formula I are further those, wherein X is CHR.
  • Preferred compounds from this group are those, wherein Y is phenyl substituted by halogen, CF 3 , or CH 3 :
  • Preferred compounds of formula I are further those, wherein X is CHRCHR′.
  • Preferred compounds from this group are those, wherein Y is optionally substituted phenyl,
  • Preferred compounds of formula I are further those, wherein X is OCH 2 and Y is optionally substituted phenyl.
  • Preferred compounds of formula I are further those, wherein X is CH 2 OCHR.
  • Preferred compounds from this group are those, wherein Y is phenyl optionally substituted by halogen:
  • Preferred compounds of formula I are further those, wherein X is —(CH 2 ) 3 —
  • Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds
  • Preferred compounds of formula I are further those, wherein X is —SCH 2 —, —S(O) 2 CH 2 —, or —CH 2 SCH 2 —.
  • Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds
  • Preferred compounds of formula I are further those, wherein X is —CH 2 N(R)CH 2 —, cycloalkyl-CH 2 — or SiRR′—CH 2 —;
  • Preferred compounds from this group are those, wherein Y is optionally substituted phenyl, for example the following compounds
  • Preferred compounds of formula I are further those, wherein X is described above and Y is naphthyl, pyridyl, cyclohexyl, 2,3-dihydrobenzo[1,4]dioxin or 1,2,3,4-tetrahydronaphthalen.
  • the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
  • Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the reaction sequence is not limited to the one displayed in schemes 1 to 9, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
  • Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • Step A Reduction of an acid group (R′ ⁇ H) can be effected by treatment with LiAlH 4 , BH 3 -THF, BH 3 -Me 2 S complex in the presence of BF 3 -etherate or Red-Al in a solvent such as 1,2-dimethoxyethane, THF, diethylether or toluene at r.t. ⁇ reflux for 1-24 hrs.
  • reduction of an acid group (R′ ⁇ H) can be effected by treatment with LiBH 4 in the presence of Me 3 SiCl in a solvent such as methanol at 0° C. ⁇ r.t. for 1-24 hrs.
  • Reduction of an ester group can be effected by treatment with LiAlH 4 , LiBH 4 , NaBH 4 or Red-Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at ⁇ 78° C. ⁇ reflux for 1-24 hrs.
  • a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at ⁇ 78° C. ⁇ reflux for 1-24 hrs.
  • Preferred conditions for acids and esters are LiAlH 4 in THF at r.t. overnight, or LiBH 4 /Me 3 SiCl in methanol at 0° C. ⁇ r.t. overnight.
  • Step B Cyclisation of the aminoalcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Step A Wittig reaction between Garner's aldehyde IV and a benzyl-substituted phosphonic acid diethyl ester V can be accomplished by using a base such as NaH, KOtBu, NaOMe, NaOEt, n-BuLi, LiHMDS, NaHMDS, KHMDS, LDA in a solvent such as THF, dioxane, acetonitrile, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from ⁇ 78° C.-80° C.
  • a base such as NaH, KOtBu, NaOMe, NaOEt, n-BuLi, LiHMDS, NaHMDS, KHMDS, LDA
  • a solvent such as THF, dioxane, acetonitrile, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from ⁇ 78° C.-80
  • the base, the carbonyl compound and the base and the optional crown ether can be added to the reaction mixture at the same time without preformation of the ylide at temperatures from ⁇ 78° C.-80° C.
  • Preferred conditions are ylide formation at 0° C. using n-buthyl lithium solution in hexane as base and 1,2-dimethoxyethane as solvent, reacting the phosphonic acid ester for 5 min at 0° C., and then condensation with the carbonyl component at reflux overnight.
  • Step B Reduction of the alkene can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO 2 , Pd—C or Raney nickel in solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
  • the reduction of the alkene can be effected by Mg in MeOH or by LiAlH 4 in THF or diethylether.
  • Preferred conditions are hydrogenation in the presence of Pd/C as catalyst with EtOH as solvent.
  • Step C Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
  • organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
  • a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step D Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Step A The synthesis of the Julia reagent (benzothiazole-2-sulfonyl derivative) IX from ‘Garner's alcohol’ VIII was accomplished as described in literature (Dandanpani, S. et al., Journal of Organic Chemistry 2005, 70(23), 9447).
  • Step B Julia reaction between an Y-aldehyde or ketone and and the benzothiazole sulfonyl compound can be accomplished by using a base such as LiHMDS, NaHMDS, KHMDS, LDA, KOtBu, DBU in a solvent such as THF, diethyl ether, 1,2-dimethoxyethane, dichloromethane, DMF or mixtures thereof at temperatures from ⁇ 100° C.—r.t. for 15 min-8 hrs for anion generation and then condensing the ylide with the carbonyl compound in the same solvent at temperatures between ⁇ 100° C. and r.t. for 1-24 hrs.
  • Preferred conditions are anion generation with LiHMDS at ⁇ 78° C. in THF and subsequent condensation with the carbonyl component under the same conditions.
  • Step C Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
  • organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
  • a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step D Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Step A Mitsunobu reaction of ‘Garner's alcohol’ VIII with phenol derivatives X or thiophenol derivatives X can be accomplished by using a phosphine such as triphenylphosphine and an azodicarboxylate reagent such as diethylazodicarboxylate, diisopropylazodicarboxylate, or di-tert-butylazodicarboxylate in a solvent such as THF at temperatures from 50° C.-70° C. for 1-18 hrs.
  • Preferred conditions are triphenylphosphine and di-tert-butylazodicarboxylate in THF at 60° C. for 16 h.
  • Step B Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
  • organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
  • a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step C Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Step A Conversion of Garner's aldehyde IV to the dibromo-alkene derivative XII can be accomplished by using a brominating agent such as carbon tetrabromide in the presence of a phosphine such as triphenylphosphine in a chlorinated solvent such as dichloromethane at temperatures between 0° C. and room temperature.
  • a brominating agent such as carbon tetrabromide
  • a phosphine such as triphenylphosphine
  • a chlorinated solvent such as dichloromethane
  • Step B Suzuki reaction of dibromo-alkene derivative XII with an arylboronic acid XIII can be accomplished using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (0) in the presence of a phosphine such as tris(2-furyl)phosphine and a base such as aqueous sodium carbonate in a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from 50° C.-100° C. for 1-18 hrs.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (0)
  • a phosphine such as tris(2-furyl)phosphine
  • a base such as aqueous sodium carbonate
  • a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzen
  • Negishi reaction of bromo-alkene derivative XIV with a dialkylzinc reagent XV can be accomplished using a palladium catalyst such as bis(tri-tert-butylphosphine)dipalladium (0) in a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from 20° C.-100° C. for 1-18 hrs. Preferred conditions are a THF-toluene mixture at room temperature.
  • a palladium catalyst such as bis(tri-tert-butylphosphine)dipalladium (0)
  • a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from 20° C.-100° C. for 1-18 hrs.
  • Preferred conditions are a THF-toluene mixture at room temperature.
  • Step D Reduction of the alkene can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO 2 , Pd—C or Raney nickel in solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
  • the reduction of the alkene can be effected by Mg in MeOH or by LiAlH 4 in THF or diethylether.
  • Preferred conditions for R 1 ⁇ chlorine are hydrogenation in the presence of Pd/C as catalyst with EtOH as solvent.
  • Step E Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
  • organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
  • a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Steps D and E can also be carried out in the opposite order, in which case the stereochemical preference of the hydrogenation step is typically reversed.
  • Step F Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Step A Coupling of 4-ethinyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate XVIII (Dickson, H. D. et al Tetrahedron Lett. 2004, 45 (29), 5597-5599; Pietruszka, J. et al Eur. I. Org. Chem. 2003, 3219-3229) with an aryl or hetaryl bromide or iodide XIX in the presence of a palladium and a copper(I) salt in a solvent such as dioxane, tetrahydrofurane, benzene, triethylamine or the like.
  • a solvent such as dioxane, tetrahydrofurane, benzene, triethylamine or the like.
  • Preferred conditions are the use of copper(I)-iodide and bis(triphenylphosphine)palladium(II) chloride with triethylamine as solvent at room temperature.
  • Step B Reduction of the alkyne XX can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO 2 , Pd—C or Raney nickel in solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
  • the reduction of the alkyne can be effected by Mg in MeOH or by LiAlH 4 in THF or diethylether.
  • Preferred conditions are transfer hydrogenation using ammonium formiate in the presence of Pd/C as catalyst with MeOH as solvent.
  • Step C Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
  • organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
  • a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step D Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Step A Deprotonation of bis-lactimether XXI (also called “Schöllkopf's chiral auxiliary”) with a suitable base such as n-butyl-lithium or tert-butyl-lithium in an appropriate organic solvent such as tetrahydrofuran at a low temperature followed by addition of the organic halide XXII and reaction for several hours leads to product XXIII (Vassiliou, S. et al Synlett 2003, 2398-2400; Schöllkopf, U. Topics Curr. Chem. 1983, 109, 65).
  • Preferred conditions are the use of tert-butyllithium and an organic iodide in tetrahydrofuran at ⁇ 78° C. and allowing the mixture to reach room temperature overnight.
  • Step B Cleavage of bis-lactim ether product XXIII under acidic conditions using a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as acetonitrile, CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
  • organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
  • a solvent such as acetonitrile, CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are a 10% trifluoroacetic acid in a mixture of water and acetonitrile (1:3) at 40° C. overnight.
  • Step C Reduction of the ester XXIV can be effected by treatment with LiAlH 4 , LiBH 4 , NaBH 4 or Red-Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at ⁇ 78° C. ⁇ reflux for 1-24 hrs.
  • a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at ⁇ 78° C. ⁇ reflux for 1-24 hrs.
  • Preferred conditions for acids and esters are LiAlH 4 in THF at r.t. overnight.
  • Step D Cyclisation of the amino alcohol II-4 to the corresponding 2-aminooxazoline 1-4 can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Homochiral alcohols of formula XXVIII may be prepared by a variety of methods reported in the chemical literature, for instance starting from carboxylic acids of formula XXV and using the methodologies of Evans et al. (ref [1]) or Meyers et al. (ref [2]). According to these procedures, introduction of a chiral auxilliary, such as the Evans oxazolidinone auxiliary (ref [1]) or the Meyers pseudoephedrine-derived auxiliary (ref [2]) affords a homochiral acyl compound of formula XXVI. Enolisation of the acyl compound XX with a suitable base followed by treatment with an alkyl halide affords compounds of formula XXVII. Reductive removal of the chiral auxiliary then affords the homochiral alcohols of formula XXVIII.
  • a chiral auxilliary such as the Evans oxazolidinone auxiliary (ref [1]) or the Meyers
  • Step A: Homochiral alcohol XXVIII may be converted to the corresponding alkyl iodide XXIX using a reagent system comprising imidazole, triphenylphosphine and iodine in dichloromethane (Müller, P. & Boléa, C. Helv. Chim. Acta 2002, 85, 483-494) or sequential treatment with p-toluensulphonyl chloride/pyridine and sodium iodide in acetone (Taber, D. F. et al. J. Am. Chem. Soc. 1985, 107, 196-199).
  • Preferred conditions are the use of imidazole, triphenylphosphine and iodine in dichloromethane.
  • Step B Deprotonation of bis-lactimether XXI (also called “Schöllkopf's chiral auxiliary”) with a suitable base such as n-butyl-lithium or tert-butyl-lithium in an appropriate organic solvent such as tetrahydrofuran at a low temperature followed by addition of the homochiral alkyl iodide XXIX and reaction for several hours leads to product XXX (Vassiliou, S. et al Synlett 2003, 2398-2400; Schöllkopf, U. Topics Curr. Chem. 1983, 109, 65).
  • Preferred conditions are the use of n-butyllithium at ⁇ 78° C. and allowing the mixture to reach room temperature overnight.
  • Step C Cleavage of bis-lactim ether product XXX under acidic conditions using a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as acetonitrile, CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are a 10% trifluoroacetic acid in a mixture of water and acetonitrile (1:3) at room temperature overnight.
  • Step D Reduction of the ester XXXI can be effected by treatment with LiAlH 4 , LiBH 4 , NaBH 4 or Red-Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at ⁇ 78° C. ⁇ reflux for 1-24 hrs.
  • a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at ⁇ 78° C. ⁇ reflux for 1-24 hrs.
  • Preferred conditions for acids and esters are LiAlH 4 in THF at r.t. overnight.
  • Step E Cyclisation of the amino alcohol II-5 to the corresponding 2-aminooxazoline I-5 can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • a primary amine compound of formula XXXII-1 can be accomplished by a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl 2 or Ti(OiPr) 4 at a temperature of ⁇ 10 to 60° C. for 1-40 h.
  • a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3
  • a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis
  • Preferred conditions are heating of compound XXXII-1 and compound IV in MeOH at 60° C. overnight, followed by treatment with NaBH 4 in MeOH at room temperature.
  • Step B Alkylation of the compound of formula XXXIII-1 to compound of formula XXXIII-2 can by accomplished by treatment with a suitable aldehyde RCHO in the presence of a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl 2 or Ti(OiPr) 4 at a temperature of ⁇ 10 to 60° C. for 1-40 h.
  • a suitable aldehyde RCHO in the presence of a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane
  • Step C Preparation of a compound of formula XXXIII-2 may alternatively be accomplished by reductive amination of a secondary amine compound of formula XXXIII-2 and Garner's aldehyde (from L- or D-serine; Garner, P.; Park, J. M. Org. Synth.
  • a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc)3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl 2 or Ti(OiPr) 4 at a temperature of ⁇ 10 to 60° C. for 1-40 h.
  • Preferred conditions are NaBH 3 CN and ZnCl 2 in MeOH at r.t.—40° C. overnight.
  • Step D Simultaneous cleavage of the amino alcohol protecting groups of the compound of formula XXXIII-2 can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step E Cyclisation of the amino alcohol II-6 to the corresponding 2-aminooxazoline I-6 can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
  • the compounds of formula I are basic and may be converted to a corresponding acid addition salt.
  • the conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid,
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent.
  • an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like.
  • the temperature is maintained between 0° C. and 50° C.
  • the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
  • the acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have a good affinity to the trace amine associated receptors (TAARs), especially TAAR1.
  • TAARs trace amine associated receptors
  • HEK293 cells (ATCC #CRL-1573) were cultured essentially as described Lindemann et al. (2005).
  • HEK293 cells were transfected with the pIRESneo2 expression plasmids containing the TAAR coding sequences (described above) with Lipofectamine 2000 (Invitrogen) according to the instructions of the manufacturer, and 24 hrs post transfection the culture medium was supplemented with 1 mg/ml G418 (Sigma, Buchs, Switzerland).
  • Cells at confluence were rinsed with ice-cold phosphate buffered saline without Ca 2+ and Mg 2+ containing 10 mM EDTA and pelleted by centrifugation at 1000 rpm for 5 min at 4° C. The pellet was then washed twice with ice-cold phosphate buffered saline and cell pellet was frozen immediately by immersion in liquid nitrogen and stored until use at ⁇ 80° C. Cell pellet was then suspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA, and homogenized with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 s.
  • PT 3000, Kinematica Polytron
  • the homogenate was centrifuged at 48,000 ⁇ g for 30 min at 4° C. and the pellet resuspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA (buffer A), and homogenized with a Polytron at 10,000 rpm for 10 s. The homogenate was then centrifuged at 48,000 ⁇ g for 30 min at 4° C. and the pellet resuspended in 20 ml buffer A, and homogenized with a Polytron at 10,000 rpm for 10 s. Protein concentration was determined by the method of Pierce (Rockford, Ill.).
  • the homogenate was then centrifuged at 48,000 ⁇ g for 10 mM at 4° C., resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl 2 (10 mM) and CaCl 2 g protein per ml and (2 mM) (buffer B) at 200 homogenized with a Polytron at 10,000 rpm for 10 s.
  • Binding assay was performed at 4° C. in a final volume of 1 ml, and with an incubation time of 30 mM.
  • the radioligand [ 3 H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline was used at a concentration equal to the calculated K d value of 60 nM to give a bound at around 0.1% of the total added radioligand concentration, and a specific binding which represented approximately 70-80% of the total binding.
  • Non-specific binding was defined as the amount of [ 3 H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline bound in the presence of the appropriate unlabelled ligand (10 ⁇ M).
  • Competing ligands were tested in a wide range of concentrations (10 pM-30 ⁇ M). The final dimethylsulphoxide concentration in the assay was 2%, and it did not affect radioligand binding. Each experiment was performed in duplicate. All incubations were terminated by rapid filtration through UniFilter-96 plates (Packard Instrument Company) and glass filter GF/C, pre-soaked for at least 2 h in polyethylenimine 0.3%, and using a Filtermate 96 Cell Harvester (Packard Instrument Company). The tubes and filters were then washed 3 times with 1 ml aliquots of cold buffer B. Filters were not dried and soaked in Ultima gold (45 ⁇ l/well, Packard Instrument Company) and bound radioactivity was counted by a TopCount Microplate Scintillation Counter (Packard Instrument Company).
  • the preferred compounds show a Ki value ( ⁇ M) in mouse or rat on TAAR1 in the range of ⁇ 0.01 ⁇ M.
  • Ki value ⁇ M
  • the values for representative compounds are shown in the table below.
  • the present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
  • compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the present invention also provides a method for the manufacture of pharmaceutical compositions. Such process comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • the most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
  • the present invention provides methods of the treatment of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD) which comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.
  • the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Tablet Formulation mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831 Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50° C. 3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press.
  • Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 2 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.
  • the reaction flask was removed from the tritiation apparatus and the residue was suspended in ethanol.
  • the specific activity was 17.5 Ci/mole according to mass spectrometry.
  • the enantiomeric purity was over 99% according to HPLC (column: Chiralpak AD 10 ⁇ m 4.6 ⁇ 250 mm; mobile phase: 10% ethanol in n-heptane; flow rate: 1 ml/min; UV: 220 nm).

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Abstract

The invention relates to compounds of formula I
Figure US20100120864A1-20100513-C00001
wherein
  • X, Y, R1, R2, and n are as defined herein
    or to a pharmaceutically suitable acid addition salt thereof. The invention also relates to pharmaceutical compositions containing such compounds and methods for the treatment of diseases related to the biological function of the trace amine associated receptors, which diseases include depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Description

    PRIORITY TO RELATED APPLICATION(S)
  • This application is a continuation of U.S. application Ser. No. 12/011,384, filed Jan. 25, 2008, now pending; which claims the benefit of European Patent Application No. 07101681.0, filed Feb. 2, 2007. The entire contents of the above-identified applications are hereby incorporated by reference.
    • BACKGROUND OF THE INVENTION
  • 2-Aminooxazolines are described in the literature as hypertensive agents with good affinity to the adrenergic receptor or as intermediates in processes for preparation of pharmaceutical active agents, for example in EP 0 167 459, U.S. Pat. No. 4,311,840, DE 2,253,555, Tetrahedron (2001), 57(1), 195-200 or in Bioorganic and Medicinal Chemistry Letters (2004), 14(2), 313-316.
  • Some of the physiological effects (i.e. cardiovascular effects, hypotension, induction of sedation) which have been reported for compounds which may bind to adrenergic receptors (WO02/076950, WO97/12874 or EP 0717 037) may be considered to be undesirable side effects in the case of medicaments aimed at treating diseases of the central nervous system as described above. Therefore it is desirable to obtain medicaments having selectivity for the TAAR1 receptor vs adrenergic receptors. Objects of the present invention show selectivity for TAAR1 receptor over adrenergic receptors, in particular good selectivity vs the human and rat alpha1 and alpha2 adrenergic receptors.
  • The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system [1]. Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions [2-5]. A second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlap with the classical biogenic amines regarding structure, metabolism and subcellular localization. The TAs include p-tyramine, β-phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines [6].
  • Their dysregulation has been linked to various psychiatric diseases like schizophrenia and depression [7] and for other conditions like attention deficit hyperactivity disorder, migraine headache, Parkinson's disease, substance abuse and eating disorders [8,9].
  • For a long time, TA-specific receptors had only been hypothesized based on anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10,11]. Accordingly, the pharmacological effects of TAs were believed to be mediated through the well known machinery of classical biogenic amines, by either triggering their release, inhibiting their reuptake or by “crossreacting” with their receptor systems [9,12,13]. This view changed significantly with the recent identification of several members of a novel family of GPCRs, the trace amine associated receptors (TAARs) [7,14]. There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene). The TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located next to each other on the same chromosomal segment. The phylogenetic relationship of the receptor genes, in agreement with an in-depth GPCR pharmacophore similarity comparison and pharmacological data suggest that these receptors form three distinct subfamilies [7,14]. TAAR1 is in the first subclass of four genes (TAAR1-4) highly conserved between human and rodents. TAs activate TAAR1 via Gαs. Dysregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and therefore TAAR1 ligands have a high potential for the treatment of these diseases.
  • Therefore, there is a broad interest to increase the knowledge about trace amine associated receptors.
    • REFERENCES USED
    • 1 Deutch, A. Y. and Roth, R. H. (1999) Neurotransmitters. In Fundamental Neuroscience (2nd edn) (Zigmond, M. J., Bloom, F. E., Landis, S. C., Roberts, J. L, and Squire, L. R., eds.), pp. 193-234, Academic Press;
    • 2 Wong, M. L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat. Rev. Neurosci. 2, 343-351;
    • 3 Carlsson, A. et al. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu. Rev. Pharmacol. Toxicol. 41, 237-260;
    • 4 Tuite, P. and Riss, J. (2003) Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investig. Drugs 12, 1335-1352,
    • 5 Castellanos, F. X. and Tannock, R. (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci. 3, 617-628;
    • 6 Usdin, Earl; Sandler, Merton; Editors. Psychopharmacology Series, Vol. 1: Trace Amines and the Brain. [Proceedings of a Study Group at the 14th Annual Meeting of the American College of Neuropsychoparmacology, San Juan, Puerto Rico] (1976);
    • 7 Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends in Pharmacol. Sci. 26, 274-281;
    • 8 Branchek, T. A. and Blackburn, T. P. (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr. Opin. Pharmacol. 3, 90-97;
    • 9 Premont, R. T. et al. (2001) Following the trace of elusive amines. Proc. Natl. Acad. Sci. U.S.A. 98, 9474-9475;
    • 10 Mousseau, D. D. and Butterworth, R. F. (1995) A high-affinity [3H] tryptamine binding site in human brain. Prog. Brain Res. 106, 285-291;
    • 11 McCormack, J. K. et al. (1986) Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system. J. Neurosci. 6, 94-101;
    • 12 Dyck, L. E. (1989) Release of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor. Life Sci. 44, 1149-1156;
    • 13 Parker, E. M. and Cubeddu, L. X. (1988) Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J. Pharmacol. Exp. Ther. 245, 199-210;
    • 14 Lindemann, L. et al. (2005) Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 85, 372-385.
    SUMMARY OF THE INVENTION
  • The invention provides compounds of formula I
  • Figure US20100120864A1-20100513-C00002
  • wherein
    • R1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, phenyloxy, benzyl, benzyloxy, —COO-lower alkyl, —O—(CH2)o—O-lower alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the substituents for n>1 are the same or different;
    • X is a bond, —CHR—, —CHRCHR′—, —OCH2—, —CH2OCHR—, —CH2CH2CH2—, —SCH2—, —S(O)2CH2—, —CH2SCH2—, —CH2N(R)CH2—, -cycloalkyl-CH2— or SiRR′—CH2—;
    • R and R′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen;
    • R2 is hydrogen, phenyl or lower alkyl;
    • Y is phenyl, naphthyl, thiophenyl, pyridinyl, cycloalkyl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl or benzo[1,3]dioxol-5-yl;
    • n is 0, 1, 2 or 3; and
    • o is 2 or 3;
    • and pharmaceutically suitable acid addition salts thereof.
  • The invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. In addition, all tautomeric forms of compounds of formula I are also encompassed by the present invention.
  • The invention also provides pharmaceutical compositions containing one or more compound of the invention and a pharmaceutically acceptable carrier. The invention further provides methods for the manufacture of the compounds and compositions of the invention. Compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The invention provides a method for the treatment of diseases related to the biological function of trace amino associated receptors. Such diseases include depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
  • The preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
    • DETAILED DESCRIPTION OF THE INVENTION
  • Unless otherwise stated, the following terms used in the present description have the definitions given in the following. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural forms unless the context clearly dictates otherwise.
  • As used herein, the term “lower alkyl” denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.
  • As used herein, the term “lower alkoxy” denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.
  • As used herein, the term “lower alkyl substituted by halogen” denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF3, CHF2, CH2F, CH2CF3, CH2CH2CF3, CH2CF2CF3 and the like.
  • As used herein, the term “lower alkoxy substituted by halogen” denotes an alkoxy group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example OCF3, OCHF2, OCH2F, OCH2CF3, OCH2CH2CF3, OCH2CF2CF3 and the like.
  • The term “halogen” denotes chlorine, iodine, fluorine and bromine.
  • The term “cycloalkyl” is an alkylene ring, containing from 3 to 6 carbon ring atoms.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • The compounds mentioned below are specific novel and preferred for the uses as described above.
  • Preferred compounds of formula I are those, wherein X is a bond.
  • Preferred compounds of this group of formula I are those, wherein Y is phenyl, substituted by one or more halogen atoms:
  • Figure US20100120864A1-20100513-C00003
    • R1 is halogen, for n>1 the halogen atoms are the same or different;
    • R2 is hydrogen, phenyl or lower alkyl; and
    • n is 1, 2 or 3;
    • or a pharmaceutically suitable acid addition salt, for example
    • (S)-4-(2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,3-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3,4-dichlorophenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,3-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-methyl-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-methyl-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-methyl-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(5-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-methyl-4-(4-chloro-2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (−)-(R)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2,5-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
    • (−)-(R)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(2-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
    • (S)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine.
  • Further preferred compounds from this group are those, wherein Y is phenyl substituted by CH3, CF3, OCH3, OCF3 or OCH2-phenyl,
  • Figure US20100120864A1-20100513-C00004
    • R1 is CH3, CF3, OCH3, OCF3 or OCH2-phenyl; for n>1, each R1 is the same or different;
    • R2 is hydrogen, phenyl or lower alkyl; and
    • n is 1, 2 or 3;
    • or a pharmaceutically suitable acid addition salt, for example the following compounds
    • (RS)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-benzyloxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
    • (+)-(S)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
  • Further preferred compounds from this group are those, wherein Y is phenyl substituted by phenyl, which is optionally substituted by halogen:
  • Figure US20100120864A1-20100513-C00005
    • R2 is hydrogen, phenyl or lower alkyl;
    • or a pharmaceutically suitable acid addition salt, for example the following compounds
    • (RS)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine, and
    • (RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine.
  • Further preferred compounds from this group are those, wherein Y is phenyl substituted by halogen and CF3, halogen and CH3, halogen and cycloalkyl or by halogen and OCH3,
  • Figure US20100120864A1-20100513-C00006
    • R1 is halogen and CF3, or is halogen and CH3, or is halogen and cycloalkyl, or is halogen and OCH3; and
    • R2 is hydrogen, phenyl or lower alkyl;
    • or a pharmaceutically suitable acid addition salt, for example the following compounds
    • (RS)-4-(3-chloro-4-methoxyphenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (−)-(R)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(5-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (+)-(S)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(3-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
    • (S)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is CHR.
  • Preferred compounds from this group are those, wherein Y is phenyl substituted by halogen, CF3, or CH3:
  • Figure US20100120864A1-20100513-C00007
    • R1 is halogen, CF3 or CH3, wherein substituents for n>1 are the same or different;
    • R2 is hydrogen, phenyl or lower alkyl;
    • R is hydrogen, lower alkyl or lower alkyl substituted by halogen; and
    • n is 1 or 2;
    • or a pharmaceutically suitable acid addition salt, for example the following compounds
    • (S)-4-(2-chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine, and
    • (RS)-4-(2-fluoro-5-methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is CHRCHR′.
  • Preferred compounds from this group are those, wherein Y is optionally substituted phenyl,
  • Figure US20100120864A1-20100513-C00008
    • R1 is hydrogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or is halogen, wherein the substituents for n>1 are the same or different;
    • R and R′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen;
    • R2 is hydrogen, phenyl or lower alkyl; and
    • n is 0, 1, 2 or 3;
    • or a pharmaceutically suitable acid addition salt, for example the following compounds
    • (R)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-3-methoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • ((S)-4-[2-(2,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,5-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-o-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-m-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-p-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (R)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-chloro-2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-3-methyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-}2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-fluoro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-3-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2,3-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(1-methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,5-difluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,5-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,4-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-fluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3,4-dichloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(4-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-((R)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-chloro-6-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2,4-dichloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-chloro-5-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine, and
    • (S)-4-[2-(5-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is OCH2 and Y is optionally substituted phenyl.
  • Figure US20100120864A1-20100513-C00009
    • R1 is lower alkyl, lower alkyl substituted by halogen or halogen, wherein the substituents for n>1 are the same or different;
    • R2 is hydrogen, phenyl or lower alkyl; and
    • n is 0, 1, 2 or 3;
    • or a pharmaceutically suitable acid addition salt, for example the following compounds
    • (S)-4-(4-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,4-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3,5-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(4-bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(3-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(2,4-difluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine, and
    • (S)-4-(2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is CH2OCHR.
  • Preferred compounds from this group are those, wherein Y is phenyl optionally substituted by halogen:
  • Figure US20100120864A1-20100513-C00010
    • R1 is hydrogen or halogen; and
    • n is 0 or 1;
    • or a pharmaceutically suitable acid addition salt, for example the following compound
    • (S)-4-benzyloxymethyl-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is —(CH2)3—
  • Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds
    • (S)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine and
    • (R)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is —SCH2—, —S(O)2CH2—, or —CH2SCH2—.
  • Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds
    • (R)-4-phenylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine,
    • (R)-4-benzenesulfonylmethyl-4,5-dihydro-oxazol-2-ylamine,
    • (R)-4-benzylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine, and
    • (R)-4-(4-chloro-phenylsulfanylmethyl)-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is —CH2N(R)CH2—, cycloalkyl-CH2— or SiRR′—CH2—;
  • Preferred compounds from this group are those, wherein Y is optionally substituted phenyl, for example the following compounds
    • (S)-4-[1-(4-chloro-phenyl)-cyclopropylmethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[1-(4-chloro-phenyl)-cyclobutylmethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-(1-phenyl-cyclopropylmethyl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[(benzyl-ethyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine, and
    • (R)-4-[(dimethyl-phenyl-silanyl)-methyl]-4,5-dihydro-oxazol-2-ylamine.
  • Preferred compounds of formula I are further those, wherein X is described above and Y is naphthyl, pyridyl, cyclohexyl, 2,3-dihydrobenzo[1,4]dioxin or 1,2,3,4-tetrahydronaphthalen.
  • Examples of such compounds are
    • (RS)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-naphthalen-1-yl-4,5-dihydro-oxazol-2-ylamine,
    • (R)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-naphthalen-2-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
    • (RS)-4-(1,2,3,4-tetrahydro-naphthalen-2-yl)-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(3-fluoro-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-[2-(2-methyl-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine, and
    • (S)-4-(2-cyclohexyl-ethyl)-4,5-dihydro-oxazol-2-ylamine.
  • A further embodiment of the invention is compounds of formula
  • Figure US20100120864A1-20100513-C00011
  • wherein
    • R1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, phenyloxy, benzyl, benzyloxy, or —COO-lower alkyl; wherein the substituents for n>1 are the same or different;
    • X is a bond, —CHR— or —CHRCH2—;
    • R is hydrogen or lower alkyl;
    • R2 is hydrogen or lower alkyl;
    • Y is aryl, heteroaryl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl or benzo[1,3]dioxol-5-yl; and
    • n is 0, 1, 2 or 3;
    • or pharmaceutically suitable acid addition salt with the exception of
    • (S)-4-phenyl-4,5-dihydro-oxazol-2-ylamine,
    • (R)-4-phenyl-4,5-dihydro-oxazol-2-ylamine,
    • (S)-4-benzyl-4,5-dihydro-oxazol-2-ylamine, and
    • (RS)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine.
  • The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
    • a) Reacting a compound of formula
  • Figure US20100120864A1-20100513-C00012
  • with cyanogen bromide
    • to obtain a compound of formula
  • Figure US20100120864A1-20100513-C00013
  • wherein the definitions are as described above, or
  • if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
  • The preparation of compounds of formula I of the present invention can be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes 1-9. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.
  • In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in schemes 1 to 9, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
    • General Procedure
  • Figure US20100120864A1-20100513-C00014
  • Step A: Reduction of an acid group (R′═H) can be effected by treatment with LiAlH4, BH3-THF, BH3-Me2S complex in the presence of BF3-etherate or Red-Al in a solvent such as 1,2-dimethoxyethane, THF, diethylether or toluene at r.t.→reflux for 1-24 hrs. Alternatively, reduction of an acid group (R′═H) can be effected by treatment with LiBH4 in the presence of Me3SiCl in a solvent such as methanol at 0° C.→r.t. for 1-24 hrs.
  • Reduction of an ester group (R′=methyl or ethyl) can be effected by treatment with LiAlH4, LiBH4, NaBH4 or Red-Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at −78° C.→reflux for 1-24 hrs.
  • Preferred conditions for acids and esters are LiAlH4 in THF at r.t. overnight, or LiBH4/Me3SiCl in methanol at 0° C.→r.t. overnight.
  • Step B: Cyclisation of the aminoalcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00015
  • Step A: Wittig reaction between Garner's aldehyde IV and a benzyl-substituted phosphonic acid diethyl ester V can be accomplished by using a base such as NaH, KOtBu, NaOMe, NaOEt, n-BuLi, LiHMDS, NaHMDS, KHMDS, LDA in a solvent such as THF, dioxane, acetonitrile, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from −78° C.-80° C. for 15 min-8 hrs and if appropriate optional addition of a crown ether for ylide generation and then condensing the ylide with the carbonyl compound in the same solvent at temperature between 0 and 80° C. for 1-24 hrs. Alternatively, the base, the carbonyl compound and the base and the optional crown ether can be added to the reaction mixture at the same time without preformation of the ylide at temperatures from −78° C.-80° C.
  • Preferred conditions are ylide formation at 0° C. using n-buthyl lithium solution in hexane as base and 1,2-dimethoxyethane as solvent, reacting the phosphonic acid ester for 5 min at 0° C., and then condensation with the carbonyl component at reflux overnight.
  • Step B: Reduction of the alkene can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO2, Pd—C or Raney nickel in solvents such as MeOH, EtOH, H2O, dioxane, THF, HOAc, EtOAc CH2Cl2, CHCl3, DMF or mixtures thereof. Alternatively, the reduction of the alkene can be effected by Mg in MeOH or by LiAlH4 in THF or diethylether. Preferred conditions are hydrogenation in the presence of Pd/C as catalyst with EtOH as solvent.
  • Step C: Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H2SO4 or H3PO4 or an organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step D: Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00016
  • Step A: The synthesis of the Julia reagent (benzothiazole-2-sulfonyl derivative) IX from ‘Garner's alcohol’ VIII was accomplished as described in literature (Dandanpani, S. et al., Journal of Organic Chemistry 2005, 70(23), 9447).
  • Step B: Julia reaction between an Y-aldehyde or ketone and and the benzothiazole sulfonyl compound can be accomplished by using a base such as LiHMDS, NaHMDS, KHMDS, LDA, KOtBu, DBU in a solvent such as THF, diethyl ether, 1,2-dimethoxyethane, dichloromethane, DMF or mixtures thereof at temperatures from −100° C.—r.t. for 15 min-8 hrs for anion generation and then condensing the ylide with the carbonyl compound in the same solvent at temperatures between −100° C. and r.t. for 1-24 hrs. Preferred conditions are anion generation with LiHMDS at −78° C. in THF and subsequent condensation with the carbonyl component under the same conditions.
  • Step C: Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H2SO4 or H3PO4 or a organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step D: Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00017
  • Step A: Mitsunobu reaction of ‘Garner's alcohol’ VIII with phenol derivatives X or thiophenol derivatives X can be accomplished by using a phosphine such as triphenylphosphine and an azodicarboxylate reagent such as diethylazodicarboxylate, diisopropylazodicarboxylate, or di-tert-butylazodicarboxylate in a solvent such as THF at temperatures from 50° C.-70° C. for 1-18 hrs. Preferred conditions are triphenylphosphine and di-tert-butylazodicarboxylate in THF at 60° C. for 16 h.
  • Step B: Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H2SO4 or H3PO4 or a organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step C: Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00018
  • Step A: Conversion of Garner's aldehyde IV to the dibromo-alkene derivative XII can be accomplished by using a brominating agent such as carbon tetrabromide in the presence of a phosphine such as triphenylphosphine in a chlorinated solvent such as dichloromethane at temperatures between 0° C. and room temperature.
  • Step B: Suzuki reaction of dibromo-alkene derivative XII with an arylboronic acid XIII can be accomplished using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (0) in the presence of a phosphine such as tris(2-furyl)phosphine and a base such as aqueous sodium carbonate in a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from 50° C.-100° C. for 1-18 hrs.
  • Step C: Negishi reaction of bromo-alkene derivative XIV with a dialkylzinc reagent XV can be accomplished using a palladium catalyst such as bis(tri-tert-butylphosphine)dipalladium (0) in a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from 20° C.-100° C. for 1-18 hrs. Preferred conditions are a THF-toluene mixture at room temperature.
  • Step D: Reduction of the alkene can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO2, Pd—C or Raney nickel in solvents such as MeOH, EtOH, H2O, dioxane, THF, HOAc, EtOAc CH2Cl2, CHCl3, DMF or mixtures thereof. Alternatively, the reduction of the alkene can be effected by Mg in MeOH or by LiAlH4 in THF or diethylether.
  • Preferred conditions for R1≠chlorine are hydrogenation in the presence of Pd/C as catalyst with EtOH as solvent.
  • Preferred conditions for R1=chlorine are hydrogenation in the presence of Pt/C as catalyst with EtOH as solvent.
  • Step E: Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H2SO4 or H3PO4 or an organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Steps D and E can also be carried out in the opposite order, in which case the stereochemical preference of the hydrogenation step is typically reversed.
  • Step F: Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00019
  • Step A: Coupling of 4-ethinyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate XVIII (Dickson, H. D. et al Tetrahedron Lett. 2004, 45 (29), 5597-5599; Pietruszka, J. et al Eur. I. Org. Chem. 2003, 3219-3229) with an aryl or hetaryl bromide or iodide XIX in the presence of a palladium and a copper(I) salt in a solvent such as dioxane, tetrahydrofurane, benzene, triethylamine or the like.
  • Preferred conditions are the use of copper(I)-iodide and bis(triphenylphosphine)palladium(II) chloride with triethylamine as solvent at room temperature.
  • Step B: Reduction of the alkyne XX can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO2, Pd—C or Raney nickel in solvents such as MeOH, EtOH, H2O, dioxane, THF, HOAc, EtOAc CH2Cl2, CHCl3, DMF or mixtures thereof. Alternatively, the reduction of the alkyne can be effected by Mg in MeOH or by LiAlH4 in THF or diethylether. Preferred conditions are transfer hydrogenation using ammonium formiate in the presence of Pd/C as catalyst with MeOH as solvent.
  • Step C: Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H2SO4 or H3PO4 or an organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C.
  • Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step D: Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00020
  • Step A: Deprotonation of bis-lactimether XXI (also called “Schöllkopf's chiral auxiliary”) with a suitable base such as n-butyl-lithium or tert-butyl-lithium in an appropriate organic solvent such as tetrahydrofuran at a low temperature followed by addition of the organic halide XXII and reaction for several hours leads to product XXIII (Vassiliou, S. et al Synlett 2003, 2398-2400; Schöllkopf, U. Topics Curr. Chem. 1983, 109, 65). Preferred conditions are the use of tert-butyllithium and an organic iodide in tetrahydrofuran at −78° C. and allowing the mixture to reach room temperature overnight.
  • Step B: Cleavage of bis-lactim ether product XXIII under acidic conditions using a mineral acid such as HCl, H2SO4 or H3PO4 or an organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as acetonitrile, CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C.
  • Preferred conditions are a 10% trifluoroacetic acid in a mixture of water and acetonitrile (1:3) at 40° C. overnight.
  • Step C: Reduction of the ester XXIV can be effected by treatment with LiAlH4, LiBH4, NaBH4 or Red-Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at −78° C.→reflux for 1-24 hrs.
  • Preferred conditions for acids and esters are LiAlH4 in THF at r.t. overnight.
  • Step D: Cyclisation of the amino alcohol II-4 to the corresponding 2-aminooxazoline 1-4 can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00021
  • Homochiral alcohols of formula XXVIII may be prepared by a variety of methods reported in the chemical literature, for instance starting from carboxylic acids of formula XXV and using the methodologies of Evans et al. (ref [1]) or Meyers et al. (ref [2]). According to these procedures, introduction of a chiral auxilliary, such as the Evans oxazolidinone auxiliary (ref [1]) or the Meyers pseudoephedrine-derived auxiliary (ref [2]) affords a homochiral acyl compound of formula XXVI. Enolisation of the acyl compound XX with a suitable base followed by treatment with an alkyl halide affords compounds of formula XXVII. Reductive removal of the chiral auxiliary then affords the homochiral alcohols of formula XXVIII.
    • [1] Evans, D. A. et al. J. Am. Chem. Soc. 1982, 104, 1737-1739.
    • [2] Meyers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6496-5611.
  • Step A: Homochiral alcohol XXVIII may be converted to the corresponding alkyl iodide XXIX using a reagent system comprising imidazole, triphenylphosphine and iodine in dichloromethane (Müller, P. & Boléa, C. Helv. Chim. Acta 2002, 85, 483-494) or sequential treatment with p-toluensulphonyl chloride/pyridine and sodium iodide in acetone (Taber, D. F. et al. J. Am. Chem. Soc. 1985, 107, 196-199). Preferred conditions are the use of imidazole, triphenylphosphine and iodine in dichloromethane.
  • Step B: Deprotonation of bis-lactimether XXI (also called “Schöllkopf's chiral auxiliary”) with a suitable base such as n-butyl-lithium or tert-butyl-lithium in an appropriate organic solvent such as tetrahydrofuran at a low temperature followed by addition of the homochiral alkyl iodide XXIX and reaction for several hours leads to product XXX (Vassiliou, S. et al Synlett 2003, 2398-2400; Schöllkopf, U. Topics Curr. Chem. 1983, 109, 65). Preferred conditions are the use of n-butyllithium at −78° C. and allowing the mixture to reach room temperature overnight.
  • Step C: Cleavage of bis-lactim ether product XXX under acidic conditions using a mineral acid such as HCl, H2SO4 or H3PO4 or an organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as acetonitrile, CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C. Preferred conditions are a 10% trifluoroacetic acid in a mixture of water and acetonitrile (1:3) at room temperature overnight.
  • Step D: Reduction of the ester XXXI can be effected by treatment with LiAlH4, LiBH4, NaBH4 or Red-Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at −78° C.→reflux for 1-24 hrs. Preferred conditions for acids and esters are LiAlH4 in THF at r.t. overnight.
  • Step E: Cyclisation of the amino alcohol II-5 to the corresponding 2-aminooxazoline I-5 can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
  • Figure US20100120864A1-20100513-C00022
  • Step A: Reductive amination of optically active Garner's aldehyde (R2═H; from L- or D-serine; Garner, P.; Park, J. M. Org. Synth. 1998, IX, 300) or α-methyl-substituted Garner's aldehyde (R2=methyl; from L- or D-α-methylserine; Avenoza, A. et al. Tetrahedron Asymm. 2001, 12, 949) with a primary amine compound of formula XXXII-1 can be accomplished by a reducing agent such as NaBH4, LiBH4, NaBH(OAc) 3 or Na(CN)BH3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr)4 at a temperature of −10 to 60° C. for 1-40 h.
  • Preferred conditions are heating of compound XXXII-1 and compound IV in MeOH at 60° C. overnight, followed by treatment with NaBH4 in MeOH at room temperature.
  • Step B: Alkylation of the compound of formula XXXIII-1 to compound of formula XXXIII-2 can by accomplished by treatment with a suitable aldehyde RCHO in the presence of a reducing agent such as NaBH4, LiBH4, NaBH(OAc)3 or Na(CN)BH3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr)4 at a temperature of −10 to 60° C. for 1-40 h.
  • Step C: Preparation of a compound of formula XXXIII-2 may alternatively be accomplished by reductive amination of a secondary amine compound of formula XXXIII-2 and Garner's aldehyde (from L- or D-serine; Garner, P.; Park, J. M. Org. Synth. 1998, IX, 300) in the presence of a reducing agent such as NaBH4, LiBH4, NaBH(OAc)3 or Na(CN)BH3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr)4 at a temperature of −10 to 60° C. for 1-40 h. Preferred conditions are NaBH3CN and ZnCl2 in MeOH at r.t.—40° C. overnight.
  • Step D: Simultaneous cleavage of the amino alcohol protecting groups of the compound of formula XXXIII-2 can be effected with a mineral acid such as HCl, H2SO4 or H3PO4 or a organic acid such as CF3COOH, CHCl2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH2Cl2, CHCl3, THF, MeOH, EtOH or H2O at 0 to 60° C. Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs or 4N HCl in dioxane at r.t. overnight.
  • Step E: Cyclisation of the amino alcohol II-6 to the corresponding 2-aminooxazoline I-6 can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0° C. to r.t. overnight.
    • Isolation and Purification of the Compounds
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
    • Salts of Compounds of Formula I
  • The compounds of formula I are basic and may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0° C. and 50° C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
  • The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have a good affinity to the trace amine associated receptors (TAARs), especially TAAR1.
  • The compounds were investigated in accordance with the test given hereinafter.
    • Materials and Methods Construction of TAAR Expression Plasmids and Stably Transfected Cell Lines
  • For the construction of expression plasmids the coding sequences of human, rat and mouse TAAR 1 were amplified from genomic DNA essentially as described by Lindemann et al. [14]. The Expand High Fidelity PCR System (Roche Diagnostics) was used with 1.5 mM Mg2+ and purified PCR products were cloned into pCR2.1-TOPO cloning vector (Invitrogen) following the instructions of the manufacturer. PCR products were subcloned into the pIRESneo2 vector (BD Clontech, Palo Alto, Calif.), and expression vectors were sequence verified before introduction in cell lines.
  • HEK293 cells (ATCC #CRL-1573) were cultured essentially as described Lindemann et al. (2005). For the generation of stably transfected cell lines HEK293 cells were transfected with the pIRESneo2 expression plasmids containing the TAAR coding sequences (described above) with Lipofectamine 2000 (Invitrogen) according to the instructions of the manufacturer, and 24 hrs post transfection the culture medium was supplemented with 1 mg/ml G418 (Sigma, Buchs, Switzerland). After a culture period of about 10 d clones were isolated, expanded and tested for responsiveness to trace amines (all compounds purchased from Sigma) with the cAMP Biotrak Enzyme immunoassay (EIA) System (Amersham) following the non-acetylation EIA procedure provided by the manufacturer. Monoclonal cell lines which displayed a stable EC50 for a culture period of 15 passages were used for all subsequent studies.
    • Membrane Preparation and Radioligand Binding
  • Cells at confluence were rinsed with ice-cold phosphate buffered saline without Ca2+ and Mg2+ containing 10 mM EDTA and pelleted by centrifugation at 1000 rpm for 5 min at 4° C. The pellet was then washed twice with ice-cold phosphate buffered saline and cell pellet was frozen immediately by immersion in liquid nitrogen and stored until use at −80° C. Cell pellet was then suspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA, and homogenized with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 s. The homogenate was centrifuged at 48,000×g for 30 min at 4° C. and the pellet resuspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA (buffer A), and homogenized with a Polytron at 10,000 rpm for 10 s. The homogenate was then centrifuged at 48,000×g for 30 min at 4° C. and the pellet resuspended in 20 ml buffer A, and homogenized with a Polytron at 10,000 rpm for 10 s. Protein concentration was determined by the method of Pierce (Rockford, Ill.). The homogenate was then centrifuged at 48,000×g for 10 mM at 4° C., resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl2 (10 mM) and CaCl2 g protein per ml and (2 mM) (buffer B) at 200 homogenized with a Polytron at 10,000 rpm for 10 s.
  • Binding assay was performed at 4° C. in a final volume of 1 ml, and with an incubation time of 30 mM. The radioligand [3H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline was used at a concentration equal to the calculated Kd value of 60 nM to give a bound at around 0.1% of the total added radioligand concentration, and a specific binding which represented approximately 70-80% of the total binding. Non-specific binding was defined as the amount of [3H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline bound in the presence of the appropriate unlabelled ligand (10 μM). Competing ligands were tested in a wide range of concentrations (10 pM-30 μM). The final dimethylsulphoxide concentration in the assay was 2%, and it did not affect radioligand binding. Each experiment was performed in duplicate. All incubations were terminated by rapid filtration through UniFilter-96 plates (Packard Instrument Company) and glass filter GF/C, pre-soaked for at least 2 h in polyethylenimine 0.3%, and using a Filtermate 96 Cell Harvester (Packard Instrument Company). The tubes and filters were then washed 3 times with 1 ml aliquots of cold buffer B. Filters were not dried and soaked in Ultima gold (45 μl/well, Packard Instrument Company) and bound radioactivity was counted by a TopCount Microplate Scintillation Counter (Packard Instrument Company).
  • The preferred compounds show a Ki value (μM) in mouse or rat on TAAR1 in the range of <0.01 μM. The values for representative compounds are shown in the table below.
  • Ki (μM)
    Example mouse/rat
     4 0.0012
     5 0.0021
     6 0.0038
     7 0.0083
     8 0.0058
     9 0.0034
     10 0.0025
     12 0.008
     14 0.0005
     16 0.0048
     17 0.0057
     18 0.0022
     19 0.0018
     20 0.0009
     21 (S) 0.0008
     22 0.0011
     29 (S) 0.0054
     31 0.0022
     32 0.0029
     33 0.0007
     34 0.0011
     35 0.0033
     36 0.0034
     37b (S) 0.0087
     39a (S) 0.0025
     48 0.0002
     49 0.0054
     60 0.0047
     63 0.0086
     73 0.0089
     78 0.0064
     80 (S) 0.0008
     80 (R) 0.0083
     81 (S) 0.0064
     82 (S, S) 0.0080
     82 (S, R) 0.0016
     84 0.0017
     85 0.0011
     86 0.0008
     88 0.001
     89 0.0013
     91 0.0006
    101 0.0034
    103 0.0004
    105 0.0007
    107 0.004
    109 0.0014
    110 0.0018
    111 0.0011
    112 0.0012
    113 0.0016
    114 0.0021
    115 0.001
    116 0.0012
    118 0.003
    119 0.0026
    120 0.0014
    122 0.0034
    124 0.0044
    127 0.0003
    129 0.0029
    131 0.0024
    132 0.0007
    133 0.0022
    135 0.0009
    136 0.0038
    137 0.0025
    138 0.0012
    139 0.0019
    140 0.001
    141 0.0027
    142 0.0018
    143 0.0007
    144 0.0012
    145 0.0026
    146 0.0041
    147 0.0041
    149 0.0019
    150 0.0009
    151 0.001
    153 0.0083
    154 0.0034
    156 0.0064
    158 0.0068
    159 0.001
    160 0.0028
    161 0.0062
    162 0.0025
    163 0.0037
    165 0.0012
    166 0.0047
    168 0.0006
    169 0.0014
    170 0.0011
    172 0.0019
    174 0.0006
    176 0.002
    178 0.0004
    180 0.0088
    184 0.0063
    185 0.005
    186 0.0045
    187 0.0021
    188 0.0038
    189 0.0008
    190 0.0008
    192 0.0019
    193 0.0043
    194 0.0073
    195 0.0018
    196 0.0066
    198 0.002
    199 0.0093
    201 0.0002
    202 0.0017
    203 0.0039
    206 0.0032
    210 0.0014
    211 0.0024
    212 0.0068
    213 0.003
    215 0.0024
    216 0.002
    217 0.0015
    219 0.0009
    220 0.0084
    221 0.0022
    222 0.0048
    223 0.0059
    224 0.0063
    225 0.0062
    226 0.0054
    227 0.0081
    228 0.004
    229 0-003
    231 0.0025
    232 0.0006
    234 0.0093
    235 0.001
    236 0.002
    237 0.0025
    238 0.003
    240 0.0032
    242 0.0072
    243 0.0094
    244 0.0057
    246 0.0055
    248 0.0029
    249 0.0075
    250 0.0022
    251 0.0086
    252 0.0008
    255 0.0074
    256 0.0006
    257 0.0074
    259 0.0088
    260 0.0013
    263 0.0023
    265 0.0009
    266 0.0016
    267 0.0011
    269 0.0083
    270 0.0016
    271 0.0013
    272 0.0013
    273 0.0095
    274 0.0011
    277 0.0016
    281 0.0019
    rat
    284 0.0028
    rat
    285 0.0045
    rat
    287 0.0027
    rat
    289 0.0017
    291 0.0008
    292 0.0035
    293 0.0062
    294 0.0038
    295 0.0082
    296 0.0004
    298 0.0004
    299 0.0042
    301 0.0023
    302 0.0017
    303 0.0011
    304 0.0033
    306 0.0027
    308 0.0009
    310 0.009
    rat
    311 0.0042
    rat
    313 0.005
    rat
    314 0.003
    rat
    315 0.0016
    rat
    316 0.0003
    rat
    318 0.002
    rat
    321 0.0014
    rat
    322 0.002
    rat
    326 0.001
    328 0.0052
    330 0.0008
    332 0.0061
    333 0.0021
    337 0.0034
    338 0.0031
    340 0.002
    341 0.0046
    342 0.0045
    343 0.0028
    344 0.0025
    348 0.0036
    349 0.0023
    350 0.0064
    351 0.0024
    353 0.0014
    354 0.0003
    355 0.0043
    356 0.0043
    357 0.0068
    358 0.0084
    359 0.0021
    364 0.0020
    365 0.0029
    367 0.001
    369 0.0009
    370 0.0037
    371 0.0096
    374 0.0006
    D 0.001
  • The present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
  • The pharmaceutical compositions of the invention, in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • The present invention also provides a method for the manufacture of pharmaceutical compositions. Such process comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD). Thus, the present invention provides methods of the treatment of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD) which comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.
  • The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Tablet Formulation (Wet Granulation)
    mg/tablet
    Item Ingredients 5 mg 25 mg 100 mg 500 mg
    1. Compound of formula I 5 25 100 500
    2. Lactose Anhydrous DTG 125 105 30 150
    3. Sta-Rx 1500 6 6 6 30
    4. Microcrystalline Cellulose 30 30 30 150
    5. Magnesium Stearate 1 1 1 1
    Total 167 167 167 831
    Manufacturing Procedure
    1. Mix items 1, 2, 3 and 4 and granulate with purified water.
    2. Dry the granules at 50° C.
    3. Pass the granules through suitable milling equipment.
    4. Add item 5 and mix for three minutes; compress on a suitable
    press.
  • Capsule Formulation
    mg/capsule
    Item Ingredients 5 mg 25 mg 100 mg 500 mg
    1. Compound of formula I 5 25 100 500
    2. Hydrous Lactose 159 123 148 —
    3. Corn Starch 2 35 40 70
    4. Talc 10 15 10 25
    5. Magnesium Stearate 1 2 2 5
    Total 200 200 300 600
    Manufacturing Procedure
    1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
    2. Add items 4 and 5 and mix for 3 minutes.
    3. Fill into a suitable capsule.
    • Experimental
  • The following examples illustrate the invention but are not intended to limit its scope.
    • Example 1 (RS)-4-Methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00023
    • a) (RS)-2-Amino-2-phenyl-propan-1-ol
  • To a stirred, cooled suspension of 2-amino-2-phenyl-propionic acid (488 mg) at r.t. in THF (10 ml) under an argon atmosphere was added portionwise LiAlH4 (244 mg). The ice bath was removed and stirring at r.t. was then continued for 20 h. The mixture was cooled in an ice bath, diluted with 5 ml THF and H2O (0.23 ml), 4 N NaOH (0.23 ml) and H2O (0.92 ml) were added successively and carefully. After 30 min stirring at r.t., the mixture was filtered and the cake was washed with THF. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 2-amino-2-phenyl-propan-1-ol (266 mg) as colorless viscous oil. MS (ISP): 152.3 ([M+H]+)
    • b) (RS)-4-Methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine
  • To a stirred, cooled (0° C.) mixture of 2-amino-2-phenyl-propan-1-ol (266 mg) and K2CO3 (292 mg) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (292 mg) in THF (5 ml). The ice bath was removed and stirring at r.t. was continued for 18 h. The mixture (white suspension) was taken up in EtOAc/H2O 1:1. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 4-methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine (204 mg) as white solid. MS (ISP): 177.1 ([M+H]+)
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 2 (S)-4-(4-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00024
  • From L-4-(trifluoromethyl)phenylglycine. Off-white solid.
  • MS (ISP): 231.3 ([M+H]+)
    • Example 3 (S)-4-(4-Fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00025
  • From L-4-fluorophenylglycine. Off-white solid.
  • MS (ISP): 180.9 ([M+H]+)
    • Example 4 (S)-4-(2-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00026
  • From L-2-chlorophenylglycine. Light yellow solid.
  • MS (ISP): 197.3 ([M+H]+)
    • Example 5 (RS)-4-(4-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00027
  • From DL-4-chlorophenylglycine. Light yellow solid.
  • MS (ISP): 197.1 ([M+H]+)
    • Example 6 (RS)-4-(2-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00028
  • From DL-2-(trifluoromethyl)phenylglycine. Off-white solid.
  • MS (ISP): 231.3 ([M+H]+)
    • Example 7 (RS)-4-(2,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00029
  • From DL-2,4-difluorophenylglycine. Off-white solid.
  • MS (ISP): 198.9 ([M+H]+)
    • Example 8 (RS)-4-o-Tolyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00030
  • From (RS)-α-amino-(2-methylphenyl)acetic acid. Off-white solid.
  • MS (ISP): 177.3 ([M+H]+)
    • Example 9 (S)-4-(2,3-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00031
  • From L-2,3-difluorophenylglycine. Off-white solid.
  • MS (ISP): 199.3 ([M+H]+)
    • Example 10 (RS)-4-Biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00032
  • From (RS)-amino-biphenyl-4-yl-acetic acid. Off-white solid.
  • MS (ISP): 239.1 ([M+H]+)
    • Example 11 (RS)-4-(2-Fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00033
  • From DL-2-fluorophenylglycine. Off-white solid.
  • MS (ISP): 180.9 ([M+H]+)
    • Example 12 (RS)-4-(4-Trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00034
  • From DL-4-(trifluoromethoxy)phenylglycine. Off-white solid.
  • MS (ISP): 247.3 ([M+H]+)
    • Example 13 (RS)-4-(3-Trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00035
  • From DL-3-(trifluoromethoxy)phenylglycine. Off-white solid.
  • MS (ISP): 247.3 ([M+H]+)
    • Example 14 (RS)-4-(3,4-Dichlorophenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00036
  • From DL-3,4-dichlorophenylglycine. Off-white solid. MS (ISP): 231.1 ([M+H]+)
    • Example 15 (RS)-4-(2-Methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00037
  • From DL-2-methoxyphenylglycine. Off-white solid.
  • MS (ISP): 193.4 ([M+H]+)
    • Example 16 (RS)-4-(2,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00038
  • From DL-2,5-difluorophenylglycine. Off-white solid.
  • MS (ISP): 199.1 ([M+H]+)
    • Example 17 (RS)-4-(2,3,4-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00039
  • From DL-2,3,4-trifluorophenylglycine. Off-white solid.
  • MS (ISP): 217.3 ([M+H]+)
    • Example 18 (RS)-4-(3-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00040
  • From DL-3-chloro-2-fluorophenylglycine. Off-white solid.
  • MS (ISP): 215.1 ([M+H]+)
    • Example 19 (RS)-4-(5-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00041
  • From DL-5-chloro-2-fluorophenylglycine. Off-white solid.
  • MS (ISP): 215.1 ([M+H]+)
    • Example 20 (RS)-4-(4-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00042
  • From DL-4-bromophenylglycine. Off-white solid. MS (ISP): 243.1 ([M+H]+)
    • Example 21 (S)-4-Biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine and (R)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00043
  • (RS)-4-Biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine (example 10) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (S)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 239.3 ([M+H]+)) and (R)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 239.3 ([M+H]+))
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 22 (RS)-4-(4-Benzyloxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00044
  • From (RS)-amino-(4-benzyloxy-phenyl)-acetic acid methyl ester. White solid.
  • MS (ISP): 269.4 ([M+H]+)
    • Example 23 (RS)-4-(4-Phenoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00045
  • From (RS)-amino-(4-phenoxy-phenyl)-acetic acid methyl ester. White solid.
  • MS (ISP): 255.4 ([M+H]+)
    • Example 24 (RS)-4-(3-Benzyloxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00046
  • From (RS)-amino-(3-benzyloxy-phenyl)-acetic acid methyl ester. White solid.
  • MS (ISP): 269.3 ([M+H]+)
    • Example 25 (RS)-4-(3-Phenoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00047
  • From (RS)-amino-(3-phenoxy-phenyl)-acetic acid methyl ester. White solid.
  • MS (ISP): 255.4 ([M+H]+)
    • Example 26 (S)-4-Methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine and (R)-4-methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00048
  • (RS)-4-Methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine (example 1) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (S)-4-methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 177.3 ([M+H]+)) and (R)-4-methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 177.4 ([M+H]+))
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 27 (RS)-4-Biphenyl-3-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00049
  • From (RS)-amino-biphenyl-3-yl-acetic acid. Off-white solid.
  • MS (ISP): 239.1 ([M+H]+)
    • Example 28 (RS)-4-Ethyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00050
  • From (RS)-2-amino-2-phenylbutyric acid. Off-white solid.
  • MS (ISP): 191.3 ([M+H]+)
    • Example 29 (S)-4-(3-Bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine and (R)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00051
    • a) (RS)-4-(3-Bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • A solution of lithium diisopropylamide in THF (2 M, 5.05 ml) was cooled to −55° C. and treated with (RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (667 mg, example 7) in THF (6 ml). The reaction mixture was stirred at −55° C. for 2 hrs, then treated dropwise with 1,2-dibromoethane (0.58 ml). The reaction mixture was warmed to r.t., then stirred overnight at r.t. It was quenched with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2→CH2Cl2/MeOH 95:5) to give (RS)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (61 mg) as light yellow solid.
  • MS (ISP): 279.1 ([M+H]+)
    • b) (S)-4-(3-Bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine and (R)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3-Bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (S)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 279.1 ([M+H]+)) and (R)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 279.1 ([M+H]+))
    • Example 30 (RS)-4-(4′-Fluoro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00052
  • To a stirred solution of (RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (80 mg; example 20) at r.t. in 1,2-dimethoxyethane (4 ml) under an argon atmosphere were added PdCl2(dppf) (24 mg), 10% aq. Na2CO3 (1 ml) and 4-fluorophenylboronic acid (186 mg). The mixture was heated to 85° C. and stirring at that temperature was continued for 18 h. The dark brown mixture was cooled to r.t., diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-4-(4′-fluoro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine (46 mg) as off-white solid. MS (ISP): 257.0 ([M+H]+)
    • Example 31 (RS)-4-(4′-Chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00053
  • In analogy to example 30, (RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine was reacted with 4-chlorophenylboronic acid to give (RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine. Off-white solid. MS (ISP): 273.1 ([M+H]+)
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 32 (RS)-4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00054
  • From (RS)-amino-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetic acid. Off-white solid.
  • MS (ISP): 221.1 ([M+H]+)
    • Example 33 (RS)-4-Naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00055
  • From (RS)-amino-naphtalen-2-yl-acetic acid. Light yellow solid.
  • MS (ISP): 213.1 ([M+H]30 )
    • Example 34 (RS)-4-Naphthalen-1-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00056
  • From (RS)-amino-naphtalen-1-yl-acetic acid. Light yellow solid.
  • MS (ISP): 213.1 ([M+H]+)
    • Example 35 (RS)-4-(4-Methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00057
  • From (RS)-amino-(4-methoxy-3-methylphenyl)-acetic acid. Off-white solid.
  • MS (ISP): 207.1 ([M+H]+)
    • Example 36 (RS)-4-(3-Chloro-4-methoxyphenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00058
  • From (RS)-amino-(3-chloro-4-methoxyphenyl) acetic acid. Off-white solid.
  • MS (ISP): 227.3 ([M+H]+)
    • Example 37 (S)-4-(2,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine and (R)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00059
  • (RS)-4-(2,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 7) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (S)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (light yellow solid; MS (ISP): 199.1 ([M+H]+)) and (R)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 199.1 ([M+H]+))
    • Example 38 (S)-4-(2,4-Difluoro-3-[3H]-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00060
  • A solution of (S)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (3.5 mg; example 29.b) in EtOAc (1 ml) was treated with 1.2 mg of 10% palladium on charcoal (1.2 mg) and triethylamine (20 μml) was stirred for 1 h at room temperature under tritium gas. The volatiles were removed by vacuum transfer and 5 ml of ethanol/water 9:1 were added in three portions to the reaction flask. After brief stirring the volatiles were removed by vacuum transfer.
  • The reaction flask was removed from the tritiation apparatus and the residue was suspended in ethanol. The suspension was filtered through a 0.45 μm PTFE filter cartouche (Ø=13 mm) and the filter was rinsed 5× with ethanol, the filtrate was evaporated to about 0.5 ml and then partitioned between dichloromethane and water plus 10% sodium carbonate. After a second extraction with dichloromethane the organic phase was dried over potassium carbonate. Filtration, evaporation, dissolution in toluene and evaporation to remove residual triethylamine furnished the crude product, which was dissolved in 50 ml of ethanol. The total activity was 229 mCi. Half of the crude product was purified by HPLC (column: XTerra RP-18 5 μm 10×150 mm; mobile phase: A/B=65:35; A: 100 mM ammonium-carbonate pH=10+5% acetonitrile; B: acetonitrile; flow rate: 5 ml/min; UV: 220 nm). The HPLC-eluate was evaporated to about half of its volume and then partitioned between dichloromethane and water plus 10% sodium carbonate as described above. Finally the purified product was dissolved in 25 ml of ethanol. The total activity was 98.29 mCi and the radiochemical purity was 100% and 98% according to radio-HPLC and radio-TLC respectively. The specific activity was 17.5 Ci/mole according to mass spectrometry. The enantiomeric purity was over 99% according to HPLC (column: Chiralpak AD 10 μm 4.6×250 mm; mobile phase: 10% ethanol in n-heptane; flow rate: 1 ml/min; UV: 220 nm).
    • Example 39 (S)-4-o-Tolyl-4,5-dihydro-oxazol-2-ylamine and (R)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00061
  • (RS)-4-o-Tolyl-4,5-dihydro-oxazol-2-ylamine (example 8) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (S)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine (light yellow solid; MS (ISP): 177.1 ([M+H]+)) and (R)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine (light yellow solid; MS (ISP): 177.1 ([M+H]+))
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 40 (RS)-4-(2,3,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00062
  • From 2,4,5-trifluoro-DL-phenylglycine. White solid.
  • MS (ISP): 217.3 ([M+H]+)
    • Example 41 (RS)-4-(2-Amino-4,5-dihydro-oxazol-4-yl)-benzoic acid methyl ester
  • Figure US20100120864A1-20100513-C00063
  • From (RS)-4-(amino-methoxycarbonyl-methyl)-benzoic acid methyl ester. White solid.
  • MS (ISP): 221.13 ([M+H]+)
    • Example 42 (RS)-4-Thiophen-2-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00064
  • From DL-α-aminothiophene-2-acetic acid methyl ester hydrochloride. Off-white solid.
  • MS (ISP): 169.1 ([M+H]+)
    • Example 43 (RS)-(4-(5-Chloro-thiophen-2-yl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00065
  • From (RS)-amino-(5-chloro-thiophen-2-yl)-acetic acid methyl ester hydrochloride. Off-white solid. MS (ISP): 203.3 ([M+H]+)
    • Example 44 (RS)-4-Pyridin-3-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00066
  • From (RS)-3-pyridyl-aminoacetic acid hydrochloride. Light yellow solid. In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 45 (R)-4-Naphthalen-2-ylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00067
  • From (R)-2-amino-3-naphthalen-2-yl-propionic acid. Light yellow viscous oil.
  • MS (ISP): 227.4 ([M+H]+)
    • Example 46 (R)-4-Naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00068
  • From (R)-2-amino-3-naphthalen-1-yl-propionic acid. Light yellow viscous oil.
  • MS (ISP): 227.4 ([M+H]+)
    • Example 47 (R)-4-Benzyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00069
  • From D-phenylalanine. Light yellow solid.
  • MS (ISP): 177.1 ([M+H]+)
    • Example 48 (S)-4-Naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00070
  • From (S)-2-amino-3-naphthalen-1-yl-propionic acid. Off-white solid.
  • MS (ISP): 227.4 ([M+H]+)
    • Example 49 (S)-4-Naphthalen-2-ylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00071
  • From (S)-2-amino-3-naphthalen-2-yl-propionic acid. Light yellow amorphous solid.
  • MS (ISP): 227.1 ([M+H]+)
    • Example 50 (RS)-4-Benzyl-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00072
  • From α-methyl-DL-phenylalanine. Colorless viscous oil.
  • MS (ISP): 191.1 ([M+H]+)
    • Example 51 (S)-4-(4-Chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00073
  • From L-4-chlorophenylalanine. Light yellow viscous oil.
  • MS (ISP): 211.1 ([M+H]+)
    • Example 52 (S)-4-(4-Methoxy-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00074
  • From L-4-methoxyphenylalanine. Off-white solid.
  • MS (ISP): 207.1 ([M+H]+)
    • Example 53 (S)-4-(4-Benzyloxy-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00075
  • From L-4-benzyloxyphenylalanine. Off-white solid.
  • MS (ISP): 283.3 ([M+H]+)
    • Example 54 (S)-4-(3-Fluoro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00076
  • From L-3-fluorophenylalanine. Light yellow amorphous solid.
  • MS (ISP): 195.1 ([M+H]+)
    • Example 55 (S)-4-(2-Fluoro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00077
  • From L-2-fluorophenylalanine. Light yellow amorphous solid.
  • MS (ISP): 195.1 ([M+H]+)
    • Example 56 (S)-4-(2-Trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00078
  • From L-2-trifluoromethylphenylalanine. Light yellow solid.
  • MS (ISP): 245.1 ([M+H]+)
    • Example 57 (S)-4-Benzo[1,3]dioxol-5-ylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00079
  • From (S)-2-amino-3-benzo[1,3]dioxol-5-yl-propionic acid. Light yellow amorphous solid. MS (ISP): 221.3 ([M+H]+)
    • Example 58 (S)-4-(3-Methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00080
  • From L-3-methylphenylalanine. Yellow amorphous solid.
  • MS (ISP): 191.4 ([M+H]+)
    • Example 59 (S)-4-(4-Methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00081
  • From L-4-methylphenylalanine. Light yellow solid.
  • MS (ISP): 191.4 ([M+H]+)
    • Example 60 (S)-4-(2-Chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00082
  • From L-2-chlorophenylalanine. Light yellow oil.
  • MS (ISP): 211.1 ([M+H]+)
    • Example 61 (S)-4-(3-Chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00083
  • From L-3-chlorophenylalanine. Light yellow oil.
  • MS (ISP): 210.9 ([M+H]+)
    • Example 62 (S)-4-(2-Methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00084
  • From L-2-methylphenylalanine. Yellow oil.
  • MS (ISP): 191.4 ([M+H]+)
    • Example 63 (S)-4-(3-Trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00085
  • From L-3-trifluoromethylphenylalanine. Yellow oil.
  • MS (ISP): 245.3 ([M+H]+)
    • Example 64 (S)-4-(4-Trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00086
  • From L-4-trifluoromethylphenylalanine. Yellow oil.
  • MS (ISP): 245.3 ([M+H]+)
    • Example 65 (S)-4-(4-Fluoro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00087
  • From L-4-fluorophenylalanine. Yellow oil. MS (ISP): 195.1 ([M+H]+)
    • Example 66 (RS)-4-(2,6-Dimethyl-benzyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00088
  • From (RS)-2-amino-3-(2,6-dimethyl-phenyl)-2-methyl-propionic acid hydrochloride. White solid.
  • MS (ISP): 219.4 ([M+H]+)
    • Example 67 (S)-4-(4-tert-Butoxy-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00089
  • From L-4-tert-butoxyphenylalanine. Light yellow solid.
  • MS (ISP): 249.4 ([M+H]+)
    • Example 68 4-(1-Phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00090
  • From 2-amino-3-phenylbutanoic acid hydrochloride. Off-white solid.
  • MS (ISP): 191.4 ([M+H]+)
    • Example 69 (RS)-4-(2-Chloro-6-fluoro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00091
  • From DL-2-chloro-6-fluorophenylalanine. Off-white solid.
  • MS (ISP): 229.4 ([M+H]+)
    • Example 70 (S)-4-(3,4-Difluoro-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00092
  • From L-3,4-difluorophenylalanine. Off-white solid.
  • MS (ISP): 213.1 ([M+H]+)
    • Example 71 (S)-4-(3,4-Dimethoxy-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00093
  • From L-3,4-dimethoxyphenylalanine. Light yellow gum.
  • MS (ISP): 237.1 ([M+H]+)
    • Example 72 (RS)-4-(2-Phenoxy-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00094
  • From DL-2-phenoxyphenylalanine. Colorless oil.
  • MS (ISP): 269.4 ([M+H]+)
    • Example 73 (RS)-4-(2-Fluoro-5-methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00095
  • From DL-2-fluoro-5-methylphenylalanine. Light yellow viscous oil.
  • MS (ISP): 209.1 ([M+H]+)
    • Example 74 (RS)-4-(2,6-Difluoro-3-methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00096
  • From DL-2,6-difluoro-3-methylphenylalanine. Off-white solid.
  • MS (ISP): 227.1 ([M+H]+)
    • Example 75 (RS)-4-(2-Fluoro-6-trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00097
  • From DL-2-fluoro-6-trifluoromethylphenylalanine. Light yellow viscous oil.
  • MS (ISP): 263.0 ([M+H]+)
    • Example 76 (RS)-4-(2,6-Dimethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00098
  • From DL-2,6-dimethylphenylalanine. White solid.
  • MS (ISP): 205.1 ([M+H]+)
    • Example 77 (RS)-4-(2,6-Diethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00099
  • From DL-2,6-diethylphenylalanine. Off-white amorphous solid.
  • MS (ISP): 233.3 ([M+H]+)
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 78 (RS)-4-Methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00100
  • From (RS)-2-amino-2-methyl-4-phenyl-butyric acid. Off-white solid.
  • MS (ISP): 205.1 ([M+H]+)
    • Example 79 (S)-4-(2-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00101
    • a) (S)-2,2-dimethyl-4-((E)-2-phenyl-propenyl)-oxazolidine-3-carboxylic acid tert-butyl ester
  • A solution of diethyl 1-phenylethyl phosphonate (2.35 ml) in 1,2-dimethoxyethane (15 ml) was cooled under an argon atmosphere to 0° C. and treated dropwise with an n-butyllithium solution (5.9 ml; 1.6 M in hexane). The reaction mixture was stirred for 5 min at 0° C., then treated dropwise with a solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.5 g) in 1,2-dimethoxyethane (15 ml). The solution was warmed to r.t., then refluxed overnight. After cooling to r.t., the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was isolated by column chromatography (SiO2; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give (S)-2,2-dimethyl-4-((E)-2-phenyl-propenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (720 mg) as light yellow viscous oil.
  • MS (ISP): 318.3 ([M+H]+)
    • b) (S)-2-amino-4-phenyl-pentan-1-ol
  • A solution of (S)-2,2-dimethyl-4-((E)-2-phenyl-propenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (700 mg) in EtOH (30 ml) and CHCl3 (15 ml) was treated with 10% Pd/C (200 mg) and hydrogenated with a balloon overnight. The catalyst was filtered off, washed with EtOH and concentrated. The residue was dissolved in EtOH (10 ml) and treated with 2N HCl (15 ml). The mixture was heated for 90 min to 100° C., then concentrated. The residue was taken up in 1N NaOH and extracted with CH2Cl2/MeOH 4:1. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (S)-2-amino-4-phenyl-pentan-1-ol (342 mg) as off-white waxy solid.
  • MS (ISP): 180.3 ([M+H]+))
    • c) (S)-4-(2-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-4-phenyl-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-(2-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine. Off-white waxy solid.
  • MS (ISP): 205.1 ([M+H]+))
    • Example 80 (S)-4-Phenethyl-4,5-dihydro-oxazol-2-ylamine and (R)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00102
  • (RS)-4-Phenethyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (S)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 191.3 ([M+H]+)) and (R)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 191.3 ([M+H]+))
    • Example 81 (S)-4-Methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine and (R)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00103
  • (RS)-4-Methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine (example 75) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (S)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 205.3 ([M+H]+)) and (R)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 205.1 ([M+H]+))
    • Example 82 (S)-4-((R)-2-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine and (S)-4-((S)-2-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00104
  • (S)-4-(2-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine (example 79.c) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (S)-4-((R)-2-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 205.1 ([M+H]+)) and (R)-4-((S)-2-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 205.3 ([M+H]+))
    • Example 83 (R)-4-[2-(4-Fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00105
    • a) (S)-4-(Benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred, cooled (0° C.) solution of (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g; CAS 108149-65-1), 2-mercaptobenzothiazole (1.48 g) and triphenylphosphine (2.32 g) in THF (80 ml) under an argon atmosphere was added diethyl azodicarboxylate (4.1 ml; 40% solution in toluene). The mixture (soon turning to a yellow suspension, slowly warming up to r.t.) was stirred for 18 h overnight, then diluted with EtOAc and washed with sat. aq. Na2CO3. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane→cyclohexane/EtOAc 85:15) to give (S)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.0 g) as light yellow viscous oil.
    • b) (S)-4-(Benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of (S)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.0 g) at 0° C. in dichloromethane (80 ml) under an argon atmosphere was added 3-chloroperbenzoic acid (2.29 g) in one portion. The mixture (slowly warming up to r.t.) was stirred overnight. The mixture was washed with 10% aq. sodium bisulfite (80 ml), sat. aq. Na2CO3 and brine, dried over MgSO4, filtered and concentrated. The crude product was isolated by column chromatography (SiO2; gradient: cyclohexane→cyclohexane/EtOAc 3:2) to give (S)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.64 g) as white solid. MS (ISP): 413.3 ([M+H]+))
    • c) ((R)-4-[(E)-2-(4-Fluoro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred, cooled (−78° C.) solution of (S)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.484 mg) in THF (12 ml) under an argon atmosphere was added slowly a 1 M solution of LiHMDS in THF (1.1 ml). The mixture was warmed to −40° C. and stirring at that temperature was continued for 30 min. The mixture was cooled again to −78° C. and a solution of 4-fluorobenzaldehyde (0.112 g) in THF (3 ml) was then added slowly via a syringe. Stirring at −78° C. was continued for 2 h, and then the reaction mixture was slowly allowed to warm to 0° C. The mixture was quenched by the addition of sat. aq. NH4Cl (15 ml) and H2O (15 ml) and extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane→cyclohexane/EtOAc 85:15) to give (R)-4-[(E)-2-(4-fluoro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.201 g) as colorless viscous oil. MS (ISP): 322.4 ([M+H]+))
    • d) (R)-4-[2-(4-Fluoro-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of (R)-4-[(E)-2-(4-fluoro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.205 g) at r.t. in ethanol (5 ml) under an argon atmosphere was added 10% Pd/C (20 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 3 hrs. The catalyst was filtered off and the filtrate was concentrated to give (R)-4-[2-(4-fluoro-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.195 g) as light brown viscous oil. MS (ISP): 324.5 ([M+H]+))
    • e) (R)-2-Amino-4-(4-fluoro-phenyl)-butan-1-ol
  • To a stirred solution of (R)-4-[2-(4-fluoro-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (190 mg) at r.t. in dioxane (3.5 ml) under an argon atmosphere was added 4 M HCl solution in dioxane (1.47 ml). The mixture was stirred for 16 h. The mixture was concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (R)-2-amino-4-(4-fluoro-phenyl)-butan-1-ol (78 mg) as off-white solid. MS (ISP): 184.1 ([M+H]+))
    • f) (R)-4-[2-(4-Fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (R)-2-amino-4-(4-fluoro-phenyl)-butan-1-ol was reacted with cyanogen bromide to give (R)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 209.3 ([M+H]+))
  • In analogy to example 1 and starting from the respective amino acid or amino acid derivative was prepared:
    • Example 84 (RS)-4-(1,2,3,4-Tetrahydro-naphthalen-2-yl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00106
  • From (RS)-amino-(1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic acid. Off-white solid.
  • MS (ISP): 217.3 ([M+H]+)
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 85 (S)-4-[2-(4-Fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00107
  • From 4-fluorobenzaldehyde. White solid. MS (ISP): 209.3 ([M+H]+)
    • Example 86 (S)-4-[2-(4-Fluoro-3-methoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00108
  • From 4-fluoro-3-methoxybenzaldehyde. Off-white solid. MS (ISP): 239.3 ([M+H]+)
    • Example 87 (R)-4-Phenoxymethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00109
    • a) (R)-2,2-Dimethyl-4-phenoxymethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate (400 mg; CAS 108149-63-9) in THF (20 ml) were added phenol (197 mg), triphenylphosphine (573 mg) and di-tert-butyl azodicarboxylate (488 mg). The resulting yellow solution was stirred at 70° C. for 18 h overnight, then concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→70:30) to give (R)-2,2-dimethyl-4-phenoxymethyl-oxazolidine-3-carboxylic acid tert-butyl ester (336 mg, 63%) as a colourless viscous oil. MS (ISP): 308.3 ([M+H]+)).
    • b) (S)-2-Amino -3-phenoxy-prop an-1-ol
  • To a stirred solution of (R)-2,2-dimethyl-4-phenoxymethyl-oxazolidine-3-carboxylic acid tert-butyl ester (300 mg) at r.t. in dioxane (5 ml) under an argon atmosphere was added 4 M HCl solution in dioxane (2.44 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was resuspended in saturated aq sodium carbonate solution and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-phenoxy-propan-1-ol (108 mg, 66%) as a white solid. MS (ISP): 168.3 ([M+H]+)).
    • c) (R)-4-Phenoxymethyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-3-phenoxy-propan-1-ol was reacted with cyanogen bromide to give (R)-4-phenoxymethyl-4,5-dihydro-oxazol-2-ylamine. Colourless gum. MS (ISP): 193.1 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 88 ((S)-4-[2-(2,4-Difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00110
  • From 2,4-difluoro-benzaldehyde. Off-white solid. MS (ISP): 227.1 ([M+H]+)
    • Example 89 (S)-4-[2-(3,4-Difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00111
  • From 3,4-difluoro-benzaldehyde. Off-white solid. MS (ISP): 227.1 ([M+H]+)
    • Example 90 (R)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00112
  • (RS)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 14) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (R)-4-(3,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid. MS (ISP): 231.1 ([M+H]+))
    • Example 91 (S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00113
  • (RS)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 14) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (S)-4-(3,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid. MS (ISP): 231.1 ([M+H]+))
    • Example 92 (RS)-4-(3-Cyclohexylamino-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00114
    • a) (RS)-tert-Butoxycarbonylamino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester
  • A solution of (3-amino-phenyl)-tert-butoxycarbonylamino-acetic acid methyl ester (165 mg, CAS 180081-34-9) in MeOH (5 ml) was treated under an argon atmosphere with cyclohexanone (0.07 ml), zinc chloride (321 mg) and NaBH3CN (111 mg) and stirred overnight at 40° C. The MeOH was distilled off. The residue was taken up in EtOAc and H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with water, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 14:1) to give (RS)-tert-butoxycarbonylamino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (200 mg, 94%) as viscous colorless oil.
  • MS (ISP): 363.4 ([M+H]+)
    • b) (RS)-Amino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester
  • A solution of (RS)-tert-butoxycarbonylamino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (200 mg) in dioxane (5 ml) was treated with 4M HCl in dioxane (2.76 ml) and stirred at r.t. overnight, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-amino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (126 mg, 87%) as light yellow viscous oil.
  • MS (ISP): 263.0 ([M+H]+))
    • c) (RS)-2-Amino-2-(3-cyclohexylamino-phenyl)-ethanol
  • A solution of (RS)-amino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (120 mg) in THF (1 ml) was treated under an argon atmosphere with lithium chloride (78 mg), sodium borohydride (68 mg) and EtOH (1.8 ml) and stirred at r.t. overnight. The mixture was filtrated. The residue was washed with EtOH. The filtrate was concentrated. The residue was taken up in CH2Cl2. The solids were removed by filtration. The filtrate was concentrated. The crude product was isolated by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-2-amino-2-(3-cyclohexylamino-phenyl)-ethanol (87 mg, 65%) as colorless viscous oil.
  • MS (ISP): 235.3 ([M+H]+))
    • d) (RS)-4-(3-Cyclohexylamino-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1.b (RS)-2-amino-2-(3-cyclohexylamino-phenyl)-ethanol was converted to the title compound. Colorless viscous oil.
  • MS (ISP): 235.3 ([M+H]+))
    • Example 93 (R)-4-[2-(3,5-Difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00115
  • In analogy to example 83, the title compound was prepared starting from (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 3,5-difluorobenzaldehyde. Off-white solid. MS (ISP): 227.4 ([M+H]+)
    • Example 94 (RS)-4-[3-(Tetrahydro-pyran-4-yloxy)-phenyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00116
    • a) (RS)-(tert-Butoxycarbonylamino-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid methyl ester
  • A solution of (RS)-tert-butoxycarbonylamino-(3-hydroxy-phenyl)-acetic acid methyl ester (CAS 526217-60-7) in THF (10 ml) was treated under an argon atmosphere with tetrahydro-pyran-4-ol (0.24 ml), triphenylphosphine (649 mg) and di-tert-butyl azodicarboxylate (570 mg) and stirred at r.t. overnight. The reaction mixture was concentrated. The crude product was purified by column chromatography (silical gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give (RS)-tert-butoxycarbonylamino-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid methyl ester (884 mg, 82%) as viscous light yellow oil.
  • MS (ISP): 366.3 ([M+H]+)
    • b) (RS)-4-[3-(Tetrahydro-pyran-4-yloxy)-phenyl]-4,5-dihydro-oxazol-2-ylamine
  • In analogy to examples 92.b, 1.a and 92.d, (RS)-tert-butoxycarbonylamino-[3-(tetrahydro-pyran-4-yloxy)-phenyl[-acetic acid methyl ester was converted to the title compound. Light yellow solid.
  • MS (ISP): 263.0 ([M+H]+))
  • In analogy to example 87 were prepared:
    • Example 95 (R)-4-(4-Chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00117
  • From tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-chlorophenol. White solid.
  • MS (ISP): 229.2 ([{37Cl}M+H]+), 227.2 ([{35Cl}M+H]+).
    • Example 96 (R)-4-(4-Trifluoromethyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00118
  • From tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-(trifluoromethyl)-phenol. White solid.
  • MS (ISP): 261.0 ([M+H]+).
    • Example 97 (R)-4-(4-Fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00119
  • From tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-fluorophenol. White solid.
  • MS (ISP): 211.1 ([M+H]+).
    • Example 98 (R)-4-(4-Bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00120
  • From tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-bromophenol. White solid.
  • MS (ISP): 273.0 ([{81Br}M+H]+), 271.0 ([{79Br}M+H]+).
    • Example 99 (RS)-4-[4-(2-Methoxy-ethoxy)-phenyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00121
    • a) (RS)-tert-Butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid methyl ester
  • A solution of (RS)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid methyl ester (500 mg, CAS 143323-49-3) in DMF (4 ml) was treated under an argon atmosphere with 2-bromoethyl methyl ether (0.34 ml), cesium carbonate (695 mg) and tetrabutylammonium iodide (66 mg) and stirred at r.t. overnight. Then it was quenched with H2O and extracted with EtOAc. The organics were washed with water, dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 4:1) to give (RS)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid methyl ester (434 mg, 72%) as viscous colorless oil.
  • MS (ISP): 340.4 ([M+H]+)
    • b) (RS)-4-[4-(2-Methoxy-ethoxy)-phenyl]-4,5-dihydro-oxazol-2-ylamine
  • In analogy to examples 92.b, 1.a and 92.d, (RS)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid methyl ester was converted to the title compound. White solid.
  • MS (ISP): 237.1 ([M+H]+))
    • Example 100 (R)-4-(2,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00122
  • (RS)-4-(2,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 16) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to give (R)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Light yellow solid.
  • MS (ISP): 199.1 ([M+H]+))
    • Example 101 (S)-4-(2,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00123
  • (RS)-4-(2,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 16) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to give (S)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Light yellow solid.
  • MS (ISP): 199.1 ([M+H]+))
    • Example 102 (R)-4-Naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00124
  • (RS)-4-Naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine (example 33) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (R)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid. MS (ISP): 213.3 ([M+H]+))
    • Example 103 (S)-4-Naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00125
  • (RS)-4-Naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine (example 33) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (S)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid. MS (ISP): 213.3 ([M+H]+))
    • Example 104 (R)-4-(4-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00126
  • (RS)-4-(4-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 20) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (R)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid. MS (ISP): 241.1 ([M+H]+))
    • Example 105 (S)-4-(4-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00127
  • (RS)-4-(4-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 20) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (S)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 241.1 ([M+H]+))
    • Example 106 (R)-4-(2,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00128
    • a) (RS)-4-(2,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 2,4,5-trifluoro-DL-phenylglycine. Off-white solid.
  • MS (ISP): 217.1 ([M+H]+)
    • b) ((R)-4-(2,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 20) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=10:90) to give (R)-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 217.1 ([M+H]+))
    • Example 107 (S)-4-(2,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00129
  • (RS)-4-(2,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 106) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=10:90) to give (S)-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 217.4 ([M+H]+))
    • Example 108 (R)-4-(3-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00130
  • (RS)-4-(3-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 18) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=1:9) to give (R)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 215.3 ([M+H]+))
    • Example 109 (S)-4-(3-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00131
  • (RS)-4-(3-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 18) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=1:9) to give (S)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 215.1 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 110 (S)-4-[2-(2-Trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00132
  • From 2-trifluoromethylbenzaldehyde. White solid. MS (ISP): 259.0 ([M+H]+)
    • Example 111 (S)-4-[2-(2-Fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00133
  • From 2-fluorobenzaldehyde. White solid. MS (ISP): 209.3 ([M+H]+)
    • Example 112 (S)-4-[2-(3-Fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00134
  • From 3-fluorobenzaldehyde. White solid. MS (ISP): 209.1 ([M+H]+)
    • Example 113 (S)-4-[2-(3,5-Difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00135
  • From 3,5-difluorobenzaldehyde. White solid. MS (ISP): 227.1 ([M+H]+)
    • Example 114 (S)-4-(2-o-Tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00136
  • From o-tolylaldehyde. Off-white solid. MS (ISP): 205.3 ([M+H]+)
    • Example 115 (S)-4-(2-m-Tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00137
  • From m-tolylaldehyde. Off-white solid. MS (ISP): 205.3 ([M+H]+)
    • Example 116 (S)-4-(2-p-Tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00138
  • From p-tolylaldehyde. Off-white solid. MS (ISP): 205.3 ([M+H]+)
    • Example 117 (R)-4-(2,3,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00139
  • (RS)-4-(2,3,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 40) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=10:90) to give (R)-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 217.4 ([M+H]+))
    • Example 118 (S)-4-(2,3,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00140
  • (RS)-4-(2,3,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 40) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=10:90) to give (S)-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 217.4 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 119 (S)-4-[2-(4-Trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00141
  • From 4-trifluoromethylbenzaldehyde. Off-white solid. MS (ISP): 259.1 ([M+H]+)
    • Example 120 (S)-4-[2-(3-Trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00142
  • From 3-trifluoromethylbenzaldehyde. White solid. MS (ISP): 259.1 ([M+H]+)
    • Example 121 (R)-4-(2-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00143
  • (RS)-4-(2-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 40) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=5:95) to give (R)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 231.4 ([M+H]+))
    • Example 122 (S)-4-(2-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00144
  • (RS)-4-(2-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 40) was separated by chiral HPLC (Chiralpak AD, isopropanol/heptane=5:95) to give (S)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 231.4 ([M+H]+))
  • In analogy to example 87 was prepared:
    • Example 123 (R)-4-p-Tolyloxymethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00145
  • From tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-methylphenol. White solid.
  • MS (ISP): 207.1 ([M+H]+).
  • In analogy to example 83, starting from the respective benzaldehyde was prepared:
    • Example 124 (R)-4-[2-(3,4-Dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00146
  • From 3,4-dichlorobenzaldehyde. Colorless gum. MS (ISP): 259.0 ([M+H]+) In analogy to example 1 and starting from the respective amino acid were prepared:
    • Example 125 (S)-4-Biphenyl-4-ylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00147
  • From (S)-2-amino-3-phenyl-propionic acid. Off-white solid. MS (ISP): 253.1 ([M+H]+)
    • Example 126 (S)-4-(4-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00148
    • a) ((RS)-4-(4-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 2-(4-fluorophenyl)alanine. White solid.
  • MS (ISP): 195.3 ([M+H]+)
    • b) (S)-4-(4-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(4-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 2:8) to give (S)-4-(4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 195.3 ([M+H]+))
  • In analogy to example 83 and starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and the respective benzaldehyde was prepared:
    • Example 127 (S)-4-[2-(3,4-Dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00149
  • From 3,4-dichlorobenzaldehyde. Viscous colorless oil. MS (ISP): 259.0 ([M+H]+)
    • Example 128 (R)-4-(4-Methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00150
  • (RS)-4-(4-Methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 35) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (R)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 206.9 ([M+H]+))
    • Example 129 (S)-4-(4-Methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00151
  • (RS)-4-(4-Methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 35) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (S)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 207.1 ([M+H]+))
    • Example 130 (R)-4-(3-Chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00152
  • (RS)-4-(3-Chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 36) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (R)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 227.1 ([M+H]+))
    • Example 131 (S)-4-(3-Chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00153
  • (RS)-4-(3-Chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 36) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to give (S)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 227.1 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 132 (S)-4-[2-(4-Chloro-2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00154
  • From 4-chloro-2-fluorobenzaldehyde. White solid. MS (ISP): 243.3 ([M+H]+)
    • Example 133 (S)-4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00155
  • From 4-fluoro-3-trifluoromethyl-benzaldehyde. Off-white solid. MS (ISP): 277.0 ([M+H]+)
    • Example 134 (R)-4-(3,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00156
    • a) (RS)-2-Amino-2-(3,4-dichloro-phenyl)-propionic acid hydrochloride
  • A solution of 5-(3,4-dichloro-phenyl)-5-methyl-imidazolidine-2,4-dione (3.0 g; CAS 52715-57-8) in 3N NaOH (30 ml) was refluxed overnight. The reaction mixture was cooled to 0°, then brought to pH 1 by dropwise addition of concentrated HCl. The resulting white slurry was filtered. The solid was washed extensively with H2O, dried in the vacuum, resuspended in EtOH (25 ml), collected by filtration, washed with EtOH and diethylether and dried in the vacuum to give (RS)-2-amino-2-(3,4-dichloro-phenyl)-propionic acid hydrochloride (1.35 g, 27%) as off white solid.
  • MS (ISP): 266.9 ([M+Na]+)
    • b) (RS)-4-(3,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1 (RS)-2-amino-2-(3,4-dichloro-phenyl)-propionic acid hydrochloride was converted to the title compound. Off-white solid.
  • MS (ISP): 244.9 ([M+H]+))
    • c) (R)-4-(3,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • ((RS)-4-(3,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to give (R)-4-(3,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 245.3 ([M+H]+))
    • Example 135
  • Figure US20100120864A1-20100513-C00157
    • (S)-4-(3,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • ((RS)-4-(3,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to give (S)-4-(3,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 245.3 ([M+H]+))
    • Example 136 (S)-4-(4-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00158
  • In analogy to example 126 (RS)-2-amino-2-(4-chloro-phenyl)-propionic acid was converted to (RS)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine which was subsequently separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. Off-white solid.
  • MS (ISP): 211.1 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 137 (S)-4-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00159
  • From 3-fluoro-4-trifluoromethyl-benzaldehyde. Off-white solid. MS (ISP): 277.0 ([M+H]+)
    • Example 138 (S)-4-[2-(3,5-Dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00160
  • From 3,5-dichloro-benzaldehyde. Light yellow solid. MS (ISP): 259.0 ([M+H]+)
    • Example 139 (S)-4-[2-(2-Chloro-4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00161
  • From 2-chloro-4-fluoro-benzaldehyde. Off-white solid. MS (ISP): 243.3 ([M+H]+)
    • Example 140 (S)-4-[2-(4-Fluoro-3-methyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00162
  • From 4-fluoro-3-methyl-benzaldehyde. White solid. MS (ISP): 223.3 ([M+H]+)
    • Example 141 (S)-4-{2-[3-(1,1,2,2-Tetrafluoro-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00163
  • From 3-(1,1,2,2-tetrafluoro-ethoxy)-benzaldehyde. Colorless oil. MS (ISP): 307.0 ([M+H]+)
    • Example 142 (S)-4-[2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00164
  • From 2-fluoro-3-trifluoromethyl-benzaldehyde. Off-white solid. MS (ISP): 277.0 ([M+H]+)
    • Example 143 (S)-4-[2-(3-Bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00165
  • From 3-bromo-benzaldehyde. Off-white waxy solid. MS (ISP): 269.0 ([M+H]+)
    • Example 144 (S)-4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00166
  • From 4-chloro-3-trifluoromethyl-benzaldehyde. Colorless viscous oil. MS (ISP): 293.0 ([M+H]+)
    • Example 145 (S)-4-[2-(3-Fluoro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00167
  • From 3-fluoro-4-trifluoromethoxy-benzaldehyde. Off-white solid. MS (ISP): 293.0 ([M+H]+)
    • Example 146 (S)-4-[2-(4-Fluoro-3-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00168
  • From 4-fluoro-3-trifluoromethoxy-benzaldehyde. Viscous colorless oil. MS (ISP): 293.0 ([M+H]+)
    • Example 147 (S)-4-Methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00169
    • a) (RS)-(5-Methyl-5-(4-trifluoromethyl-phenyl)-imidazolidine-2,4-dione
  • A solution of 2-(trifluoremethyl)acetophenone (4.0 g) in EtOH/H2O 1:1 (60 ml) were treated under an argon atmosphere with ammoniumcarbonate (10.21 g) and NaCN (1.25 g). The reaction mixture was heated to 60° C. and stirred for 3 hours. It was cooled to 0° C. and the solution was brought to acidic pH by dropwise addition of 3N HCl (ca. 80 ml). Then, N2 was bubbled through the solution for 90 minutes to remove the remaining HCN.
  • EtOH and part of the water were removed by distillation. The remaining aqueous solution was extracted with EtOAc. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:7) to give 5-methyl-5-(4-trifluoromethyl-phenyl)-imidazolidine-2,4-dione (3.14 g, 57%) as off-white solid.
  • MS (ISP): 276.3 ([M+H]+)
    • b) (RS)-2-Amino-2-(4-trifluoromethyl-phenyl)-propionic acid
  • In analogy to example 134.a 5-methyl-5-(4-tri-fluoromethyl-phenyl)-imidazolidine-2,4-dione was converted to (RS)-2-amino-2-(4-trifluoromethyl-phenyl)-propionic acid.
  • MS (ISP): 234.1 ([M+H]+))
    • c) (RS)-4-Methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1 (RS)-2-amino-2-(4-trifluoromethyl-phenyl)-propionic acid was converted to the title compound. Off-white solid.
  • MS (ISP): 245.3 ([M+H]+))
    • c) (S)-4-Methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-Methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to give (S)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
  • (−)-Enantio-mer. Light yellow solid.
  • MS (ISP): 245.3 ([M+H]+))
    • Example 148 (R)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00170
  • (RS)-4-Methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 147) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to give (R)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 245.3 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 149 (S)-4-[2-(2,3-Dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00171
  • From 2,3-dichloro-benzaldehyde. Light yellow solid. MS (ISP): 259.0 ([M+H]+)
    • Example 150 (S)-4-[2-(3-Chloro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00172
  • From 3-chloro-4-trifluoromethoxy-benzaldehyde. Light yellow viscous oil. MS (ISP): 309.3 ([M+H]+)
    • Example 151 (S)-4-[2-(2-Chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00173
  • From 2-chloro-3-trifluoromethyl-benzaldehyde. Off-white solid. MS (ISP): 293.1 ([M+H]+)
    • Example 152 (R)-4-(3-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00174
    • a) (RS)-4-(3-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 2-(3-trifluoromethyl-phenyl)-DL-glycine. Off-white solid.
  • MS (ISP): 231.3 ([M+H]+)
    • b) (R)-4-(3-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (R)-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 231.4 ([M+H]+))
    • Example 153 (S)-4-(3-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00175
  • ((RS)-4-(3-Trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 231.1 ([M+H]+))
    • Example 154 (S)-4-(1-Methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00176
    • a) (R)-4-(1-Hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • A solution of (R)-4-acetyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.80 g, CAS 167102-63-8) in THF (40 ml) was cooled under an argon atmosphere to 0° C. and treated dropwise with benzylmagnesium chloride solution (1M in diethylether, 34.5 ml). The reaction mixture was stirred at r.t. overnight, then quenched with saturated aqueous NH4Cl (50 ml) and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:1) to give (R)-4-(1-hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.45 g, 89%) as off-white waxy solid.
  • MS (ISP): 336.4 ([M+H]+)
    • b) (S)-2-Amino-3-methyl-4-phenyl-butan-1-ol
  • A stirred solution of (R)-4-(1-hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.50 g) in THF (25 ml) was cooled under an argon atmosphere to −78° C. and treated dropwise with 1M lithium-bis-(trimethylsilyl)amide in THF (1.79 ml). The solution was allowed to warm to r.t.. Then, phenyl chlorothionoformate (0.3 ml) was added. After stirring at r.t. for 2 hrs, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to give crude (R)-2,2-dimethyl-4-(1-methyl-1-phenoxythiocarbonyloxy-2-phenyl-ethyl)-oxazoli-dine-3-carboxylic acid tert-butyl ester as pale yellow oil which was used in the next reaction step without further purification.
  • A solution of crude (R)-2,2-dimethyl-4-(1-methyl-1-phenoxythiocarbonyloxy-2-phenyl-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (700 mg) in toluene (5 ml) was treated under an argon atmosphere with 2,2′azobis(2-methylproponitrile) (122 mg) and tri-N-butyltin hydride (0.79 ml). The reaction mixture was refluxed for 30 min, then cooled to r.t. and then directly purified by column chromatography (silica gel, gradient: cyclohexane→cyclohexane/EtOAc 10:1) to give (S)-2,2-dimethyl-4-(1-methyl-2-phenyl-vinyl)-oxazo-lidine-3-carboxylic acid tert-butyl ester (279 mg, 59%) as light yellow waxy solid. MS (ISP): 318.3 ([M+H]+))
  • A solution of (S)-2,2-dimethyl-4-(1-methyl-2-phenyl-vinyl)-oxazolidine-3-carboxylic acid tert-butyl ester (250 mg) in 4M HCl in dioxane (2 ml) was stirred at r.t. overnight. The reaction mixture was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-methyl-4-phenyl-but-3-en-1-ol (122 mg, 87%) as light yellow oil. MS (ISP): 177.9 ([M+H]+))
  • A solution of (S)-2-amino-3-methyl-4-phenyl-but-3-en-1-ol (115 mg) in EtOH (5 ml) was hydrogenated at normal pressure (balloon) overnight in the presence of 10% Pd/C (10 mg). The reaction mixture was filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-methyl-4-phenyl-butan-1-ol (57 mg, 49%) as light yellow oil. MS (ISP): 180.3 ([M+H]+))
    • c) (S)-4-(1-Methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-3-methyl-4-phenyl-butan-1-ol was reacted with cyanogen bromide to give (S)-4-(1-methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine. Off-white amorphous solid.
  • MS (ISP): 205.1 ([M+H]+))
  • In analogy to example 83, starting from (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and using the respective benzaldehyde were prepared:
    • Example 155 (S)-4-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00177
  • From 3,5-bis-trifluoromethyl-benzaldehyde. Off-white solid. MS (ISP): 327.3 ([M+H]+)
    • Example 156 (S)-4-[2-(2-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00178
  • From 2-fluoro-5-trifluoromethyl-benzaldehyde. White solid. MS (ISP): 277.0 ([M+H]+)
    • Example 157 (S)-4-[2-(6-Trifluoromethyl-pyridin-3-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00179
  • From 6-(trifluoromethyl)pyridine-3-carboxaldehyde. Colorless gum. MS (ISP): 260.3 ([M+H]+)
    • Example 158 (S)-4-[2-(3-Fluoro-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00180
  • From 3-fluoro-isonicotinaldehyde. Light yellow solid. MS (ISP): 210.1 ([M+H]+)
    • Example 159 (S)-4-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00181
  • From 3-fluoro-5-trifluoromethyl-benzaldehyde. Colorless viscous oil. MS (ISP): 277.1 ([M+H]+)
    • Example 160 (S)-4-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00182
  • From 2,5-bis-trifluoromethyl-benzaldehyde. Colorless viscous oil. MS (ISP): 327.1 ([M+H]+)
    • Example 161 (S)-4-Methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00183
    • a) (RS)-4-Methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from DL-2-(4-methylphenyl)alanine. White solid.
  • MS (ISP): 191.3 ([M+H]+)
    • b) (S)-4-Methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-Methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 191.3 ([M+H]+))
    • Example 162 (S)-4-[2-(4-Chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00184
    • a) (S)-4-(2,2-Dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred, cooled (0° C.) solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.30 g; CAS 95715-87-0 and triphenylphosphine (9.15 g) in dichloromethane (100 ml) was added portionwise carbon tetrabromide (6.94 g). The mixture was stirred at 0° C. for 20 min and then at r.t. for 2 h. The mixture was concentrated in vacuo to ca 20 ml, then diluted with hexane (100 ml) and concentrated in vacuo to half-volume. The residue was stirred at 0° C. for 15 min, then the mixture was filtered and the filtrate was concentrated in vacuo to afford (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.18 g, 92%) as a colourless oil. MS (EI): 330.9 ([{81Br}M-C4H8]+), 328.9 ([{81Br79Br}M-C4H8]+), 326.9 ([{79Br}M-C4H8]+).
    • b) (S)-4-[(Z)-2-Bromo-2-(4-chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.6 g) in dioxane (48 ml) were added 4-chlorophenylboronic acid (1.75 g), tris(dibenzylideneacetone)dipalladium (0) (290 mg), tris(2-furyl)phosphine (326 mg) and aqueous sodium carbonate solution (18.7 ml, 1 M solution). The mixture was stirred at 50° C. for 90 min. The mixture was diluted with ethyl acetate and washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.77 g, 45%) as a light yellow oil. MS (ISP): 420.0 ([{37Cl81Br}M+H]+), 418.0 ([{37Cl79Br, 35Cl81Br}M+H]+), 416.0 ([{35Cl79Cl}M+H]+).
    • c) (S)-4-[(E)-2-(4-Chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of (S)-4-[(Z)-2-bromo-2-(4-chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.04 g) in THF (8 ml) were added bis(tri-tert-butylphosphine)dipalladium (0) (64 mg) and diethylzinc (4.99 ml, 1.1 M solution in toluene). The mixture was stirred at r.t. for 90 min then was diluted with ethyl acetate and washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[(E)-2-(4-chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (824 mg, 90%) as a colourless oil. MS (ISP): 368.5 ([{37Cl}M+H]+), 366.5 ([{35Cl}M+H]+).
    • d) (E)-(S)-2-Amino-4-(4-chloro-phenyl)-hex-3-en-1-ol
  • To a stirred solution of (S)-4-[(E)-2-(4-chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (820 mg) at r.t. in dioxane (8 ml) was added 4 M HCl solution in dioxane (11.2 ml). The mixture was stirred at 35° C. for 3.5 h. The mixture was then diluted with ethyl acetate and made basic by addition of 2 N aq sodium hydroxide solution. The phases were separated and the organic phase was washed with saturated brine, dried over sodium sulphate and concentrated in vacuo to give (E)-(S)-2-amino-4-(4-chloro-phenyl)-hex-3-en-1-ol (524 mg, quant.) as a yellow oil. MS (ISP): 228.2 ([{37Cl}M+H]+), 226.2 ([{35Cl}M+H]+).
    • e) (S)-2-Amino-4-(4-chloro-phenyl)-hexan-1-ol
  • To a stirred solution of (E)-(S)-2-amino-4-(4-chloro-phenyl)-hex-3-en-1-ol (0.52 g) at r.t. in ethanol (30 ml) under an argon atmosphere was added 5% Pt/C (180 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 16 hrs. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2-amino-4-(4-chloro-phenyl)-hexan-1-ol (mainly one epimer) (0.157 g, 30%) as colourless oil. MS (ISP): 230.3 ([{37Cl}M+H]+), 228.2 ([{35Cl}M+H]+).
    • f) (S)-4-[2-(4-Chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-4-(4-chloro-phenyl)-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). Colourless oil. MS (ISP): 255.2 ([{37Cl}M+H]+), 253.2 ([{35Cl}M+H]+).
    • Example 163 (S)-4-(2-Phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00185
    • a) (S)-4-((Z)-2-Bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • In analogy to example 162b (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with phenylboronic acid to give (S)-4-((Z)-2-bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Light yellow crystalline solid.
    • b) (S)-2,2-Dimethyl-4-((E)-2-phenyl-but-1-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester
  • In analogy to example 162c (S)-4-((Z)-2-bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with diethylzinc to give (S)-2,2-dimethyl-4-((E)-2-phenyl-but-1-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester. Colourless oil. MS (ISP): 332.3 ([M+H]+).
    • c) (E)-(S)-2-Amino-4-phenyl-hex-3-en-1-ol
  • In analogy to example 162d (S)-2,2-dimethyl-4-((E)-2-phenyl-but-1-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with hydrogen chloride to give (E)-(S)-2-amino-4-phenyl-hex-3-en-1-ol. Yellow crystalline solid.
    • d) (S)-2-Amino-4-phenyl-hexan-1-ol
  • To a stirred solution of (E)-(S)-2-amino-4-phenyl-hex-3-en-1-ol (1.0 g) at r.t. in methanol (50 ml) under an argon atmosphere was added 10% Pd/C (278 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 30 min. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: dichloromethane/methanol) to give (S)-2-amino-4-phenyl-hexan-1-ol (mainly one epimer) (0.81 g, 80%) as a colourless oil. MS (ISP): 194.4 ([M+H]+).
    • e) (S)-4-(2-Phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-4-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). White crystalline solid. MS (ISP): 219.4 ([M+H]+).
  • In analogy to example 163 were prepared:
    • Example 164 (R)-4-[2-(4-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00186
  • From (R)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-(trifluoromethyl)phenyl boronic acid and dimethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.3 ([M+H]+).
    • Example 165 (S)-4-[2-(4-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00187
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-(trifluoromethyl)phenyl boronic acid and dimethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.3 ([M+H]+).
    • Example 166 (S)-4-(3,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00188
    • a) (RS)-4-(3,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from DL-3,4-difluorophenylglycine. Off-white solid.
  • MS (ISP): 199.3 ([M+H]+)
    • b) (S)-4-(3,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3,4-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(3,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 199.1 ([M+H]+))
    • Example 167 (R)-4-(2,3-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00189
    • a) (RS)-4-(2,3-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from DL-amino-(2,3-dichloro-phenyl)-acetic acid. Light yellow solid.
  • MS (ISP): 231.1 ([M+H]+)
    • b) (R)-4-(2,3-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2,3-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (R)-4-(2,3-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 231.1 ([M+H]+))
    • Example 168 (S)-4-(2,3-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00190
  • (RS)-4-(2,3-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(2,3-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 231.3 ([M+H]+))
    • Example 169 (S)-4-(4-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00191
  • In analogy to example 1, the title compound was obtained from (S)-4-chlorophenyl glycine. Light yellow solid.
  • MS (ISP): 197.3 ([M+H]+)
    • Example 170 (S)-4-(3,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00192
    • a) (RS)-4-(3,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 3,4,5-trifluoro-DL-phenylglycine. Light yellow solid.
  • MS (ISP): 217.4 ([M+H]+)
    • b) (S)-4-(3,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3,4,5-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Colorless viscous oil.
  • MS (ISP): 217.3 ([M+H]+))
    • Example 171 (R)-4-(3-Chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00193
    • a) (RS)-4-(3-Chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 3-chloro-4-fluoro-DL-phenylglycine. Light yellow waxy solid.
  • MS (ISP): 215.1 ([M+H]+)
    • b) (R)-4-(3-Chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3-Chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (R)-4-(3-chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 215.4 ([M+H]+))
    • Example 172 (R)-4-(3-Chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00194
  • (RS)-4-(3-Chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(3-chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 215.1 ([M+H]+))
    • Example 173 (R)-4-(4-Chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00195
    • a) (RS)-4-(4-Chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 4-chloro-3-fluoro-DL-phenylglycine. Yellow waxy solid.
  • MS (ISP): 215.1 ([M+H]+)
    • b) (R)-4-(4-Chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(4-Chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (R)-4-(4-chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 215.1 ([M+H]+))
    • Example 174 (S)-4-(4-Chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00196
  • (RS)-4-(4-Chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(4-chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 215.3 ([M+H]+))
    • Example 175 (R)-4-(3,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00197
    • a) ((RS)-4-(3,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 3,5-difluoro-DL-phenylglycine. Yellow solid.
  • MS (ISP): 199.1 ([M+H]+)
    • b) (R)-4-(3,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (R)-4-(3,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Light yellow solid.
  • MS (ISP): 199.1 ([M+H]+))
    • Example 176 (S)-4-(3,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00198
  • (RS)-4-(3,5-Difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(3,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 199.3 ([M+H]+))
    • Example 177 (R)-4-(3-Chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00199
    • a) (RS)-4-(3-Chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1, the title compound was obtained from 3-chloro-5-fluoro-DL-phenylglycine. Waxy yellow solid.
  • MS (ISP): 215.3 ([M+H]+)
    • b) (R)-4-(3-Chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3-Chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (R)-4-(3-chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Light yellow solid.
  • MS (ISP): 215.3 ([M+H]+))
    • Example 178 (S)-4-(3-Chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00200
  • (RS)-4-(3-Chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:85) to give (S)-4-(3-chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Light yellow solid.
  • MS (ISP): 215.1 ([M+H]+))
    • Example 179 (R)-4-(2-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00201
    • a) (RS)-4-(2-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147, the title compound was obtained starting from 2′-chloro-acetophenone. White solid.
  • MS (ISP): 211.1 ([M+H]+)
    • b) (R)-4-(2-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (R)-4-(2-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 211.1 ([M+H]+))
    • Example 180 (S)-4-(2-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00202
  • (RS)-4-(2-Chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(2-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 211.1 ([M+H]+))
  • In analogy to example 165, except that the order of the hydrogenation and deprotection steps was reversed, was prepared:
    • Example 181 (S)-4-[2-(4-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00203
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-(trifluoromethyl)phenyl boronic acid and dimethylzinc. Mainly one epimer, which is different from the major epimer produced in example 165. Colourless amorphous solid. MS (ISP): 273.4 ([M+H]+).
  • In analogy to example 164, except that the order of the hydrogenation and deprotection steps was reversed, was prepared:
    • Example 182 (R)-4-[2-(4-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00204
  • From (R)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-(trifluoromethyl)phenyl boronic acid and dimethylzinc. Mainly one epimer, which is different from the major epimer produced in example 164. Colourless oil. MS (ISP): 273.1 ([M+H]+).
  • In analogy to example 184, except that the order of the hydrogenation and deprotection steps was reversed, was prepared:
    • Example 183 (S)-4-[2-(4-Trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00205
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-(trifluoromethyl)phenyl boronic acid and diethylzinc. Mainly one epimer, which is different from the major epimer produced in example 184. Colourless oil. MS (ISP): 287.1 ([M+H]+).
  • In analogy to example 163 was prepared:
    • Example 184 (S)-4-[2-(4-Trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00206
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-(trifluoromethyl)phenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 287.1 ([M+H]+).
    • Example 185 (RS)-4-(3-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00207
    • a) (RS)-2-Amino-2-(3-chloro-phenyl)-ethanol
  • To a stirred solution of lithium borohydride in THF (10.5 ml, 2 M solution) under an argon atmosphere was added dropwise chlorotrimethylsilane (5.34 ml). The resulting suspension was cooled to 0° C. and amino-(3-chlorophenyl)-acetic acid (2.0 g) was added portionwise. The ice bath was removed and stirring at r.t. was then continued for 16 h. The mixture was quenched by dropwise addition of methanol (15 ml) and then concentrated in vacuo. The residue was suspended in ethyl acetate and washed with 2 N aq NaOH. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo to afford (RS)-2-amino-2-(3-chloro-phenyl)-ethanol (1.84 g, quant.) as a yellow viscous oil. MS (ISP): 174.2 ([{37Cl}M+H]+), 172.2 ([{35Cl}M+H]+).
    • b) (RS)-4-(3-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1.b (RS)-2-amino-2-(3-chloro-phenyl)-ethanol was converted to (RS)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine by treatment with cyanogen bromide and potassium carbonate. White solid. MS (ISP): 199.0 ([{37Cl}M+H]+), 197.0 ([{35Cl}M+H]+). In analogy to example 185 and starting from the respective amino acid or amino acid derivative was prepared:
    • Example 186 (RS)-4-(3-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00208
  • From (RS)-2-amino-2-(3-bromophenyl)-acetic acid. White solid.
  • MS (ISP): 243.2 ([{81Br}M+H]+), 241.1 ([{79Br}M+H]+).
    • Example 187 (S)-4-(2,5-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00209
    • a) (RS)-4-(2,5-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147, the title compound was obtained starting from 2′,3′,6′-trifluoroacetophenone (one of the ortho fluorine atoms gets lost during the lithium aluminium hydride reduction). White solid.
  • MS (ISP): 213.3 ([M+H]+)
    • b) (S)-4-(2,5-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2,5-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 213.3 ([M+H]+)
  • In analogy to example 186 and starting from the respective amino acid or amino acid derivative were prepared:
    • Example 188 (RS)-4-(3-Fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00210
  • From (RS)-2-amino-2-(3-fluorophenyl)-acetic acid. White solid.
  • MS (ISP): 181.1 ([M+H]+).
    • Example 189 (RS)-4-(3,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00211
  • From (RS)-2-amino-2-(3,5-dichlorophenyl)-acetic acid. White solid.
  • MS (ISP): 235.1([{37Cl}M+H]+), 233.1([{37Cl35Cl}M+H]+), 231.2 ([{35Cl}M+H]+).
    • Example 190 (+)-(S)-4-(5-Chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00212
  • (RS)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 19) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (+)-(S)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 217.1 ([{37Cl}M+H]+), 215.1 ([{35Cl}M+H]+)).
    • Examples 191 & 192 (−)-(R)-4-(3-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(3-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00213
  • (RS)-4-(3-Chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 185) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (−)-(R)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (light yellow solid; MS (ISP): 199.0 ([{37Cl}M+H]+), 197.0 ([{35Cl}M+H]+)) and (+)-(S)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (light yellow solid; MS (ISP): 199.0 ([{37Cl}M+H]+), 197.0 ([{35Cl}M+H]+)).
  • In analogy to example 163 were prepared:
    • Example 193 (S)-4-[2-(3-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00214
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-(trifluoromethyl)phenyl boronic acid and dimethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.3 ([M+H]+).
    • Example 194 (S)-4-[2-(3-Trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00215
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-(trifluoromethyl)phenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 287.1 ([M+H]+).
    • Example 195 (R)-4-Phenylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00216
    • a) (R)-2-Amino-3-phenylsulfanyl-propionic acid methyl ester hydrochloride
  • To a solution of S-phenyl-L-cysteine (5.0 g, 25.4 mmol) in methanol (50 ml) was added acetylchloride (2.7 ml, 38 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was recrystallised from ethyl acetate/methanol (3:1) to yield a white solid (3.81 g, 61%). MS (ISP): 211.9 ([M+H]+).
    • b) (R)-2-Amino-3-phenylsulfanyl-propan-1-ol
  • To a stirred suspension of (R)-2-amino-3-phenylsulfanyl-propionic acid methyl ester hydrochloride (0.50 g, 2.0 mmol) in tetrahydrofuran (10 ml) under an argon atmosphere was added slowly lithium aluminum hydride (0.153 g, 4.0 mmol) and the mixture was stirred overnight at room temperature. For work-up water (1.5 ml) and 2N sodium hydroxide solution (0.5 ml) were added and the mixture was stirred for 30 min. After filtration the solvent was evaporated and the residue was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/EtOAc=1:1 to yield a light yellow oil, (0.095 g, 26%); MS (ISP): 183.9 ((M+H)+.).
    • c) (R)-4-Phenylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine
  • To a stirred mixture of (R)-2-amino-3-phenylsulfanyl-propan-1-ol (0.09 g, 0.49 mmol) and K2CO3 (0.081 g, 0.59 mmol) in THF (3 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.062 g, 0.59 mmol) in THF (1 ml). The mixture was stirred overnight, then ethyl acetate and water were added. The aqueous phase was back-extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: EtOAc/MeOH=95:5) to yield a light yellow solid, (0.026 g, 26%); MS (ISP): 209.1 ((M+H)+.).
    • Example 196 (R)-4-(2-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00217
    • a) (RS)-4-(2-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147, the title compound was obtained starting from 2′-fluoro-acetophenone. Viscous colorless oil.
  • MS (ISP): 195.1 ([M+H]+)
    • b) (R)-4-(2-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (R)-4-(2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 195.1 ([M+H]+))
    • Example 197 (S)-4-(2-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00218
  • (RS)-4-(2-Fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 195.1 ([M+H]+))
    • Example 198 (+)-(S)-4-(3-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00219
  • (RS)-4-(3-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 186) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (+)-(S)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 243.2 ([{81Br}M+H]+), 241.1 ([{79Br}M+H]+)).
    • Example 199 (+)-(S)-4-(3-Fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00220
  • (RS)-4-(3-Fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 188) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (+)-(S)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 181.1 ([M+H]+)).
    • Examples 200 & 201 (−)-(R)-4-(3,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine& (+)-(S)-4-(3,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00221
  • (RS)-4-(3,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 189) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=15:85) to yield (−)-(R)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 235.1([{37Cl}M+H]+), 233.1([{37Cl35Cl}M+H]+), 231.2 ([{35Cl}M+H]+)) and (+)-(S)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 235.1([{37Cl}M+H]+), 233.1([{37Cl35Cl}M+H]+), 231.2 ([{35Cl}M+H]+)).
  • In analogy to example 163 were prepared:
    • Example 202 (S)-4-[2-(3,5-Difluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00222
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3,5-difluorophenyl boronic acid and dimethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 241.4 ([M+H]+).
    • Example 203 (S)-4-[2-(3,5-Difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00223
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3,5-difluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 255.3 ([M+H]+).
    • Example 204 (S)-4-(2,6-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00224
    • a) (RS)-4-(2,6-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147, the title compound was obtained starting from 2′,6′-difluoroacetophenone. White solid.
  • MS (ISP): 213.3 ([M+H]+)
    • b) (S)-4-(2,6-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2,6-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(2,6-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 213.3 ([M+H]+)
    • Example 205 (R)-4-(2,6-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00225
  • (RS)-4-(2,6-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (R)-4-(2,6-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 213.3 ([M+H]+)
    • Example 206 (S)-4-(2,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00226
    • a) (RS)-(2-Amino-2-(2,4-difluoro-phenyl)-propionic acid hydrochloride
  • In analogy to example 147.a and 147.b, the title compound was obtained starting from 2′,4′-difluoroacetophenone. White solid.
  • MS
    • b) (RS)-2-Amino-2-(2,4-difluoro-phenyl)-propan-1-ol
  • To a stirred 2 M LiBH4 solution (16.22 ml) at r.t. in THF under an argon atmosphere was added chlorotrimethylsilane (5.47 ml) over 2 min. The white suspension was cooled to 0° C. and (RS)-(2-amino-2-(2,4-difluoro-phenyl)-propionic acid hydrochloride (2.57 g) was added portionwise over 5 min. The ice bath was removed and the compact off-white suspension was stirred at r.t. for 20 h. The mixture was cooled again to 0° C. and treated carefully with methanol (15 ml). The mixture was stirred at r.t. for 30 min, filtered and the cake was washed with MeOH. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-2-amino-2-(2,4-difluoro-phenyl)-propan-1-ol (1.47 g, 73%) as colorless viscous oil.
  • MS (ISP): 188.3 ([M+H]+)
    • c) (RS)-4-(2,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1.b (RS)-2-amino-2-(2,4-difluoro-phenyl)-propan-1-ol was converted to the title compound. White solid.
  • MS (ISP): 213.3 ([M+H]+)
    • d) (S)-4-(2,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 213.1 ([M+H]+)
    • Example 207 (R)-4-Benzenesulfonylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00227
    • a) (R)-3-Benzenesulfonyl-2-tert-butoxycarbonylamino-propionic acid methyl ester
  • To a stirred suspension of (R)-2-amino-3-phenylsulfanyl-propionic acid methyl ester hydrochloride (1.0 g, 4.0 mmol, Example 195a) in 1 M bicarbonate solution (10 ml) was added a solution of di-tert.-butyl dicarbonate (0.969 g, 4.4 mmol) in dioxane (10 ml) and the mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was partitioned between water and ethyl acetate. The combined organic layers were dried (MgSO4) and filtered and cooled to 0° C. Then meta-chloroperbenzoic acid (1.38 g, 10 mmol) was added slowly at 0° C. and the mixture was stirred for an additional 4 hours at room temperature. For work-up saturated sodium sulfite solution (6 ml) and saturated sodium bicarbonate solution (6 ml) were added. After stirring the mixture for additional 30 min it was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1) to yield a white solid, (1.068 g, 78%); MS (ISP): 344.0 ((M+H)+.); 244.0 ((M+H-BOC)+.).
    • b) ((R)-2-Benzenesulfonyl-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester
  • To a solution of lithium borohydride in tetrahydrofuran (2M, 1.14 ml, 2.28 mmol) was added slowly at 0° C. a solution of (R)-3-benzenesulfonyl-2-tert-butoxycarbonylamino-propionic acid methyl ester (0.52 g, 1.51 mmol) in tetrahydrofuran (3 ml). After stirring at room temperature for 2.5 hours methanol was added (0.5 ml). The mixture was partitioned between ethyl acetate and saturated ammoniumchloride solution. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield a white solid, (0.292 g, 61%); MS (ISP): 316.0 ((M+H)+.); 216.1 ((M+H-BOC)+.).
    • c) (R)-4-Benzenesulfonylmethyl-4,5-dihydro-oxazol-2-ylamine
  • ((R)-2-Benzenesulfonyl-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester (0.29 g, 0.92 mmol) was dissolved in ethanol (2 ml), hydrochloric acid in ethanol (5M, 5 ml) was added and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated and the residue was taken up in tetrahydrofuran (5 ml). K2CO3 (0.326 g, 2.36 mmol) and cyanogen bromide (0.136 g, 1.29 mmol) were added. The mixture was stirred overnight and afterwards partitioned between ethyl acetate and water. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=95:5 to yield a white solid, (0.062 g, 28%); MS (ISP): 241.1 ((M+H)+.).
  • In analogy to example 163 were prepared:
    • Example 208 (S)-4-[3-Methyl-2-(3-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00228
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-(trifluoromethyl)phenyl boronic acid and diisopropylzinc. Mainly one epimer. Colourless oil. MS (ISP): 301.5 ([M+H]+).
    • Example 209 (S)-4-[2-(3,5-Difluoro-phenyl)-3-methyl-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00229
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3,5-difluorophenyl boronic acid and diisopropylzinc. Mainly one epimer. Colourless oil. MS (ISP): 269.5 ([M+H]+).
    • Example 210 (S)-4-[2-(4-Fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00230
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 4-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 237.1 ([M+H]+).
    • Example 211 (S)-4-[2-(3,4-Difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00231
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3,4-difluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 255.4 ([M+H]+).
    • Example 212 (S)-4-[2-(6-Trifluoromethyl-pyridin-2-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00232
    • a) (S)-2,2-Dimethyl-4-(6-trifluoromethyl-pyridin-2-ylethynyl)-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a solution of tert.-butyl (4S)-4-ethinyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (0.9 g, 4.0 mmol) in triethylamine (8 ml) were added 2-bromo-6-trifluoromethyl)pyridine (0.9 g, 4.0 mmol), copper(I) iodide (0.076 g, 0.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.281 g, 0.4 mmol) and the mixture was stirred for 1 hour at room temperature. The solvent was evaporated, ether was added and the brown suspension was filtered through Celite. The filtrate was evaporated and purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield an orange solid, (1.0 g, 67.5%); MS (ISP): 371.4 ((M+H)+.).
    • b) (S)-2,2-Dimethyl-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a solution of (S)-2,2-dimethyl-4-(6-trifluoromethyl-pyridin-2-ylethynyl)-oxazolidine-3-carboxylic acid tert-butyl ester (0.58 g, 1.56 mmol) in methanol (8 ml) were added ammonium formate (0.983 g, 15.6 mmol) and palladium on charcoal (10% Pd, 0.58 g). The mixture was refluxed for 1 hour. After cooling the solid was filtered off, the filtrate was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=7:3 to yield a light colourless liquid, (0.538 g, 92%); MS (ISP): 375.5 ((M+H)+.).
    • c) (S)-2-Amino-4-(6-trifluoromethyl-pyridin-2-yl)-butan-1-ol
  • (S)-2,2-Dimethyl-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester (0.522 g, 1.39 mmol) was dissolved in ethanol (2.5 ml), hydrochloric acid in ethanol (5N, 2.5 ml) was added and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane. A solution of ammonia in methanol (2N, 2 ml) was added and the mixture was evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded a colourless liquid, (0.237 g, 73%); MS (ISP): 235.1 ((M+H)+.).
    • d) (S)-4-[2-(6-Trifluoromethyl-pyridin-2-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • To a stirred mixture of (S)-2-amino-4-(6-trifluoromethyl-pyridin-2-yl)-butan-1-ol (0.224 g, 0.96 mmol) and K2CO3 (0.198 g, 1.43 mmol) in THF (7 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.152 g, 1.05 mmol) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded the title compound as off-white solid, (0.096 g, 39%); MS (ISP): 260.0 ((M+H)+.).
  • In analogy to example 87 was prepared:
    • Example 213 (S)-4-(4-Fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00233
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-fluorophenol. Colourless viscous oil.
  • MS (ISP): 211.1 ([M+H]+).
    • Example 214 (R)-4-(2-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00234
    • a) (RS)-4-(2-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 2′-fluoro-4′-(trifluoromethyl)acetophenone. White solid.
  • MS (ISP): 263.3 ([M+H]+)
    • b) (R)-4-(2-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(2-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 5:95) to give (R)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Colorless viscous oil.
  • MS (ISP): 263.0 ([M+H]+)
    • Example 215 (S)-4-(2-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00235
  • (RS)-4-(2-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 5:95) to give (S)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Colorless viscous oil.
  • MS (ISP): 263.0 ([M+H]+)
  • In analogy to example 87 was prepared:
    • Example 216 (S)-4-(4-Chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00236
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-chlorophenol. White solid.
  • MS (ISP): 229.3 ([{37Cl}M+H]+), 227.1 ([{35Cl}M+H]+).
  • In analogy to example 163 was prepared:
    • Example 217 (S)-4-[2-(2-Fluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00237
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 2-fluorophenyl boronic acid and dimethylzinc. Mainly one epimer. White crystalline solid. MS (ISP): 223.3 ([M+H]+).
    • Example 218 (R)-4-Methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00238
    • a) ((RS)-4-Methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 2′-fluoro-4′-(trifluoromethyl)acetophenone. Viscous colorless oil.
  • MS (ISP): 245.1 ([M+H]+)
    • b) (R)-4-Methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-Methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 5:95) to give (R)-4-methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Colorless viscous oil.
  • MS (ISP): 245.1 ([M+H]+)
    • Example 219 (S)-4-Methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00239
  • (RS)-4-Methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 5:95) to give (S)-4-methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Colorless viscous oil.
  • MS (ISP): 245.1 ([M+H]+)
    • Example 220 (S)-4-[2-(2-Methyl-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00240
  • The title compound, MS (ISP): 206.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 212 using 4-bromo-2-methylpyridine instead of 2-bromo-6-trifluoromethyl)pyridine in step a).
    • Example 221 (S)-4-[2-(3,4-Dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00241
    • a) (E)-(S)-2-Amino-4-phenyl-hex-3-en-1-ol
  • In analogy to example 162a-d (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was treated sequentially with triphenylphosphine/carbon tetrabromide, 3,4-dichlorophenylboronic acid, dimethyl zinc and hydrogen chloride to give (E)-(S)-2-amino-4-phenyl-hex-3-en-1-ol. Yellow oil.
    • b) (S)-2-Amino-4-(3,4-dichloro-phenyl)-pentan-1-ol
  • To a stirred solution of (E)-(S)-2-amino-4-phenyl-hex-3-en-1-ol (390 mg) at r.t. in THF (50 ml) under an argon atmosphere were added 10% Pd/C (280 mg) and zinc bromide (36 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 16. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient:dichloromethane/methanol) to give (S)-2-amino-4-(3,4-dichloro-phenyl)-pentan-1-ol (mainly one epimer) (69 mg, 18%) as a colourless oil. MS (ISP): 252.2([{37Cl}M+H]+), 250.2 ([{37Cl35Cl}M+H]+), 248.1 ([{35Cl}M+H]+).
    • c) (S)-4-[2-(3,4-Dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-4-(3,4-dichloro-phenyl)-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). Colourless oil. MS (ISP): 277.1([{37Cl}M+H]+), 275.0 ([{37Cl35Cl}M+H]+), 273.1 ([{35Cl}M+H]+).
  • In analogy to example 221 was prepared:
    • Example 222 (S)-4-[2-(3,4-Dichloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00242
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3,4-dichlorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 291.1([{37Cl}M+H]+), 289.0 ([{37Cl35Cl}M+H]+), 287.1 ([{35Cl}M+H]+).
  • In analogy to example 163 was prepared:
    • Example 223 (S)-4-[2-(2-Fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00243
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 2-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Courless oil. MS (ISP): 237.1 ([M+H]+).
    • Example 224 (RS)-4-(4-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00244
    • a) (RS)-Amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetonitrile
  • To a stirred solution of 4-fluoro-2-(trifluoromethyl)benzaldehyde (5.0 g) in methanol (20 ml) were added sequentially ammonia solution (28.9 ml, 7 M solution in methanol) and tetraisopropyl orthotitanate (9.0 ml) and the resulting mixture was stirred at r.t. for 1 h. Trimethylsilylcyanide (3.3 ml) was then added dropwise and stirring continued at r.t. overnight. The reaction mixture was poured onto ice-water (400 ml) and the mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with brine and then dried over sodium sulphate and concentrated in vacuo to afford (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetonitrile (4.48 g, 81%) as an orange viscous oil. MS (ISP): 219.1 ([M+H]+).
    • b) (RS)-2-Amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide hydrochloride
  • A solution of (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetonitrile (4.47 g) in formic acid (15 ml) saturated with hydrogen chloride was stirred at room temperature for 90 min. The mixture was then concentrated in vacuo and the residue was resuspended in acetone whereby white crystals formed The crystals were collected by filtration, washed with acetone and dried in vacuo to afford (RS)-2-amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide hydrochloride (1.40 g, 25%) as a white solid. MS (ISP): 273.1 ([M+H]+).
    • c) (RS)-Amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetic acid
  • 2-amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide hydrochloride (1.39 g) was suspended in 5 N aq hydrochloric acid (15 ml) and the mixture was heated at reflux for 3 h. The mixture was then concentrated in vacuo, and the residue was resuspended in isopropanol and concentrated in vacuo again. The residue was taken up in water and neutralised by dropwise addition of 1 N aq NaOH, whereby white crystals slowly formed. The crystals were collected by filtration and dried in vacuo at 50° C. to afford (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetic acid (0.75 g, 62%) as a white solid. MS (ISP): 237.9 ([M+H]+).
    • d) (RS)-2-Amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-ethanol
  • In analogy to example 185.a (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetic acid was converted to (RS)-2-amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-ethanol_by treatment with lithium borohydride and chlorotrimethylsilane. Light yellow oil. MS (ISP): 224.3 ([M+H]+).
    • e) (RS)-4-(4-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1.b (RS)-2-amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-ethanol was converted to (RS)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine by treatment with cyanogen bromide and potassium carbonate. White solid. MS (ISP): 249.1 ([M+H]+).
  • In analogy to example 224 and starting from the respective aldehyde were prepared:
    • Example 225 (RS)-4-(5-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00245
  • From 5-chloro-2-(trifluoromethyl)benzaldehyde. Off-white solid.
  • MS (ISP): 267.1 ([{37Cl}M+H]+), 265.0 ([{35Cl}M+H]+).
    • Example 226 (RS)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00246
  • From 4-chloro-2-(trifluoromethyl)benzaldehyde. White solid.
  • MS (ISP): 267.1 ([{37Cl}M+H]+), 265.0 ([{35Cl}M+H]+).
    • Example 227 (RS)-4-Methyl-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00247
  • In analogy to example 206, the title compound was obtained starting from 2,3,5-trifluoroacetophenone. White solid.
  • MS (ISP): 231.1 ([M+H]+)
    • Example 228 (S)-4-[2-(2-Chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00248
    • a) (2S,5R)-2-[2-(2-Chloro-phenyl)-ethyl]-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydro-pyrazine
  • A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine (1.0 g, 5.0 mmol) in tetrahydrofuran (23 ml) was cooled to −70° C., then tert.butyllithium (1.7 M in pentane, 3.26 ml, 5.55 mmol) was added and the mixture was stirred for 1 hour. A solution of 1-(2-bromo-ethyl)-2-chlorobenzene (1.44 g, 6.56 mmol) in tetrahydrofuran (10 ml) was added slowly and the mixture was stirred overnight at −70° C. At room temperature saturated ammonium chloride solution was added and the mixture was extracted three times with ether. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield an orange solid, (1.22 g, 72%); MS (ISP): 337.1; 339.1 ((M+H)+.).
    • b) (S)-2-Amino-4-(2-chloro-phenyl)-2-methyl-butyric acid methyl ester
  • To a solution of (2S,5R)-2-[2-(2-chloro-phenyl)-ethyl]-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydro-pyrazine (1.22 g, 3.62 mmol) in acetonitrile (12 ml) were added water (4 ml) and trifluoroacetic acid (2 ml). The mixture was stirred overnight at 40° C. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane three times. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=95:5 to yield a colorless oil, (0.46 g, 52%); MS (ISP): 242.1; 244.1 ((M+H)+.).
    • c) (S)-2-Amino-4-(2-chloro-phenyl)-2-methyl-butan-1-ol
  • To a suspension of lithium aluminum hydride (0.072 g, 1.9 mmol) in tetrahydrofuran (10 ml) was added a solution of (S)-2-amino-4-(2-chloro-phenyl)-2-methyl-butyric acid methyl ester (0.23 g, 0.95 mmol) in tetrahydrofuran (3 ml) and the mixture was stirred for 2 hours. Sodium sulphate solution (2M, 0.3 ml) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) to yield a colourless oil, (0.190 g, 93%); MS (ISP): 214.0; 216.0 ((M+H)+.).
    • d) (S)-4-[2-(2-Chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • To a stirred mixture of (S)-2-amino-4-(2-chloro-phenyl)-2-methyl-butan-1-ol (0.190 g, 0.89 mmol) and K2CO3 (0.155 g, 1.12 mmol) in THF (10 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.119 g, 1.12 mmol) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded the title compound as off-white solid, (0.070 g, 33%); MS (ISP): 239.2; 241.2 ((M+H)+.).
  • In analogy to example 224 and starting from the respective aldehyde was prepared:
    • Example 229 (RS)-4-(4-Methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00249
  • From 4-methoxy-2-(trifluoromethyl)benzaldehyde. White solid.
  • MS (ISP): 261.1 ([M+H]+).
    • Example 230 (R)-4-(4-Bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00250
    • a) (RS)-4-(4-Bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147, the title compound was obtained starting from 4-bromoacetophenone. White solid.
  • MS (ISP): 255.1 ([M+H]+)
    • b) (R)-4-(4-Bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(4-Bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 20:80) to give (R)-4-(4-bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 255.1 ([M+H]+)
    • Example 231 (S)-4-(4-Bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00251
  • (RS)-4-(4-Bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 20:80) to give (S)-4-(4-bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 255.2 ([M+H]+)
    • Example 232 (S)-4-[2-(3-Chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00252
    • a) (R)-4-(Benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • In analogy to example 83a. from (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Yellow viscous oil.
    • b) (R)-4-(Benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • In analogy to example 83b. from (R)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Off-white solid. MS (ISP): 413.3 ([M+H]+)).
    • c) (S)-4-[(E)-2-(3-Chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • In analogy to example 83c. from (R)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 3-chloro-benzaldehyde. Off-white solid. MS (ISP): 340.2 ([{37Cl}M+H]+), 338.2 ([{35Cl}M+H]+).
    • d) (E)-(S)-2-Amino-4-(3-chloro-phenyl)-but-3-en-1-ol
  • In analogy to example 83e. from (S)-4-[(E)-2-(3-chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Off-white solid.
    • e) (S)-2-Amino-4-(3-chloro-phenyl)-butan-1-ol
  • To a stirred solution of (E)-(S)-2-amino-4-(3-chloro-phenyl)-but-3-en-1-ol (155 mg) at r.t. in ethanol (5 ml) under an argon atmosphere was added 5% Pt/C (16 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 20 hrs. The catalyst was filtered off and the filtrate was concentrated to give (S)-2-amino-4-(3-chloro-phenyl)-butan-1-ol (102 mg, 65%) as light yellow oil. MS (ISP): 202.2 ([{37Cl}M+H]+), 200.2 ([{35Cl}M+H]+).
    • f) (S)-4-[2-(3-Chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 1b (S)-2-amino-4-(3-chloro-phenyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow viscous oil. MS (ISP): 227.2 ([{37Cl}M+H]+), 225.1 ([{35Cl}M+H]+).
  • In analogy to example 224 and starting from the respective aldehyde were prepared:
    • Example 233 (RS)-4-(3-Chloro-2-fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00253
  • From 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde. White solid.
  • MS (ISP): 284.9 ([{37Cl}M+H]+), 283.1 ([{35Cl}M+H]+).
    • Example 234 (RS)-4-(4,5-Dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00254
  • From 4,5-dichloro-2-(trifluoromethyl)benzaldehyde. Orange solid.
  • MS (ISP): 303.0 ([{37Cl}M+H]+), 301.0 ([{37Cl35Cl}M+H]+), 299.0 ([{35Cl}M+H]+).
  • In analogy to example 185 and starting from the respective amino acid or amino acid derivative was prepared:
    • Example 235 (RS)-4-(2,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00255
  • From amino-(2,4-dichloro-phenyl)-acetic acid. White solid.
  • MS (ISP): 235.1 ([{37Cl}M+H]+), 233.1 ([{37Cl35Cl}M+H]+), 231.2 ([{35Cl}M+H]+).
    • Example 236 (S)-4-(4-Chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00256
    • a) (RS)-4-(4-Chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 4-bromoacetophenone. White solid.
  • MS (ISP): 229.4 ([M+H]+)
    • b) (S)-4-(4-Chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(4-Chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 5:95) to give (S)-4-(4-chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 229.1 ([M+H]+)
  • In analogy to example 185 and starting from the respective amino acid or amino acid derivative was prepared:
    • Example 237 (RS)-4-(2-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00257
  • From amino-(2-bromo-phenyl)-acetic acid. White solid.
  • MS (ISP): 243.1 ([{81Br}M+H]+), 241.1 ([{79Br}M+H]+).
    • Examples 238 & 239 (+)-(S)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (−)-(R)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00258
  • (RS)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 226) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (+)-(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 267.1 ([{37Cl}M+H]+), 265.0 ([{35Cl}M+H]+)) and (−)-(R)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 267.1 ([{37Cl}M+H]+), 265.0 ([{35Cl}M+H]+)).
    • Examples 240 & 241 (+)-(S)-4-(4-Methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (−)-(R)-4-(4-Methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00259
  • (RS)-4-(4-Methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 229) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (+)-(S)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (colourless gum; MS (ISP): 261.1 ([M+H]+)) and (−)-(R)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (colourless gum; MS (ISP): 261.1 ([M+H]+)).
    • Examples 242 & 243 (+)-(S)-4-(4,5-Dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (−)-(R)-4-(4,5-Dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00260
  • (RS)-4-(4,5-Dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 234) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (+)-(S)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 303.0 ([{37Cl}M+H]+), 301.0 ([{37Cl35Cl}M+H]+), 299.0 ([{35Cl}M+H]+)) and (−)-(R)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 303.0 ([{37Cl}M+H]+), 301.0 ([{37Cl35Cl}M+H]+), 299.0 ([{35Cl}M+H]+)).
    • Example 244 (S)-4-[2-(4-Chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00261
  • The title compound, MS (ISP): 239.1; 241.2 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using 1-(2-bromo-ethyl)-4-chlorobenzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 245 (S)-4-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00262
  • The title compound, MS (ISP): 273.0 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using 1-(2-iodo-ethyl)-3-trifluoromethyl-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 246 (S)-4-[2-(3-Chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00263
  • The title compound, MS (ISP): 239.1; 241.2 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using 1-(2-bromo-ethyl)-3-chlorobenzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Examples 247 & 248 (−)-(R)-4-(4-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00264
  • (RS)-4-(4-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 224) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (−)-(R)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (colourless oil; MS (ISP): 249.1 ([M+H]+) and (+)-(S)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (colourless oil; MS (ISP): 249.1 ([M+H]+).
  • In analogy to example 224 and starting from the respective aldehyde were prepared:
    • Example 249 (RS)-4-(5-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00265
  • From 5-fluoro-2-(trifluoromethyl)benzaldehyde. Light yellow solid.
  • MS (ISP): 249.1 ([M+H]+).
    • Example 250 (RS)-4-(5-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00266
  • From 5-fluoro-2-methyl-benzaldehyde. White solid.
  • MS (ISP): 195.1 ([M+H]+).
    • Example 251 (RS)-4-Methyl-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00267
  • In analogy to example 206, the title compound was obtained starting from 2,4,5-trifluoroacetophenone. Viscous colorless oil.
  • MS (ISP): 231.3 ([M+H]+)
    • Example 252 (RS)-4-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00268
    • a) (RS)-2-Amino-2-(4-bromo-3-fluoro-phenyl)-ethanol
  • In analogy to example 224a-d 4-bromo-3-fluorobenzaldehyde was treated sequentially with ammonia/tetraisopropyl orthotitanate/trimethylsilyl cyanide, hydrogen chloride in formic acid, hydrochloric acid, and lithium borohydride/chlorotrimethylsilane to give (RS)-2-amino-2-(4-bromo-3-fluoro-phenyl)-ethanol. Yellow viscous oil. MS (ISP): 236.1 ([{81Br}M+H]+), 234.1 ([{79Br}M+H]+).
    • b) (RS)-4-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • To a stirred, cooled (0° C.) solution of (RS)-2-amino-2-(4-bromo-3-fluoro-phenyl)-ethanol (3.26 g) and sodium acetate (2.22 g) in methanol (25 ml) was added dropwise a solution of cyanogen bromide (1.52 g) in methanol (10 ml) over 10 min. The mixture was then allowed to warm to at r.t. and stirring continued for 16 h. The mixture was concentrated in vacuo and the residue was resuspended in water and made basic by addition of 1 M aq sodium hydroxide solution. The mixture was then extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was triturated in dichloromethane and the resulting crystals washed with ether to give (RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (1.09 g, 30%) as a white solid. MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+).
    • Example 253 (−)-(S)-4-(3-Chloro-2-fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00269
  • (RS)-4-(3-Chloro-2-fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 233) was separated by chiral HPLC (Chiralpak AD, iPrOH/heptane=5:95) to yield (−)-(S)-4-(3-chloro-2-fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 284.9 ([{37Cl}M+H]+), 283.1 ([{35Cl}M+H]+).
    • Example 254 (S)-4-Methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00270
    • a) (RS)-4-Methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147, the title compound was obtained starting from 4′-(trifluoromethoxy)acetophenone. Viscous colorless oil.
  • MS (ISP): 261.0 ([M+H]+)
    • b) (S)-4-Methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • ((RS)-4-Methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 10:90) to give (S)-4-methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Viscous colorless oil.
  • MS (ISP): 261.0 ([M+H]+)
    • Example 255 (S)-4-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00271
  • The title compound, MS (ISP): 223.3 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using 1-(2-bromo-ethyl)-4-fluorobenzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 256 (S)-4-[2-(4-Chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00272
  • The title compound, MS (ISP): 225.3; 227.2 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 1-(2-bromo-ethyl)-4-chloro-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 257 (S)-4-[1-(4-Chloro-phenyl)-cyclopropylmethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00273
    • a) 1-Chloro-4-(1-iodomethyl-cyclopropyl)-benzene
  • To a stirred solution of triphenylphosphine (3.45 g, 13 mmol) and imidazole (0.90 g, 13 mmol) in dichloromethane (25 ml) under an argon atmosphere was added slowly iodine (3.33 g, 13 mmol) and [1-(4-chlorophenyl)-cyclopropyl]-methanol (2.00 g, 11 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (75 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (100 ml) and hydrochloric acid (1N, 50 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow oil, (2.30 g, 72%); MS (EI): 292.0 (M+.).
    • b) (S)-4-[1-(4-Chloro-phenyl)-cyclopropylmethyl]-4,5-dihydro-oxazol-2-ylamine
  • The title compound, MS (ISP): 251.1; 253.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 1-chloro-4-(1-iodomethyl-cyclopropyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 258 (S)-4-[2-(3,4-Difluoro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00274
  • The title compound, MS (ISP): 241.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using 1-(2-iodo-ethyl)-3,4-difluorobenzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 259 (+)-(S)-4-(5-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00275
  • (RS)-(S)-4-(5-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 249) was separated by chiral HPLC (Chiralpak AD, iPrOH/heptane=5:95) to yield (+)-(S)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 249.1 ([M+H]+).
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 260 (RS)-4-(2,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00276
  • From 2,5-dichlorobenzaldehyde. White solid. MS (ISP): 235.0 ([{37Cl}M+H]+), 233.0 ([{37Cl35Cl}M+H]+), 231.1 ([{35Cl}M+H]+)).
    • Example 261 (RS)-4-(2-Chloro-4,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00277
  • In analogy to example 206, the title compound was obtained starting from 2-chloro-4,5-difluoroacetophenone. White solid.
  • MS (ISP): 247.1 ([M+H]+)
    • Example 262 (RS)-4-(3,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00278
  • In analogy to example 206, the title compound was obtained starting from 3,4-difluoroacetophenone. White solid.
  • MS (ISP): 213.3 ([M+H]+)
    • Example 263 (RS)-4-(4-Chloro-3-methyl-phenyl)-4-methyl-4, 5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00279
  • In analogy to example 206, the title compound was obtained starting from 4-chloro-3-methylacetophenone. White solid.
  • MS (ISP): 225.1 ([M+H]+)
    • Examples 264 & 265 (−)-(R)-4-(2-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(2-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00280
  • (RS)-4-(2-Bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 237) was separated by chiral HPLC (Chiralpak AD, iPrOH/heptane=5:95) to yield (−)-(R)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 243.1 ([{81Br}M+H]+), 241.1 ([{79Br}M+H]+) and (+)-(S)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 243.1 ([{81Br}M+H]+), 241.1 ([{79Br}M+H]+).
    • Example 266 (S)-4-(3-Chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00281
    • a) (RS)-4-(3-Chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 3′-chloro-5′-fluoroacetophenone. White solid.
  • MS (ISP): 229.1 ([M+H]+)
    • b) (S)-4-(3-Chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3-Chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:850) to give (S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 229.1 ([M+H]+)
    • Example 267 (S)-4-[2-(2-Chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00282
  • The title compound, MS (ISP): 225.1; 227.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 1-(2-bromo-ethyl)-2-chloro-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 268 (RS)-4-(4-Chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00283
    • a) (RS)-2-Amino-2-(4-chloro-phenyl)-butyronitrile
  • A solution of 4′-chloropropiophenone (5 g) in MeOH (20 ml) was treated under an argon atmosphere and at r.t. with 7M NH3 in MeOH (33.9 ml). Then, tetraisopropyl orthotitanate (10.54 ml) was added dropwise. The reaction mixture was stirred for 1 hr at r.t. Then, trimethylsilyl cyanide (3.72 ml) was added and stirring was continued at r.t. overnight. The reaction mixture was poured in ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The crude (RS)-2-amino-2-(4-chloro-phenyl)-butyronitrile (4.95 g) was used in the next reaction step without further purification.
    • b) (RS)-2-Amino-2-(4-chloro-phenyl)-butyric acid hydrochloride
  • A solution of (RS)-2-amino-2-(4-chloro-phenyl)-butyronitrile (4.9 g) in 5 HCl (30 ml) was refluxed overnight, then cooled to r.t. and washed with EtOAc. The aqueous layer was concentrated. The crude (RS)-2-amino-2-(4-chloro-phenyl)-butyric acid hydrochloride (3.0 g) was used in the next reaction step without further purification.
    • c) (RS)-4-(4-Chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206.b and c (RS)-2-amino-2-(4-chloro-phenyl)-butyric acid hydrochloride was converted to the title compound. White solid.
  • MS (ISP): 225.1 ([M+H]+)
    • Example 269 (RS)-4-Methyl-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00284
  • In analogy to example 206, the title compound was obtained starting from 2,3,4-trifluoroacetophenone. Off-white solid.
  • MS (ISP): 231.1 ([M+H]+)
    • Example 270 (S)-4-(5-Chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00285
    • a) (S)-4-(5-Chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 5′-chloro-2′-fluoroacetophenone. White solid.
  • MS (ISP): 229.3 ([M+H]+)
    • b) (RS)-4-(5-Chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(5-Chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 5:95) to give (S)-4-(5-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 229.1 ([M+H]+)
    • Example 271 (RS)-4-Methyl-4-(4-chloro-2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00286
    • a) (RS)-4-(4-Chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 147.a, but stirring the reaction mixture overnight instead of 3 hrs, the title compound was obtained starting from 4-chloro-2,5-difluoro-acetophenone. Off-white solid.
  • MS (ISP): 247.1 ([M+H]+)
    • b) (RS)-4-(4-Chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • The title compound was obtained in analogy to example 206.b and 206.c. Off-white solid.
  • MS (ISP): 247.1 ([M+H]+)
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 272 (RS)-4-(5-Chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00287
  • From 5-chloro-2-methylbenzaldehyde. White solid. MS (ISP): 213.1 ([{37Cl}M+H]+), 211.1 ([{35Cl}M+H]+)).
    • Example 273 (RS)-4-Methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00288
  • The title compound was obtained in analogy to example 268 starting from 3′,4′,5′-trifluoro-acetophenone. White solid.
  • MS (ISP): 231.3 ([M+H]+)
    • Example 274 (RS)-4-(4-Chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00289
  • The title compound was obtained in analogy to example 268 starting from 4-chloro-2-fluoro-5-methyl-acetophenone. White solid.
  • MS (ISP): 2434.1 ([M+H]+)
    • Example 275 (S)-4-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00290
    • a) 1-Chloro-4-(1-iodomethyl-cyclobutyl)-benzene
  • To a stirred solution of triphenylphosphine (4.91 g, 18.7 mmol) and imidazole (1.28 g, 18.7 mmol) in dichloromethane (40 ml) under an argon atmosphere was added slowly iodine (4.75 g, 18.7 mmol) and [1-(4-chlorophenyl)-cyclopropyl]-methanol (3.07 g, 15.6 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (100 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (100 ml) and hydrochloric acid (1 N, 50 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a colourless oil, (2.50 g, 52%); MS (EI): 306.0 (M+.); 179.0 ((M−I)+.).
    • b) (S)-4-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-4,5-dihydro-oxazol-2-ylamine
  • The title compound, MS (ISP): 265.0; 267.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 1-chloro-4-(1-iodomethyl-cyclobutyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 276 (R)-4-(3-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00291
    • a) (R)-4-(3-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 3-chloro-4-fluoro-acetophenone. Viscous colorless oil.
  • MS (ISP): 229.4 ([M+H]+)
    • b) ((R)-4-(3-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-(3-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (R)-4-(3-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 229.1 ([M+H]+)
    • Example 277 (R)-4-(3-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00292
  • (RS)-4-(3-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give (S)-4-(3-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 229.1 ([M+H]+)
    • Examples 278 & 279 (−)-(R)-4-(5-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(5-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00293
  • (RS)-4-(5-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 250) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (−)-(R)-4-(5-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 195.1 ([M+H]+) and (+)-(S)-4-(5-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 195.1 ([M+H]+).
    • Example 280 (R)-4-(4-Chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00294
  • (RS)-4-(4-Chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 263) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=1:9) to give (R)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 225.1 ([M+H]+))
    • Example 281 (S)-4-(4-Chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00295
  • (RS)-4-(4-Chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 263) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=1:9) to give (S)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 225.3 ([M+H]+))
    • Example 282 (R)-4-(3,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00296
  • (RS)-4-(3,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 262) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=1:9) to give (R)-4-(3,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (−)-Enantiomer. White solid.
  • MS (ISP): 213.1 ([M+H]+))
    • Example 283 (S)-4-(3,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00297
  • (RS)-4-(3,4-Difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 262) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=1:9) to give (S)-4-(3,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
  • MS (ISP): 213.3 ([M+H]+))
  • In analogy to example 87 were prepared:
    • Example 284 (S)-4-(3,4-Dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00298
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 3,4-dichlorophenol. White solid. MS (ISP): 265.0 ([{37Cl}M+H]+), 263.0 ([{37Cl35Cl}M+H]+), 261.0 ([{35Cl}M+H]+)).
    • Example 285 (S)-4-(3,5-Dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00299
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 3,5-dichlorophenol. Courless oil. MS (ISP): 265.1 ([{37Cl}M+H]+), 263.1 ([{37Cl35Cl}M+H]+), 261.1 ([{35Cl}M+H]+)).
    • Example 286 (S)-4-(3-Trifluoromethyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00300
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 3-(trifluoromethyl)phenol. Courless oil. MS (ISP): 261.0 ([M+H]+).
  • In analogy to example 162 was prepared:
    • Example 287 (S)-4-[2-(3-Chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00301
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-chlorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 255.3 ([{37Cl}M+H]+), 253.3 ([{35Cl}M+H]+)).
    • Example 288 (S)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00302
  • The title compound, MS (ISP): 205.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine methylpyrazine and (3-bromo-propyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 289 (S)-4-(4-Chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00303
  • (RS)-4-(4-Chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 271) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to give the title compound. (+)-Enantiomer. White solid.
  • MS (ISP): 247.1 ([M+H]+))
  • In analogy to example 252 and starting from the respective aldehyde were prepared:
    • Example 290 (RS)-4-(2-Fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00304
  • From 2-fluoro-6-trifluoromethyl-benzaldehyde. White solid. MS (ISP): 248.9 ([M+H]+).
    • Example 291 (RS)-4-(4-Bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00305
  • From 4-bromo-2-chloro-benzaldehyde. White solid. MS (ISP): 278.9 ([{81Br37Cl}M+H]+), 276.9 ([{81Br35Cl or 79Br37Cl}M+H]+), 274.9 ([{79Br35Cl}M+H]+).
    • Example 292 (S)-4-((S)-2-Phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00306
    • a) ((R)-1-Iodomethyl-propyl)-benzene
  • To a solution of triphenylphosphine (15.4 g, 59 mmol) and imidazole (3.99 g, 59 mmol) in dichloromethane (150 ml) at room temperature was added portionwise iodine (14.9 g, 50 mmol) at such a rate that the temperature of the reaction mixture did not rise above 30° C. To the mixture was then added a solution of (R)-2-phenyl-butan-1-ol (7.34 g, 41 mmol, CAS 16460-75-6) in dichloromethane (50 ml) and the mixture was then stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was resuspended in ether and the resulting crystals collected by filtration. The filtrate was concentrated in vacuo and the residue was triturated in heptane. The resulting crystals were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a colourless oil, (6.38 g, 60%).
    • b) (2R,5S)-2-Isopropyl-3,6-dimethoxy-5-((S)-2-phenyl-butyl)-2,5-dihydro-pyrazine
  • A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine (4.25 g, 23.1 mmol) in tetrahydrofuran (30 ml) was cooled to −78° C., then n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmol) was added and the mixture was stirred for 1 hour. A solution of ((R)-1-iodomethyl-propyl)-benzene (6.30 g, 24.2 mmol) in tetrahydrofuran (30 ml) was added dropwise over 30 min and the mixture was stirred overnight while being allowed to warm slowly from −70° C. to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a light yellow oil (4.69 g, 64%); MS (ISP): 317.0 ([M+H]+).
    • c) (2S,4S)-2-Amino-4-phenyl-hexanoic acid methyl ester
  • To a solution of trifluoroacetic acid (3.4 ml) in water (440 ml) was added dropwise over 15 min a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-((S)-2-phenyl-butyl)-2,5-dihydro-pyrazine (4.69 g, 14.8 mmol) in acetonitrile (75 ml). The mixture was stirred overnight at room temperature then made basic by addition of saturated aqueous sodium carbonate solution and the mixture was extracted with ethyl acetate. The phases were separated and the organic phase was washed sequentially with water and with saturated brine, then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc/heptane) to yield a yellow oil (2.78 g, 85%); MS (ISP): 222.1 ([M+H]+).
    • d) (2S,4S)-2-Amino-4-phenyl-hexan-1-ol
  • To a suspension of lithium aluminum hydride (121 mg, 3.18 mmol) in tetrahydrofuran (8 ml) was added a solution of (2S,4S)-2-amino-4-phenyl-hexanoic acid methyl ester (320 mg, 1.45 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred for 16 hours. The reaction was quenched by dropwise addition of ethyl acetate, then acidified to pH 5 by addition of hydrochloric acid and then made basic by addition of saturated aqueous sodium bicarbonate solution. The mixture was taken up in ethyl acetate/tetrahydrofuran (1:1), the phases were separated and the organic phase was washed sequentially with water and with saturated brine. The organic phase was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/MeOH) to yield a yellow oil, (116 mg, 42%); MS (ISP): 194.4 ([M+H]+).
    • e) (S)-4-((S)-2-Phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
  • To a stirred, cooled (0° C.) solution of (2S,4S)-2-amino-4-phenyl-hexan-1-ol (270 mg, 1.40 mmol) and sodium acetate (229 mg, 2.70 mmol) in methanol (20 ml) was added dropwise a solution of cyanogen bromide (180 mg, 1.68 mmol) in methanol (2 ml) over 10 min. The mixture was then allowed to warm to r.t. and stirring was continued for 16 h. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and with saturated brine. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/EtOAc/MeOH) to yield a light yellow solid. MS (ISP): 219.3 ([M+H]+).
    • Example 293 (S)-4-((R)-2-Phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00307
  • The title compound, MS (ISP): 219.4 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 292 starting from (S)-2-phenyl-butan-1-ol (CAS 33442-47-6). Colourless oil. MS (ISP): 219.4 ([M+H]+).
    • Example 294 (RS)-4-(2,4-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00308
  • The title compound was obtained in analogy to example 268 starting from 2′,4′-dichloro-acetophenone. Off-white viscous oil.
  • MS (ISP): 245.3 ([M+H]+)
    • Examples 295 & 296 (−)-(R)-4-(2,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(2,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00309
  • (RS)-4-(2,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 235) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (−)-(R)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 235.0 ([{37Cl}M+H]+), 233.0 ([{37Cl35Cl}M+H]+), 231.1 ([{35Cl}M+H]+)) and (+)-(S)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 235.0 ([{37Cl}M+H]+), 233.0 ([{37Cl35Cl}M+H]+), 231.1 ([{35Cl}M+H]+)).
    • Examples 297 & 298 (−)-(R)-4-(2,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(2,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00310
  • (RS)-4-(2,5-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 260) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (−)-(R)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 235.0 ([{37Cl}M+H]+), 233.0 ([{37Cl35Cl}M+H]+), 231.1 ([{35Cl}M+H]+)) and (+)-(S)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 235.0 ([{37Cl}M+H]+), 233.0 ([{37Cl35Cl}M+H]+), 231.1 ([{35Cl}M+H]+)).
    • Example 299 (RS)-4-(2,5-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00311
  • The title compound was obtained in analogy to example 271 starting from 2′,5′-dichloro-acetophenone. Off-white viscous oil.
  • MS (ISP): 245.3 ([M+H]+)
    • Examples 300 & 301 (−)-(R)-4-(2,3,4-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(2,3,4-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00312
  • (RS)-4-(2,3,4-Trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 17) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (−)-(R)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 217.3 ([M+H]+)) and (+)-(S)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 217.3 ([M+H]+)).
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 302 (RS)-4-(4-Bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00313
  • From 4-bromo-2-trifluoromethyl-benzaldehyde. White solid. MS (ISP): 311.0 ([{81Br}M+H]+), 309.1 ([{79Br}M+H]+).
    • Example 303 (S)-4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00314
  • The title compound, MS (ISP): 243.0; 245.1 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 2-chloro-6-fluoro-1-(2-iodo-ethyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 304 (S)-4-[2-(2,4-Dichloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00315
  • The title compound, MS (ISP): 273.1; 275.0 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 228 using 2,4-dichloro-1-(2-iodo-ethyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 305 (R)-4-Methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00316
  • (RS)-4-Methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 273) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=1:9) to give the title compound. (−)-Enantiomer. White solid.
  • MS (ISP): 231.1 ([M+H]+))
    • Example 306 (S)-4-Methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00317
  • (RS)-4-Methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 273) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=1:9) to give the title compound. (+)-Enantiomer. White solid.
  • MS (ISP): 231.1 ([M+H]+))
    • Example 307 (R)-4-(4-Chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00318
  • (RS)-4-(4-Chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 274) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to give the title compound. (−)-Enantiomer. Waxy white solid.
  • MS (ISP): 243.3 ([M+H]+))
    • Example 308 (S)-4-(4-Chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00319
  • (RS)-4-(4-Chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (example 274) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to give the title compound. (+)-Enantiomer. Waxy white solid.
  • MS (ISP): 243.3 ([M+H]+))
    • Example 309 (RS)-4-(4-Methoxy-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00320
  • The title compound was obtained in analogy to example 271 starting from 4-methoxy-acetophenone. White solid.
  • MS (ISP): 206.9 ([M+H]+)
  • In analogy to example 87 was prepared:
    • Example 310 (S)-4-(4-Bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00321
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-bromophenol. White solid. MS (ISP): 273.1 ([{37Cl}M+H]+), 271.1 ([{35Cl}M+H]+)).
    • Example 311 (RS)-4-(3-Chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00322
  • The title compound was obtained in analogy to example 268 starting from 3-chloro-2-fluoro-acetophenone. White solid.
  • MS (ISP): 229.1 ([M+H]+)
    • Example 312 (R)-4-(4-Chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00323
  • (RS)-4-(4-Chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine (example 268) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to give the title compound. (−)-Enantiomer. White solid.
  • MS (ISP): 225.1 ([M+H]+))
    • Example 313 (S)-4-(4-Chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00324
  • (RS)-4-(4-Chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine (example 268) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to give the title compound. (+)-Enantiomer. White solid.
  • MS (ISP): 225.1 ([M+H]+))
    • Example 314 (+)-(S)-4-(5-Chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00325
  • (RS)-4-(5-Chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 272) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (+)-(S)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 213.1 ([{37Cl}M+H]+), 211.1 ([{35Cl}M+H]+)).
    • Examples 315 & 316 (−)-(R)-4-(4-Bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00326
  • (RS)-4-(4-Bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 291) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (−)-(R)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 278.9 ([{81Br37Cl}M+H]+), 276.9 ([{81Br35Cl or 79Br37Cl}M+H]+), 274.9 ([{79Br35Cl}M+H]+)) and (+)-(S)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 278.9 ([{81Br37Cl}M+H]+), 276.9 ([{81Br35Cl or 79Br37Cl}M+H]+), 274.9 ([{79Br35Cl}M+H]+)).
    • Example 317 (−)-(S)-4-(2-Fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00327
  • (RS)-4-(2-Fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 290) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield (−)-(S)-4-(2-fluoro-6-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 248.9 ([M+H]+).
    • Example 318 (RS)-4-(2-Chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00328
  • The title compound was obtained in analogy to example 206 starting from 2-chloro-4-fluoro-acetophenone. Off-white solid.
  • MS (ISP): 229.1 ([M+H]+)
  • In analogy to example 87 was prepared:
    • Example 319 (S)-4-p-Tolyloxymethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00329
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-methyl-phenol. White solid. MS (ISP): 207.3 ([M+H]+).
    • Examples 320 & 321 (−)-(R)-4-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00330
  • (RS)-4-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 252) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to yield (−)-(R)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+)) and (+)-(S)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+)).
    • Example 322 (S)-4-[2-(2-Bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00331
  • The title compound, MS (ISP): 191.3([M−Br+H]+.); 269.1; 271.1 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 2-bromo-1-(2-iodo-ethyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Example 323 (R)-4-Benzylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00332
  • The title compound, MS (ISP): 223.2 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 195 using S-benzyl-L-cysteine instead of S-phenyl-L-cysteine in step a).
  • In analogy to example 87 was prepared:
    • Example 324 (S)-4-(4-Chloro-2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00333
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-chloro-2-fluoro-phenol. White solid. MS (ISP): 247.2 ([{37Cl}M+H]+), 245.2 ([{35Cl}M+H]+)),
    • Example 325 ((S)-4-Cyclohexyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00334
  • The title compound was obtained in analogy to example 1.b starting from (S)-2-amino-2-cyclohexyl-ethanol. White solid.
  • MS (ISP): 169.1 ([M+H]+)
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 326 (RS)-4-(4-Bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00335
  • From 4-bromo-3-chloro-benzaldehyde. White solid. MS (ISP): 278.9 ([{81Br37Cl}M+H]+), 277.0 ([{81Br35Cl or 79Br37Cl}M+H]+), 274.9 ([{79Br35Cl}M+H]+)).
    • Example 327 (RS)-4-(3,4-Dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00336
    • a) (S)-4-(3,4-Dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00337
  • In analogy to example 206, the title compound was obtained starting from 3,4-dichloropropiophenone. White solid.
    • b) (R)-4-(3,4-Dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • (S)-4-(3,4-Dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give the title compound. (−)-Enantiomer. Off-white solid.
  • MS (ISP): 259.0 ([M+H]+)
    • Example 328 (S)-4-(3,4-Dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00338
  • (RS)-4-(3,4-Dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, EtOH/heptane 1:9) to give the title compound. (+)-Enantiomer. Off-white solid.
  • MS (ISP): 258.8 ([M+H]+)
    • Examples 329 & 330 (−)-(R)-4-(4-Bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00339
  • (RS)-4-(4-Bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 326) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to yield (−)-(R)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 278.9 ([{81Br37Cl}M+H]+), 277.0 ([{81Br35Cl or 79Br37Cl}M+H]+), 274.9 ([{79Br35Cl}M+H]+)) and (+)-(S)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 278.9 ([{81Br37Cl}M+H]+), 277.0 ([{81Br35Cl or 79Br37Cl}M+H]+), 274.9 ([{79Br35Cl}M+H]+)).
    • Example 331 (RS)-4-(2,3-Dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00340
  • The title compound was obtained in analogy to example 271 starting from 2,3-dichloro-acetophenone. White solid.
  • MS (ISP): 245.3 ([M+H]+)
    • Example 332 (S)-4-(2-Cyclohexyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00341
  • The title compound was obtained in analogy to example 1 starting from (+)-ethyl-(S)-2 amino-4-cyclohexylbutyrate. Off-white solid.
  • MS (ISP): 197.1 ([M+H]+)
    • Example 333 (S)-4-[2-(2,5-Dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00342
  • The title compound, MS (ISP): 258.9; 261.0 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and 1-(2-bromo-ethyl)-2,5-dichloro-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
  • In analogy to example 163 were prepared:
    • Example 334 (S)-4-[2-(2,4-Difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00343
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 2,4-difluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 255.1 ([M+H]+).
    • Example 335 (S)-4-[2-(2,3,4-Trifluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00344
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 2,3,4-trifluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.1 ([M+H]+).
    • Example 336 (S)-4-[2-(3,4,5-Trifluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00345
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3,4,5-trifluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.1 ([M+H]+).
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 337 (RS)-4-(4-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00346
  • From 4-fluoro-2-methyl-benzaldehyde. White solid. MS (ISP): 195.1 ([M+H]+)
    • Examples 338 & 339 (+)-(S)-4-(4-Bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (−)-(R)-4-(4-Bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00347
  • (RS)-4-(4-Bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 302) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to yield (−)-(R)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (colourless viscous oil; MS (ISP): 311.0 ([{81Br}M+H]+), 309.1 ([{79Br}M+H]+)) and (+)-(S)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (colourless viscous oil; MS (ISP): 311.0 ([{81Br}M+H]+), 309.1 ([{79Br}M+H]+)).
  • In analogy to example 163 was prepared:
    • Example 340 (S)-4-[2-(3-Fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00348
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 237.3 ([M+H]+).
    • Example 341 (+)-(S)-4-(5-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00349
  • (RS)-4-(5-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 225) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to yield (−)-(S)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 267.1 ([{37Cl}M+H]+), 265.0 ([{35Cl}M+H]+).
    • Example 342 (S)-4-(1-Phenyl-cyclopropylmethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00350
  • The title compound, MS (ISP): 217.1 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 257 using (1-phenyl-cyclopropyl)-methanol instead of [1-(4-chlorophenyl)-cyclopropyl]-methanol in step a).
  • In analogy to example 87 was prepared:
    • Example 343 (S)-4-(3-Chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00351
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 3-chloro-phenol. Colourless oil. MS (ISP): 229.2 ([{37Cl}M+H]+), 227.2 ([{35Cl}M+H]+)).
    • Example 344 (RS)-4-(4-Chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00352
    • a) 4-Chloro-2-ethyl-benzaldehyde
  • The title compound was obtained starting from 4-chloro-2-fluoro-benzaldehyde by sequential treatment with N-butylaminine/p-toluenesulphonic acid and ethylmagnesium chloride/manganese(II) chloride according to the procedures described in Synthesis 1999, 2138-2144 and WO 2007/085557. Yellow oil.
    • b) (RS)-4-(4-Chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 252, the title compound was obtained starting from 4-chloro-2-ethyl-benzaldehyde. Light yellow solid. MS (ISP): 227.1 ([{37Cl}M+H]+), 225.1 ([{35Cl}M+H]+)).
    • Examples 345 (−)-(R)-4-Methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00353
    • a) (RS)-4-Methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • In analogy to example 206, the title compound was obtained starting from 1-(2,3,6-trifluoro-phenyl)-ethanone. White solid. MS (ISP): 231.3 ([M+H]+)
    • a) (−)-(R)-4-Methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • (RS)-4-Methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine was separated by chiral HPLC (Chiralpak AD, iPrOH/heptane=5:95) to yield (−)-(R)-4-methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 231.1 ([M+H]+).
    • Examples 346 (+)-(S)-4-Methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00354
  • (RS)-4-Methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (Example 345.a) was separated by chiral HPLC (Chiralpak AD, iPrOH/heptane=5:95) to yield (+)-(S)-4-methyl-4-(2,3,6-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 231.1 ([M+H]+).
    • Examples 347 & 348 (−)-(R)-4-(4-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00355
  • (RS)-4-(4-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 337) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (−)-(R)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 195.1 ([M+H]+) and (+)-(S)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 195.1 ([M+H]+).
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 349 (RS)-4-(4-Bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00356
  • From 4-bromo-2-fluoro-benzaldehyde. White solid. MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+)).
  • In analogy to example 1 was prepared:
    • Example 350 (S)-4-Benzyloxymethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00357
  • From O-benzyl-L-serine methyl ester. Colourless oil. MS (ISP): 206.9 ([M+H]+)
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 351 (RS)-4-(3-Chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00358
  • From 3-chloro-4-methyl-benzaldehyde. White solid. MS (ISP): 213.1 ([{37Cl}M+H]+), 211.0 ([{35Cl}M+H]+)).
    • Example 352 (+)-(R)-4-(5-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00359
  • (RS)-4-(5-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 225) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to yield (+)-(R)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (off-white solid; MS (ISP): 267.1 ([{37Cl}M+H]+), 265.0 ([{35Cl}M+H]+).
  • In an analogy to example 87 were prepared:
    • Example 353 (S)-4-(2,4-Difluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00360
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 2,4-difluorophenol. Colourless oil. MS (ISP): 229.2 ([M+H]+).
    • Example 354 (S)-4-(2-Fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00361
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 2,4-difluorophenol. Colourless oil. MS (ISP): 211.1 ([M+H]+).
  • In analogy to example 162 were prepared:
    • Example 355 (S)-4-[2-(3-Chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00362
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-chloro-2-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.2 ([{37Cl}M+H]+), 271.3 ([{35Cl}M+H]+)).
    • Example 356 (S)-4-[2-(3-Chloro-4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00363
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-chloro-4-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.1 ([{37Cl}M+H]+), 271.1 ([{35Cl}M+H]+)).
    • Example 357 (S)-4-[2-(3-Chloro-5-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00364
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 3-chloro-5-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.3 ([{37Cl}M+H]+), 271.3 ([{35Cl}M+H]+)).
    • Example 358 (S)-4-[2-(5-Chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00365
  • From (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester by sequential treatment with 5-chloro-2-fluorophenyl boronic acid and diethylzinc. Mainly one epimer. Colourless oil. MS (ISP): 273.1 ([{37Cl}M+H]+), 271.1 ([{35Cl}M+H]+)).
  • In analogy to example 344 was prepared:
    • Example 359 (RS)-4-(4-Chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00366
  • Starting from 4-chloro-2-fluoro-benzaldehyde. White solid. MS (ISP): 239.1 ([{37Cl}M+H]+), 237.1 ([{35Cl}M+H]+)).
  • In analogy to example 1 were prepared:
    • Example 360 (S)-4-Cyclohexylmethyl-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00367
  • From (S)-2-amino-3-cyclohexyl-propan-1-ol. White amorphous solid.
  • MS (ISP): 183.2 ([M+H]+)
    • Example 361 (R)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00368
  • From D-2-amino-5-phenyl-pentanoic acid. Light yellow amorphous solid.
  • MS (ISP): 205.3 ([M+H]+)
    • Example 362 (S)-4-[(Benzyl-ethyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00369
    • a) (S)-4-(Benzylamino-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of tert-butyl (R)-(−)-4-formyl-2,2-dimethyl-3-oxazolinecarboxylate (2.0 g) at r.t. in methanol (20 ml) under an argon atmosphere was added benzylamine (0.935 g) and the mixture was stirred overnight at 60° C. Then at room temperature NaBH4 (0.495 g) was added and the mixture was stirred for additional 4 h. This was taken up in dichloromethane and aqueouos sodium bicarbonate solution. The aqueous phase was back extracted with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/ethyl acetate=1:1) to give (S)-4-(benzylamino-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.72 g, 61%) as colourless oil. MS (ISP): 321.1 ([M+H]+)
    • b) (S)-4-[(Benzyl-ethyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
  • To a stirred solution of (S)-4-(benzylamino-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (800 mg) at r.t. in methanol (10 ml) under an argon atmosphere were added acetaldehyde (0.70 ml), ZnCl2 (1.36 g) and NaBH3CN (0.47 g). The mixture was warmed to 50° C. and stirring at that temperature was continued for 17 h. The mixture was cooled to r.t. and partitioned between ammonium chloride solution and dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/ethyl acetate=1:1) to give (S)-4-[(benzyl-ethyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (160 mg, 18%) as colorless oil. MS (ISP): 293.5 ([M−tBu+H]+)
    • c) (S)-4-[(Benzyl-ethyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine
  • To a stirred solution of (S)-4-(benzylamino-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (155 mg) in ethanol (2 ml) under an argon atmosphere was added HCl solution (5 M in ethanol; 2.0 ml). The mixture was stirred at 60° C. for 2 hours and concentrated. The residue was taken up in EtOAc and washed with 1N NaOH. The aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated. The residue was dissolved in methanol (2 ml) and sodium acetate (79 mg) was added. Under ice cooling cyanogen bromide (51 mg) was added and stirring was continued for 18 h. The mixture was directly adsorbed on silica gel and purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to provide (R)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (25 mg, 22%) as colourless oil. MS (ISP): 234.3 ([M+H]+)
    • Examples 363 & 364 (−)-(R)-4-(4-Chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00370
  • (RS)-4-(4-Chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 344) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (−)-(R)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 227.1 ([{37Cl}M+H]+), 225.1 ([{35Cl}M+H]+)) and (+)-(S)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 227.1 ([{37Cl}M+H]+), 225.1 ([{35Cl}M+H]+)).
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 365 (RS)-4-(3-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00371
  • From 3-fluoro-2-methyl-benzaldehyde. Light yellow solid. MS (ISP): 195.3 ([M+H]+)).
    • Examples 366 & 367 (−)-(R)-4-(4-Bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00372
  • (RS)-4-(4-Bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 349) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (−)-(R)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+)) and (+)-(S)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+)).
    • Examples 368 & 369 (−)-(R)-4-(4-Chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(4-Chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00373
  • (RS)-4-(4-Chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 359) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield (−)-(R)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 239.1 ([{37Cl}M+H]+), 237.1 ([{35Cl}M+H]+)) and (+)-(S)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 239.1 ([{37Cl}M+H]+), 237.1 ([{35Cl}M+H]+)).
  • In analogy to example 87 was prepared:
    • Example 370 (R)-4-(4-Chloro-phenylsulfanylmethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00374
  • From tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 4-chloro-thiophenol. White crystals. MS (ISP): 245.2 ([{37Cl}M+H]+), 243.2 ([{35Cl}M+H]+)).
  • In analogy to example 252 and starting from the respective aldehyde was prepared:
    • Example 371 (RS)-4-(3-Fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00375
  • From 3-fluoro-2-(trifluoromethyl)-benzaldehyde. Yellow solid. MS (ISP): 249.3 ([M+H]+)).
  • In analogy to example 332 was prepared:
    • Example 372 (R)-4-(2-Cyclohexyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00376
  • Starting from (+)-ethyl-(5)-2 amino-4-cyclohexylbutyrate. White crystals. MS (ISP): 197.2 ([M+H]+)).
    • Examples 373 & 374 (−)-(R)-4-(3-Chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine & (+)-(S)-4-(3-Chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00377
  • (RS)-4-(3-Chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (example 351) was separated by chiral HPLC (Chiralpak AD, EtOH/heptane=20:80) to yield (−)-(R)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 213.1 ([{37Cl}M+H]+), 211.0 ([{35Cl}M+H]+)) and (+)-(S)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (white solid; MS (ISP): 213.1 ([{37Cl}M+H]+), 211.0 ([{35Cl}M+H]+)).
    • Example 375 (S)-4-[2-(3-Chloro-phenyl)-5,5,5-trifluoro-pentyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00378
    • a) rac-2-(3-Chloro-phenyl)-5,5,5-trifluoro-pentanoic acid
  • To a stirred solution of m-chlorophenylacetic acid (2.38 g, 14 mmol) in tetrahydrofuran (85 ml) was added at −78° C. lithium diisopropylamide solution (31 ml 1M in THF, 31 mmol). After stirring the mixture for 20 min 1-iodo-3,3,3-trifluoropropane (4.38 g, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. Water (5 ml) was added followed by 2N hydrochloric acid (10 ml). The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a colourless oil, (1.75 g, 47%); MS (EI): 264.9 (M+.).
    • b) rac-2-(3-Chloro-phenyl)-5,5,5-trifluoro-pentan-1-ol
  • To a stirred solution of 2-(3-chloro-phenyl)-5,5,5-trifluoro-pentanoic acid (1.75 g, 7 mmol) in tetrahydrofuran (40 ml) under an argon atmosphere was added slowly lithium aluminum hydride (0.4 g, 11 mmol) and the mixture was stirred for 17 hours at room temperature. For work-up water (1.5 ml) and 2N sodium hydroxide solution (0.5 ml) were added and the mixture was stirred for 30 min. After filtration the solvent was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield a colourless oil, (1.25 g, 75%); MS (EI): 311.0 ((M+OAc)+.).
    • c) rac-1-Chloro-3-(4,4,4-trifluoro-1-iodomethyl-butyl)-benzene
  • To a stirred solution of triphenylphosphine (1.56 g, 6.0 mmol) and imidazole (0.41 g, 6.0 mmol) in dichloromethane (16 ml) under an argon atmosphere was added slowly iodine (1.51 g, 6.0 mmol) and 2-(3-chloro-phenyl)-5,5,5-trifluoro-pentan-1-ol (1.26 g, 5.0 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (50 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (50 ml) and hydrochloric acid (1N, 25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow liquid, (1.73 g, 96%); (EI): 235.0 ((M−I)+.).
    • d) (S)-4-[2-(3-Chloro-phenyl)-5,5,5-trifluoro-pentyl]-4,5-dihydro-oxazol-2-ylamine
  • The title compound, MS (ISP): 321.1 ((M+H)+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and rac-1-chloro-3-(4,4,4-trifluoro-1-iodomethyl-butyl)-benzene instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
  • Analagously to Example 1 there were prepared:
    • Example 376 (R)-4-((R)-1-Benzyloxy-ethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00379
  • From O-Benzyl-L-threonine. White solid. MS (ISP): 221.4 ([M+H]+).
    • Example 377 (S)-4-(4-Chloro-benzyloxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00380
  • From O-p-chlorobenzyl-L-serine. Light yellow oil. MS (ISP): 241.2; 243.3 ([M+H]+).
    • Example 378 (R)-4-[(Dimethyl-phenyl-silanyl)-methyl]-4,5-dihydro-oxazol-2-ylamine
  • Figure US20100120864A1-20100513-C00381
  • The title compound, MS (ISP): 158.2 ([M−Ph+H]+.), 235.1 ([M+H]+.) was obtained in comparable yield analogous to the procedure described for Example 228 using (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine instead of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine and chloromethyl dimethyl phenylsilane instead of 1-(2-bromo-ethyl)-2-chlorobenzene in step a).
    • Examples A-G
  • Additionally the following known compounds were prepared as TAAR1 ligands using procedures analogous to those describe above:
    • A: (S)-4-Phenyl-4,5-dihydro-oxazol-2-ylamine (CAS 165035-65-4)
    • B: (R)-4-Phenyl-4,5-dihydro-oxazol-2-ylamine (CAS 165035-66-5)
    • C: (S)-4-Benzyl-4,5-dihydro-oxazol-2-ylamine (CAS 856899-65-5)
    • D: (RS)-4-Phenethyl-4,5-dihydro-oxazol-2-ylamine (CAS 103522-08-3)
    • E: 4,4-Diphenyl-4,5-dihydro-oxazol-2-ylamine (CAS 132798-69-7)
    • F: (RS)-4-Benzyloxymethyl-4,5-dihydro-oxazol-2-ylamine (CAS 103521-92-2)
    • G: (RS)-4-Cyclohexyl-4,5-dihydro-oxazol-2-ylamine (CAS 63204-74-0)

Claims (53)

1. A method of treating a disorder selected from the group consisting of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders comprising administering to an individual a therapeutically effective amount of a compound of formula I
Figure US20100120864A1-20100513-C00382
wherein
R1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, phenyloxy, benzyl, benzyloxy, —COO-lower alkyl, —O—(CH2)o—O-lower alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the substituents for n>1 are the same or different;
X is a bond, —CHR—, —CHRCHR′—, —OCH2—, —CH2OCHR—, —CH2CH2CH2—, —SCH2—, —S(O)2CH2—, —CH2SCH2—, —CH2N(R)CH2—, -cycloalkyl-CH2— or SiRR′—CH2—;
R and R′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen;
R2 is hydrogen, phenyl or lower alkyl;
Y is phenyl, naphthyl, thiophenyl, pyridinyl, cycloalkyl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl or benzo[1,3]dioxol-5-yl;
n is 0, 1, 2 or 3; and
o is 2 or 3;
or of a pharmaceutically suitable acid addition salt thereof.
2. The method of claim 1, wherein X is a bond.
3. The method of claim 2, wherein Y is phenyl, substituted by one or more halogen atoms.
4. The method of claim 3, wherein the compound administered is selected from the group consisting of
(S)-4-(2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3,4-dichlorophenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,(S)-4-(3,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine;
(S)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine;
(S)-4-(4-chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(5-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(4-chloro-2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine.
5. The method of claim 2, wherein Y is phenyl substituted by CH3, CF3, OCH3, OCF3 or OCH2-phenyl.
6. The method of claim 5, which compound administered is selected from the group consisting of
(RS)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-benzyloxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
(+)-(S)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
7. The method of claim 2, wherein Y is phenyl substituted by phenyl, which is optionally substituted by halogen.
8. The method of claim 7, which compound administered is selected from the group consisting of
(RS)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine, and
(RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine.
9. The method of claim 2, wherein Y is phenyl substituted by OCH3 or by halogen and CF3, halogen and CH3, halogen and cycloalkyl or by halogen and OCH3.
10. The method of claim 9, wherein the compound administered is selected from the group consisting of
(RS)-4-(3-chloro-4-methoxyphenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
11. The method of claim 1, wherein X is CHR and Y is phenyl.
12. The method of claim 11, wherein the compound administered is selected from the group consisting of
(S)-4-(2-chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine, and
(RS)-4-(2-fluoro-5-methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine.
13. The method of claim 1, wherein X is CHRCHR′ and Y is phenyl.
14. The method of claim 13, wherein the compound administered is selected from the group consisting of (R)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-methoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
((S)-4-[2-(2,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-o-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-m-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-p-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(R)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-methyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-{2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,3-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(1-methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-((R)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-6-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,4-dichloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-5-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-[2-(5-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine.
15. The method of claim 1, wherein X is OCH2 and Y is phenyl.
16. The method of claim 15, wherein the compound administered is selected from the group consisting of
(S)-4-(4-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,5-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine.
17. The method of claim 1, wherein X is CH2OCHR and Y is phenyl.
18. The method of claim 17, wherein the compound administered is (S)-4-benzyloxymethyl-4,5-dihydro-oxazol-2-ylamine.
19. The method of claim 1, wherein X is —(CH2)3— and Y is phenyl.
20. The method of claim 19, wherein the compound administered is selected from the group consisting of
(S)-4-(3-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine and
(R)-4-(3-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine.
21. The method of claim 1, wherein X is —SCH2—, —S(O)2CH2—, or —CH2SCH2— and Y is phenyl.
22. The method of claim 21, wherein the compound administered is selected from the group consisting of
(R)-4-phenylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-benzenesulfonylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-benzylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine, and
(R)-4-(4-chloro-phenylsulfanylmethyl)-4,5-dihydro-oxazol-2-ylamine.
23. The method of claim 1, wherein X is —CH2N(R)CH2—, cycloalkyl-CH2— or SiRR′—CH2— and Y is phenyl.
24. The method of claim 23, wherein the compound administered is selected from the group consisting of
(S)-4-[1-(4-chloro-phenyl)-cyclopropylmethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[1-(4-chloro-phenyl)-cyclobutylmethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(1-phenyl-cyclopropylmethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[(benzyl-ethyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine, and
(R)-4-[(dimethyl-phenyl-silanyl)-methyl]-4,5-dihydro-oxazol-2-ylamine.
25. The method of claim 1, wherein Y is naphthyl, pyridyl, cyclohexyl, 2,3-dihydrobenzo[1,4]dioxin or 1,2,3,4-tetrahydronaphthalen.
26. The method of claim 25, wherein the compound administered is selected from the group consisting of
(RS)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-naphthalen-1-yl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-2-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(1,2,3,4-tetrahydro-naphthalen-2-yl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-methyl-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(2-cyclohexyl-ethyl)-4,5-dihydro-oxazol-2-ylamine.
27. A compound of formula I
Figure US20100120864A1-20100513-C00383
wherein
R1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, phenyloxy, benzyl, benzyloxy, —COO-lower alkyl, —O—(CH2)o—O-lower alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the substituents for n>1 are the same or different;
X is a bond, —CHR—, —CHRCHR′—, —OCH2—, —CH2OCHR—, —CH2CH2CH2—, —SCH2—, —S(O)2CH2—, —CH2SCH2—, —CH2N(R)CH2—, -cycloalkyl-CH2— or SiRR′—CH2—;
R and R′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen;
R2 is hydrogen, phenyl or lower alkyl;
Y is phenyl, naphthyl, thiophenyl, pyridinyl, cycloalkyl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl or benzo[1,3]dioxol-5-yl;
n is 0, 1, 2 or 3; and
o is 2 or 3;
or of a pharmaceutically suitable acid addition salt thereof.
28. The compound of claim 1, having formula I-A
Figure US20100120864A1-20100513-C00384
wherein
R1 is halogen, for n>1 the halogen atom is the same or different;
R2 is hydrogen, phenyl or lower alkyl; and
n is 1, 2 or 3;
or a pharmaceutically suitable acid addition salt thereof.
29. The compound of claim 28, which is selected from the group consisting of
(S)-4-(2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3,4-dichlorophenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(5-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(4-chloro-2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine.
30. The compound of claim 27, having formula I-B
Figure US20100120864A1-20100513-C00385
R1 is CH3, CF3, OCH3, OCF3 or OCH2-phenyl, wherein the substituents for n>1 are the same or different;
R2 is hydrogen, phenyl or lower alkyl;
n is 1, 2 or 3;
or a pharmaceutically suitable acid addition salt thereof.
31. The compound of claim 30, which is selected from the group consisting of
(RS)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-benzyloxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
(+)-(S)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
32. The compound of claim 27, having formula I-C
Figure US20100120864A1-20100513-C00386
wherein
R2 is hydrogen, phenyl or lower alkyl;
or a pharmaceutically suitable acid addition salt thereof.
33. The compound of claim 32, which is selected from the group consisting of
(RS)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine, and
(RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine.
34. The compound of claim 27, having formula I-D
Figure US20100120864A1-20100513-C00387
wherein
R1 is halogen and CF3, halogen and CH3, halogen and cycloalkyl, or is halogen and OCH3; and
R2 is hydrogen, phenyl or lower alkyl;
or a pharmaceutically suitable acid addition salt thereof.
35. The compound of claim 34, which is selected from the group consisting of
(RS)-4-(3-chloro-4-methoxyphenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, and
(RS)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
(S)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
(RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
(S)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine
(RS)-4-(3-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine or
(S)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine.
36. The compound of claim 27, having formula I-E
Figure US20100120864A1-20100513-C00388
wherein
R1 is halogen, CF3 or CH3, wherein the substituents for n>1 are the same or different;
R2 is hydrogen, phenyl or lower alkyl;
R is hydrogen, lower alkyl or lower alkyl substituted by halogen; and
n is 1 or 2;
or a pharmaceutically suitable acid addition salt thereof.
37. The compound of claim 36, which is selected from the group consisting of
(S)-4-(2-chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine, and
(RS)-4-(2-fluoro-5-methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine.
38. The compound of claim 27, having formula I-F
Figure US20100120864A1-20100513-C00389
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or is halogen, wherein the substituents for n>1 are the same or different;
R and R′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen;
R2 is hydrogen, phenyl or lower alkyl; and
n is 0, 1, 2 or 3;
or a pharmaceutically suitable acid addition salt thereof.
39. The compound of claim 38, which is selected from the group consisting of
(R)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-methoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
((S)-4-[2-(2,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-o-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-m-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-p-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(R)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-methyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-{2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,3-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(1-methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-((R)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-6-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,4-dichloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-5-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-[2-(5-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine.
40. The compound of claim 27, having formula I-G
Figure US20100120864A1-20100513-C00390
wherein
R1 is lower alkyl, lower alkyl substituted by halogen or halogen, wherein the substituents for n>1 are the same or different;
R2 is hydrogen, phenyl or lower alkyl; and
n is 0, 1, 2 or 3;
or a pharmaceutically suitable acid addition salt thereof.
41. The compound of claim 40, which is selected from the group consisting of
(S)-4-(4-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,5-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine.
42. The compound of claim 27, having formula I-H
Figure US20100120864A1-20100513-C00391
wherein
R1 is hydrogen or halogen; and
n is 0 or 1;
or a pharmaceutically suitable acid addition salt thereof.
43. The compound of claim 42, which is
(S)-4-benzyloxymethyl-4,5-dihydro-oxazol-2-ylamine.
44. The compound of claim 27, wherein X is —(CH2)3— and Y is phenyl.
45. The compound of claim 44, which is selected from the group consisting of
(S)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine and
(R)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine.
46. The compound of claim 27, wherein X is —SCH2—, —S(O)2CH2—, —CH2S(O)2CH2— or —CH2SCH2— and Y is phenyl.
47. The compound of claim 46, which is selected from the group consisting of
(R)-4-phenylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-benzenesulfonylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-benzylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine, and
(R)-4-(4-chloro-phenylsulfanylmethyl)-4,5-dihydro-oxazol-2-ylamine.
48. The compound of claim 27, wherein X is —CH2N(R)CH2—, cycloalkyl-CH2— or SiRR′—CH2— and Y is phenyl.
49. The compound of claim 48, which is selected from the group consisting of
(S)-4-[1-(4-chloro-phenyl)-cyclopropylmethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[1-(4-chloro-phenyl)-cyclobutylmethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(1-phenyl-cyclopropylmethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[(benzyl-ethyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine, and
(R)-4-[(dimethyl-phenyl-silanyl)-methyl]-4,5-dihydro-oxazol-2-ylamine.
50. The compound of claim 27, wherein Y is naphthyl, pyridyl, cyclohexyl, 2,3-dihydrobenzo[1,4]dioxin or 1,2,3,4-tetrahydronaphthalen.
51. The compound of claim 50, which is selected from theg group consisting of
(RS)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-nap hthalen-1-yl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-2-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(1,2,3,4-tetrahydro-naphthalen-2-yl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-methyl-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(2-cyclohexyl-ethyl)-4,5-dihydro-oxazol-2-ylamine.
52. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
Figure US20100120864A1-20100513-C00392
wherein
R1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, phenyloxy, benzyl, benzyloxy, —COO-lower alkyl, —O—(CH2)o—O-lower alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the substituents for n>1 are the same or different;
X is a bond, —CHR—, —CHRCHR′—, —OCH2—, —CH2OCHR—, —CH2CH2CH2—, —SCH2—, —S(O)2CH2—, —CH2SCH2—, —CH2N(R)CH2—, -cycloalkyl-CH2— or SiRR′—CH2—;
R and R′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen;
R2 is hydrogen, phenyl or lower alkyl;
Y is phenyl, naphthyl, thiophenyl, pyridinyl, cycloalkyl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl or benzo[1,3]dioxol-5-yl;
n is 0, 1, 2 or 3; and
o is 2 or 3;
or of a pharmaceutically suitable acid addition salt thereof and a pharmaceutically acceptable carrier.
53. The composition of claim 52, wherein the compound of formula I is selected from the group consisting of
(S)-4-(2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3,4-dichlorophenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,3-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-5-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-chloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(3,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,3,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(5-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(4-chloro-2,5-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2,5-difluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,4-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,5-dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,5-dichloro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(2,3,4-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(3,4,5-trifluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-2-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-chloro-4-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-3-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-2-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-benzyloxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-p-tolyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-(3-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-4-methoxyphenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(−)-(R)-4-(4,5-dichloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-3-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-fluoro-5-methyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-bromo-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(+)-(S)-4-(4-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-ethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-2-cyclopropyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(3-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-4-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-chloro-benzyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-trifluoromethyl-benzyl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2-fluoro-5-methyl-benzyl)-4,5-dihydro-oxazol-2-ylamine,
(R)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-methyl-4-phenethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-methoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
((S)-4-[2-(2,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-o-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-m-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-p-tolyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(R)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-2-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-methyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-{2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-3-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,3-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-4-trifluoromethoxy-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-3-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(1-methyl-2-phenyl-ethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-trifluoromethyl-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,5-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-difluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3,4-dichloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(4-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-((R)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-chloro-6-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,4-dichloro-phenyl)-ethyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-bromo-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2,5-dichloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-chloro-5-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(5-chloro-2-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,4-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3,5-dichloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(4-bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-chloro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2,4-difluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-benzyloxymethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine,
(R)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine,
(R)-4-phenylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-benzenesulfonylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-benzylsulfanylmethyl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-(4-chloro-phenylsulfanylmethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[1-(4-chloro-phenyl)-cyclopropylmethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[1-(4-chloro-phenyl)-cyclobutylmethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-(1-phenyl-cyclopropylmethyl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[(benzyl-ethyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine,
(R)-4-[(dimethyl-phenyl-silanyl)-methyl]-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-naphthalen-1-yl-4,5-dihydro-oxazol-2-ylamine,
(R)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-1-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-2-ylmethyl-4,5-dihydro-oxazol-2-ylamine,
(RS)-4-(1,2,3,4-tetrahydro-naphthalen-2-yl)-4,5-dihydro-oxazol-2-ylamine,
(S)-4-naphthalen-2-yl-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(3-fluoro-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine,
(S)-4-[2-(2-methyl-pyridin-4-yl)-ethyl]-4,5-dihydro-oxazol-2-ylamine, and
(S)-4-(2-cyclohexyl-ethyl)-4,5-dihydro-oxazol-2-ylamine
or a pharmaceutically suitable acid addition salt thereof.
US12/639,076 2007-02-02 2009-12-16 2-aminooxazolines as taar1 ligands Abandoned US20100120864A1 (en)

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