WO1999045006A1 - Heterocyclic compounds as inhibitors of rotamase enzymes - Google Patents

Heterocyclic compounds as inhibitors of rotamase enzymes Download PDF

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Publication number
WO1999045006A1
WO1999045006A1 PCT/IB1999/000259 IB9900259W WO9945006A1 WO 1999045006 A1 WO1999045006 A1 WO 1999045006A1 IB 9900259 W IB9900259 W IB 9900259W WO 9945006 A1 WO9945006 A1 WO 9945006A1
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Prior art keywords
oxadiazol
alkylene
compound
benzyl
piperidyl
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PCT/IB1999/000259
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French (fr)
Inventor
David John Bull
Robert John Maguire
Michael John Palmer
Martin James Wythes
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Pfizer Ltd Great Britain
Pfizer Inc
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Pfizer Ltd Great Britain
Pfizer Inc
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Priority to AU21810/99A priority Critical patent/AU2181099A/en
Priority to AT99901847T priority patent/ATE248836T1/en
Priority to CA002322442A priority patent/CA2322442A1/en
Priority to JP2000534548A priority patent/JP3668133B2/en
Priority to DE69910984T priority patent/DE69910984T2/en
Priority to EP99901847A priority patent/EP1060178B1/en
Priority to DK99901847T priority patent/DK1060178T3/en
Priority to US09/380,427 priority patent/US6610707B1/en
Priority to BR9908480-5A priority patent/BR9908480A/en
Publication of WO1999045006A1 publication Critical patent/WO1999045006A1/en
Anticipated expiration legal-status Critical
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D211/40—Oxygen 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to 2-heteroaryl-pyrrolidine, -piperidine and - homopiperidine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
  • WO-A-96/40140, WO-A-96/40633 and WO-A-97/16190 disclose compounds that have neurotrophic activity but which lack inhibitory action at the protein phosphatase calcineurin and therefore which have no immunosuppressive activity.
  • the present compounds are neurotrophic agents which have an affinity for FKBP-type immunophilins.
  • they are potent inhibitors of the enzyme activity and especially of the cis-trans prolyl -2- isomerase (rotamase) activity of FKBP-type immunophilins, particularly the immunophilin FKBP-12.
  • the present compounds do not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
  • the present compounds therefore moderate neuronal degeneration and promote neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases or other disorders involving nerve damage.
  • the neurological disorders that may be treated include senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar-brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g.
  • peripheral neuropathy both diabetic and non-diabetic
  • trigeminal neuralgia glossopharyngeal neuralgia
  • Bell's Palsy all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases.
  • the present compounds can be used for treating senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, -3-
  • Huntingdon's disease a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabetic or non-diabetic), multiple sclerosis or a hearing disorder such as tinnitus.
  • central or peripheral nervous system e.g. spinal cord
  • peripheral neuropathy either diabetic or non-diabetic
  • multiple sclerosis or a hearing disorder such as tinnitus.
  • the present invention provides a compound of the formula:
  • R 1 is a 5- or 6-membered ring heteroaryl group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or
  • heteroaryl group being linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by from 1 to 3 substituents each independently selected from C, -C 6 alkyl, C 2 -C 6 alkenyl, -X-
  • R 2 is H, phenyl or C 3 -C 7 cycloalkyl, said phenyl or cycloalkyl being optionally benzo- or C 3 -C 7 cycloalkyl-fused and optionally substituted, including in the benzo- or cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C 1 -C 6 alkyl, C -C 6 alkoxy, -OH, -(C,-C 6 alkylene)OH, halo and halo(C C 6 alkylene)-,
  • R 2 is a 5-, 6- or 7-membered ring heterocyclic group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heterocyclic group being saturated or partially or fully unsaturated, optionally benzo-fused and optionally substituted, including -4. in the benzo-fused portion, by from 1 to 3 substituents each independently selected from C, -C 6 alkyl, C ⁇ -C 6 alkoxy, halo, halo(C 1 -C 6 alkylene)- and -C0 2 R 5 ; said R 2 group being attached to W by any mono- or bicyclic ring carbon atom or heteroatom;
  • R 3 and R 4 are either each independently selected from H, C, -C 6 alkyl, C 3 -C 6 cycloalkyl and -(C 1 -C 6 alkylene)(C 3 -C 6 cycloalkyl), or, when taken together, represent unbranched C 3 -C 6 alkylene optionally containing O or NR 5 ;
  • R 5 is H, C, -C 6 alkyl, C 3 -C 6 cycloalkyl, -(C r C 6 alkylene)(C 3 -C 6 cycloalkyl) or -(C, - C 6 alkylene)aryl;
  • A is unbranched C 3 -C 5 alkylene optionally substituted by C ⁇ Cg alkyl;
  • W is a direct link, C, -C 6 alkylene or C 2 -C 6 alkenylene
  • X is a direct link, C ⁇ alkylene or -(C 0 -C 6 alkylene)-Z-(C 0 -C 6 alkylene)-;
  • Y is SO 2 , carbonyl, -CONR 5 -, -CO.CO-, -CH 2 CO-, -CS.CO-, -CO.CS- or - CO.CH(OH)-;
  • Z is O, S, -CR 5 NR 3 R 4 -, -CR 5 NR 5 (CO 2 R 5 )-, -CR 5 (aryl 1 )-, -NR 5 -, -NR 5 CO 2 -, -CONR 5 - or -NR 5 CO-;
  • aryl is phenyl optionally substituted by from 1 to 3 substituents each independently selected from C, -C 6 alkyl, -(C
  • heterocyclic group is a 5-, 6- or 7-membered ring heterocyclic group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heterocyclic group being saturated or partially or fully unsaturated, or "het” is azetidinyl, said "het” being optionally substituted by from 1 to 3 substituents each independently selected from C, -C 6 alkyl, -(C r C 6 alkyiene)(C 3 -C 7 cycloalkyl), C -C 6 alkoxy, C 3 -C 7 cycloalkyl, -(C -C 6 alkylene)(C r C 6 alkoxy), halo, halo(C 1 -C 6 alkylene)-, -NR 3 R 4 , -C0 2 R 5 , -(C, -C 6 alkylene)aryl and -(C ⁇ Cg alky
  • the heteroaryl group of R 1 is not substituted by -(C 0 -C 6 alkylene)-Z-(C 0 alkylene)(-OH or -C r C 4 alkoxy or -CN or -NR 3 R 4 ) when Z is O, S, -NR 5 -, - NR 5 C0 2 - or -CONR 5 -; and
  • halo means fluoro, chloro, bromo or iodo and alkyl, alkoxy, alkenyl, alkylene and alkenylene groups containing the requisite number of carbon atoms, except where indicated, can be unbranched- or branched-chain.
  • R 3 and R 4 when taken together, represent unbranched C 3 -C 6 alkylene optionally containing O or NR 5 , the heteroatom may be positioned either at a terminal position of, or in an intermediate position in, the unbranched C 3 -C 6 alkylene group.
  • -NR 3 R 4 groups include piperazino and morpholino.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, -8-
  • Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
  • the pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
  • a compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Where a compound of the formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur.
  • the present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
  • Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof.
  • An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • Particularly preferred are compounds of the formula (I ):
  • R 1 , R 2 , A, W and Y are as previously defined for a compound of the formula (I).
  • R 1 is triazolyl, isoxazolyl, oxadiazolyl, tetraazolyl, thiazolyl or thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by 1 , 2 or 3 substituents each independently selected from C C ⁇ alkyl, -X-aryl, -X-het, -X-CO 2 R 5 and -X-NR 3 R 4 .
  • R is triazolyl, isoxazolyl, oxadiazolyl, tetraazolyl, thiazolyl or thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by 1 , 2 or 3 substituents each independently selected from C r C ⁇ alkyl, -X-aryl, -X-het, -X-C0 2 R 5 and -X- NR 3 R 4 , wherein
  • X is a direct link, C r C 6 alkylene or -(C 0 -C 6 alkylene)-Z-(C 0 -C 6 alkylene)-;
  • Z is O, -CR 5 NR 3 R 4 , -CR 5 NR 5 (CO 2 R 5 )-, -NR 5 - or -NR 5 C0 2 -;
  • aryl is phenyl optionally substituted by from 1 to 3 substituents each independently selected from -(C r C 6 alkylene)NR 3 R 4 , -0-(C C e alkylene)NR 3 R 4 , -(C C 6 alkylene)(phthalimido) and -(C,-C 6 alkylene) OH;
  • hetero is piperidyl, pyrazinyl, furyl, piperazinyi, pyrimidinyl or morpholinyl, optionally substituted by from 1 to 3 -(C C 6 alkylene)aryl, -(C C 6 a!kylene)(C 3 - C 7 cycloalkyl) substituents, -10-
  • R 5 is -(C,-C 6 alkylene) aryl or C r C 6 alkyl; or -(C r C 6 alkylene) NR 3 R 4 where "het" is furyl; R 3 and R 4 are either each independently selected from H and C r C 6 alkyl or, when taken together, represent unbranched C 3 -C 6 alkylene; and R 5 is H or C r C 6 alkyl.
  • R 1 is 1 ,2,4-triazolyl, isoxazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl or 1 ,3,4-thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by 1 , 2 or 3 substituents each independently selected from methyl, benzyl, ⁇ -(amino)benzyl, ⁇ -(tert- butoxycarbonylamino)benzyl, benzylamino, benzylaminoethyl, aminomethylphenoxymethyl, methylaminomethylphenoxymethyl, dimethylaminomethylphenoxymethyl, pyrrolidinylmethylphenoxymethyl, aminoethoxybenzyl, phthalimidomethylphenoxymethyl, piperidyloxymethyl, benzylpiperidyloxymethyl, benzylpiperidyloxyethyl, morpholinomethyl, benzyl
  • R 1 is 5-benzyl-1 ,2,4-oxadiazol-3-yl
  • R 1 is
  • R 2 is H, phenyl or C 3 -C 7 cycloalkyl, said phenyl or cycloalkyl being optionally substituted by from 1 to 3 halo substituents, or R 2 is a 5- or 6- membered ring heterocyclic group containing either 1 or 2 nitrogen heteroatoms or 1 oxygen heteroatom, said heterocyclic group being saturated or partially or fully unsaturated, optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by from 1 to 3 C ⁇ Cg alkyl, arylalkoxycarbonyl (e.g. benzyloxycarbonyl), halo or halo (C r C 6 ) alkyl, substituents, -14-
  • R 2 being attached to W by any mono- or bicyclic ring carbon atom or heteroatom. More preferably, R 2 is H, phenyl, cyclopentyl, cyclohexyl or cydoheptyl, said phenyl being optionally substituted by from 1 to 3 fluoro substituents, or R 2 is imidazoly, pyrrolidinyl, piperidinyl or tetrahydrofuranyl, said imidazolyl or tetrahydrofuranyl group being optionally benzo-fused and optionally substituted, including in the benzo- fused portion, by from by from 1 to 3 methyl or bromine or fluorine substituents,
  • R 2 group being attached to W by any mono- or bicyclic ring carbon atom.
  • R 2 is H, fluorophenyl, cyclohexyl, methylimidazolyl, benzimidazolyl, furanyl, cyclopentyl, cydoheptyl, bromobenzimidazolyl or fluorobenzimidazoyl.
  • R 2 is H, 4-fluorophenyl, cyclohexyl, 1-methyl-1 H- imidazol-4-yl, 1 H-benzo[d]imidazol-2-yl, tetrahydrofuran-3-yl, cyclopentyl, cydoheptyl or 5-bromo-1 H-benzo[d]imidazol-2-yl.
  • W is a direct link or C C 6 alkylene.
  • W is a direct link, methylene, ethylene or 2,2-dimethyl- 1 ,3-propylene. Most preferably, W is a direct link or methylene.
  • Y is S0 2 or -CONR 5 -. Most preferably, Y is S0 2 or -CONH-. -15-
  • Preferred examples of -Y-W-R 2 include:
  • -Y-W-R 2 include: 5-bromo1H-benzo[d]imidazol-2-yl sulphonyl,
  • A is unbranched C 3 -C 4 alkylene (i.e. 1 ,3-propylene or 1 ,4-butylene). Most preferably A is C 4 alkylene.
  • R 1 is 1 ,2,4 or 1 ,3,4 oxadiazole, that is linked to the adjacent carbon atom by a ring carbon -16-
  • X is preferably selected from -(C 0 -C 2 alkylene)-Z-(C 0 -C 2 alkylene), more preferably -(C alkylene)-Z-(C 0 alkylene) where Z is -O-; or X is a direct link or -(C ⁇ C ; , alkylene); or X is -(C 0 alkylene)-Z-(C 0 alkylene) where Z is -CR 5 NR 3 R 4 , or -CR 5 NR 5 (CO 2 R 5 ) where R 3 and R 4 are selected from H,-(C C 3 alkylene), more preferably H,-(C C 2 alkylene) and R 5 is H or -(C C 4 alkylene), or -(C ⁇ O, alkylene)aryl; or X is -(C r C 2
  • aryl of -X-aryl is phenyl optionally substituted by from 1 to 3 susbtituents independently selected from -(C,-C 3 alkylene) NR 3 R 4 , -(C C 6 alkylene)(phthalimido); -O(C r C 3 alkylene) NR 3 R 4 or -CO 2 R 5 wherein
  • R 3 and R 4 are each independently selected from H, C.,-C 3 alkyl or, when taken together, represent unbranched C 3 -C 5 alkylene; and R 5 is H, C ⁇ O; alkyl or -(C r C 2 alkylene) aryl;
  • het of -X-het is piperidinyl, furyl, pyrazinyl, pyrimidinyl or piperazinyl optionally substituted by -(C C 3 alkylene)(-C 3 -C 6 cycloalkyl), - C0 2 R 5 , -(C r C 3 alkylene)NR 3 R 4 or -(C C 2 alkylene)aryl wherein aryl is phenyl and wherein R 3 and R 4 are selected from H,-(C C 3 alkylene), more preferably H,-(C 1 -C 2 alkylene) and R 5 is H or -(C r C 4 alkylene), or - (C r C 2 alkylene)aryl;
  • X is -(C 1 -C 2 alkylene) -Z- ⁇ -C j alkylene)(aryl) where Z is NR 5 and R 5 is H or -(C C 2 alkylene)-.
  • optional substituent on the -X-het group is not C 3 -C 7 cycloalkyl or -(C.,-C 6 alkylene)( C 3 -C 7 cycloalkyl).
  • the compounds of the formula (I) can be prepared using conventional procedures such as by the following illustrative methods.
  • R 1 and A are as previously defined for a compound of the formula (I), with a compound of the formula:
  • R 2 , W and Y are as previously defined for a compound of the formula (I) and L is a suitable leaving group, e.g. fluoro, chloro or bromo; or
  • an acid addition salt of a compound of the formula (II) is used as the starting material, this may be converted to the free base ]n situ using a suitable acid acceptor, e.g. ethyldiisopropylamine.
  • L 1 may be chloro and the reaction can be carried out in the presence of a suitable additional acid acceptor, e.g. ethyldiisopropylamine or triethylamine, and in a suitable solvent, e.g. dichloromethane.
  • a suitable additional acid acceptor e.g. ethyldiisopropylamine or triethylamine
  • a suitable solvent e.g. dichloromethane.
  • L 1 may be fluoro and the reaction can be carried out under similar conditions.
  • L 1 may also be a group that forms an activated derivative of a carboxylic acid, e.g. an activated ester or imidazol-1-yl. The reaction may be carried out under conventional conditions.
  • the intermediate compounds of the formula (II) may be prepared by conventional methods, for example, where the heteroaryl group of R 1 is a 1 ,2,4-oxadiazol-3-yl group, by the route shown in Scheme 1. -21 - Scheme 1
  • Amide formation e.g. ethyl chloroformate, aqueous ammonia, triethylamine, tetrahydrofuran
  • Coupling e.g. HO 2 C-R 1A , hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine, N-methylmorpholine, dichloromethane) O.
  • Ring closure e.g. xylene, heat
  • A is as previously defined for a compound of the formula (I) and R 1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R 1 for a compound of the formula (I).
  • a salt of the formula (I I A) is usually used directly in the reaction with a compound of the formula (III) where it may be converted to the corresponding free base of the formula (II) in sjtu using a suitable acid acceptor, e.g. ethyldiisopropylamine.
  • the intermediate compounds of the formula (III) may be prepared by conventional methods.
  • R 2 and W are as previously defined for a compound of the formula (I).
  • the reaction may be carried out in a suitable solvent, e.g. dichloromethane.
  • the intermediate compounds of the formula (XI) can be prepared by conventional methods. -24-
  • the compounds of the formula (I) wherein Y is -CONR 5 - and R 1 , R 2 , R 5 , A and W are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula (II) wherein R 1 and A are as previously defined for a compound of the formula (I), first with a suitable carbonylation reagent, e.g. phosgene [or an equivalent thereof (e.g. triphosgene)] or 1 ,1 -carbonyldiimidazole, and then with a compound of the formula:
  • a suitable carbonylation reagent e.g. phosgene [or an equivalent thereof (e.g. triphosgene)] or 1 ,1 -carbonyldiimidazole
  • R 2 , R 5 and W are as previously defined for a compound of the formula (I), the reaction being optionally carried out in the presence of a suitable acid acceptor, e.g. triethylamine.
  • a suitable acid acceptor e.g. triethylamine.
  • the reaction may be carried out in a suitable solvent, e.g. dichloromethane.
  • the intermediate amines of the formula (XII) can be prepared by conventional methods.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) and R 1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R 1 for a compound of the formula (I).
  • the reaction may be carried out in a suitable solvent, e.g. xylene or pyridine, and at the reflux temperature thereof.
  • a suitable solvent e.g. xylene or pyridine
  • the intermediate compounds of the formula (XIIA) can be prepared by a similar method to that used to prepare a compound of the formula (IX) in Scheme 1 by initially converting a compound of the formula (IV) to a compound of the formula:
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I), using a conventional method, and then by following the route indicated therein.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) and R 1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R for a compound of the formula (I).
  • a compound of the formula (XIV) can be prepared by reaction of a compound of the formula (XIII) with a compound of the formula:
  • R 1B (as previously defined for R 1 ) and R 2 , A, W and Y are as previously defined for a compound of the formula (I) can be prepared by ring closure of a compound of the formula: -27-
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) and R 1B is a relevant optionally substituted amino substituent as defined above.
  • the reaction may be carried out using mercuric oxide in 1 ,4-dioxane and at the reflux temperature.
  • a compound of the formula (XVI) can be prepared by reaction of a compound of the formula (XIII) first with a carboxyl group activating reagent (e.g. 1 ,1 ' -carbonyldiimidazole) followed by a compound of the formula:
  • a carboxyl group activating reagent e.g. 1 ,1 ' -carbonyldiimidazole
  • R 1B is as previously defined for this method, under conventional conditions.
  • the compounds of the formula (I) wherein R 1 is an optionally substituted 1 ,3,4-thiadiazolyI heteroaryl group and R 2 , A, W and Y are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula (XIV) wherein R 2 , A, W, Y and R 1A are as previously defined for a compound of the formula (XIV) with a thionating agent, e.g. P 4 S 10 or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1 ,3- -28-
  • a thionating agent e.g. P 4 S 10 or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1 ,3- -28-
  • dithia-2,4-diphosphetane-2,4-disulphide in a suitable solvent, e.g. toluene, preferably at the reflux temperature thereof.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) and R 0 is C,-C 4 alkyl, e.g. methyl or ethyl, with a compound of the formula:
  • R 1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R 1 for a compound of the formula (I).
  • a compound of the formula (XVIII) can be prepared by reaction of a compound of the formula: -29-
  • R 2 , A, Y and W are as previously defined for a compound of the formula (I), with a tri(C C 4 a!kyl)oxonium hexafluorophosphate in dichloromethane.
  • a compound of the formula (XX) can be prepared as described in
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) and R 1C is relevant group corresponding to a substituent on the heteroaryl group as previously defined for R 1 for a compound of the formula (I) that is linked to the ring nitrogen atom by a methylene group, can be prepared by alkylation of a compound of the formula:
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) (a compound of the formula (IB) is prepared by the route described in Method (8) above, i.e. where R 1A is H) using an appropriate alkylating agent and under conventional conditions. Regioisomers may be formed in this reaction and they may be separated by chromatography.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I), with a compound of the formula (XV) wherein R A is as previously defined for a compound of the formula (XV), in the presence of mercuric oxide.
  • reaction may be carried out in a suitable solvent, e.g. 1 ,4-dioxane or dimethylacetamide, and at the reflux temperature.
  • a suitable solvent e.g. 1 ,4-dioxane or dimethylacetamide
  • a compound of the formula (XXI) can be prepared under conventional conditions as shown in Scheme 2.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) and R 1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R 1 for a compound of the formula (I).
  • the reaction may be carried out using mesyl chloride, triethylamine and dichloromethane as the solvent.
  • a compound of the formula (XXIII) can be prepared as shown in Scheme 3.
  • R 2 , A, W, Y and R 1A are as previously defined for this method.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I) with trimethylsilyl azide and dibutyltin oxide.
  • the reaction may be carried out in a suitable solvent such as toluene and at the reflux temperature thereof.
  • Compounds such as formula (XXV) can be N- alkylated using an appropriate alkylating agent and under conventional conditions regioisomers may be formed which can be separated be standard chromatogaphical methods.
  • R 2 , A, W and Y are as previously defined for a compound of the formula (I), in a suitable solvent such as xylene at reflux temperature.
  • the compound of the formula (XXVI) can be prepared by reacting a compound of the formula (XIII) with a N 1 -hydroxyimidamide, such as N 1 - hydroxyethanimidamide.
  • a N 1 -hydroxyimidamide such as N 1 - hydroxyethanimidamide.
  • Suitable reaction conditions would be for example, in the presence of hydroxybenzotriazole hydrate, N-methyl morpholine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, in a solvent such as dichloromethane, at room temperature.
  • a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the affinity of the compounds of the formula (I) for FKBP-12 can be determined in vitro in a coupled colorimetric PPIase assay using similar procedures to published methods (e.g. see Kofron, J.L., et a]., Biochemistry, 1991 , 30, 6127-6134, Zarnt, T., et __[., Biochem. J. 1995, 305, 159-164, Holt, D.A., et a]., J. Am. Chem. Soc, 1993, 115, 9925-9938).
  • the cis-trans isomerisation of a hydrophobic amino acid-proline bond in a tetrapeptide substrate e.g.
  • the phenylalanine-proline bond in N-succinyl-ala- phe-pro-phe-p-nitroanilide can be determined by monitoring cleavage of pNA from the transPro-containing peptide by an excess of chymotrypsin.
  • IC 50 the concentration of the compound of the formula (I) producing 50% inhibition
  • Assay buffer 2.175ml
  • DTT dithiothreitol
  • Assay buffer (2.175ml) (50mM HEPES, 100mM NaCI, 1 mM DTT, pH 8.0) is equilibrated to 10°C in a cuvette. 12.5 ⁇ l of a solution of the present compound in DMSO, 250 ⁇ l of a 60mg/ml solution of ⁇ -chymotrypsin in 1 mM aqueous hydrochloric acid and then 50 ⁇ L of a solution of human recombinant FKBP-12 (1.5 ⁇ M) in assay buffer are added and mixed.
  • the reaction is initiated by adding 12.5 ⁇ l of a solution of anhydrous succinyl-ALPF-pNA (100 ⁇ M final concentration) in a 400mM solution of LiCI in trifluoroethanol.
  • the absorbance at 390nM is monitored for 3 minutes collecting data every 0.5 second.
  • Data are fitted with a first order rate equation with offset and the initial velocity (v) is calculated from the concentration of cis (re leu-pro bond)-succinyl-ALPF-pNA at t 0 and the first order rate constant at different inhibitor concentrations (I).
  • the compounds of the invention have inhibitory activity against the FKBP-12 enzyme. Early experimentation suggests that the compounds of the invention also have inhibitory activity against the FKPB-52 enzyme.
  • the neurite outgrowth promoting activity of the compounds of the formula (I) can be determined in explant cultures of embryonic chick dorsal root -37-
  • DRG Dorsal root ganglia
  • the individual ganglia were kept in Ca 2 7Mg 2+ - free Tyrodes buffer on ice until a number of ganglia had been collected.
  • Individual ganglia were then transferred into collagen-coated 24-well culture plates containing Neurobasal medium plus B27 supplements and incubated at 37°C in a 5% CO 2 atmosphere. The present compound was added after allowing 4 hours for the ganglia to attach.
  • the explants were fixed and stained with Coomassie blue after 24 or 48 hours in culture.
  • 4 to 6 ganglia were analysed and scored by estimating the extent of neurite outgrowth relative to the diameter of the explant using image analysis.
  • the present compounds were tested with and without 10ng/ml nerve growth factor (NGF) present and compared to outgrowth in the presence of 10ng/ml nerve growth factor alone.
  • NGF nerve growth factor
  • An alternative system for measuring neurite outgrowth promoting activity of FKBP-12 PPIase inhibitors is the SH-SY-5Y neuroblastoma model described by Gold, B.G., et al, in Exp. Neural. ,1997, 147(2), 269-278.
  • Cells are maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% Foetal calf serum (FCS), 50U/mI penicillin, 50 ⁇ g/ml streptomycin at 37°C in a 7% CO 2 atmosphere.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS Foetal calf serum
  • 50U/mI penicillin 50 ⁇ g/ml streptomycin at 37°C in a 7% CO 2 atmosphere.
  • Cells are plated at 1x10 6 cells per well and treated for 5 days with 400nM aphidicolin.
  • the neurotrophic activity of the present compounds can be evaluated in vivo using the sciatic nerve crush model in rat as a model for peripheral nerve regeneration (see Bridge, P.M., et aj. , Experimental Neurology, 1994, 127, -38-
  • the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the formula (I) can be administered orally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate or controlled release applications.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the compounds of the formula (I) can also be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrasternaliy, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well- known to those skilled in the art.
  • the daily dosage level of the compounds of the formula (I) will usually be from 1 microgram/kg to 25 mg/kg (in single or divided doses).
  • tablets or capsules of the compound of the formula (I) may contain from 0.05 mg to 1.0 g of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container or a nebuiiser with the use of a suitable propellant, e.g.
  • dichlorodifluoromethane trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134A [trade mark] or 1 ,1 , 1 ,2,3,3,3- heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable -40-
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioieate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff contains from 20 ⁇ g to 20 mg of a compound of the formula (I) for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 20 ⁇ g to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the compounds of. the formula (I) may also be transdermally administered by the use of a skin patch. They may also be administered by the ocular route, particularly for -treating neurological disorders of the eye.
  • the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • a preservative such as a benzylalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the -41-
  • mineral oil liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the formula (I) can also be administered together with other neutrophic agents such as neurotrophic growth factor (NGF), glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and/or neurotrophin-3.
  • neutrophic agents such as neurotrophic growth factor (NGF), glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and/or neurotrophin-3.
  • the dosage level of the neurotrophic agent will depend upon the neurotrophic effectiveness of the combination and the route of administration used. It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
  • NGF neurotrophic growth factor
  • a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
  • a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof for use as a medicament;
  • the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof for the manufacture of a medicament for the treatment of neuronal degeneration;
  • a neurological disease or disorder such as a neurodegenerative disease
  • a neurological disease or disorder such as a neurodegenerative disease
  • the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g.
  • cerebellar- brainstem atrophies syndromes of progressive ataxias
  • all forms of muscular dystrophy progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), herniated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g.
  • the neurological disease or disorder is senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, Huntington's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system -43-
  • a method of treatment of a human to treat neuronal degeneration which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
  • a method of treatment of a human to promote neuronal regeneration and outgrowth which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
  • a method of treatment of a human to treat a neurological disease or disorder such as a neurodegenerative disease which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
  • a method as in (x) where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's)
  • cerebellar- brainstem atrophies syndromes of progressive ataxias
  • all forms of muscular dystrophy progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), hemiated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. -44-
  • Ethyldiisopropylamine (383 ⁇ l) was added to a mixture of 5-benzyl-3-[(2S)-2- piperidyl]-1 ,2,4-oxadiazole hydrochloride (279.8mg) [see Preparation 7] and 1H-benzo[c(]imidazole-2-sulfonyl chloride (325mg) [see Preparation 8] in dichloromethane (5ml).
  • the reaction mixture was stirred at room temperature for 18 hours after which time the mixture was diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate, and the solvent removed under reduced pressure.
  • Example 2 were prepared by a similar method to that of Example 1 using the appropriate sulphonyl chloride and 5-benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride [see Preparation 7].
  • Triphosgene (45mg) in dichloromethane (2ml) was added dropwise to a solution of 5-benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride (140mg) [see Preparation 7] and triethylamine (139ml) in dichloromethane (2ml).
  • the reaction mixture was stirred at room temperature for 1 hour.
  • a solution of neopentylamine (78mg) and triethylamine (70 ⁇ l) in dichloromethane was added to the mixture and stirred for 18 hours.
  • the reaction mixture was then diluted with dichloromethane and water, the organic phase was separated, dried over magnesium sulphate and the solvent removed under reduced pressure.
  • Formaldehyde (37% w/w aqueous solution) (65 ⁇ l) was added to a solution of 4- (3-[(2S)-1 -(1 H-benzo[o]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzylamine (75mg) [see Example 11] in acetonitrile (2ml), followed by sodium triacetoxyborohydride (170mg). The reaction mixture was stirred at room temperature for 18 hours, after which time glacial acetic acid was added until the solution was at pH 7.0. The mixture was then diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution.
  • the title compound was prepared by a similar method to Example 13 from 4-(3- [1 -(1 H-benzo[c midazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzaldehyde [see Preparation 22] and methylamine hydrochloride to afford ⁇ /-[4-(3-[1-(1H-benzo[c/]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)benzyl]-/V-methylamine as a white solid.
  • the title compound was prepared by a similar method to Example 11 from 2- [4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzyl]-1 ,3-isoindolinedione [see Preparation 23] and methylamine.
  • -60- Th e compound of Preparation 29 (464mg) was dissolved in pyridine (5 ml) and heated under reflux for 18 hours. The reaction mixture was then cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated , dried over magnesium sulphate and the solvent removed under reduced pressure.
  • the crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:0.4:0.2 changing to 93:7:1 , by volume, dichloromethane : methanol : 0.88 aqueous ammonia solution to afford 5-[(1- benzyl-4-piperidyl)oxymethyl]-3-[(2S)-1-cyclohexylmethylsuIfonyl-2-piperidyl]- 1 ,2,4-oxadiazole (357mg) as a yellow oil.
  • the title compound was prepared by a similar method to Example 11 from 2-[5- (3-(2S)-1 -[(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)-2- furyi]methyl-1 ,3-isoindolinedione [see Preparation 100] and methylamine.
  • the title compound was prepared by a similar method to Example 16 from the compound of Preparation 37 and pyridine.
  • the crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 -changing to 60:40, by volume, hexane : ethyl acetate to afford benzyl ⁇ .-(2-(3- [1 -(1 H-benzo[c(jimidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- yl)ethyl)carbamate as a colourless oil.
  • the title compound was prepared by a similar method to Example 13 from 2-(3- [1 -(1 H-benzo[ ⁇ f]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- y[)ethylamine [see Example 27] and benzaldehyde.
  • the cmde product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:1 changing to 98:2, by volume, dichloromethane : methanol to afford ⁇ /-(2- (3-[1 -(1 H-benzo[c0imidazol-2-ylsulfonyI)-2-piperidyl]-1 ,2,4-oxadiazol-5-yl)ethyl)- benzylamine.
  • Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane- 2,4-disulphide] (271 mg) was added to a solution of /V2-acetyl-(2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarbohydrazide (192mg) [see Preparation 39] in toluene (10ml).
  • reaction mixture was heated under reflux for 3 hours and the cooled mixture was then purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70 (in 10% increments), by volume, hexane : ethyl acetate, to afford 2-[(2S)-1-[(4-fluorophenyl)sulfonyl]- 2-piperidyl]-5-methyl-1 ,3,4-thiadiazole (106mg) as a clear oil.
  • Phenylacetic hydrazide (180mg) was added to a solution of ⁇ /2-methyl-(2S)-1- [(4-fluorophenyl)sulfonyl]-2-piperidinecarbothioamide (270mg) [see Preparation 44] and mercuric oxide (202mg) in 1 ,4-dioxane (10ml). The reaction mixture was heated under reflux and stirred for 18 hours. The dioxane was then removed under reduced pressure and dimethylacetamide (10ml) added followed by phenylacetic hydrazide (180mg) and mercuric oxide (202mg). The reaction mixture was heated to 140°C and stirred for 18 hours.
  • Benzaldehyde (101 ⁇ l) was added to a solution of 2-amino-5-[(2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidyl]-1 ,3,4-oxadiazole (163mg) [see Example 32] in tetrahydrofuran (2ml), followed by acetic acid (172 ⁇ l) and sodium triacetoxyborohydride (297mg).
  • the reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and -75- saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure.
  • the title compound was prepared by a similar method to Preparation 6 from the compound of Preparation 53 and xylene.
  • the cmde product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70, by volume, ethyl acetate : hexane. This gave 5-benzyl-3- [(2S)-1-[(4-fluorophenyl)sulfonyI]-2-pyrrolidyl]-1 ,2,4-oxadiazole as a colourless oil.
  • the cmde product was pre-absorbed onto silica gel and purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70, by volume, ethyl acetate : hexane, to afford 2-(1 S)-2-[(4-fluorophenyl)sulfonyl]cyclohexyl-5-methyl-1 ,3,4- oxadiazole (87mg) as an oil.
  • 2-(1 S)-2-[(4-fluorophenyl)sulfonyl]cyclohexyl-5-methyl-1 ,3,4- oxadiazole 87mg
  • CH 2 CI 2 requires C, 58.43; H, 4.94;
  • N N.
  • S O N- ⁇ N
  • Example 43 was prepared from (2S)-1-[(4-Fluorophenyl)sulfonyl]-2-(2tf-1 ,2,3,4-tetraazol-5-yl)piperidine [see Preparation 79] and benzyl bromide.
  • Example 44 was prepared from (2S)- 1 -[(4-Fluorophenyl)sulfonyl]-2-(2H-1 ,2,3,4-tetraazol-5-yl)piperidine [see Preparation 79] and methyl iodide.
  • Acetyl chloride (91 ml) was added to a stirred solution of ethyl (2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarboximidate (288mg) [see Preparation 41] and triethylamine (178ml) in toluene (5ml).
  • the reaction mixture was stirred at room temperature for 1 hr after which time hydrazine hydrate (62ml) was added.
  • Th e title compound was prepared by a similar method to Example 29 from (2S)-1 -[(4-fluorophenyl)sulfonyl]-/V 2 -(2-oxopropyl)-2- piperidinecarboxamide [see Preparation 81] and Lawesson's reagent.
  • the title compound was prepared by a similar method to Preparation 6 from ⁇ / 11 - [((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide [see Preparation 82] and xylene.
  • the crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 80:20, by volume, hexane : ethyl acetate in 10% increments, to afford (2S)-1- [(4-fluorophenyl)sulfonyl]-2-(3-methyl-1 ,2,4-oxadiazol-5-yl)piperidine as an oil.
  • the aqueous layer was separated and basified to pH 8 with 0.88 aqueous ammonia, the product was re-extracted with dichloromethane, dried over magnesium sulphate and the solvent was removed under reduced pressure.
  • the crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 50:50, by volume, hexane : ethyl acetate, -89- in 5% increments, to afford /V 2 -cyclohexyl-5-(2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidyl-1 ,3,4-oxadiazol-2-amine (59mg) as a white gum.
  • HN s > - N HN > N Y ⁇ /
  • Benzoyl chloride (0.07ml) was added to a solution of 2-3-[1-(1H- benzo[d]imidazol-2-yIsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylethylamine (0.2g) [see Example 27] and triethylamine (0.11 ml) in dichloromethane (5ml).
  • the reaction mixture was stirred at room temperature for 18hrs, after which time a white solid was filtered off, and the filtrate concentrated under reduced pressure. The remaining residue was dissolved in ethyl acetate and washed with water and 1 N aqueous hydrochloric acid.
  • the title compound was prepared by a similar method to Example 1 from 5- benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride [see Preparation 7] and 5-bromo-1 /-.-benzo[d]imidazole-2-sulfonyl chloride [see Preparation 88].
  • the title compound was prepared by a similar method to Example 1 from 2-[4- (3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzyl]-1 ,3-isoindolinedione hydrochloride [see Preparation 15] and 5-bromo-1 /-/-benzo[d]imidazole-2- sulfonyl chloride [see Preparation 88].
  • the title compound was prepared by a similar method to Example 11 from 2-4- [(3-(2S)-1-[(5-bromo-1H-benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl-1,2,4- oxadiazol-5-yl)methoxy]benzyl-1 ,3-isoindolinedione [see Example 55] and 33% methylamine in ethanol.
  • the cmde product was purified by recrystaiiisation from methanol and diethyl ether, to afford 4-[(3-(2S)-1-[(5-bromo-1H- benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5- yl)methoxy]benzylamine as a white solid.
  • the title compound was prepared by a similar method to Example 16 from tert- butyl 4-(3-[((Z)-amino(1 S)-2-[(cyclohexylmethyl)sulfonyl]-2- piperidylmethylidene)amino]oxy-3-oxopropyl)-1-piperazinecarboxylate [see Preparation 91] and pyridine.
  • the crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing
  • Trifluoroacetic acid (10ml) was added to a solution of tert-butyl 4-[2-(3-(1 S)-2- [(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)ethyl]-1- piperazinecarboxylate (265mg) [see Example 57] in dichloromethane (10ml).
  • the reaction mixture was stirred at room temperature for 3hrs, after which time the solvent was removed under reduced pressure and the residue partitioned -103- between ethyl acetate and saturated sodium hydrogen carbonate.
  • Benzyl isocyanate (68ml) was added to a suspension of 5-benzyl-3-[(2S)-2- piperidyl]-1 ,2,4-oxadiazole hydrochloride (279.8mg) [see Preparation 7] (140mg) and triethylamine (70ml) in dichloromethane (5ml).
  • the title compound was prepared and purified by a similar method to Example 1 from benzyl N-[(R)-phenyl ⁇ 3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5- yl ⁇ methyl]carbamate hydrochloride [see Preparation 103] and cyclohexylmethylsulphonyl chloride to afford benzyl N-[(R)-(3- ⁇ (2S)-1- (cyclohexylmethyl)sulfonyl-2-piperidyl ⁇ -1 ,2,4-oxadiazol-5- yl)(phenyl)methyl]carbamate as a gum.
  • the title compound was prepared by the method of Preparation 13 from 1-(1H- benzo[d]imidazol-2-ylsulfonyl)-N '2 -[(2-pyrimidinylcarbonyl)oxy]-2- piperidinecarboximidamide [see Preparation 105] and pyridine, to afford 2-( ⁇ (2- [5-(2-pyrimidinyl)-1 ,2,4-oxadiazol-3-yl]-2-piperidyl ⁇ sulfonyl)-1 - - benzo[d]imidazoie as a solid.
  • (2S)-2-Piperidinecarboxylic acid L-tartrate (55.0g) (see WO-A-96/11185) was dissolved in water (200ml). The resulting solution was cooled to 0°C and di-t- butyldicarbonate (86g) in 1 ,4-dioxane (203ml) was added followed by 1 N aqueous sodium hydroxide solution (610ml) over a period of 20 mins.. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 56 hours. The solvent was then removed under reduced pressure and the resulting solid was dissolved in water (100ml) and washed with diethyl ether (1000ml).
  • Triethylamine 14.46ml was added to a solution of (2S)-1-( etf-butoxycarbonyl)- 2-piperidinecarboxylic acid (18.3g) [see Preparation 1] in tetrahydrofuran (240ml) at -20°C under an atmosphere of nitrogen.
  • Ethyl chloroformate (7.52ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at -10°C and then 0.88 aqueous ammonia solution (32ml) added.
  • the reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water.
  • Oxalyl chloride (8.54ml) was added to a stirred solution of dimethylformamide (7.57ml) in acetonitrile (440ml) at -5°C under an atmosphere of nitrogen. The mixture was stirred for 15 mins., after which time a solution of tert-butyl (2S)-2- (aminocarbonyl)-l -piperidinecarboxvlate (18.63g) [see Preparation 2] and pyridine (16.50ml) in acetonitrile (100ml) was added and the resulting solution was stirred for 10 mins.. The mixture was then reduced to low volume under reduced presssure and diluted with ethyl acetate (1000ml) and water (1000ml). The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (2S)-2-cyano-1- piperidinecarboxylate (13.7g) as a white solid.
  • tert-Butyl (Z)-(2S)-2-(amino[(2-phenylacetyl)oxy]iminomethyl)-1- piperidinecarboxylate (17.5g) [see Preparation 5] was dissolved in xylene (500ml) and heated under reflux for 17 hours. The crude reaction mixture was chromatographed on silica gel eluting with a solvent gradient of 0:100 changing to 20:80, by volume, ethyl acetate : hexane to afford tert-butyl (2S)-2-(5-benzyl- 1 ,2,4-oxadiazol-3-yl)-1 -piperidinecarboxylate (10.56g) as a yellow oil.
  • 1H-2-Benzo[o]imidazolethiol (1.5g) was suspended in 20% v/v acetic acid/water (60ml) and cooled to 0°C. Chlorine gas was bubbled through the mixture until a point of saturation. The reaction mixture was stirred for 1 hour after which time it was filtered and the resulting solid was washed with ice-cold water and dried under reduced pressure to afford 1/-/-benzo[c midazole-2-sulfonyl chloride (2.38g) as a light brown solid.

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Abstract

Compounds of formula (I) wherein R1, Y, W, A and R2 as defined above are inhibitors of rotamase enzymes in particular FKBP-12 and FKBP-52. The compounds therefore moderate neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases and nerve damage.

Description

- 1-
HETEROCYCLIC COMPOUNDS AS INHIBITORS OF ROTAMASE ENZYMES
This invention relates to 2-heteroaryl-pyrrolidine, -piperidine and - homopiperidine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
It has been reported that the immunosuppressant FK-506 promotes neurite outgrowth in vitro in neuronal cell line and culture models (see Lyons et aj, Pro. Natl. Acad. Sci., 1994, 91 , 3191-95 and Snyder et al, Nature Medicine, 1995, 1 , 32-37). WO-A-96/40140, WO-A-96/40633 and WO-A-97/16190 disclose compounds that have neurotrophic activity but which lack inhibitory action at the protein phosphatase calcineurin and therefore which have no immunosuppressive activity.
It has been suggested in WO-A-96/40140 and WO-A-96/40633 that the neurotrophic effect of these compounds is mediated, at least in part, by a high affinity interaction with the FK-506 binding proteins, such as FKBP-12, or FKBP-52. However, the mechanism by which this interaction with FKBP- type immunophilins results in a neurotrophic effect is at present unknown. The range of neurotrophic activity that can be realised through this neurotrophic/non-immunosuppressant class of compounds has been explored and it has been found that axon regeneration can be promoted after facial nerve crush and sciatic nerve crush in the rat. It has also been observed that the functional regeneration of dopamine neurons damaged with the toxin MPTP was promoted by the compounds disclosed therein in mice. Additionally, it was reported that restoration of striatal innervation in the rat was promoted by the compounds disclosed therein following 6-hydroxydopamine lesioning of dopaminergic neurons (see Hamilton & Steiner, Current Pharmaceutical Design, 1997, 3, 405-428).
It has now been found that the present compounds are neurotrophic agents which have an affinity for FKBP-type immunophilins. In particular, they are potent inhibitors of the enzyme activity and especially of the cis-trans prolyl -2- isomerase (rotamase) activity of FKBP-type immunophilins, particularly the immunophilin FKBP-12. The present compounds do not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
The present compounds therefore moderate neuronal degeneration and promote neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases or other disorders involving nerve damage. The neurological disorders that may be treated include senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar-brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), hemiated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases.
Preferably, the present compounds can be used for treating senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, -3-
Huntingdon's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabetic or non-diabetic), multiple sclerosis or a hearing disorder such as tinnitus.
The present invention provides a compound of the formula:
DH-R1
Y-W-R2
(I) or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 is a 5- or 6-membered ring heteroaryl group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or
2 nitrogen heteroatoms, said heteroaryl group being linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by from 1 to 3 substituents each independently selected from C, -C6 alkyl, C2-C6alkenyl, -X-
(C3-C7 cycloalkyl), -X-aryl, -X-het, -X-OH, -X-(C1-C4alkoxy), -X-CO2R5, -X-CN, and -X-NR3R4;
R2 is H, phenyl or C3-C7 cycloalkyl, said phenyl or cycloalkyl being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C1 -C6 alkyl, C -C6 alkoxy, -OH, -(C,-C6 alkylene)OH, halo and halo(C C6 alkylene)-,
or R2 is a 5-, 6- or 7-membered ring heterocyclic group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heterocyclic group being saturated or partially or fully unsaturated, optionally benzo-fused and optionally substituted, including -4. in the benzo-fused portion, by from 1 to 3 substituents each independently selected from C, -C6 alkyl, C^ -C6 alkoxy, halo, halo(C1 -C6 alkylene)- and -C02R5; said R2 group being attached to W by any mono- or bicyclic ring carbon atom or heteroatom;
R3 and R4 are either each independently selected from H, C, -C6 alkyl, C3-C6 cycloalkyl and -(C1-C6 alkylene)(C3-C6 cycloalkyl), or, when taken together, represent unbranched C3 -C6 alkylene optionally containing O or NR5;
R5 is H, C, -C6 alkyl, C3-C6 cycloalkyl, -(CrC6 alkylene)(C3-C6 cycloalkyl) or -(C, - C6 alkylene)aryl;
A is unbranched C3-C5 alkylene optionally substituted by C^Cg alkyl;
W is a direct link, C, -C6 alkylene or C2-C6 alkenylene;
X is a direct link, C^ alkylene or -(C0-C6alkylene)-Z-(C0-C6 alkylene)-;
Y is SO2 , carbonyl, -CONR5 -, -CO.CO-, -CH2CO-, -CS.CO-, -CO.CS- or - CO.CH(OH)-;
Z is O, S, -CR5NR3R4-, -CR5NR5(CO2R5)-, -CR5(aryl1)-, -NR5-, -NR5CO2 -, -CONR5- or -NR5CO-;
"aryl" is phenyl optionally substituted by from 1 to 3 substituents each independently selected from C, -C6 alkyl, -(C|-C6 alkylene) OH, C1 -C6 alkoxy, - (C, -C6 alkylene)(CrC6 alkoxy), halo, halo(C1 -C6 alkylene)-, -NR3R4 , -(C^Cβ alkylene)NR3R4, -O(C1 -C6 alkylene)NR3R4 and -(CrC6 alkylene)(phthalimido); -5- "aryl1 " is phenyl optionally substituted by from 1 to 3 substituents each independently selected from C1 -C6 alkyl, C, -C6 alkoxy, - C^ -C6 alkylene)(C C6 alkoxy), halo and halo(C1 -C6 alkylene)-; and
"het" is a 5-, 6- or 7-membered ring heterocyclic group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heterocyclic group being saturated or partially or fully unsaturated, or "het" is azetidinyl, said "het" being optionally substituted by from 1 to 3 substituents each independently selected from C, -C6 alkyl, -(Cr C6 alkyiene)(C3-C7 cycloalkyl), C -C6 alkoxy, C3-C7 cycloalkyl, -(C -C6 alkylene)(CrC6 alkoxy), halo, halo(C1 -C6 alkylene)-, -NR3R4, -C02R5, -(C, -C6 alkylene)aryl and -(C^Cg alkylene)NR3R4:
with the provisos that
(a) the heteroaryl group of R1 is not substituted by -(C0-C6alkylene)-Z-(C0 alkylene)(-OH or -CrC4 alkoxy or -CN or -NR3R4) when Z is O, S, -NR5-, - NR5C02 - or -CONR5-; and
(b) when W is a direct link, R2 is only H when Y is -CONR5- ;
(c) when A is C3 alkylene, Y is sulphonyl, W is a direct link, and R2 is para methyl substituted phenyl, then R1 is not
N(CH3)2 N O
N- N- _^ or - Λ
NH2 NH, (d) when A is C4 alkylene, Y is carbonyl, W is C-, alkylene and R2 is H, then R1 is not
O
Figure imgf000008_0001
CH,
(e) when A is C4 alkylene, Y is carbonyl, W is a direct link and R2 is 3-hydroxy phenyl,
then R1 is not
N. .Ph
-i
Ph
(f) when A is C3 alkylene, Y is carbonyl, W is a direct link and R2 is phenyl, then R1 is not 2-furyl.
Disclaimers (c) to (f) are based on the following documents: Agr.Biol.Chem. (1971 ), 35(10), 1572-7; Tetrahedron Lett. (1981 ), 22(2), 141-4; WO-A-9703973 published 6 February 1997 and Chemical Abstracts, vol. 56, no. 11 , abstract no. 13001g.
With the aforementioned disclaimers (c ) to (f), the aforementioned compounds for formula (I) are novel. However, if one or more broader disclaimers are required for validity they may be based on the following disclaimers: -7-
(c ) wherein when A is C3 alkylene and Y is sulphonyl, W is a direct link, and R2 is substituted phenyl, then R1 is not a diamino substituted triazine (relates to aforementioned disclaimer ( c));
(d) wherein Y-W-R2 does not represent a C C4 acyl group, when R1 is an optionally substituted furanyl group (relates to aforementioned disclaimers (d) and (f)); and
(e) wherein R1 is not an oxazole disubstituted by aryl (relates to aforementioned disclaimer (e)).
Throughout the above definitions, "halo" means fluoro, chloro, bromo or iodo and alkyl, alkoxy, alkenyl, alkylene and alkenylene groups containing the requisite number of carbon atoms, except where indicated, can be unbranched- or branched-chain.
When R3 and R4, when taken together, represent unbranched C3-C6 alkylene optionally containing O or NR5, the heteroatom may be positioned either at a terminal position of, or in an intermediate position in, the unbranched C3-C6 alkylene group. Examples of such -NR3R4 groups include piperazino and morpholino.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, -8-
β-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
The pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) are polymorphs and radiolabelled derivatives thereof.
A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Where a compound of the formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate. Particularly preferred are compounds of the formula (I ):
A H
N R1 d')
Y-W-FT
wherein R1, R2, A, W and Y are as previously defined for a compound of the formula (I).
In the above definitions of a compound of the formula (I) and (I'), the following definitions are preferred.
Preferably, R1 is triazolyl, isoxazolyl, oxadiazolyl, tetraazolyl, thiazolyl or thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by 1 , 2 or 3 substituents each independently selected from C Cβ alkyl, -X-aryl, -X-het, -X-CO2R5 and -X-NR3R4.
More preferably, R is triazolyl, isoxazolyl, oxadiazolyl, tetraazolyl, thiazolyl or thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by 1 , 2 or 3 substituents each independently selected from CrCβ alkyl, -X-aryl, -X-het, -X-C02R5 and -X- NR3R4, wherein
X is a direct link, CrC6 alkylene or -(C0-C6 alkylene)-Z-(C0-C6 alkylene)-;
Z is O, -CR5NR3R4, -CR5NR5(CO2R5)-, -NR5- or -NR5C02-;
"aryl" is phenyl optionally substituted by from 1 to 3 substituents each independently selected from -(CrC6 alkylene)NR3R4, -0-(C Ce alkylene)NR3R4, -(C C6 alkylene)(phthalimido) and -(C,-C6 alkylene) OH;
"het" is piperidyl, pyrazinyl, furyl, piperazinyi, pyrimidinyl or morpholinyl, optionally substituted by from 1 to 3 -(C C6 alkylene)aryl, -(C C6 a!kylene)(C3- C7 cycloalkyl) substituents, -10-
or -CO2R5 where R5 is -(C,-C6 alkylene) aryl or CrC6 alkyl; or -(CrC6 alkylene) NR3 R4 where "het" is furyl; R3 and R4 are either each independently selected from H and CrC6 alkyl or, when taken together, represent unbranched C3-C6 alkylene; and R5 is H or CrC6 alkyl.
Yet more preferably, R1 is 1 ,2,4-triazolyl, isoxazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl or 1 ,3,4-thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by 1 , 2 or 3 substituents each independently selected from methyl, benzyl, α-(amino)benzyl, α-(tert- butoxycarbonylamino)benzyl, benzylamino, benzylaminoethyl, aminomethylphenoxymethyl, methylaminomethylphenoxymethyl, dimethylaminomethylphenoxymethyl, pyrrolidinylmethylphenoxymethyl, aminoethoxybenzyl, phthalimidomethylphenoxymethyl, piperidyloxymethyl, benzylpiperidyloxymethyl, benzylpiperidyloxyethyl, morpholinomethyl, benzyloxycarbonylaminoethyl, amino, aminoethyl, R-<χ-(amino)benzyl, S-∞- (amino)benzyl, pyrazinyl, benzyloxycarbonylpiperidinyloxymethyl, methylaminofuryl, cyclopropylmethylpiperidyloxymethyl,
-hyd roxymethyl phenoxymethyl , tertbutyloxycarbonyl piperazinylethyl , pyrimid inyl , benzylaminomethyl, (S)-α-(benzyloxycarbonylamino)benzyl, piperazinoethyl, phenylcarbonylaminoethyl, dimethylaminomethyl, hydrogen, phenyl, cyclohexylamino or ( R)-α-(benzyloxycarbonylamino)benzyl.
More preferably still, R1 is 5-benzyl-1 ,2,4-oxadiazol-3-yl,
5-(4-[phthalimidomethyl]phenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-aminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-dimethylaminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, -11-
5- 4-pyrrolidinomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5- 4-methylaminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5- 1 -benzylpiperid-4-yioxymethyl)-1 ,2,4-oxadiazol-3-yl, 5- α-[tert-butoxycarbonylamino]benzyl)-1 ,2,4-oxadiazol-3-yl,
5-morpholinomethyl-1 ,2,4-oxadiazol-3-yl,
5-(2-[1 -benzylpiperid-4-yloxy]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(1 H-piperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-fα-[amino]benzyl)-1 ,2,4-oxadiazol-3-yl,
5-(2-[benzyloxycarbonylamino]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(2-aminoethyl)-1 ,2,4-oxadiazol-3-yl,
5-(2-[benzylamino]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(4-[2-aminoethoxy]benzyl)-1 ,2,4-oxadiazol-3-yl,
5-methyl-1 ,3,4-thiadiazol-2-yl,
1 H-1 ,2,4-triazol-3-yl,
1-benzyl-1 H-1 ,2,4-triazol-3-yl,
5-benzyl-4-methyl-4H-1 ,2,4-triazol-3-yl,
5-amino-1 ,3,4-oxadiazol-2-yl,
5-benzylamino-1 ,3,4-oxadiazol-2-yl,
3-methylisoxazol-5-yl,
5-(pyrazi n-2-yl)- 1 ,2 ,4-oxod iazol-3-yl ,
5-( R)-[α-(amino)benzyl]-1 ,2,4-oxadiazol-3-yl,
5-(S)-[α-(amino)benzyl]-1 ,2,4-oxadiazol-3-yl,
5-(5-methylaminofuran-2-yl)-1 ,2,4-oxadiazoI-3-yl,
5-(1-benzyloxycarbonylpiperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-(1 -cyclopropylmethylpiperid-4-yloxymethyl) -1 ,2,4-oxadiazol-3-yI,
5-(4-hydroxymethylphenoxymethyl) -1 ,2,4-oxadiazol-3-yl,
5-[2-(4-tert-butoxycarbonylpiperazin-4-yl)ethyl] -1 ,2,4-oxadiazol-3-yl,
5-(pyrimidin-2-yl) -1 ,2,4-oxadiazol-3-yl, -12-
5-methyl-1 ,2,4-oxadiazol-3-yl, 5-benzylaminomethyl-1 ,2,4-oxadiazol-3-yl,
5-(S)-(α-[benzyloxycarbonylamino]benzyl) -1 ,2,4-oxadiazol-3-yl,
5-(R)-(α-[benzyloxycarbonylamino]benzyl) -1 ,2,4-oxadiazol-3-yl,
5-[2-(4H-piperazin-1-yl)ethyl] -1 ,2,4-oxadiazol-3-yl,
5-[2-(phenylcarbonylamino)ethyl] -1 ,2,4-oxadiazol-3-yl, 5-[2-(dimethylamino)ethyl] -1 ,2,4-oxadiazol-3-yl,
1 ,2,4-oxadiazol-3-yl,
5-phenyl -1 ,2,4-oxadiazol-3-yl,
2-benzyl-2H -1 ,2,3,4-tetraazol-5-yl,
5-benzyl-1 ,3,4-oxadiazol-2-yl, 5-[2-(phenyl)ethyl] -1 ,3,4-oxadiazol-2-yl,
5-methyl-2H-1 ,2,3,4-tetraazol-5-yl,
5-cyclohexylamino -1 ,3,4-oxadiazol-2-yl,
5-methyl -1 ,3,4-oxadiazol-2-yl,
3-methyl -1 ,2,4-oxadiazol-3-yI, 5-methyl -1 ,3-thiazol-2-yl,
5-methyl-1 H- 1 ,2,4-triazol-3-yl,
5-aminomethyl -1 ,2,4-oxadiazol-3-yl or
2H- 1 ,2,3,4-tetraazol-5-yl.
Most preferably R1 is
5-benzyl-1 ,2,4-oxadiazol-3-yl,
5-(4-[phthalimidomethyl]phenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-aminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-dimethylaminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-pyrrolidinomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-(4-methylaminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, -13-
5-(1-benzylpiperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-(α-[tert-butoxycarbonylamino]benzyl)-1 ,2,4-oxadiazol-3-yl, 5-(2-[1 -benzylpiperid-4-yloxy]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(1 H-piperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-[α-[amino]benzyl)-1 ,2,4-oxadiazol-3-yl,
5-(2-[benzylamino]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(4-[2-aminoethoxy]benzyl)-1 ,2,4-oxadiazol-3-yl, 5-(pyrazin-2-yl)-1 ,2,4-oxodiazol-3-yl,
5-( R)-[α-(amino)benzyl]-1 ,2,4-oxadiazol-3-yl,
5-(S)-[α-(amino)benzyl]-1 ,2,4-oxadiazol-3-yl,
5-(5-methylaminofuran-2-yl)-1 ,2,4-oxadiazoI-3-yl,
5-(1-benzyloxycarbonylpiperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(1-cyclopropylmethylpiperid-4-yloxymethyl) -1 ,2,4-oxadiazol-3-yl,
5-(4-hydroxymethylphenoxymethyl) -1 ,2,4-oxadiazol-3-yl,
5-[2-(4-tert-butoxycarbonylpiperazin-4-yl)ethyl] -1 ,2,4-oxadiazol-3-yl,
5-(pyrimidin-2-yl) -1 ,2,4-oxadiazol-3-yl,
5-benzylaminomethyl-1 ,2,4-oxadiazol-3-yl, 5-(S)-(α-[benzyloxycarbonylamino]benzyl) -1 ,2,4-oxadiazol-3-yl or
5-[2-(4H-piperazin-1-yl)ethyl] -1 ,2,4-oxadiazol-3-yl.
Preferably, R2 is H, phenyl or C3-C7 cycloalkyl, said phenyl or cycloalkyl being optionally substituted by from 1 to 3 halo substituents, or R2 is a 5- or 6- membered ring heterocyclic group containing either 1 or 2 nitrogen heteroatoms or 1 oxygen heteroatom, said heterocyclic group being saturated or partially or fully unsaturated, optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by from 1 to 3 C^Cg alkyl, arylalkoxycarbonyl (e.g. benzyloxycarbonyl), halo or halo (CrC6) alkyl, substituents, -14-
said R2 group being attached to W by any mono- or bicyclic ring carbon atom or heteroatom. More preferably, R2 is H, phenyl, cyclopentyl, cyclohexyl or cydoheptyl, said phenyl being optionally substituted by from 1 to 3 fluoro substituents, or R2 is imidazoly, pyrrolidinyl, piperidinyl or tetrahydrofuranyl, said imidazolyl or tetrahydrofuranyl group being optionally benzo-fused and optionally substituted, including in the benzo- fused portion, by from by from 1 to 3 methyl or bromine or fluorine substituents,
said R2 group being attached to W by any mono- or bicyclic ring carbon atom.
Yet more preferably, R2 is H, fluorophenyl, cyclohexyl, methylimidazolyl, benzimidazolyl, furanyl, cyclopentyl, cydoheptyl, bromobenzimidazolyl or fluorobenzimidazoyl.
Most preferably, R2 is H, 4-fluorophenyl, cyclohexyl, 1-methyl-1 H- imidazol-4-yl, 1 H-benzo[d]imidazol-2-yl, tetrahydrofuran-3-yl, cyclopentyl, cydoheptyl or 5-bromo-1 H-benzo[d]imidazol-2-yl.
Preferably, W is a direct link or C C6 alkylene.
More preferably, W is a direct link, methylene, ethylene or 2,2-dimethyl- 1 ,3-propylene. Most preferably, W is a direct link or methylene.
Preferably, Y is S02 or -CONR5-. Most preferably, Y is S02 or -CONH-. -15-
Preferred examples of -Y-W-R2 include:
5-bromo1 H-benzo[d]imidazol-2-yl sulphonyl,
1 H-benzo[d]imidazol-2-ylsulphonyl,
1-methyl-1 H-imidazol-4-ylsulphonyl, tetrahydrofuran-3-ylmethylsulphonyl, cyclohexylmethylsulphonyl, 4-fluorophenylsulphonyl,
N-(2,2-dimethylprop-1-yl)aminocarbonyl, cyclopentylmethyl sulphonyl, cycloheptylmethyl sulphonyl,
1-(benzyioxycarbonyl)pyrrolidin-3-ylmethylsulphonyl, 1 -(benzyloxycarbonyI)piperid-3-ylmethylsulphonyl, benzylaminocarbonyl or phenethylaminocarbonyl.
Highly preferred examples of -Y-W-R2 include: 5-bromo1H-benzo[d]imidazol-2-yl sulphonyl,
1 H-benzo[d]imidazol-2-ylsulphonyl, cyclohexylmethylsulphonyl,
4-fluorophenylsulphonyl, cyclopentylmethyl sulphonyl or cycloheptylmethyl sulphonyl.
Preferably, A is unbranched C3-C4 alkylene (i.e. 1 ,3-propylene or 1 ,4-butylene). Most preferably A is C4 alkylene.
In a preferred embodiment of the present invention R1 is 1 ,2,4 or 1 ,3,4 oxadiazole, that is linked to the adjacent carbon atom by a ring carbon -16-
atom which is optionally preferably-mono-substituted by one of -X-aryl or -X-het wherein X is preferably selected from -(C0-C2 alkylene)-Z-(C0-C2 alkylene), more preferably -(C alkylene)-Z-(C0 alkylene) where Z is -O-; or X is a direct link or -(C^C;, alkylene); or X is -(C0 alkylene)-Z-(C0 alkylene) where Z is -CR5NR3R4, or -CR5 NR5 (CO2R5) where R3 and R4 are selected from H,-(C C3 alkylene), more preferably H,-(C C2 alkylene) and R5 is H or -(C C4 alkylene), or -(C^O, alkylene)aryl; or X is -(CrC2 alkylene) -Z-(CrC2 alkylene)(aryl) where Z is NR5 and R5 is H or -(C,-C2 alkylene)-;
wherein aryl of -X-aryl is phenyl optionally substituted by from 1 to 3 susbtituents independently selected from -(C,-C3 alkylene) NR3 R4, -(C C6 alkylene)(phthalimido); -O(CrC3 alkylene) NR3 R4 or -CO2R5 wherein
R3 and R4 are each independently selected from H, C.,-C3 alkyl or, when taken together, represent unbranched C3-C5 alkylene; and R5 is H, C^O; alkyl or -(CrC2 alkylene) aryl;
wherein "het" of -X-het is piperidinyl, furyl, pyrazinyl, pyrimidinyl or piperazinyl optionally substituted by -(C C3 alkylene)(-C3-C6 cycloalkyl), - C02R5, -(CrC3 alkylene)NR3R4 or -(C C2 alkylene)aryl wherein aryl is phenyl and wherein R3 and R4 are selected from H,-(C C3 alkylene), more preferably H,-(C1-C2 alkylene) and R5 is H or -(CrC4 alkylene), or - (CrC2 alkylene)aryl;
or X is -(C1-C2 alkylene) -Z-^-Cj alkylene)(aryl) where Z is NR5 and R5 is H or -(C C2 alkylene)-.
Further preferred embodiments of the present invention are as follows: -17-
1 H-Benzo[d]imidzol-2-yl[2S]-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl)-1 - piperidylsulphone, 2-[4-(3-[(2S)-1 -(1 /-/-Benzo[o]imidazol-2- yisulfonyl)piperidyl]-1 ,2,4-oxadiazol- 5-ylmethoxy)benzyl]-1 ,3- isoindolinedione, 4-(3-[(2S)-1 -(1 H-Benzo[c rnidazol-2-ylsulfonyI)-2- piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzylamine, Λ/-[4-(3-[(2S)-1- (1/- -Benzo[ /]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol- 5-ylmethoxy)benzyl]-Λ/,Λ/-dimethylamine, 3-[1 -(1 H-Benzo[d]imidazoI-2- ylsuIfonyl)-2-piperidyl]-5-[4-(1- pyrrolidylmethyl)phenoxy]methyl-1 ,2,4- oxadiazole, A/-[4-(3-[1 -(1 H-Benzo[ ]imidazol-2-ylsulfonyl)-2-piperidyl]- 1 ,2,4-oxadiazol-5-ylmethoxy)benzyl]- V-methylamine, 4-[3-((2S)-1-[Cyclohexylmethylsulfonyl]-2-piperidyl)-1 ,2,4-oxadiazol-5- ylmethoxyjbenzylamine, 5-[(1 -Benzyl-4-piperidyI)oxymethyl]-3-[(2S)-1 - cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4-oxadiazole, 3-[(2S)-1-
Cyclohexylmethylsulfonyl-2-piperidyl]-5-[4-piperidyloxymethyl]-1 ,2,4- oxadiazole, (3-[(2S)-1 -Cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4- oxadiazol-5-yl)(phenyl)methylamine, 5-(3-(2S)-1 - [(Cyclohexylmethyl)sulfonyl]-2-piperidyl-1,2,4-oxadiazol-5-yI)-2- furyljmethylamine, /V-(2-(3-[1 -(1 H-Benzo[o]imidazol-2-ylsuifonyl)-2- piperidyl]-1 ,2,4-oxadiazol-5-yl)ethyl)benzyiamine,
2-[4-(3-[1 -(1 H-Benzo[c imidazol-2-ylsulfonyl)-2-piperidyI]-1 ,2,4-oxadiazol- 5-ylmethyl)phenoxy]ethylamine, N-(3- -(1 H-benzo[d]imidazol-2- ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethyl)-/V-benzylamine, 2-[(2S)-2-5-[(4-Piperidyloxy)methyl]-1 ,2,4-oxadiazoI-3-yl-1 - piperidyl]sulfonyl-1 H-benzo[d]imidazole, 2-[(2S)-2-[5-([1 - (Cyclopropylmethyl)-4-piperidyl]oxymethyl)-1 ,2,4-oxadiazoI-3- yl]-1 -piperidyl]sulfonyl-1 H-benzo[d]imidazole, 2-[(2S)-2-(5-Benzyl-1 ,2,4- oxadiazol-3-yl)-1 -piperidyl]sulfonyl-5-bromo-1 H- benzo[d]imidazole, 2-4-[(3-(2S)-1 -[(5-Bromo-1 /-/-benzo[d]imidazol-2-yi)sulfonyl]-2-piperidyl-
1 ,2,4-oxadiazol-5-yl)methoxy]benzyl-1 ,3-isoindolinedione, -18-
4-[(3-(2S)-1-[(5-Bromo-1H-benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl- 1 ,2,4-oxadiazol-5-yi)methoxy]benzylamine, terf-Butyl 4-[2-(3-(1 S)-2- [(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)ethyl]-1 - piperazinecarboxylate, (R)-(3-{(2S)-1-[(Cyclohexylmethyl)sulfonyl]-2- piperidyl}-1 ,2,4-oxadiazol-5-yl)(phenyl)methylamine, (S)-(3-{(2S)-1-[(Cyclohexylmethyl)sulfonyl]-2-piperidyl}-1 ,2,4-oxadiazol-5- yl)(phenyl)methylamine, 2-({2-[5-(2-pyrimidinyl)-1 ,2,4-oxadiazol-3-yl]-2- piperidyl}sulfonyl)-1H- benzo[d]imidazole, Benzyl 4-(3-[(2S)-1-(1H- benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)- 1-piperidinecarboxyiate, (2S)-2-(5-Benzyl-1 ,2,4-oxadiazol-3-yl)-1- [(cyclopentylmethyl)sulphonyl]piperidine, (2S)-2-(5-Benzyl-1 ,2,4- oxadiazol-3-yl)-1 - [(cyclohexylmethyI)sulphonyl]piperidine, (2S)-2-(5- Benzyl-1 ,2,4-oxadiazol-3-yl)-1-[(cycloheptylmethyl)suiphonyl]piperidine, tert-Butyl-N-(3-{(2S)-1-(cyclohexylmethyl)suiphonyl-2-piperidyl}-1 ,2,4- oxadiazol 5-yl)(phenyl)methylcarbamate, (2S)-2-(5-{2-[(1 -Benzyl-4- piperidyl)oxy]ethyl}-1 ,2,4-oxadiazol-3-yl)-1 - (cyclohexylmethyl)sulphonyl]piperidine, {4-{3-{2S-1-[4- Fluorophenyl)sulphonyl]piperidyl}-1 ,2,4-oxadiazol-5- yl)methoxy]phenyll}methanol, 2-(3-{(2S)-1-[4-
Fluorophenyl)sulphonyl]piperidyl}-1 ,2,4-oxadiazol-5-yl)pyrazine or 1-[2-(3- (1S)-2-[(Cyclohexylmethyl)sulphonyl]-2-piperidyl-1 ,2,4-oxadiazol-5- yl)ethyl]piperazine.
According to a further aspect of the invention there are provided compounds of formula (I) as defined herein before but wherein the optional substituent on R2, where R2 is a 5-, 6-, or 7-membered ring heterocyclic group, is not, CO2R5; or wherein the optional substituent on the "aryl" group of -X-aryl or R5 is not -(CrC6 alkylene)OH; or wherein the -19-
optional substituent on the -X-het group is not C3-C7 cycloalkyl or -(C.,-C6 alkylene)( C3-C7 cycloalkyl).
Particularly preferred examples of the compounds of the formula (I) are as described in the Examples section hereafter.
The compounds of the formula (I) can be prepared using conventional procedures such as by the following illustrative methods.
1. All the compounds of the formula (I) can be prepared by
(a) reaction of a compound of the formula:
A. I CH-R1 (II)
N' H
wherein R1 and A are as previously defined for a compound of the formula (I), with a compound of the formula:
L1-Y-W-R2 (III)
wherein R2, W and Y are as previously defined for a compound of the formula (I) and L is a suitable leaving group, e.g. fluoro, chloro or bromo; or
(b) by ring formation or ring closure of a corresponding open ring structure, to formula (II), wherein the said open ring corresponds to an optionally substituted heterocycle R1 followed by reaction with a compound of formula (III) as detailed herein before; or -20-
by ring formation or ring closure of a corresponding open ring structure, to formula (I), wherein the said open ring corresponds to an optionally substituted heterocycle R1 .
If an acid addition salt of a compound of the formula (II) is used as the starting material, this may be converted to the free base ]n situ using a suitable acid acceptor, e.g. ethyldiisopropylamine.
For all definitions of Y, L1 may be chloro and the reaction can be carried out in the presence of a suitable additional acid acceptor, e.g. ethyldiisopropylamine or triethylamine, and in a suitable solvent, e.g. dichloromethane. Where Y is SO2, L1 may be fluoro and the reaction can be carried out under similar conditions.
Where Y is carbonyl, -CONR5-, -CO.CO-, -CO.CS- or -CO.CH(OH)-, L1 may also be a group that forms an activated derivative of a carboxylic acid, e.g. an activated ester or imidazol-1-yl. The reaction may be carried out under conventional conditions.
The intermediate compounds of the formula (II) may be prepared by conventional methods, for example, where the heteroaryl group of R1 is a 1 ,2,4-oxadiazol-3-yl group, by the route shown in Scheme 1. -21 - Scheme 1
A
I * CO2H (IV)
N H
Carbamate formation
(e.g. di-t-butyldicarbonate, aqueous sodium hydroxide, 1 ,4-dioxane)
fr N B-C02 zH (V)
O^ "O
*Bu
Amide formation (e.g. ethyl chloroformate, aqueous ammonia, triethylamine, tetrahydrofuran)
!bB-CONH2 (VI)
N z
O ^O ώu
Dehydration
(e.g. oxalyl chloride, dimethylformamide, pyridine, acetonitrile)
VII)
N C CN (
O^O
*Bu
Hydroxyamidine formation (e.g. hydroxylamine hydrochloride, aqueous sodium carbonate, methanol) -22- Scheme 1 Contd./
A^H N— OH
(VIII)
A 0 NH„
O^O
Bu
Coupling (e.g. HO2C-R1A, hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine, N-methylmorpholine, dichloromethane) O.
1A
R
AXH N— O
(IX) NH.
O^O
Bu
Ring closure (e.g. xylene, heat)
A H N-0 y N' 1A (X)
R
0^0
Bu
Deprotection (e.g. hydrogen chloride, dichloromethane)
A^H N-O y .HCI
H 'N 1A
R (NA) -23-
wherein A is as previously defined for a compound of the formula (I) and R1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I).
A salt of the formula (I I A) is usually used directly in the reaction with a compound of the formula (III) where it may be converted to the corresponding free base of the formula (II) in sjtu using a suitable acid acceptor, e.g. ethyldiisopropylamine.
The intermediate compounds of the formula (III) may be prepared by conventional methods.
2. The compounds of the formula (I) wherein Y is -CONH- and R\ R2, A and W are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula (II) wherein R1 and A are as previously defined for a compound of the formula (I), with an isocyanate of the formula:
R2-W-NCO (XI)
wherein R2 and W are as previously defined for a compound of the formula (I).
The reaction may be carried out in a suitable solvent, e.g. dichloromethane.
The intermediate compounds of the formula (XI) can be prepared by conventional methods. -24-
3. The compounds of the formula (I) wherein Y is -CONR5- and R1, R2, R5, A and W are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula (II) wherein R1 and A are as previously defined for a compound of the formula (I), first with a suitable carbonylation reagent, e.g. phosgene [or an equivalent thereof (e.g. triphosgene)] or 1 ,1 -carbonyldiimidazole, and then with a compound of the formula:
R2-W-NHR5 (XII)
wherein R2, R5 and W are as previously defined for a compound of the formula (I), the reaction being optionally carried out in the presence of a suitable acid acceptor, e.g. triethylamine.
The reaction may be carried out in a suitable solvent, e.g. dichloromethane.
The intermediate amines of the formula (XII) can be prepared by conventional methods.
4. The compounds of the formula (I) wherein R1 is an optionally substituted 1 ,2,4-oxadiazol-3-yl heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by ring closure of a compound of the formula: -25-
O
A 1A
N-0 R ι?^y (XIIA)
NH.
Y-W-R2
wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I).
The reaction may be carried out in a suitable solvent, e.g. xylene or pyridine, and at the reflux temperature thereof.
The intermediate compounds of the formula (XIIA) can be prepared by a similar method to that used to prepare a compound of the formula (IX) in Scheme 1 by initially converting a compound of the formula (IV) to a compound of the formula:
,OCHCO2H (XIII)
N
Y-W-R2
wherein R2, A, W and Y are as previously defined for a compound of the formula (I), using a conventional method, and then by following the route indicated therein.
5. The compounds of the formula (I) wherein R is an optionally substituted 1 ,3,4-oxadiazolyl heteroaryl group and R2, A, W and Y are as previously -26-
6. defined for a compound of the formula (I) can be prepared by ring closure of a compound of the formula:
A-.
I "CHCONHNHCOR1A (XIV)
Y-W-R2
wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R for a compound of the formula (I).
The reaction may be carried out under suitable conditions such as using a mixture of triphenylphosphine, iodine and triethylamine in dichloromethane. A compound of the formula (XIV) can be prepared by reaction of a compound of the formula (XIII) with a compound of the formula:
R1A CONHNH2 (XV)
under conventional dehydration conditions.
6. The compounds of the formula (I) wherein R1 is a 1 ,3,4-oxadiazolyl heteroaryl group bearing an optionally substituted amino substituent
(R1B) (as previously defined for R1) and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by ring closure of a compound of the formula: -27-
A^
ACHCONHNHCSR16 (XVI)
N
Y-W-R2
wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R1B is a relevant optionally substituted amino substituent as defined above.
The reaction may be carried out using mercuric oxide in 1 ,4-dioxane and at the reflux temperature.
A compound of the formula (XVI) can be prepared by reaction of a compound of the formula (XIII) first with a carboxyl group activating reagent (e.g. 1 ,1'-carbonyldiimidazole) followed by a compound of the formula:
R BCSNHNH2 (XVII)
wherein R1B is as previously defined for this method, under conventional conditions.
7. The compounds of the formula (I) wherein R1 is an optionally substituted 1 ,3,4-thiadiazolyI heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula (XIV) wherein R2, A, W, Y and R1A are as previously defined for a compound of the formula (XIV) with a thionating agent, e.g. P4S10 or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1 ,3- -28-
dithia-2,4-diphosphetane-2,4-disulphide) in a suitable solvent, e.g. toluene, preferably at the reflux temperature thereof.
8. The compounds of the formula (I) wherein R1 is an optionally substituted 1 ,2,4-triazol-3-yl heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula:
10
A OR
. ."CH— (XVIII) N NH
Y-W-R2
where R2, A, W and Y are as previously defined for a compound of the formula (I) and R 0 is C,-C4 alkyl, e.g. methyl or ethyl, with a compound of the formula:
R1ANHNHCHO (XIX)
wherein R1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I).
The reaction may be carried out in a suitable solvent such as a mixture of toluene and 1 ,4-dioxane, and at the reflux temperature thereof. A compound of the formula (XVIII) can be prepared by reaction of a compound of the formula: -29-
l. CH— CONH2 (XX)
N
Y-W-R2
wherein R2, A, Y and W are as previously defined for a compound of the formula (I), with a tri(C C4 a!kyl)oxonium hexafluorophosphate in dichloromethane.
A compound of the formula (XX) can be prepared as described in
Method (4) above or by treatment of a compound of the formula (XXIV) with ammonia.
9. The compounds of the formula:
>1C
A\
(IA)
N^ Y-W-R"
wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R1C is relevant group corresponding to a substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I) that is linked to the ring nitrogen atom by a methylene group, can be prepared by alkylation of a compound of the formula:
A Z/^NH y <'J
Y-W-R2 <|B) -30-
wherein R2, A, W and Y are as previously defined for a compound of the formula (I) (a compound of the formula (IB) is prepared by the route described in Method (8) above, i.e. where R1A is H) using an appropriate alkylating agent and under conventional conditions. Regioisomers may be formed in this reaction and they may be separated by chromatography.
10. The compounds of the formula (I) wherein R1 is an optionally substituted 4-(CrC6 alkyl)-4H-1 ,2,4-triazol-3-yl heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by reaction of a compound of the formula:
A H-CSNH(C C6 alkyl) (χχ|)
Y"W" R2
wherein R2, A, W and Y are as previously defined for a compound of the formula (I), with a compound of the formula (XV) wherein R A is as previously defined for a compound of the formula (XV), in the presence of mercuric oxide.
The reaction may be carried out in a suitable solvent, e.g. 1 ,4-dioxane or dimethylacetamide, and at the reflux temperature. -31-
A compound of the formula (XXI) can be prepared under conventional conditions as shown in Scheme 2.
Scheme 2
J N HCO2H ( iii)
Y-W-R2
(CrC6 alkyl)NH2
A.
^-CHCONH^-Cβ alkyl) (χχ| |)
Y-W-R"
Lawesson's reagent
(XXI) wherein R2, A, W and Y are as previously defined for a compound of the formula (I).
11. The compounds of the formula (I) wherein R is an optionally 3- substituted isoxazol-5-yl heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by ring closure of a compound of the formula:
A.
I ;CHCOCH2C(RiA)=N-OH
N
Y-W-R^ (XXIII) -32-
wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I).
The reaction may be carried out using mesyl chloride, triethylamine and dichloromethane as the solvent.
A compound of the formula (XXIII) can be prepared as shown in Scheme 3.
Scheme 3
A.
ACHCO H N
(XXIII)
Y-W-R2
Esterification
A, i HC02CH3
N
1 2 (XXIV)
Y-W-R2
CH3C(R1A )=N-OH, n-butyllithium, tetrahydrofuran
(XXIII)
wherein R2, A, W, Y and R1A are as previously defined for this method. -33-
12. The compounds of the formula (I) wherein R1 is an optionally substituted 1 ,2,3,4-tetraazol-5-yl heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by known methods such as, for example, by reaction of a compound of the formula (XXV):
Γ CH- -C≡N (XXV)
N
Y-W-R'
where R2, A, W and Y are as previously defined for a compound of the formula (I) with trimethylsilyl azide and dibutyltin oxide. The reaction may be carried out in a suitable solvent such as toluene and at the reflux temperature thereof. Compounds such as formula (XXV) can be N- alkylated using an appropriate alkylating agent and under conventional conditions regioisomers may be formed which can be separated be standard chromatogaphical methods.
13. The compounds of the formula (I) wherein R1 is an optionally substituted 1 ,2,4-oxadiazol-5-yI heteroaryl group and R2, A, W and Y are as previously defined for a compound of the formula (I) can be prepared by standard methods such as for example, by heat treatment of a compound of the formula (XXVI):
H2N
/ >/- (XXV1 )
A /0_ N ι ^H-c
Y 2 o
Y-W-R2 -34-
where R2, A, W and Y are as previously defined for a compound of the formula (I), in a suitable solvent such as xylene at reflux temperature.
The compound of the formula (XXVI) can be prepared by reacting a compound of the formula (XIII) with a N1-hydroxyimidamide, such as N1- hydroxyethanimidamide. Suitable reaction conditions would be for example, in the presence of hydroxybenzotriazole hydrate, N-methyl morpholine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, in a solvent such as dichloromethane, at room temperature.
14. It will be appreciated that certain compounds of the formula (I) can be converted to other compounds of the formula (I) by conventional methods, e.g. using standard functional group interconversion techniques.
All of the above reactions and the preparations of novel starting materials using in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.
A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. -35-
The affinity of the compounds of the formula (I) for FKBP-12 can be determined in vitro in a coupled colorimetric PPIase assay using similar procedures to published methods (e.g. see Kofron, J.L., et a]., Biochemistry, 1991 , 30, 6127-6134, Zarnt, T., et __[., Biochem. J. 1995, 305, 159-164, Holt, D.A., et a]., J. Am. Chem. Soc, 1993, 115, 9925-9938). In these methods, the cis-trans isomerisation of a hydrophobic amino acid-proline bond in a tetrapeptide substrate (e.g. the phenylalanine-proline bond in N-succinyl-ala- phe-pro-phe-p-nitroanilide [succinyl-AFPF-pNA]) can be determined by monitoring cleavage of pNA from the transPro-containing peptide by an excess of chymotrypsin.
The IC50 (the concentration of the compound of the formula (I) producing 50% inhibition) values were determined using the following assay methodology. Assay buffer (2.175ml) (50mM 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES), 100mM NaCI, 1 mM dithiothreitol (DTT), pH 8.0) is equilibrated to 10°C in a cuvette. 12.5μl of a solution of the present compound in DMSO, 250μl of a 60mg/ml solution of α-chymotrypsin in 1mM aqueous hydrochloric acid and then 50μl of a solution of human recombinant FKBP-12 (4.5μM) in assay buffer are added and mixed. The reaction is initiated by addition of 12.5μl of a solution of 20mM succinyl-AFPF-pNA in DMSO. The absorbance at 390nM is monitored for one minute collecting data every 0.25 second. Data are fitted with a first order rate equation with offset and the rate constant obtained corrected for the rate of uncatalysed isomerisation of the substrate. The rate constant determined at different inhibitor concentrations (10nM to 100μM) is expressed as % inhibition of the control rate constant. The IC50 is estimated using a non-linear least squares curve fitting routine of the sigmoidal dose response data. -36-
K, app (the apparent inhibition constant) was determined for the present compounds using the assay procedure described below. Assay buffer (2.175ml) (50mM HEPES, 100mM NaCI, 1 mM DTT, pH 8.0) is equilibrated to 10°C in a cuvette. 12.5μl of a solution of the present compound in DMSO, 250μl of a 60mg/ml solution of α-chymotrypsin in 1 mM aqueous hydrochloric acid and then 50μL of a solution of human recombinant FKBP-12 (1.5μM) in assay buffer are added and mixed. The reaction is initiated by adding 12.5μl of a solution of anhydrous succinyl-ALPF-pNA (100μM final concentration) in a 400mM solution of LiCI in trifluoroethanol. The absorbance at 390nM is monitored for 3 minutes collecting data every 0.5 second. Data are fitted with a first order rate equation with offset and the initial velocity (v) is calculated from the concentration of cis (re leu-pro bond)-succinyl-ALPF-pNA at t0 and the first order rate constant at different inhibitor concentrations (I). Data in the form ιnr/ controi v- ['] are fitted w'tn an equation for reversible tight binding inhibition to generate values for K,app (see Morrison, J.F., et al, Comments Mol. Cell Biophys., 1985, 2, 347-368). This analysis is used when the Kι app approaches the concentration of FKBP-12 in the assay (30nM). Dixon analysis (see Dixon, M., Biochem. J.,1953, 55, 170-171 ) is used for generating values of Kι app for -less potent compounds.
The same methodlogy is used to generate Kι app for FKBP52 with the following modifications: Forty microlitres human recombinant FKBP52 (5.2μM) is substituted for FKBP12 and 2.185ml assay buffer are used in the assay.
The compounds of the invention have inhibitory activity against the FKBP-12 enzyme. Early experimentation suggests that the compounds of the invention also have inhibitory activity against the FKPB-52 enzyme. The neurite outgrowth promoting activity of the compounds of the formula (I) can be determined in explant cultures of embryonic chick dorsal root -37-
ganglia. Dorsal root ganglia (DRG) are isolated aseptically according to the method of Bray (see "Culturing Nerve Cells", Ed. G. Banker and K. Goslin, MIT Press, Cambridge, MA, 1991, p.119). The individual ganglia were kept in Ca27Mg2+- free Tyrodes buffer on ice until a number of ganglia had been collected. Individual ganglia were then transferred into collagen-coated 24-well culture plates containing Neurobasal medium plus B27 supplements and incubated at 37°C in a 5% CO2 atmosphere. The present compound was added after allowing 4 hours for the ganglia to attach. The explants were fixed and stained with Coomassie blue after 24 or 48 hours in culture. For each treatment 4 to 6 ganglia were analysed and scored by estimating the extent of neurite outgrowth relative to the diameter of the explant using image analysis. The present compounds were tested with and without 10ng/ml nerve growth factor (NGF) present and compared to outgrowth in the presence of 10ng/ml nerve growth factor alone.
An alternative system for measuring neurite outgrowth promoting activity of FKBP-12 PPIase inhibitors is the SH-SY-5Y neuroblastoma model described by Gold, B.G., et al, in Exp. Neural. ,1997, 147(2), 269-278. Cells are maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% Foetal calf serum (FCS), 50U/mI penicillin, 50μg/ml streptomycin at 37°C in a 7% CO2 atmosphere. Cells are plated at 1x106 cells per well and treated for 5 days with 400nM aphidicolin. Cells are then washed and treated with NGF at 10ng/ml ± various compound concentrations for 7 days to determine if the compounds promote neurite outgrowth in the presence of suboptimal NGF concentrations (and/or in the absence of NGF). Neurite outgrowth is determined by using image analysis to measure neurite lengths in 20 random fields.
The neurotrophic activity of the present compounds can be evaluated in vivo using the sciatic nerve crush model in rat as a model for peripheral nerve regeneration (see Bridge, P.M., et aj. , Experimental Neurology, 1994, 127, -38-
284-290, Medinaceli, L., et ah, Expl. Neurology, 1982, 77, 634-643, Gold, B.G.,et aL, Restorative Neurology and Neuroscience, 1994, 6, 287-296), the 1- methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine models in various species as a model for regeneration in Parkinson's disease (see Mokry, J., Physiol. Res., 1995, 44(3), 143-150) and fimbria-fornix lesions as a model for regeneration in Alzheimer's disease (see Cassel, J.C., Duconseille, E., Jeltsch, H. and Will, B., Prog. Neural., 1997, 51 , 663-716). The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the formula (I) can be administered orally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate or controlled release applications.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose or milk sugar as well as high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. -39-
The compounds of the formula (I) can also be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrasternaliy, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well- known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will usually be from 1 microgram/kg to 25 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the formula (I) may contain from 0.05 mg to 1.0 g of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container or a nebuiiser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134A [trade mark] or 1 ,1 , 1 ,2,3,3,3- heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable -40-
gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioieate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff contains from 20μg to 20 mg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20μg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. The compounds of. the formula (I) may also be transdermally administered by the use of a skin patch. They may also be administered by the ocular route, particularly for -treating neurological disorders of the eye.
For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the -41-
following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the formula (I) can also be administered together with other neutrophic agents such as neurotrophic growth factor (NGF), glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and/or neurotrophin-3. The dosage level of the neurotrophic agent will depend upon the neurotrophic effectiveness of the combination and the route of administration used. It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. Thus the invention further provides:-
(i) a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier; (ii) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament; (iii) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of neuronal degeneration; (iv) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the promotion of neuronal regeneration and outgrowth; -42-
(v) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a neurological disease or disorder such as a neurodegenerative disease; (vi) use as in (v) where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar- brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), herniated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases; (vii) use as (vi) where the neurological disease or disorder is senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, Huntington's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system -43-
(e.g. spinal cord), a peripheral neuropathy (either diabetic or non- diabetic), multiple sclerosis or a hearing disorder such as tinnitus; (viii) a method of treatment of a human to treat neuronal degeneration which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; (ix) a method of treatment of a human to promote neuronal regeneration and outgrowth which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; (x) a method of treatment of a human to treat a neurological disease or disorder such as a neurodegenerative disease which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; (xi) a method as in (x) where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar- brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), hemiated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. -44-
multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases; (xii) a method as in (xi) where the neurological disease or disorder is senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, Huntington's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabetic or non- diabetic), multiple sclerosis or a hearing disorder such as tinnitus; and (xiii) any novel intermediates described herein.
The following Examples illustrate the preparation of the compounds of the formula (I). The ACD/IUPAC Pro software programme was used as the basis for naming the prepared compounds.
-45-
Example 1
1 H-Benzorcπimidazol-2-yl f(2S..-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl)-1 - piperidvNsulfone
HCI
Figure imgf000047_0001
Figure imgf000047_0002
Ethyldiisopropylamine (383μl) was added to a mixture of 5-benzyl-3-[(2S)-2- piperidyl]-1 ,2,4-oxadiazole hydrochloride (279.8mg) [see Preparation 7] and 1H-benzo[c(]imidazole-2-sulfonyl chloride (325mg) [see Preparation 8] in dichloromethane (5ml). The reaction mixture was stirred at room temperature for 18 hours after which time the mixture was diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluting with a solvent gradient of 0:100 changing to 20:80, by volume, ethyl acetate: hexane to give the product as a white solid. This solid was dissolved in dichloromethane and the solvent was removed under reduced pressue to give 1 H-benzo[c/]imidazol-2-yl [(2S)-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl)-1 -piperidyl] sulfone (245mg) as a white solid. 1H-NMR (CDCI3) δ: 10.80 (1 H, s), 7.80 (1 H, s), 7.40-7.10 (8H, m), 5.50 (1 H, m), 3.95 (1 H, d), 3.85 (2H, q), 3.20 (1 H, m), 2.25 (1 H, d), 2.05 (1 H, m), 1.80-1.50 (4H, m) ppm.
MS (mass spectrometry): 424 (MH+).
Analysis: Found C.58.07; H, 4.97; N, 15.81 ; C21H21N503S. 0.6 H20 requires C, 58.08; H, 5.15; N, 16.13%. -46-
25
Rotation: [α]D = -56.37° (c = 0.1 , methanol).
Examples 2 - 8
The compounds of the following tabulated Examples (Table 1 ) of the general formula :
N
~N
Figure imgf000048_0001
O Y
W R2 \\ /
were prepared by a similar method to that of Example 1 using the appropriate sulphonyl chloride and 5-benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride [see Preparation 7].
-47- Table 1
Example Starting Y-W-R2 Analytical data no. material prep.no.
2 V Η-NMR (CDCI3) δ : 7.40-7.2- (6H, m), 7.15 (1H,s), 5.40(1 H,
S=o m), 4.20 (2H, s), 3.90(1 H, d),
N— Λ 3.60 (3H,s), 3.45(1 H, m), 2.00 (2H, m), 1.60 (4H,m).
N Analysis : Found C, 55.61; H, 5.50; N, 17.87, C18H21N5O3S requires C, 55.80; H, 5.46; N, 18.07%.
3 11 1H-NMR (CDCI3) δ : 7.40-7.20
I J o (5H, m), 5.25(1 H,s), 4.20 (2H, s), 3.95(1 H,m), 3.80-3.60 (3H, m), 3.45 (1H, m), 3.20-3.00 (3H, m), 2.70 (1H,m), 2.25(1 H,m), 2.10 (1H, m), 1.95 (1H, m), 1.80- 1.40 (5H,m).
Analysis : Found C, 56.98; H, 6.39; N, 10.21; C19H25N3O4S 0.1 CH2CI2 requires C, 57.17; H, 6.33; N, 10.46%.
4 58 1H-NMR (CDCI3) δ : 7.40-7.20 (10H, m), 5.30(1 H,m), 5.15 (2H, s), 4.20 (2H, s), 3.80 (2H, m), 3.55 (1H,m), 3.35(1 H,m), 3.20-3.00 (4H, m), 2.70 (1H, m), 2.40 (1H,d), 2.00 (1H, m), 1.80- 1.50 (6H,m).
Analysis : Found C, 61.52; H, 6.11; N, 10.61; C27H32N4O5S requires C, 61.81; H, 6.15; N,
Figure imgf000049_0001
10.68%. -48-
62 Η-NMR (d6-DMSO) δ : 7.40- ^ 7.20 (10H, m), 5.15 (1H, m),
Figure imgf000050_0001
5.00 (2H,s), 4.30 (2H,s), 4.15 (1H,d), 4.05 (1H,m), 3.80 (1H, o ) m), 3.60 (1H,m), 3.00 (3H,m), 2.80 (1H,m), 2.60 (1H,m), 2.05
Figure imgf000050_0002
(1H,d), 1.80 (3H,m), 1.55 (3H, m), 1.40-1.10 (3H,m). Analysis : Found C, 62.11; H, 6.34; N, 10.27; C^NAS requires C, 62.43; H, 6.36; N, 10.40%.
65 MS : 390 (MH+).
Figure imgf000050_0003
Analysis : Found C, 61.40; H,
O 6.96; N, 10.76; C20H27N3O3S requires C, 61.67; H, 6.99; N,
10.79%.
Figure imgf000050_0004
[α]D = -41.93° (C = 0.1, methanol).
1H-NMR (CDCI3) δ : 7.40-7.20 (5H, m), 5.35(1 H, m), 4.25 (2H, s), 3.80 (1H,d), 3.20(1 H,m), 2.90 (2H, m), 2.25(1 H, d), 2.00 (3H, m), 1.80-1.40 (8H, m), 1.30- 1.10 (3H, m), 1.00 (2H, m).
Figure imgf000050_0005
Analysis : Found C, 62.47; H, 7.29; N, 10.33; C^H^NaOsS requires C, 62.50; H, 7.24; N, 10.41%
68 1H-NMR (CDCI3) δ : 7.40-7.20 (5H, m), 5.25(1 H,d), 4.20 (2H, m), 3.75(1 H.d), 3.20(1 H.t), 2.90 (2H, m), 2.25(1 H, d), 2.10 (1H, m), 2.00-1.80 (3H, m), 1.70- 1.40 (12H,m), 1.25 (2H,m).
Figure imgf000050_0006
Analysis : Found C, 62.97; H, 7.42; N, 9.99; C22H31N3O3S requires C, 63.28; H, 7.48; N, 10.06% -49-
Example 9
JV1 -Neopentyl-((2S -2-(5-benzyl-1.2.4-oxadiazol-3-yl))-1 ■ piperidinecarboxamide
.HCI
Figure imgf000051_0001
Figure imgf000051_0002
Triphosgene (45mg) in dichloromethane (2ml) was added dropwise to a solution of 5-benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride (140mg) [see Preparation 7] and triethylamine (139ml) in dichloromethane (2ml). The reaction mixture was stirred at room temperature for 1 hour. A solution of neopentylamine (78mg) and triethylamine (70μl) in dichloromethane was added to the mixture and stirred for 18 hours. The reaction mixture was then diluted with dichloromethane and water, the organic phase was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 83:17, by volume, hexane : ethyl acetate to afford Λ.1 -neopentyl-((2S)-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl))-1 - piperidinecarboxamide (66mg) as a clear oil.
1H-NMR (CDCI3) δ : 7.30 (5H, m), 5.50 (1 H, s), 4.80 (1 H, s), 4.20 (2H, s), 3.70 (1 H, d), 3.20-3.00 (3H, m), 2.25 (1H, d), 1.90 (1H, m), 1.70-1.40 (4H, m), 0.90 (9H, s).
25
Rotation : [α]D = -43.41° (c = 0.1 , methanol). -50-
Analysis : Found C, 66.95; H, 7.99; N, 15.18; C20H28N4O2.0.2 H2O requires C, 66.71 ; H, 7.95; N, 15.56%.
Example 10
2-r4-(3-K2S)-1 -d H-Benzof c |imidazol-2-ylsulfonyl)-2-piperidvn-1.2,4- oxadiazol-5-ylmethoxy)benzvn-1 ,3-isoindolinedione
.HCI
Figure imgf000052_0001
Figure imgf000052_0002
-51- The title compound was prepared by a similar method to Example 1 from 2-[4- (3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzyl]-1 ,3-isoindolinedione hydrochloride [see Preparation 15] and 1 -/-benzo[c(]imidazole-2-sulfonyl chloride [see Preparation 8] to afford 2-[4-(3-[(2S)-1-(1H-benzo[d]imidazol-2- ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzyl]-1 ,3-isoindolinedione (956mg).
1H-NMR (CDCI3) δ : 7.85 (2H, m), 7.75 (2H, m), 7.70 (2H, bs), 7.40 (2H, d), 7.30 (2H, d), 6.80 (2H, d), 5.60 (1 H, d), 4.80 (4H, 2xd), 4.00 (1 H, d), 3.20 (1 H, t), 2.30 (1 H, d), 2.10 (1 H, m), 1.80-1.40 (4H, m).
Analysis : Found C, 59.04; H, 4.60; N, 13.24; C30H26N6O6S.0.3EtOAc.0.5 H20 requires C, 59.10; H, 4.67; N, 13.25% (EtOAc = ethyl acetate).
25 [α]D = -46° (c = 0.1 , methanol).
Example 11
4-(3-r(2S)-1 -d H-Benzorcηimidazol-2-ylsulfonvn-2-piperidvπ-1 ,2,4- oxadiazol-5-ylmethoxy)benzylamine
Figure imgf000053_0001
Q-ζ NH.
Figure imgf000053_0003
Figure imgf000053_0002
-52-
2-[4-(3-[(2S)-1 -(1 H-benzo[cφmidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzyl]-1 ,3-isoindoiinedione (885mg) [see Example 10] was added to a solution of 33% w/w methylamine in ethanol (2.2ml). The reaction mixture was stirred at room temperature for 5 hours after which time the solvent was removed under reduced pressure. The resulting solid was dissolved in 1 N aqueous hydrochloric acid solution and dichloromethane. The aqueous layer was then separated and basified to pH 12 with 0.88 aqueous ammonia solution. The mixture was then extracted with ethyl acetate, the organic layer dried over magnesium sulphate and the solvent removed under reduced pressure to afford 4-(3-[(2S)-1 -(1 H-benzo[cφmidazoI-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)benzylamine (369mg) as a white solid.
1H-NMR (d6- DMSO) δ : 7.60 (2H, d), 7.35 (2H, d), 7.20 (2H, d), 7.00 (2H, d), 5.40 (1 H, s), 5.20 (2H, q), 3.90 (1 H, d), 3.80 (2H, s), 3.20 (3H, bs), 1.90 (1 H, d), 1.80 (1 H, m), 1.50 (2H, t), 1.30 (2H, m).
Analysis : Found C, 55.91 ; H, 5.10; N, 17.68; C22H24N6O4S. 0.1 H2O requires C, 56.18; H, 5.19; N, 17.87%.
25 [α]D = -54° (c = 0.1 , methanol).
-53-
Example 12
/V-r4-(3-r(2S)-1 -d H-Benzorc limidazol-2-ylsulfonvn-2-piperidvπ-1.2,4- oxadiazol-5-ylmethoxy)benzvπ-Λ/,/V-dimethylamine
N-O
N 'N
Figure imgf000055_0001
^NH2
O=S=O HN^N
CH .3
N" ^ N^CH
Figure imgf000055_0003
Formaldehyde (37% w/w aqueous solution) (65μl) was added to a solution of 4- (3-[(2S)-1 -(1 H-benzo[o]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzylamine (75mg) [see Example 11] in acetonitrile (2ml), followed by sodium triacetoxyborohydride (170mg). The reaction mixture was stirred at room temperature for 18 hours, after which time glacial acetic acid was added until the solution was at pH 7.0. The mixture was then diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent -54- 1H-NMR (CDCy δ : 7.70 (2H, m), 7.40 (2H, d), 7.25 (2H, d), 6.80 (2H, d), 5.60 (1 H, d), 4.90 (2H, q), 4.00 (1 H, d), 3.40 (2H, s), 3.20 (1 H, m), 2.40 (1 H, d), 2.20 (6H, s), 2.16 (1 H, m), 1.80 (1 H, m), 1.30 (1 H, m), 0.90 (2H, m). 25
Rotation : [α]D = - 48.41° (c = 0.1 , methanol).
Analysis : Found C, 58.15; H, 6.01 ; N, 16.02; C24H28N6O4S. 0.2 hexane. 0.5 H2O requires C, 58.07; H, 5.84; N, 16.12%.
-55-
Example 13
3-π -( 1 H-Benzorcnimidazol-2-ylsulfonyl)-2-piperidvn-5-r4-(1 ■ pyrrolidylmethyl phenoxy1methyl-1,2,4-oxadiazole
Figure imgf000057_0001
O= N^o
I O HN^N
Figure imgf000057_0002
H o
Figure imgf000057_0003
Pyrrolidine (19μl) was added to a solution of 4-(3-[1-(1/-/-benzo[c midazol-2- yisulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzaldehyde (85mg) [see Preparation 22] in tetrahydrofuran (10ml). Sodium triacetoxyborohydride (64mg) was added followed by glacial acetic acid (11.5μl). The reaction mixture was stirred under an atmosphere of nitrogen for 6 hours. Sodium triacetoxyborohydride (21 mg) was added and the mixture was stirred for 56 hours after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with -56- a solvent gradient of 97.5:2.5:0.25 changing to 95:5:0.5, by volume, dichloromethane : methanol : 0.88 aqueous ammonia solution to afford 3-[1- (1 H-benzo[c ]imidazol-2-ylsulfonyl)-2-piperidyl]-5-[4-(1 - pyrrolidylmethyl)phenoxy]methyl-1 ,2,4-oxadiazole (90mg) as a white solid.
1H-NMR (CDCIg) δ : 7.70 (2H, s), 7.40 (2H, m), 7.30 (2H, m), 6.80 (2H, m), 5.60 (1 H, d), 4.90 (2H, q), 4.00 (1 H, d), 3.60 (2H, s), 3.20 (1 H, m), 2.60 (4H, bs), 2.30 (1 H, d), 2.00-0.95 (8H, m). Analysis : Found C, 59.24; H, 5.94; N, 15.10; C26H30N6O4S. H2O. 0.3 hexane requires C, 59.20; H, 6.04; N, 14.90%.
-57-
Example 14
/V-r4-(3-M -f 1 H-Benzorcπimidazol-2-ylsulfonyl)-2-piperidvn-1.2,4-oxadiazol-
5-ylmethoxy)benzyπ-Λ/-methylamine
Figure imgf000059_0001
The title compound was prepared by a similar method to Example 13 from 4-(3- [1 -(1 H-benzo[c midazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzaldehyde [see Preparation 22] and methylamine hydrochloride to afford Λ/-[4-(3-[1-(1H-benzo[c/]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)benzyl]-/V-methylamine as a white solid. -58- 1H-NMR (CDCI3) δ : 7.70 (2H, bs), 7.40 (2H, m), 7.30 (2H, m), 6.80 (2H, m), 5.60 (1 H, d), 4.90 (2H, q), 4.00 (1 H, d), 3.75 (2H, s), 3.20 (1 H, m), 2.50 (3H, s), 2.40-2.00 (4H, m), 1.80 (2H, m). Analysis : Found C, 54.74; H, 5.50; N, 15.56; C23H26N604S. H2O. 0.2 CH2CI2. 0.2 hexane requires C, 54.97; H, 5.60; N, 15.76%.
Example 15 4-r3-(f2S)-1-rCvclohexylmethylsulfonvn-2-piperidyl)-1,2,4-oxadiazol-5- ylmethoxylbenzylamine
N-
Figure imgf000060_0001
•N N
O=S=O
Figure imgf000060_0002
y°
Q ~N' -T N3
O=S=O
Figure imgf000060_0003
°^c NH,
The title compound was prepared by a similar method to Example 11 from 2- [4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzyl]-1 ,3-isoindolinedione [see Preparation 23] and methylamine. The crude product was purified by column chromatography on silica gel eluting -59- with a solvent gradient of 100:0:0 changing to 90:10:1 , by volume, dichloromethane : methanol : 0.88 aqueous ammonia solution to afford 4-[3- ((2S)-1-[cyclohexylmethylsulfonyl]-2-piperidyl)-1 ,2,4-oxadiazol-5- ylmethoxy]benzyiamine as a colourless oil.
1H-NMR (CDCI3) δ : 7.30 (2H, d), 7.00 (2H, d), 5.40 (1 H, d), 5.30 (2H, s), 3.85 (2H, s), 3.80 (1 H, d), 3.20 (1 H, m), 2.90 (2H, m), 2.30 (1 H, d), 2.00-1.00 (18H, m). Accurate MS : 449.2216 (MH+).
Example 16 5-[(1-Benzyl-4-piperidyl)oxymethvn-3->(2S)-1 -cvclohexylmethylsulfonyl-2- piperidyl]-1 ,2,4-oxadiazole
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
Figure imgf000061_0004
N N -.
0 O=S: = O N
-O
Figure imgf000061_0005
Figure imgf000061_0006
-60- Th e compound of Preparation 29 (464mg) was dissolved in pyridine (5 ml) and heated under reflux for 18 hours. The reaction mixture was then cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated , dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:0.4:0.2 changing to 93:7:1 , by volume, dichloromethane : methanol : 0.88 aqueous ammonia solution to afford 5-[(1- benzyl-4-piperidyl)oxymethyl]-3-[(2S)-1-cyclohexylmethylsuIfonyl-2-piperidyl]- 1 ,2,4-oxadiazole (357mg) as a yellow oil.
1H-NMR (CDCI3) δ : 7.30 (5H, m), 5.30 (1 H, d), 4.80 (2H, s), 3.80 (1 H, d), 3.55 (1 H, m), 3.50 (2H, s), 3.20 (1 H, m), 2.90 (2H, m), 2.75 (2H, m), 2.20 (3H, m), 2.00 (6H, m), 1.70 (8H, m), 1.50-1.00 (6H, m).
Analysis : Found C, 62.53; H, 7.84; N, 10.82; C27H40N4O4S requires C, 62.76; H, 7.80; N, 10.84%.
Examples 17 - 22 The compounds of the following tabulated Examples (Table 2) of the general formula:
Figure imgf000062_0001
were prepared by a similar method to Example 16 from the corresponding hydroxyamidine derivatives and pyridine. -61- Table 2
Example Starting Analytical data no. material R1A prep.no.
17 31
C 3 O Η-NMR (CDCI3) δ : 7.40 (5H,
IH 3 0 m), 6.10 (1H, bs), 5.50 (1H,s),
CH3-^O^ ^ 5.35 (1H,s), 3.80(1 H, d), 3.20 CH3 H (1H, q), 2.90 (2H,m), 2.25(1 H, d), 2.00 (4H, m), 1.80-1.00 (21 H, m).
Analysis : Found C, 58.53; H, 7.33; N, 10.18; C26H38N4O5S.0.8 H2O requires C, 58.58; H, 7.48; N, 10.51%.
18 32 Η-NMR (CDCI3) δ : 5.35 (1H, d), 3.80 (2H, m), 3.75 (4H, m), 3.25 (1H, t), 2.90 (2H,m), 2.60 (4H, o t), 2.25 (1H,d), 2.00 (4H,m), 1.70 (6H,m), 1.40-1.00 (7H,m). Analysis : Found C, 54.67; H, 7.82; N, 13.23; C19H32N4O4S.0.1 CH2CI2 requires C, 54.49; H, 7.71; N, 13.31%.
19 36 ^cno 1H-NMR (CDCI3) δ : 7.30 (5H, m), 5.30 (1H,s), 3.90 (2H,m), 3.80 (1H,d), 3.45 (2H, s), 3.40 (1H, m), 3.20 (1H,m), 3.15 (2H, m), 2.95 (2H, m), 2.70 (2H, m), 2.25 (1H, d), 2.10 (2H, t), 2.00- 1.00(20H,m).
Analysis : Found C, 61.49; H, 7.82; N, 10.07; C28H42N4O4S. 0.75 H2O requires C, 61.79; H,
Figure imgf000063_0001
8.06; N, 10.29%. -62- Table 2 (continued)
69 Η-NMR (CDCI3) δ : 5.30 (1H, d), 3.80 (1H,d), 3.20(1 H, t), 3.05
I (2H, t), 2.90 (2H, m), 2.80 (2H, t), 2.25 (6H, s), 2.20(1 H, s), 2.00-1.85 (4H,m), 1.70 (6H,m), 1.50 (1H,m), 1.30-1.00 (5H,m). Analysis : Found C, 56.13; H, 8.44; N, 14.44; C18H32N4O3S requires C, 56.22; H, 8.39; N, 14.57%.
Rotation : [α]D = -25.81° (c = 0.1, methanol).
70 H 1H-NMR(CDCI3)δ:8.70(1H, s),
5.40 (1H,d), 3.80(1 H, d), 3.25
(1H,t), 2.95 (2H,m), 2.30(1 H, d), 2.00 (4H, m), 1.80-1.60 (6H, m), 1.50(11-1, m), 1.35-1.05 (5H, m).
Analysis : Found C, 53.61; H,
7.43; N, 13.09; C14H23N3O3S requires C, 53.65; H, 7.40; N,
13.41%.
Rotation : [α]D = -27.60° (c = 0.1 , methanol).
71 CH3 1H-NMR(CDCI3)δ:5.30(1H,d),
3.80 (1H,d), 3.25(1 H, t), 2.95
(2H, m), 2.60 (3H,s), 2.25(1 H, d), 2.00 (4H, m), 1.80-1.60 (6H, m), 1.50 (1H,m), 1.40-1.05 (5H, m).
Analysis : Found C, 55.19; H,
7.80; N, 12.40; C15H25N3O3S.
O.IEtOAc requires C, 55.01; H,
7.73; N, 12.50%.
Rotation : [α]D = -26.70° (c = 0.1,
Figure imgf000064_0001
methanol). -63-
Example 23
3-f(2S)-1-Cyclohexylmethylsulfonyl-2-piperidyl]-5-f4-piperidyloxymethvn-
1,2,4-oxadiazole
Figure imgf000065_0001
o
0= =S=O N
Figure imgf000065_0002
Figure imgf000065_0003
Figure imgf000065_0004
0=S=O N=
-O
Figure imgf000065_0005
Figure imgf000065_0006
α-Chloroethyl chloroformate (95μl) was added to a solution of 5-[(1-benzyl-4- o piperidyl)oxymethyl]-3-[(2S)-1 -cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4- oxadiazole (325mg) [see Example 16] in dichloromethane (20ml) at 0°C . The reaction mixture was stirred for 1.5 hours after which time the dichloromethane was removed under reduced pressure and the residue dissolved in methanol. The mixture was then heated under reflux for 2 hours, the solvent removed 5 under reduced pressure and the residue partitioned between diethyl ether and 2N aqueous hydrochloric acid solution. The aqueous layer was washed twice -64-
with diethyl ether and then neutralised (pH7) with sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 3-[(2S)-1- cyclohexylmethylsulfonyl-2-piperidyl]-5-[4-piperidyloxymethyl]-1 ,2,4-oxadiazole (170mg) as a brown oil.
1H-NMR (CDCI3) δ : 5.30 (1 H, d), 4.80 (2H, s), 3.80 (1 H, d), 3.60 (1 H, m), 3.25 (1 H, m), 3.15 (2H, m), 2.90 (2H, m), 2.75 (2H, m), 2.30 (1 H, d), 2.00 (6H, m), 1.80-1.00 (15H, m).
Analysis : Found C, 54.69; H, 8.06; N, 12.71 ; C^H^N^S.O^ CH2CI2 requires C, 54.70; H, 7.82; N, 12.63%.
-65-
Example 24 (3-r(2S -1-Cvclohexylmethylsulfonyl-2-piperidvn-1.2,4-oxadiazol-5- yl)(phenyl)methylamine
Figure imgf000067_0001
*N'
O=S=O N \
Figure imgf000067_0003
H
Figure imgf000067_0002
}~O CH,
0 YCH.. CH/
Figure imgf000067_0004
The title compound was prepared by the method of Preparation 7 from tert- o butyl Λ/-[(3-[(2S)-1 -cyclohexylmethylsulfonyi-2-piperidyl]-1 ,2,4-oxadiazol-5- yl)(phenyl)methyl]carbamate [see Example 17]. The crude product was purified by high pressure liquid chromatography eluting with 30:70:0.1 , by volume, acetonitrile : water : trifluoroacetic acid to afford (3-[(2S)-1 - cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4-oxadiazol-5-yl)(phenyl)methylamine 5 as a colourless oil. -66- H-NMR (d4-CH3OH) δ : 7.50-7.30 (5H, m), 5.45 (1 H, s), 5.25 (1 H, s), 3.75 (1 H, d), 3.30 (1 H, m), 2.90 (2H, d), 2.25 (1 H, d), 2.00-1.00 (18H, m). Accurate MS : 419.2123 (MH+).
Example 25
r5-(3-f2S -1-r(Cvclohexylmethvnsulfonvπ-2-piρeridyl-1.2.4-oxadiazol-5-yl)-
2-furyl]methylamine
Figure imgf000068_0002
Figure imgf000068_0001
The title compound was prepared by a similar method to Example 11 from 2-[5- (3-(2S)-1 -[(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)-2- furyi]methyl-1 ,3-isoindolinedione [see Preparation 100] and methylamine. The crude product was purified by column chromatography on silica gel eluting with 95 : 5 : 0.5, by volume, dichloromethane : methanol : 0.88 ammonia to afford [5-(3-(2S)-1-[(cyclohexyimethyl)sulfonyl]-2-piperidyl-1,2,4-oxadiazol-5-yl)-2- furyl]methylamine as a solid. -67- 1H-NMR (d4-MeOH) δ : 7.40 (1 H, d), 6.60 (1 H, d), 5.30 (1 H, d), 3.90 (2H, s), 3.80 (1 H, d), 3.30 (1 H, m), 3.05 (2H, m), 2.30 (1 H, d), 2.00-1.90 (4H, m), 1.80- 1.60 (7H, m), 1.40-1.00 (5H, m). Accurate MS : Found 409.1928 (MH+). C19H28N404S requires 409.1910 (MH+).
Example 26
Benzyl /V-(2-(3-π -d H-benzorcπimidazol-2-ylsulfonyl)-2-piperidyl 1-1 ,2,4-
oxadiazol-5-yl)ethyl)carbamate
Figure imgf000069_0001
H
0=S=O NH
Figure imgf000069_0002
,0
Ύ
Figure imgf000069_0003
HIN N o
Figure imgf000069_0005
Figure imgf000069_0004
The title compound was prepared by a similar method to Example 16 from the compound of Preparation 37 and pyridine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 -changing to 60:40, by volume, hexane : ethyl acetate to afford benzyl Λ.-(2-(3- [1 -(1 H-benzo[c(jimidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- yl)ethyl)carbamate as a colourless oil.
1H-NMR (d6-DMSO) δ : 13.60 (1 H, bs), 7.80 (1 H, bs), 7.60 (1 H, bs), 7.30 (7H, m), 5.40 (1 H, d), 5.00 (2H, s), 3.90 (2H, d), 3.40 (1 H, d), 3.20 (2H, t), 2.75 (2H, m), 2.00 (1 H, d), 1.80 (1 H, m), 1.60 (1 H, d), 1.50-1.20 (2H, m). Analysis : Found C, 55.48; H, 5.22; N, 15.57; C24H26N605S. O.I EtOAc. 0.5 H2O requires C, 55.46; H, 5.30; N, 15.90%. (EtOAc = ethyl acetate). -68-
Example 27
2-(3-π -d H-Benzorcπimidazol-2-ylsulfonvn-2-piperidvn-1 ,2,4-oxadiazol-5- vOethylamine
Figure imgf000070_0002
Figure imgf000070_0001
,NN A
N Nk
0=S=0 N H O
0=S=0 N^ NH
X Nγ0
Figure imgf000070_0003
2
HN" N O HN^N
Figure imgf000070_0004
Figure imgf000070_0005
Benzyl Λ/-(2-(3-[1-(1 H-benzo[d]imidazoI-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-yl)ethyl)carbamate (1.88g) [see Example 26] was dissolved in 45% w/w hydrogen bromide in glacial acetic acid (30ml). The reaction mixture was stirred at room temperature for 3.5 hours after which time the mixture was diluted with water and washed with diethyl ether. The aqueous layer was then basified with potassium carbonate and then extracted with ethyl acetate. The organic layer was dried over magnesium sulphate, and the solution was left to stand for 18 hours after which time a solid had formed. This was filtered off to afford 2-(3-[1-(1 H-benzo[c midazoI-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- yl)ethylamine (0.71 g) as a white solid.
1H-NMR (CDCI3) δ : 11.50 (1 H, s), 7.80 (4H, d), 5.60 (1 H, s), 4.00 (1 H, d), 3.80 (2H, d), 3.45 (3H, m), 3.30 (1 H, m), 2.60 (1 H, d), 2.20 (1 H, m), 1.90-1.60 (3H, m), 1.40 (1 H, m).
Analysis : Found C, 48.93; H, 5.25; N, 21.09; C16H20N6SO3. 0.9 H2O requires C, 48.94; H, 5.60; N, 21.40%. -69-
Example 28
Λ/-(2-(3-M -d H-Benzorcπimidazol-2-ylsulfonvn-2-piperidvn-1.2.4-oxadiazol-
5-yl)ethvPbenzylamine
N,
Figure imgf000071_0001
H °NX ^ N°
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000071_0004
The title compound was prepared by a similar method to Example 13 from 2-(3- [1 -(1 H-benzo[αf]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- y[)ethylamine [see Example 27] and benzaldehyde. The cmde product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:1 changing to 98:2, by volume, dichloromethane : methanol to afford Λ/-(2- (3-[1 -(1 H-benzo[c0imidazol-2-ylsulfonyI)-2-piperidyl]-1 ,2,4-oxadiazol-5-yl)ethyl)- benzylamine.
1H-NMR (d4-CH3OH) δ : 7.60 (2H, d), 7.40-7.20 (7H, m), 5.45 (1 H, d), 4.10 (1 H, d), 3.60 (2H, s), 3.40 (1 H, t), 2.60 (4H, m), 2.10 (1 H, d), 2.00 (1H, m), 1.70 (1H, m), 1.50 (3H, m).
Analysis : Found C, 57.42; H, 5.61 ; N, 17.43; C23H26N6O3S.0.8 H2O requires C, 57.44; H, 5.78; N, 17.47%. -70-
Example 29
2-r(2S)-1-r(4-Fluorophenvnsulfonvn-2-ρiperidvn-5-methyl-1.3,4-thiadiazole
O
Figure imgf000072_0001
u
N CH,
0=S=O O H
Figure imgf000072_0002
Figure imgf000072_0003
Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane- 2,4-disulphide] (271 mg) was added to a solution of /V2-acetyl-(2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarbohydrazide (192mg) [see Preparation 39] in toluene (10ml). The reaction mixture was heated under reflux for 3 hours and the cooled mixture was then purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70 (in 10% increments), by volume, hexane : ethyl acetate, to afford 2-[(2S)-1-[(4-fluorophenyl)sulfonyl]- 2-piperidyl]-5-methyl-1 ,3,4-thiadiazole (106mg) as a clear oil.
1H-NMR (CDCI3) δ : 7.85 (2H, m), 7.20 (2H, m), 5.60 (1 H, s), 3.90 (1 H, d), 3.20 (1 H, t), 2.80 (3H, s), 2.40 (1 H, d), 1.80-1.40 (5H, m).
Analysis : Found C, 48.07; H, 4.63; N, 11.60; C14H16N3O2S.0.5 H2O requires C, 47.98; H, 4.89; N, 11.99%.
25
Rotation : [α]D= -64.01°. (c = 0.1 , methanol). -71-
Example 30
(2S)-2-d -Benzyl-1 H-1.2.4-triazol-3-yl)-1 -K4- fluorophenyl)sulfonvnpiperidine
Figure imgf000073_0002
0=S=0 N=/
Figure imgf000073_0004
Figure imgf000073_0001
Figure imgf000073_0003
Benzyl bromide (40μl) was added to a solution of (2S)-1-[(4- fluorophenyl)sulfonyl]-2-(1/- -1 ,2,4-triazol-3-yl)piperidine (95mg) [see Preparation 42] and potassium carbonate (47 mg) in dimethylformamide (5ml). The reaction mixture was stirred at 50°C for 7 hours, after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic solution was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 100:0 changing to 50:50, by volume, hexane : ethyi acetate (in 10% increments), to afford (2S)-2-(1-benzyl-1H-1 ,2,4-triazol-3-yl)-1-[(4-fIuorophenyl) sulfonyl]piperidine (35mg) as a white solid.
1H-NMR (CDCi3) δ : 7.70 (1 H, s), 7.60 (2H, t), 7.40 (2H, d), 7.20 (3H, m), 6.80 (2H, t), 5.40 (1 H, s), 5.10 (2H, s), 3.80 (1 H, d), 3.40 (1 H, t), 2.05 (1 H, m), 1.90 (1H, m), 1.70-1.50 (4H, m).
Analysis : Found C, 59.42; H, 5.25; N, 13.66; C20H21N4O2S.0.05 CH2CI2 requires C, 59.50; H, 5.25; N, 13.84%. -72-
Example 31
(2S)-2-(5-Benzyl-4-methyl-4H-1 ,2,4-triazol-3-ylH -f(4- fluorophenvOsulfonyπpiperidine
ζ \
O=S=O S CH,
Figure imgf000074_0001
Figure imgf000074_0002
Phenylacetic hydrazide (180mg) was added to a solution of Λ/2-methyl-(2S)-1- [(4-fluorophenyl)sulfonyl]-2-piperidinecarbothioamide (270mg) [see Preparation 44] and mercuric oxide (202mg) in 1 ,4-dioxane (10ml). The reaction mixture was heated under reflux and stirred for 18 hours. The dioxane was then removed under reduced pressure and dimethylacetamide (10ml) added followed by phenylacetic hydrazide (180mg) and mercuric oxide (202mg). The reaction mixture was heated to 140°C and stirred for 18 hours. After this time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with 1 N aqueous hydrochloric acid solution, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100, by volume, hexane:ethyl acetate (in 10% increments). The product was further purified on a MCI (trade mark) reverse phase gel column eluting with a solvent gradient of 50:50 changing to 0:100 (in 5% increments), by volume, water : methanol. This gave (2S)-2-(5-benzyl-4- methyl-4/-/-1 ,2,4-triazol-3-yl)-1-[(4-fluorophenyl)sulfonyl]piperidine (57mg) as a yellow solid. -73-
1H-NMR (CDCI3) δ : 7.60 (2H, d), 7.30 (2H, m), 7.25 (1 H, m), 7.20 (2H, d). 7.10 (2H, t), 5.10 (1 H, s), 4.10 (2H, s), 3.60 (1 H, d), 3.50 (3H, s), 3.40 (1 H, t), 2.25 (1 H, m), 2.00 (1 H, d), 1.75 (1 H, m), 1.50 (2H, m), 1.25 (1 H, m).
25
Rotation : [α]D = 0.21 ° (c = 0.1 , methanol).
Analysis : Found C, 60.44; H, 5.56; N, 13.33; C21H23FN4O2S requires C, 60.85; H, 5.59; N, 13.52%.
Example 32 2-Amino-5-r(2S)-1-r(4-fluorophenyl)sulfonvn-2-piperidvn-1 ,3,4-oxadiazole
H S
Figure imgf000075_0001
,N>
I 'N^NΛ 'rNH.
0=S=O O H N
O=S=0 0-<7
NH.
Figure imgf000075_0002
Figure imgf000075_0003
Mercuric oxide (204mg) was added to a solution of 2-((2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidylcarbonyl)-1-hydrazinecarbothioamide (170mg) [see Preparation 45] in 1 ,4-dioxane (5ml). The reaction mixture was heated under reflux and stirred for 4 hours. The resulting suspension was filtered through a plug of ARBOCEL (trade mark) filter aid, washing with dichloromethane:methanol (90:10, by volume). The filtrate was evaporated under reduced pressure and purified by column chromatography on silica gel eluting with 100:0 changing to 90:10 (in 5% increments), by volume, -74- dichloromethane:methanol. The product was further purified by column chromatography on silica gel eluting with 0:100 changing to 60:40, by volume, ethyl acetate:hexane, to afford 2-amino-5-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidyl]-1 ,3,4-oxadiazole (64mg) as a white solid.
Η-NMR (CDCI3) δ : 7.80 (2H, m), 7.10 (2H, m), 5.30 (1 H, s), 5.00 (2H, s), 3.80 (1 H, d), 3.10 (1 H, t), 2.10 (1 H, d), 1.90-1.60 (5H, m).
25 Rotation : [α]D = -39.21 ° (c = 0.1 , methanol).
Analysis : Found C, 47.49; H, 4.59; N, 16.79; C13H15FN4O3S.0.2 H2O requires C, 47.32; H, 4.70; N, 16.98%.
Example 33
2-Benzylamino-5-r(2S)-1-r(4-fluorophenvnsulfonvn-2-piperidvn-1.3,4- oxadiazole
Figure imgf000076_0001
T N
O=S :O O
~<
NH.
Figure imgf000076_0002
Figure imgf000076_0003
Benzaldehyde (101μl) was added to a solution of 2-amino-5-[(2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidyl]-1 ,3,4-oxadiazole (163mg) [see Example 32] in tetrahydrofuran (2ml), followed by acetic acid (172μl) and sodium triacetoxyborohydride (297mg). The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and -75- saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 40:60 (in 10% increments), by volume, ethyl acetate:hexane, to afford 2-benzylamino-5-[(2S)- 1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-1 ,3,4-oxadiazole (6mg) as a white solid.
1H-NMR (CDCI3) δ : 7.80 (2H, m), 7.35 (5H, m), 7.05 (2H, t), 5.25 (1 H, s), 5.00 (1 H, s), 4.40 (2H, s), 3.70 (1 H, d), 3.10 (1 H, t), 2.05 (1 H, t), 1.80 (1 H, m), 1.50- 1.35 (4H, m). MS : 417(MH+).
Example 34 5-r(2SM-r(4-Fluorophenyl)sulfonvπ-2-piperidvπ-3-methylisoxazole
Figure imgf000077_0002
Figure imgf000077_0001
Figure imgf000077_0003
Mesyl chloride (57μl) was added to a solution of the compound of Preparation 47 (211 mg) and triethylamine (111μl) in dichloromethane (4ml) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. After this time the mixture was purified by column chromatography on silica gel eluting with a -76- solvent gradient of 0:100 changing to 10:90 (in 5% increments), by volume, ethyl acetate:hexane. The product was further purified by column chromatography on silica gel as above to afford 5-[(2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidyl]-3-methylisoxazole (26mg) as a clear oil.
1H-NMR (CDCI3) δ : 7.80 (2H, t), 7.10 (2H, t), 5.80 (1H, s), 5.30 (1 H, d), 3.75 (1 H, d), 3.05 (1 H, t), 2.20 (3H, s), 2.10 (1 H, d), 1.80 (1 H, m), 1.60 (2H, m), 1.40 (2H, m).
25
Rotation : [α]D = - 49.61° (c = 0.1 , methanol).
MS : 325 (MH+).
Example 35 5-Benzyl-3-rf2S)-1-r(4-fluorophenvπsulfonvπ-2-pyrrolidvn-1.2.4-oxadiazole
Figure imgf000078_0001
Figure imgf000078_0004
0=S=0 0=S=O =( /==
Figure imgf000078_0003
Figure imgf000078_0002
Figure imgf000078_0005
The title compound was prepared by a similar method to Preparation 6 from the compound of Preparation 53 and xylene. The cmde product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70, by volume, ethyl acetate : hexane. This gave 5-benzyl-3- [(2S)-1-[(4-fluorophenyl)sulfonyI]-2-pyrrolidyl]-1 ,2,4-oxadiazole as a colourless oil. -77- 1H-NMR (CDCI3) δ : 7.80 (2H, t), 7.40 (5H, m), 7.05 (2H, t), 5.00 (1 H, d), 4.15 (2H, s), 3.50 (2H, m), 2.20 (3H, m), 1.90 (1H, m).
25 Rotation : [α]D = -100.22° (c = 0.1 , methanol).
Analysis : Found C, 58.24; H, 4.65; N, 10.64; C19H18N3FO3S.0.05 CH2CI2 requires C, 58.42; H, 4.66; N, 10.73%.
Example 36 to 39
The compounds of the following tabulated Examples (Table 3) of the general formula:
N
Figure imgf000079_0001
O
O=S_=O N=
1A
Figure imgf000079_0002
R
Figure imgf000079_0003
were prepared by a similar method to Preparation 6, either from the corresponding hydroxyamidine derivative and xylene (Examples 36,38) or from the corresponding hydroxyamidine derivative and pyridine (Examples 37,39). -78-
Table 3
Example Starting R 1A Analytical data No. material prep. No.
36 74 1H-NMR (CDCI3) δ : 7.70 (2H, m), 7.40-7.20 (5H, m), 6.90 (2H, t), 5,40 (1H, d), 4.10 (2H, s), 3.80 (1H, d), 3.30 (1H, t), 2.00 (2H, m), 1.80- 1.60 (4H,m).
Analysis : Found C, 59.72; H, 4.83; N, 10.34; C20H20N3O3SF requires C, 59.84; H, 5.02; N, 10.47%.
37 75 H-NMR (CDCI3) δ : 7.70 (2H, m), 7.30 (2H, d), 7.00 (2H, t), 6.95 (2H, d), 5.40 (1H,d), 5.15 (2H,s), 4.60
Figure imgf000080_0001
(2H, d), 3.80 (1H,d), 3.25(1 H, t), 2.10 (1H,m), 2.00(1 H, m), 1.70- 1.40 (4H,m).
Analysis : Found C, 55.22; H, 4.88; N, 8.98; C^H^NASF.O.δ H2O requires C, 55.25; H, 5.08; N, 9.20%.
38 76 1H-NMR (CDCI3) δ : 8.00 (2H, d), 7.75 (2H, m), 7.55(1 H, m), 7.50
Figure imgf000080_0002
(2H, m), 7.00 (2H, m), 5.45 (1H, d), 3.80 (1 H, d), 3.40(1 H, t), 2.20(1 H, d), 2.00 (1H, m), 1.80-1.50 (4H, m). Analysis : Found C, 58.87; H, 4.60; N, 10.72; C19H18N3O3SF requires C, 58.90; H, 4.68; N, 10.85%. Rotation : [α]D = -33.21° (c = 0.1 , methanol).
39 97 1H-NMR(CDCI3)δ:9.25(1H,s), 8.80 (2H, m), 7.80 (2H, m), 7.00 (2H, m), 5.50 (1H,d), 3.85(1 H,d),
Figure imgf000080_0003
3.40 (1H, t), 2.20 (1H, d), 2.00 (1H, m), 1.80-1.40 (4H,m). Analysis : Found C, 52.50; H, 4.09; N, 17.85; C17H16N5O3SF requires C, 52.44; H, 4.14; N, 17.98%. Rotation : [α]D = -55.61° (c = 0.1 , methanol). -79-
Example 40 2-(1S)-2-f(4-Fluoropheny0sulfonyl1cvclohexyl-5-methyl-1.3.4-oxadiazole
O
H
N. N
N' *N
H
Figure imgf000081_0003
N
O=S=O O O=S=O
Figure imgf000081_0001
Figure imgf000081_0004
Figure imgf000081_0002
Figure imgf000081_0005
Iodine (239mg) was added to a stirred solution of triphenylphosphine (247mg) in dichloromethane (6ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 10mins, then triethylamine (0.269ml) was added followed by ΛT2-acetyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidinecarbohydrazide (160mg) [see Preparation 39] in dichloromethane (2ml). The reaction mixture was stirred for 18hrs, after which time the solvent was removed under reduced pressure. The cmde product was pre-absorbed onto silica gel and purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70, by volume, ethyl acetate : hexane, to afford 2-(1 S)-2-[(4-fluorophenyl)sulfonyl]cyclohexyl-5-methyl-1 ,3,4- oxadiazole (87mg) as an oil. -80-
1H-NMR (CDCy δ : 7.80 (2H, m), 7.20 (2H, m), 5.40 (1 H, m), 3.80 (1 H, d), 3.20 (1 H, t), 2.40 (3H, s), 2.15 (1 H, d), 2.00 (1 H, m), 1.80-1.50 (4H, m). Analysis : Found C, 51.52; H, 4.97; N, 12.57; C14H16N3O3SF requires C, 51.68; H, 4.96; N, 12.91 %.
25
Rotation : [α]D = -71.41° (c = 0.1 , methanol).
Examples 41 and 42
The compounds of the following tabulated Examples (Table 4) of the general formula :
N N N
O=S=O ό— ^
R 1A
Figure imgf000082_0001
Figure imgf000082_0002
were prepared by a similar method to Example 40 from the corresponding hydrazide, iodine, triphenylphosphine and triethylamine. -81-
Table 4
Example Starting R1A Analytical data No. material prep. No.
41 77 H-NMR (CDCI3) δ : 7.75 (2H, m),
7.45-7.20 (5H, m), 7.00 (2H, t), k^ 5.40 (1H, d), 4.10 (2H, d), 3.80 (1H, d), 3.20 (1H, t), 2.20-1.90 (2H, m),
1.80-1.50 (4H,m),
Analysis : Found C, 58.43; H, 4.98;
N, 10.06;C20H20N3O3SF.0.15
CH2CI2 requires C, 58.43; H, 4.94;
N, 10.14%.
Rotation : [α]D = -42.01° (c = 0.1, methanol).
42 78 1H-NMR (CDCI3) δ : 7.75 (2H, m),
7.30-7.10 (7H,m), 5.40(1 H,s),
3.80 (1H,d), 3.20-3.00 (5H,m),
2.10 (1H,d), 2.00 (1H,m), 1.70-
1.50 (4H,m).
Analysis : Found C, 58.40; H, 5.18;
N, 9.57;
C21H22N3O3SF.0.1 CH2CI2.0.5H2O requires C, 58.53; H, 5.40; N,
9.70%.
Rotation : [α]D = -49.41° (c = 0.1,
Figure imgf000083_0001
methanol).
-82-
Examples 43 and 44
The compounds of the following tabulated Examples (Table 5) of the general formula:
N.
Figure imgf000084_0001
N O=S=O N- ■N
1A
Figure imgf000084_0002
R
Figure imgf000084_0003
were prepared by a similar method to Example 30. Example 43 was prepared from (2S)-1-[(4-Fluorophenyl)sulfonyl]-2-(2tf-1 ,2,3,4-tetraazol-5-yl)piperidine [see Preparation 79] and benzyl bromide. Example 44 was prepared from (2S)- 1 -[(4-Fluorophenyl)sulfonyl]-2-(2H-1 ,2,3,4-tetraazol-5-yl)piperidine [see Preparation 79] and methyl iodide.
Purification of both Examples was achieved by chromatography on silica, eluting with 100:0, changing to 75:25, by volume, ethyl acetate:hexane, with desired product isolated as the less polar regioisomer -83-
Table 5
Example Starting RiA Analytical data No. material prep. No.
43 79 1H-NMR (CDCI3) δ : 7.60 (2H, m), 7.40- fT^l 7.30 (5H, m), 6.80 (2H, t), 5.60 (3H, m),
3.85 (1 H, d), 3.35 (1 H, t), 2.05 (2H, m),
1.80-1.60 (4H, m).
Analysis : Found C, 56.64; H, 4.98; N,
17.34; C19H20N5O2SF requires C, 56.84;
H, 5.02; N, 17.44%.
Rotation : [α]D = -37.3° (c = 0.1 , methanol).
44 79 CH3 1H-NMR (CDCI3) δ : 7.70 (2H, m), 7.05
(2H, t), 5.60 (1 H, s), 4.20 (3H, s), 3.85
(1 H, d), 3.35 (1 H, t), 2.05 (2H, m), 1.80-
1.60 (4H, m).
Analysis : Found C, 47.69; H, 4.89; N,
21.27; C13H16N5O2SF requires C, 47.99;
H, 4.96; N, 21.52%.
Rotation : [α]D = -54.34° (c = 0.1 ,
Figure imgf000085_0001
methanol).
-84-
Example 45 (2S)-1 -r(4-Fluorophenyl)sulfonvn-2-(5-methyl-4 -1,2,4-triazol-3- yOpiperidine
N
^N
,N
O=S=O O^ O=S=O
H
\'
Figure imgf000086_0001
Figure imgf000086_0003
Figure imgf000086_0002
Figure imgf000086_0004
Acetyl chloride (91 ml) was added to a stirred solution of ethyl (2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarboximidate (288mg) [see Preparation 41] and triethylamine (178ml) in toluene (5ml). The reaction mixture was stirred at room temperature for 1 hr after which time hydrazine hydrate (62ml) was added.
The mixture was stirred for 18hrs and then poured into a column containing silica gel, and the product eluted with a solvent gradient of 1 :1 , by volume, ethyl acetate : hexane followed by 95:5 ethyl acetate : methanol. The fractions containing the product were combined and the solvent removed under reduced pressure, the remaining residue was dissolved in toluene (10ml) and the reaction mixture was heated to reflux for 1 hr. Tosic acid (5mg) was then added and the mixture was heated to reflux for a further 18hrs. The cooled reaction -85-
mixture was then purified by column chromatography on silica gel eluting with a
solvent gradient of 1 :1 , changing to 0:100, by volume, hexane : ethyl acetate, in 10% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-4H- 1 ,2,4-triazol-3-yl)piperidine (60mg) as a white solid.
1H-NMR (CDCI3) δ : 7.80 (2H, m), 7.15 (2H, t), 5.30 (1 H, s), 3.80 (1 H, d), 3.30 (1 H, bs), 2.40 (3H, s), 2.30 (1 H, d), 1.80 (1 H, bs), 1.50 (3H, m), 1.45 (1 H, m). Analysis : Found C, 51.53; H, 5.25; N, 17.15; C14H17N4O2SF requires C, 51.84; H, 5.28; N, 17.27%.
25
Rotation : [α]D = -136.76° (c = 1.0, methanol).
Example 46
(2S)-1-r(4-fluorophenvnsulfonvn-2-(5-methyl-1,3-thiazol-2-vnpiperidine
H
N*.
N O I
Figure imgf000087_0001
O=S=O O
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000087_0004
-86-
Th e title compound was prepared by a similar method to Example 29 from (2S)-1 -[(4-fluorophenyl)sulfonyl]-/V2-(2-oxopropyl)-2- piperidinecarboxamide [see Preparation 81] and Lawesson's reagent. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane : ethyl acetate, in 5% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5- methyl-1 ,3-thiazol-2-yl)piperidine as a white solid.
Η-NMR (CDCI3) δ : 7.85 (2H, m), 7.25 (1 H, s), 7.20 (2H, t), 5.40 (1 H, d), 3.90 (1 H, d), 3.25 (1 H, t), 2.45 (3H, s), 2.40 (1 H, d), 1.80 (1 H, m), 1.60 (3H, m), 1.40 (1 H, m).
Analysis : Found C, 52.78; H, 5.03; N, 8.12; C15H17N2O2S2F requires C, 52.92; H, 5.03; N, 8.23%.
Rotation : [α]D = -47.32° (c = 0.1 , methanol).
-87-
Example 47
(2S)-1-r(4-Fluorophenvnsulfonvn-2-(,3-methyl-1,2,4-oxadiazol-5- yl)piperidine
NHL
O
N N
I
Figure imgf000089_0003
If N
O=S=O O o=s=o N-y
Figure imgf000089_0001
Figure imgf000089_0004
Figure imgf000089_0002
Figure imgf000089_0005
The title compound was prepared by a similar method to Preparation 6 from Λ/11- [((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide [see Preparation 82] and xylene. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 80:20, by volume, hexane : ethyl acetate in 10% increments, to afford (2S)-1- [(4-fluorophenyl)sulfonyl]-2-(3-methyl-1 ,2,4-oxadiazol-5-yl)piperidine as an oil.
Η-NMR (CDCI3) δ : 7.75 (2H, m), 7.10 (2H, t), 5.50 (1 H, d), 3.85 (1 H, d), 3.30 (1 H, t), 2.25 (3H, s), 2.05 (2H, m), 1.80-1.60 (3H, m), 1.50 (1 H, m). Analysis : Found C, 51.30; H, 4.89; N, 12.38; C14H16N3O3SF.0.25H2O requires C, 50.98; H, 5.04; N, 12.74%.
25 Rotation : [α]D = -71.01° (c = 0.1 , methanol). -88-
Example 48 Λ/2-Cvclohexyl-5-(2S)-1-r(4-fluorophenvnsulfonvn-2-piperidyl-1 ,3,4- oxadiazol-2 -amine
N N
*N' N N
Figure imgf000090_0004
N
O=S=O ό^ O=S=O O--^
Figure imgf000090_0001
N
Figure imgf000090_0005
N H
Figure imgf000090_0003
Figure imgf000090_0006
Figure imgf000090_0002
Figure imgf000090_0007
F
Sodium borohydride (71 mg) was added to a stirred solution of //2- cyclohexyliden-5-(2S)-1-[(4-fluorophenyl)sulfonyI]-2-piperidyl-1 ,3,4-oxadiazoI-2- amine [see Preparation 83] in ethanol (15ml) and methanol (5ml). The reaction mixture was stirred for 3hrs after which time further sodium borohydride (30mg) was added to the mixture. The mixture was stirred for a further 18hrs and then the solvent was removed under reduced pressure, the residue was partitioned between dichloromethane and 1 N aqueous hydrochloric acid. The aqueous layer was separated and basified to pH 8 with 0.88 aqueous ammonia, the product was re-extracted with dichloromethane, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 50:50, by volume, hexane : ethyl acetate, -89- in 5% increments, to afford /V2-cyclohexyl-5-(2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidyl-1 ,3,4-oxadiazol-2-amine (59mg) as a white gum.
-NMR (CDCI3) δ : 7.75 (2H, m), 7.10 (2H, t), 5.25 (1 H, d), 4.30 (1 H, d), 3.75
(1 H, d), 3.40 (1 H, m), 3.10 (1 H, t), 2.00 (3H, m), 1.85 (1 H, m), 1.70-1.60 (5H, m), 1.40 (2H, m), 1.25 (4H, m), 0.95 (1 H, m).
Analysis : Found C, 55.28; H, 6.35; N, 12.22; C19H25N403SF 0.3 hexane. H20 requires C, 55.52; H, 6.45; N, 12.45%. 25
Rotation : [α]D = -13.00° (c = 0.1 , methanol).
-90-
Example 49
2-r4-(3-π -d H-Benzorcπimidazol-2-ylsulfonyl)-2-piperidvn-1.2.4-oxadiazol-5- ylmethyl)phenoxy]ethylamine
Figure imgf000092_0001
The title compound was prepared by a similar method to Example 27 from benzyl Λ/-(2-[4-(3-[1-(1H-benzo[c]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethyl)phenoxy]ethyl)carbamate [see Preparation 56] and 45% w/w hydrogen bromide in glacial acetic acid to afford 2-[4-(3-[1-(1H- benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethyl)phenoxy]ethylamine as a white solid. -91-
Η-NMR (CDCI3) δ : 7.40 (2H, m), 7.25 (2H, m), 7.10 (2H, d), 6.85 (2H, d), 5.55 (1H, d), 4.00 (3H, m), 3.90 (2H, s), 3.20 (1 H, m), 3.10 (2H, m), 2.30 (1 H, d), 2.10 (1 H, m), 1.80-1.40 (7H, m).
Analysis : Found C, 55.33; H, 5.49; N, 15.84; C23H26N6O4S. 0.6 EtOAc. 0.7 H2O requires C, 55.67; H, 5.92; N, 15.33%. (EtOAc = ethyl acetate).
Example 50
/W2-3-H -(1 H-Benzord1ιmidazol-2-ylsulfonyl)-2-piperidinyl 1-1.2.4- oxadiazol-5-ylethyObenzamide
A. N
N O
0=S=O N O=S=O N
Figure imgf000093_0001
Figure imgf000093_0003
HN s>- N HN > N Y
Figure imgf000093_0002
\\ /
-92-
Benzoyl chloride (0.07ml) was added to a solution of 2-3-[1-(1H- benzo[d]imidazol-2-yIsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylethylamine (0.2g) [see Example 27] and triethylamine (0.11 ml) in dichloromethane (5ml). The reaction mixture was stirred at room temperature for 18hrs, after which time a white solid was filtered off, and the filtrate concentrated under reduced pressure. The remaining residue was dissolved in ethyl acetate and washed with water and 1 N aqueous hydrochloric acid. The organic layer was then dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 1 :1 , by volume, ethyl acetate : hexane, to afford /V1-(2-3-[1-(1/-/- benzo[d]imidazol-2-ylsulfonyl)-2-piperidinyl]-1 ,2,4-oxadiazol-5- ylethyl)benzamide (63mg) as a white solid.
Η-NMR (d6-DMSO) δ : 13.60 (1 H, bs), 8.60 ( 1 H, bs), 7.80 (2H, d), 7.70 (2H, m), 7.60-7.20 (5H, m), 5.40 (1 H, m), 3.90 (1 H, d), 3.50 (2H, m), 3.30 (1 H, m), 2.90 (2H, m), 2.00 (1 H, m), 1.80 (1 H, m), 1.50 (1 H, d), 1.40 (1 H, m), 1.35-1.10 (2H, m). Analysis : Found C, 57.23; H, 5.03; N, 17.15; C23H24N6O4S requires C, 57.49; H, 5.03, 17.49%.
-93-
Example 51
Λ/-(3-π -(1 fy-benzord1imidazol-2-ylsulfonyl)-2-piperidvn-1.2,4-oxadiazol-5- ylmethyl)-Λ/-benzylamine
N
^N O
0=S=O N-
H
HN ^N
Figure imgf000095_0002
Figure imgf000095_0001
\\ //
Benzaldehyde (0.06ml) was added to a solution of 3-[1-(1H-benzo[d]imidazol-2- ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethylamine (0.2g) [see Preparation
86] in tetrahydrofuran (5ml). The reaction mixture was stirred at room temperature for 30mins, after which time sodium triacetoxyborohydride (0.16g) and glacial acetic acid (0.03ml) were added, and the mixture was then stirred for 18hrs. The mixture was then diluted with water and basified with saturated sodium hydrogen carbonate, and the product was extracted with ethyl acetate.
The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 -94-
changing to 50:50, by volume, hexane : ethyl acetate, in 10% increments, to afford Λ/-(3-[1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethyl)-/V-benzylamine (0.08g) as a white solid.
Η-NMR (d6-DMSO) δ : 7.75 (1 H, bs), 7.55 (1 H, bs), 7.40-7.20 (9H, m), 5.40 (1 H, d), 3.90 (1 H, d), 3.60 (4H, m), 3.40 (1 H, m), 2.00 (1 H, m), 1.80 (1 H, m), 1.65 (1 H, m), 1.55 (1 H, m), 1.40 (2H, m). Analysis : Found C, 57.38; H, 5.45; N, 17.91 ; C^H^N^S .0.5 H2O requires C, 57.25; H, 5.46; N, 18.21%.
Example 52
2-r(2S)-2-5-r(4-Piperidyloxy)methvπ-1 ,2,4-oxadiazol-3-yl-1 ■ piperidynsulfonyl-1H-benzo[d1imidazole
Figure imgf000096_0002
Figure imgf000096_0001
The title compound was prepared by the method of Example 27 from benzyl 4- (3-[(2S)-1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- -95-
ylmethoxy)-1-piperidinecarboxylate [see Preparation 96] and hydrogen bromide in glacial acetic acid. The crude product was recrystaliised from isopropanol to afford 2-[(2S)-2-5-[(4-piperidyloxy)methyl]-1 ,2,4-oxadiazol-3-yl-1 - piperidyl]sulfonyl-1H-benzo[d]imidazole as an off-white solid.
-NMR (d6-DMSO) δ : 7.65 (2H, m), 7.35 (2H, m), 5.40 (1 H, d), 4.50 (2H, s), 3.95 (1 H, d), 3.60 (1 H, m), 3.35 (1H, t), 3.15 (2H, m), 2.95 (2H, m), 2.00-1.80 (4H, m), 1.75-1.30 (6H, m).
25
Rotation : [α]D = -19.10° (c = 0.05, methanol).
Example 53 2-r(2S)-2-r5-(ri-fCvclopropylmethyl)-4-piperidvnoxymethyl)-1.2,4- oxadiazol-3-yl 1-1 -piperidyllsulfonyl-1 H-benzordyimidazole
Figure imgf000097_0001
Figure imgf000097_0002
-96-
Cyclopropyl methyl bromide (21.4ml) was added to a solution of 2-[(2S)-2-5-[(4- piperidyloxy)methyl]-1 ,2,4-oxadiazol-3-yl-1 -piperidyl]sulfonyl-1 H- benzo[d]imidazole (100mg) [see Example 52], sodium hydrogen carbonate (18.8mg) and sodium iodide (33.6mg) in acetonitrile (2ml). The reaction mixture was stirred for 18hrs at room temperature under an atmosphere of nitrogen, after which time the mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with saturated sodium hydrogen carbonate, brine, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 98 : 1.75 : 0.25, changing to 80 : 20 : 3, by volume dichloromethane : methanol : 0.88 aqueous ammonia to afford 2-[(2S)-2-[5-([1-(cyclopropylmethyl)-4-piperidyl]oxymethyl)- 1 ,2,4-oxadiazol-3-yl]-1-piperidyl]suIfonyl-1H-1 ,3-benzo[d]imidazoIe (35mg) as a white solid.
Η-NMR (CDCI3) δ : 7.75 (2H, m), 7.40 (2H, m), 5.60 (1 H, d), 4.45 (2H, s), 3.95 (1 H, d), 3.40 (1 H, m), 3.15 (1 H, m), 2.85 (2H, m), 2.35 (1 H, d), 2.20-2.00 (4H, m), 1.90 (2H, m), 1.80-1.60 (7H, m), 0.90 (1H, m), 0.50 (2H, d), 0.10 (2H, d). Analysis : Found C, 57.30; H, 6.54; N, 16.13; C24H32N604S. 0.5CH3OH requires -C, 56.96; H, 6.63; N, 16.27%.
25
Rotation : [α]D = -52.00° (c = 0.05, methanol).
-97-
Example 54 2-r(2S)-2-(5-Benzyl-1.2,4-oxadiazol-3-yl)-1 -piperidvnsulfonyl-5-bromo-1 H- benzojcψmidazole
/ \
Figure imgf000099_0001
O=S=O N-O
N HCI
'N H N Ύ
N- 7- NH
O
\\ /
Br
The title compound was prepared by a similar method to Example 1 from 5- benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride [see Preparation 7] and 5-bromo-1 /-.-benzo[d]imidazole-2-sulfonyl chloride [see Preparation 88]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane : ethyl acetate, in 10% increments, to afford 2-[(2S)-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl)- 1 -piperidyl]sulfonyl-5-bromo-1 H-benzo[d]imidazole as a white solid. -98-
Η-NMR (d6-DMSO) δ : 7.85 (1 H, s), 7.60 (1 H, d), 7.45 (1 H, m), 7.30 (3H, m), 7.20 (2H, m), 5.35 (1H, d), 4.05 (2H, s), 3.95 (1H, d), 3.20 (1H, d), 2.00 (1H, d), 1.80 (1H, m), 1.60 (1H, d), 1.55 (1H, m), 1.40-1.20 (2H, m). Analysis : Found C, 50.17; H.4.16; N, 13.75; C21H20N5O3SBr requires C, 50.21; H,4.01;N, 13.94%.
Rotation : [α]D = -29.41° (c = 0.1, methanol).
Example 55
2-4-r(3-(2S)-1-rt5-Bromo-1H-benzord1imidazol-2-yl)sulfonvn-2-piperidyl- 1 ,2,4-oxadiazol-5-yl)methoxy1benzyl-1 ,3-isoindolinedione
Figure imgf000100_0001
-99-
The title compound was prepared by a similar method to Example 1 from 2-[4- (3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzyl]-1 ,3-isoindolinedione hydrochloride [see Preparation 15] and 5-bromo-1 /-/-benzo[d]imidazole-2- sulfonyl chloride [see Preparation 88]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 40:60, by volume, hexane : ethyl acetate, in 10% increments, to afford 2-4-[(3-(2S)-1 -[(5-bromo-1 /-/-benzo[d]imidazoI-2-yl)sulfonyl]-2-piperidyl- 1 ,2,4-oxadiazol-5-yl)methoxy]benzyl-1 ,3-isoindolinedione as a white solid.
Η-NMR (d6-DMSO) δ : 7.85 (5H, m), 7.60 (1 H, d), 7.40 (1 H, d), 7.20 (2H, m), 6.90 (2H, d), 5.40 (1 H, d), 5.20 (2H, d), 4.70 (2H, s), 3.90 (1 H, d), 3.20 (1 H, m), 2.00 (1 H, d), 1.80 (1 H, m), 1.60 (2H, m), 1.40-1.20 (2H, m). Analysis : Found C, 52.20; H, 3.54; N, 11.92; C30H25N6O6SBr 0.6H2O requires C, 52.21 ; H, 3.86; N, 12.18%.
-100-
Example 56
4-r(3-(2S)-1 -r(5-Bromo-1 H-benzord,imidazol-2-vnsulfonvπ-2-piperidyl-1 ,2,4- oxadiazol-5-yl)methoxy,benzylamine
Figure imgf000102_0001
The title compound was prepared by a similar method to Example 11 from 2-4- [(3-(2S)-1-[(5-bromo-1H-benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl-1,2,4- oxadiazol-5-yl)methoxy]benzyl-1 ,3-isoindolinedione [see Example 55] and 33% methylamine in ethanol. The cmde product was purified by recrystaiiisation from methanol and diethyl ether, to afford 4-[(3-(2S)-1-[(5-bromo-1H- benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5- yl)methoxy]benzylamine as a white solid.
-NMR (d4-CH3OH) δ : 7.75 (1 H, m), 7.50 (1 H, m), 7.40-7.30 (3H, m), 6.95 (2H, m), 5.50 (1 H, m), 4.80 (2H, s), 4.10 (1 H, m), 3.95 (2H, m), 3.35 (1 H, m), 2.05 (1 H, m), 1.95 (1 H, m), 1.60 (1 H, m), 1.40 (3H, m). Analysis : Found C, 47.83; H, 3.98; N, 14.97; C^H^N SBr requires C, 48.27; H, 4.23; N, 15.35%. -101-
Example 57 fert-Butyl 4-f2-f3-(1 S)-2-Kcvclohexylmethvnsulfonvn-2-piperidyl-1 ,2,4- oxadiazol-5-yl)ethyn-1-piperazinecarboxylate
Figure imgf000103_0001
N 0 0=S=0 NH,
Figure imgf000103_0002
Figure imgf000103_0003
The title compound was prepared by a similar method to Example 16 from tert- butyl 4-(3-[((Z)-amino(1 S)-2-[(cyclohexylmethyl)sulfonyl]-2- piperidylmethylidene)amino]oxy-3-oxopropyl)-1-piperazinecarboxylate [see Preparation 91] and pyridine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing
-102-
to 50:50, by volume, hexane : ethyl acetate, to afford tetf-butyl 4-[2-(3-(1 S)-2- [(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)ethyl]-1- piperazinecarboxylate as a gum.
Η-NMR (CDCI3) δ : 5.30 (1 H, d), 3.80 (1 H, d), 3.40 (4H, m), 3.20 (1 H, m), 3.10 (2H, m), 3.00-2.80 (4H, m), 2.45 (4H, m), 2.25 (1 H, d), 2.00 (4H, m), 1.80-1.60 (6H, m), 1.50 (9H, s), 1.40-1.00 (6H, m). MS = 527.7 (MH+).
Example 58 1 -r2-(3-(1 S)-2-r(Cvclohexylmethyl)sulfonvπ-2-piperidyl-1.2,4-oxadiazol-5- yl)ethyl]piperazine
Figure imgf000104_0001
Trifluoroacetic acid (10ml) was added to a solution of tert-butyl 4-[2-(3-(1 S)-2- [(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)ethyl]-1- piperazinecarboxylate (265mg) [see Example 57] in dichloromethane (10ml). The reaction mixture was stirred at room temperature for 3hrs, after which time the solvent was removed under reduced pressure and the residue partitioned -103- between ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was separated and washed with brine, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-[2-(3-(1 S)-2- [(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)ethyl]piperazine (136mg) as a brown oil.
Η-NMR (CDCI3) δ : 5.30 (1 H, d), 3.80 (1 H, d), 3.25 (1 H, t), 3.10 (2H, m), 3.00- 2.80 (8H, m), 2.55 (4H, s), 2.25 (1 H, d), 2.00 (5H, m), 1.80-1.60 (5H, m), 1.50 (1 H, m), 1.40-1.00 (5H, m). Analysis : Found C, 53.50; H, 8.08; N, 14.97; C20H35N5O3S .1.5H20 requires C, 53.07; H, 8.46; N, 15.47%.
Example 59 (2S)-Λ^-Benzyl-2-(5-benzyl-1,2,4-oxadiazol-3-yl)-1 -piperidinecarboxamide
// w
N HCI N H
N ■o
Figure imgf000105_0001
Benzyl isocyanate (68ml) was added to a suspension of 5-benzyl-3-[(2S)-2- piperidyl]-1 ,2,4-oxadiazole hydrochloride (279.8mg) [see Preparation 7] (140mg) and triethylamine (70ml) in dichloromethane (5ml). The reaction mixture was stirred for 2hrs, the crude product was then purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 50:50, by volume, hexane : ethyl acetate, to afford a solid which was triturated with diethylether to afford (2S)-/v -benzyl-2-(5-benzyl-1 ,2,4-oxadiazol- 3-yl)-1 -piperidinecarboxamide (150mg) as a white solid. -104-
Η-NMR (CDCI3) δ : 7.25 (10H, m), 5.60 (1 H, d), 4.95 (1 H, bs), 4.40 (2H, s), 4.20 (2H, s), 3.70 (1 H, d), 3.10 (1 H, t), 2.25 (1 H, d), 1.85 (1 H, t), 1.65 (2H, m), 1.45 (2H, m). Analysis : Found C, 70.02; H, 6.44; N, 14.87; C22H24N4O2 requires C, 70.19; H, 6.43; N, 14.88%.
Example 60
(2S)-2-(5-Benzyl-1 ^^-oxadiazol-S-vD-Λ^-phenethyl-l - piperidinecarboxamide
// \\
N HCI
^N H i ^
N -o
Figure imgf000106_0001
The title compound was prepared and purified by a similar method to Example
59 from 5-benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride [see
Preparation 7] and phenethyl isocyanate to afford (2S)-2-(5-benzyl-1 ,2,4-
oxadiazol-3-yl)-/V1-phenethyl-1 -piperidinecarboxamide as a gum.
-NMR (CDCy δ : 7.35-7.15 (10H, m), 5.55 (1 H, d), 4.65 (1 H, bs), 4.20 (2H, s), 3.45 (3H, m), 3.10 (1 H, t), 2.80 (2H, m), 2.20 (1 H, d), 1.85 (1 H, m), 1.65 (2H, m), 1.50-1.35 (2H, m).
Analysis : Found C, 70.43; H, 6.77; N, 14.22; C23H26N402 requires C, 70.75; H, 6.71 ; N, 14.35%. -105-
Example 61
Benzyl N-r(RH3-{(2SM -fcvclohexylmethyl)sulfonyl-2-piperidylM .2.4- oxadiazol-5-yl)(phenyl)methyl carbamate
Figure imgf000107_0001
The title compound was prepared and purified by a similar method to Example 1 from benzyl N-[(R)-phenyl{3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5- yl}methyl]carbamate hydrochloride [see Preparation 103] and cyclohexylmethylsulphonyl chloride to afford benzyl N-[(R)-(3-{(2S)-1- (cyclohexylmethyl)sulfonyl-2-piperidyl}-1 ,2,4-oxadiazol-5- yl)(phenyl)methyl]carbamate as a gum.
Η-NMR (CDCI3) δ : 7.35 (10H, m), 6.20 (1 H, d), 5.75 (1 H, d), 5.30 (1 H, m), 5.05 (2H, m), 3.75 (1 H, d), 3.20 (1 H, m), 2.80 (2H, m), 2.10 (1 H, d), 1.90 (4H, m), 1.60 (6H, m), 1.40 (1 H, m), 1.10 (2H, m), 1.05 (1 H,m), 0.95 (2H,m). Analysis : Found C, 62.66; H, 6.55; N, 9.91 ; C^H^Sϋs. 0.2 H2O requires C, 62.61 ; H, 6.60; N, 10.07%.
25
Rotation : [α]D = -30° (c = 0.1 , methanol). -106-
Example 62
(R)-(3-(('2S)-1-r(Cvclohexylmethvnsulfonvn-2-piperidyl>-1.2.4-oxadiazol-5- yl)(phenyl)methylamine
// w
N
^N ^
O=S=O N- NH.
Figure imgf000108_0002
Figure imgf000108_0001
The title compound was prepared and purified by a similar method to Example 27 from benzyl N-[(R)-(3-{(2S)-1-(cyclohexylmethyl)sulfonyl-2-piperidyl}-1 ,2,4- oxadiazol-5-yl)(phenyl)methyl]carbamate [see Example 61 ] and 45% w/w hydrogen bromide in glacial acetic acid to afford (R)-(3-{(2S)-1- [(cyclohexylmethyi)sulfonyl]-2-piperidyl}-1 ,2,4-oxadiazol-5- yl)(phenyl)methylamine as a gum. " -NMR (CDCI3) δ : 7.40 (5H, m), 5.40 (1 H, s), 5.30 (1 H, m), 3.75 (1 H, d), 3.20 (1 H, m), 2.85 (2H, m), 2.30 (1 H, m), 1.95 (6H, m), 1.65 (6H, m), 1.50 (1 H, m), 1.20 (3H, m), 0.95 (2H,m).
Analysis : Found C, 59.97; H, 7.21 ; N, 13.00; C21H30N4SO3. requires C, 60.26; H, 7.22; N, 13.39%.
25
Rotation : [α]D = -49° (c = 0.1 , methanol). -107-
Example 63
Benzyl N-f(S)-(3-{(2S)-1 -(cvclohexylmethyl)sulfonyl-2-piperidylM .2,4- oxadiazol-5-yl)(phenyl)methyl carbamate
0=S=O
Figure imgf000109_0001
Figure imgf000109_0002
The title compound was prepared and purified by a similar method to Example 16 from benzyl-N-[(1 S)-2-{[((Z)-amino{(2S)-1-[(cyclohexylmethyl)sulfonyI]-2- o piperidyl}methylidene)amino]oxy}-2-oxo-1 -phenylethyl]carbamate [see Preparation 104] and toluene to afford benzyl N-[(S)-(3-{(2S)-1- (cyclohexylmethyl)sulfonyI-2-piperidyI}-1 ,2,4-oxadiazol-5- yl)(phenyl)methyl]carbamate as a gum.
5 Η-NMR (CDCI3) δ : 7.40 (10H, m), 6.20 (1 H, d), 5.70 (1 H, s), 5.30 (1 H, m), 5.15 (2H, m), 3.75 (1 H, d), 3.20 (1 H, m), 2.80 (2H, m), 2.15 (1 H, m), 1.90 (4H, m), 1.60 (6H, m), 1.40 (1 H, m), 1.20 (3H, m), 0.95 (2H,m). Analysis : Found C, 62.92; H, 6.59; N, 10.05; C29H36N4S05. requires C, 63.02; H, 6.57; N, 10.14%. 0 25
Rotation : [α]D = -20° (c = 0.1 , methanol). -108-
Example 64
(S -(3-((2S)-1-r(Cvclohexylmethvnsulfonvn-2-piperidyl>-1.2,4-oxadiazol-5- yl)(phenyl)methylamine
/ X
N
^N
0=S=O N-o NH,
Figure imgf000110_0001
The title compound was prepared and purified by a similar method to Example 27 from benzyl N-[(S)-(3-{(2S)-1-(cyclohexylmethyl)sulfonyl-2-piperidyl}-1 ,2,4- oxadiazol-5-yl)(phenyl)methyl]carbamate [see Example 63 ] to afford (S)-(3- {(2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidyl}-1 ,2,4-oxadiazol-5- yl)(phenyl)methylamine as a gum.
-NMR (CDCI3) δ : 7.30 (5H, m), 5.40 (1 H, s), 5.30 (1H, d), 3.75 (1 H, d), 3.20
(1 H, m), 2.85 (2H, m), 2.25 (1 H, m), 2.10 (2H, m), 1.90 (4H, m), 1.60 (6H, m),
1.45 (1 H, m), 1.20 (3H, m), 0.95 (2H,m).
Analysis : Found C, 60.07; H, 7.21 ; N, 13.04; C^HsoN.SO,. requires C, 60.26;
H, 7.22; N, 13.39%. 25
Rotation : [α]D = -46.2° (c = 0.1 , methanol). -109-
Example 65
2-( 2-r5-(2-pyrimidinvn-1,2,4-oxadiazol-3-vn-2-piperidyl sulfonvn-1H- benzofdlimidazole
O-S=O NH,
Figure imgf000111_0002
Figure imgf000111_0003
HN N
Figure imgf000111_0001
\\ //
The title compound was prepared by the method of Preparation 13 from 1-(1H- benzo[d]imidazol-2-ylsulfonyl)-N'2-[(2-pyrimidinylcarbonyl)oxy]-2- piperidinecarboximidamide [see Preparation 105] and pyridine, to afford 2-({(2- [5-(2-pyrimidinyl)-1 ,2,4-oxadiazol-3-yl]-2-piperidyl}sulfonyl)-1 - - benzo[d]imidazoie as a solid.
Η-NMR (CDCI3) δ : 9.10 (2H, s), 7.85 (1 H, d), 7.65 (2H, m), 7.35 (2H, m), 5.80 (1H, s), 3.90 (1H, d), 3.00 (1H, t), 2.55 (1 H, d), 2.15 (1 H, m), 1.90-1.60 (4H, m). Analysis : Found C, 52.12; H, 4.13; N, 23.09; C18H17N7SO3. 0.1 CH2CI2 requires C, 51.77; H, 4.13; N, 23.35%.
It should be noted that Preparations 21 , 23, 42, 79, 86 and 96 in the following Preparations section also illustrate the syntheses of compounds of the formula (!)•
The following Preparations describe the preparation of certain intermediates used in the preceding Examples. -110-
Preparation 1
(2S)-1 -(fe/f-Butoxycarbonyl)-2-piperidinecarboxylic acid
Figure imgf000112_0001
.L-tartrate
Figure imgf000112_0002
(2S)-2-Piperidinecarboxylic acid L-tartrate (55.0g) (see WO-A-96/11185) was dissolved in water (200ml). The resulting solution was cooled to 0°C and di-t- butyldicarbonate (86g) in 1 ,4-dioxane (203ml) was added followed by 1 N aqueous sodium hydroxide solution (610ml) over a period of 20 mins.. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 56 hours. The solvent was then removed under reduced pressure and the resulting solid was dissolved in water (100ml) and washed with diethyl ether (1000ml). The aqueous layer was acidified to pH 2.0 with 1M aqueous citric acid solution (500ml) and the product was extracted with ethyl acetate (4x500ml). The combined organic layers were dried over magnesium sulphate and the solvent was removed under reduced pressure to afford (2S)-1-(tetf butoxycarbonyl)-2-piperidinecarboxylic acid (19.55g) as a white solid. -NMR (d6-DMSO) δ: 12.7 (1 H, bs), 4.55 (1 H, d), 3.80 (1 H, s), 2.90-2.60 (1 H, m), 2.05 (1 H, m), 1.60 (3H, m), 1.30 (10H, d), 1.10 (1 H, m).
-11 1-
Preparation 2 fetf-Butyl (2S)-2-(aminocarbonyl)-1 -piperidinecarboxylate
Figure imgf000113_0001
Figure imgf000113_0002
Triethylamine (14.46ml) was added to a solution of (2S)-1-( etf-butoxycarbonyl)- 2-piperidinecarboxylic acid (18.3g) [see Preparation 1] in tetrahydrofuran (240ml) at -20°C under an atmosphere of nitrogen. Ethyl chloroformate (7.52ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at -10°C and then 0.88 aqueous ammonia solution (32ml) added. The reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water. The organic layer was separated and dried over magnesium sulphate and the solvent was removed under reduced pressure to afford fet -butyl (2S)- 2-(aminocarbonyl)-1 -piperidinecarboxvlate (18.65g) as a white solid.
Η-NMR (CDCI3) δ: 6.0 (1 H, bs), 5.40 (1 H, bs), 4.80 (1 H, s). 4.00 (1 H, m), 2.85 (1 H, t), 2.30 (1 H, d), 1.80-1.40 (14H, m).
-112-
Preparation 3 tert-Butyl (2S)-2-cyano-1 -piperidinecarboxylate
Figure imgf000114_0001
Figure imgf000114_0002
Oxalyl chloride (8.54ml) was added to a stirred solution of dimethylformamide (7.57ml) in acetonitrile (440ml) at -5°C under an atmosphere of nitrogen. The mixture was stirred for 15 mins., after which time a solution of tert-butyl (2S)-2- (aminocarbonyl)-l -piperidinecarboxvlate (18.63g) [see Preparation 2] and pyridine (16.50ml) in acetonitrile (100ml) was added and the resulting solution was stirred for 10 mins.. The mixture was then reduced to low volume under reduced presssure and diluted with ethyl acetate (1000ml) and water (1000ml). The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (2S)-2-cyano-1- piperidinecarboxylate (13.7g) as a white solid.
-NMR (CDCI3) δ: 5.20 (1 H, s), 4.00 (1 H, m), 2.90 (1 H, t), 1.90 (1 H, d), 1.80- 1.60 (4H, m), 1.40 (9H, s), 1.40 (1 H, m).
25
Rotation : [α]D = -136.83° (c = 0.1 , methanol). -113-
Preparation 4 terf-Butyl (Z)-(2S)-2-famino(hydroxyimino)methvπ-1 -piperidinecarboxylate
Figure imgf000115_0002
,N. 0 Q NH2
Figure imgf000115_0001
A solution of tert-butyl (2S)-2-cyano-1 -piperidinecarboxylate (13.10g) [see Preparation 3] in methanol (500ml) was added to a solution of hydroxylamine hydrochloride (21.6g) and sodium carbonate (33. Og) in water (600ml). The reaction mixture was warmed to the reflux temperature and stirred for 8 hours after which time the methanol was removed under reduced pressure and the product extracted from the aqueous layer with ethyl acetate (3x500ml). The combined organic layers were washed with water (500ml), dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1 -piperidinecarboxylate (14.1 g) as a white solid.
-NMR (CDCI3) δ: 7,10 (1 H, bs), 4.95 (1 H, s), 4.70 (2H, bs), 4.00 (1 H, d), 2.90 (1 H, t), 2.15 (1 H, d), 1.80 (1 H, t), 1.60-1.30 (13H, m). MS : 244 (MH+). -114-
Preparation 5 tert-Butyl (Z)-(2S)-2-(aminof(2-phenylacetyl)oxy1iminomethyl)-1 - piperidinecarboxylate
Figure imgf000116_0001
Figure imgf000116_0002
1 -Hydroxybenzotriazole hydrate (8.67g), phenylacetic acid (8.0g), N- methyimorpholine (14.69ml), 4-dimethylaminopyridine (3.3g) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.29g) were added to a solution of tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1- piperidinecarboxylate (13.0g) [see Preparation 4] in dichloromethane (180ml). The reaction mixture was stirred for 2 hours under an atmosphere of nitrogen, after which time the mixture was diluted with dichloromethane and 1 N aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (Z)- (2S)-2-(amino[(2-phenylacetyl)oxy]iminomethyl)-1 -piperidinecarboxylate (17.63g) as a white solid.
-NMR (CDCI3) δ: 7.30 (5H, m), 4.90 (1 H, s), 4.80 (2H, bs), 4.00 (1 H, d), 3.75 (2H, s), 2.75 (1 H, t), 2.20 (1 H, d), 1.80 (1 H, m), 1.60-1.30 (13H, m).
25
Rotation : [α]D = -64.0° (c = 0.1 , methanol). -115-
Preparation 6 ferf-Butyl (2S)-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl)-1 -piperidinecarboxylate
Figure imgf000117_0001
Figure imgf000117_0002
tert-Butyl (Z)-(2S)-2-(amino[(2-phenylacetyl)oxy]iminomethyl)-1- piperidinecarboxylate (17.5g) [see Preparation 5] was dissolved in xylene (500ml) and heated under reflux for 17 hours. The crude reaction mixture was chromatographed on silica gel eluting with a solvent gradient of 0:100 changing to 20:80, by volume, ethyl acetate : hexane to afford tert-butyl (2S)-2-(5-benzyl- 1 ,2,4-oxadiazol-3-yl)-1 -piperidinecarboxylate (10.56g) as a yellow oil.
-NMR (CDCI3) δ: 7.30 (5H, m), 5.40 (1 H, s), 4.20 (2H, s), 4.00 (1 H, d), 3.00 (1 H, t), 2.20 (1 H, d), 1.80 (1 H, m), 1.60-1.30 (13H, m).
-116-
Preparation 7 5-Benzyl-3-r(2S)-2-piperidvπ-1 ,2,4-oxadiazole hydrochloride
.HCI
Figure imgf000118_0001
Figure imgf000118_0002
tert-Butyl (2S)-2-(5-benzyl-1 ,2,4-oxadiazol-3-yl)-1 -piperidinecarboxylate (10.59g) [see Preparation 6] was dissolved in dichloromethane (150ml) and cooled to 0°C. Hydrogen chloride gas was then bubbled through until the point of saturation. The reaction mixture was then stirred for 30 mins. at 0°C, the solvent was removed under reduced pressure and the product azeotroped with dichloromethane to afford 5-benzyl-3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazole hydrochloride (8.3g) as a yellow solid.
-NMR (CDCI3): δ 10.00 (1 H, bs), 7.30 (5H, m), 4.45 (1 H, s), 4.20 (2H, s), 3.65 (1 H, m), 3.20 (1 H, m), 2.40 (1 H, m), 2.10 (1 H, m), 2.00 (1 H, m), 1.90-1.60 (3H, m).
25
Rotation : [α]D = -15.20° (c = 0.1 , methanol).
Analysis : Found C, 59.38; H, 6.47; N, 14.76; C14H17N3O.HCI. 0.05 CH2CI2 requires C, 59.42; H, 6.42; N, 14.79% -117-
Preparation 8
1 H-Benzofcπimidazole-2-sulfonyl chloride
γ sπ rV c,
H H
1H-2-Benzo[o]imidazolethiol (1.5g) was suspended in 20% v/v acetic acid/water (60ml) and cooled to 0°C. Chlorine gas was bubbled through the mixture until a point of saturation. The reaction mixture was stirred for 1 hour after which time it was filtered and the resulting solid was washed with ice-cold water and dried under reduced pressure to afford 1/-/-benzo[c midazole-2-sulfonyl chloride (2.38g) as a light brown solid.
-NMR (d6-DMSO) δ: 7.70 (2H, d), 7.55 (2H, d).
Preparation 9
3-(Bromomethyl)tetrahydrofuran
, / OH ^Br — -
A solution of triphenylphosphine (7.34g) in dichloromethane (65ml) was added to a solution of 3-(hydroxymethyl)tetrahydrofuran (1.93ml) and carbon tetrabromide (7.95g) in dichloromethane (55ml) at 0°C. The solution was warmed to room temperature and the reaction mixture was stirred for 3.5 hours after which time the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a solvent gradient of 15:1 changing to 10:1 , by volume, hexane : ethyl acetate to afford 3- (bromomethyl)tetrahydrofuran (2.49g) as a colourless oil.
-NMR (CDCI3) δ: 3.85 (2H, m), 3.75 (1 H, q), 3.58 (1 H, m), 3.40 (2H, q), 2.65 (1 H, m), 2.10 (1 H, m), 1.65 (1 H, m). -118-
Preparation 10
Sodium tetrahvdrofuran-3-vlmethanesulfonate r Br- s-o Na+
Figure imgf000120_0001
y sulfite heptahydrate (6.1 Og) w y O
Sodium as added to a solution of 3-
(bromomethyl)tetrahydrofuran (2.0g) [see Preparation 9] in 1 ,4-dioxane (9ml) and water (9ml). The reaction mixture was then heated under reflux and stirred for 18 hours, cooled and the solvent removed under reduced pressure. The resulting solid was dissolved in water and concentrated to a low volume. The solid formed was then collected to afford sodium tetrahydrofuran-3- ylmethanesulfonate (1.30g) as a white solid. -NMR (D2O) δ: 3.95 (1 H, m), 3.80-3.60 (2H, m), 3.45 (1 H, m), 3.00 (2H, m), 2.60 (1 H, m), 2.20 (1 H, m), 1.65 (1 H, m).
Preparation 11
Tetrahvdrofuran-3-ylmethanesulfonyl chloride
■SO3Na A^SO2Cl
Γ r o
Sodium tetrahydrofuran-3-ylmethanesulfonate (1.0g) [see Preparation 10] was dissolved in dimethylformamide (0.05ml) and thionyl chloride (5.3ml) was added. The reaction mixture was heated under reflux for 5 hours, cooled and toluene (10ml) added. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tetrahydrofuran-3-ylmethanesulfonyl chloride (0.22g) as a yellow oil. -NMR (CDCI3) δ : 3.95 (1 H, m), 3.90-3.60 (2H, m), 3.45 (1 H, m), 3.00 (2H, m), 2.30 (1 H, m), 2.10 (1 H, m), 1.80 (1 H, m). -119-
Preparation 12 fert-Butyl (ZH2S)-2-aminor(2-r4-
(hydroxymethyl)phenoxy]acetyloxy)imino1methyl-1 -piperidinecarboxylate
Figure imgf000121_0001
Figure imgf000121_0002
To a stirred solution of tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1- piperidinecarboxylate [see Preparation 4] (2.43g) in dichloromethane (75ml) was added 4-(hydroxymethyl)phenoxyacetic acid (2.19g), 1-(3- dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (2.30g), 4- dimethylaminopyridine (0.611g) and N-methylmorpholine (1.30ml). The reaction mixture was stirred for 56 hours, after which time it was diluted with dichloromethane (200ml) and washed with 1M aqueous hydrochloric acid solution (50ml) followed by saturated aqueous sodium hydrogen carbonate solution (50ml). The organic layer was separated, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert- butyl (Z)-(2S)-2-amino[(2-[4-(hydroxymethyl)phenoxy]acetyloxy)imino]methyl-1- piperidinecarboxylate (2.94g).
-NMR (CDCI3) δ : 7.30 (2H, m), 7.00 (2H, m), 6.85 (1 H, d), 5.55 (1 H, bs), 5.30 (2H, s), 5.20 (1H, s), 4.60 (3H, m), 4.00 (1 H, d), 3.00 (1 H, d), 2.30 (1 H, d), 1.90 (1 H, m), 1.80-1.30 (13H, m). -120-
Preparation 13 terf-Butyl f2S)-2-(5-r4-(hvdroxymethvπphenoxymethvn-1.2.4-oxadiazol-3- yl)-1 -piperidinecarboxylate
O
Figure imgf000122_0001
O^O NH
Figure imgf000122_0002
C N^o
O O
Figure imgf000122_0003
tert-Butyl (Z)-(2S)-2-amino[(2-[4-(hydroxymethyl)phenoxy]acetyloxy) imino]methyI-1-piperidinecarboxylate [see Preparation 12] (2.94g) was dissolved in pyridine (30ml) and heated under reflux for 18 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated , dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50 changing to 0:100 (in 10% increments), by volume, hexane : ethyl acetate to afford tert-butyl (2S)-2-(5-[4- (hydroxymethyl)phenoxymethyl]-1 ,2,4-oxadiazol-3-yl)-1 -piperidinecarboxylate (1.06g).
-NMR (CDCI3) δ : 7.30 (2H, d), 7.00 (2H, d), 5.50 (1 H, bs), 5.25 (2H, s), 4.65 (2H, d), 4.00 (1 H, d), 3.00 (1 H, t), 2.25 (1 H, d), 1.90 (1 H, m), 1.75-1.40 (13H, m). -121-
Preparation 14 ferf-Butyl (2S)-2-r5-(4-f 1 ,3-dioxo-2,3-dihvdro-1 H-2- isoindolyl)methyllphenoxymethyl)-1 ,2,4-oxadiazol-3-vn-1 ■ piperidinecarboxylate
Figure imgf000123_0001
Figure imgf000123_0002
N cAo
Figure imgf000123_0003
Phthalimide (480mg) was added to a solution of tert-butyl (2S)-2-(5-[4- (hydroxymethyl)phenoxymethyl]-1 ,2,4-oxadiazol-3-yl)-1 -piperidinecarboxylate [see Preparation 13] (1.06g) in tetrahydrofuran (10ml). The mixture was cooled to 0°C and triphenylphosphine (1.07g) was added followed by diethylazodicarboxylate (0.642ml). The resulting yellow solution was stirred at 0°C for 10mins. and then at room temperature for 1 hour. The mixture was evaporated to a low volume under reduced pressure and partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by -122- volume, hexane : ethyl acetate to afford tert-butyl (2S)-2-[5-(4-[(1 ,3-dioxo-2,3- dihydro-1 H-2-isoindolyl)methyl]phenoxymethyl)-1 ,2,4-oxadiazol-3-yl]-1 - piperidinecarboxylate (1.09g) as a white solid.
Η-NMR (CDCy δ : 7.90 (2H, s), 7.70 (2H, s), 7.40 (2H, m), 6.90 (2H, m), 5.45
(1 H, bs), 5.20 (2H, d), 4.80 (2H, d), 4.00 (1 H, m), 3.00 (1 H, bs), 2.25 (1 H, m),
1.80 (1 H, bs), 1.70-1.30 (13H, m).
Analysis : Found C, 63.85; H, 5.91 ; N, 10.03; C28H30N4O6. 0.5 EtOAc requires C, 64.04; H, 6.09; N, 9.96%. (EtOAc = ethyl acetate).
-123-
Preparation 15
2-r4-(3-r(2S)-2-Piperidvn-1 ,2,4-oxadiazol-5-ylmethoxy)benzyll-1,3- isoindolinedione hydrochloride
Figure imgf000125_0001
N o O 9
Figure imgf000125_0002
Figure imgf000125_0003
.HCI
"-0-. N ^O
The title compound was prepared by the method of Preparation 7 from tert- butyl (2S)-2-[5-(4-[(1 ,3-dioxo-2,3-dihydro-1 H-2-isoindolyl)methyI]- phenoxymethyl)-1 ,2,4-oxadiazol-3-yl]-1 -piperidinecarboxylate [see Preparation 14] and hydrogen chloride gas to afford 2-[4-(3-[(2S)-2- piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzyl]-1 ,3-isoindolinedione hydrochloride as a white solid.
-NMR (d6-DMSO) δ : 7.85 (4H, m), 7.30 (2H, d), 7.00 (2H, d), 5.60 (2H, s), 4.70 (3H, d), 3.05 (1 H, t), 2.20 (1 H, d), 1.90-1.50 (6H, m). -124-
Preparation 16
1 -(1 H-Benzord1imidazol-2-ylsulfonyl)-2-piperidinecarboxylic acid
Figure imgf000126_0001
.L-tartrate
Figure imgf000126_0002
(2S)-2-Piperidinecarboxylic acid L-tartrate (42g) [see Preparation 1] was dissolved in 10% w/w aqueous sodium hydroxide solution (600ml) and 1 H- benzo[o]imidazole-2-sulfonyl chloride (39g) [see Preparation 8] was added. The reaction mixture was stirred at room temperature for 56 hours after which time the product was extracted with ethyl acetate. The organic layer was separated, 2N aqueous hydrochloric acid solution added and the acidic aqueous layer extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 95:5:0.5, by volume, dichloromethane : methanol : glacial acetic acid to afford 1-(1H-benzo[c midazol-2-ylsulfonyl)-2-piperidinecarboxyiic acid (17.5g).
-NMR (d6-DMSO) δ : 7.25 (2H, m), 7.10 (2H, m), 4.65 (1 H, s), 3.85 (1 H, d), 3.20 (1 H, t), 2.30 (1 H, d), 1.50 (3H, m), 1.20 (2H, m). -125-
Preparation 17 1 -(1 H-Benzofc/|imidazol-2-ylsulfonyl)-2-piperidinecarboxamide
Figure imgf000127_0001
Figure imgf000127_0002
1-(1H-Benzo[c ]imidazol-2-ylsulfonyl)-2-piperidinecarboxylic acid (17.5g) [see Preparation 16] was dissolved in tetrahydrofuran (180ml) and cooled to -20°C. Triethylamine (10.2ml) was added to the mixture followed by ethyl chloroformate (5.4ml). The reaction mixture was stirred for 1 hour at -20°C and 0.88 aqueous ammonia solution (25ml) was added. The mixture was then stirred for a further 2 hours at room temperature. The organic solvent was removed under reduced pressure and ethyl acetate added. The organic layer was separated, washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-(1H-benzo[ ]imidazol-2- ylsulfonyl)-2-piperidinecarboxamide (14.73g).
Η-NMR (CDCI3) δ : 8.80 (1 H, s), 7.70 (2H, m), 7.40 (2H, m), 6.00 (1 H, bs), 5.00 (1 H, s), 3.80 (1 H, d), 3.20 (1 H, t), 2.60 (1 H, d), 1.80-1.50 (5H, m). -126-
Preparation 18
1 -(1 rt-Benzorcπimidazol-2-ylsulfonyl)-2-piperidinecarbonitrile
Figure imgf000128_0002
Oxalyl chloride (5.00ml) was added dropwise to a solution of dimethylformamide (4.43ml) in acetonitrile (200ml) at 0°C. The mixture was stirred for 20 mins. and a suspension of pyridine (9.66ml) and 1-(1H- benzo[c ]imidazol-2-ylsulfonyl)-2-piperidinecarboxamide (14.73g) [see
Preparation 17] in acetonitrile (100ml) was added over a period of 10 mins.. The reaction mixture was stirred for a further 20 mins. after which time the solvent was removed under reduced pressure. The residue was diluted with diethyl ether and washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 70:30, by volume, hexane : ethyl acetate to afford 1-(1 /- -benzo[c midazol-2-ylsuIfonyl)-2- piperidinecarbonitrile (4.9g).
-NMR (CDCI3) δ : 7.80 (1 H, m), 7.60 (1 H, m), 7.30 (2H, m), 5.20 (1 H, s), 4.00 (1 H, d), 3.00 (1 H, t), 2.00 (1 H, m), 1.80 (2H, m), 1.40 (3H, m). -127-
Preparation 19
(Z)-1 -(1 H-Benzord1imidazol-2-ylsulfonyl)-N'2-hvdroxy-2- piperidinecarboximidamide
Figure imgf000129_0001
Figure imgf000129_0002
The title compound was prepared by a similar method to Preparation 4 from 1- (1H-benzo[c midazol-2-ylsulfonyl)-2-piperidinecarbonitrile [see Preparation 18] to afford the title compound as an oil.
-NMR (d6-DMSO) δ : 9.40 (1 H, bs), 7.70 (2H, s), 7.40 (2H, m), 5.60 (2H, bs), 4.80 (1 H, s), 3.80 (1 H, d), 3.20 (1 H, t), 2.00 (1 H, d), 1.60-1.30 (5H, m).
-128-
Preparation 20
(Z -1 -(1 H-Benzord1imidazol-2-ylsulfonvn-N'2-(2-r4-
(hvdroxymethyl)phenoxy1acetyloxy)-2-piperidinecarboximidamide
Figure imgf000130_0001
The title compound was prepared by a similar method to Preparation 12 from the compound of Preparation 19 and 4-(hydroxymethyl)phenoxyacetic acid. The cmde title compound was used without purification in Preparation 21.
-129-
Preparation 21
4-(3-π -(1 rt-Benzorc/limidazol-2-ylsulfonvπ-2-piperidyl 1-1 ,2,4-oxadiazol-5- ylmethoxy)phenylmethanol
Figure imgf000131_0001
The title compound was prepared by a similar method to Preparation 13 from the compound of Preparation 20 and pyridine to afford 4-(3-[1-(1H- benzo[c0imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)phenylmethanol as an oil.
-NMR (CDCI3) δ : 7.80 (1 H, m), 7.50 (1 H, m), 7.30 (4H, m), 6.80 (2H, m), 5.60 (1 H, d), 4.80 (2H, d), 4.60 (2H, s), 4.00 (1 H, d), 3.20 (1 H, m), 2.30 (1 H, d), 2.10 (1 H, m), 1.80 (4H, m). -130-
Preparation 22
4-(3-H -(1 H-Benzorcπimidazol-2-ylsulfonvn-2-piperidvn-1 ,2,4-oxadiazol-5- ylmethoxy)benzaldehyde
Figure imgf000132_0001
Figure imgf000132_0002
Tetrapropylammonium permthenate (14.4mg) was added to a stirred suspension of 4-(3-[1 -(1 /-/-benzo[o]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)phenylmethanol (384mg) [see Preparation 21], N- methylmorpholine oxide (166mg) and 4A° molecular sieves in 10% v/v acetonitrile/dichloromethane (4ml). The reaction mixture was stirred for 1 hour after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to afford 4-(3-[1 -(1 H-benzo[o imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)benzaldehyde (342mg).
-NMR (CDCI3) δ : 10.40 (1 H, bs), 9.95 (1 H, s), 7.85 (2H, d), 7.50-7.20 (4H, m), 7.00 (2H, d), 5.50 (1 H, d), 4.80 (2H, q), 4.05 (1 H, d), 3.25 (1 H, t), 2.25 (1 H, m), 2.10 (1 H, m), 1.80 (4H, m). -131-
Preparation 23
2-r4-(3-r(2S)-1-Cvclohexylmethylsulfonyl-2-piperidvn-1.2.4-oxadiazol-5- ylmethoxy)benzvn-1,3-isoindolinedione
N-O
Figure imgf000133_0001
o~~^\ • .HCI
Figure imgf000133_0002
Figure imgf000133_0003
Cyclohexylmethanesulfonyl chloride (359mg) [King. J.F. et al., J.Am.Chem.Soc, 1992, 114(5), 1743-9] was added to a solution of 2-[4-(3- o [(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)benzyI]-1 ,3-isoindolinedione hydrochloride (627mg) [see Preparation 15] and triethylamine (0.4ml) in dichloromethane (2ml). The reaction mixture was stirred at room temperature for 18 hours after which time it was heated to 30°C and stirred for a further 56 hours. The mixture was diluted with dichloromethane and washed with dilute 5 aqueous hydrochloric acid solution, the organic layer dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent -132-
gradient of 100:0 changing to 75:25, by volume, hexane : ethyl acetate to afford 2-[4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzyl]-1 ,3-isoindoiinedione (192mg).
-NMR (CDCI3) δ : 7.85 (2H, d), 7.70 (2H, d), 7.40 (2H, d), 6.95 (2H, d), 5.40 (1 H, d), 5.20 (2H, s), 4.80 (2H, s), 3.80 (1 H, d), 3.20 (1H, t), 2.90 (2H, m), 2.20 (1 H, d), 2.00-1.00 (16H, m).
Preparation 24 (2S)-2-(Methoxycarbonyl)piperidine hydrochloride
Figure imgf000134_0002
Figure imgf000134_0001
Thionyl chloride (161 ml) was added dropwise to a suspension of (2S)-2- piperidinecarboxylic acid L-tartrate (60g) [see Preparation 1] in methanol (800ml) at 0°C . The reaction mixture was stirred for 18 hours at room temperature after which time the solvent was removed under reduced pressure and the product azeotroped with toluene, precipitated out using methanol and filtered to afford (2S)-2-(methoxycarbonyl)piperidine hydrochloride (37.7g) as a white solid.
Η-NMR (D2O) δ : 3.95 (1 H, d), 3.70 (3H, s), 3.40 (1 H, d), 3.00 (1 H, t), 2.20 (1 H, d), 1.80 (2H, d), 1.70-1.40 (3H, m). -133-
Preparation 25
Methyl (2S)-1 -r(cyclohexylmethyl)sulfonvπ-2 -piperidinecarboxylate
OCH,
OCH '3, .HCI
Figure imgf000135_0001
Figure imgf000135_0002
Triethylamine (22.15ml) was added to a solution of (2S)-2- (methoxycarbonyl)piperidine hydrochloride (10g) [see Preparation 24] and cydohexylmethanesulfonyl chloride (16.42g) [King. J.F. et al,. J.Am.Chem.Soc, 1992, 114(5), 1743-9] in dichloromethane (100ml). The reaction mixture was stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, hexane : ethyl acetate to afford methyl (2S)-1- [(cyclohexylmethyl)sulfonyI]-2-piperidinecarboxylate (11.9g) as a white solid.
-NMR (CDCI3) δ : 4.70 (1 H, d), 3.75 (3H, s), 3.70 (1 H, d), 3.20 (1 H, t), 2.80 (2H, d), 2.20 (1 H, d), 2.00-1.00 (16H, m).
-134-
Preparation 26
(2S)-1-f(Cyclohexylmethyl)sulfonvπ-2-piperidinecarboxamide
Figure imgf000136_0001
0= :S=00 —
Figure imgf000136_0002
Figure imgf000136_0003
Methyl (2S)-1-[(cyclohexylmethyl)sulfonyI]-2-piperidinecarboxylate (3.0g) [see Preparation 25] was dissolved in 1 ,4-dioxane (30ml) and 0.88 aqueous ammonia solution (25ml) was added. Ammonia gas was bubbled through the mixture for 20 mins. and the reaction mixture was heated to 100°C in a sealed vessel for 56 hours. After this time the mixture was cooled and the solvent removed under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford (2S)-1-[(cyclohexylmethyl)sulfonyl]-2- piperidinecarboxamide (1.77g) as a colourless oil.
-NMR (CDCl3) δ : 4.80 (1 H, d), 3.70 (1 H, d), 3.20 (1 H, t), 2.95 (2H, d), 2.30 (1 H, d), 2.00-1.00 (16H, m).
25
Rotation : [α]D = -15.8° (c = 0.1 , methanol). -135-
Preparation 27 (2S)-1-r(Cvclohexylmethyl)sulfonyπ-2-piperidinecarbonitrile
Figure imgf000137_0001
0=S=00
Figure imgf000137_0002
Figure imgf000137_0003
The title compound was prepared by a similar method to Preparation 3 from (2S)-1 -[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxamide [see Preparation 26], oxalyl chloride, dimethylformamide and pyridine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 changing to 20:80, by volume (in 10% increments), hexane : ethyl acetate to afford (2S)-1-[(cyclohexyimethyl)sulfonyl]-2-piperidinecarbonitrile as an oil.
Η-NMR (CDCI3) δ : 4.90 (1 H, s), 3.80 (1 H, d), 3.00-2.80 (3H, m), 2.00-1.00 (17H, m).
-136-
Preparation 28
(Z)-(2S)-1-rCvclohexylmethylsulfonvn-N,2-hvdroxy-2- piperidinecarboximidamide
Figure imgf000138_0002
O=S=O NH.
Figure imgf000138_0001
Figure imgf000138_0003
The title compound was prepared by a similar method to Preparation 4 from (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarbonitrile [see Preparation 27], hydroxylamine hydrochloride and sodium carbonate. The title compound was obtained as a white solid.
-NMR (CDCI3) δ : 7.00 (1 H, bs), 5.00 (2H, bs), 4.50 (1 H, s), 3.75 (1 H, d), 3.05 (1 H, d), 2.85 (2H, d), 2.20 (1H, d), 2.00-1.00 (16H, m).
-137-
Preparation 29
(Z)-(2S)-N'2-(2-lϊ1 -Benzyl-4-piperidinvπoxy1acetyloxy)-1 - r(cvclohexylmethyl)sulfonyn-2-piperidinecarboximidamide
Figure imgf000139_0002
Figure imgf000139_0001
N. ,N.
N' O
O=S=O NH, O=S=O NH 2
Figure imgf000139_0003
Figure imgf000139_0004
Figure imgf000139_0005
The title compound was prepared by a similar method to Preparation 5 from the compound of Preparation 28, sodium 2-[(1-benzyl-4-piperidyl)oxy]acetate [J.Med.Chem., 1987, 30(8), 999-1003], N-methylmorpholine, 1 -hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride. The title compound was obtained as a brown liquid.
-NMR (CDCI3) δ : 7.30 (5H, m), 5.20 (1 H, d), 4.60 (1 H, d), 4.30 (2H, s), 3.80 (1 H, d), 3.55 (3H, s), 3.10 (1 H, m), 2.95 (2H, d), 2.75 (2H, m), 2.35 (1 H, d), 2.15 (2H, t), 2.00-1.00 (20H, m).
-138-
Preparation 30 alpha-f(ter -Butoxycarbonyl)amino1phenylacetic acid
Figure imgf000140_0001
Figure imgf000140_0002
The title compound was prepared by a similar method to Preparation 1 from alpha-aminophenylacetic acid and di-t-butyldicarbonate to afford alpha-[(tert- butoxycarbonyl)amino]phenylacetic acid as a white solid.
-NMR (CDCI3) δ : 7.40 (5H, m), 5.40-5.10 (1 H, bs), 1.50-1.20 (9H, bs).
Preparation 31 tert-Butyl N-(2-f((Z)-amino(2S)-1- (cvclohexylmethvnsulfonvn-2- piperidylmethylidene)amino1oxy-2-oxo-1-phenylethyl)carbamate
Figure imgf000140_0003
Figure imgf000140_0004
O=S=O NH O=S=O NH,
T o
Figure imgf000140_0005
Figure imgf000140_0006
The title compound was prepared by a similar method to Preparation 5 from the compound of Preparation 28 and alpha-[(tert-butoxycarbonyl)amino] phenylacetic acid [see Preparation 30]. The crude product was purified -139- by column chromatography on silica gel eluting with 80:20, by volume, hexane : ethyl acetate to afford the title compound as an oil.
-NMR (CDCI3) δ : 7.50 (5H, m), 5.50 (2H, m), 5.20 (2H, bs), 4.60 (1 H, s), 3.75 (1 H, d), 3.05 (1 H, m), 2.90 (2H, s), 2.30 (1 H, t), 2.00-1.00 (25H, m).
Preparation 32 fZ)-(2S)-1-r Cvclohexylmethyl)sulfonvn-N'2-r(2-morpholinoacetyl)oxy1-2- piperidinecarboximidamide
Figure imgf000141_0001
N~OH O=S=O NH
Figure imgf000141_0002
O=S=O NH.
Figure imgf000141_0003
Figure imgf000141_0004
The title compound was prepared by a similar method to Preparation 5 from the compound of Preparation 28 and 2-morpholinoacetic acid [J. Med. Chem., 1993, 36(3), 320] to afford the title compound (240mg) as a clear oil.
-NMR (CDCI3) δ : 5.25 (2H, s), 4.60 (1 H, s), 3.80 (5H, m), 3.40 (2H, s), 3.10 (1 H, t), 2.95 (2H, d), 2.65 (4H, m), 2.40 (1 H, d), 2.00-1.00 (16H, m). -140-
Preparation 33
2-[(1 -Benzyl-4-piperidyl)oxy1ethyl cyanide
OH ,0.
"ON
Figure imgf000142_0001
Figure imgf000142_0002
Sodium hydride [50% w/w in mineral oil] (2.0g) was added to a slurry of 1- benzyl-4-piperidinol (400g) and acrylonitrile (530g) at 0°C over 1 hour. The reaction mixture was warmed slowly to room temperature and stirred for 18 hours after which time the acrylonitrile was removed under reduced pressure and the residue taken up in isopropanol (1 L). The resulting yellow precipitate was filtered off. The filtrate was evaporated under reduced pressure to afford an orange oil which was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by distillation to afford 2-[(1-benzyl-4-piperidyl)oxy]ethyl cyanide (308g), b.p. 150- 160°C @ 0.2mmHg.
-NMR (CDCy δ : 7.70 (2H, m), 7.45 (3H, m), 4.10 (2H, m), 3.80 (1H, s), 3.65 (2H, t), 3.25 (2H, m), 3.00 (2H, m), 2.60 (4H, m), 2.00 (2H, d).
-141-
Preparation 34
Methyl 3-[(1 -benzyl-4-piperidyl)oxy1propanoate
o.
CN
Figure imgf000143_0001
O. .O.
CH 3
Figure imgf000143_0002
O
2-[(1-Benzyl-4-piperidyl)oxy]ethyl cyanide (10g) [see Preparation 33] was dissolved in a 20% w/w solution of hydrogen chloride in methanol (100ml). The reaction mixture was then heated under reflux for 3 hours. After this time the mixture was cooled and the white precipitate was filtered off. The filtrate was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford methyl 3-[(1-benzyl-4- -piperidyl)oxy]propanoate (7.8g) as an oil.
-NMR (CDCI3) δ : 7.30-7.20 (5H, m), 3.75 (5H, m), 3.50 (2H, s), 3.30 (1 H, m), 2.75 (2H, m), 2.60 (2H, m), 2.20 (2H, m), 1.90 (2H, m), 1.60 (2H, m). -142-
Preparation 35
3-f(1 -Benzyl-4-piperidyl)oxy]propanoic acid
O O.
CH,
Figure imgf000144_0001
O
Figure imgf000144_0002
0
Lithium hydroxide (7.21 ml of a 1 N aqueous solution) was added to a solution of methyl 3-[(1-benzyl-4-piperidyl)oxy]propanoate (1.00g) [see Preparation 34] in methanol (43.3ml). The reaction mixture was stirred for 36 hours at room temperature after which time the methanol was evaporated under reduced pressure. The crude product was dissolved in a small amount of water and purified on a Dowex 50WX8-200 (trade mark) ion-exchange resin eluting with 0:100 changing to 50:50 (in 10% increments), by volume, water : 0.88 aqueous ammonia solution. The aqueous eluted solution was concentrated under reduced pressure and the residue was frozen and lyophilised to afford 3-[(1- benzyl-4-piperidyl)oxy]propanoic acid (269mg) as an off-white solid.
Η-NMR (d6-DMSO) δ : 7.30 (5H, m), 3.60 (3H, t), 3.25 (2H, m), 2.60 (2H, m), 2.40 (2H, t), 2.00 (2H, m), 1.80 (2H, m), 1.40 (2H, m). -143-
Preparation 36
(Z)-(2S)-N'2-(3-ri -Benzyl-4-piperidinyl)oxy]propanoyloxy)-1 - r(cvclohexylmethyl)sulfonyπ-2-piperidinecarbox»midamide
Figure imgf000145_0002
O
N > O
Figure imgf000145_0003
Figure imgf000145_0001
0=S=0 NH. - 0=S=O NH
Figure imgf000145_0004
Figure imgf000145_0005
The title compound was prepared by a similar method to Preparation 5 from the compound of Preparation 28 and 3-[(1-benzyl-4-piperidyl)oxy]propanoic acid [see Preparation 35] to afford the title compound as a clear gum.
-NMR (CDCI3) δ : 7.30 (5H, m), 5.25 (2H, s), 4.60 (1 H, s), 3.80 (3H, m), 3.50 (2H, m), 3.40 (1 H, bs), 3.10 (1 H, t), 3.00 (2H, m), 2.70 (4H, m), 2.40 (1 H, d), 2.10-1.00 (20H, m).
Preparation 37 Benzyl N-3-f((Z)-aminoπ -(1 H-1 ,3-benzimidazol-2-ylsulfonyl)-2- piperidyrjmethylideneamino)oxyl-3-oxopropylcarbamate
Figure imgf000145_0006
Figure imgf000145_0007
The title compound was prepared by a similar method to Preparation 5 from the compound of Preparation 19 and N-benzyloxycarbonyl-beta-alanine to afford the title compound as an oil. -NMR (d6-DMSO) δ : 7.70 (2H, d), 7.30 (5H, m), 6.65 (2H, s), 5.05 (2H, s), 4.85 (1 H, s), 3.70 (1 H, d), 3.30 (1 H, t), 3.25 (2H, m), 2.55 (2H, m), 2.05 (1 H, d),
1.50 (4H, m), 1.20 (1 H, m). -144-
Preparation 38
(2S)-1 -f(4-Fluorophenyl)sulfonvn-2-piperidinecarboxylic acid
Figure imgf000146_0001
.L-tartrate
Figure imgf000146_0002
F (2S)-2-PiperidinecarboxyIic acid L-tartrate (10g) [see Preparation 1] was dissolved in 1 N aqueous sodium hydroxide solution (107.4ml) and diethylisopropylamine (9.35ml) was added followed by a solution of 4- fluorobenzenesulphonyl chloride (10.45g) in acetone (107ml) at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with 1 N aqueous sodium hydroxide solution. The aqueous solution was washed with diethyl ether and acidified with concentrated hydrochloric acid. The product was extracted with ethyl acetate, the organic layers dried over magnesium sulphate and the solvent was removed under reduced pressure to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidinecarboxylic acid (9.89g).
Η-NMR (d6-DMSO) δ : 7.80 (2H, d), 7.40 (2H, d), 4.50 (1 H, s), 3.60 (1 H, d), 3.20 (1 H, t), 2.00 (1 H, d), 1.55 (3H, m), 1.20 (2H, m). -145-
Preparation 39
/^2-Acetyl-(2S)-1-r(4-fluorophenyl)sulfonyl]-2-piperidinecarbohvdrazide
H 9
Figure imgf000147_0002
γ >NΛCH; O=S=O O H
Figure imgf000147_0001
Figure imgf000147_0003
1 -Hydroxybenzotriazole hydrate (162mg), acethydrazide (81 mg), N- methylmorpholine (275μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (230mg) were added to a stirred solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidinecarboxylic acid [see Preparation 38] (287mg) in dichloromethane (3ml). The reaction mixture was stirred for 3 hours after which time the mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford /V2-acetyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidinecarbohydrazide (340mg) as a white solid.
-NMR (CDCI3) δ : 8.00 (2H, d), 7.20 (2H, d), 4.60 (1 H, d), 3.90 (1 H, d), 3.40 (1 H, t), 2.25 (1 H, d), 2.05 (3H, s), 1.50-1.00 (5H, m).
-146-
Preparation 40
(2S)-1-f(4-Fluorophenyl)sulfonyl]-2-piperidinecarboxamide
Figure imgf000148_0001
Figure imgf000148_0002
The title compound was prepared by a similar method to Preparation 2 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38]. The cmde product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50 changing to 0:100 (in 10% increments), by volume, hexane : ethyl acetate to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidinecarboxamide as a white solid.
-NMR (CDCI3) δ : 8.00 (2H, d), 7.40 (2H, d), 6.60 (1 h, bs), 5.50 (1 H, bs), 4.60 (1 H, d), 4.00 (1 H, d), 3.20 (1 H, t), 2.25 (1 H, d), 1.50 (3H, m), 1.10 (2H, m).
25
Rotation : [α]D = -43.01° (c = 0.1 , methanol).
-147-
Preparation 41
Ethyl (2S)-1-r(4-fluorophenyl)sulfonyπ-2-piperidinecarboximidate
Figure imgf000149_0002
a
Figure imgf000149_0001
Figure imgf000149_0003
(2S)-1 -[(4-Fluorophenyl)sulfonyl]-2-piperidinecarboxamide (286mg) [see Preparation 40] was added to a solution of triethyloxonium hexafluorophosphate (304mg) in dichloromethane (5ml). The reaction mixture was stirred at room temperature for 18 hours after which time the mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford ethyl (2S)-1 -[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (290mg).
-NMR (CDCI3) δ : 7.90 (2H, d), 7.20 (2H, d), 4.70 (1 H, d), 4.20 (2H, m), 3.80 (1 H, d), 3.10 (1 H, t), 2.20 (1 H, d), 1.60-1.20 (8H, m).
-148-
Preparation 42
(2S)-1 -r(4-Fluorophenvnsulfonvn-2-(1 H-Λ .2.4-triazol-3-vnpiperidine
Figure imgf000150_0001
NH O=S=O O^CH.
Figure imgf000150_0002
Figure imgf000150_0003
Formylhydrazine (120mg) was added to a solution of ethyl (2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarboximidate (295mg) [see Preparation 41] in toluene (5ml) and 1 ,4-dioxane (5ml). The reaction mixture was stirred at reflux for 26 hours after which time the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100 (in 10% increments), by volume, hexane:ethyl acetate to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(1H-1 ,2,4-triazol-3-yl)piperidine (95mg) as an off-white foam.
-NMR (CDCI3) δ : 8.05 (1 H, s), 7.80 (2H, d), 7.10 (2H, t), 5.40 (1H, bs), 3.75 (1 H, d), 3.20 (1 H, t), 2.30 (1 H, d), 1.80-1.40 (5H, m). -149-
Preparation 43
Λ/2-Methyl-(2S)-1-r(4-fluorophenyl)sulfonvn-2 -piperidinecarboxamide
Figure imgf000151_0001
Figure imgf000151_0002
F F The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxyiic acid [see Preparation 38] and methylamine to afford Λ/2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidinecarboxamide as an oil.
Η-NMR (CDCy δ : 7.90 (2H, t), 7.20 (2H, m), 6.60 (1 H, bs), 4.45 (1 H, s), 3.90 (1 H, d), 3.10 (1 H, t), 2.85 (3H, s), 2.30 (1 H, d), 1.45 (3H, m), 1.10 (2H, m).
25
Rotation : [α]D = -44.4° (c = 0.1 , methanol).
Preparation 44
Λ/2-Methyl-(2S)-1-r(4-fluorophenyl sulfonvn-2-piperidinecarbothioamide
Figure imgf000151_0003
Figure imgf000151_0004
F F
The title compound was prepared by a similar method to Example 20 from Λ/2- methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxamide [see Preparation 43] and Lawesson's reagent. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 25:75 (in 5% increments), by volume, ethyl acetate : hexane, to -150-
afford Λ/2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbothioamide as a white solid.
Η-NMR (CDCIg) δ : 8.60 (1 H, bs), 7.90 (2H, t), 7.30 (2H, m), 4.65 (1 H, s), 3.95 (1 H, d), 3.30 (3H, d), 2.95 (2H, d), 1.45 (3H, m), 1.10 (2H, m).
Preparation 45 2-((2S)-1 -r(4-FluorophenvDsulfonvπ-2-piperidylcarbonyl)-1 • hydrazinecarbothioamide
O - Q —=S r> —=O /~v. IO- 3 NH. Π
Figure imgf000152_0001
Figure imgf000152_0002
F F
1 ,1 '-Carbonyldimidazole (195mg) was added to a solution of (2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287mg) [see Preparation 38] in tetrahydrofuran (5ml). The reaction mixture was stirred and heated under reflux for 1 hour and then evaporated under reduced pressure to afford a yellow gum. The gum was dissolved in 1 ,4-dioxane (5ml) and thiosemicarbazide (182mg) was added. The reaction mixture was heated under reflux for 1.25 hour. After this time the cooled mixture was purified by column chromatography on MCI (trade mark) reverse phase gel eluting with a solvent gradient of 30:70 changing to 70:30, by volume, methanol : water to afford 2-((2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidylcarbonyl)-1 -hydrazinecarbothioamide (178mg) as a white foam.
-NMR (d6-DMSO) δ : 9.90 (1 H, bs), 9.20 (1 H, bs), 7.80 (2H, d), 7.40 (2H, d), 4.60 (1 H, s), 3.60 (1 H, m), 3.40 (1 H, m), 2.10 (1 H, d), 1.60-1.00 (5H, m). -151-
Preparation 46
Methyl (2S)-1-r(4-fluorophenyl)sulfonyl'|-2 -piperidinecarboxylate
Figure imgf000153_0001
Figure imgf000153_0002
4-Dimethylaminopyridine (61 mg), methanol (45μl) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192mg) were added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287mg) [see Preparation 38] in dichloromethane (6ml). The reaction mixture was stirred at room temperature for 56 hours after which time it was diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid solution followed by saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 50:50, by volume, hexane : ethyl acetate, to afford methyl (2S)-1-[(4- fluorophenyI)sulfonyl]-2-piperidinecarboxylate (239mg) as an oil.
-NMR (CDCI3) δ : 7.80 (2H, t), 7.10 (2H, t), 4.70 (1 H, d), 3.70 (1 H, d), 3.50 (3H, s), 3.20 (1 H, t), 2.10 (1 H, d), 1.80-1.20 (5H, m). -152-
Preparation 47
1 -(2S)-1 -r(4-Fluorophenyl)sulfonyn-2-piperidyl-1 ,3-butanedione 3-oxime
Figure imgf000154_0002
A .CH.
N'
0=S=00 N .
OH
Figure imgf000154_0001
Figure imgf000154_0003
n-Butyllithium (1.98ml) [1.6M in hexane] was added dropwise to a solution of acetone oxime (116mg) in tetrahydrofuran (5ml) at 0°C. The reaction mixture was stirred for 1 hour at 0°C and a solution of methyl (2S)-1-[(4- fluorophenyl)sulfonyl]-2-piperidinecarboxylate (239mg) [see Preparation 46] in tetrahydrofuran (1.5ml) was added. The mixture was stirred for 4 hours after which time saturated aqueous ammonium chloride solution (3ml) was added. The mixture was partitioned between dichloromethane and aqueous ammonium chloride solution, the aqueous phase was separated and acidified with 1 N aqueous hydrochloric acid solufion and the product was extracted with dichloromethane. The organic layer was separated , dried over magnesium sulphate, and the solvent removed under reduced pressure to afford the title compound (211mg). The crude product was used without further purification.
-153-
Preparation 48 Benzyl (2S)-1-f(4-fluorophenyl)sulfonvn-2-pyrrolidinecarboxylate
Figure imgf000155_0001
Figure imgf000155_0002
The title compound was prepared by a similar method to Example 1 from L- proline benzyl ester hydrochloride and 4-fluorobenzenesulphonyl chloride. The cmde product was purified by column chromatography on silica gel eluting with dichloromethane to afford benzyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2- pyrrolidinecarboxylate as a clear oil.
-NMR (CDCy δ : 7.90 (2H, m), 7.40 (5H, m), 7.20 (2H, t), 5.10 (2H, s), 4.45 (1 H, m), 3.40 (2H, m), 2.20-1.80 (4H, m). 25
Rotation : [α]D = -93.62° (c = 0.1 , methanol).
-154-
Preparation 49
(2S)-1 -r(4-Fluorophenvπsulfonyπ-2-pyrrolidinecarboxylic acid
Figure imgf000156_0002
Figure imgf000156_0001
Benzyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylate (10.03g) [see Preparation 48] was dissolved in ethanol (200ml) and hydrogenated over 10% w/w palladium-on-charcoal (2.0g) at 60psi (414kPa) for 18 hours. The reaction mixture was then filtered through a plug of ARBOCEL (trade mark) filter aid and the filtrate evaporated under reduced pressure. The residue was azeotroped with dichloromethane to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2- pyrrolidinecarboxylic acid (5.50g) as a white solid.
-NMR (CDCI3) δ : 8.00 (2H, t), 7.20 (2H, t), 4.40 (1 H, s), 3.50 (1 H, m), 3.30 (1 H, m), 2.20-2.00 (3H, m), 1.80 (1 H, m).
25
Rotation : [α]D = -92.62° (c = 0.1 methanol). -155-
Preparation 50 (2S)-1-f(4-Fluorophenyl)sulfonvπ-2-pyrrolidinecarboxamide
Figure imgf000157_0001
Figure imgf000157_0002
The title compound was prepared by a similar method to Preparation 2 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid [see Preparation 49] to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxamide as an oil.
-NMR (CDCy δ : 7.85 (2H, m), 7.20 (2H, t), 6.80 (1 H, bs), 5.60 (1 H, bs), 4.00 (1 H, t), 3.60 (1 H, m), 3.10 (1 H, m), 2.20 (1 H, m), 1.80 (1 H, m), 1.60 (2H, m).
-156-
Preparation 51
(2S)-1-r(4-Fluorophenyl)sulfonvn-2-pyrrolidinecarbonitrile
Figure imgf000158_0002
o=s=o
Figure imgf000158_0001
Figure imgf000158_0003
The title compound was prepared by a similar method to Preparation 3 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxamide [see Preparation 50] and oxalyl chloride. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to afford (2S)-1-[(4- fluorophenyl)sulfonyl]-2-pyrroIidinecarbonitrile as a white solid.
-NMR (CDCI3) δ : 7.90 (2H, m), 7.20 (2H, t), 4.60 (1H, m), 3.40 (1 H, m), 3.25 (1 H, m), 2.25-2.00 (4H, m).
25
Rotation : [α]D = -118° (c = 0.1 , methanol).
-157-
Preparation 52
(ZW2S)-1-r(4-Fluorophenvnsulfonvπ-N,2-hvdroxy-2- pyrrolidinecarboximidamide
Figure imgf000159_0001
.
OH
Η
0=S=O
Figure imgf000159_0002
Figure imgf000159_0003
The title compound was prepared by the method of Preparation 4 from (2S)-1- [(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarbonitrile [see Preparation 51] and hydroxylamine hydrochloride to afford the title compound as a white solid.
-NMR (CDCy δ : 7.90 (2H, m), 7.30 (2H, t), 6.50 (1H, bs), 5.00 (2H, bs), 4.10 (1 H, m), 3.60 (1 H, m), 3.20 (1 H, m), 2.20 (1 H, m), 2.00 (1 H, m), 1.60 (2H, m).
25 Rotation : [ ]D = -124.22° (c = 0.1 , methanol).
-158-
Preparation 53
(Z)-f2S)-1-r(4-Fluorophenvnsulfonvn-N,2-r(2-phenylacetvnoxy1-2- pyrrolidinecarboximidamide
O
Figure imgf000160_0001
0=S=0 NH
Figure imgf000160_0002
Figure imgf000160_0003
Saturated aqueous sodium hydrogen carbonate solution (10ml) was added to a solution of the compound of Preparation 52 (250mg) in dichloromethane (10ml), followed by phenylacetyl chloride (127μl). The reaction mixture was stirred at room temperature for 1 hour after which time the mixture was diluted with dichloromethane. The organic layer was separated , dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 90:10 changing to 70:30 (in 10% increments), by volume, dichloromethane : ethyl acetate, to afford the title compound (186mg) as a white foam.
Η-NMR (CDCI3) δ : 7.90 (2H, m), 7.40-7.10 (7H, m), 5.10 (2H, bs), 4.20 (1H, m), 3.80 (2H, s), 3.60 (1 H, m), 3.20 (1 H, q), 2.25 (1 H, m), 1.90 (1 H, m), 1.80- 1.60 (2H, m). -159-
Preparation 54
2-r4-(2-rBenzyloxycarbonylamino1ethoxy)phenyl]acetic acid
HO
Figure imgf000161_0001
-NH,
HO
H
Figure imgf000161_0002
•A
Figure imgf000161_0003
o 0
Sodium hydroxide (222mg) was added to a solufion of 2-[4-(2-aminoethoxy)- phenyl]acetic acid (394mg) (see DE-A-2250400) in 1 ,4-dioxane : water (1 :1 , by volume) (20ml) at 0°C. The reaction mixture was stirred for 20 minutes then benzyl chloroformate (319mg) was added to the mixture and the solufion was stirred for 4 hours. Additional benzyl chloroformate (70mg) was added to the reaction mixture and it was sfirred for a further 1 hour. The solvent was removed under reduced pressure. The resulting solid was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and the product was extracted with ethyl acetate. The organic solution was dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-[4-(2- [benzyioxycarbonylamino]ethoxy)phenyl]acetic acid (375mg) as a solid.
-NMR (CDCy δ : 7.40 (5H, m), 7.20 (2H, d), 6.90 (2H, d), 5.25 (1 H, bs), 5.15 (2H, s), 4.05 (2H, s), 3.60 (4H, s). -160-
Preparation 55
Benzyl N-r2-(4-2-lϊ tZ)-aminoπ -f 1 H-1.3-benzimidazol-2-ylsulfonvn-2- piperidvnmethylideneamino)oxy-|-2-oxoethylphenoxy)ethyllcarbamate
Figure imgf000162_0001
2-[4-(2-(Benzyloxycarbonyiamino]ethoxy)phenyl]acetic acid (350mg) [see Preparafion 54] was dissolved in dichloromethane (10ml) and the compound of Preparation 19 (323mg) was added followed by 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (230mg) and N-methylmorpholine (132μl). The reaction mixture was sfirred for 56 hours after which time the crude mixture was purified by column chromatography on silica gel eluting with 100:0 changing to 60:40, by volume, hexane:ethyl acetate (in 10% increments), to afford the title compound (384mg) as an oil.
-NMR (CDCI3) δ : 7.85 (2H, bs), 7.40-7.20 (9H, m), 6.90 (2H, d), 5.20 (3H, bs), 5.15 (2H, s), 4.90 (1H, m), 4.10 (2H, m), 3.80 (2H, s), 3.65 (2H, q), 3.50 (1 H, d), 3.30 (1 H, m), 2.10 (1 H, m), 1.90 (1 H, m), 1.80-1.50 (4H, m). -161-
Preparation 56
Benzyl A/-(2-f4-(3-n- 1 H-benzor ]imidazol-2-ylsulfonvn-2-piperidvn-1 , 2,4- oxadiazol-5-ylmethyl)phenoxy1ethyl)carbamate
Figure imgf000163_0001
The title compound was prepared by a similar method to Example 16 from the compound of Preparation 55 and pyridine. The crude product was purified by column chromatography on silica gel eluting with 100:0 changing to 60:40, by volume, hexane:ethyl acetate (in 10% increments) to afford benzyl Λ/-(2-[4-(3- [1 -(1 H-benzo[o imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethyl)phenoxy]ethyl)carbamate as an oil.
Η-NMR (CDCI3) δ : 7.80 (1H, d), 7.40-7.20 (8H, m), 7.05 (2H, d), 6.80 (2H, d), 5.50 (1 H, d), 5.20 (1 H, bs), 5.10 (2H, s), 4.00 (3H, m), 3.85 (2H, s), 3.60 (2H, m), 3.20 (1 H, m), 2.30 (1 H, d), 2.10 (1 H, m), 1.80-1.60 (4H, m). -162-
Preparation 57 1 -rf Benzyloxy)carbonyll-3-pyrrolidinylmethanesulfonic acid
Figure imgf000164_0001
Figure imgf000164_0002
1H-3-Pyrrolidinylmethanesulfonic acid (1.55g) [Labouta, Ibrahim M, et al Acta Chem Scand, Ser B, (1982), B36(10), 669-74] was dissolved in dioxan (20ml) and 1 N aqueous sodium hydroxide (40ml) was added followed by benzyl chloroformate (1.62ml). The reaction mixture was stirred at room temperature for 1 hr, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water. The aqueous phase was separated and acidified with cone, aqueous hydrochloric acid, the product was then extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-[(benzyloxy)carbonyl]-3-pyrrolidinylmethanesulfonic acid (2.20g) as a gum.
Η-NMR (D20) δ : 7.35 (5H, m), 5.05 (2H, s), 3.65 (1 H, m), 3.60 (1 H, m), 3.30 (1 H, m), 3.10 (1 H, m), 2.90 (2H, m), 2.55 (1 H, m), 2.10 (1 H, m), 1.60 (1 H,m). -163-
Preparation 58
Benzyl 3-(chlorosulfonylmethyl)-1 -pyrrolidinecarboxylate
Figure imgf000165_0001
Figure imgf000165_0002
Thionyl chloride (5ml) was added to a solution of 1 -[(benzyloxy)carbonyl]-3- pyrrolidinylmethanesulfonic acid (600mg) [Preparafion 57] in dimethylformamide (50ml). The reaction mixture was heated to reflux for 20mins after which time the cooled mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford benzyl 3-(chlorosulfonylmethyl)-1- pyrrolidinecarboxylate (560mg) as an oil.
Η-NMR (CDCI3) δ : 7.35 (5H, m), 5.15 (2H, s), 3.90 (1 H, m), 3.80 (2H, m), 3.60 (1 H, m), 3.40 (1 H, m), 3.20 (1 H, t), 2.90 (1 H, m), 2.30 (1 H, bs), 1.80 (1 H, m). -164-
Preparation 59 Benzyl 3-(hydroxymethyl)-1 -piperidinecarboxylate
H
N H
Figure imgf000166_0001
Benzyl chloroformate (7.88ml) was added over ten minutes to an ice-cold solufion of 3-hydroxymethyl piperidine (5.76g) and ethyldiisopropylamine (9.58ml) in dichloromethane (300ml). The reacfion mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction was then diluted with dichloromethane (500ml), washed with 1 N aqueous hydrochloric acid (200ml), dried over magnesium sulphate, and evaporated to afford benzyl 3- (hydroxymethyl)-l -piperidinecarboxylate as an oil (12.4g).
-NMR (d6-DMSO) δ : 7.30 (5H, m), 5.00 (2H, s), 4.45 (1 H, t), 4.00 (1 H, d), 3.85 (1 H, d), 3.25 (2H, m), 3.15 (1 H, m), 2.75 (1 H, bs), 1.60 (2H, m), 1.50 (1 H, m), 1.30 (1 H, m), 1.10 (1 H, m).
-165-
Preparation 60
Benzyl 3-(bromomethyl)-1 -piperidinecarboxylate
^4
Figure imgf000167_0001
The title compound was prepared by the method of Preparation 9 from benzyl 3-(hydroxymethyl)-1 -piperidinecarboxylate [Preparation 59] and carbon tetrabromide. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 80:20, by volume ethyl acetate : hexane, in 10% increments, to afford benzyl 3-(bromomethyl)-1- piperidinecarboxylate as an oil.
Η-NMR (d6-DMSO) δ : 7.30 (5H, m), 5.00 (2H, s), 4.05 (1 H, d), 3.80 (1 H, d), 3.40 (2H, m), 2.80-2.60 (2H, m), 1.80 (1 H, m), 1.75 (1 H, m), 1.60 (1 H, m), 1.40 (1 H, m), 1.20 (1 H, m).
-166-
Preparation 61 1 -IT Benzyloxy)carbonyn-3-piperidylmethanesulfonic acid
Figure imgf000168_0001
Figure imgf000168_0002
Sodium sulphite (12.6g) in water (25ml) was added to a stirred solufion of benzyl 3-(bromomethyl)-1 -piperidinecarboxylate (7.8g) [Preparation 60] in dioxan (25ml). The reacfion mixture was sfirred at reflux for 18hrs, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous solution was separated and acidified with 2N aqueous hydrochloric acid. The product was then extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-[(benzyloxy)carbonyl]-3- piperidylmethanesulfonic acid as a hygroscopic solid (4.5g).
Η-NMR (d6-DMSO) δ : 7.30-7.25 (5H, m), 5.00 (2H, s), 4.20 (1 H, d), 4.00 (1 H, m), 3.80-3.20 (2H, m), 2.80 (1 H, m), 2.15 (1 H, d), 1.90 (1 H, s), 1.80 (1 H, m), 1.55 (1H, m), 1.30 (1H, m), 1.10 (1 H, m). -167-
Preparation 62 Benzyl 3-f(chlorosulfonyl)methvπ-1 -piperidinecarboxylate
Figure imgf000169_0001
Figure imgf000169_0002
The title compound was prepared by the method of Preparation 58 from 1- [(benzyloxy)carbonyl]-3-piperidylmethanesulfonic acid [see Preparation 61]and thionyl chloride to afford benzyl 3-[(chlorosulfonyl)methyl]-1- piperidinecarboxylate as an oil.
-NMR (CDCI3) δ : 7.30 (5H, m), 5.10 (2H, s), 4.00 (1 H, d), 3.75 (1 H, m), 3.70- 3.55 (2H, m), 3.20-3.05 (2H, m), 2.45 (1 H, m), 2.10 (1 H, m), 1.80-1.50 (3H, m).
-168-
Preparation 63 1 -(Bromomethyl)cyclopentane
.OH ,Br
Figure imgf000170_0001
Figure imgf000170_0002
The subtitle compound was prepared by the method of Preparation 9 from cyclopentylmethanol and carbon tetrabromide. The crude product was purified by fractional distillation b.pt. 80°C @ 30mmHg to afford 1- (bromomethyl)cyclopentane as a colourless oil.
-169-
Preparation 64
Sodium cvclopentylmethanesulfonate
O
,Br ,0 O
Na
Figure imgf000171_0001
Figure imgf000171_0002
The subtitle compound was prepared by the method of Preparafion 61 from 1- (bromomethyl)cyclopentaπe [Preparation 63] and sodium sulphite. The crude product was purified by recrystallisation from water to afford sodium cyclopentylmethanesulfonate as a white solid.
-NMR (D20) δ : 2.85 (2H, d), 2.10 (1 H, m), 1.80 (2H, m), 1.60-1.40 (4H, m), 1.20 (2H, m).
-170-
Preparation 65 Cyclopentylmethanesulfonyl chloride
O O y O XI
Ό Ό
Na
Figure imgf000172_0001
Figure imgf000172_0002
The subtitle compound was prepared by the method of Preparafion 58 from sodium cyclopentylmethanesulfonate [Preparafion 64] and thionyl chloride, to afford cyclopentylmethanesulfonyl chloride as a solid.
-NMR (CDCI3) δ : 3.75 (2H, d), 2.60 (1 H, m), 2.05 (2H, m), 1.80-1.60 (4H, m), 1.40 (2H, m).
-171-
Preparation 66 1 -(Bromomethyl)cycloheptane
Figure imgf000173_0001
Figure imgf000173_0002
The subtitle compound was prepared by the method of Preparation 9 from cycloheptylmethanol and carbon tetrabromide. The crude product was purified by fractional disfillation, b.pt. 115°C - 120°C @ 30mmHg to afford 1- (bromomethyl)cycloheptane as an oil.
-NMR (CDCI3) δ : 3.25 (2H, d), 1.80 (2H, m), 1.70-1.20 (11 H, m).
-172-
Preparation 67
Sodium cycloheptylmethanesulfonate
Na
Figure imgf000174_0001
Figure imgf000174_0002
The subtitle compound was prepared by the method of Preparation 61 from 1- (bromomethyl)cycloheptane [Preparafion 66] and sodium sulfite. The crude product was purified by recrystallisation from water to afford sodium cycloheptylmethanesulfonate as a white solid.
Η-NMR (D2O) δ : 2.75 (2H, d), 1.90 (1 H, m), 1.75 (2H, m), 1.60-1.20 (10H, m).
-173-
P reparation 68 Cycloheptylmethanesulfonyl chloride
Na
Figure imgf000175_0001
Figure imgf000175_0002
The subtitle compound was prepared by the method of Preparation 58 from sodium cycloheptylmethanesulfonate [Preparation 67] and thionyl chloride, to afford cycloheptylmethanesulfonyl chloride as a colourless oil.
Η-NMR (CDCI3) δ : 3.65 (2H, d), 2.40 (1 H, m), 2.00 (2H, m), 1.70-1.40 (10H, m).
-174-
Preparation 69
(Z)-(2S)-1-r(Cvclohexylmethvnsulfonvπ-Λ '2-r3-
(dimethylamino)propanoyl]oxy-2-piperidinecarboximidamide
O
N
N' 4 ^OH N N' i 0=S=0 NH 0=S=0 NH.
The title compound was prepared by the method of Preparafion 5 from (Z)-(2S)- 1-[cyclohexylmethylsulfonyl]-N'2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], 3-(dimethylamino)propanoic acid [Papapoulos, et __ , WO 9619998A1], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1- [(cyclohexylmethyl)sulfonyl]-Λ/,2-[3-(dimethylamino)propanoyl]oxy-2- piperidinecarboximidamide as an oil.
-NMR (CDCy δ : 4.60 (1 H, d), 3.75 (1 H, d), 3.20 (1 H, t), 2.90 (2H, m), 2.60 (4H, m), 2.30 (1 H, d), 2.25 (6H, s), 2.00 (4H, m), 1.80-1.60 (6H, m), 1.50 (1 H, m), 1.35-1.05 (5H, m).
-175-
Preparation 70
(Z)-f2S -1-r Cvclohexylmethvnsulfonvn-Λr2-(formyloxy)-2- piperidinecarboximidamide
O
N, , N.
N 'OH "N' ^ O A H I
Figure imgf000177_0001
O=S=O NH, O=S=O NH.
Figure imgf000177_0002
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N'2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], formic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-ΛT2-(formyloxy)-2- piperidinecarboximidamide as a colourless oil.
Η-NMR (CDCI3) δ : 8.55 (1 H, s), 5.35 (2H, bs), 4.60 (1 H, d), 3.80 (1 H, d), 3.10 (1 H, t), 2.95 (2H, d), 2.35 (1 H, d), 2.00 (3H, m), 1.80-1.40 (7H, m), 1.35-1.05 (6H, m). -176-
Preparation 71
(Z)-(2S)-Λr2-(Acetyloxy -1-r(cvclohexylmethyl)sulfonvn-2- piperidinecarboximidamide
O
N >^ ^OH N
Figure imgf000178_0001
O=S=O NH, O=S=O NH,
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N,2-hydroxy-2-piperidinecarboximidamide [see Preparafion 28], acetic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-ΛT2-(acetyIoxy)-1-[(cyclohexylmethyl)sulfonyl]-2- piperidinecarboximidamide as a colourless oil.
Η-NMR (CDCI3) δ : 5.20 (2H, bs), 4.60 (1 H, d), 3.80 (1 H, d), 3.10 (1 H, t), 2.95 (2H, d), 2.40 (1 H, d), 2.20 (3H, s), 2.00 (3H, m), 1.90 (1H, m), 1.80-1.40 (7H, m), 1.35-1.05 (5H, m). -177-
Preparation 72 (2S)-1-f(4-Fluorophenyl)sulfonyl]-2-piperidylcarbonitrile
H,
N ^N' I I • N
O= =s= :O O O=S=O
Figure imgf000179_0001
Figure imgf000179_0003
Figure imgf000179_0004
The title compound was prepared by a similar method to Preparation 3 from (2S)-1-[(4-fluorophenyI)sulfonyl]-2-piperidinecarboxamide [see Preparafion 40] and oxalyl chloride. The crude product was filtered through a pad of silica eluting with dichloromethane to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2- piperidylcarbonitrile as an oil.
-NMR (CDCy δ : 7.90 (2H, m), 7.30 (2H, m), 5.00 (1 H, s), 3.85 (1 H, d), 2.75 (1 H, t), 2.00-1.50 (6H, m).
25
Rotation : [α]D = -111.40° (c = 0.1 , methanol). -178-
Preparation 73
(Z)-(2S)-1-r(4-Fluorophenyl)sulfonvn-Λ 1-hvdroxy-2- piperidylcarboximidamide
N
O=S ,=O r NH, OH
Figure imgf000180_0002
Figure imgf000180_0003
Figure imgf000180_0001
The title compound was prepared by a similar method to Preparafion 4 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonitrile [see Preparation 72] and hydroxylamine, to afford (Z)-(2S)-1-[(4-fluorophenyl)sulfonyl]-/V1-hydroxy-2- piperidylcarboximidamide as an oil.
-NMR (CDCI3) δ : 7.90 (2H, m), 7.25 (2H, m), 6.45 (1 H, bs), 5.00 (2H, bs), 4.60 (1H, d), 3.90 (1 H, d), 3.10 (1 H, m), 2.00 (1 H, d), 1.80 (1 H, m), 1.50 (2H, m), 1.20 (2H, m).
-179-
Preparation 74 fZ)-f2S)-1-r(4-Fluorophenyl)sulfonvn-Ar1-R2-phenylacetvnoxyl-2- piperidylcarboximidamide
O
'N' ^ OH 'N' ^ o
O=S— O NH, O=S=O NH,
Figure imgf000181_0001
Figure imgf000181_0003
Figure imgf000181_0002
Figure imgf000181_0004
The title compound was prepared by a similar method to Preparation 53 from (Z)-(2S)-1-[(4-fluorophenyl)sulfonyl]-Λ/,l-hydroxy-2-piperidylcarboximidamide [see Preparafion 73] and phenylacetyl chloride, to afford (Z)-(2S)-1-[(4- fluorophenyl)sulfonyl]-N'1-[(2-phenylacetyl)oxy]-2-piperidylcarboximidamide, which was used immediately without isolation.
-180-
Preparation 75 fZ)-(2S)-1-r(4-Fluorophenyl)sulfonyll-/V1-(2-r4-
(hydroxymethyl)phenoxy1acetyloxy)-2-piperidylcarboximidamide
N ^/*
O=S ,=O rA NH, OH
Figure imgf000182_0001
Figure imgf000182_0002
Figure imgf000182_0003
The title compound was prepared by a similar method to Preparation 5 from o (Z)-(2S)-1 -[(4-fluorophenyl)sulfonyI]-A/,1-hydroxy-2-piperidylcarboximidamide [see Preparation 73], 4-(hydroxymethyl)phenoxyacetic acid, N-methyl morpholine, hydroxybenzotriazole hydrate, and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(4-fluorophenyl)sulfonyl]- /V -(2-[4-(hydroxymethyl)phenoxy]acetyloxy)-2-piperidylcarboximidamide as a 5 white solid.
-NMR (CDCI3) δ : 7.85 (2H, m), 7.25 (2H, m), 6.85 (2H, m), 6.80 (2H,m), 5.15 (3H, m), 4.80 (2H, s), 4.60 (2H, m), 3.80 (1 H, d), 3.10 (1 H, t), 2.15 (1 H, d), 1.80
(1 H, m), 1.50 (2H, m), 1.20 (2H, m). -181-
Preparation 76
(ZH2S)-Λr1-(BenzoyloxyH-r(4-fluorophenyl)sulfonvπ-2- piperidylcarboximidamide
O
N ~N' ^ O
O=S ι=O Y NH, °H O=S=O NH,
Figure imgf000183_0001
Figure imgf000183_0002
Figure imgf000183_0003
The title compound was prepared by a similar method to Preparafion 5 from (Z)-(2S)-1-[(4-fluorophenyl)sulfonyl]-Λ/,1-hydroxy-2-piperidylcarboximidamide [see Preparation 73], benzoic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-N'1-(benzoyloxy)-1 -[(4-fluorophenyl)sulfonyl]-2- piperidylcarboximidamide as a white solid.
-NMR (CDCI3) δ : 8.05 (2H, d), 7.90 (2H, t), 7.60 (1 H, m), 7.45 (2H, m), 7.25 (2H, m), 5.25 (2H, m), 4.60 (1 H, d), 3.85 (1 H, d), 3.20 (1 H, t), 2.30 (1 H, d), 1.90
(1 H, m), 1.50 (2H, m), 1.20 (2H, m). -182-
Preparation 77
(2S -1-r(4-Fluorophenyl)sulfonvn-JV1-r2-phenylacetyl)-2- piperidylcarbohydrazide
OH
N I
Figure imgf000184_0001
Figure imgf000184_0006
O=S=O O 0=S=O O
Figure imgf000184_0002
Figure imgf000184_0004
Figure imgf000184_0003
Figure imgf000184_0005
The title compound was prepared by a similar method to Preparafion 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38], phenylacetic acid hydrazide, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (2S)-1 -[(4-fluorophenyl)sulfonyl]-/V1-(2-phenylacetyl)-2- piperidylcarbohydrazide as a white foam.
-NMR (CDCI3) δ : 7.90 (2H, m), 7.70 (1 H, bs), 7.40-7.20 (7H, m), 4.60 (1 H, d), 3.90 (1 H, d), 3.65 (2H, s), 3.40 (1 H, t), 2.20 (1 H, d), 1.60-1.40 (3H, m), 1.30-
1.10 (2H, m). -183-
Preparation 78
(2S)-1-r 4-Fluorophenyl)sulfonvn-Λ/'1-(3-phenylpropanoyl -2- piperidylcarbohvdrazide
OH
N I O=S=O O
Figure imgf000185_0002
Figure imgf000185_0003
Figure imgf000185_0004
The title compound was prepared by a similar method to Preparafion 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38], 3-phenylpropanohydrazide, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-N,1-(3-phenylpropanoyl)-2- piperidylcarbohydrazide as a colourless gum.
-NMR (CDCI3) δ : 8.60 (1H, bs), 7.95 (2H, m), 7.65 (1H, bs), 7.40-7.20 (7H, m), 4.65 (1 H, s), 3.95 (1 H, d), 3.40 (1 H, t), 3.00 (2H, t), 2.60 (2H, t), 2.25 (1 H,d),
1.60-1.40 (3H, m), 1.30-1.15 (2H, m). -184-
Preparation 79
(2S)-1-r(4-Fluorophenvnsulfonvn-2-(2 y-1,2,3,4-tetraazol-5-vnpiperidine
N
Tl N
O=S=O N-N H
Figure imgf000186_0002
Figure imgf000186_0003
Figure imgf000186_0001
Trimethylsilyi azide (0.66ml) and dibutyltin oxide (62mg) were added to a solufion of (2S)-1-[(4-Fluorophenyl)sulfonyl]-2-piperidylcarbonitrile (670mg) [see Preparafion 72] in toluene (10ml). The reacfion mixture was heated to reflux and sfirred for 18hrs, after which time the cooled reacfion mixture was purified by coloumn chromatography on silica gel eluting with a solvent gradient of 100 : 0 changing to 98 :2, by volume, dichloromethane : methanol followed by 98:1.98:0.02 changing to 95:4.95:0.05, by volume, dichloromethane : methanol : acetic acid. The fractions containing the product were evaporated under reduced pressure and the residue partitioned between diethyl ether and saturated sodium bicarbonate solution. The aqueous layer was separated and acidified with cone, aqueous hydrochloric acid and the product extracted with dichloromethane, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(2H- 1 ,2,3,4-tetraazol-5-yl)piperidine (735mg) as a white foam.
Η-NMR (CDCI3) δ : 7.90 (2H, m), 7.25 (2H, m), 5.20 (1 H, s), 3.80 (1 H, d), 2.95 (1 H, t), 2.55 (1 H, d), 1.80-1.60 (4H, m), 1.40 (1 H, m).
25
Rotation : [α]D = -43.46° (c = 0.1 , methanol). -185-
Preparation 80
(2S)-1-r(4-Fluorophenyl)sulfonvn-Λ/2-(2-hvdroχypropyn-2- piperidinecarboxamide
OH
N I
Figure imgf000187_0001
O=S=O O
Figure imgf000187_0002
Figure imgf000187_0003
Figure imgf000187_0004
Hydroxybenzotriazole hydrate (297mg), (3-dimethylminopropyl)-3-ethyl carbodiimide (421 mg) and N-methylmorpholine (241ml) were added to a solufion of (2S)-1-[(4-fluorophenyi)sulfonyl]-2-piperidinecarboxylic acid (575mg) [see Preparation 38]. The reacfion mixture was stirred for 15mins, then 2- aminopropanol (170ml) was added and stirring continued for 18hrs at room temperature. The mixture was then diluted with ethyl acetate and washed with 2M aqueous hydrochloric acid, saturated sodium hydrogen carbonate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-[(4- fluorophenyI)sulfonyl]-.Λ/2-(2-hydroxypropyl)-2-piperidinecarboxamide (555mg) as an oil.
Η-NMR (CDCI3) δ : 7.90 (2H, m), 7.30 (2H, m), 6.95 (1 H, bs), 4.55 (1 H, m), 3.90 (2H, m), 3.50 (1 H, m), 3.20 (2H, m), 2.30 (1H, d), 1.50 (3H, m), 1.20 (5H, s). -186-
Preparation 81
(2S)-1-r 4-Fluorophenvnsulfonvn-Λ/2-(2-oxoproρyl)-2- piperidinecarboxamide
Figure imgf000188_0001
Figure imgf000188_0002
Dess-Martin reagent (814mg) was added to a sfirred solufion of (2S)-1-[(4- fluorophenyl)sulfonyl]-/\/2-(2-hydroxypropyl)-2-piperidinecarboxamide (548mg) [see Preparafion 80] and triethylamine (0.89ml) in dichloromethane (20ml). The reaction mixture was stirred for 1hr after which time the mixture was filtered through a pad of basic alumina and washed through with dichloromethane to afford (2S)-1 -[(4-fluorophenyl)sulfonyl]-/\r2-(2-oxopropyl)-2- piperidinecarboxamide (300mg).
-187-
Preparation 82
Λr1-r((2S)-1-r(4-Fluorophenyl)sulfonvπ-2- piperidylcarbonyl)oxy]ethanimidamide
NH,
OH O,
N N 'N I I O=S=O O O=S=O O
Figure imgf000189_0001
Figure imgf000189_0003
Figure imgf000189_0002
Figure imgf000189_0004
The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparafion 38], ΛT1-hydroxyethanimidamide [La Manna, et al, Theochem (1990), 69, 161- 68], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3- dimethylaminopropyl)-3-ethyicarbodiimide hydrochloride, to afford /V1-[((2S)-1- [(4-fluorophenyl)suIfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide as a colourless gum.
-NMR (CDCI3) δ : 7.90 (2H, m), 7.20 (2H, t), 4.90 (1 H, bs), 3.50 (1 H, d), 3.20 (1 H, t), 2.00 (3H, s), 1.70 (4H, m), 1.50 (1 H, m), 1.30 (1 H, m). -188-
Preparation 83
Λ/2-Cvclohexyliden-5-f2S -1-r(4-fluorophenyl)sulfonvn-2-piperidyl-1,3.4- oxadiazol-2-amine
N
^N N N
Figure imgf000190_0003
N o=s=o o— 0 O=S = =0
Figure imgf000190_0001
NH,
Figure imgf000190_0004
N
Figure imgf000190_0006
Figure imgf000190_0002
Figure imgf000190_0005
Tosic acid (2.0mg) was added to a solufion of 5-(2S)-1-[(4- fluorophenyl)sulfonyI]-2-piperidyl-1 ,3,4-oxadiazol-2-amine (245mg) [see Example 32] and cyclohexanone (155ml) in toluene (20ml). The reaction mixture was fitted with a dean-stark tube and heated to reflux for 22hrs, after which time the mixture was evaporated under reduced pressure to a low volume and used immediately for Example 48.
-189-
Preparation 84 terf-Butyl /V-2-rf(.Z)-aminori -d H-benzofd .imidazol-2-ylsulfonvn-2- piperidvnmethylideneamino)oxy]-2-oxoethylcarbamate
O
H
"N' ^ OH ^N' ^ O 0=S=O NH, 0=S=O NH, Nγ o °
HN ^ N HN N N
\\ / \\ /
The subtitle compound was prepared by a similar method to Preparation 5 from (Z)-1-(1 H-benzo[d]imidazol-2-ylsulfonyl)-N-2-hydroxy-2- piperidinecarboximidamide [see Preparafion 19], 4- (hydroxymethyl)phenoxyacetic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, to afford, tert-buty\ /V-2-[((Z)-amino[1-(1H- benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]methylideneamino)oxy]-2- oxoethylcarbamate as an oil.
Η-NMR (CDCI3) δ : 7.70 (2H, d), 7.35 (2H, m), 6.80 (2H, bs), 4.90 (1 H, s), 3.85 (2H, d), 3.70 (1H, m), 3.35 (1 H, t), 2.10 (1 H, m), 1.60 (4H, m), 1.40 (9H, s), 1.25 (1 H,m). -190-
Preparation 85 terf-Butyl Λ/-(3-π -(1 H-benzord1imidazol-2-ylsulfonyl)-2-piperidvn-1.2,4- oxadiazol-5-ylmethyl)carbamate
Figure imgf000192_0001
The title compound was prepared by the method of Example 16 from tert-butyl A/-2-[((Z)-amino[1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2- piperidyl]methylideneamino)oxy]-2-oxoethylcarbamate [see Preparafion 84] and pyridine. The crude product was purified by column chromatography on silica gel eluting with 70:30, by volume, hexane : ethyl acetate, to afford tert-butyl N- (3-[1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethyl)carbamate as an oil.
-NMR (d6-DMSO) δ : 13.65 (1 H, bs), 7.80 (1 H, d), 7.60 (2H, m), 7.40-7.30 (2H, m), 5.40 (1H, d), 4.20 (2H, d), 3.95 (1H, d), 3.40 (1 H, m), 2.00 (1 H, m), 1.80 (1 H, m), 1.60-1.50 (2H, m), 1.40 (9H, s), 1.30-1.20 (2H, m). -191 -
Preparation 86 3-f1 -(1 f -Benzord1imidazol-2-ylsulfonyl)-2-piperidyn-1 ,2,4-oxadiazol-5- ylmethylamine
N N O
0=S=O N- NH,
HN ^> -
N
Figure imgf000193_0001
\\ /
tert-Butyl /V-(3-[1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethyl)carbamate (0.88g) [see Preparafion 85] was dissolved in dioxan (20ml) and cooled to 0°C. Hydrogen chloride gas was then bubbled through for 10mins. The reacfion mixture was then stirred at room temperature for 1hr, the solvent was then removed under reduced pressure to afford 3-[1- (1/-/-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethylamine (0.67g) as the hydrochloride salt as a white solid.
Η-NMR (d6-DMSO) δ : 9.00 (3H, bs), 7.70 (2H, d), 7.40 (2H, m), 5.45 (1H, m), 4.40 (2H, s), 3.90 (1 H, d), 3.40 (1 H, t), 2.05 (1 H, bs), 1.80 (1 H, m), 1.55 (2H, m), 1.40-1.15 (2H, m). -192-
Preparation 87
5-Bromo-1tf-benzofd1imidazole-2 -thiol
Figure imgf000194_0001
Figure imgf000194_0002
Platinum dioxide (5.7g) was hydrogenated in ethanol (300ml) at 50psi for 30 mins, 4-bromo-2-nitroaniline (15.0g) was then added and the solufion was hydrogenated at 50psi for a further 3hrs. The mixture was then filtered through a plug of Arbocel and the ethanoiic solufion added to a solufion of potassium hydroxide (5.8g) and carbon disulphide (17.51 ml) in water (50ml). The reacfion mixture was then refluxed at 85°C for 2hrs, after which time the cooled reaction mixture was diluted with water and acidified with 2M aqueous hydrochloric acid. A green solid formed which was filtered off and washed with water. The solid was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford crude product. The filtration mother liquors were then extracted with ethyl acetate, the organic layer was washed with 2M aqueous hydrochloric acid, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford further crude product. The combined crude products were purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 changing to 0:100, by volume, hexane : ethyl acetate, in 10% increments, to afford 5-bromo-1 H-benzo[d]imidazole-2-thiol (5.64g) as a white solid. -NMR (d6-DMSO) δ : 7.25 (2H, d), 7.05 (1 H, d). -193-
Preparation 88 5-Bromo-1 H-benzofdlimidazole-2-sulfonyl chloride
Figure imgf000195_0001
Figure imgf000195_0002
Chlorine gas was bubbled through a solution of 5-bromo-1H-benzo[d]imidazole-
2-thiol (4.98g) [see Preparation 87] in 20% glacial acetic acid (100ml) at 0°C for δmins. The precipitate formed was quickly filtered and the solid washed with ice cold water to afford 5-bromo-1 /-/-benzo[d]imidazole-2-sulfonyl chloride as a solid which was used immediately for Examples 54 and 55.
-194-
Preparation 89 ferf-Butyl 4-(3-ethoxy-3-oxopropylM -piperazinecarboxylate
O. .O
,N
"y
~N O
Figure imgf000196_0001
H O
Ethyl-3-bromoproprionate (1.67ml) was added to a suspension of tert-butyl-1- piperazine carboxylate (2.43g) and potassium carbonate (2.16g) in acetonitrile (30ml). The reaction mixture was stirred for 56hrs at room temperature, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl 4-(3-ethoxy-3-oxopropyl)-1- piperazinecarboxylate (2.44g) as an oil.
Η-NMR (CDCI3) δ : 4.20 (2H, q), 3.40 (4H, m), 2.70 (2H, t), 2.50 (2H, t), 2.40 (4H, m), 1.45 (9H, s), 1.25 (3H, t). -195-
Preparation 90 3-r4-(terf-Butoχycarbonyl)piperazinolpropanoic acid
O .O
,N. y
*N' O N' o
Figure imgf000197_0001
O
Figure imgf000197_0002
OH
1 N Aqueous lithium hydroxide (15.6ml) was added to a solufion of tert-butyl 4- (3-ethoxy-3-oxopropyl)-1 -piperazinecarboxylate (2.23g) [see Preparation 89] in ethanol (95ml). The reacfion mixture was sfirred for 18hrs at room temperature, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on reverse phase MCI gel eluting with 1 :1 , acetonitrile : water and further purified on Dowex 50W-X8-100 ion-exchange resin eluting with water and then 10% ammonia to afford 3-[4- (tert-butoxycarbonyl)piperazino]propanoic acid (1.33g) as a white solid.
-NMR (d4-CH3OH) δ : 3.55 (2H, m), 3.20 (2H, m), 2.80 (4H, m), 2.50-2.40 (4H, m), 1.45 (9H, s). -196-
Preparation 91 te/ -Butyl 4-f3-r(i/^-amino(2S)-1-r(cvclohexylmethyl)sulfonvn-2- piperidylmethylidene)amino1oxy-3-oxopropyl)-1 -piperazinecarboxylate
Figure imgf000198_0001
The title compound was prepared by a similar method to Preparafion 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N'2-hydroxy-2-piperidinecarboximidamide [see Preparafion 28] and 3-[4-(tert-butoxycarbonyl)piperazino]propanoic acid [see Preparation 90] to afford tert-butyl 4-(3-[((Z)-amino(2S)-1- [(cyclohexylmethyl)sulfonyl]-2-piperidylmethylidene)amino]oxy-3-oxopropyl)-1- piperazinecarboxylate as a brown oil.
-NMR (CDCy δ : 5.50 (2H, bs), 4.60 (1 H, d), 3.80 (1 H, d), 3.45 (6H, m), 3.15 (1H, t), 2.95 (2H, m), 2.75 (3H, m), 2.65 (2H, m), 2.50 (6H, m), 2.00 (4H, m), 1.80-1.60 (4H, m), 1.50 (9H, s), 1.35 (2H, m), 1.20 (2H, m).
-197-
Preparation 92
2-(1 -r(Benzyloxy)carbonvn-4-piperidyloxy)acetic acid
Figure imgf000199_0001
Figure imgf000199_0002
Trifluoroacetic acid (25ml) was added to a solution of benzyl 4-[2-(tert-butoxy)- 2-oxoethoxy]-1 -piperidinecarboxylate (5.90g) [J. Med. Chem, (1992), 35(23), 4405] in dichloromethane (50ml) at 0°C. The reacfion mixture was then sfirred at room temperature for 2hrs, after which time the solvent was removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was separated and washed with 2N aqueous hydrochloric acid, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford 2-(1-[(benzyloxy)carbonyl]-4-piperidyloxy)acetic acid (5.13g) as a clear oil.
Η-NMR (CDCI3) δ : 9.45 (1 H, bs), 7.20 (5H, m), 5.20 (2H, s), 4.20 (2H, s), 3.85 (2H, m), 3.65 (1 H, m), 3.30 (2H, m), 1.90 (2H, m), 1.65 (2H, m). -198-
Preparation 93 terf-Butyl (ZH2S)-2-[amino(r2-( 1 -r(benzyloxy)carbonvn-4- piperidyloxy)acetvnoxyimino)methyl]-1 -piperidinecarboxylate
O
N.
N AH o
N o y^y
NH, yy NH, M
O o (T O 2 Y o
The title compound was prepared by a similar method to Preparafion 5 from tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1 -piperidinecarboxylate [see Preparafion 4] and 2-(1-[(benzyloxy)carbonyI]-4-piperidyloxy)acetic acid [see Preparation 92] to afford tert-butyl (Z)-(2S)-2-[amino([2-(1- [(benzyloxy)carbonyl]-4 piperidyloxy)acetyl]oxyimino) methyl]-1- piperidinecarboxylate as a brown oil.
Η-NMR (CDCI3) δ : 7.40 (5H, m), 5.15 (2H, s), 5.05 (2H, bs), 4.95 (1 H, d), 4.35 (2H, s), 4.05 (1 H, d), 3.80 (2H, m), 3.65 (1 H, m), 3.25 (2H, m), 2.80 (1 H, t), 2.25 (1 H, d), 1.90-1.60 (8H, m), 1.55 (9H, m), 1.40 (1H,m).
-199-
Preparation 94 ferf-Butyl (2S)-2-(5-f 1 -r(benzyloxy)carbonvn-4-piperidyloxy)methvn-1.2,4- oxadiazol-3-yl}-1 -piperidinecarboxylate
Figure imgf000201_0001
The title compound was prepared by a similar method to Preparafion 13 from
(Z)-(2S)-2-[amino([2-(1-[(benzyloxy)carbonyl]-4 piperidyloxy)acetyl]oxyimino)
methyl]-1 -piperidinecarboxylate [see Preparation 93] and pyridine. The crude product was purified by column chromatography on silica gel elufing with a solvent gradient of 80 : 20, changing to 50 :50, by volume, hexane : ethyl acetate, in 5% increments, to afford tert-butyl (2S)-2-{5-[(1- [(benzyloxy)carbonyl]-4-piperidyloxy)methyI]-1,2,4-oxadiazol-3-yl}-1- piperidinecarboxylate.
-NMR (CDCy δ : 7.40 (5H, m), 5.50 (1 H, bs), 5.15 (2H, s), 4.75 (2H, s), 4.10 (1 H, m), 3.80 (2H, m), 3.50 (1 H, m), 3.30 (2H, m), 3.00 (1 H, t), 2.25 (1 H, d), 1.90 (3H, m), 1.65 (5H, m), 1.45 (9H, s), 1.40 (1 H,m). -200-
Preparation 95 Benzyl 4-(3-lϊ2S)-2-piperidvπ-1 ,2,4-oxadiazol-5-ylmethoxy)-1 - piperidinecarboxylate
Figure imgf000202_0002
Figure imgf000202_0001
o
Trifluoroacetic acid (25ml) was added to a solufion of tert-butyl (2S)-2-{5-[(1- [(benzyloxy)carbonyl]-4-piperidyloxy)methyl]-1 ,2,4-oxadiazol-3-yl}-1- piperidinecarboxylate (1.73g) [see Preparafion 94] in dichloromethane (25ml) at 0°C. The reaction mixture was stirred for 2hrs at room temperature, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with 2N aqueous hydrochloric acid and brine, the combined aqueous layers were then neutralised with saturated sodium hydrogen carbonate and the product re-extracted with ethyl acetate. The organic layer was then separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford benzyl 4-(3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol- 5-ylmethoxy)-1 -piperidinecarboxylate (1.33g) as a brown oil.
Η-NMR (CDCI3) δ : 7.40 (5H, m), 5.15 (2H, s), 4.75 (2H, s), 4.00 (1 H, d), 3.80 (2H, m), 3.70 (1 H, m), 3.30-3.15 (3H, m), 2.80 (1 H, t), 2.10 (1 H, m), 1.90 (3H, m), 1.80-1.55 (6H, m). -201-
Preparation 96
Benzyl 4-(3-IY2S)-1 -(1 H-benzord1imidazol-2-ylsulfonvn-2-piperidyll-1.2.4- oxadiazol-5-ylmethoxy)-1 -piperidinecarboxylate
Figure imgf000203_0001
Figure imgf000203_0002
The title compound was prepared by a similar method to Example 1 from benzyl 4-(3-[(2S)-2-piperidyl]-1 ,2,4-oxadiazol-5-ylmethoxy)-1- piperidinecarboxylate [see Preparation 95] and 1H-benzo[c ]imidazol-2-sulfonyl chloride [see Preparation 8]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80 : 20 changing to 0 :100, by volume, hexane : ethyl acetate, in 5% increments, to afford benzyl 4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)-1 -piperidinecarboxylate as a clear oil.
Η-NMR (CDCI3) δ : 10.65 (1 H, bs), 7.85 (1 H, d), 7.60 (1 H, d), 7.40 (7H, m), 5.60 (1 H, d), 5.15 (2H, s), 4.40 (2H, s), 4.00 (1 H, d), 3.80 (2H, m), 3.55 (1 H, m), 3.20 (3H, m), 2.30 (1H, d), 2.05 (1 H,m) 1.85-1.50 (8H, m). -202-
Preparation 97
(Z)-ι2S)-1-r(4-Fluorophenyl)sulfonyll-Λ 2-f(2-pyrazinylcarbonyl)oxy1-2- piperidinecarboximidamide
O
Figure imgf000204_0003
N
N
O=S ,=O Y NH, °H O= YS=O Y NH, ° ^ y"
N
Figure imgf000204_0001
Figure imgf000204_0002
Figure imgf000204_0004
The title compound was prepared by a similar method to Preparafion 5 from (Z)-(1S)-2-[(4-fluorophenyl)sulfonyl]-Λ/,1-hydroxy-2-piperidylcarboximidamide [see Preparafion 73], 2-pyrazinecarboxyIic acid, N-methyl morpholine, hydroxybenzotriazole hydrate, dimethylaminopyridine and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1- [(4-fluorophenyl)sulfonyl]-/V2-[(2-pyrazinylcarbonyl)oxy]-2- piperidinecarboximidamide as a white solid.
Η-NMR (CDCy δ : 9.40 (1 H, s), 8.80 (1 H, s), 8.75 (1 H, s), 7.95 (2H, m), 7.25 (2H, m), 5.50 (2H, bs), 4.70 (1 H, m), 3.90 (1 H, d), 3.20 (1 H, t), 2.30 (1 H, d), 1.90 (1H, m), 1.55 (2H, m), 1.20 (2H, m). -203-
Preparation 98
5- 1.3-Dioxo-2,3-dihvdro-1 H-2-isoindolvDmethvπ-2-furoic acid
Figure imgf000205_0001
Figure imgf000205_0002
2-Furoic acid (10.0g) was dissolved in cold concentrated sulphuric acid (50ml). The mixture was then added to N-hydroxy methylphthalimide (12.0g) and the reaction mixture allowed to stand for 18hrs at room temperature. The mixture was then poured into ice and the product extracted with dichloromethane, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was triturated with diethyl ether and recrystaliised from methanol to afford 5-[(1 ,3-dioxo-2,3-dihydro-1/-/-2-isoindolyl)methyl]-2-furoic acid (9.70g) as a brown solid.
Analysis : Found C, 59.48; H, 3.72; N, 5.03; C14H9N05. 0.5 H20 requires C, 60.00; H, 3.60; N, 5.04%.
-204-
Preparation 99
(ZH2SH -r(Cvclohexylmethvnsulfonvn-Λ 2-r(5-f(1 ,3-dioxo-2.3-dihvdro-1 H-
2-isoindolyl)methvπ-2-furylcarbonyl)oxy1-2-piperidinecarboximidamide
Figure imgf000206_0001
N OH
0=S=0 NH,
Figure imgf000206_0002
Figure imgf000206_0003
The title compound was prepared by a similar method to Preparafion 5 from (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N'2-hydroxy-2-piperidinecarboximidamide [see Preparafion 28] and 5-[(1 ,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-2- furoic acid [see Preparafion 98], to afford (Z)-(2S)-1- [(cyclohexylmethyl)sulfonyl]-N,2-[(5-[(1 ,3-dioxo-2,3-dihydro-1 H-2- isoindolyl)methyl]-2-furylcarbonyl)oxy]-2-piperidinecarboximidamide as a yellow oil.
Η-NMR (CDCI3) δ : 7.90 (2H, m), 7.80 (2H, m), 7.20 (1 H, s), 6.45 (1 H, d), 5.30 (2H, bs), 4.95 (2H, s), 4.65 (1 H, d), 3.80 (1 H, d), 3.20 (1 H, t), 2.95 (2H, m), 2.40 (1 H, d), 2.00 (4H, m), 1.80-1.60 (7H, m), 1.50 (1 H, m), 1.40-1.10 (4H, m).
-205-
Preparation 100
2-r5-ι3-f2S)-1-rfCvclohexylmethyl)sulfonvn-2-piperidyl-1.2.4-oxadiazol-5- yl)-2-furyr|methyl-1,3-isoindolinedione
Figure imgf000207_0001
o=s= -O NH
Figure imgf000207_0002
Figure imgf000207_0003
(Z)-(2S)-1-[(Cyclohexylmethyl)sulfonyl]-N,2-[(5-[(1 ,3-dioxo-2,3-dihydro-1 H-2- isoindolyl)methyl]-2-furylcarbonyl)oxy]-2-piperidinecarboximidamide (154mg) (see Preparafion 99) was dissolved in toluene (4ml) and heated to reflux for 18hrs. The toluene was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluting with 2 : 1 , by volume, hexane : ethyl acetate, to afford 2-[5-(3-(2S)-1- [(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)-2-furyl]methyl-1 ,3- isoindolinedione (62mg) as an oil.
-NMR (CDCI3) δ : 7.90 (2H, m), 7.75 (2H, m), 7.25 (1H, d), 6.60 (1 H, s), 5.40
(1H, d), 5.35 (1H, s), 5.00 (2H, s), 3.80 (1H, d), 3.25 (1 H, t), 3.00 (2H, m), 2.30
(1 H, d), 2.00 (4H, m) 1.80-1.60 (6H, m), 1.50 (1 H, m), 1.40-1.00 (4H, m). -206-
Preparation 101 førf-Butyl 2S)-2-r(Z,5/?)-1-amino-4,7-dioxo-5,9-diphenyl-3.8-dioxa-2,6- diaza-1 -nonen-1 -yll-1 -piperidinecarboxylate
Figure imgf000208_0001
OH 0 Q NH2
Figure imgf000208_0002
The title compound was prepared by a similar method to Preparafion 5 from tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1 -piperidinecarboxylate [see Preparation 4] and (2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoic acid to afford tert-butyl (2S)-2-[(Z,5R)-1-amino-4,7-dioxo-5,9-diphenyl-3,8-dioxa-2,6- diaza-1-nonen-1-yl]-1 -piperidinecarboxylate as an oil.
-NMR (CDCI3) δ : 8.20 (0.5H, d), 7.35 (10H, m), 6.55 (0.5H, d), 5.90 (1 H, m), 5.55 (1 H, d), 5.10 (2H, m), 4.90 (2H, m), 3.95 (1 H, m), 2.70 (1 H, m), 2.40 (1 H, m), 2.20 (1 H, m), 1.80 (2H, m), 1.60 (2H, m), 1.45 (9H, s).
-207-
Preparation 102 terf-Butyl (2S)-2- 5-r( ?)- rιbenzyloxy)carbonvnaminoV(phenvnmethvn-
1 ,2,4-oxadiazol-3-yl}-1 -piperidinecarboxylate
Figure imgf000209_0002
Figure imgf000209_0001
The title compound was prepared by a similar method to Preparafion 6 from tert-butyl (2S)-2-[(Z,5R)-1 -amino-4,7-dioxo-5,9-diphenyl-3,8-dioxa-2,6-diaza-1 - nonen-1-yl]-1 -piperidinecarboxylate [see Preparafion 101] and pyridine to afford tert-butyl (2S)-2-{5-[(R)-{[(benzyloxy)carbonyl]amino}(phenyl)methyl]-1 ,2,4- oxadiazol-3-yl}-1 -piperidinecarboxylate as an oil.
Η-NMR (CDCI3) δ : 7.40 (10H, m), 6.20 (1 H, d), 5.85 (1 H, s), 5.45 (1 H, s), 5.10 (2H, m), 4.00 (1 H, d), 2.95 (1 H, m), 2.15 (1 H, d), 1.85 (1 H, m), 1.60 (2H, m), 1.45 (11 H, m).
-208-
Preparation 103
Benzyl (R)-phenylf3-r(2S)-piperidvπ-1.2,4-oxadiazol-5-yl}methylcarbamate hydrochloride
Figure imgf000210_0001
The title compound was prepared by a similar method to Preparafion 7 from tert-butyl (2S)-2-{5-[(R)-{[(benzyloxy)carbonyl]amino}(phenyl)methyl]-1 ,2,4- oxadiazol-3-yl}-1 -piperidinecarboxylate [see Preparafion 102] and anhydrous hydrogen chloride gas to afford benzyl (f?)-phenyl{3-[(2S)-piperidyl]-1 ,2,4- oxadiazol-5-yl}methylcarbamate hydrochloride as a foam.
Η-NMR (CDCI3) δ : 7.30 (10H, m), 6.25 (1 H, s), 6.20 (1 H, s), 5.10 (2H, s), 4.40 (1 H, s), 3.55 (1 H, s), 2.30 (1 H, s), 1.95 (5H, m), 1.60 (1 H, m).
-209-
Preparation 104
Benzyl N-K1 S)-2-W(Z)-amino«2S)-1 - (cvclohexylmethyl)sulfonyllpiperidyl>methylidene)aminoloxy}-2-oxo-1 ' phenylethyllcarbamate
Figure imgf000211_0002
O=S=O 0= ΎS=O r ^o
HN. ^O
Figure imgf000211_0001
Figure imgf000211_0003
O.
The title compound was prepared by a similar method to Preparafion 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N'2-hydroxy-2-piperidinecarboximidamide [see Preparafion 28] and (2S)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoic acid to afford benzyl N-[(1S)-2-{[((Z)-amino{(2S)-1- [(cyclohexylmethyl)sulfonyl]piperidyl}methylidene)amino]oxy}-2-oxo-1- phenylethyl]carbamate as an oil.
-NMR (CDCy δ : 7.40 (10H, m), 5.90 (2/3H, m), 5.80 (1/3H, m), 5.55 (2/3H, m), 5.40 (1/3H, m), 5.10 (4H, m), 4.55 (1 H, s), 3.70 (1 H, m), 3.00 (1 H, m), 2.90 (2H, m), 2.15 (1H, m), 1.95 (3H, m), 1.70 (6H, m), 1.40 (1 H, m), 1.30 (3H, m), 1.05 (3H, m). -210-
Preparation 105 1-(1tf-Benzord1imidazol-2-ylsulfonvπ-N'2-|-(2-pyrimidinylcarbonyl)oxy1-2- piperidinecarboximidamide
~N' ^OH 'N' ^ o O=S=O NH, O=S=O NH,
Figure imgf000212_0001
^
HN N HN' ^N
V\ // \\ /
The title compound was prepared by a similar method to Preparation 20 from (Z)-1-(1 H-benzo[d]imidazol-2-ylsulfonyl)-N'2-hydroxy-2- piperidinecarboximidamide [see Preparation 19] and pyrimidine-2-carboxylic acid (see Chem. Ind. (London), 1954, 786) to afford 1-(1H-benzo[d]imidazol-2- ylsulfonyl)-N'2-[(2-pyrimidinylcarbonyl)oxy]-2-piperidinecarboximidamide as a gum. The title compound was used directly in Example 65.
-211-
It will be appreciated that what will be claimed is as follows: (i) a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(ii) a process for the preparafion of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof; (iii) a pharmaceufical composifion comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
(iv) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composifion thereof, for use as a medicament; (v) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of neuronal degeneration;
(vi) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the promotion of neuronal regeneration and outgrowth; (vii) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a neurological disease or disorder such as a neurodegenerative disease; (viii) use as in (vii) where the neurological disease or disorder is selected from the group consisting of senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar- brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or -212-
peripheral nervous system (e.g. spinal cord), hemiated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy
(both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases; (ix) use as (viii) where the neurological disease or disorder is senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, Huntington's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabetic or non- diabetic), multiple sclerosis or a hearing disorder such as tinnitus;
(x) a method of treatment of a human to treat neuronal degenerafion which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; (xi) a method of treatment of a human to promote neuronal regenerafion and outgrowth which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composifion thereof; (xii) a method of treatment of a human to treat a neurological disease or disorder such as a neurodegenerative disease which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; -213-
(xiii) a method as in (xii) where the neurological disease or disorder is selected from the group consisting of senile demenfia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar-brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), herniated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of autoimmune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain- Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neurifis), hearing disorders such as finnitus, and prion diseases; (xiv) a method as in (xiii) where the neurological disease or disorder is senile dementia (Alzheimer's disease) or another demenfia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease,
Huntington's disease, a neurological deficit associated with stroke, -214-
physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabefic or non- diabetic), mulfiple sclerosis or a hearing disorder such as finnitus; and
(xv) any novel intermediates described herein.
Table 6
EXAMPLE \C.n (nm) FKBP-12
25 81
14 91
1 95
23 336
65 442
43 1675
42 2010
11 685 (FKBP-52, K,)
Figure imgf000216_0001

Claims

-215- CLAIMS
1. A compound of the formula:
-R1 y
Y-W-R2 (I) or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 is a 5- or 6-membered ring heteroaryl group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heteroaryl group being linked to the adjacent carbon atom by a ring carbon atom and optionally substituted by from 1 to 3 substituents each independently selected from C, -C6 alkyl, C2-C6 alkenyl, -X-(C3-C7 cycloalkyl), -X-aryl, -X-het, -X-OH, -X-(CrC4 alkoxy), -X-CO2R5, -X-CN, and -X-NR3R4;
R2 is H, phenyl or C3-C7 cycloalkyl, said phenyl or cycloalkyl being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C^ -Cg alkyl, C^ -Cg alkoxy, -OH, -(CrC6 alkylene)OH, halo and halo(C1-C6 alkylene)-,
or R2 is a 5-, 6- or 7-membered ring heterocyclic group containing either 1 , 2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heterocyclic group being saturated or partially or fully unsaturated, optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by from 1 to 3 substituents each independently selected from C1 -C6 alkyl, C, -C6 alkoxy, halo, halo(C1 -C6 alkylene)- and -CO2R5 ,
said R2 group being attached to W by any mono- or bicyclic ring carbon atom or heteroatom; R3 and R4 are either each independently selected from H, C, -C6 alkyl, -216- C3-C6 cycloalkyl and -(C C6 alkylene)(C3-C6 cycloalkyl), or, when taken together, represent unbranched C3 -C6 alkylene opfionally containing O or NR5;
R5 is H, C, -C6 alkyl, C3-C6 cycloalkyl, -(CrC6 alkylene)(C3-C6 cycloalkyl) or -(C, -C6 alkylene)aryl;
A is unbranched C3-C5 alkylene opfionally substituted by C^ -C6 alkyl;
W is a direct link, C1 -C6 alkylene or C2-C6 alkenylene;
X is a direct link, C^Cg alkylene or -(C0-C6 alkylene)-Z-(C0-C6 alkylene)-;
Y is SO2 , carbonyl, -CONR5-, -CO.CO-, -CH2CO-, -CS.CO-, -CO.CS- or - CO.CH(OH)-;
Z is O, S, -CR5NR3R4-, -CR5NR5(CO2R5)-, -CR5(aryl1)-, -NR5-, -NR5CO2 -, -CONR5- or -NR5CO-;
aryl" is phenyl opfionally substituted by from 1 to 3 substituents each independenfiy selected from C^ -C6 alkyl, C, -C6 alkoxy, -(C, -C6 alkylene)(C C6 alkoxy), halo, halo(C1 -C6 alkylene)-, -NR3R4 , -(C, -C6 alkylene)NR3R4, -(C^Cg alkylene)OH, -0(C, -C6 alkylene)NR3R4 and -(CrC6 alkylene)(phthalimido);
"aryl1 " is phenyl optionally substituted by from 1 to 3 substituents each independenfiy selected from C, -C6 alkyl, C, -C6 alkoxy, -(C1 -C6 alkylene)(C1-C6 alkoxy), halo and halo(C1 -C6 alkylene)-; and
"het" is a 5-, 6- or 7-membered ring heterocyclic group containing either 1 ,
2, 3 or 4 nitrogen heteroatoms, or 1 oxygen or sulphur heteroatom and, optionally, 1 or 2 nitrogen heteroatoms, said heterocyclic group being saturated or partially or fully unsaturated, or "het" is azetidinyl, said "het" being opfionally substituted by from 1 to 3 substituents each independently selected from C, -C6 alkyl, C, -C6 alkoxy, C3-C7 -217- cycloalkyl, -(C^Cg alkylene)(CrC6 alkoxy), -(C^Cg alkylene)(C3-C7 cycloalkyl), halo, halo(C1 -C6 alkylene)-, -NR3R4, -CO2R5, -(C, -C6 alkylene)aryi and -(C, -C6 alkyiene)NR3R4:
with the provisos that
(a) the heteroaryl group of R1 is not substituted by -(C0-C6 alkylene)-Z-(C0 alkylene)(-OH or -C C4 alkoxy or -CN or -NR3R4) when Z is O, S, -NR5-, -
NR5CO2 - or -CONR5-;
(b) when W is a direct link, R2 is only H when Y is -CONR5- ;
(c) when A is C3 alkylene, Y is sulphonyl, W is a direct link, and R2 is para methyl substituted phenyl, then R1 is not
N(CH3)2 N O // N . v\ N V_/
N or // N
N- N
N NH 2
(d) when A is C4 alkylene, Y is carbonyl, W is C, alkylene and R 22 is H, then R1 is not
Figure imgf000219_0001
CH3
(e) when A is C4 alkylene, Y is carbonyl, W is a direct link and R2 is 3-hydroxy phenyl,
then R1 is not
< ; and -218- (f) when A is C3 alkylene, Y is carbonyl, W is a direct link and R2 is phenyl, then R1 is not furan-2yl.
A compound as claimed in claim 1 having the stereochemical formula (I')
A H
N R1 C)
Y-W-R2 wherein R1, R2, A, W and Y are as defined in claim 1 formula (I).
3. A compound as claimed in claims 1 or 2 wherein R1 is triazolyl, isoxazolyl, oxadiazolyl, tetraazolyl, thiazolyl or thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and opfionally substituted by 1 , 2 or 3 substituents each independently selected from C.,-C6 alkyl, -X-aryl, -X-het, -X- CO2R5 and -X-NR3R4.
4. A compound as claimed in claim 3 wherein X is a direct link, C^Cg alkylene or (C0-C6 alkylene)-Z-(C0-C6 alkylene)-; Z is O, -CR5NR3R4, -CR5NR5(CO2R5)-, -NR5- or -NR5CO2-; wherein said aryl of -X-aryl is phenyl optionally substituted by from 1 to 3 substituents each independently selected from -(C1-C6alkylene)OH,-(C1-C6 aikylene)NR3R4,-O-(CrCg alkylene)NR3R4 and -(C Cβ alkylene)(phthalimido); and said "het" of -X-het is piperidyl, pyrazinyl, furyl, piperazinyl, pyrimidinyl or morpholinyl, opfionally substituted by from 1 to 3 -(C C6 alkylene)(C3-C7 cycloalkyl),-(CrCg alkylene)aryl substituents; or C02R5 where R5 is (C C6 alkylene) aryl; or (C,-Cβ) alkyl; or (CrC6 alkylene) NR3R4 where "het" is furyl
R3 and R4 are either each independently selected from H and C,-C6 alkyl or, when taken together, represent unbranched C3-C6 alkylene; and R5 is H or CrC6 alkyl.
5. A compound as claimed in any one of the preceding claims wherein R1 is 1 ,2,4- -219- triazolyl, isoxazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl or 1 ,3,4-thiadiazolyl, that is linked to the adjacent carbon atom by a ring carbon atom and opfionally
substituted by 1 , 2 or 3 substituents each independently selected from methyl, benzyl, α-(amino)benzyl, R or S-oc-(amino)benzyl, α-(tert- butoxycarbonylamino)benzyl, benzylamino, benzylaminoethyl, aminomethylphenoxymethyl, methylaminomethylphenoxymethyl, dimethylaminomethylphenoxymethyl, amino methylphenoxymethyl, hydroxymethylphenoxymethyi, benzylaminoethyl, butoxycarbonylethypiperazinyl, benzoaminomethyl, pyrrolidinylmethylphenoxymethyl, aminoethoxybenzyl, pyrazinyl, cyclopropylmethylpiperidyloxymethyl, hydroxymethylphenoxymethyi, tertbutyloxycarbonylpiperazinylethyl, pyrimidinyl, (S)-α-
(benzyloxycarbonylamino)benzyl, piperazinoethyl, phenylcarbonyiaminoethyl, dimethylaminoethyl, hydrogen, phenyl, phenethyl, cyclohexylamino phthalimidomethylphenoxymethyl, piperidyloxymethyl, benzylpiperidyloxymethyl, benzylpiperidyloxyethyl, morpholinomethyl, benzyloxycarbonylaminoethyl, amino, aminoethyl, benzyloxycarbonylpiperidinyloxymethyl, methylaminofuranyl or ( R)-α- (benzyloxycarbonylamino)benzyl.
6. A compound as claimed in claims 4 or 5 wherein R1 is 5-benzyl-1 ,2,4-oxadiazol-3-yI,
5-(4-[phthalimidomethyl]phenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-aminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-dimethylaminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-pyrrolidinomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(4-methylaminomethylphenoxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-(1 -benzylpiperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl, 5-(α-[tert-butoxycarbonylamino]benzyl)-1 ,2,4-oxadiazol-3-yl, 5-morpholinomethyl-1 ,2,4-oxadiazol-3-yl, -220-
5-(2-[1 -benzylpiperid-4-yloxy]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(1 H-piperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-[α-[amino]benzyl)-1 ,2,4-oxadiazol-3-yl, 5-(2-[benzyloxycarbonylamino]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(2-aminoethyl )- 1 ,2 ,4-oxadiazol-3-yl ,
5-(2-[benzylamino]ethyl)-1 ,2,4-oxadiazol-3-yl,
5-(4-[2-aminoethoxy]benzyl)-1 ,2,4-oxadiazol-3-yl,
5-methyl-1 ,3,4-thiadiazol-2-yl, 1 H-1 ,2,4-triazol-3-yl,
1-benzyl-1 H-1 ,2,4-triazol-3-yl,
5-benzyl-4-methyl-4H-1 ,2,4-triazol-3-yl,
5-amino-1 ,3,4-oxadiazol-2-yl,
5-benzylamino-1 ,3,4-oxadiazol-2-yl, 3-methylisoxazol-5-yl,
5-(pyrazin-2-yl)-1 ,2,4-oxodiazol-3-yl,
5-( R)-[ -(amino)benzyl]-1 ,2,4-oxadiazol-3-yl,
5-(S)-[α-(amino)benzyl]-1 ,2,4-oxadiazol-3-yl,
5-(5-methylaminofuran-2-yl)-1 ,2,4-oxadiazol-3-yl, 5-(1-benzyloxycarbonylpiperid-4-yloxymethyl)-1 ,2,4-oxadiazol-3-yl,
5-(1 -cyclopropylmethylpiperid-4-yloxymethyl) -1 ,2,4-oxadiazol-3-yl,
5-(4-hydroxymethylphenoxymethyl) -1 ,2,4-oxadiazol-3-yl,
5-[2-(4-tert-butoxyca rbonyl pi perazin-4-yl )ethyl] - 1 ,2 ,4-oxad iazol-3-yl ,
5-(pyrimidin-2-yl) -1 ,2,4-oxadiazol-3-yl, 5-methyl-1 ,2,4-oxadiazol-3-yl,
5-benzylaminomethyl-1 ,2,4-oxadiazol-3-yl,
5-(S)-(α-[benzyloxycarbonylamino]benzyl) -1 ,2,4-oxadiazoI-3-yl,
5-(R)-(α-[benzyloxycarbonylamino]benzyl) -1 ,2,4-oxadiazol-3-yl,
5-[2-(4H-piperazin-1-yl)ethyl] -1 ,2,4-oxadiazol-3-yl, 5-[2-(phenylcarbonylamino)ethyl] -1 ,2,4-oxadiazol-3-yl,
5-[2-(dimethylamino)ethyi] -1 ,2,4-oxadiazol-3-yl,
1 ,2,4-oxadiazol-3-yl,
5-phenyl -1 ,2,4-oxadiazol-3-yl, -221-
2-benzyl-2H -1 ,2,3,4-tetraazol-5-yl, 5-benzyl-1 ,3,4-oxadiazol-2-yl, 5-[2-(phenyl)ethyl] -1 ,3,4-oxadiazol-2-yl, 5-methyl-2H-1 ,2,3,4-tetraazol-5-yl,
5-cyclohexylamino -1 ,3,4-oxadiazol-2-yl, 5-methyl -1 ,3,4-oxadiazol-2-yl, 3-methyl -1 ,2,4-oxadiazol-3-yl, 5-methyl -1 ,3-thiazol-2-yl, 5-methyl-1 H- 1 ,2,4-triazol-3-yl,
5-aminomethyl -1 ,2,4-oxadiazol-3-yl or 2H- 1 ,2,3,4-tetraazol-5-yl.
7. A compound according to any one of the preceding claims wherein R1 is 1 ,2,4 or 1 ,3,4 oxadiazole, that is linked to the adjacent carbon atom by a ring carbon atom which is optionally preferably-mono-substituted by one of -X-aryl or -X-het wherein X is preferably selected from -(C0-C2 alkylene)-Z-(C0-C2 alkylene), more preferably -(C1 alkylene)-Z-(C0 alkylene) where Z is -0-; or X is a direct link or - (CrC2 alkylene); or X is -(C0 alkylene)-Z-(C0 alkylene) where Z is -CR5NR3R4, or -CR5 NR5 (CO2R5) where R3 and R4 are selected from H,-(C1-C3 alkylene), more preferably H,-(CrC2 alkylene) and R5 is H or -(C C4 alkylene), or -(C C2 alkylene)aryl; or X is -(CrC2 alkylene) -Z-(CrC2 alkylene)(aryl) where Z is NR5 and R5 is H or -(C^C, alkylene)-;
wherein aryl of -X-aryl is phenyl opfionally substituted by from 1 to 3 susbtituents independently selected from -(C,-C3 alkylene) NR3 R4, -(^-Cg alkylene)(phthalimido); -0(C C3 alkylene) NR3 R4 or -C02R5 wherein R3 and R4 are each independently selected from H, CrC3 alkyl or, when taken together, represent unbranched C3-C5 alkylene; and R5 is H, C C4 alkyl or -(C C2 alkylene) aryl;
wherein "het" of -X-het is piperidinyl, furyl, pyrazinyl, pyrimidinyl or piperazinyl opfionally substituted by -(C,-C3 alkylene)(-C3-C6 cycloalkyl), -C02R5, -(C C3 -222- alkylene)NR3R4 or -(C.,-C2 alkylene)aryl wherein aryl is phenyl and wherein R3 and R4 are selected from H,-(C C3 alkylene), more preferably H,-(C C2 alkylene) and R5 is H or -(C C4 alkylene), or -(C C2 alkylene)aryl;
or X is -(C1-C2 alkylene) -Z-(CrC2 alkylene)(aryl) where Z is NR5 and R5 is H or - (0,-02 alkylene)-.
8. A compound as claimed in any one of the preceding claims wherein R2 is H, phenyl or C3-C7 cycloalkyl, said phenyl or cycloalkyl being optionally substituted by from 1 to 3 halo substituents, or R2 is a 5- or 6- membered ring heterocyclic group containing either 1 or 2 nitrogen heteroatoms or 1 oxygen heteroatom, said heterocyclic group being saturated or partially or fully unsaturated, optionally benzo-fused and opfionally substituted, including in the benzo-fused portion, by from 1 to 3 halo, halo(C1-C6 alkyl), C1-C6 alkyl substituents, said R2 group being attached to W by any mono- or bicyclic ring carbon atom or heteroatom.
9. A compound as claimed in claim 8 wherein R2 is H, phenyl, cyclopentyl cyclohexyl or cydoheptyl, said phenyl being opfionally substituted by from 1 to
3 fluoro substituents, or R2 is imidazolyl, pyrrolidinyl, piperidinyl or tetrahydrofuranyl, said imidazolyl or tetrahydrofuranyl group being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by from 1 to 3 methyl, bromine or fluorine substituents, said R2 group being attached to W by any mono- or bicyclic ring carbon atom.
10. A compound as claimed in claim 9 wherein R2 is H, fluorophenyl, cyclopentyl, cyclohexyl, cydoheptyl, methylimidazolyl, benzimidazolyl, bromobenzimidazolyl or furanyl,
11. A compound as claimed in claim 10 wherein R2 is H, 4-fluorophenyl, cyclopentyl, cyclohexyl, cydoheptyl, 1-methyl-1 H-imidazol-4-yl, 1 H-benzo[d]imidazol-2-yl, 5- bromo-1 H-benzo[d]imidazol-2-yl or -223- tetrahydrofuran-3-yl,
12. A compound as claimed in any one of the preceding claims wherein W is a direct link, methylene, ethylene or 2,2-dimethyl-1 ,3-propylene.
13. A compound as claimed in any one of the preceding claims wherein Y is SO2 or -CONR5-., and wherein R5 is as defined in any one of the preceding claims.
14. A compound as claimed in claim 13 wherein Y is S02 or -CONH-.
15. A compound as claimed in any one of the preceding claims wherein -Y-W-R2 are
5-bromo-1 H-benzo[d]imidazolll-2-yl sulphonyl,
1 H-benzo[d]imidazol-2-ylsulphonyl,
1 -methyl-1 H-imidazol-4-ylsulphonyl, tetrahydrofuran-3-ylmethylsulphonyl, cyclohexylmethylsulphonyl,
4-fluorophenylsulphonyl,
N-(2,2-dimethylprop-1-yl)aminoca rbonyl, cyclopentylmethylsulphonyl, cycloheptylmethylsulphonyl, 1-(benzyloxycarbonyl)pyrrolidin-3-ylmethylsulphonyl,
1-(benzyloxycarbonyl)piperid-3-ylmethylsulphonyl, benzylaminocarbonyl or phenethylaminocarbonyl.
16. A compound as claimed in any one of the preceding claims selected from the group consisting of:
1 H-Benzo[d]imidzol-2-yl[2S]-2-(5-benzyl-1 ,2,4-oxadiazol-3-yI)-1 - piperidylsulphone, -224-
2-[4-(3-[(2S)-1-(1H-Benzo[c ]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-
5-ylmethoxy)benzyl]-1 ,3-isoindoiinedione,
4-(3-[(2S)-1 -(1 /-/-Benzo[α midazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzylamine,
Λ/-[4-(3-[(2S)-1 -(1 H-Benzo[αrjimidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-
5-ylmethoxy)benzyl]-/V, /-dimethylamine,
3-[1 -(1 H-Benzo[cφmidazol-2-ylsulfonyl)-2-piperidyl]-5-[4-(1 - pyrrolidylmethyl)phenoxy]methyl-1 ,2,4-oxadiazole, Λ/-[4-(3-[1 -(1 H-Benzo[c0imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethoxy)benzyl]-/V-methylamine,
4-[3-((2S)-1-[Cyclohexylmethylsulfonyl]-2-piperidyl)-1 ,2,4-oxadiazol-5- ylmethoxyjbenzylamine,
5-[(1-Benzyl-4-piperidyl)oxymethyl]-3-[(2S)-1-cyclohexylmethylsulfonyl-2- piperidyl]-1 ,2,4-oxadiazole,
S-^SJ-l-Cyclohexylmethylsuifonyl^-piperidy -δ-μ-piperidyloxymethylj-l ^^- oxadiazole,
(3-[(2S)-1-Cyclohexylmethylsulfonyl-2-piperidyl]-1 ,2,4-oxadiazol-5- yl)(phenyl)methylamine, 5-(3-(2S)-1 -[(Cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4-oxadiazol-5-yl)-2- furyljmethylamine,
Λ/-(2-(3-[1 -(1 H-Benzo[cGimidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- yl)ethyl)benzylamine, 2-[4-(3-[1 -(1 H-Benzo[σ]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethyl)phenoxy]ethylamine,
Λ/-(3-[1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4-oxadiazol-5- ylmethyl)-/\/-benzylamine, -[(2S)-2-5-[(4-Piperidyloxy)methyl]-1 ,2,4-oxadiazol-3-yl-1-piperidyl]sulfonyl-
1 /- -benzo[d] imidazole, 2-[(2S)-2-[5-([1 -(Cyclopropylmethyl)-4-piperidyI]oxymethyl)-1 ,2,4-oxadiazol-3- yl]-1 -piperidyl]sulfonyl-1 H-benzo[d]imidazole,
2-[(2S)-2-(5-Benzyl-1 ,2,4-oxadiazol-3-yl)-1 -piperidyl]sulfonyl-5-bromo-1 H- benzo[d]imidazole, -225-
2-4-[(3-(2S)-1 -[(5-Bromo-1 H-benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl-1 ,2,4- oxadiazol-5-yl)methoxy]benzyl-1 ,3-isoindolinedione, 4-[(3-(2S)-1 -[(5-Bromo-1 H-benzo[d]imidazol-2-yl)sulfonyl]-2-piperidyl-1 ,2,4- oxadiazol-5-yl)methoxy]benzylamine, etf-Butyl 4-[2-(3-(1 S)-2-[(cyclohexylmethyl)sulfonyl]-2-piperidyl-1 ,2,4- oxadiazol-5-yl)ethyl]-1 -piperazinecarboxylate,
(R)-(3-{(2S)-1-[(Cyclohexylmethyl)sulfonyl]-2-piperidyl}-1 ,2,4-oxadiazol-5- yl)(phenyl)methylamine, (S)-(3-{(2S)-1 -[(Cyclohexylmethyl)sulfonyl]-2-piperidyl}-1 ,2,4-oxadiazol-5- yl)(phenyl)methylamine,
2-({2-[5-(2-pyrimidinyl)-1 ,2,4-oxadiazol-3-yl]-2-piperidyl}sulfonyl)-1H- benzo[d]imidazole,
Benzyl 4-(3-[(2S)-1 -(1 H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1 ,2,4- oxadiazol-5-ylmethoxy)-1 -piperidinecarboxylate,
(2S)-2-(5-Benzyl-1 ,2,4-oxadiazol-3-yl)-1- [(cyclopentylmethyl)sulphonylpiperidine, (2S)-2-(5-Benzyl-1 ,2,4-oxadiazol-3-yl)-1 - [(cyclohexylmethyl)sulphonylpiperidine, (2S)-2-(5-Benzyl-1 ,2,4-oxadiazol-3-yl)-1 -
[(cycloheptylmethyl)sulphonylpiperidine, tert-Butyl-N-(3-{(2S)-1-(cyclohexylmethyl)sulphonyl-2-piperidyl}-1 ,2,4-oxadiazol
5-yl)(phenyl)methylcarbamate, (2S)-2-(5-{2-[(1-Benzyl-4-piperidyl)oxy]ethyl}-1 ,2,4-oxadiazol-3-yl)-1- [(cyclohexylmethyl)sulphonyl]piperidine,
{4-{3-{2S-1-[4-Fluorophenyl)sulphonyl]piperidyl}-1 ,2,4-oxadiazol-5- yl)methoxy]phenyll}methanol, 2-(3-{(2S)-1-[4-Fluorophenyl)sulphonyl]piperidyl}-1 ,2,4-oxadiazol-5-yi)pyrazine or 1 -[2-(3-(1 S)-2-[(Cyclohexylmethyl)sulphonyl]-2-piperidyl-1 ,2,4-oxadiazol-5- yl)ethyl]piperazine. -226-
17. A pharmaceutical composifion comprising a compound as claimed in any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
18. A compound as claimed in any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or composifion thereof, for use as a medicament.
19. The use of a compound as claimed in any one of claims 1 to 16 or of a pharmaceutically acceptable salt, solvate or composifion thereof, for the manufacture of a medicament for the treatment or prophylaxis of neuronal degeneration.
20. The use of a compound as claimed in any one of claims 1 to 16 or of a pharmaceutically acceptable salt, solvate or composifion thereof, for the manufacture of a medicament for the promotion of neuronal regeneration and outgrowth.
21. The use of a compound as claimed in any one of claims 1 to 16 or of a pharmaceutically acceptable salt, solvate or composifion thereof, for the manufacture of a medicament for the treatment of a neurological disease or disorder selected from the group consisting of senile demenfia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neuron disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar-brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), herniated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of -227- peripheral neuropathy (both diabefic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases.
22. Use as claimed in claim 20 where the neurological disease or disorder is senile demenfia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron disease, Parkinson's disease, Huntington's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabefic or non-diabetic), mulfiple sclerosis or a hearing disorder such as finnitus;
23. A method of treatment of a human to treat neuronal degenerafion which comprises treating said human with an effective amount of a compound as claimed in any one of claims 1 to 16 or with a pharmaceutically acceptable salt, solvate or composition thereof.
24. A process for the preparafion of a compound of formula (I) comprising:
(a) reacfion of a compound of the formula:
"CH-R1 (II) H wherein R1 and A are as defined in claim 1 for a compound of formula (I), with a compound of the formula (III):
L1-Y-W-R2 (III) -228- wherein R2, W and Y are as previously defined in claim 1 for a compound of the formula (I) and L1 is a suitable leaving group; or
(b) by ring formation of R1 or ring closure of a corresponding open ring structure of R1, in formula (II) wherein A is as defined in claim 1 for a compound of formula (I), and wherein the said open ring corresponds to an optionally substituted heterocycle R1 , as is defined in claim 1 for a compound of formula (I), followed by reacfion with a compound of formula (III); or
(c) by ring formation of R1 or ring closure of a corresponding open ring structure of R1, in formula (I):
H-RI y
Y-W-R2 (I) wherein A is as defined in claim 1 for a compound of formula (I), and wherein the said open ring corresponds to an opfionally substituted heterocycle R , as is defined in claim 1.
25. A compound having the general formula (II):
^CH-R1 (II)
N
H wherein R1 and A are as defined in claim 1 for a compound of formula (I).
26. A compound of general formula (XIIA):
O
/\ 1A
A N-O R1A
I H — <7 (XIIA)
I NH2 Y~W-R2 99/45006
-229- wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R1A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I).
27. A compound of general formula (XIV):
ACHCONHNHCOR1* (XIV)
N
Y-W-R2 wherein R2, A, W and Y are as previously defined for a compound of the formula (I) and R A is a relevant group corresponding to an optional substituent on the heteroaryl group as previously defined for R1 for a compound of the formula (I).
PCT/IB1999/000259 1998-03-02 1999-02-15 Heterocyclic compounds as inhibitors of rotamase enzymes Ceased WO1999045006A1 (en)

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AT99901847T ATE248836T1 (en) 1998-03-02 1999-02-15 HETEROCYCLIC COMPOUNDS AS INHIBITORS OF ROTAMASE ACTIVITY
CA002322442A CA2322442A1 (en) 1998-03-02 1999-02-15 Heterocyclic compounds as inhibitors of rotamase enzymes
JP2000534548A JP3668133B2 (en) 1998-03-02 1999-02-15 Heterocyclic compounds as inhibitors of rotamase enzymes
DE69910984T DE69910984T2 (en) 1998-03-02 1999-02-15 HETEROCYCLIC COMPOUNDS AS INHIBITORS OF ROTAMASE ACTIVITY
EP99901847A EP1060178B1 (en) 1998-03-02 1999-02-15 Heterocyclic compounds as inhibitors of rotamase enzymes
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US6689800B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. β3-adrenergic receptor agonist crystal forms, processes for the production thereof, and uses thereof
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