AU4076593A - Azacyclic compounds - Google Patents

Azacyclic compounds

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Publication number
AU4076593A
AU4076593A AU40765/93A AU4076593A AU4076593A AU 4076593 A AU4076593 A AU 4076593A AU 40765/93 A AU40765/93 A AU 40765/93A AU 4076593 A AU4076593 A AU 4076593A AU 4076593 A AU4076593 A AU 4076593A
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AU
Australia
Prior art keywords
methyloxy
phenyl
methyl
trifluoromethyl
phenylpiperidino
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Granted
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AU40765/93A
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AU675786B2 (en
Inventor
Raymond Baker
Tamara Laddhwahetty
Eileen Mary Seward
Christopher John Swain
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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Priority claimed from GB929208323A external-priority patent/GB9208323D0/en
Priority claimed from GB929216065A external-priority patent/GB9216065D0/en
Priority claimed from GB929219686A external-priority patent/GB9219686D0/en
Priority claimed from GB929226069A external-priority patent/GB9226069D0/en
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of AU4076593A publication Critical patent/AU4076593A/en
Application granted granted Critical
Publication of AU675786B2 publication Critical patent/AU675786B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

AZACYCLIC COMPOUNDS
This invention relates to a class of azacyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention
comprise an azacyclic ring system substituted by an arylmethyloxy or arylmethylthio moiety.
The tachykinins are a group of naturally-occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the-peripheral nervous and circulatory systems. The structures of three known mammalian tachykinins are as follows:
Substance P:
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
Neurokinin A:
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2
Neurokinin B:
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2
For example, substance P is believed inter alia to be involved in the neurotransmission of pain
sensations [Otsuka et al, "Role of Substance P as a
Sensory Transmitter in Spinal Cord and Sympathetic
Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (Dec. 1987) 8.506-510], specifically in the transmission of pain in migraine (B.E.B. Sandberg et al, J. Med Chem, (1982) 25 1009; S.L. Shepheard et al. , Br. J. Pharmacol. (1993), 108. 11-12) and in
arthritis [Levine et al in Science (1984) 226 547-549]. These peptides have also been implicated in
gastrointestinal (GI) disorders and diseases of the GI tract such as inflammatory bowel disease [Mantyh et al in Neuroscience (1988) 25 (3) 817-37 and D. Regoli in
"Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)]. It is also hypothesised that there is a neurogenic mechanism for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Grδnblad et al
"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988)
15(12) 1807-10]. Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [0'Byrne et al in Arthritis and Rheumatism (1990) 33 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],
immunoregulation [Lotz et al Science (1988) 2411218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 85 3235-9] and, possibly by arresting or slowing β-amyloid-mediated neurodegenerative changes [Yankner et al Science, (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
Substance P may also play a role in
demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992 ] , and in disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet. 16th May, 1992, 1239).
It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and
Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent application no. 0 436 334), ophthalmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989) and emesis (European patent application no. 0533 280).
In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that nonpeptide tachykinin antagonists are sought.
European patent application no. 0 436 334 discloses 4- to 7-membered azacyclic compounds
substituted at the 3-position by a substituted amino moiety. The compounds are said to be tachykinin
antagonists.
The present invention provides a compound of formula (I), or a salt or prodrug thereof:
wherein
n is 1, 2 or 3;
X represents O or S;
Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo;
R1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl,
trimethylsilyl, -ORa, SRa, SORa, SO2Ra, -NRaRb, -NRaCORb, -NRaCO2Rb, -CO2Ra or -CONRaRb;
R2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;
benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C1-6alkyl, C1-6alkoxy, halo or trifluoromethyl;
R4 and R5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, C1-6alkyl, oxo, CH2ORa, CO2Ra or
CONRaRb;
R8 represents an optionally substituted
aromatic heterocycle; and Ra and Rb each independently represent H, trifluoromethyl, C1-6alkyl or phenyl optionally
substituted by C1-6alkyl, halo or trifluoromethyl.
As used herein, the definition of each expression, when it occurs more than once in any
structure, is intended to be independent of its
definition elsewhere in the same structure.
The alkyl, alkenyl and alkynyl groups referred to with respect to the above formula may represent straight, branched or cyclic groups, or combinations thereof. Thus, for example, suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such as
cyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl.
The term "halo" as used herein includes fluoro, chloro, bromo and iodo, especially chloro and fluoro.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily
convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The compounds according to the invention may exist both as enantiomers and as diastereomers. In particular, the relative orientation of the 2- and 3-substituents on the azacyclic ring may give rise to cis and trans diastereoisomers, of which the cis
stereochemistry is preferred. It is to be understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention.
Preferably n is 2 or 3, more preferably 3.
Preferably X represents O.
Suitably Y represents a hydrocarbon chain of 1 or 2 carbon atoms optionally substituted by oxo, such as CH2, C=O, CH(CH3), CH2(C=O) or (C=O)CH2. Preferably Y represents CH2, CH(CH3) or CH2(C=O), more preferably CH2 or CH(CH3). A particularly preferred subgroup of
compounds according to the invention is represented by compounds of formula (I) wherein Y is CH(CH3).
Preferably R1 represents substituted phenyl. When R1 is substituted phenyl suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, C1-6alkyl such as methyl, ethyl, i-propyl, i-butyl, t-butyl and cyclopropyl,
C2-6alkenyl such as vinyl, C1-6alkoxy such as methoxy, ethoxy and i-propoxy, phenoxy, amino, carboxamido and carbonylmethoxy. Preferably R1 represents phenyl
substituted by one or more groups selected from
C1-4alkyl, such as methyl and t-butyl, trifluoromethyl and halo such as iodo, bromo chloro and fluoro.
Suitably R1 represents monosubstituted phenyl, such as 3-substituted phenyl or, preferably,
disubstituted phenyl, such as 3,5-disubstituted phenyl. Preferably R1 represents phenyl substituted at the 3-position by trifluoromethyl or a C1-6alkyl group such as t-butyl, or 3,5-disubstituted phenyl wherein the
substituents are independently selected from
trifluoromethyl, chloro, fluoro, methyl and t-butyl.
Preferred values for R1 include 3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-t-butyl-5-methylphenyl, 3-chloro-5-methylphenyl, 3-t-butyl-5-chlorophenyl, 3-bis(trifluoromethyl)phenyl and 3-t- butylphenyl. Particularly preferred is 3,5-bis(trifluoromethyl)phenyl.
Suitably R2 represents benzhydryl or optionally substituted phenyl, such as phenyl optionally substituted by halo such as fluoro or chloro, preferably in the 3-position. Preferably R2 represents unsubstituted phenyl or unsubstituted benzhydryl, more preferably
unsubstituted phenyl.
Suitable values for R4 and R5 include H,
C1-6alkyl, especially methyl, hydroxymethyl and oxo. The substitutents R4 and R5 may be located on any available carbon atom of the azacyclic ring including, except in the case where the substituent R4 or R in question represents oxo, C-2 and C-3. Preferably at least one of R4 and R5 represents H. In one preferred group of compounds R4 and R5 both represent H. In a further preferred group of compounds one of R and R5 is H and the other of R4 and R5 is methyl, preferably 2-methyl.
When R represents a substituted aromatic heterocycle, suitable substituents in the heterocyclic ring include one or more of C1-6alkyl, C1-6alkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NRaRb,
NRaCORb, CONRaRb, CO2Ra, SRa, SO2Ra and CH2ORa, where Ra and Rb are as previously defined. Particular examples of suitable substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH2, SCH3, CONH2 and cyano. Particularly preferred substituents include oxo and NH2.
Suitable values for R8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl,
isoxazolyl, quinolyl, isothiazolyl, imidazolyl,
benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl, any of which may be
substituted.
In particular, R8 may represent optionally substituted thienyl, furyl, pyridyl, triazolyl,
tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl,
pyridazinyl, triazinyl, oxazolyl, oxadiazolyl,
thiadiazolyl, imidazolyl, benzimidazolyl or benzoxazolyl.
In one group of compounds according to the invention R8 represents optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, oxadiazolyl, thiadiazolyl, imidazolyl,
benzimidazolyl, benzoxazolyl, benzothiophenyl,
benzofuranyl or indolyl.
Preferably R8 represents a substituted or unsubstituted 5- or 6-membered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl,
triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl. More preferably R8 represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl,
pyridazinyl or triazinyl, or tetrazolyl substituted by C1-6alkyl, preferably methyl.
In one preferred group of compounds according to the invention, R8 represents substituted or
unsubstituted oxadiazolyl, for example, oxadiazolyl substituted by halo, amino, dialkylamino or methyl. More preferably R8 represents 5-(3-aminooxadiazolyl).
In a further preferred group of compounds according to the invention, R8 represents substituted or unsubstituted triazolyl, for example, unsubstituted triazolyl or triazolyl subtituted by oxo or thioxo, more preferably, triazolyl substituted by oxo. It will be appreciated that, when the
heterocyclic moiety R8 is substituted by an oxo or thioxo substituent, different tautomeric forms are possible so that the substituent may be represented as =O or -OH, or =S or -SH, respectively. For the avoidance of doubt, all such tautomeric forms are embraced by the present
invention.
One subgroup of compounds according to the invention is represented by compounds of formula (IA), and salts and prodrugs thereof:
wherein
n is 1, 2 or 3 and where any carbon atom of (CH2)n may be substituted by R12 and/or R13;
X represents O or S;
R10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl,
trimethylsilyl, -ORc, SRc, SORc, SO2Rc, -NRcRd, -NRcCORd, -NRcCO2Rd, -CO2Rc or -CONRcRd;
R11 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;
benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C1-6alkyl, C1-6alkoxy, halo or trifluoromethyl; R12 and R13 each independently represent H, halo, C1-6alkyl, oxo, CO2Rc or CONRcRd;
R14 represents C1-4alkyl, optionally substituted by oxo, substituted by an optionally
substituted aromatic heterocycle; and
Rc and Rd each independently represent H,
C1-6alkyl, phenyl optionally substituted by C1-6alkyl or halo or trifluoromethyl.
Suitable values for the heterocyclic moiety of R14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,
quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl.
in one sub-class of compounds of formula (IA),
Rc and Rd each independently represent H, C1-6alkyl, phenyl or trifluoromethyl.
A further subclass of compounds of formula (IA) is represented by compounds wherein n is 2 or 3; R12 and R13 each independently represent H, halo, C1-6alkyl,
CO2Rc or CONRcRd; R14 represents C1-4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and Rc and Rd each independently represent H, C1-6alkyl, phenyl or trifluoromethyl. For the
compounds of this subclass, suitable values for the heterocyclic moiety of R14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,
isoxazolyl, isothiazolyl and imidazolyl.
A preferred sub-class of compounds according to the invention is represented by compounds of formula (IB), and salts and prodrugs thereof:
wherein
X represents O or S, preferably O;
Y is as defined for formula (I), preferably C1-2alkyl optionally substituted by oxo, more preferably CH2 or CH(CH3);
R2 represents phenyl or benzhydryl wherein any of the phenyl rings of the phenyl or benzhydryl moieties may optionally be substituted by halo or trifluoromethyl, preferably unsubstituted phenyl;
R8 is as defined for formula (I); and
R20 and R21 independently represent H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, bromo, chloro, fluoro, iodo, cyano, nitro, trifluoromethyl,
trimethylsilyl, ORa, SRa SORa, SO2Ra, NRaRb, NRaCORb, NRaCO2Rb, CORa, CO2Ra or CONRaRb, where Ra and Rb are as previously defined; and
z is 1 or 2.
Particular values of R20 and R21 include H, methyl, t-butyl, methoxy, i-propoxy, chloro, fluoro, nitro, amino, carbonylmethoxy, carboxamido and
trifluoromethyl. Preferably R20 and R21 are both other than H, more preferably C1-6alkyl, halo or trifluoromethyl, and are located at the 3- and 5-positions of the phenyl ring.
One sub-class of compounds according to the invention are compounds of formula (IB) wherein R8 is optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl,
benzimidazolyl, benzoxazolyl, benzothiophenyl,
benzofuranyl, indolyl, thiadiazolyl or oxadiazolyl, more preferably oxadiazolyl.
A further sub-class of compounds according to the invention are compounds of formula (IB) wherein R8 is optionally substituted oxadiazolyl, pyridinyl,
benzimidazolyl, tetrazolyl, thiazolyl, furyl, thienyl, triazolyl, thiadiazolyl, benzoxazolyl, oxazolyl,
pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl or
imidazolyl.
A particularly preferred group of compounds according to the invention are compounds of formula (Ia) wherein R8 is optionally substituted triazolyl,
especially triazole substituted by oxo.
For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention (such as the dibenzoyltartrate salts) or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically
acceptable acid such as hydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable
pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
Preferred salts of the compounds according to the invention include the hydrochloride and p-toluenesulphonic acid salts.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically
acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or
suppositories, for oral, parenteral or rectal
administration, or administration by inhalation or insufflation.
The invention further provides a process for the preparation of a pharmaceutical composition
comprising a compound of formula (I), or a salt or prodrug thereof, and a pharmaceutically acceptable carrier, which process comprises bringing a compound of formula (I), or a salt or prodrug thereof into
association with a pharmaceutically acceptable carrier.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose. sucrose, sorbitol, talc, stearic acid, magnesium
stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a nontoxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as
homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of
polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose
acetate.
The liquid forms in which the novel
compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin..
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable
excipients as set out above. Preferably the compositions are adminsitered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. These may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia;
neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotropic lateral
sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral
neuropathy, for example, diabetic or chemotherapy-induced neuropathy, and postherpetic and other neuralgias;
respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma;
inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis;
hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact
dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome;
dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; ernesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyper-reflexia;
fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. For example, the compounds of formula (I) may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of the Alzheimer type,
Alzheimer's disease and Down's syndrome; respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
The compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and
chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P. The present invention also provides a method for the treatment or prevention of physiological
disorders associated with an excess of tachykinins, especially substance P, which method comprises
administration to a patient in need thereof of a
tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I) .
For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another
pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a β2-adrenergic receptor
antagonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the
bronchodilator may be administered to a patient
simultaneously, sequentially or in combination.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable
carrier.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg of a compound of formula (I) per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be
administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
According to one general process (A), the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula (II):
wherein R1, R2, R4, R5, X and n are as defined for formula (I) above, with a reagent suitable to introduce the group Y-R8, for example, a halide or acyl halide, or corresponding mesylate or tosylate, of formula R8-Y-L, where L represents halo, such as chloro, bromo or iodo, methylsulphonate or p- toluenesulphonate,or any other suitable leaving group, in the presence of a base.
Suitable bases of use in the reaction include inorganic bases such as alkali metal carbonates, for example, potassium carbonate.
Conveniently the reaction is effected in a suitable organic solvent, for example, dimethylformamide.
According to a second process (B), compounds of formula (I) wherein R8 represents 5-oxadiazolyl may be prepared by reaction of a compound of formula (III) with a compound of formula (IV):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), R30 represents an alkyl group and R31 represents H or a suitable substituent such as C1-6alkyl, C1-6alkoxy, halo, NRaRb or NRaCORb, where Ra and Rb are as previously defined, in the presence of a base.
Suitable bases of use in the reaction include alkali metals, such as, for example, sodium, and alkali metal hydrides, such as, for example, sodium hydride.
The reaction is conveniently effected in a suitable organic solvent. Which solvents will be
appropriate will depend on the nature of the base used. For example, where the base used is an alkali metal, suitable solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali
hydride, suitable solvents will include ethers, for example, tetrahydrofuran.
Preferably the reaction is conducted at
elevated temperature, such as the reflux temperature of the chosen solvent.
According to a further process, (C), compounds of formula (I) wherein R8 represents tetrazolyl may be prepared from intermediates of formula (V):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I) by treatment with an alkali metal azide, such as sodium azide.
The reaction is conveniently effected in a high boiling organic solvent, such as, for example,
N-methylpyrrolidinone.
According to a further process, (D), compounds of formula (I) wherein R8 represents thiazolyl may be prepared from intermediates of formula (VI):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), by reaction with a compound of formula
Hal-CH2C(O)-R60, where Hal represents halo, such as bromo, chloro or iodo, and R60 represents H or a suitable substituent such as C1-6alkyl. The reaction is conveniently effected in a suitable organic solvent, such as a ketone, for example, acetone, or an alcohol, for example, methanol, or a mixture of solvents, preferably at elevated temperature, such as the reflux temperature of the chosen solvent.
According to a futher process, (E), compounds of formula (I) wherein R8 represents thioxotriazolyl may be prepared from intermediates of formula (VII)
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), by reaction with a compound of formula
R61NCS, wherein R61 represents H or a suitable
substituent such as C1-6alkyl, in the presence of a base.
Suitable bases of use in the reaction include organic bases such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is conveniently effected in a suitable orgainc solvent, such as alcohol, e.g. butanol.
According to a further process, (F), compounds of formula (I) wherein R8 represents unsubstituted or substituted triazolyl may be prepared by reaction of intermediates of formula (II) with a compound of formula
(VIII):
wherein Y and Hal are as previously defined and R18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates, such as, for example, potassium carbonate.
Suitably R18 represents H, OCH3 (which is converted to an oxo substituent under the reaction conditions) or CONH2.
The reaction is conveniently effected in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140ºC.
According to a further process, (G), compounds of formula (I) wherein R8 represents substituted or unsubstituted 1,3,5-triazine may be prepared by reaction of intermediates of formula (IX):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with substituted or unsubstituted 1,3,5-triazine.
The reaction is conveniently effected in a suitable organic solvent, such as acetronitrile, at elevated temperature, such as 80-90ºC, preferably about
82'C.
According to a further process, (H), compounds of formula (I) wherein R represents substituted or unsubstituted 1,2,5-triazine may be prepared by reaction of an intermediate of formula (X) with a dicarbonyl compound of formula (XI):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I) and R35 and R36 each independently represnt H or a suitable substituent such as C1-6alkyl, e.g. methyl.
The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g.
tetrahydrofuran, conveniently at ambient temperature.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (VIII) may be prepared as described in J. Med. Chem. 27, (1984), 849.
Compounds of formula (I) may also be prepared from other compounds of formula (I) using suitable interconversion procedures. For example, compounds of formula (I) wherein Y represents C1-4alkyl substituted by an aromatic heterocycle may be prepared from compounds of formula (I) wherein Y represents C1-4alkyl substituted by oxo by reduction, for example, using borane. Suitable interconversion procedures are described in the
accompanying Examples, or will be readily apparent to those skilled in the art.
Intermediates of formula (III) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-CO2R30, where Hal represents halo such as chloro, bromo or iodo and R30 and Y are as above defined, in the presence of a base. Suitable bases include tertiary amines, for example, triethylamine.
Conveniently the reaction is effected in a suitable organic solvent, such as an ether, for example,
tetrahydrofuran, at elevated temperature, such as the reflux temperature of the solvent.
Intermediates of formula (IV) are commercially available or may be prepared from commercially available materials by conventional procedures well-known to those skilled in the art. Intermediates of formula (II) may be prepared as described in published European patent application no. 0 528 495.
Intermediates of formula (V) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-CN, wherein Hal is halo such as bromo, chloro or iodo and Y is as previously defined.
Intermediates of formula (VI) may be prepared from intermediates of formula (V) by treatment with an alkylthioamide, such as, for example, thioacetamide.
Intermediates of formula (VII) may be prepared from intermediates of formula (III) by treatment with hydrazine. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for
example, ethanol, at elevated temperature.
Intermediates of formula (IX) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NH2, where Hal and Y are as previously defined.
Intermediates of formula (X) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NHNH-Boc, wherein Hal and Y are as previously defined and Boc stands for
t-butoxycarbonyl, followed by deprotection under acidic conditions.
Compounds of formula (XI) are commercially available or may be prepared from commercially available compounds by known methods.
Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. For example, any suitable intermediates may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric esters or amides, followed by chromatographic separation or separation by fractional crystallization and removal of the chiral auxiliary. The diastereomeric intermediates can then be used to prepare optically pure compounds of formula (I) .
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in
Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Orσanic Synthesis. John Wiley & Sons, 1991. The
protecting groups may be removed at a convenient
subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds according to the invention.
The substance P antagonising activity of the compounds described herein was evaluated using the human NK1R assay described in published European patent
application no. 0 528 495. The method essentially involves determining the concentration of the test compound required to reduce by 50% the amount of
radiolabelled substance P binding to human NK1R, thereby affording an IC50 value for the test compound. The compounds of Examples 1-10, for example, were found to have IC50 values less than 500nM. DESCRIPTION 1: cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyl oxy)-2-phenylpiperidine hydrochloride salt
a) A solution of methyl 4-nitrobutyrate (23g) and benzaldehyde (16ml) in acetic acid (39ml) containing ammonium acetate (12.12g) was heated at reflux under nitrogen for 2h. The reaction mixture was cooled to 5°C, whereby a pale-yellow solid crystallised- This was isolated by filtration, then dissolved in dichloromethane, washed cautiously with saturated aqueous sodium bicarbonate solution (2 x), then dried (MgSO4) and concentrated to leave a yellow solid. Recrystallisation from ethyl acetate provided 5-nitro-2-oxo-6-phenylpiperidine (12.5g) as a crystalline, white solid, 1H NMR (CDCl3) d 7.46-7.26 (m), 6.0 (br s), 5.24 (dd, J = 1.4, 7.0Hz), 4.70 (m), 2.70-2.50 (m), 2.38-2.24 (m).
b) Potassium t-butoxide (1.68g) was added to a solution of
5-nitro-2-oxo-6-phenylpiperidine (3g) in a mixture of dichloromethane (50ml) and methanol (50ml) and the mixture was cooled to -78°C under nitrogen. Ozone was bubbled through the solution for 3h. A yellow-green solution resulted, and TLC indicated no starting material remained. The reaction mixture was purged with oxygen for 5 min to remove excess ozone, then dimethylsulfide (7ml) was added and the reaction mixture was allowed to warm to 23°C. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, then dried (K2CO3) and concentrated to leave a yellow solid.
This crude material was slurried in dry tetrahydrofuran and added to lithium aluminium hydride (1M in THF, 50ml) then heated at reflux for 12h. After cooling to 23°C, the reaction mixture was quenched by the cautious addition of water (dropwise) under nitrogen, then 2M sodium hydroxide. The mixture was filtered through a pad of Hyflo, the filtrate was washed with brine, then dried ( K2CO3) and concentrated to leave a yellow sohd. Purification by sihca-gel chromatography
(CH2Cl2/MeOH/NH3 97:3:1 then CH2Cl2/MeOH 95:5) provided 3-hvdroxy- 2-phenylpiperidine as a ca 4:1 mixture of dLSr and iαms-isomers respectively. 1H NMR (CDCl3) 7.44-7.20 (m), 3.84 (2), 3.76 (s), 3.54 (m), 3.4 (s), 3.3 (d, J = 8Hz), 3.26 (m), 3.04 (m) 2.78 (ddd, J = 2.9, 11.9, 11.9Hz), 2.70 (ddd, J = 2.9, 11.9,
11.9Hz), 2.18-1.78 (m), 1.48 (m). MS (El) m/z 177 (M+).
c) Di-t-butyldicarbonate (1.36g) was added to a solution of 3-hydroxy-2-phenylpiperidine (lg) in dichloromethane (8ml) under nitrogen and the mixture stirred at 23°C for 3h. The solvent was removed in vacuo, and the residue purified by silica-gel chromatography (CH2Cl2/MeOH/NH3 97:3:0.5) to provide cis- and tran s-1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (1.4g) as a clear, viscous oil. 1H NMR (CDCl3) d 7.50-7.42 (m), 7.40-7.14 (m), 5.36 (d, J = 5.6Hz), 4.50 (m), 4.44 (m), 4.12-3.92 (m), 3.02 (ddd, J = 3.0, 12.5, 12.5Hz), 2.87 (ddd, J
= 3.0, 12.5, 12.5Hz), 1.88-1.66 (m), 1.46 (s), 1.36 (s).
d) To a cooled (0°C) solution of 1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (1.4g) in dry dimethylformamide (5ml) was added sodium hydride (80% dispersion in mineral oil; 182mg). The cooling bath was removed and the reaction mixture stirred at 23°C for 30 min. A solution of 3,5-bis(trifluoromethyl)benzyl bromide (1.87g) in dry dimethylformamide (1ml) was added and stirring was continued for 2h at room temperature. The mixture was diluted with water (100ml) and extracted with ethyl acetate (3 × 40ml). The combined organic extracts were washed with brine (1 × 30ml), dried (MgSO4) and evaporated to yield a pale yellow oil. Purification by chromatography on silica using gradient elution of hexane in ethyl acetate (9:1 - 4:1) afforded the product cis-1-t-butyloxycarbonyl-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidine (350mg) as an oil. 1H NMR
(250MHz, CDCl3) d 7.77 (1H, s, ArH), 7.71 (2H, s, ArH), 7.53-7.57 (2H, m, ArH), 7.2-7.4 (3H, m, ArH), 5.70 (1H, br d, app. J = 7.0Hz, NCHPh), 4.73 (2H, brs, OCH2), 3.84-3.98 (2H, m, NCHCHO + NCHH), 2.77 (1H, ddd, J = 13.0, 13.0, 3.0Hz), NCHH), 2.00 (2H, mc, CH2), 1.6-1.8 (2H, m, CH2), 1.40 (9H, s,
C(CH3)3).
e) Trifluoroacetic acid (3ml) was added to the product of (d) above (800mg) under nitrogen and the resulting solution was stirred for lh. Excess trifluoroacetic acid was removed in vacuo and the residue was partitioned between 2M sodium hydroxide and dichloromethane. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford a colourless oil. Purification on silica (dichloromethane in methanol, 98:2 - 95:5) afforded the product cιs-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy-2-phenylpiperidine (360mg) as a colourless oil. 1H
NMR (360MHz, CDCl3) d 7.78 (1H, s, ArH), 7.44 (2H, s, ArH), 7.18-7.38 (5H, s, ArH), 4.52 (1H, d, J = 12.5Hz, OCHH), 4.13 (1H, d, J = 12.5Hz, OCHH), 3.84 (1H, d, J = 1.0Hz, NCHPh), 3.68 (1H, d, J = 1.5Hz), 3.28 (1H, m, NCHCHO), 2.84 (1H, ddd, J = 3.0, 12.5, 12.5Hz, NCHH), 2.20 (1H, mc, NCHH), 1.8-1.98
(2H, m, CH2), 1.64-1.78 (1H, m, CHH), 1.50-1.58 (1H, m, CHH); MS m/z 404 ((M+1)+, 90%).
The oil was dissolved in ether to which was added excess ethereal hydrogen chloride. Upon standing a white solid crystallised. This was filtered and recrystalhsed from ethyl acetate-methanol to afford the title compound as white crystals: mp 200-203°C. 1H NMR (360MHz, DMSO) d 7.95 (1H, s, ArH), 7.81 (2H, s, ArH), 7.37-7.47 (5H, m, ArH), 4.78 (1H, d, J = 13.0Hz, OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J = 13.0Hz, OCHH), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J = 13.0Hz, NCHH), 2.23 (1H, d, J = 13.0Hz, NCHH), 1.64-2.00 (4H, m, CH2
× 2); MS (CI+) m/z 404 ((M+1)+, 90%); Found: C, 54.08; H, 4.47; N, 3.13. Calcd. for C20H20F6NOCl.0.25H2O: C, 54.06; H, 4.65; N, 3.15%. DESCRTPTTON 2: (2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-1-(carbomethoxy)methyl-2-phenylpiperidine
cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-pheny lpiperidine hydrochloride (Description 1, 1g) was liberated from the hydrochloride salt by partitioning between ethyl acetate and 2M sodium hydroxide. The organic phase was washed successively with water, saturated brine, dried (MgSO4) and evaporated in vacuo. To a solution of the residual oil in tetrahydrofuran (20ml) was added triethylamine (0.4ml) and methyl bromoacetate (400mg) and the solution was heated at reflux under an atmosphere of nitrogen for 16h. To the cooled solution was added ethyl acetate and water and the organic phase washed further with water and dried (MgSO4). After the solvent had been removed in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petroleum ether (3:10). The product was recrystallised from diethyl ether/petroleum ether to give the title compound: mp 81-83°C. Found: C, 57.35; H, 4.98; N, 2.84; C23H23F6NO3.0.1(H2O) requires C, 57.71; H, 4.86; N, 2.93%. MS
(CI+) m/z 476 (M+H)+. DESCRIPTION 3: (+)-(2S,3S)-cis-3-((3,5-Bis(trifluoromethyl) phenyl)methyloxy)-2- phenylpiperidine hydrochloride salt
a) The mixture of cis- and frans-isomers of 3-hydroxy-2-phenylpiperidine (Description 1, (2b)) and 4-toluenesulfonic acid monohydrate was crystallized from methanol/ethyl acetate to give cis-3-hydroxy-2-phenylpiperidimum tosylate: mp 266-267°C.
b) The tosylate salt (Description 3(a) above) was dissolved in a mixture of ethyl acetate and 10% aqueous Na2CO3 with warming. The organic phase was washed with saturated brine, dried (K2CO3) and evaporated to give crystalline cis-3-hydroxy-2-phenylpiperidine. mp 110-110.5°C.
c) cis-3-Hydroxy-2-phenylpiperidine (Description 3b) and (-)dibenzoyltartrate were dissolved in methanol and crystalhzed by addition of ethyl acetate. The sohd was recrystaHised from hot methanol to give the hemi dibenzoyltartrate salt: mp 223-224°C. This was liberated from the salt as described above to give the single enantiomer (+)-cis-3-hydroxy-2-phenylpiperidine, mp 93-95°C. [a] D = +98.5° (c=1, MeOH). The mother liquors were converted to the free base as described in Description 3b and crystallization using (+)dibenzoyltartrate in an analogous manner to that described above gave (-)-3-hydroxy-2-phenylpiperidine. mp 93-95°C. [a]23 D = -97.2° (c=1, MeOH).
d) (+)-cis-3-Hydroxy-2-phenylpiperidine was reacted according to the procedure detailed in Description lc-e to give (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidine hydrochloride as a crystalline solid: mp 215-216°C. [a]D = +87.3° (c=1, MeOH). % NMR (360MHz, DMSO-d6) d 7.95 (1H, s, ArH), 7.81 (1H, s, ArH), 7.47 (2H, m,
ArH), 7.37 (3H, m, ArH), 4.78 (1H, d, J = 13.0Hz, OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J = 13.0Hz, OCHH), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J = 13.0Hz, NCHH), 2.23 (1H, d, J = 13.0Hz, NCHH), 2.00-1.64 (4H, m, CH2 × 2); MS (CI+) m/z 404 (M+l+, 90%); Found: C, 54.52; H, 4.60; N, 3.11. Calcd. for C20H19F6NO.HCl: C, 54.62; H, 4.58; N, 3.18%.
DESCRIPTION 4: (+)-(2S,3S)-3-((3,5-Pis(trifluoromethyl) phenyl)methyloxy)-1-(carbomethoxy)methyl-2-phenylpiperidine The title compound was prepared from (+)-cis-3-((3,5-bis (trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine
(Description 3) using the procedure detailed in Description 2: mp 60-70°C. [a]D = +132.3° (c=1, MeOH). 1H NMR (360MHz, CDCl3) d 1.57-1.63 (3H, m, CH2 + CHH), 2.04-2.17 (2H, m, CHH, CHHN), 3.07-3.10 (1H, m, NCHCHO), 3.20 (1H, d, J = 17.0Hz, NCHHCO2CH3), 3.31 (1H, d, J = 17.0Hz, NCHH
CO2CH3), 3.58 (3H, s, CH3), 3.93 (1H, s, NCHPh), 4.07 (1H, d, J = 12.0Hz, OCHH), 4.49 (1H, d, J = 12.0Hz, OCHH), 7.28-7.34 (3H, m, ArH), 7.43-7.45 (2H, m, ArH), 7.54 (2H, s, ArH), 7.71 (1H, s, ArH). MS (CI+) m/z 476 (M+1+, 100%). Found: C, 58.31; H, 4.90; N, 2.94. Calcd. for C23H23F6NO3: 58.11; H, 4.88; N,
2.95%.
DESCRIPTION 5: (2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-1-(cyanomethyl)-2-phenylpiperidinium
hydrochloride
The compound of Description 1 (5g), potassium carbonate (1.7g) and bromoacetonitrile (0.87ml) were suspended in dimethylformamide (15ml) and the mixture was stirred tinder nitrogen at 60°C for 3 h. The mixture was cooled, diluted with water (200ml) and extracted with ethyl acetate (2 × 50ml). The organic extracts were washed with brine, dried (MgSO4) and evaporated, affording a brown oil. This was purified on silica using ethyl acetate in petrol (10%) as eluant. This afforded the product as a colourless oil. The hydrochloride salt was prepared by dissolution in ethereal hydrogen chloride and the salt was recrystallised from ether-hexane: mp 133-134°C. 1H NMR
(360MHz, CDCl3) d 1.75 (2H, mc, CHH), 1.90 (2H, mc, CHH), 2.31 (1H, mc, CHH), 2.71 (1H, mc, CHH), 3.19 (1H, mc, CHHN), 3.72 (1H, mc, CHHN), 3.81 (1H, d, J = 17.5Hz, NCHHCN), 3.86 (1H, s, CHO), 4.02 (1H, d, J = 17.5Hz, NCHHCN), 4.09 (1H, s, CHPh), 4.35 (1H, d, J = 13.0Hz, OCHH), 4.73 (1H, d, J =
13.0Hz, OCHH), 7.4 (3H, mc, ArH), 7.69-7.73 (5H, m, ArH); MS (CI+) m/z 443 (M++1, 30%). Found: C, 54.87; H, 4.30; N, 5.66. Calcd. for C22H18F6N2O.HCl : C, 55.18; H, 4.42; N, 5.85%. DESCRIPTION 6: (2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenyl-1-(thiocarboxamidomethyl)piperidine
The compound of Description 5 (lg) was dissolved in dimethylformamide (anhydrous, 10ml) and the solution was saturated with dry hydrogen chloride gas. The reaction was heated to 100°C under nitrogen and thioacetamide (0.34g) was added; this mixture was allowed to stir at 100°C for 3h. Dimethyfformamide was removed in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil. This was purified on silica using a gradient elution of ethyl acetate in petrol (10-50%). The product was further purified by recrystalhsation from ethyl acetate-petrol: mp 164-166°C; 1H NMR (360MHz, CDCl3) d 1.56-1.70 (2H, m, CH2), 1.96-2.10 (1H, m, CHH), 2.15-2.32 (2H, m, CHHN + CHH), 2.98-3.06 (1H, bd, NCHH), 3.09 (1H, d, J = 18.0Hz, CHHSNH2), 3.50 (1H, d, J = 18.0Hz, NCHHCSNH2), 3.50 (1H, s, CHO), 3.60 (1H, s, NCHPh), 4.04 (1H, d, J = 12.0Hz, OCHHAr), 4.47 (1H, d, J = 12.0Hz, OCHHAr), 7.26-7.36 (5H, m, CHPh), 7.53 (2H, s, Ar-H), 7.75 (H, s, Ar-H), 7.61 (1H, bs, NHH), 8.99 (1H, bs, NHH); MS (CI+) m/z 477 (M++1, 15%); Found: C, 55.09; H, 4.58; N, 5.97. Calc for
C22H22F6N2OS : C, 55.46; H, 4.65; N, 5.88.
DESCRTPTION 7: (2R*,3R* )-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-1-(carboxyhydrazidomethyl)-2-phenylpiperidinium hydrochloride
Hydrazine hydrate (3.0ml) was added to a solution of the compound of Description 2 (2.95g) in ethanol (80ml). The solution was heated at reflux for 18h after which the ethanol was removed in vacuo. The residue was extracted into ethyl acetate and the organic layer was washed with brine, dried
(MgSO4) and concentrated to give the title compound (2.79g). This was dissolved in methanol (5ml) and a methanolic solution of hydrogen chloride was added. Methanol was removed in vacuo and the salt was recrystallised from diethyl ether to give the hydrochloride salt. 1H NMR (360MHz, DMSO) d 1.77-1.93
(2H, m, CH2), 2.08-2.21 (1H, m, CH2), 2.22-2.35 (1H, m, CH2), 3.56 (1H, d, NCHHCH2), 3.64 (1H, d, J = 16.5Hz, NCHHCO), 3.77 (1H, d, NCHHCH2), 3.92 (1H, d, J = 16.5Hz, NCHHCO), 3.96 (1H, brs, CHO), 4.37 (1H, d, J = 13.0Hz, OCHH), 4.83 (1H, d, J = 13.0Hz, OCHH), 4.95 (1H, s, CHPh), 7.36-7.46 (3H, m,
ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (1H, s, ArH); MS (CI)+ m/z 475.
DESCRIPTION 8: (2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-1-(carboxyhydrazidomethyl)-2-phenylpiperidinium hydrochloride The title compound was prepared according to the procedure outlined in Description 7 using the compound of Description 4 as a starting material. 1H NMR (360MHz, DMSO) d 1.77-1.93 (2H, m, CH2), 2.08-2.21 (1H, m, CH2), 2.22-2.35 (1H, m, CH2), 3.56 (1H, d, NCHHCH2), 3.64 (1H, d, J = 16.5Hz, NCHHCO), 3.77 (1H, d, NCHHCH2), 3.92 (1H, d, J = 16.5Hz, NCHHCO), 3.96 (1H, brs, CHO), 4.37 (1H, d, J = 13.0Hz, OCHH), 4.83 (1H, d, J = 13.0Hz, OCHH), 4.95 (1H, s, CHPh), 7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (1H, s, ArH); MS (CD+ m/z 475.
DESCRIPTION 9: (2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-1- (cyanomethyl)-2-phenyIpiperidine
The title compound was prepared from the reaction of bromoacetonitrile and the compound of Description 3 according to the procedure detailed in Description 5. Purification by chromatography on silica using 10% hexane in ethyl acetate afforded the product as a colourless oil. 1H NMR (360MHz, CDCl3) d 1.75 (2H, mc, CH2CH2N), 2.14 (2H, mc, CH2CH2N), 2.63-2.74 (1H, m, CHHN), 2.96-3.06 (1H, m, CHHN), 3.35 (1H, d, J=17.0Hz, CHHCN), 3.48 (1H, d, J=2.0Hz, CHO), 3.55 (1H, d, J=17.0Hz, CHHN), 3.64 (1H, d, J=2.0Hz, CHPh), 4.07 (1H, d, J=12.0Hz, OCHH), 4.52 (1H, d, J=12.0Hz, OCHH), 7.28-7.38 (3H, m, ArH), 7.4-7.48 (2H, m, ArH), 7.56 (2H, m ArH), 7.73 (1H, m, ArH).
DESCRIPTION 10: (2S,3S)-3-((3-t-ButyI-5-methylphenyl) methyloxy) 2-phenvlpiperidine
This compound was prepared from the compound of Description 3c and 3-t-butyl-5-methylbenzyl bromide, following the procedure described in Descriptions 1c-e. mp 180-182°C. MS (CI+) m/z 338 (M++1, 100%). Found: C, 73.81; H, 8.63; N, 3.74. Calcd. for C23H31NO.HCl: C, 73.87; H, 8.62; N, 3.75%.
DESCRTPTION 11 : (2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidine
This compound was prepared from the compound of Description 3c and 3,5-dichlorobenzyl chloride, following the procedure described in Descriptions lc-e. 1H NMR (CDCl3) 5 1.49-1.53 (1H, m, CHH), 1.60-1.70 (1H, m, CHH), 1.82-1.95 (1H, m, CHH), 2.14-2.18 (1H, m, CHH), 2.79-2.87 (1H, m, NCHH),
3.27-3.31 (1H, m, NCHH), 3.60 (1H, s, CHO), 3.82 (1H, s, CHPh), 4.02-4.05 (1H, d, J=13Hz, OCHH), 4.31-4.35 (1H, d, J=13Hz, OCHH), 6.80 (2H, s, ArH), 7.15 (1H, s, ArH), 7.25-7.35 (5H, m, ArH). Found: C, 58.24; H, 5.38; N, 3.91. Calcd. for C18H19Cl2NO.HCl: C, 58.01; H, 5.41; N, 3.76%.
DESCRIPTION 12: (2S,3S)-3-((3-Chloro-5-methylphenyl) methyloxy)-2-phenylpiperidine
This compound was prepared from the compound of Description 3c and 3-chloro-5-methylbenzyl bromide, following the procedure described in Descriptions lc-e: mp 235-237°C. MS
(CI+) m/z 316 (M++H, 100%). Found: C, 64.68; H, 6.50; N, 3.98.
Calcd. for C19H22CINO.HCI: C, 64.78; H, 6.58; N, 3.98%. DESCRIPTION 13: (2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-(diphenylmethyl)pyrrolidinium hydrochloride
(a) N-t-Butyloxycarbonyl-(S)-diphenvlalanal
A solution of methyl sulfoxide (4.4ml) in dichloromethane
(13ml) was added dropwise to a cooled (-78°C) solution of oxalyl chloride (4ml) in dichloromethane (50ml). After 15 min, a solution of N-t-butyloxycarbonyl-(S)-diphenylalanol (10g) in dichloromethane (150ml) was added dropwise at -30°C. The solution was allowed to stir for 30 min, triethylamine (17ml) was added and the solution was allowed to warm to -10°C. Ice- water (200ml) was added to the solution which was then poured onto hexane (600ml). The organic phase was separated, washed successively with citric acid (200ml), saturated aqueous sodium bicarbonate (2 × 150ml), brine (1 × 150ml) then dried (MgSO4) and concentrated in vacuo to leave a white crystalline sohd. 1H NMR (250MHz, CDCl3) 5 1.42 (9H, s, C(CH3)3), 4.48 (1H, d), 4.86 (1H, d), 5.10 (1H, t), 7.26 (10H, m, ArH), 9.6 (1H, s, CHO).
(b) N-t-Butyloxycarbonyl-1-(diphenylmethyl)-2-hydroxypent-4-enyl-1-amine
A solution of N-t-butyloxycarbonyl-(S)-diphenylalanal (10.9g) in tetrahydrofuran (60ml) was added dropwise to a soluton of allyl magnesium chloride (2M in tetrahydrofuran,
36ml) at -10°C. After 30 min the mixture was poured onto icecold saturated aqueous ammonium chloride and the resulting mixture was extracted with ethyl acetate (3 × 150ml). The combined organic extracts were washed with brine (1 × 100ml), then dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using hexane in ethyl acetate (gradient elution of 9:1 to 4:1) as eluant to afford the compound as a white sohd. 1H NMR (360MHz, CDCl3) 5 1.42 (9H, s, (CH3)3), 2.22 (2H, m), 2.68 (3H, brs), 3.48 (t), 3.57 (1H, m), 3.86 (1H, s), 4.07 (d, J = 11Hz), 5.04 (1H, m), 5.71 (1H, m),
6.97-7.36 (10H, m, ArH).
(c) 2-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-N-t-butyloxycarbonyl-1-(diphenylmethyl)-pent-4-enyl-1-amine
Sodium hydride (80% in oil, 0.53g) was added to a solution of 3,5-bis(trifluoromethyl)benzyl bromide (5ml) and the compound of (13b) above (5g) in dimethylformamide (8ml). After stirring for lh water (80ml) was added and the mixture was extracted with ethyl acetate (3 × 100ml). The combined organics extracts were washed with brine (1 × 100ml) then dried (MgSO4) and concentrated to leave an oil which was purified on silica using hexane in ethyl acetate as eluant (gradient elution of 97:3 to 4:1). This afforded the title compound as a colourless oil. 1H NMR (360MHz, CDCl3) 5 1.25 (s), 1.30 (s), 2.35 (m), 3.31 (m), 3.40 (dd, J = 5.2, 8.3Hz), 3.97 (d), 4.27 (d), 4.38 (m), 4.65 (m), 4.85 (d), 5.16-5.02 (m), 5.77 (m), 7.35-7.13 (m), 7.76 (s), 7.85 (s).
(d) (2S,3S)-3-((3,5-Pis(triflupromethyl)phenyl)
methyloxy-2-(diphenylmethyl)pyrrolidinium hydrochloride
A solution of the compound of (c) above (5.2g) in dichloromethane (40ml) and methanol (40ml) was treated with a stream of ozone in oxygen at -78°C for lh. Methyl sulfide (3ml) was added and the mixture was warmed to 23°C and concentrated in vacuo. The residue was dissolved in chloroform (50ml), triethylsilane (5.6ml) was added followed by dropwise addition of a solution of trifluoroacetic acid (6.9ml) in chloroform (5ml). After lh the solvent was evaporated in vacuo and trifluoroacetic acid (10ml) was added to the residue. After stirring for 30 min the mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried (K2CO3) and concentrated to leave a brown oil. This was purified on silica gel eluting with dichloromethane/methanol
(99:1) to provide the title compound as the free base. This was converted to the salt by treatment with methanolic hydrogen chloride: mp >230°C. [α]23 D = +46.6° (c=l, CH3OH). Found: C, 59.95; H, 4.74; N, 2.63%. Calcd. for C26H23F6NO.HCl.0.2H2O: C, 60.11; H, 4.73; N, 2.70%. DESCRIPTION 14: (2R-3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-(diphenylmethyl)pyrrolidinium hydrochloride
The title compound was prepared from N-t-butyloxycarbonyl-(R)-diphenyIalanol by a procedure analagous to that described in Description 13: mp > 230°C. [αPD = +12.1°
(c=1, CH3OH).
DESCRIPTION 15: (2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)- 2-(diphenyl methyl)pyrrolidinium hydrochloride
(a) N-t-Butyloxycarbonyl-2-((3,5-dichlorophenyl) methyloxy-1-(diphenylmethyl)pent-4-enyl-1-amine
The compound of Description 13b was alkylated with 3,5-dichlorobenzyl chloride by a procedure analagous to that described in Description 13c, to afford the title compound as an oil. 1H NMR (360MHz, CDCl3) 5 1.25 (9H, s), 2.41-2.27 (2H, m),
3.32 (1H, m), 4.07 (1H, d, J=11Hz), 4.13 (1H, d, J=12Hz), 4.30 (1H, d, J=12Hz), 4.65 (2H, m), 5.13 (2H, m), 5.76 (1H, m), 7.356.60 (13H, m). MS (CI+) m/z 526, 528 (M++1, 100%, 80%).
(b) (2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-(diphenylmethyl)pyrrolidinium hydrochloride
The compound of Description 15a above was treated with ozone followed by triethylsilane-trifluoroacetic acid by a procedure analagous to that described in Description 13d to afford the title compound as a white crystalline solid: mp>230° C. Found: C, 64.52; H, 5.34; N, 3.12. Calcd. for
C24H23Cl2NO.HCl: C, 64.23; H, 5.39; N, 3.12%.
DESCRIPTION 16: (2S,3S)-3-((3-t-Butyl-5-chlorophenyl) methyloxy)-2-phenylpiperidinium hydrochloride
(a) 4-t-Butyl-2-chloro-6-(methylthiomethyl)amline 4-t-Butyl-2-chloroaniline (30g) was dissolved in dichloromethane (1.21) and the solution was cooled to -5°C. N-chlorosucdnimide (21.7g) was added portionwise to the vigorously stirred solution and stirring was continued for 1h. Dimethyl sulfide (35ml) was added to the solution (-5°C) and stirring was continued for a further 1h. The solution was then cooled to -65°C and triethylamine (27ml) was added. This solution was allowed to warm to room temperature overnight. The solution was evaporated to half volume, washed with sodium hydroxide (1N), water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant. This afforded the product (31.2g) as a red oil. 1H NMR (CDCl3, 250MHz) 5 1.27 (9H, s, (CH3)3), 1.99 (3H, s, SCH3), 3.69 (2H, s, CH2SCH3), 4.38 (2H, br s, NH2), 6.92 (1H, d, J=2.0Hz, ArH),
7.21 (1H, d, J=2.0Hz, ArH). MS (CI+) m/z 244 (M++1, 100%).
(b) 4-t-Butyl-2-chloro-6-methylamline
4-t-Butyl-2-chloro-6-(methylthiomethyl)aniline (1.3g) was dissolved in methanol (50ml) and Raney nickel (prewashed to pH 7) was added portionwise until t.l.c. indicated all starting material had reacted (ether-hexane, 1:10). The Raney nickel was removed by filtration through celite and the filtrate was evaporated. The residue was dissolved in ether and washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using hexane - 5% ether in hexane as eluant to afford the product as a yellow liquid. 1H NMR (360MHz, CDCl3) 5 1.26 (9H, s, (CH3)3), 2.19 (3H, s, CH3), 3.97 (2H, s, NH2), 6.97 (1H, d, J=2.0Hz, ArH), 7.14 (1H, d, J=2.0Hz, ArH).
(c) 3-t-Butyl-5-chlorotoluene
4-t-Butyl-2-chloro-6-methylaniline (1.97g) was dissolved in ethanol (50ml); sulphuric add (1.88ml, cone.) was added dropwise and the resulting blue solution was heated at reflux. Sodium nitrite (1.72g) was added portionwise over 30 min. The resulting mixture was heated at reflux for a further 30 min, then cooled and was poured onto ice-water and extracted with ether (2 × 50ml). The ethereal extract was dried (MgSO4) and evaporated and the residue was purified on silica gel using hexane as eluant. This afforded the product as a colourless oil. 1H NMR (360MHz, CDCl3) 5 1.29 (9H, s, (CH3)3), 2.31 (3H, s, CH3), 6.98 (1H, brs, ArH), 7.05 (1H, brs, ArH), 7.15 (1H, brs, ArH). MS (CI-) m/z 181 (M+-H, 100%).
(d) 3-t-Butyl-5-chlorobenzyl bromide
3-t-Butyl-5-chlorotoIuene (5.7g) was dissolved in carbon tetrachloride (80ml) and N-bromosucdnimide (5.56g) was added followed by benzoyl peroxide (750mg). This mixture was heated at reflux for 6h. The mixture was cooled, filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica using hexane as eluant. This afforded the title compound as a colourless liquid. 1H NMR (360MHz, CDCl3) 5 1.31 (9H, s, (CH3)3), 4.42 (2H, s, CH2), 7.20 (1H, t, J=1.5Hz, ArH), 7.26 (1H, t, J=1.5Hz, ArH), 7.28 (1H, t,
J=1.5Hz, ArH).
(e) (2S,3S)-1-t-Butyloxycarbonyl-3-((3-t-butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidine.
(+)-cis-3-Hydroxy-2-phenylpiperidine (Description 3c) was reacted with 3-t-butyl-5-chlorobenzyl bromide (Description 15d above) according to the procedure detailed in Description 1c-d to afford the title compound. 1H NMR (360MHz, CDCl3) 5 1.27 (9H, s, C(CH3)3), 1.46 (9H, s, C(CH3)3), 1.52-1.66 (2H, m), 1.8-2.0 (2H, m), 2.69 (1H, td, J=3.5Hz, 13.0Hz, NCHH), 3.81 (1H, q, J=5Hz, NCHH), 3.92 (1H, brd, CHO), 4.60 (2H, q, J=12Hz,
OCH2), 5.70 (1H, brs, CHPh), 7.10 (1H, s, ArH), 7.18 (1H, s, ArH), 7.22 (2H, s, ArH), 7.43-7.47 (2H, m, ArH), 7.57-7.59 (2H, m, ArH).
(f) The compound of Description 15e above was dissolved in methanolic hydrogen chloride overnight. The solution was then concentrated in vacuo and the residue triturated with ether. This afforded the title compound as a white crystalline powder: mp 210-211°C. 1H NMR (360MHz, DMSO-d6) 5 1.21 (9H, s, C(CH3)3), 1.66-1.80 (2H, m, CH2), 1.86-1.93 (1H, m, CHH), 2.18-2.22 (1H, m, CHH), 3.04-3.11 (1H, m, NCHH), 3.3 (1H, m, NCHH), 3.88 (1H, brs, CHO), 4.14 (1H, d, J=12Hz,
OCHH), 4.52 (1H, s, CHPh), 4.53 (1H, d, J=12Hz, OCHH), 6.95 (1H, s, ArH), 7.00 (1H, s, ArH), 7.24 (1H, t, J=1.8Hz, ArH), 7.37.5 (5H, m, ArH), MS (CI+) m/z 358 (M++1, 100%). Found: C, 66.68; H, 7.29; N, 3.40. Calcd. for C22H28ClNO.HCl: C, 67.00; H, 7.41; N, 3.55%.
DESCRIPTION 17: (2R*,3R*)-3-((3-Carbomethoxyphenyl) methyloxy)-2-phenylpiperidine
(a) (2R*,3R*)-1-t-Butyloxycarbonyl-3-((3-cvanophenyl; methyloxy)-2-phenylpiperidine
This compound was prepared from 1-t-butyloxycarbonyl3-hydroxy-2-phenylpiperidine (Description lc) and α-bromo-mtolunitrile according to the procedure described in Example Id. 1H NMR (360MHz, CDCl3) 5 1.49 (9H,s, (CH3)3), 1.6-1.72 (2H, m), 1.87-1.99 (2H, m), 2.72 (1H, dt, J = 13, 4Hz, NCHH), 3.80- 3.95 (2H, m, CHO + NCHH), 4.65 (2H, q, J = 12Hz, OCH2), 5.69 (1H, brs, CHPh), 7.1-7.5 (9H, m, ArH).
(b) (2R*,3R*)-3-((3-Carbomethoxyphenyl)methyloxy-2-phenylpiperidine
The compound of (a) above (1.5g) was dissolved in methanol
(15ml) and concentrated hydrochloric add (aqueous, 10ml) was added. The contents were heated at reflux for 12h. The solution was cooled and evaporated to leave a brown oil. This was dissolved in methanolic hydrogen chloride and the resulting solution was stirred overnight, then evaporated. The residue was purified by dispersion between water and ethyl acetate and the organic layer was dried (MgSO4) and concentrated. The residue was purified by chromatography on silica using a gradient elution of 2%-6% methanol in dichloromethane. The first compound to elute was characterised as the hydrochloride salt by dissolution in methanolic hydrogen chloride. The salt was recrystallised from ethyl acetate methanol: mp 206-208°C.
(c) (2R*,3R*)-3-((3-(Carbomethoxy)phenyl)methyloxy)-2-phenylpiperidine
1H NMR (CDCl3) 5 1.45-1.71 (2H, m, NCH2CH2CH2), 1.83-2.02 (1H, m, NCH2CHH), 2.12-2.23 (1H, m, NCH2CHH), 2.44 (1H, bs, NH), 2.77-2.90 (1H, m, NCHH), 3.24-3.34 (1H, m, NCHH), 3.61-3.66 (1H, bs, CHO), 3.8-3.83 (1H, d, J = 15Hz, CHPh), 3.90 (3H, s, COOCH3), 4.15 (1H, d, J=12Hz, OCHH), 4.39 (1H, d, J=12Hz, OCHH), 7.09 (7H, m, ArH), 7.71 (1H, bs, ArH), 7.83-7.89 (1H, m, ArH); MS (CI+) m/z 326 (M++1, 100%).
Found: C, 66.31; H, 6.36; N, 3.80. Calcd. for C20H23NO3.HCl: C, 66.38; H, 6.69; N, 3.87%.
DESCRTPTTON 18: (2R*,3R*)-3-((3-Carboxamidophenyl) methyloxy)-2-phenylpiperidine
The second compound to elute from the column described in 17b above was isolated as a colourless oil. 1H NMR (360MHz, CDCl3) 5 1.2-2.2 (4H, m), 2.82 (1H, mc), 3.27 (1H, mc), 3.66 (1H, s), 3.82 (1H, s), 4.16 (1H, d, J = 12Hz, OCHH), 4.48 (1H, d, J = 12Hz, OCHH), 5.53 (1H, brs, CONHH), 6.18 (1H, brs, CONHH),
7.0-7.4 (9H, m, ArH). DESCRIPTION 19: (2R*.3R*)-3-((2-Methoxy-3-nitrophenyl) methyloxy)-2-phenylpiperidinium hydrochloride
This compound was prepared from the compound of Description lc and 2-methoxy-5-nitrobenzyl bromide, following the procedure described in Descriptions lc-e. mp 246-248°C. MS
(CI+) m/z 343 (M++1, 45%). Found: C, 60.52; H, 5.96; N, 7.45.
Calcd. for C19H22N2O4.HCl: C, 60.24; H, 6.12; N, 7.39%. DESCRIPTION 20: (2R*,3R*)-3-((5-Amino-2-methoxyphenyl) methyloxy)-2-phenylpiperidinium hydrochloride
The compound of Description 19 (0.342g) was dissolved in methanol (20ml) with hydrochloric add (1ml, 2N). Palladium on charcoal (50mg) was added and the mixture placed under an atmosphere of hydrogen for lh at room temperature. The solvent was removed in vacuo and the residue basified with sodium hydroxide (2M). This solution was extracted with ethyl acetate and the organic extracts were dried (MgSO4) and concentrated to leave a brown oil; this was purified by column chromatography on silica using 8% methanol in dichloromethane as eluent. The resulting oil was characterised as the salt prepared by treatment with methanolic hydrogen chloride: mp 241-243°C. The following piperidines were prepared according to the procedures outlined in Descriptions 1 and 3, using the appropriate benzyl halide.
DESCRIPTION 21: (2S,3S)-2-Phenyl-3-((3-(trifluoromethyl) phenyl)methyloxy)piperidine 1H NMR (CDCl3) 5 1.4-2.2 (4H, m), 2.45 (1H, brs), 2.83 (1H, td, J=13Hz and 4Hz), 3.3 (1H, m), 3.64 (1H, d, J=2Hz), 3.82 (1H, d, J=2Hz), 4.13 (1H, d, J=12Hz, OCHH), 4.42 (2H, J=12Hz, OCHH), 7.75 (m, 9H, ArH).
DESCRTPTION 22: (2S,3S)-3-((3,4-Dichlorophenyl)methyloxy)- 2-phenylpiperidinium hydrochloride
1H NMR (DMSO-d6), 1.65-1.8 (2H, m), 1.8 (1H, m), 2.16 (1H, d, J=12Hz), 3.05 (1H, m), 3.25 (1H, m), 3.83 (1H, s), 4.12 (1H, d, J=12Hz), 4.5 (2H, m), 7.05 (1H, dd, J=7 & 2Hz), 7.28 (1H, d, J=2Hz), 7.35-7.5 (6H, m), 9.05 (1H, br s), 9.8 (1H, br s).
DESCRIPTION 23: (2S,3S)-3-((2,3-Dimethylphenyl)methyloxy)-2-phenylpiperidinium hydrochloride
Ethyl acetate (10ml) was saturated with hydrogen chloride by passing HCl gas for 5 min and a solution of 0.254g of (2S,3S)-1-t-butoxycarbonyl-3-((2,3-dimethylphenyl)methoxy)-2-phenylpiperidine (prepared according to Description 3d) in 7ml of ethyl acetate was added. After stirring for 2h, the reaction mixture was concentrated in vacuo. The residual white sohd was washed with ether, filtered and dried to obtain 0.23g of (2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidinium hydrochloride. 1H NMR (DMSO-d6) 5 1.6-1.9 (3H, m), 1.75 (3H, s), 2.15 (3H, s), 2.2 (1H, m), 3.05 (1H, m), 3.25 (1H, m), 3.84 (1H, s), 4.05 (1H, d, J=14Hz), 4.45 (1H, d,
J=14Hz), 4.48 (1H, s), 6.95-7.5 (8H, m), 8.8 (1H, br s), 9.4 (1H, br s).
DESCRIPTION 24: (2S,3S)-3-((3-t-Butylphenyl)methyloxy)-2-phenylpiperidinium hydrochloride 1H NMR (360MHz, CDCl3) 5 1.21 (9H, s, C(CH3)3), 1.45 (3H, s), 1.52-1.67 (2H, m, CH2), 2.04-2.12 (1H, m, CHH), 2.30-2.34 (1H, m, CHH), 2.93-2.96 (1H, m, NCHH), 3.54 (1H, d, J=13Hz, NCHH), 3.72 (1H, s, NCHCHO), 4.14 (1H, d, J=2Hz, NCHCHO), 4.28-4.36 (2H, q, J=13Hz, OCHH), 6.87-6.89 (1H, m,
ArH), 7.05 (1H, s, ArH), 7.11-7.15 (1H, m, ArH), 7.20-7.34 (4H, m, ArH), 7.55-7.58 (2H, m, ArH). MS (CI+) m/z 323 (M++1, 100%). DESCRIPTION 25: (2R*,3R*)-3-((3,5-Dimethylphenyl) methyloxy)-2-phenylpiperidinium hydrochloride
1H NMR (360MHz, CDCl3) 5 1.48 (m), 1.62 (m), 1.86 (m), 2.20 (s), 2.82 (ddd, J=3.0. 3.0, 12.6Hz), 3.26 (dt, J=2.15, 2.15, 12.5Hz), 3.63 (s), 3.78 (s), 4.10 (d, J=12.0Hz), 4.33 (d, J=12.0Hz), 6.31 (s), 7.2-7.4 (m). MS (CI+) m/z 296 (M++1).
DESCRIPTION 26: (2R*,3R*)-3-((3,5- Bis(trifluoromethyl)phenyl) methyloxy)-2-(3-chlorophenyl)piperidine
(a) Methyl-4-nitrobutyrate and 3-chlorobenzaldehyde were reacted in an analogous manner to that described in Description la to give 2-(3-chlorophenyl)-3-nitro-6-oxopiperidine: mp 131-133°C. 1H NMR (360MHz, CDCl3) 52.26-2.36 (1H, m), 2.50-2.72 (3H, m), 4.66-4.71 (1H, m), 5.24-5.28 (1H, d), 6.57 (1H, s), 7.17-7.40 (4H, m).
(b) The product of part a) was treated analogously to that described in Description 1b to give 2-(3-chlorophenyl)-3,6-dioxo piperidine: mp 144-147°C. 1H NMR (360MHz, CDCl3) 5 2.8 (4H, m), 5.0 (1H, d), 6.4 (1H, s), 7.22-7.42 (4H, m). c) The product of part b) was treated analogously to that described in Description lc and 3a to give cis-2-(3-chlorophenyl)-3-hydroxypiperidine tosylate salt: mp > 250°C. 1H NMR (360MHz, CDCl3) 5 1.60-2.07 (4H, m), 2.28 (3H, s), 3.00-3.11 (1H, m), 4.02 (1H, s), 4.62-4.66 (1H, d), 5.96 (1H, s), 7.10-7.20
(2H, d), 7.41-7.59 (6H, m).
d) The product of part c) was treated analogously to that described in Description lc to give cis-1-t-butyloxycarbonyl-2-(3-chlorophenyl)-3-hydroxypiperidine as a dear, viscous oil. 1H NMR (360MHz, CDCl3) 5 1.40 (9H, s), 1.61-1.90 (4H, m), 2.88- 3.01 (1H, ddd), 3.93-3.99 (1H, dd), 4.03-4.10 (1H, m), 5.33 (1H, d), 7.20-7.26 (2H, m), 7.34-7.38 (1H, m), 7.47-7.52 (1H, m). m/z (CI-) 310, 312; m/z (CI+) 312, 314.
e) The product of part d) and 3,5-bis(trifluoromethyl)benzylbromide were treated in an analogous manner to that described in Description Id to give cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1-t-butyloxy-carbonyl-2-(3-chlorophenyl)piperidine. 1H NMR (250MHz, CDCl3) 5 1.24-1.30 (1H, m), 1.47 (9H, s), 1.60-2.00 (3H, m), 2.67-2.80 (1H, ddd), 3.81-4.01 (2H, m), 4.8 (2H, s), 5.61-5.67 (1H, d), 7.23-7.27
(2H, m), 7.39-7.44 (1H, m), 7.6 (1H, s), 7.78 (2H, s), 7.8 (1H, s). f) The product of part e) was treated in an analogous manner to that described in Description 1e to give cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl) piperidine hydrochloride salt, mp = 158°C. 1H NMR (360MHz,
DMSO-d6) 5 1.70-1.96 (4H, m), 2.19-2.28 (1H, m), 3.02-3.13 (1H, m), 3.84 (1H, s), 4.35-4.39 (2H, d), 4.60 (1H, s), 4.79-4.85 (2H, d), 7.39-7.44 (3H, m), 7.58 (1H, s), 7.84 (2H, s), 7.97 (1H, s), 9.2 (br s), 10.05 (br s). Found: C, 50.44; H, 4.13; N, 3.01. C20H18ClF6NO.HCl requires C, 50.65; H, 4.04; N, 2.95%. m/z
(CI+), 438, 440. DESCRIPTION 27: 2S,3S)-3-((3-Fluoro-5-methylphenyl) methyloxy)-2-phenylpiperidine
mp 219-221°C. 1H NMR (360MHz, CDCl3) 5 1.50-1.68 (2H, m), 2.11-2.15 (1H, m), 2.20 (3H, s, CH3), 2.31-2.35 (1H, m), 2.94- 2.98 (1H, m, NCHH), 3.55-3.58 (1H, d, J = 12Hz, NCHH), 3.69 (1H, bs, CHO), 4.15-4.18 (1H, m, CHPh), 4.18 (1H, d, J = 13Hz, OCHH), 4.33 (1H, d, J = 13Hz, OCHH), 6.47 (1H, d, ArH), 6.59 (1H, s, ArH), 6.66 (1H, d, ArH), 7.26-7.37 (3H, m, ArH), 7.52-7.54 (2H, m, ArH). MS (CI+) m/z 300 (M++1, 100%).
DESCRIPTION 28: (3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-methyl-2-(2R*)-2-phenyIpiperidine
(a) 3,6-Dioxo-2-phenylpiperidine (Description 1b) (5g) was dissolved in dimethylformamide (25ml) at 0°C. Sodium hydride
(873mg, 80% dispersion in oil) was added portionwise and the mixture stirred for 15 min. Methyl iodide was added (1.8ml) and the mixture was stirred for 12h. The mixture was diluted with water (250ml) and extracted with ethyl acetate (3 x). The combined organic extracts were washed with brine, dried
(MgSO4) and concentrated to leave a solid: 3,6-dioxo-2-methyl-2-phenylpiperidine.
(b) The ketone of (a) above (3.2g) was suspended in methanol under nitrogen and the temperature brought to -40°C. Sodium borohydride (0.3g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64ml, 1.0M in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was then concentrated in vacuo. The resulting residue was dissolved in ethanol (100ml) and potassium carbonate (4.2g) was added. The mixture was heated at reflux for 12h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgSO4) and evaporated to afford 3-hydroxy-2-methyl-2-phenylpiperidine as a white solid. 1H NMR (360MHz, CDCl3) 5 7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m, ArH), 3.89 (1H, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s, CH3).
(c) The alcohol of (b) above (3g) was dissolved in dichloromethane (50ml) and di-t-butyldicarbonate (3.48g) was added. The solution was aHowed to stir for 12h. The solution was concentrated in vacuo and the residue was purified by chromatography on silica using ethyl acetate in petrol (20:80) as eluent. This afforded N-t-butyloxycarbonyl-2-hydroxy-2-methyl-2-phenylpiperidine as a dear oil. 1H NMR (250MHz, CDCl3) 5 1.08 (9H,s, (CH3)3), 1.80 (3H, s, CH3), 1.6-2.0 (4H, m), 3.6-3.74 (2H, m), 3.8-3.92 (1H, m, CHO), 7.2-7.36 (5H, m, ArH).
(d) The alcohol of (c) above (2.2g) was dissolved in dry dimethylformamide (12ml). Sodium hydride was added (0.36g, 60% dispersion in oil) portionwise and the mixture was allowed to stir at room temperature for 30 min. 3,5- Bis(trifluoromethyl)benzyl bromide (3.5g) was added dropwise and the mixture was allowed to stir for 5h. The mixture was diluted with aqueous ammonium chloride, extracted with ethyl acetate and the organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue as purified by column chromatography on silica using a gradient elution, 100% petrol to 10% ethyl acetate in petrol as eluant, to afford the product 3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-1-t- butyloxycarbonyl-2-methyl-2-phenylpiperidine as a colourless oil. 1H NMR (360MHz, CDCl3) 5 1.13 (9H, s (CH3)3), 1.85 (3H, s, CH3), 1.85-1.99 (4H, m, CH2CH2), 3.48 (1H, brs, NCHH), 3.68-3.75 (1H, m, NCHH), 3.80-3.85 (1H, m, CHO), 3.85 (1H, d, J = 12Hz, OCHH), 4.36 (1H, d, J = 12Hz, OCHH), 7.17-7.32 (5H, m,
ArH), 7.42 (2H, s, ArH), 7.71 (1H, s, ArH).
(e) The compound of (d) above (2.1g) was dissolved in trifluoroacetic add (30ml) for 10 min and was then evaporated in vacuo. The residue was dissolved in dichloromethane, washed with sodium hydroxide (2M), water and brine, then dried (MgSO4) and concentrated in vacuo. Methanolic hydrogen chloride was added to the residue and when dissolved the solvent was evaporated. The residue was triturated with ether to afford the product as a white powder: (3R*)-3-((3,5-Bis(trifluoromethyl) phenyl)methyloxy)-2-methyl-(2R*)-2-phenyl-piperidine. 1H NMR (360MHz, DMSO) 5 1.67 (3H, s, CH3), 1.70 (1H, m), 1.84-1.91 (1H, m), 1.99-2.06 (2H, m), 3.16 (1H, m), 3.33 (1H, m), 4.19 (1H, s), 4.29 (1H, d, J=12Hz, OCHH), 4.75 (1H, d, J=12Hz, OCHH), 7.29-7.33 (1H, m, ArH), 7.37-7.41 (3H, m, ArH), 7.54 (2H, s, ArH), 7.56 (1H, brs, ArH), 7.89 (1H, s,
ArH). Found: C, 55.38; H, 4.92; N, 3.08 Calcd. for C21H21F6NO: C, 55.58; H, 4.89; N, 3.09%.
DESCRIPTION 29: (2S,3S)-3-((3,4-Dimethylphenyl) methyloxy)-2-phenylpiperidine
1H NMR (CDCl3) 5 1.4-1.9 (3H, m), 2.11 (3H, s), 2.17 (3H, s),
2.1-2.3 (1H, m), 2.78 (1H, m), 3.25 (1H, m), 3.60 (1H, s), 3.76 (1H, s), 4.08 (1H, d, J=12Hz), 4.27 (1H, d, J=12Hz), 6.7 (2H, m),
6.92 (1H, d, J=9Hz), 7.2-7.5 (5H, m). DESCRIPTTON 30: (2S,3S)-3-((3-(isoPropoxy)phenyl) methyloxy)-2-phenylpiperidine
1H NMR (250MHz, CDCl3) 5 1.6-1.9 (3H, m), 1.97 (1H, d, J=7Hz), 2.16 (1H, m), 3.05 (1H, m), 3.3 (1H, m), 3.84 (1H, s), 4.09 (1H, d, J=12Hz), 4.41 (1H, d, J=12Hz), 4.44 (1H, m), 4.5 (1H, s), 6.6 (2H, m), 6.72 (1H, m), 7.09 (1H, t, J=8Hz), 7.3-7.5 (5H, m).
DESCRIPTION 31: (2S,3S)-3-((3,5-Bis(trifiuoromethyl) phenyl)methyloxy)-2-(3-fluorophenyl)piperidine
1H NMR (360MHz, CDCl3) 5 1.66-1.9 (3H, m), 2.2-2.3 (1H, m), 2.43-2.5 (1H, m), 3.0-3.2 (1H, m), 3.98 (1H, s), 4.37 (1H, d,
J=12Hz), 4.62 (1H, s), 4.79 (1H, d, J=12Hz), 7.04-7.46 (4H, m,
ArH), 7.80 (2H, s, ArH), 7.96 (1H, s, ArH).
EXAMPLE !
3-Amino-5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl]-1,2,4-oxadiazole
Hydroxyguanidine sulphate hydrate (2.3g) was dissolved in water and freeze-dried overnight. Ethanol (35ml) and powdered molecular sieves (1g) were added to the sohd hydroxyguanidine and the suspension was stirred under nitrogen for 1 hour. Sodium (670mg) was added to the mixture whidi was stirred until aH sodium had reacted. The suspension assumed an orange colour at this time and was placed in an ultrasound bath for 15 min. The ester of Description 2 (1.4g) was added to the mixture which was then heated at reflux for 2h. The reaction mixture was cooled and filtered through celite. Ethanol was removed in vacuo and the residue was extracted into ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and evaporated. The residue was purified on silica using 25% ethyl acetate in petrol as eluant. This afforded the product (800mg) as a solid which was recrystaHised from ether/hexane to afford colourless prisms: mp 160-161°C. 1H NMR (360MHz, DMSO-d6) d 1.47-1.54 (2H, m, CH2), 1.85-1.9 (1H, m, CHH), 2.14-2.17 (1H, m, CHH), 2.35-2.40 (1H, m, CHHN), 2.99-3.02 (1H, m, CHHN), 3.35 (1H, d, J = 15.0Hz, N-CHH-oxadiazole), 3.60 (2H, brs, NCHCHO), 3.65 (1H, d, J = 15.0Hz, N-CHH-oxadiazole), 4.06 (1H, d, J = 13.0Hz, OCHH), 4.62 (1H, d, J = 13.0Hz, OCHH), 6.2 (2H, brs, NHg), 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI+) m/z 501 ((M+l)+, 75%). Found: C, 54.81; H, 4.47; N, 11.2. Calcd. for C23H22F6N4O2: C,
55.20; H, 4.43; N, 11.2%.
EXAMPLE 2
5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl )phenyl) methyloxy)-2-phenylpiperidino}methyl]-3-methyl-1,2,4-oxadiazole
Acetamideoxime (117mg) and powdered molecular sieves were suspended in dry tetrahydrofuran (10ml) and stirred under nitrogen for 1 hour. Sodium hydride (63mg of 60% suspension in oil) was added and the mixture heated to 50°C until all hydrogen evolution had ceased. The ester of Description 2 (500mg) was dissolved in tetrahydrofuran (2ml) and added to the above mixture. This mixture was heated at reflux for 2h, cooled, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and then brine. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was purified by medium pressure chromatography (Lobar) using 25% ethyl acetate in petrol as eluant. This afforded the product as a crystalline soKd: mp 85-86°C; 1H NMR (360MHz, DMSO-d6) d 1.47-1.54 (2H, m, CH2), 1.85-1.89 (1H, m, CHH), 2.13-2.17 (1H, m, CHH), 2.31 (3H, s, CH3), 2.34-2.40 (1H, m, CHHN), 2.98-3.01 (1H, m, CHHN), 3.51 (1H, d, J = 15.0Hz, NCHH-oxadiazole), 3.60 (2H, s, NCHCHO), 3.81 (1H, d, J = 15.0Hz,
NCHH-oxadiazole), 4.06 (1H, d, J = 13.0Hz, OCHH), 4.62 (1H, d, J = 13.0Hz, OCHH), 7.25-7.31 (3H, m, ArH), 7.43-7.45 (2H, m, ArH), 7.70 (2H, s, ArH), 7.93 (1H, s, ArH); MS (El) m/z 500 ((M+l)+, 100%). Found: C, 57.94; H, 4.79; N, 8.23. Calcd. for C24H23F6N3O2: C, 57.72; H, 4.64; N, 8.41%.
EXAMPLE 3
(+) 3-Amino-5-[{(2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole The title compound was prepared from the ester of
Description 4 using the procedure described in Example 1: mp 138-139°C; [a]23 D = +147.7° (c=1, MeOH). . 1H NMR (360MHz, CDCl3) d 1.47-1.50 (2H, m, CH2), 1.85-1.89 (1H, m, CHH), 2.14-2.17 (1H, m, CHH), 2.35-2.41 (1H, m, CHHN), 2.99-3.02 (1H, m, CHHN), 3.29 (1H, s, NCHCHO), 3.33 (1H, d, J = 15.0Hz,
NCHH-het), 3.65 (1H, d, J = 15.0Hz, NCHH-het), 3.60 (1H, brs, NCHPh), 4.05 (1H, d, J = 13.0Hz, OCHH), 4.62 (1H, d, J = 13.0Hz, OCHH), 6.20 (2H, s, NH2), 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI+) m/z 501 (M+1+, 75%). Found: C, 54.81; H, 4.47; N, 11.2. Calcd. for C23H22F6N4O2: C, 54.98; H, 4.54; N, 11.30%.
EXAMPLE 4 3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl]pyridinium
hydrochloride
The compound of Description 1 (410mg), 3-picolyl chloride (167mg) and potassium carbonate were suspended in dimethylformamide (3ml) and the mixture heated at 60°C for
12h. The mixture was cooled, diluted with water (50ml) and extracted with ethyl acetate (2 × 10ml). The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using a gradient elution of 25-50% etiiyl acetate in petrol. The product was dissolved in ethereal hydrogen chloride to form the dihydrochloride salt which was recrystaHised from benzene: mp 198-200°C. 1H NMR (360MHz, DMSO-d6, 353K) d 1.68-1.82 (2H, m, CH2), 2.09-2.18 (2H, m, CH2), 3.06 (1H, mc, CHHN), 3.37 (1H, mc, CHHN), 3.89 (1H, s, NCHCHO), 4.16 (1H, brd, NCHH-pyridine), 4.20 (1H, brd,
NCHH-pyridine), 4.26 (1H, d, J = 13.0Hz, CHHO), 4.56 (1H, brs, NCHPh), 4.72 (1H, d, J = 13.0Hz, CHHO), 7.37-7.41 (3H, m, ArH), 7.60-7.64 (1H, m, ArH), 7.71-7.72 (2H, m, ArH), 7.86 (1H, s, ArH), 7.89 (2H, s, ArH), 8.08 (1H, d, J = 8.0Hz, ArH), 8.64 (1H, s, ArH), 8.68 (1H, d, J = 5.0Hz, ArH); MS (CI+) m/z 495
(M++1, 60%); Found: C, 52.45; H, 4.90; N, 4.52. Calcd. for C26H24F6N2O.2HCl.1.5H2O : C, 52.54; H, 4.92; N, 4.71%. EXAMPLE 5
2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxyl-2-phenylpiperidinolmethyl]pyridinium
hydrochloride The compound of Description 1 was reacted with 2-picolyl chloride following the procedure illustrated in Example 4: mp 175-180°C. 1H NMR (360MHz, DMSO-d6) d 1.65-1.83 (2H, m, CH2), 2.08-2.15 (2H, m, CH2), 3.16-3.20 (1H, m, CHHN), 3.30-3.40 (1H, m, CHHN), 3.70 (1H, s, NCHCHO), 4.18 (1H, d, J = 14.0Hz, CHH-pyridine), 4.23 (1H, d, J = 14.0Hz, CHH-pyridine), 4.30 (1H, d, J = 13.0Hz, OCHH), 4.79 (1H, d, J = 13.0Hz, OCHH), 4.78 (1H, s, CHPh), 7.24 (1H, d, J = 7.5Hz, ArH), 7.36-7.4 (3H, m, ArH), 7.47-7.51 (1H, m, ArH), 7.62 (2H, mc, ArH), 7.85 (1H, dt, J = 7.5, 2.0Hz, ArH), 7.94 (2H, s, ArH), 7.97 (1H, s, ArH), 8.65 (1H, d, J = 7.5Hz, ArH); MS (CI+) m/z
495 (M+1)+, 100%). Found: C, 53.01; H, 4.79; N, 4.69. Calcd. for C26H24F6N2O.2HCl.H2O : C, 53.30; H, 4.82; N, 4.78%.
EXAMPLE 6
2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]benzimidazole
The compound of Description 1 was reacted with 2-(chloromethyl)benzimidazole following the procedure ffiustrated-in Example 4: mp 152-153°C. 1H NMR (360MHz,
DMSO-d6) d 1.44-1.59 (2H, m, NCH2CH2CH2), 1.85-1.89 (1H, m, CHHCH2N), 2.15-2.18 (2H, m, NCHH+CHHCH2N), 2.86-2.89 (1H, m, NCHH), 3.15-3.19 (1H, d, J = 14.0Hz, NCHH-imidazole), 3.57 (1H, s, NCHCHO), 3.63 (1H, s, NCHCHO), 3.80-3.84 (1H, d, J = 14.0Hz, NCHH-imidazole), 4.10-4.13 (1H, d, J = 13.0Hz, -OCHH), 4.63-4.66 (1H, d, J = 13.0Hz, -OCHH), 7.07-7.15 (2H, m, ArH), 7.24-7.34 (3H, m, ArH), 7.43-7.52 (2H, m, ArH), 7.60-7.62 (2H, m, ArH), 7.67 (2H, s, ArH), 7.94 (1H, s, ArH), 12.10 (1H, s, NH); MS (CI+) m/z 534 ((M+1)+, 100%).
EXAMPLE 7 5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl]tetrazole
The compound of Description 5 (1.0g), triethylamine hydrochloride (467mg) and sodium azide (441mg) were dissolved in 1-methyl-2-pyrrolidinone (5ml) and the reaction mixture was heated at reflux under nitrogen for 2h. The mixture was then cooled, and diluted with ice/water (80ml) and addified to pH = 2 with methanolic hydrogen chloride. This predpitated the product as a white sohd, which was purified on silica using a gradient elution of methanol in dichloromethane (0-5%). The product was recrystallised from ether-hexane: mp 114-115°C.
1H NMR (360MHz, DMSO-d6) d 1.59-1.65 (2H, m, NCH2CH2CH2), 2.02-2.22 (2H, m, NCH2CH2), 2.39-2.46 (1H, m, CHHN), 2.98-3.02 (1H, m, CHHN), 3.62 (1H, s, NCHCHO), 3.66 (1H, s, NCHCHO), 3.70-3.74 (1H, d, J = 15.5Hz, NCHH-tetrazole), 4.05-4.10 (1H, d, J = 15.5Hz,
NCHH-tetrazole), 4.08-4.12 (1H, d, J = 12.0Hz, OCHH), 4.51-4.54 (1H, d, J = 12.0Hz, OCHH), 5.30 (1H, s, NH), 7.30-7.35 (3H, m, ArH), 7.45-7.47 (2H, m, ArH), 7.51 (2H, s, ArH), 7.74 (1H, s, ArH); MS (CI+) m/z 486 (M++l, 85%). Found: C, 53.14; H, 4.58; N, 13.96. Calcd. for C22H21F6N5O.0.5H2O : C, 53.44; H, 4.48; N, 14.16%.
EXAMPLE 8
2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-4-methyl-1,3-thiazole
Anhydrous acetone (2ml) and methanol (2ml) and tetrabutylarmnonium perbromide (111mg) were stirred under nitrogen to generate a solution of bromoacetone in situ. The compound of Description 6 (150mg) was added to this mixture and the resulting solution was stirred for 2h. A second equivalent of bromoacetone was added and the mixture was stirred for a further 2h. The volatile solvents were removed in vacuo and the residue was dispersed between aqueous potassium carbonate and ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo affording a brown ofl. This was purified on silica using a gradient elution of ethyl acetate in petrol (10-30%) which gave the product as a dear oil: 1H NMR (360MHz, CDCl3) 1.51-1.68 (2H, m, CH2), 1.98-2.22 (2H, m, CH2), 2.26-2.37 (1H, m, NCHH),
2.38 (3H, s, CH3), 3.18-3.26 (1H, m, NCHH), 3.47 (1H, d, J = 15.0Hz, NCHH), 3.54 (H, bs, CHO), 3.58 (H, bs, CHPh), 3.94 (1H, d, J = 15.0Hz, NCHH), 4.01 (1H, d, J = 12.5Hz, OCHH), 4.47 (1H, d, J = 12.5Hz, OCHH), 6.80 (1H, s, SCH), 7.24-7.35 (3H, m, Ar-H), 7.52-7.54 (2H, m, Ar-H), 7.58 (2H, s, Ar-H), 7.72 (1H, s, Ar-H); MS (CI+) m/z 515 (M++1, 100%). Found: C, 58.59; H, 4.88; N, 5.48 Calc for C25H24F6N2OS : C, 58.36; H, 4.70; N, 5.44%. EXAMPLE 9
(2R*.3R*)-3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy)l-(2-furovl)-2-phenvlpiperidine
The compound of Description 1 (400mg) and triethylamine (300mg) were dissolved in dichloromethane and the mixture was stirred for 10 min at 0°C. 2-Furoyl chloride (155mg) was added to the solution and the reaction mixture was stirred for 15 min. The mixture was then washed with brine; the organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica using 20% ethyl acetate in petrol, affording a dear oil. 1H NMR (360MHz, DMSO-d6) d 1.6-1.8 (2H, m, CH2), 1.9-2.1 (2H, m, CH2), 2.99 (1H, mc, CHHN), 4.02 (1H, q, J = 5.0Hz, CHO), 4.0-4.2 (1H, m, CHHN), 4.78 (1H, d, J = 13.0Hz, OCHH), 4.86 (1H, d, J = 13.0Hz, OCHH), 5.95 (1H, s,
CHPh), 6.62 (1H, s, furan-H), 6.99 (1H, s, furan-H), 7.25-7.36 (3H, m, ArH), 7.51-7.54 (2H, m, ArH), 7.83 (1H, s, furan-H), 7.90 (2H, s, ArH), 7.99 (1H, s, ArH); MS (CI+) m/z 498 (M++1, 20%). EXAMPLE 10
2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]furan
The compound of Example 9 (340mg) was dissolved in tetrahydrofuran. To this solution was added borane-dimethyl sulfide complex (0.18ml of 10M solution) and the resulting solution was heated at reflux for 8h. The mixture was cooled, methanol added to quench excess borane, and the solvents were removed in vacuo. The residue was dissolved in methanol (10ml) and potassium carbonate was added (238mg). This mixture was heated at reflux for 1 hour; the methanol was removed in vacuo and the residue was dispersed between ethyl acetate and brine. The ethyl acetate layer was dried (MgSO4) and evaporated. The residue was purified by diromatography on silica using 10% ethyl acetate in petrol. The product was recrystallised from ether-hexane: mp 103-104°C. 1H NMR d 1.4-1.5 (2H, m, CH2CH2), 1.8-1.9 (1H, m, CHHCH2N), 2.1-2.2 (2H, m, CHHCH2N and CHHN), 2.95-3.0 (1H, m, CHHN), 3.11-3.15 (1H, d, J = 15.0Hz, NCHH-furan), 3.38 (1H, s,
NCHCHO), 3.54-3.58 (1H, d, J = 15.0Hz, NCHH-furan), 3.56 (1H, s, NCHCHO), 4.02-4.06 OH, d, J = 13.0Hz, OCHH-), 4.59-4.62 (1H, d, J = 13.0Hz, OCHH-), 6.08-6.09 (1H, m, furan H), 6.35-6.36 (1H, m, furan-H), 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H, m, ArH), 7.55 (1H, s, furan-H), 7.68 (2H, s, ArH),
7.93 (1H, s, ArH); MS (CI+) m/z 485 (M++1, 100%). Found: C, 62.11; H, 4.80; N, 2.90. Calcd. for C25H23NF6O: C, 62.27; H, 4.83; N, 2.96. EXAMPLE 11
5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-bromo-1,2,4-oxadiazol e hydrochloride
Diisopropylethylamine (220μl) was added to a stirred suspension of the compound of Description 1 (200mg) and
5-bromo-3-(chloromethyl)-1,2,4-oxadiazole (99mg) (J.
Heterocydic Chem. 1989, 26, 23) in dry acetonitrile. The resulting solution was allowed to stir at room temperature for 48 hrs. After this time the solvent was removed under reduced pressure and the residual oil purified by column chromatography on silica using ethyl acetate in hexane (20%) as eluant to afford a waxy sohd. Treatment of an ethereal solution of this sohd with ethereal hydrogen chloride yielded a white predpitate. Recrystallisation from ether afforded the title compound as an amorphous white sohd: mp 100-102°C. 1H
NMR (360MHz, DMSO-d6) d 1.67-1.70 (2H, m, CH2), 1.83 (1H, m, CHH), 2.30 (1H, m, CHH), 2.74 (1H, m, CHHN), 3.10 (1H, m, CHHN), 3.70 (1H, d, J = 11.0Hz, CH-OCH2), 3.82 (1H, brs, N-CH-Ph), 4.34 (1H, d, J = 16.0Hz, NCHH-oxadiazole), 4.36 (1H, d, J = 11.0Hz, OCHH-Ar), 4.58 (1H, d, J = 16.0Hz,
NCHH-oxadiazole), 4.73 (1H, d, J = 11.0Hz, OCHH-Ar), 7.34-7.42 (5H, m, ArH), 7.68 (2H, s, ArH), 7.73 (1H, s, ArH); MS (CI+) m/z 564 ((M+1)+, 20%). Found: C, 45.64; H, 3.63; N, 6.70. Calcd. for C23H20N3O2F6Br.HCl: C, 45.98; H, 3.52; N, 6.99%.
EXAMPLE 13
5-[{(2R*,3R*)-3-( (3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl)-3-dimethvlamino-1,2,4-oxadiazole hydrochloride The compound of Example 11 (169mg) in dimethylamine
(33% in ethanol) was heated to 40°C for 30 min. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica using ethyl acetate in hexane (20%) as eluant. The compoτmd was dissolved in ether and treated with excess ethereal hydrogen chloride to afford a white predpitate. Recrystallisation from ether afforded the product as white powder (110mg): mp 179-180°C. 1H NMR (360MHz, DMSO-d6) d 1.59 (2H, m, CH2), 2.1-2.21 (2H, m, CH2), 2.4-2.45 (1H, m, CHHN), 3.01 (6H, s, N(CH3)2), 3.10 (1H, m, CHHN), 3.60 (1H, brs, CH-O-CH2), 3.70 (1H, d, J = 16.0Hz, NCHH-oxadiazole), 3.78 (1H, d, J = 1.0Hz, N-CH-Ph), 3.82 (1H, d, J = 16.0Hz, NCHH-oxadiazole), 4.01 (1H, d, J = 15.0Hz, O-CHH-Ar), 4.49 (1H, d, J = 15.0Hz, O-CHH-Ar), 7.3 (3H, m, ArH), 7.4 (2H, m, ArH), 7.49 (2H, s, ArH), 7.64 (1H, s, ArH); MS (CI+) m/z (M++1) 529. Found: C, 51.87; H, 4.93; N, 9.62. Calcd. for C25H26N4O2F6.HCl.H2O. C, 51.51; H, 5.01; N, 9.61%.
EXAMPLE 13 (2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenyl-1-(2-thienoyl)piperidine
The compound of Description 1 was reacted with 2-thiophenecarbonyl chloride as outlined in Example 9. The oil obtained after work-up and removal of solvent was purified by chromatography on silica, eluting with 10% ethyl acetate in petroleum ether to afford the pure product as a dear oil. 1H NMR (250MHz, CDCl3) d 1.6-1.8 (2H, m, CH2), 2.1-2.2 (2H, m, CH2), 3.0 (1H, m, CHN), 4.0 (1H, dt, J = 5Hz, 2Hz, CH), 4.1 (1H, brs, CHN), 4.7 (1H, d, J = 7Hz, CHAr), 4.8 (1H, d, J = 7Hz, CHAr), 6.2 (1H, brs, NCHPh), 7.02 (1H, dd, J = 1, 2Hz, thiophene-H), 7.3-7.44 (4H, m, Ar-H), 7.5 (1H, dd, J = 1, 3Hz, thiophene-H), 7.6-7.92 (5H, m, Ar-H).
EXAMPLE 14
(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenyl-1-(2-thienylmethyl)piperidine
The compound of Example 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was recrystallised from ether and hexane to give the product as a white crystalline sohd. 1H NMR (250MHz, CDCl3) d 1.44-1.64 (2H, m, CH2), 1.9-2.2 (2H, m, CH2), 2.24 (1H, d, J = 7Hz, CHN), 3.14 (1H, d, J = 7Hz, CHN), 3.4 (1H, s, CHO), 3.56 (1H, s, NCHPh), 3.6 (1H, s, CH-thiophene), 4.88 (1H, d, J = 10Hz,
CH-thiophene), 4.0 (1H, d, J = 10Hz, CHAr), 4.24 (1H, d, J = 10Hz, CHAr), 6.7 (1H, d, J = 1Hz, thiophene-H), 6.9 (H, dd, J * 2Hz, 3Hz, thiophene-H), 7.2 (1H, d, J = 3Hz, thiophene-H), 7.28 (4H, m, Ar-H), 7.5 (3H, m, Ar-H), 7.68 (1H, s, Ar-H). MS m/z 500 (M+, 100%).
EXAMPLE 15 5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidinolmethyl)-2,3-dihydro-4-methyl-3- thioxo-1,2,4-triazole hydrochloride
A suspension of the compound of Description 7 (0.50g) and methyl isothiocyanate (0.09ml) in 1-butanol (10ml) was heated under reflux for 10 min.
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1ml) was added and the reaction mixture was heated under reflux for 2.5h. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated. The residue was purified on silica using 5% methanol in dichloromethane as eluant to give the title compound. The product (470mg) was characterised as the hydrochloride salt. 1H NMR (360MHz, DMSO-d6) d 1.77-1.93 (2H, m, CH2), 2.05-2.22 (1H, m, CHH), 2.31 (1H, d, J -= 13.5Hz, CHH), 3.42 (3H, s, CH3), 3.45-3.51 (1H, m, NCHHCH2), 3.83 (1H, d, J = 12.0Hz, NCHHCH2), 3.97 (1H, brs, CHO), 4.24 (1H, d, J = 15.5Hz, N-CHH-het), 4.32 (1H, d, J = 15.5Hz, N-CHH-het), 4.33 (1H, d, J = 12.5Hz, O-CHH), 4.76 (1H, s, NCH), 4.80 (1H, d, J = 12.5Hz, O-CHH), 7.42-7.50 (3H, m, ArH), 7.59 (2H, brs, ArH), 7.85 (2H, s, ArH), 7.89 (1H, s, ArH), 9.15 (1H, brs, NH); MS (FAB) m/z 530 ((M+1)+, 13%).
EXAMPLE 16
3-[{(2R*-3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazole
The compound of Description 1 (1.0g), anhydrous potassium carbonate (0.94g) and N-formyl-2-chloroacetamidohydrazone (0.46g), (prepared according to Yanagisawa, L, J. Med. Chem. 1984, 27, 849) were heated to 60°C in anhydrous dimethylformamide for 3h, followed by heating at 130°C for 12h. The reaction mixture was cooled, diluted with ethyl acetate (100ml) and washed with water, (3 ×
20ml). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to give a brown oil. This was purified on silica using ethyl acetate in petrol (70:30) as eluant. This afforded the product as a white solid. 1H NMR (250MHz, CDCl3) d 1.6 (2H, m, CH2), 1.95-2.24 (2H, m, CH2), 2.34 (1H, m, NCHH), 3.06 (1H, m, NCHH), 3.44 (1H, d, NCHH-triazole), 3.5 (1H, bs, CHO), 3.6 (1H, bs, NCHPh), 3.8 (1H, d, N-CHH-triazole), 4.04 (1H, d, OCHH-Ar), 4.50 (1H, d, OCHHAr), 7.3 (3H, m, ArH), 7.44 (2H, m, ArH), 7.5 (2H, s, ArH), 7.7 (1H, s, ArH), 7.9 (1H, s, triazole-H). MS (CI+) m/z 485 (M++1, 35%). EXAMPLE 17
5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenvlpiperidino)methyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole The compound of Description 7, potassium thiocyanate
(0.45g) and cone, hydrochloric add (2.3ml) in water (12ml) were heated under reflux for 2h. After cooling, solid sodium hydroxide was added until pH = 8 and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to give the crude semi-carbazide which was heated at reflux in 2N sodium hydroxide solution (10ml) for 2h. After cooling the solution was aridified to pH 5-6 and the product extracted into ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The crude triazole was chromatographed on sUica eluting with
40% ethyl acetate/60-80 petroleum ether to give the title compound as a white sohd. 1H NMR (250MHz, CDCl3) d 1.6 (2H, m, CH2), 1.9-2.3 (3H, m, CH2 + NCHH), 2.95 (1H, bd, NCHH), 3.16 (1H, d, N-CHH-Het), 3.20 (1H, bs, CHO), 3.6 (1H, bs, NCHPh), 3.78 (1H, d, N-CHH-Het), 4.1 (1H, d, CHH-Ar),
4.58 (1H, d, CHH-Ar), 7.32 (5H, m, ArH), 7.5 (2H, s, Ar-H), 7.78 (1H, s, ArH). MS (FAB) m/z 517 (M++l, 80%).
EXAMPLE 18 5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl1-2-methyltetrazole
The compound of Example 7 (500mg) was suspended in water (4ml) and sodium hydroxide (44mg) added. This was heated to an external temperature of 96°C and dimethyl sulphate (65mg) added. The reaction mixture was allowed to stir under nitrogen at 96°C for 1h after which time stirring was continued for 24h at 5°C. After this time, the product was extracted into dichloromethane and washed with water and brine. The organic layer was dried (MgSO4) and evaporated. The residue was purified on silica using medium pressure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol. The first compound to be eluted was isolated, and this afforded the product (50mg) as a crystalline sohd, which was recrystallised from ether/hexane to afford white crystals: mp 139-141°C. 1H NMR (360MHz, DMSO) d 1.44-1.51 (2H, m, CH2), 1.79-1.82 (1H, m, CHH), 2.12-2.15 (1H, m, CHH), 2.19-2.25 (1H, m, CHHN), 2.97-3.00 (1H, m, CHHN), 3.37 (1H, d, J = MHz, N-CHH-tetrazole), 3.52 (1H, s, NCHCHO), 3.58 (1H, s, NCHCHO), 3.81 (1H, d, J = MHz, N-CHH-tetrazole), 4.03 (1H, d, J = 13Hz, OCHH), 4.31 (3H, s, CH3), 4.60 (1H, d, J = 13Hz, OCHH), 7.23-7.33 (3H, m, ArH), 7.49-7.51 (2H, m, ArH), 7.68 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI+) m/z 500 ((M+1)+, 100%). Found: C, 55.56; H, 4.76; N, 14.20. Calculated for C23H23N5OF6: C, 55.31; H, 4.64; N, 14.02%.
EXAMPLE 19
5-[{(2R*,3R*)-3-((3,5-Bis(trifluorpmethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl]-1-methyltetrazole
The title compound was prepared as described in Example 18. During purification, the second compound to be eluted was isolated, and this afforded the product (120mg) as a crystalline sohd, which was recrystallised from ether/hexane to afford yellow crystals: mp 75-77°C. 1H NMR (360MHz, DMSO) d 1.51-1.55 (2H, m, CH2), 1.84-1.87 (1H, m, CHH), 2.12-2.16 (1H, m, CHH), 2.31-2.37 (1H, m, CHHN), 2.81-2.84 (1H, m, CHHN), 3.52 (1H, d, J = 15Hz, NCHH-tet), 3.54 (1H, s, NCHCHO), 3.60 (1H, s, NCHCHO), 3.82 (1H, d, J = MHz, NCHH-tet), 3.84 (3H, s, CH3), 4.14 (1H, d, J = 13Hz, OCHH), 4.85 (1H, d, J = 13Hz, OCHH), 7.26-7.32 (3H, m, ArH), 7.45-7.48 (2H, m, ArH), 7.74 (2H, s, ArH), 7.94 (1H, s, ArH); MS (CI+) m/z 500 ((M+l)+, 20%).
EXAMPLE 20
3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidinolmethyl]-5-dimethylamino-1,2,4-thiadiazole a) 5-Dimethylamino-3-(chloromethyl)-1,2,4-thiadiazole
A solution of dimethylamine in ethanol (0.5ml × 33%) was added to a stirred suspension of 5-chloro-3-(chloromethyl)1,2,4-thiadiazole (540mg) (J. Goerdeler, Chem. Ber. 1957, 90, p 182 or ICI EP 0006679) and potassium carbonate (1.0g) in methanol. The solution was stirred at room temperature for three hours, and then the solvent removed under reduced pressure. The residue was taken up in ethyl acetate (40ml), washed with water (20ml) and brine (20ml). The organic layers were dried (MgSO4), filtered and the solvent removed to afford a yellow gum. Flash chromatography using 10% ethyl acetate in hexane as eluent, afforded the product as a yellow oil (330mg). 1H NMR (360MHz, CDCl3) d 3.15 (6H, s, N(CH3)2), 4.51 (2H, s, Cl-CH2); MS (CI+) m/z 178 ((M+1)+, 95%).
b) A solution of the compound of Description 1 (223mg), 5-dimethylamino-3-(chloromethyl)-1,2,4-thiadiazole (100mg) and diisopropylethylamine (0.2ml) were heated at reflux in dry acetonitrile for three hours. The reaction was then allowed to cool to room temperature and the solvent removed under reduced pressure. Purification of the residue by flash chromatography (40% EtOAc/nHex) gave a yellow gum.
Recrystallisation from n-hexane afforded the product as yellow plates: mp 144-145°C. 1H NMR (360MHz, CDCl3) d l.57 (2H, m, CH2), 2.11 (3H, m, CH2+CHH), 2.42 (1H, m, CHH), 3.11 (6H, s, N(CH3)2), 3.20 (1H, m, CH-OCH2), 3.47 (1H, d, J = 14.5Hz, CHH-thiadiazole), 3.56 (1H, m, CHPh), 3.75 (1H, d, J = 14.5Hz,
CHH-thiadiazole), 4.03 (1H, d, J = 10.5Hz, OCHH-Ar), 4.45 (1H, d, J = 10.5Hz, OCHH-Ar), 7.30 (3H, m, ArH), 7.51 (2H, s, ArH), 7.53 (2H, m, ArH), 7.69 (1H, s, ArH); MS (CI+) m/z 545 ((M+1)+, 60%). Found: C, 55.12; H, 4.75; N, 10.38. Calcd. for C25H20F6N4SO: C, 55.14; H, 4.81; N, 10.30%.
EXAMPLE 21
2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl]-4,7-dimethylbenzoxazole A solution of 2-(chloromethyl)-4,7-dimethylbenzoxazole
(285mg) in dry acetonitrile (10ml) was added to a solution of the compound of Description 1 in dry acetonitrile (10ml) containing dnsopropylethylamine (0.4ml). The resulting mixture was heated at reflux for three hours, cooled to room temperature and the residue purified by flash diromatography on silica gel using
20% ethyl acetate/n-hexane as eluant. Recrystallisation of the isolated material from n-hexane afforded the product as white needles: mp 109-110°C. 1H NMR (CDCl3) 1.49-1.53 (2H, m, CH2), 1.56-1.60 (1H, m, CHH), 2.03-2.09 (1H, m, CHH), 2.10-2.16 (1H, m, CHHN), 2.36-2.40 (1H, m, CHHN), 2.47 (3H, s, Ar-CH3), 2.54 (3H, s, ArCH3), 3.24 (1H, m, CHN), 3.59 (1H, m, CHOCH2), 3.67 (1H, d, J = 12.0Hz, N-CHH-benzoxazole), 3.79 (1H, d, J = 12.0Hz, N-CHH-benzoxazole), 3.96 (1H, d, J = 10.0Hz, OCHH), 4.47 (1H, d, J = 10.0Hz, OCHH), 6.99 (2H, s, ArH), 7.32 (3H, m, ArH), 7.54 (2H, s, ArH), 7.57 (2H, m, ArH),
7.71 (1H, s, ArH); MS (CI+) m/z 563 ((M+1)+, 70%). Found: C, 64.09; H, 5.04; N, 5.12. Calcd for C30H28N2O2F6: C, 64.05; H, 5.01; N, 5.00%. EXAMPLE 22
2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidinolmethyl]benzoxazole
This compound was prepared following the procedure described in Example 21, using 2-(chloromethyl)benzoxazole as the alkylating agent: mp 95-97°C. 1H NMR (CDCl3) d 1.47-1.60
(2H, m, CH2), 2.06-2.19 (2H, m, CH2), 2.42-2.56 (1H, dd, 1H, J = 6.0, 4.0Hz, NCHH), 3.26 (1H, dd, J = 4.0, 2.0Hz, NCHH), 3.61 (1H, s, CHO), 3.66 (1H, d, J = 15.0Hz, NCΗH-benzoxazole), 3.66 (1H, d, J = 2.0Hz, CHPh), 4.02 (1H, d, J = 15.0Hz, CHH-benzoxazole), 4.04 (1H, d, J = 12.0Hz, OCHH), 4.48 (1H, d,
J = 12.0Hz, OCHH), 7.26-7.67 (12H, m, ArH); MS (CI+) m/z 535 ((M+1)+ 65%). Found: C, 62.36; H, 4.67; N, 5.27. Calc for C28H24F6N2 . ¼H2O: C, 62.39; H, 4.58; N, 5.20%. EXAMPLE 23
4-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinolmethyl]oxazole 1,3-oxazole-4-carboxaldehyde was prepared following the procedure described by J. Hodges, W. Patt and C. Connolly, J. Org. Chem. 1991, 56, 449-452. a) 4-(Hydroxymethyl)-1,3-oxazole
1,3-Oxazole-4-carboxaldehyde (0.38g) was dissolved in anhydrous methanol and stirred under nitrogen; sodium borohydride (0.074g) was added carefully. After 1 hour no starting material was present by TLC using 50% ethyl acetate in hexane as eluent. The methanol was removed by rotary evaporator (water bath temp 40°C). The residue was purified by chromatography on silica eluting with 100% diethyl ether. This afforded the alcohol (0.27g) as a white sohd. 1H NMR d (360 MHz, CDCl3) 2.93 (OH), 4.63 (2H, s, CH2OH), 7.64 (1H, s, oxazole-H), 7.90 (1H, s, oxazole-H).
b) 4-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidinolmethyl]oxazole
4-(Hydroxymethyl)-1,3-oxazole (0.13g) was dissolved in anhydrous dichloromethane (4ml) under an atmosphere of nitrogen. Triethylamine (0.19ml) and p-toluenesulfonyl chloride
(0.13g) were added to the reaction mixture which was stirred for 1 hour at room temperature. A further portion of p-toluenesulfonyl chloride (0.13g) and a catalytic amount of dimethylaminopyridine were added to the reaction mixture. The compound of Description 3 (1.2g, free base) was dissolved in dimethylformamide (5ml) and was added to the reaction mixture followed by triethylamine (0.19ml). The mixture was heated at 60°C for 2h and the resulting mixture was diluted with water (50ml) and extracted with dichloromethane (3 × 20ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford a yellow oil. This was purified by chromatography on silica gel using a gradient elution of 30-60% ether in hexane to afford the title compound as a white solid. This was recrystallised from ether/hexane: mp 102-104°C. 1H NMR (360MHz, CDCl3) d 1.46-1.64 (1H, m, NCH2CH2CHH), 1.7-1.87 (1H, m, NCH2CH2CHH), 1.96-2.20 (2H, m, NCH2CH2),
2.32-2.48 (1H, m, NCHH), 3.20-3.46 (3H, m, NCHH + NCHH-oxazole + CHOCH2Ar), 3.55 (1H, brs, CHPh), 3.68 (1H, d, J = M.5Hz, NCHH-oxazole), 4.01 (1H, d, J = 11.5Hz, OCHHAr), 4.46 (1H, d, J = 11.5Hz, OCHHAr), 7.24-7.58 (8H, m, ArH), 7.70 (1H, s, ArH), 7.80 (1H, s, ArH); MS (CI+) 485 (M+ +
1, 100%)
EXAMPLE 24
2-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl)pyrazine a) 2-(Chloromethyl)pyrazine
2-Methylpyrazine (1g) was dissolved in carbon tetrachloride (50ml) under nitrogen. N-Chlorosucdnimide (1.42g) and benzoyl peroxide (50mg) were added and the mixture was heated at reflux for 24h. The reaction mixture was cooled and filtered through celite and the filtrate was concentrated in vacuo. The resulting oil was purified on silica using 30% ethyl acetate in petrol. 1H NMR (360MHz, CDCl3) d 4.72 (2H, s, CH2Cl), 8.56 (2H, s, ArH), 8.76 (1H, s, ArH).
b) 2-[{(2S,3S )-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]pyrazine
2-(Chloromethyl)pyrazine (0.17g), potassium carbonate (0.6g) and the compound of Description 3 (0.35g) were suspended in dimethylformamide (3ml); the reaction mixture was heated at 60°C for 12h. The mixture was cooled, diluted with water (30ml) and extracted with ethyl acetate (2 × 20ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil. The product was purified by column chromatography on silica gel using a gradient elution of l5-35% ethyl acetate in hexane. This afforded the product as a white solid, which was recrystallised from pentane to give colourless crystals: mp 108-110°C . 1H NMR (360MHz, DMSO-d6) d 1.42-1.60 (2H, m NCH2CH2CH2), 1.77-1.92 (1H, m, NCH2CHH), 2.13-2.25 (2H, m, NCHH + NCH2CHH), 2.84-2.92 (1H, m, NCHH), 3.12 (1H, d, J = M.OHz,
NCHH-pyrazine), 3.55 (1H, m, CHO), 3.63 (1H, m, CHPh), 3.78 (1H, d, 14.0Hz, NCHH-pyrazine), 4.11 (1H, d, J = 13.0Hz, OCHHAr), 4.64 (1H, d, J = 13.0Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H, s, ArH), 7.93 (1H, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI+) 496 (M++1, 60%).
Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C25 F6N3O: C, 60.60; H, 4.68; N, 8.48%.
EXAMPLE 2$ 4-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidino}methyl]-2-methyl-1,3-thiazolium
dihydrochloride
4-(Chloromethyl)-2-methylthiazole hydrochloride (83mg) was added to a suspension ofthe compound of Description 3 and potassium carbonate in dimethylformamide (5ml). The resulting mixture was heated at 60°C for 18h, cooled to room temperature and diluted with water (50ml). This solution was extracted with ethyl acetate (2 × 25ml) and the combined organic extracts were washed with water (2 × 20ml), brine (20ml), dried (MgSO4) and filtered. The resulting solution was evaporated under reduced pressure to afford a yellow oil. This was purified by medium pressure liquid chromatography using 50% ethyl acetate in hexane to afford the product as a white solid. This was treated with ethereal hydrogen chloride and recrystallised from methyl-t-butyl ether to afford the title compound: mp 58-60°C. 1H NMR (360MHz, DMSO-d6) d 1.71 (2H, m, CH2), 2.11 (2H, mc, CH2), 2.49 (1H, m, CHHN), 2.69 (3H, s, Ar-CH3), 3.15 (1H, m, CHHN), 3.54 (1H, m, CHO), 4.12 (2H, m, CH2-thiazole), 4.16 (1H, d, J = 10.0Hz, OCHHAr), 4.58 (1H, brs, CHPh), 4.76 (1H, d, J = 10.0Hz, OCHHAr), 7.40-7.43
(5H, m, ArH), 7.64 (1H, brs, ArH), 7.92 (2H, s, ArH), 7.97 (1H, s, ArH); MS (CI+) m/z 515 (M+ + 1). Found: C, 48.17; H, 4.76; N, 4.52. Calcd. for C25H24F6N2OS.2HCl.2H2O: C, 48.16; H, 4.85; N, 4.49%.
EXAMPLE 26
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-oxadiazole hydrochloride
3-(Chloromethyl)-1,2,4-oxadiazole (270mg) was added to a rapidly stirred suspension of the compound of Description 3 and potassium carbonate in dimethylformamide (10ml). The reaction mixture heated at 60°C for 4h, cooled to room temperature and diluted with water (50ml). The aqueous solution was extracted with ethyl acetate (3 × 50ml) and the organic extracts were combined, washed with water (3 × 50ml), brine (50ml), dried (MgSO4) and filtered. The resulting solution was concentrated under reduced pressure and purified by column chromatography on silica gel using 20% ethyl acetate in hexane as eluent. The resulting oil was treated with ethereal hydrogen chloride to afford the title compound as a white powder: mp 74-75°C. 1H NMR (360MHz, DMSO-d6) d 1.62 (2H, m, CH2), 1.97-2.1 (2H, m, CH2), 2.50 (1H, m, CHHN), 3.16 (1H, m, CHHN), 3.51 (1H, m, CHO), 3.69-3.72 (3H, m, CH2-oxadiazole + CHPh), 4.14 (1H, d, J = 10.0Hz, OCHHAr), 4.70 (1H, d, J = 10.0Hz, OCHHAr), 7.32 (3H, m, ArH), 7.45 (2H, m, ArH), 7.78 (3H, m, ArH), 7.94 (1H, s, ArH).
EXAMPLE 27
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-iodo-1,2,4-thiadiazole a) 5-Iodo-3-(iodomethyl)-1,2,4-thiadiazole
Sodium iodide (excess) was added to a stirred solution of 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (3.0g) (J. Goerdeler, Chem. Ber. 1957, 20, 182) in dry butanone (15ml). The resulting solution was heated at reflux for four hours, cooled to room temperature and filtered. The filtrate was dfluted with water (20ml) and extracted with ethyl acetate (50ml). The ethyl acetate layer was dried (MgSO4), filtered and concentrated in vacuo to afford a red oil, which was used in the following reaction without further purification.
b) 3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenvl) methyloxyl-2- phenylpiperidinolmethyl]-5-iodo-1,2,4-thiadiazole
Dnsopropylethylamine (116mg) was added to a stirred solution of 5-iodo-3-(iodomethyl)-1,2,4,thiadiazoIe (160mg) and the compound of Description 3 (200mg) in dry acetonitrile
(10ml). The resulting solution was stirred at room temperature for 18h. The reaction mixture was filtered and the solvent was removed in vacuo to afford a red oil. This was purified using column chromatography on silica gel using 20% ethyl acetate in hexane as eluent. This afforded the product as a powder: mp 98-101°C. 1H NMR (360MHz, CDCl3) d 1.55 (3H, m, NCH2CH2CH2 + NCH2CHH), 2.13 (2H, m, NCH2CHH + NCHH), 2 H, m, CHHN, 3.21 (1H, m, CHO), 3.69 (2H, m, CHPh + CHH-thiadiazole), 4.02 (2H, m, CHH-thiadiazole + OCHH), 4.48 (1H, d, J = 8.0Hz, OCHH), 7.32 (5H, m ArH), 7.51 (2H, s ArH),
7.70 (1H, s, ArH).
EXAMPLE 28
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinolmethyl)-1,2,4-thiadiazole hydrochloride
Sodium borohydride (280mg) was added to a stirred solution of the compound of Example 27 (500mg) and palladium (II) chloride (280mg) in dry methanol (25ml). The resulting mixture was stirred for 30 min and then filtered through celite; the filtrate was concentrated in vacuo. The solid residue thus obtained was dissolved in ethyl acetate and the solution was washed with water (10ml), the organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow ofl. Treatment of this oil with ethereal hydrogen chloride afforded the title compound as a white powder: mp 89-90°C. 1H
NMR (360MHz, DMSO-d6) d 1.79 (2H, m, CH2), 1.9-2.20 (3H, m, CHHN + NCH2CH2), 2.6 (1H, m, CHHN), 3.8 (1H, bm, CHO), 3.89 (1H, brs, CHPh), 4.2-4.3 (3H, m, CH2-thiadiazole + OCHH), 4.76 (1H, d, J = 9.0Hz, OCHH), 7.39 (3H, m, ArH), 7.55 (2H, m, ArH), 7.89 (2H, s, ArH), 8.32 (1H, s, ArH), 10.32 (1H, s,
N-CH-S); MS (CI+) m/z 502 (M+ + 1). Found: C, 49.31; H, 4.09; N, 7.18%. Calcd. for C23H21F6N3OS.HC1.1.25H2O : C, 49.48; H, 4.37; N, 7.52%. EXAMPLE 29
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyIoxy)- 2-phenylpiperidinolmethyl]-5-methoxy-1,2,4-thiadiazole hydrochloride Sodium methoxide (34mg) was added to a stirred solution ofthe compound of Example 27 (200mg) in methanol (5ml). The solution was heated at reflux for 2h, cooled to room temperature and the solvent removed under reduced pressure affording a solid residue. The sohd was dissolved in ethyl acetate (15ml), and the organic phase was washed with water (20ml), separated, dried (MgSO4) and the solvent was removed under reduced pressure. The residual solid was treated with ethereal hydrogen chloride and the resulting solid was recrystallised from ethyl acetate to afford the product as white needles: mp 74-75°C. 1H NMR (360MHz, DMSO-d6) d l.55 (2H, m, CH2),
1.73 (1H, m, CHH), 2.09 (2H, m CH2), 2.43 (1H, m, CHH), 3.20 (1H, m, CHO), 3.49 (2H, m, CHPh + CHH-thiadiazole), 3.75 (1H, m, CHH-thiadiazole), 4.02 (1H, d, J = 10.0Hz, OCHH), 4.14 (3H, s, OCH3), 4.45 (1H, d, J = 10.0Hz, OCHH), 7.30 (3H, m ArH), 7.5l (4H, brs, ArH), 7.54 (1H, s, ArH); MS (CI+) m/z 532
(M+ + 1). Found: C, 49.89; H, 4.10; N, 7.41. Calcd. for C24H23F6N3O2S.HCl.0.5H2O: C, 49.96; H, 4.37; N, 7.28%.
EXAMPLE 30
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidino}methyl]-1,2,4-triazole dihydrochloride
The title compound was prepared according to the procedure described in Example 16, using the compound of Description 3 as starting material. The free base was treated with ethereal hydrogen chloride to afford the product as a white crystalline solid: mp (free base) 209-210°C . Found: C, 49.36; H, 4.57; N, 10.05. Calcd. for C23H22F6N4O.2HCl: C, 49.56; H, 4.34; N, 10.05%.
EXAMPLE 31
5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinolmethyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole hydrochloride
The title compound was prepared according to the procedure described in Example 17, using the compound of Description 8 as a starting material. This afforded the product as a white solid which was treated with ethereal hydrogen chloride to yield the crystalline hydrochloride: mp 154-157°C.
Found: C, 46.59; H, 4.52, N, 9.26; Cl, 5.84. Calcd. for C23H22F6N4O.HCl.2H2O: C, 46.90; H, 4.62; N, 9.51; Cl, 6.02%.
EXAMPLE 32 2-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidino}methyl]-1-(p-toluenesulfonyl)imidazole dihydrochloride
(a) N-(p-Toluenesulfonyl)imidazole-2-carboxaldehyde.
Imidazole-2-carboxaldehyde (1.92g) was suspended in dichloromethane (20ml). p-Toluenesulfonyl chloride (3.8g) and triethylamine (2.8ml) were added to the mixture which was stirred at room temperature for 12 hours. The resulting slurry was diluted with water and the organic layer was washed with brine, dried (MgSO4) and filtered. The dichloromethane layer was concentrated in vacuo and the residue was purified by column chromatography on silica using 50% ethyl acetate in hexane as eluent. This afforded the product as a yellow oil which crystallised on standing. 1H NMR (360MHz, CDCl3) d
2.44 (3H, s, ArCH3), 7.31 (1H, d, J=1.5Hz, imidazole-H), 7.37 (2H, d, J=8.0Hz, ArH), 7.83 (1H, d, J=1.5Hz, imidazole-H), 8.00 (2H, d, J=8.0Hz, ArH), 9.78 (1H, s, CHO). MS (Cl+ ) m/z 251 (M++1).
(b) 2-(Hydroxymethyl)-1-(p-toluenesulfonyl)imidazole
The aldehyde of (a) above (3g) was dissolved in methanol (15ml) and sodium borohydride (114mg) was added portionwise. This solution was stirred for 10 min. Methanol was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and filtered and the solvent was removed in vacuo to afford a crystalline solid. 1H NMR (250MHz, CDCl3) d 2.42 (3H, s, ArCH3), 4.84 (2H, s, CH2O), 7.00 (1H, d, J=-1.5Hz, imidazole-H), 7.36 (2H, d, J=8.0Hz, ArH), 7.40 (1H, d, J=1.5Hz, imidazole-H), 7.84 (2H, d, J=8.0Hz, ArH).
(c) ((N-p-Toluenesulfonyl)imidazol-2-yl)methyl methanesulfonate
The alcohol described in (b) above (12.6mg) was dissolved in dichloromethane (2.5ml) and triethylamine (.07ml). This solution was cooled to 0°C. Methanesulfonyl chloride (.04ml) was added to the solution dropwise. After stirring for 10 mins the solution was diluted with water and the organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield a white sohd which was used in the following reaction without further purification. 1H NMR (250MHz, CDCl3) d 2.44 (3H, s, ArH), 2.94 (3H, s, SO2CH3), 5.51 (2H, s, CH2SO2), 7.08 (1H, d, J=1.5Hz, imidazole-H), 7.40 (2H, d, J=8.0Hz, ArH), 7.49 (1H, d, J=1.5Hz, imidazole-H), 7.92 (2H, d, J=8.0Hz, ArH).
(d) ((N-p-Toluenesulfonyl)imidazol-2-yl)methylmethanesulfonate (1.6g) was added to a suspension of the compound of
Description 3 (2.47g) and potassium carbonate (800mg) in dimethylformamide (10ml) and the resulting mixture was heated at 100°C for 2h. The mixture was cooled, diluted with water (100ml) and extracted with ethyl acetate (3 × 20ml). The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo. This afforded a colourless oil which was purified by column chromatography on silica using 25-30% ethyl acetate in hexane. This afforded the product as a white crystalline solid which was recrystallised from dichloromethane/petrol: mp 125-126°C . 1H NMR (360MHz,
DMSO-d6) d 1.4-1.5 (1H, m, NCH2CH2CHH), 1.5-1.67 (1H, m, NCH2CH2CHH), 1.8-2.0 (1H, m, NCH2CHH), 2.06-2.1 (1H, m, NCH2CHH), 2.35 (3H, s, CH3), 2.4 (1H, mc, NCHH), 2.7-2.86 (1H, m, NCHH), 3.50 (1H, d, J = 14.0Hz, CHH-imidazole), 3.56 (1H, brs, CHO), 3.76 (1H, d, J = 1.5Hz, CHPh), 4.08 (1H, d, J =
14.0Hz, CHH-imidazole), 4.09 (1H, d, J = 12.0Hz, OCHH), 4.48 (1H, d, J = 12.0Hz, OCHH), 6.96 (1H, d, J = l.OHz, imidazole-H), 7.12 (2H, d, J = 8.5Hz, ArH), 7.2-7.3 (3H7 m, ArH), 7.34 (1H, d, J = 1.0Hz, imidazole-H), 7.46-7.58 (2H, m, ArH), 7.60 (2H, s, ArH), 7.71 (1H, ArH), 7.79 (2H, d, J = 8.5Hz, ArH);
MS (CI+) m/z 638 (M+ + 1). Found: C, 58.48; H, 4.78; N, 6.72; S, 4.81. Calcd. for C31H29F6N3O3S: C, 58.39; H, 4.58; N, 6.59; S, 5.03%. EXAMPLE 33
2-[{2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidino}methyl]imidazole dihydrochloride
The compound of Example 32 was dissolved in dichloromethane and ethereal hydrogen chloride was added.
The resulting solution was stirred for 30 minutes whereupon the title compound crystallised from solution. This was removed by filtration and recrystallised from ethyl acetate/metiianol to afford the title compound as a white crystalline compound. 1H NMR (360MHz, D2O) d 1.61-1.74 (1H, m, CHH), 1.76-1.88 (1H, m, CHH), 2.04-2.21 (2H, m, CH2), 3.07-3.23 (1H, m, NCHH), 3.41-3.5l (1H, m, NCHH), 3.66 (1H, s, CHO), 4.09 (1H, d, J=13.0Hz, OCHH), 4.25 (1H, d, J=15.5Hz, CHH-imidazole), 4.30 (1H, s, CHPh), 4.39 (1H, d, J=15.5Hz, CHH-imidazole), 4.55 (1H, d, J=13.0Hz, OCHH), 7.1-7.2 (3H, m, ArH), 7.2-7.3 (2H, m,
ArH), 7.38 (2H, s, imidazole-H), 7.48 (2H, s, ArH), 7.51 (1H, s, ArH); MS (CI+) m/z 484 (M++1, 25%). Found: C, 50.32; H, 4.92; N, 7.23; Cl, 12.58. Calcd. for C24H23F6N3O.2HCl.H2O: C, 5θ.18; H, 4.74; N, 7.32; Cl, 12.34%.
EXAMPLE 34
4-[{2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy) -2-phenylpiperidino}methyl]imidazole dihydrochloride
This was prepared following the procedure described for Example 33 using the compound of Description 3 and
4-(hydroxymethyl)imidazole as starting materials. This afforded the title compound as a white crystalline compound: mp 206-210°C. 1H NMR (360MHz, D2O) d 1.73 (1H, m, NCH2CH2CHH), 1.94-2.06 (1H, m, NCH2CH2CHH), 2.22-2.40 (2H, m, NCH2CH2), 3.33 (1H, mc, NCHH), 3.70-3.81 (1H, m, NCHH), 3.97 (1H, brs, CHO), 4.30 (1H, d, J=12.5Hz, OCHH), 4.42(2H, s, NCH2-imidazole), 4.50 (1H, s, NCHPh), 4.75 (1H, d, J=12.5Hz, OCHH), 7.48 (6H, brs, ArH+imidazole-H), 7.74 (2H, s, ArH), 7.95 (1H, s, ArH), 8.80 (1H, s, imidazole-H); MS (CI+) m/z 484 (M++l Found: C, 5θ.22; H, 4.82; N, 7.18; Cl, 12.49. Calcd. for C24H23F6N3O.2HCl.H2O: C, 5θ.18; H, 4.74; N, 7.32; Cl, 12.34%
EXAMPLE 35
5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole hydrochloride
(a) N-Carbomethoxy-2-chloroacetamidrazone
Sodium methoxide (0.032g) was added to a solution of chloroacetonitrile (1.26ml) in anhydrous methanol (15ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour and then neutralised with acetic add (0.034ml).
Methyl hydrazinocarboxylate (1.79g) was added and the reaction mixture stirred at room temperature for 0.5 hour. The solution was concentrated in vacuo to give the title compound as an orange sohd. MS (CI)+ m/z 166.
(b) The compound of Description 1 (0.50g) was stirred with N-carbomethoxy-2-chloroacetamidrazone (0.19g) and potassium carbonate (0.47g) in dimethylformamide (10ml) at 70°C for 18 hours. The reaction mixture was then stirred at M0°C for 1 hour. After cooling, the material was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica using 5% methanol in ethyl acetate as eluent. The product was recrystallised from ethyl acetate/petrol to give the title compound as a white crystalline sohd. This was characterised as its hydrochloride salt: mp 168-172°C. MS (CI)+ m/z 500 ((M+1)+, 18%). Found: C, 50.65; H, 4.43; N, 10.22; Cl, 6.71.
Calcd. for C23H24N4O2.5F6CI: C, 50.60; H, 4.43; N, 10.26; Cl, 6.49%.
EXAMPLE 36
5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl)-3-(N,N-dimethylamino)-1,2,4-thiadiazole (a) 5-(N,N-Dimethylamino)-1,3,4-oxathiazolin-2-one
A solution of chlorocarbonylsulfenyl diloride (11.5g) in acetonitrile was added to a suspension of N,N-dimethylurea (25.0g) in acetonitrile (200ml), over a period of 20 minutes. The reaction mixture was stirred for 1 hour at 23°C, then filtered. Methanol (20ml) was added to the filtrate to decompose excess chlorocarbonylsulfenyl chloride. The solvents were removed in vacuo. The residue was purified by chromatography on silica using dichloromethane in hexane (3:1) to afford the product as a yellow oil. 1H NMR (250MHz, CDCl3) d 3.04 (6H, s, (CH3)2); MS (CI+) m/z 164 (M++NH4 +)
(b) 5-(Chloromethyl)-3-(N,N-dimethylamino)thiadiazole Chloroacetonitrile (1.3ml) in dimethylformamide (1ml) was heated to 150-l55°C and 5-(N,N-dimethylamino)-1,3,4-oxathiazolin-2-one (1.0g) was added in portions. After 5 minutes the reaction mixture was cooled and concentrated in vacuo. The residue was purified by chromatography on silica using hexane/ethyl acetate (9:1) as eluent. This afforded the product as a white crystalline solid. 1H NMR (25OMHz, CDCl3) d 3.19 (6H, s, (CH3)2), 4.82 (2H, s, CH2); MS (CI+) m/z 178
(c) 5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidinolmethyl)-3-(N,N-dimethylamino)-1,2,4-thiadiazole hydrochloride
The compound of Description 1 was reacted with 5-(chloromethyl)-3-(N,N-dimethylamino)tiιiadiazole according to the procedure described in Example 4. This afforded the title compound as a white solid: mp 160-161°C; 1H NMR (360MHz, DMSO-d6 + TFA) d 1.69-1.87 (2H, m, CH2), 2.01-2.26 (2H, m, CH2), 3.10 (6H, s, (CH3)2), 3.22-3.34 (1H, m, CHH), 3.64-3.72 (1H, m, CHH), 3.90 (1H, s, CHO), 4.26-4.34 (2H, m, CH2), 4.61 (1H, d, J=20.0Hz, OCHH), 4.76-4.82 (2H, m, OCHH + CHPh),
7.36-7.62 (5H, m, ArH), 7.87 (2H, s, ArH), 7.99 (1H, s, ArH).
EXAMPLE 37
5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]tetrazole
This compound was prepared according to the procedure described in Example 7, using the compound of Description 9 as a starting material: mp 179-181°C. MS (CI+) m/z 486 (MH+,
35%). Found: C, 54.61; H, 4.53; N, 14.37. Calcd. for C22H21F6N5O: C, 54.43; H, 4.36; N, 14.43%. EXAMPLE 38
5-[{2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2-methyltetrazole
This compound was prepared according to the procedure described in Example 18 using the compound of Example 37 as a starting material. This afforded the title compound as a white crystalline material: mp 158-l59°C. MS (CI+) m/z 500 (MH+, 70%). Found: C, 55.84; H, 4.66, N, 14.13. Calcd. for C23H23F6N5O: C, 55.31; H, 4.64; N, 14.02%.
EXAMPLE 39
5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinolmethyl]-1-methyltetrazole
This compound was prepared according to the procedure described in Example 19 using the compound of Example 37 as a starting material. This afforded the title compound as a dear oil. MS (Cl+) 500 (MH+, 40%). Found: C, 55.27; H 4.69; N,
13.67. Calcd. for C23H23F6N5O: C, 55.31; H, 4.64; N, 14.02%. EXAMPLE 40
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinolmethyripyridazine
(a) 3-(Hydroxymethyl)-1,2-pyridazine
1,2-pyridazine-3-carboxaldehyde (0.89g) (G. Heimsch, E. Luszczak and M. Paller, Mh. Chem 104, 1372 (1973)) was dissolved in water and sodium iiorohydride (0.081g) was added carefully. After 1 hour no starting material was present by TLC using 10% methanol in dichloromethane as eluent. The water was removed in vacuo to afford a gum. The gum was extracted with dichloromethane, the combined organics were dried (MgSO4) and concentrated in vacuo to afford the alcohol as a sohd, which was used in the following experiment without further purification. 1H NMR (360MHz, CDCl3) d 5.04 (2H, s, CH2OH), 7.54 (1H, dd, pyridazine-H), 7.65 (1H, dd, pyridazine-H), 9.17 (1H, dd, pyridazine-H).
(b) 3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]pyridazine
3-(Hydroxymethyl)-1,2-pyridazine was dissolved in anhydrous dichloromethane under an atmosphere of nitrogen and cooled in an ice/water bath. Triethylamine (0.68ml) and methanesulfonyl chloride (0.378ml) were added and the reaction stirred for 1 hour. No starting material was present by TLC using 5% methanol in dichloromethane as eluent. The solvent was removed in vacuo to afford a solid. The compound of Description 3 (0.48g of free base) was dissolved in dimethylformamide (5ml) and added to the solid followed by potassium carbonate (0.85g). The mixture was heated at 60°C for 12 hours then poured into water (75ml), extracted with ethyl acetate (3×40ml), dried (MgSO4) and concentrated to afford a brown oil. This was purified by chromatography on silica gel using a gradient elution of 10-30% ethyl acetate in petrol. Further purification was carried out by medium pressure chromatography; elution with 50/50 ethyl acetate/petrol afforded the title compound as a white solid: mp 111-113°C. 1H NMR d (360MHz, DMSO-d6) 1.43-1.66 (2H, m, NCH2CH2CH2), 1.77-1.91 (1H, m, NCH2CHH), 2.13-2.24 (2H, m, NCHHCHH), 2.75-2.87 (1H, NCHH), 3.27-3.35 (1H, d, NCHH-pyridazine),
3.67-3.70 (2H, NCHPh + CHO), 3.83-3.93 (1H, d, NCHH-pyridazine), 4.14 (1H, d, J=13Hz, OCHHAr), 4.66 (1H, d, J=13Hz, OCHHAr), 7.23-7.35 (3H, m, Ar-H), 7.50-7.56 (2H, m, ArH), 7.66 (2H, s, pyridazine-H), 7.71 (2H, s, ArH), 7.94 (1H, s, ArH), 9.H (1H, m, 4H) MS (CI+) m/z 496 ((M++1), 30%)
EXAMPLE 41
2-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,3,5-triazine
The compound of Description 3 (2g), chloroacetamidine hydrochloride (1.17g) and dnsopropylethylamine (3.17ml) were dissolved in acetonitrile (10ml) and the resulting mixture was stirred at 60°C, under nitrogen, for 12h. The resulting mixture was evaporated and the residue was dispersed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×50ml) and dichloromethane (2×50ml). The combined organic fractions were washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica using 5% methanol in dichloromethane and gradient elution to 10% methanol, 1% aqueous ammonia in dichloromethane. This afforded the intermediate amidine as a semi-solid material, which was not further purified.
The intermediate amidine (2g) and 1,3,5-triazine (0.35g) were dissolved in acetonitrile (7ml) and heated at reflux for 12h.
The solution was cooled and evaporated and the residue was purified by chromatography on silica using 50% petrol in ethyl acetate as eluent. This afforded the product as a crystalline solid which was recrystallised from hexane: mp 117-119°C. 1H NMR (360MHz, DMSO-d6) 5 1.41-1.60 (2H, m, NCH2CH2CH2), 1.81- 1.94 (1H, m, NCH2CHH), 2.12-2.21 (1H, m, NCH2CHH), 2.34- 2.41 (1H, m, NCHH), 2.99-3.06 (1H, m, CHH), 3.26-3.30 (1H, J=15.0Hz, NCHH-triazine), 3.61 (1H, bs, CHO), 3.71 (1H, bs, CHPh), 3.80 (1H, d, J=15.0Hz, NCHH-triazine), 4.08 (1H, d, J=13.0Hz, OCHHAr), 4.63 (1H, d, J=13.0Hz, OCHHAr), 7.18-7.29 (3H, m, ArH), 7.48-7.52 (2H, m, ArH), 7.68 (2H, s, ArH), 7.13 (1H, s, ArH), 9.20 (2H, s, triazine-H). MS (CI+) m/z, 497 (M++1, 100%).
EXAMPLE 42
5-[{(2S,3S)-3-((3-t-Butyl-5-methylphenyl)methyloxy)-2-(phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole
The compound of Description 10 was reacted according to the procedure described in Example 35 to afford the title compound as a crystalline solid: mp 185-187°C. 1H NMR
(360MHz, CDCl3) 5 1.22 (10H, m, C(CH3)3 + NCH2CH2CHH),
1.38-1.58 (2H, m, NCH2CHHCHH), 1.98-2.26 (5H, m, CH3 +
NCHHCHH), 2.89 (1H, d, J=l5.0Hz, NCHH-triazole), 2.96-3.04 (1H, m, NCHH), 3.29 (1H, bs, CHO), 3.56 (1H, bs, CHPh), 3.65 (1H, J=l5.0Hz, NCHH-triazole), 4.13 (1H, d, J=12.0Hz,
OCHHAr), 4.28 (1H, d, J=12.0Hz, OCHHAr), 6.53 (1H, s, ArH).
6.89 (1H, s, ArH), 7.00 (1H, s, ArH), 7.26-7.38 (3H, m, ArH),
7.45-7.50 (2H, m, ArH). MS (CI+) m/z 435 (M++1, 60%). Found: C, 72.10; H, 7.94; N, 13.06. Calcd for C26H34N4O2: C, 71.86; H,
7.89; N, 12.89%.
EXAMPLE 43 2-[{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2- (phenylpiperidino)methyl]imidazole dihydrochloride The compound of Description 11 was reacted according to the procedure described in Examples 32/33, to afford the title compound: mp 129-131°C. 1H NMR (360MHz, DMSO-d6) 5 1.84-1.98 (2H, m, NCH2CH2CH2), 2.14-2.24 (1H, m, NCH2CHH),
2.44-2.62 (1H, m, NCH2CHH), 3.09-3.20 (1H, m, NCHH), 3.69-3.86 (2H, m, NCHH + CHO), 4.25 (1H, d, J=13.0Hz, OCHHAr), 4.53 (1H, d, J=13.0Hz, OCHHAr), 4.83 (1H, d, J=15.0Hz, NCHH-imidazole), 4.91 (1H, bs, CHPh), 5.14 (1H, d, J=15Hz, NCHH-imidazole), 7.16-7.48 (10H, m, ArH), 7.84 (1H, bs, N-H).
MS (CI+) m/z415 (M+1+, 70%). Found: C, 60.71; H, 5.28; N, 8.05. C22H23Cl2N3O.2HCl.2H2O requires; C, 50.30; H, 5.56; N, 7.99%.
EXAMPLE 44
5-[{(2S,3S)-3-((3-Chloro-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-3-oxo-1,2,4-triazole
The compound of Description 12 was reacted according to the procedure described in Example 35 to afford the title compound as a white crystalline solid: mp 227-228°C. 1H NMR
(360MHz, DMSO-d6) 5 1.35-1.55 (2H, m, NCH2CH2CH2), L78¬
1.88 (1H, m, NCH2CHH), 2.06-2.13 (2H, m, NCHHCHH), 2.20
(3H, s, CH3), 2.73 (1H, d, J=14.0Hz, NCHH-triazole), 2.89 (1H, d, J=11.0Hz, NCHH), 3.32-3.39 (1H, m, CHO), 3.42 (1H, d,
J=M.0Hz, NCHH-triazole), 3.47 (1H, s, CHPh), 3.86 (1H, d,
J=12.0Hz, OCHH), 4.29 (1H, d, J=12.0Hz, OCHH), 6.65 (1H, s,
ArH), 6.79 (1H, s, ArH), 7.07 (1H, s, ArH), 7.25-7.34 (3H, m,
ArH), 7.51-7.53 (2H, m, ArH). MS (CI+) m/z 412 (M++1, 20%). Found: C, 64.30; H, 6.13; N, 13.67. C22H25ClN4O2 requires: C,
63.99; H, 6.10; N, 13.57%. EXAMPLE 45
5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-2-(diphenylmethyl)pyrrolidinolmethyl]-2,3-dihydro-3-oxo-1,2,4-triazole
The compound of Description 13 was reacted with Ncarbomethoxy-2-chloroacetamidrazone according to the procedτire described in Example 35 to afford the product as a white crystalline sohd. 1H NMR (250MHz, CDCl3) 5 1.92 (2H, m), 2.62 (1H, m), 2.90 (1H, d, J=15Hz), 3.14 (2H, m), 3.78 (2H, m), 4.08 (1H, m), 4.28 (2H, m), 7.1-7.4 (10H, m, ArH), 7.48 (2H, s, ArH), 7.77 (1H, s, ArH). MS (CI+) m/z 577 (M++1, 100%). EXAMPLE 46
5-[{(2R,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-2-(diphenylmethyl)pyrrolidino}methyl]-2,3-dihydro-3-oxo-1,2,4- triazole
The compound of Description 14 was reacted with N-carbomethoxy-2-chloroacetamidrazone according to the procedure described in Example 35 to afford the title compound as a white crystalline solid. 1H NMR (360MHz, CDCl3) 5 2.00 (2H, m), 2.69 (1H, m), 3.03 (1H, t, J=7.5Hz), 3.26 (1H, d,
J=14.5Hz), 3.32 (1H, d, J=M.5Hz), 3.68 (2H, s), 3.76 (1H, d, J=3.5Hz), 4.31 (1H, d, J=12.5Hz), 4.42 (1H, d, J=12.5Hz), 7.40-7.19 (10H, m, ArH), 7.64 (2H, s, ArH), 7.76 (1H, s, ArH). MS (CI+) m/z 577 (M++1, 100%). EXAMPLE 47
3-[(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-(diphenylmethyl)pyrrolidino}methyl]-1,2,4-triazole
The compound of Description 15 was reacted with N-formyl-2-chloroacetamidrazone according to the procedure in Example 16 to afford the title compound as a crystalline solid: mp 128-129°C. 1H NMR (360MHz, DMSO-d6) δ 1.65 (1H, brs), 1.76 (1H, brs), 3.10 (2H, m), 3.61 (1H, d, J=12.0Hz), 3.92 (1H, brs), 4.01 (1H, brs), 4.22 (2H, m), 7.02 (2H, d, J=1.8Hz, ArH), 7.10 (1H, m, ArH), 7.14 (3H, m, ArH), 7.22 (2H, t, ArH), 7.39 (2H, d, ArH), 7.46 (3H, m, ArH). MS (CI+) m/z 493 (M++1, 60%). Found: C, 65.96; H, 5.22; N, 11.33. Calcd for C27H26Cl2N4O: C, 65.72; H, 5.31; N, 11.35%.
EXAMPLE 48
5-[{(2S,3S)-3-((3-t-Butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-3-oxo-1,2,4-triazole
The compound of Description 16 was reacted with N-carbomethoxy-2-c hloroacetamidrazone, according to the procedure described in Example 35, to afford the title compound as a white crystalline sohd: mp 181-182°C. MS (CI+) m/z 455
(M++1, 100%). Found: C, 65.99; H, 6.87; N, 12.31. Calcd for C25H31ClN4O: C, 66.47; H, 6.91; N, 12.45%. EXAMPLE 49
5-[{(2S,3S)-3-((3-Bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole hydrochloride
The titie compound was prepared according to the procedure described in Example 35, using the compound of Description 3 as starting material. The hydrochloride salt was recrystallised from ethyl acetate-methanol to give a white crystalline solid: mp 265-266°C. 1H NMR (360MHz, DMSO-d6 + TFA) 5 1.76-1.95 (2H, m, CH2), 2.04-2.30 (2H, m, CH2), 3.20-3.32 (1H, m, NCHH), 3.58-3.69 (1H, m, NCHH), 3.90 (1H, d, J=15.0Hz, NCHH-triazole), 3.93 (1H, s, CHO), 3.94 (1H, d, J=15.0Hz, NCHH-triazole), 4.30 (1H, d, J=12.0Hz, OCHH), 4.73 (1H, bs, CHPh), 4.80 (1H, d, J=12.0Hz, OCHH), 7.42 (3H, brs, ArH), 7.56 (2H, brs, ArH), 7.89 (2H, s, ArH), 7.95 (1H, s, ArH). MS (CI+) m/z 5Ol (M++1), 60%). Found: C, 51.41; H, 4.15; N, 10.58; Cl, 6.46. Calcd for C23H22F6N4O.HCl: C, 51.46; H, 4.32; N, 10.44; Cl, 6.60%.
EXAMPLE 50
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinolmethyl)-1-methyl-1,2,4-triazole
hydrochloride
The compound of Example 30 (0.5g) was dissolved in methanol in a tube. Sodium (0.03g) and iodomethane (0.075ml) were added and the container was sealed. The resulting solution was heated at 65°C for 1h, cooled and evaporated. The residue was suspended between water and ethyl acetate. The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica using ethyl acetate as eluent. This afforded the product as a colourless oil, which was converted to the hydrochloride salt by addition of ethereal hydrogen chloride. The salt was recrystallised from ether/petrol. 1H NMR (360MHz, DMSO-d6) 5 1.70-1.84 (2H, m, CH2), 2.12-2.51 (2H, m, CH2), 3.36 (3H, s, NCH3), 3.52 (1H, brs, CHHN), 3.73 (1H, brs, CHHN), 3.87 (1H, s, CHO), 4.25 (2H, m, CHH-triazole), 4.28 (1H, d, OCHHAr),
4.65 (1H, brs, NCHPh), 4.78 (1H, d, OCHHAr), 7.41 (3H, s, ArH), 7.60 (2H, brs, ArH), 7.93 (2H, s, ArH), 7.96 (1H, s, ArH), 8.05 (1H, s, CH=NH (triazole)); MS (CI+) m/z 499 (M++1, 85%). EXAMPLE 51
3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl)-5-phenyl-1,2,4-oxadiazole
hydrochloride
The compound of Description 3 was reacted with 3-chloromethyl-5-phenyl-1,2,4-oxadiazole according to the procedure described in Example 26. The product was characterised as its hydrochloride salt: mp 88-90°C. -B NMR (360MHz, CDCl3, free base) 5 1.50-1.64 (2H, m, CH2), 2.06-2.22
(2H, m, CH2), 2.44-2.56 (1H, m, CHHN), 3.18-3.28 (1H, m, CHHN), 3.60 (1H, s, CHO), 3.66-3.74 (1H, d, J=l5.0Hz, NCHH-oxadiazole), 3.78 (1H, s, CHPh), 3.88-3.98 (1H, d, J=15.0Hz, NCHH-oxadiazole), 4.02-4.10 (1H, d, J=12.0Hz, OCHHAr), 4.444.52 (1H, d, J=12.0Hz, OCHHAr), 7.28-7.64 (10H, m, ArH), 7.68 (1H, s, ArH), 8.08-8.18 (2H, m, ArH); MS (CI+) m/z 562 (M++1). EXAMPLE 62
3-[{(2R*,3R* )-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-5-thiomethyl-1,2,4-triazole hydrochloride
Sodium methoxide (.001g) was added to a solution of the compound of Example 17 (.10g) in ethanol (5ml) and the mixture was heated at reflux for 10 min. Methyl iodide (0.012ml) in ethanol (1ml) was added and the mixture was heated at reflux for 3h. The solvent was then removed in vacuo and the residue was partitioned between ethyl acetate and water. The orgamc layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica using 50% ethyl acetate in petrol as eluent. The compound was isolated as the hydrochloride salt by treatment of the free base with methanolic hydrogen chloride: mp 105-107°C. 1H NMR (360MHz, DMSO-d6 + TFA) 5 1.73-1.91 (2H, m, CH2), 2.05-2.20 (1H, m, CHH), 2.21-2.30 (1H, m, CHH), 2.63 (3H, s, CH3), 3.28 (1H, m, NCHHCH2), 3.73 (1H, m, NCHHCH2), 3.92 (1H, brs,
CHO), 4.10 (2H, dd, J=20Hz, 14.5Hz, NCH2), 4.29 (1H, d, J=13Hz, OCHH), 4.68 (1H, s, CHPh), 4.79 (1H, d, J=13Hz, OCHH), 7.42-7.48 (3H, m, ArH), 7.57 (2H, brs, ArH), 7.88 (2H, s, ArH), 7.95 (1H, s, ArH). MS (CI+) m/z 531 (M++1, 44%). Found: C, 51.29; H, 4.62; N, 9.79; Cl, 6.06. Calcd for C29H24F6N4OS.HCl:
C, 50.84; H, 4.44; N, 9.88; Cl, 6.25%.
EXAMPLE 53 5-[{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-3-oxo-1,2,4-triazole The compound of Description 11 was reacted according to the procedure described in Example 35 to afford the title compound which was recrystallised from hot dimethylformamide: mp >220°C. 1H NMR (360MHz, DMSO-d6, 353K) 5 1.45-1.58 (2H, m, CH2), 1.81-1.95 (1H, m, CHH), 2.02- 2.12 (1H, m, CHH), 2.18 (1H, dt, J=2.5, 11.5Hz, NCHHCH2), 2.82 (1H, d, J=M.2Hz, NCHH), 2.94 (1H, brd, NCHHCH2), 3.40 (1H, d, J=M.5Hz, NCHH), 3.45 (1H, d, CHO), 3.52 (1H, d, CHPh), 3.91 (1H, d, J=12.5Hz, OCHH), 4.34 (1H, d, J=12.5Hz, OCHH), 7.21-7.37 (5H, m, ArH), 7.47-7.55 (3H, m, ArH).
EXAMPLE 54
4-[{(2R*,3R*)-3-((3-Carbomethoxyphenylιmethyloxy)-2-phenylpiperidino}methyl]pyridinium dichloride
The compound of Description 17 was reacted with 4-picolyl chloride according to the procedure described in Example 4 to afford the title compound. 1H NMR (250MHz, CDCl3) δ 1.42-1.61 (2H, m, NCH2CH2CH2), 1.98-2.18 (3H, m, NCHHCH2),
2.87-3.04 (2H, m, NCHH-pyridine + NCHH), 3.31-3.39 (1H, m, CHO), 3.48-3.54 (1H, m, NCHPh), 3.86 (1H, d, J=MHz, NCHHpyridine), 3.93 (3H, s, OCH3), 4.06 (1H, d, J=llHz, OCHHAr), 4.30 (1H, d, J=11Hz, OCHHAr), 7.12 (1H, m, ArH), 7.22-7.39 (6H, m, ArH), 7.45-7.56 (2H, dd, pyridine-H), 7.77 (1H, bs, ArH),
7.85-7.92 (1H, ArH), 8.46-8.55 (2H, dd, pyridine-H). MS (CI+) m/z 417 (M++1, 50%). Found: C, 64.10; H, 6.06; N, 5.62. C26H28N2O3:2HCl requires: C, 63.80; H, 6.18; N, 5.72%. EXAMPLE 55
4-[{(2R*,3R*)-3-((3-Carboxamidophenyl)methyloxy)-2-phenylpiperidinolmethyl]pyridine
The compound of Description 18 was reacted with 4-picolyl chloride according to the procedure described in Example 4 to afford the title compound. 1H NMR (360MHz, CDCl3) 1.43-1.56 (2H, m, NCH2CH2CH2), 2.00-2.17 (3H, m, NCHHCH2), 2.88-3.04 (2H, m, NCHH + NCHHAr), 3.35 (1H, m, CHO), 3.54 (1H, bs, CHPh), 3.83 (1H, d, J=14.5Hz, NCHHAr), 4.08 (1H, d, J=12Hz, OCHHAr), 4.35 (1H, d, J^Hz, OCHHAr), 5.6-6.16 (2H, bs, CONH2), 7.11-7.74 (11H, m, ArH), 8.48 (2H, d, J=4Hz, pyridine-H). MS (CI+) m/z 402 (M++1, 20%).
EXAMPLE 56
5-[{(2R*,3R*)-3-((2-Methoxy-3-nitrophenyl)methyloxy)-2-phenylpiperidino}methyl]-3-methyl-1,2,4-oxadiazole
The compound of Description 19 was reacted according to the procedure described in Example 2 to afford the title compound. 1H NMR (360MHz, CDCl3) 5 1.48-1.64 (2H, m,
NCH2CH2CH2), 2.09-2.25 (2H, m, NCH2CH2), 2.37 (3H, s, CHg), 2.41-2.51 (1H, m, NCHH), 3.12-3.20 (1H, m, NCHH), 3.59 (1H, bs, CHO), 3.64 (1H, bs, CHPh), 3.73 (1H, d, J=16Hz, NCHH- het), 3.80 (3H, s, OCHa), 3.91 (1H, d, J=16Hz, NCHH-het), 3.98 (1H, d, J=13Hz, OCHHAr), 4.48 (1H, d, J=13Hz, OCHHAr), 6.78 (1H, d, J=9Hz, H), 7.22-7.37 (3H, m, ArH), 7.48-7.54 (2H, bd, ArH), 8.09-8.14 (1H, dd, J=9Hz, J=3Hz, ArH), 8.15-8.18 (1H, d,
J=3Hz, ArH). MS (CI+) m/z 439 (M++1, 100%). EXAMPLE 57
3-Amino-5-[{(2R*,3R*)-3-((5-amino-2-methoxyphenyl) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole
The compound of Description 20 was reacted according to the procedure described in Example 1 to afford the title compound. 1H NMR (360MHz, CDCl3) 5 1.41-1.60 (2H, m, NCH2CH2CH2), 2.13-2.24 (2H, m, NCH2C1H2), 2.31 (1H, m, NCHH), 3.12-3.21 (1H, m, NCHH), 3.39 (1H, d, J=16Hz, NCHH-het), 3.47 (1H, m, CHO), 3.56 (1H, m, NCHPh), 3.61 (3H, s, OCHa), 3.82 (1H, d, J=16Hz, NCHH-Het), 4.13 (1H, d, J=13Hz, OCHHAr), 4.34 (1H, d, J=13Hz, OCHHAr), 5.17 (2H, bs, NH2), 6.38 (1H, bs, ArH), 6.43-6.48 (1H, m, ArH), 6.54-6.68 (1H, d, J=8.5Hz, ArH), 7.26-7.58 (3H, m, ArH), 7.48-7.54 (2H, m, ArH).
EXAMPLE 58
6-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidinolmethyl]uradcil
The compound of Description 3 was reacted with 6(chloromethyl)uracil following the conditions described in Example 4 to afford the title compound. 1H NMR (360MHz, CDCl3) 1.52-1.71 (2H, m, NCH2CH2CH2), 1.99-2.25 (3H, m,
NCHHCH2), 2.69 (1H, d, J=16Hz, NCHH-uracil), 2.92-3.01 (1H, m, NCHH), 3.38-3.40 (1H, m, CHO), 3.52-3.62 (2H, m, NCHH-uracil + NCHPh), 4.08 (1H, d, J=12Hz, OCHHAr), 4.49 (1H, d, J=12Hz, OCHHAr), 5.41 (1H, s, HA), 7.32-7.40 (5H, m, ArH), 7.60 (2H, s, H), 7.56 (1H, s, H), 8.64-9.04 (2H, bs, NH + NH). MS (CI+) m/z 528 (M+1+, 100%). C25H23N3O3F6 requires C, 56.93; H, 4.40; N, 7.97%. Found C, 57.16; H, 4.03; N, 7.88%.
EXAMPLE 59
3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-5-carboxamido-1,2,4-triazole The compound of Description 1 was reacted with 2-chloro- N-carboxamidoacetamidhydrazone according to the procedure described in Example 35 to afford the title compound as a white sohd: mp 195°C. υmax (KBr) 1680cm-1; Found: C, 55.14; H, 4.58; N, 12.82. Calcd for C24H23F6N5O2: C, 54.65; H, 4.40; N, 13.27%.
EXAMPLE 60
3-[{(2R*-3R*)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-5-cyano-1,2,4-triazole
The compound of Example 59 (0.61g) was dissolved in chloroform (10ml) and the resulting solution was cooled to 0°C in an ice bath. Triethylamine (2ml) was added followed by phosphorus oxychloride (1.2ml), dropwise. The solution was stirred at room temperature for lh. The solvent was removed in vacuo and the residue was dispersed between chloroform and sodium hydrogen carbonate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 30% petrol in ethyl acetate as eluent. The product was isolated as the hydrochloride salt using ethereal hydrogen chloride: mp 81°C. MS (CI+) m/z 510 (M++1, 60%).
EXAMPLE 61
3-[(1S)-1-{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino}ethyl]-1,2,4-triazole
(a) (±) N-Formyl-2-chloropropionamidohvdrazone
Sodium methoxide (.162g) was added to a solution of 2-chloropropiomtrile (10.5g) in anhydrous methanol (150ml) at 0° C. The reaction mixture was stirred at room temperature for 1h, then neutralised with acetic add (.18ml). N-Formylhydrazine (7.04g) was added and the mixture was stirred overnight. The resulting pink solution was concentrated in vacuo to give the title compound as a pink solid.
(b) The compound of Description 11 (5.9g) was dissolved in dimethylformamide (46ml) and N-formyl-2-chloropropionamidohydrazone (3.5g) was added, followed by potassium carbonate (5.7g). The mixture was stirred at room temperature for 2h, then diluted with xylene (150ml) and heated at reflux for 2h. When cool, the mixture was filtered and concentrated in vacuo to afford a brown residue. Crude 1H NMR indicated a mixture of diastereoisomers in 3:1 ratio. The residue was purified by medium pressure chromatography (Lobar) on silica using 4% methanol in dichloromethane as eluent. The first product eluted, diastereoisomer 1, was isolated as a foam which was recrystallised from ether-hexane: mp 105-107°C 1H NMR (360MHz, CDCl3) 5 1.31 (3H, d, J=7.0Hz, -CHCH3), 1.52-1.69 (2H, m, NCH2CHHCHH), 2.02-2.05 (1H, m, NCH2CHH), 2.05- 2.16 (1H, m, NCH2CH2CHH), 2.51 (1H, t, J=11.5Hz, NCHH), 2.62 (1H, m, NCHH), 3.56 (1H, s, CHO), 3.77 (1H, s, CHPh), 3.99 (1H, d, J=12.0Hz, OCHH), 4.22 (1H, q, J=7.0Hz, -CHCH3), 4.30 (1H, d, J=12.0Hz, OCHH), 6.89 (2H, d, J=2.0Hz, ArH), 7.21 (1H, t, J=2.0Hz, ArH), 7.3-7.4 (3H, m, ArH), 7.40-7.47 (2H, m, ArH), 7.89 (1H, s, triazole-2H). MS (CI+) m/z.
EXAMPLE 62
3-[(1R)-1-{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidinolethyl]-1.2,4-triazole
The second product isolated from the column described in Example 61 was recrystallised from ether to afford the title compoτmd whose stereochemistry was established from 1H NMR n.0.e. experiments: mp 132-134°C 1H NMR (360MHz, DMSO-d6) δ 1.06-1.15 (1H, m, NCH2CH2CHH), 1.35 (3H, d, J=7.0Hz, CHCH3), 1.34-1.42 (1H, m, NCH2CHH), 1.66-1.85 (2H, m, NCHHCHH), 1.98-2.02 (1H, m, NCH2CH2CHH), 3.01-3.03 (1H, d, J=10.5Hz, NCHH), 3.39 (1H, s, CHO), 3.86 (1H, d, J=13.0Hz, OCHH), 3.98 (1H, q, J=7Hz, CΗCH3), 4.33 (1H, d, J=13.0Hz,
OCHH), 6.92 (1H, d, J=2.0Hz, ArH), 7.26-7.46 (6H, m, ArH,
EXAMPLE 63 3-[{(2S,3S)-3-((2,3-Dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole
Following the method described in Example 16, the compound of Description 23 (100mg) was reacted with 69mg of N-formyl-2-chloroacetamidohydrazone, to give the title compound. 1H NMR (CDCl3) 5 1.50 (2H, m), 1.94 (3H, s), 2.0- 2.35 (3H, m), 2.2 (3H, s), 3.02 (1H; m), 3.45 (2H, m), 3.57 (1H, s), 3.95 (1H, br s), 3.95 (1H, d, J=11Hz), 4.26 (1H, d, J=11Hz), 6.86 (1H, d, J=7Hz), 7.06 (1H, d, J=7Hz), 7.2-7.5 (6H, m), 7.7 (1H, br s).
The following compounds were prepared by the procedure described in Example 35.
EXAMPLE 64
5-[{(2S,3S)-3-((2,3-Dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole
The compound of Description 23 was used as starting material. 1H NMR (CDCl3) 5 1.4-1.55 (2H, m), 1.89 (3H, s), 1.9- 2.2 (3H, m), 2.15 (3H, s), 2.91 (1H, d, J=15Hz), 2.95 (1H, m), 3.28 (1H, s), 3.50 (1H, s), 3.66 (1H, d, J=15Hz), 4.06 (1H, d, J=12Hz), 4.29 (1H, d, J=12Hz), 6.77 (1H, d, J=7Hz), 6.9 (1H, t, J=7Hz), 6.97 (1H, d, J=7Hz), 7.2-7.45 (5H, m).
EXAMPLE 65
5-[{(2S,3S)-2-Phenyl-3-((3-(trifluoromethyl)phenyl) methyloxy)piperidino)methyl]-3-oxo-1,2,4-triazole
The compound of Description 21 was used as starting material. 1H NMR (CDCl3) 5 1.5 (2H, m), 1.9-2.2 (3H, m), 2.91 (1H, d, J=15Hz), 3.0 (1H, m), 3.3 (1H, s), 3.5 (1H, s), 3.64 (1H, d,
J=15Hz), 4.12 (1H, d, J=12Hz), 4.41 (1H, d, J=12Hz), 7.0-7.45 (9H, m), 9.9 (2H, br s). EXAMPLE 66
5-r((2S.3S)-3-((3.4-DicMorophenyl)methyloxy)-2phenylpiperidino}methvn-3-oxo-1.2.4-triazole
The compomid of Description 22 was used as starting material. 1H NMR (CDCl3) 5 1.5 (2H, m), 1.85-2.2 (3H, m), 2.88 (1H, d, J=15Hz), 3.0 (1H, m), 3.27 (1H, s), 3.48 (1H, s), 3.67 (1H, d, J=15Hz), 4.05 (1H, d, J=12Hz), 4.35 (1H, d, J=12Hz), 6.7 (1H, br d, J=7Hz), 6.95 (1H, br s), 7.16 (1H, d, J=7Hz), 7.2-7.45 (5H, m), 9.8 (1H, br s), 10.5 (1H, br s).
EXAMPLE 67
5-[{(2S,3S)-3-((3-t-Butylphenyl)methyloxy)-2-phenylpiperidino}methyl]-3-oxo-1,2,4-triazole
The compound of Description 24 was used as starting material. 1H NMR (CDCl3) 5 1.23 (9H, s, C(CH3)3), 1.40-1.51
(2H, m, CH2), 1.82-1.85 (1H, m, CHH), 2.01-2.14 (2H, m, CHH and NCHH), 2.74 (1H, d, J=14Hz, NCHH-triazolone), 2.88 (1H, m, NCHH), 3.38 (1H, d, J=MHz, NCHH-triazolone), 3.40 (1H, m, NCHCHO), 3.51 (1H, s, NCHCHO), 3.85 (1H, d, J=12Hz, OCHH), 4.23 (1H, d, J=12Hz, OCHH), 6.80-6.82 (1H, m, ArH),
7.06-7.34 (6H, m, ArH), 7.53-7.65 (2H, m, ArH), 11.16 (1H, s,
NH), 11.24 (1H, s, NH); MS (CI+) m/z 420 (M++1, 10%). Found:
C, 71.51; H,7.51; N, 13.08. Cacld. for C25H32N4O: C, 71.40; H,
7.67; N, 13.32%. EXAMPLE 68
5-[{(2R*,3R*)-3-((3,5-Dimethylphenyl)methyloxy)-2-phenylpiperidino}methyl)-3-oxo-1,2,4-triazole
The compound of Description 25 was used as starting material. 1H NMR (360MHz, DMSO-d6) 5 1.41-1.47 (2H, m, CH2), 1.81-1.85 (1H, m, CHH), 2.05-2.11 (2H, m, CHH and NCHH), 2.15 (6H, s, CH3), 2.72 (1H, d, J=14Hz, NCHHtriazolone), 2.86-2.89 (1H, m, NCHH), 3.36 (1H, d, J=2.5Hz, CHO), 3.40 (1H, d, J=MHz, NCHH-triazolone), 3.44 (1H, brs, CHPh), 3.82 (1H, d, J=12Hz, OCHH), 4.20 (1H, d, J=12Hz, OCHH), 6.50 (2H, s, ArH), 6.79 (1H, s, ArH), 7.25-7.33 (3H, m, ArH), 7.51-7.63 (2H, m, ArH), 11.16 (1H, s, NH), 11.25 (1H, s,
NH).
EXAMPLE 69 (2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(3-(1,2,4-triazoIyl) piperidine
1-Hydroxybenzotriazole hydrate (308mg), 1-(3-di methylaminopropyl)-3-ethylcarbodimide hydrochloride (436mg), triethylamine (0.3ml) and 1,2,4-triazole-3-carboxylic add (129mg) were dissolved in dimethylformamide (5ml) and the resulting mixture was stirred for 15 min. The compound of Description 3 (0.5g) was added and the resulting mixture was stirred at room temperature for 12h. The reaction mixture was diluted with water (100ml) and the product was extracted into ethyl acetate (3 × 50ml). The orgamc fractions were washed successively with ritric acid (aqueous), water, potassium carbonate and brine, then dried (MgSO4) filtered and concentrated. The residue was purified by column chromatography on sllica using 70% ethyl acetate in hexane as eluant. The product was recrystaUised from ethyl acetate/petrol to afford a crystalline white solid: mp 77-79°C. MS (CI-) m/z 478 ((M-HF) , 100%).
EXAMPLE 70
(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-1-(1-oxo-2-pyrid-4-yl)ethyl-2-phenylpiperidinium hydrochloride
The compound of Description 3 was reacted with 4pyridylacetie add following the procedure outlined in Example
69. This afforded a colourless oil which was treated with ethereal hydrogen chloride and the solid obtained was recrystallised from benzene/hexane. MS (CI+) m/z 523 (M++1, 100%). Found: C, 54.67; H, 4.86; N, 4.66; Cl, 6.16. Calcd. for C27H24F6N2O2.2H2O: C, 54.50; H, 4.91; N, 4.70; Cl, 5.96%.
EXAMPLE 71
(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-1-(2-oxo-2-pyrid-3-yl)ethyl-2-phenylpiperidine
3-(Bromoacetyl)pyridinium hydrobromide (336mg) was dissolved in dimethylformamide (3ml) and to this solution was added the compound of Description 3 (440mg) followed by potassium carbonate (550mg). The mixture was stirred at room temperature for 2h, diluted with water and extracted into ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica using 70% ether in hexane as eluant and further purified by medium pressure chromatography (Lobar) using ethyl acetate in hexane (60:40) as eluant. 1H NMR
(250MHz, DMSO-d6) 5 1.4-1.6 (2H, m), 1.8-1.98 (1H, m, CHH), 2.06-2.2 (1H, m, CHH), 2.5-2.6 (1H, m), 2.9-3.0 (1H, m), 3.54 (1H, d, NCHHCO), 3.62 (1H, brs, CHO), 3.74 (1H, d, CHPh), 3.84 (1H, d, OCHH), 7.2-7.3 (2H, m, ArH), 7.38-7.5 (3H, m, ArH), 7.5 (1H, dd, pyr-H), 7.85 (2H, s, ArH), 7.92 (1H, s, ArH),
8.14 (1H, dt, pyr-H), 8.62 (1H, dd, pyr-H), 8.94 (1H, d, pyr-H).
EXAMPLE 72 3-[(1S)-1-{(2S,3S)-3-((3,5-Bis(trifluoromethylphenyl) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole
This was prepared from the compound of Description 3 and N-formyl-2-chloropropionamidohydrazone following the procedure described in Example 61. The first compound to be eluted from the column (using 3% methanol in dichloromethane as eluant on silica) was isolated and characterised as the title compound: mp 66-68°C. MS (CI+) m/z 499 ((M+1)+, 100%).
EXAMPLE 73
3-[(1R)-1-{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole
The second product isolated from the column described in Example 72 was recrystallised from ethyl acetate/hexane to afford the title compound: mp 108-111°C. MS (CI+) m/z 499 ((M+1)+, 100%).
EXAMPLE 74 5-[(1S)-1-{(2S,3S)-3-((3,5-Bis(trifluoromethylphenyl) methyloxy)-2-phenylpiperidino)ethyl]-2,3-dihydro-3-oxo-1,2,4-triazole
This compound was prepared according to the procedure described in Example 35 using the compound of Description 3 and N-carbomethoxy-2-chloropropionamidohydrazone
(C1CH(CH3)C(=NH)NHNHC00CH3) as starting materials. 1H NMR (CDCl3) 5 0.94 (3H, d, J=7Hz), 1.4-1.58 (2H, m), 1.8 (1H, mc), 2.06-2.2 (1H, m), 2.26-2.4 (1H, m), 3.3 (1H, mc), 3.52 (1H, s), 3.64-3.72 (2H, m), 4.06 (1H, d, J=12Hz), 4.64 (1H, d, J=12Hz), 7.2-7.38 (3H, m), 7.6-7.7 (2H, m), 7.74 (2H, s), 7.94 (1H, s). MS (CI+) m/z 515 ((M+1)+, 23%).
EXAMPLE 75
3-[{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole
This was prepared from the compound of Description 11 according to the procedure described in Example 16 to afford the title compound: mp 208-212°C. MS (CI+) m/z 417 ((M+l)+, 100%). EXAMPLE 76
5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl)piperidino)methyl)-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole
This was prepared from the compound of Description 26 according to the procedure described in Example 35: mp 125-127°C. 1H NMR (360MHz, DMSO) 5 1.46-1.52 (2H, m), 1.9-1.95 (1H, m), 2.0-2.2 (2H, m) 2.92 (1H, d, J=15Hz, NCHHtriazolone), 2.98 (1H, mc), 3.35 (1H, s, CHO), 3.44 (1H, d, J=15Hz, NCHHtriazolone), 3.60 (1H, brs, CHPh), 3.96 (1H, d, J=12Hz,
OCHH), 4.43 (1H, d, J=12Hz, OCHH), 7.15-7.22 (2H, m, ArH), 7.37-7.41 (2H, m, ArH), 7.48 (2H, s, ArH), 7.65 (1H, s, ArH). MS (CI+) m/z 536, 537 (M++1, 100, 30%). EXAMPLE 77
5-[{(2S,3S)-3-((3,4-Dimethylphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole
This compound was prepared according to the procedure described in Example 35 using the compound of Description 29 as starting material. 1H NMR (CDCl3) 5 1.37-1.55 (2H, m), 1.9- 2.2 (3H, m), 2.1 (3H, s), 2.15 (3H, s), 2.85 (1H, d, J=15Hz), 2.97 (1H, m), 3.26 (1H, s), 3.51 (1H, s), 3.65 (1H, d, J=15Hz), 4.06 (1H, d, J=11Hz), 4.26 (1H, d, J=11Hz),6.65 (2H, m), 6.9 (1H, d, J=8Hz), 7.2-7.45 (5H, m), 9.5 (1H, brs).
EXAMPLE 78
5-[{(2S,3S)-3-((3-iPropoxyphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole This compound was prepared according to the procedure described in Example 35 using the compound of Description 30 as starting material. 1H NMR (CDCl3) 5 1.25 (6H, d, J=6Hz), 1.35-1.55 (2H, m), 1.9-2.2 (3H, m), 2.89 (1H, d, J=15Hz), 2.99 (1H, d, J=10Hz), 3.27 (1H, s), 3.51 (1H, s), 3.66 (1H, d, J=15Hz),
4.1 (1H, d, J=12Hz), 4.38 (1H, m), 6.48 (1H, d, J=7Hz), 6.57 (1H, s), 6.66 (1H, d, J=7Hz), 7.2-7.6 (5H, m).
EXAMPLE 79
5-[{(2S,3S)-3-((3-Fluoro-5-methylphenyl)methyloxy)-2- phenylpiperidino}methyll-2.3-dihvdro-(4H)-3-oxo-1.2.4-triazole
This was prepared by the reaction of the compound of Description 27 according to the procedure outlined in Example 35: mp 228-229°C. 1H NMR (360MHz, DMSO) 5 1.4-1.55 (2H, m, CH2), 1.8-1.9 (1H, m, CH2), 2.02-2.18 (2H, m, CH2 and NCHH), 2.21 (3H, s, CH3), 2.73 (1H, d, NCHH-het, J=MHz), 2.87-2.90 (1H, d, NCHH, J=llHz), 3.32-3.40 (1H, m, NCHCHO), 3.41 (1H, d, NCHH-het, J=MHz), 3.46 (1H, s, NCHCHO), 3.87 (1H, d, OCHH-Ar, J=12.5Hz), 4.28 (1H, d, OCHH-Ar, J=12.5Hz), 6.506.55 (2H, m, ArH), 6.80-6.83 (1H, m, ArH), 7.29-7.31 (3H, m, ArH), 7.51-7.63 (2H, m, ArH), 11.18 (1H, s, NH), 11.28 (1H, s,
NH). MS (CI+) m/z 397 (M++1, 10%).
EXAMPLE 80
5-[{3-(3R*)-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-methyl-2-(2R*)-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole
This was prepared from the compoτmd of Description 28 according to the procedure outiined in Example 35. 1H NMR (360MHz, MeOD) 51.43 (3H, s, CH3), 1.46 (1H, m), 1.91 (3H, m), 2.67 (2H, m), 2.98 (1H, d, J=15Hz, NCHHtriazolone), 3.21 (2H, m), 3.58 (1H, d, J=l5Hz, NCHH triazolone), 3.72 (1H, d, J=12Hz, OCHH), 4.36 (1H, d, J=12Hz, OCHH), 7.18 (1H, t, ArH), 7.25 (2H, t, ArH), 7.37 (2H, s, ArH), 7.63 (1H, s, ArH),
7.56 (1H, s, ArH), 7.71 (1H, s, ArH).
EXAMPLE 81 5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2- (3-fluorophenyl)piperidino}methyl]2,3-dihydro-(4H)-3-oxo-1,2,4-triazole 1H NMR (CDCl3) 5 1.42-1.62 (2H, m), 1.84-2.2 (3H, m), 2.86-3.1 (2H, m), 3.38-3.68 (3H, m), 4.08 (1H, d, J=12Hz, OCHH),
4.54 (1H, d, J=12Hz, OCHH), 6.92-7.04 (1H, m, ArH), 7.16-7.32 (3H, m, ArH), 7.54 (2H, s, ArH), 7.76 (1H, s, ArH).
EXAMPLE 82 3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazine
(a) The compound of Description 3 (lg) was dissolved in dimethylformamide (8ml) and N-t-butyloxycarbonyl-2-chloroacetamidrazone (0.6g) was added, followed by potassium carbonate (0.9g). The mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluant.
This afforded the compound as a white solid which was recrystallised from ether-hexane. 1H NMR (360MHz, CDCl3) δ 1.40 (9H, s, (CH3)3), 1.42-1.6 (3H, m), 2.13-2.2 (2H, m), 2.62 (1H, d, J=15Hz, NCHHC=NH), 3.07-3.10 (1H, m, CHHN), 3.36 (1H, d, J=15Hz, NCHHC=NH), 3.38 (1H, s, CHO), 3.57 (1H, brs, CHPh), 4.02 (1H, d, J=12Hz, OCHH), 4.45 (1H, d, J=12Hz,
OCHH), 7.25-7.40 (5H, m, ArH), 7.53 (2H, s, ArH), 7.73 (1H, s, ArH).
(b) The Boc-protected amidrazone (lg) was dissolved in methanolic hydrogen chloride and stirred for 12h. The solvent was evaporated and the crude product was used in subsequent reactions without further purification.
(c) The amidrazone hydrochloride of (b) above (200mg) was dissolved in ethanol (2ml). Magnesium sulphate was added (100mg) and the mixture stirred for 30min. Triethylamine (0.06ml) was added followed by glyoxal (90mg, trimeric dihydrate). This mixture was allowed to stir for 12h. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The orgamc layer was dried (MgSO4) and concentrated to afford a brown oil. This was purified by column chromatography on silica using hexane in ethyl acetate
(95%) to afford the title compound. 1H NMR (360MHz, CDCl3) 5 1.53-1.72 (2H, m, CH2), 1.98-2.22 (2H, m, CH2), 2.42-2.53 (1H, m, NCHH), 3.14-3.22 (1H, m, NCHH), 3.61 (1H, bs, CHO), 3.743.81 (2H, m, NCHPh + OCHH), 4.04 (1H, d, J=12Hz, NCHHtriazine), 4.19 (1H, d, J=12Hz, OCHH), 4.47 (1H, d,
J=12Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48-7.6 (4H, m, ArH), 7.70 (1H, s, ArH), 8.6 (1H, s, ArH). MS (CI+) m/z 497 (M++1, 100%). The following examples illustrate pharmaceutical compositions according to the invention.
EXAMPLE 83A Tablets containing 1-25mg of compound
Amount mg
Compound of formula (I) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0 Modified food corn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5 Magnesium Stearate 0.5 0.5 0.5
EXAMPLE 83B Tablets containing 26-100mg of compound
Amount mg
Compound of formula (I) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0
Modified food corn starch 80.0 80.0 80.0
Lactose 213.5 189.5 139.5
Magnesium Stearate 0.5 0.5 0.5
The compound of formula (X), cellulose, lactose and a portion of the corn starch are mixed and granulated with
10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1.0mg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and 100mg of the active compound per tablet.
EXAMPLE 84 Parenteral injection
Amount mg
Compound of formula (I) 1 to 100mg
Citric Acid Monohydrate 0.75mg
Sodium Phosphate 4.5mg
Sodium Chloride 9mg
Water for Injections to 1ml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula (I) is dissolved or suspended in the solution and made up to volume.
EXAMPLE 85 Topical formulation
Amount mg
Compound of formula (I) 1-10g
Emulsifying Wax 30g
Liquid paraffin 20g
White Soft Paraffin to 100g
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula (I) is added and stirring continued until dispersed. The mixture is then cooled until solid.

Claims (35)

CLAIMS:
1. A compound of formula (I), or a salt or prodrug thereof:
wherein
n is 1, 2 or 3;
X represents O or S;
Y represents a hydrocarbon chain of 1, 2 , 3 or 4 carbon atoms which may optionally be substituted by oxo;
R1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl,
trimethylsilyl, -ORa, SRa, SORa, S02Ra, -NRaRb, -NRaCORb, -NRaCO2Rb, -CO2Ra or -CONRaRb;
R2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;
benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C1-6alkyl, C1-6alkoxy, halo or trifluoromethyl;
R4 and R5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, C1-6alkyl, oxo, CH2ORa, CO2Ra or
CONRaRb;
R8 represents an optionally substituted aromatic heterocycle; and
Ra and Rb each independently represent H, trifluoromethyl, C1-6alkyl or phenyl optionally
substituted by C1-6alkyl, halo or trifluoromethyl.
2. A compound as claimed in claim 1 of formula (IA)
wherein
n is 1, 2 or 3 and any carbon atom of (CH2)n may be substituted by R12 and/or R13;
X represents O or S;
R10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl,
trimethylsilyl, -ORc, SRc, SORc, S02Rc, -NRcRd, -NRcCORd, -NRcCO2Rd, -CO2Rc or -CONRcRd;
R11 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;
benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C1-6allcyl, C1-6alkoxy, halo or trifluoromethyl; R12 and R13 each independently represent H, halo, C1-6alkyl, oxo, CO2Rc or CONRcRd;
R14 represents C1-4alkyl, optionally substituted by oxo, substituted by an optionally
substituted aromatic heterocycle; and
Rc and Rd each independently represent H, C1-6alkyl, phenyl optionally substituted by C1-6alkyl, or halo or trifluoromethyl;
or a salt or prodrug thereof.
3. A compound as claimed in claim 2 wherein n is 2 or 3; R12 and R13 each independently represent H, halo, C1-6alkyl, CO2Rc or CONRcRd; R14 represents C1- 4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and Rc and Rd each
independently represent H, C1-6alkyl, phenyl or
trifluoromethyl.
4. A compound as claimed in any preceding claim wherein R1 represents phenyl substituted by one or more groups selected from C1-4alkyl, trifluoromethyl and halo.
5. A compound as claimed in any preceding claim wherein R2 represents benzhydryl or optionally substituted phenyl.
6. A compound as claimed in any preceding claim wherein R8 represents optionally substituted thienyl, furyl, pyridyl, triazolyl, tetrazolyl,
thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, benzimidazolyl or benzoxazolyl.
7. A compound as claimed in any of claims 1 to 5 wherein R8 represents a substituted or unsubstituted 5- or 6-membered nitrogen-containing aromatic
heterocycle.
8. A compoτmd as claimed in claim 7 wherein R8 represents optionally substituted oxazolyl,
oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl,
pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by C1-6alkyl.
9. A compound as claimed in claim 8 wherein R8 represents unsubstituted triazolyl or triazolyl substituted by oxo or thioxo.
10. A compound as claimed in any preceding claim wherein n is 3.
11. A compound as claimed in claim 1 selected from:
3-amino-5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-3-methyl-1,2,4-oxadiazole;
(+)-3-amino-5-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole;
3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]pyridine;
2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]pyridine;
2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]benzimidazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]tetrazole;
2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-4-methyl-1,3-thiazole;
(2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 1-(2-furoyl)-2-phenylpiperidine;
2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]furan;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-3-bromo-1,2,4-oxadiazole;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-3-dimethylamino-1,2,4-oxadiazole;
(2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 2-phenyl-1-(2-thienoyl)piperidine;
(2R , 3R ) -3- ( (3 , 5-bis (trifluoromethyl) phenyl)methyloxy) - 2-phenyl-1-(2-thienyl)methylpiperidine;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-4-methyl-3-thioxo-1,2,4-triazole;
3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole;
5-[ ((2R*,3R*)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methyltetrazole;
5-[((2R*,3R*)3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyltetrazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-5-dimethylamino- 1,2,4-thiadiazole;
2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-4,7-dimethylbenzoxazole;
2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]benzoxazole;
4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]oxazole;
2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]pyrazine;
4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methyl-1,3-thiazole;
3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole;
3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-iodo- 1,2,4-thiadiazole;
3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-thiadiazole;
3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-methoxy- 1,2,4-thiadiazole;
3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-1-(p-toluenesulphonyl)imidazole;
2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]imidazole;
4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]imidazole;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-3-(N,N-dimethylamino)-1,2,4-thiadiazole;
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]tetrazole;
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-2-methyltetrazole;
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-1-methyltetrazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]pyridazine;
2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-1,3,5-triazine; 5-[((2S,3S)-3-((3-t-butyl-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
2-[((2S,3 )-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)methyl]imidazole;
5-[((2S,3S)-3-((3-chloro-5-methylphenyl)methyloxy)-2phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4¬triazole;
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-diphenylmethyl)pyrrolidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole; 5-[((2R,3S)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-diphenylmethyl)pyrrolidino)methyl]- 2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-diphenylmethyl)pyrrolidino)methyl]-1,2,4-triazole;
5-[((2S,3S)-3-((3-t-butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidino)methyl]-1-methyl-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)• 2-phenylpiperidino)methyl]-5-phenyl-1,2,4-oxadiazole;
3-[((2R*,3R*)-3-((3,5-bistrifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-5-thiomethyl-1,2,4-triazole;
5-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
4-[((2R*,3R*)-3-((3-carbomethoxyphenyl)methyloxy)-2-phenylpiperidino)methyl]pyridine;
4-[((2R*,3R*)-3-((3-carboxamidophenyl)methyloxy)-2-phenylpiperidino)methyl]pyridine;
5-[((2R*,3R*)-3-((2-methoxy-3-nitrophenyl)methyloxy)-2-phenylpiperidino)methyl]-3-methyl-1,2,4-oxadiazole;
3-amino-5-[((2R*,3R*)-3-((5-amino-2-methoxyphenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole;
6-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]uracil; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-carboxamido-1,2,4-triazole;
3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)
phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-cyano- 1,2,4-triazole;
3-[(1S)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;
3-[(1R)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)ethyl]-1,2,4-triazole; .
3-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole;
5-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-2-phenyl-3-((3-trifluoromethyl)phenyl)methyloxy)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo- 1,2,4-triazole;
5-[((2S,3S)-3-((3,4-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3-t-butylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2R*,3R*)-3-((3,5-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
(2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(3-(1,2,4-triazolyl))piperidine;
(2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1- (1-oxo-2-pyrid-4-yl)ethyl-2-phenylpiperidine;
(2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1- (2-oxo-2-pyrid-3-yl)ethyl-2-phenylpiperidine; 3-(IS)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;
3-(1R)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;
5-(IS)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-(3-chlorophenyl)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3,4-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3-i-propoxyphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3-fluoro-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[(3-(3R*)-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 2-methyl-2-(2R*)-phenylpiperidino)methyl-2,3-dihydro-
(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-(3-fluorophenyl)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)
methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazine; and salts and prodrugs thereof.
12. A process for the preparation of a compound as claimed in claim 1, which process comprises:
(A) reacting a compound of formula (II):
wherein R1, R2, R4, R5, X and n are as defined for formula (I), with a reagent suitable to introduce the group Y-R8; or
(B) reacting a compound of formula (III) with a compound of formula (IV):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), R30 represents an alkyl group and R31 represents H or a suitable substituent, in the presence of a base; or
(C) reacting a compound of formula (V):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with an alkali metal azide; or
(D) reacting a compound of formula (VI):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with a compound of formula Hal-CH2C(=O)R60, where Hal represents halo and R60 represents H or a suitable substituent; or
(E) reacting a compound of formula (VII):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with a compound of formula R61NCS, wherein R61 is H or a suitable substituent, in the presence of a base; or
(F) reacting a compound of formula (II) as previously defined with a compound of formula (VIII):
wherein Y and Hal are as previously defined and R18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base; or
(G) reacting a compound of formula (IX):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with a substituted or unsubstituted
triazine; or
(H) reacting a compound of formula (X) with a compound of formula (XI):
wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I) and R35 and R36 each independently represent H or a suitable. substituent.
13. A process as claimed in claim 12 wherein, for (A) or (F), the base is an alkali metal carbonate.
14. A process as claimed in claim 12 or claim 13 wherein, for (A), the reagent suitable to introduce the group Y-R8 is R8-Y-L where L is chloro, bromo, iodo, methylsulphonate or p-toluenesulphonate.
15. A process as claimed in claim 12 wherein, for (B), the base is an alkali metal or an alkali metal hydride.
16. A process as claimed in claim 12 wherein, for (C), the alkali metal azide is sodium azide and the reaction is effected in N-methylpyrrolidinone as solvent.
17. A process as claimed in claim 12 wherein, for (D), R60 is H or C1-6alkyl.
18. A process as claimed in claim 12 wherein, for (E), the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.
19. A process as claimed in claim 12 wherein, for (F), R18 is methoxy.
20. A process as claimed in claim 12 wherein, for (G), the reaction temperature is 80-90ºC.
21. A process as claimed in claim 12 wherein, for (H), R35 and R36 each represent H.
22. A compound as claimed in any one of claims 1 to 11 for use in therapy.
23. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11 in association with a pharmaceutically acceptable carrier.
24. A pharamaceutical composition as claimed in claim 23 further comprising a bronchodilator.
25. A method for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin-reducing amount of a compound according to claim 1.
26. A method according to claim 25 for the treatment or prevention of pain or inflammation.
27. A method according to claim 25 for the treatment or prevention of migraine.
28. A method according to claim 25 for the treatment or prevention of arthritis.
29. A method according to claim 25 for the treatment or prevention of postherpetic neuralgia.
30. A method for the treatment of a respiratory disease, which method comprises
administration to a patient in need thereof of an
effective amount of a compound as claimed in claim 1 and an effective amount of a bronchodilator.
31. The use of a compound as claimed in any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins.
32. The use of a compound as claimed in any one of claims 1 to 11 for the manufacture of a medicament for the treatment of pain or inflammation.
33. A compound as claimed in any of claims 1 to 11 when prepared by the process of claim 12.
34. A process for preparing a composition as claimed in claim 23 which process comprises bringing a compound as claimed in any of claims l to 11 into association with a pharmaceutically acceptable carrier.
35. A compound, composition or process as claimed in any one of the preceding claims, substantially as herein before described.
AU40765/93A 1992-04-15 1993-04-14 Azacyclic compounds Ceased AU675786B2 (en)

Applications Claiming Priority (9)

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GB9208323 1992-04-15
GB929208323A GB9208323D0 (en) 1992-04-15 1992-04-15 Therapeutic agents
GB9216065 1992-07-28
GB929216065A GB9216065D0 (en) 1992-07-28 1992-07-28 Therapeutic agents
GB9219686 1992-09-17
GB929219686A GB9219686D0 (en) 1992-09-17 1992-09-17 Therapeutic agents
GB9226069 1992-12-14
GB929226069A GB9226069D0 (en) 1992-12-14 1992-12-14 Therapeutic agents
PCT/GB1993/000788 WO1993021181A1 (en) 1992-04-15 1993-04-14 Azacyclic compounds

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Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2700472B1 (en) 1993-01-19 1995-02-17 Rhone Poulenc Rorer Sa Synergizing association having an antagonistic effect on the NK1 and NK2 receptors.
US5633266A (en) * 1993-02-18 1997-05-27 Merck Sharp & Dohme Ltd. Azacyclic compounds compositions containing them and their use as tachykinin antagonists
WO1995019344A1 (en) * 1994-01-13 1995-07-20 Merck Sharp & Dohme Limited Gem-disubstituted azacyclic tachykinin antagonists
US5728716A (en) * 1994-01-28 1998-03-17 Merck Sharp & Dohme Limited Aralkylamino substituted azacyclic therapeutic agents
RU2309953C2 (en) 1999-11-03 2007-11-10 Эймр Текнолоджи, Инк. Aryl- and heteroaryl-substituted tetrahydroisoquinolines, pharmaceutical composition and method for treatment based on thereof
ZA200701232B (en) 2004-07-15 2008-08-27 Amr Technology Inc Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
ES2382814T3 (en) 2005-05-17 2012-06-13 Merck Sharp & Dohme Ltd. Cis-4 - [(4-chlorophenyl) sulfonyl] -4- (2,5-difluorophenyl) cyclohexanopropanoic acid for cancer treatment
EP1904069B1 (en) 2005-07-15 2018-06-13 Albany Molecular Research, Inc. Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8293900B2 (en) 2005-09-29 2012-10-23 Merck Sharp & Dohme Corp Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
GB0603041D0 (en) 2006-02-15 2006-03-29 Angeletti P Ist Richerche Bio Therapeutic compounds
CA2664113C (en) 2006-09-22 2013-05-28 Merck & Co., Inc. Use of platencin and platensimycin as fatty acid synthesis inhibitors to treat obesity, diabetes and cancer
US20110218176A1 (en) 2006-11-01 2011-09-08 Barbara Brooke Jennings-Spring Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
BRPI0806245B1 (en) 2007-01-10 2022-01-25 Msd Italia S.R.L. Compounds of formula i and their uses
CA2682727C (en) 2007-04-02 2016-03-22 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
EP2170076B1 (en) 2007-06-27 2016-05-18 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
US8598184B2 (en) 2008-03-03 2013-12-03 Tiger Pharmatech Protein kinase inhibitors
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US8691825B2 (en) 2009-04-01 2014-04-08 Merck Sharp & Dohme Corp. Inhibitors of AKT activity
KR20120034644A (en) 2009-05-12 2012-04-12 알바니 몰레큘라 리써치, 인크. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
CN102638982B (en) 2009-05-12 2015-07-08 百时美施贵宝公司 Crystalline forms of (s)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorohphenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
CA2760837C (en) 2009-05-12 2018-04-03 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-.alpha.]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
WO2011046771A1 (en) 2009-10-14 2011-04-21 Schering Corporation SUBSTITUTED PIPERIDINES THAT INCREASE p53 ACTIVITY AND THE USES THEREOF
WO2011163330A1 (en) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Novel heterocyclic compounds as erk inhibitors
CA2805265A1 (en) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina)
WO2012024170A2 (en) 2010-08-17 2012-02-23 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US8883801B2 (en) 2010-08-23 2014-11-11 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors
US8946216B2 (en) 2010-09-01 2015-02-03 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
EP2615916B1 (en) 2010-09-16 2017-01-04 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel erk inhibitors
WO2012058210A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
WO2012087772A1 (en) 2010-12-21 2012-06-28 Schering Corporation Indazole derivatives useful as erk inhibitors
JP2014514321A (en) 2011-04-21 2014-06-19 メルク・シャープ・アンド・ドーム・コーポレーション Insulin-like growth factor 1 receptor inhibitor
US9023865B2 (en) 2011-10-27 2015-05-05 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
US9505728B2 (en) 2012-03-09 2016-11-29 Inception 2, Inc. Triazolone compounds and uses thereof
US20150299696A1 (en) 2012-05-02 2015-10-22 Sirna Therapeutics, Inc. SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS
WO2014052563A2 (en) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
MX363243B (en) 2012-11-28 2019-03-14 Merck Sharp & Dohme Compositions and methods for treating cancer.
RU2690663C2 (en) 2012-12-20 2019-06-05 Мерк Шарп И Доум Корп. Substituted imidazopyridines as hdm2 inhibitors
AU2013363398B2 (en) 2012-12-20 2017-06-01 Tempest Therapeutics, Inc. Triazolone compounds and uses thereof
US9540377B2 (en) 2013-01-30 2017-01-10 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as HDM2 inhibitors
US20160194368A1 (en) 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Circular polynucleotides
EA201690230A1 (en) 2013-09-06 2016-07-29 Инсепшн 2, Инк. TRIAZOLONE COMPOUNDS AND THEIR APPLICATIONS
JP6563017B2 (en) 2014-08-28 2019-08-21 エースニューロン・ソシエテ・アノニム Glycosidase inhibitor
TW201726678A (en) 2015-10-30 2017-08-01 赫孚孟拉羅股份公司 Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease
CN108884078A (en) 2016-02-25 2018-11-23 阿森纽荣股份公司 Glycosidase inhibitor
EA201891438A1 (en) 2016-02-25 2019-01-31 Асенейрон С. А. ACID ADDITIVE SALTS DERIVATIVES OF PIPERAZINE
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
WO2017144633A1 (en) 2016-02-25 2017-08-31 Asceneuron S. A. Glycosidase inhibitors
AU2017378186A1 (en) 2016-12-16 2019-06-13 Janssen Pharmaceutica Nv Monocyclic OGA inhibitor compounds
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US10947234B2 (en) 2017-11-08 2021-03-16 Merck Sharp & Dohme Corp. PRMT5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
EP3833668A4 (en) 2018-08-07 2022-05-11 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2020039029A1 (en) 2018-08-22 2020-02-27 Asceneuron S. A. Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968678A (en) * 1988-02-19 1990-11-06 Eli Lilly And Company Tetrazole excitatory amino acid receptor antagonists
MX18467A (en) * 1988-11-23 1993-07-01 Pfizer THERAPEUTIC AGENTS OF QUINUCLIDINES
UA41251C2 (en) * 1990-01-04 2001-09-17 Пфайзер, Інк. Hydrogenated nitrogen-containing heterocyclic substances, piperidine derivatives, pharmaceutical composition and method for inhibiting activity of p substance
DE69220258T2 (en) * 1991-02-11 1997-12-18 Merck Sharp & Dohme Azabicyclic compounds, pharmaceutical preparations containing them and their therapeutic use
EP0600952B1 (en) * 1991-08-20 1996-04-17 MERCK SHARP & DOHME LTD. Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them
IL111730A (en) * 1993-11-29 1998-12-06 Fujisawa Pharmaceutical Co Piperazine derivatives processes for the preparation thereof and pharmaceutical compositions containing the same

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