GB2373186A - Pharmaceutical combinations of a CCR3 antagonist and a compound which is usefulreatment of asthma, allergic disease or inflammation - Google Patents

Pharmaceutical combinations of a CCR3 antagonist and a compound which is usefulreatment of asthma, allergic disease or inflammation Download PDF

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Publication number
GB2373186A
GB2373186A GB0104534A GB0104534A GB2373186A GB 2373186 A GB2373186 A GB 2373186A GB 0104534 A GB0104534 A GB 0104534A GB 0104534 A GB0104534 A GB 0104534A GB 2373186 A GB2373186 A GB 2373186A
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alkyl
dichlorobenzyl
piperidinyl
phenyl
alkoxy
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GB0104534D0 (en
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Ash Bahl
Matthew Perry
Brian Springthorpe
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AstraZeneca AB
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AstraZeneca AB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Abstract

The invention provides a pharmaceutical combination comprising a compound of formula (I): <EMI ID=1.1 HE=20 WI=92 LX=616 LY=803 TI=CF> <PC>wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>6</SP>, Z, Q, m, n, X<SP>1</SP>, X<SP>2</SP>, X<SP>3</SP>, X<SP>4</SP> and T are as defined in the specification, and a histamine antagonist, a steroid, a leukotriene modulator, a human cytokine, a beta-agonist, a phosphodiesterase inhibitor or an antibody; a process for preparing such a combination and the use of such a combination in therapy (especially the treatment of asthma or rhinitis). In particular, the compounds of formula (I) are substituted piperidines and substituted 8-azabicyclo[3.2.1.]octanes and are described as being CCR3 antagonists.

Description

PHARMACEUTICAL COMBINATION
The present invention relates to a pharmaceutical combination comprising a piperidine CCR3 antagonist compound and compound useful in the treatment of asthma, alergic disease or inflammation, to a process for preparing such a combination and to the use of such a combination in therapy.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
CCR3 antagonists are disclosed in WOOO/58305.
The present invention provides a pharmaceutical combination comprising a compound of formula (I) :
wherein Z is CR4R5, C (O) or CR4R5-Zl1; Z is C1-4 alkylene (such as CH2), 24 alkenylene (such as CH=CH) or C (O) NH; R represents a C1-12 alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C1-6 alkoxy (such as methoxy or ethoxy), Ci- 6 alkylthio (such as methylthio), C3-7 cycloalkyl (such as cyclopropyl), C alkoxycarbonyl (such as methoxycarbonyl) and phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl (such as CF3), phenyl (C1-6 alkyl) (such as benzyl), C1-6 alkoxy, C1-6 haloalkoxy, S (Oh (C1-6 alkyl), C (O) NH2, carboxy or Cl 6 alkoxycarbonyl); or
R'represents C2-6 alkenyl optionally substituted by phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, phenyl (C1-6 alkyl), C1-6 alkoxy, C1-6 haloalkoxy, S (Oh (C1-6 alkyl), C (O) NH2, carboxy or Ci. 6 alkoxycarbonyl) ; or Ri represents a 3-to 14-membered saturated or unsaturated ring system which optionally comprises up to two ring carbon atoms that form carbonyl groups and which optionally further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents
independently selected from : halogen, cyano, nitro, oxo, hydroxyl, CI-8 alkyl, CI-6 hydroxyalkyl, Cl-6 haloalkyl, Cl-6 alkoxy (C1 6 alkyl), C3 7 cycloalkyl (Cl-6 alkyl), Ci. 6 alkylthio (CI-C6 alkyl), Cl-6 alkylcarbonyloxy (CI-6 alkyl), CI-6 alkylS (0) 2 (Cl-6 alkyl), aryl (CI-6 alkyl), heterocyclyl (CI-6 alkyl), aryIS (0) 2 (CI-6 alkyl), heterocyclyIS (0) 2 (CI-6 alkyl), aryl (Cl 6 alkyl) S (0) 2, heterocyclyl (CI-6 alkyl) S (0) 2, 2-6 alkenyl, Ci. 6 alkoxy, carboxy-substituted Cl-6 alkoxy, Cl-6 haloalkoxy, Cl-6 hydroxyalkoxy, Cl-6 alkylcarboxysubstituted Cl-6 alkoxy, aryloxy, heterocyclyloxy, Cl-6 alkylthio, C3-7 cycloalkyl (C, 6 alkylthio), C3-6 alkynylthio, Cj-6 alkylcarbonylamino, Ci-6 haloalkylcarbonylamino, SO3H, NR7R8, C (O) NR23R24, S (0) 2NR'8R, S (0) 2R, R25C (O), carboxyl, Cl-6 alkoxycarbonyl, aryl and heterocyclyl ; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, Cl-6 alkyl, Cl-6 haloalkyl, phenyl (CI-6 alkyl), Cl-6 alkoxy, Cl-C6 haloalkoxy, S (0) (Cl-6 alkyl), C (O) NH2, carboxy or Cul 6 alkoxycarbonyl ; m is 0 or 1 ; Q represents an oxygen or sulphur atom or a group NR9, C (O), C (O) NR9, NR9C (O) or CH=CH ; n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is 0 ; each R2 and R3 independently represents a hydrogen atom or a Cl-4 alkyl group, or (CR2R3) n represents C3-7 cycloalkyl optionally substituted by Cl-4 alkyl ; T represents a group NR' , C (O) Ni10, NR"C (O) NR or C (O) NRR ; Xl, X2, X3 and X4 are, independently, CH2, CHRl2 {wherein each R is, independently, 12 12 C14 alkyl or C3-7 cycloalkyl (Cl-4 alkyl)} or C=O ; or, when they are CHR, the R groups of Xl and X3 or X4, or, X2 and X3 or X4 join to form a two or three atom chain which is CH2CH2, CH2CH2CH2, CH20CH2 or CH2SCH2 ; provided always that at least two of Xl, X2, X3 and X4 are CH2 ; R4 and R each independently represent a hydrogen atom or a Ci-C4 alkyl group ; R6 is aryl or heterocyclyl, both optionally substituted by one or more of : halogen, cyano, nitro, oxo, hydroxyl, Cl s alkyl, Cl 6 hydroxyalkyl, Cl 6 haloalkyl, Cl 6 alkoxy (Cl-6 alkyl), C3-7 cycloalkyl (Ci-6 alkyl), Cl-C6 alkylthio (Cl-6 alkyl), Cl-6 alkylcarbonyloxy (Cl-6 alkyl), CI-6 alkylS (0) 2 (CI-6 alkyl), aryl (Cl-6 alkyl), heterocyclyl (Ci-6 alkyl), aryO2 (C alkyl), heterocyclylS (0) (Cl-6 alkyl), aryl (Cl-6 alkyl) S (0) 2, heterocydyl (Ci. 6 alkyl) S (0) 2, 2-6 alkenyl, Cl 6 alkoxy, carboxy-substituted CI-6 alkoxy, Cl 6 haloalkoxy, CI-6 hydroxyalkoxy,
Cl-C6 alkylcarboxy-substituted Cl 6 alkoxy, aryloxy, heterocyclyloxy, Ci. 6 alkylthio, C3-7 cycloalkyl (CI-6 alkylthio), C3-6 alkynylthio, Cl 6 alkylcarbonylamino, CI-6 6 17 2 22 13 14 haloalkylcarbonylamino, S03H,-NRR,-C (O) NRR22, S (0) 2NRR, S (0) 2R, R26C (O), carboxyl, CI-6 alkoxycarbonyl, aryl and heterocyclyl ; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, CI-6 alkyl, CI-6 haloalkyl, phenyl (CI-6 alkyl), CI-6 alkoxy, CI-6 haloalkoxy, S (0) 2 (Ci.
6 alkyl), C (O) NH2, carboxy or Cl 6 alkoxycarbonyl ; 7 13 14 16 17 18 21 22 23 24 R, R8, R9, Rlo, R", R, R, R, R, R, R'9, R, R, R and R are, independently hydrogen, CI-6 alkyl, CI-6 haloalkyl, Cl-6 hydroxyalkyl, C3-7 CYcloalkyl, C3-7 CYClOalkyl (CI4 alkyl) or phenyl (C 1-6 alkyl) ; and, Ris and R20 are, independently, Cl-6 alkyl, CI-6 hydroxyalkyl, C3-6 cycloalkyl, C3-7 cycloalkyl (C 1-4 alkyl) or C 1-6 alkyl optionally substituted by phenyl ; R25 and R26 are, independently, C 1-6 alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, Cl-6 alkyl, Cl-6 haloalkyl, phenyl (CI-6 alkyl), Cl-6 alkoxy, CI-6 haloalkoxy, S (0) (Cl-6 alkyl), C (O) NH2, carboxy or Cl 6 alkoxycarbonyl) ; or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof ; provided that when T is C (O) NR and Ru ils optionally substituted phenyl then n is not 0 ; and a histamine antagonist, a steroid, a leukotriene modulator, a human cytokine, a betaagonist, a phosphodiesterase inhibitor or an antibody.
Histamine antagonists are, for example, loratidine, desloratidine, fexofenadine, cetirizine, ebastine, astemizole, norastemizole, epinastine or efletirizine.
Steroids are, for example, budesonide, fluticasone, mometasone or rofleponide (such as rofleponide palmitate).
Leukotriene modulators are, for example, montelukast (such as in its sodium salt form), pranlukast, zafirlukast, Z4407 or zafirlukast.
Human cytokines are, for example, recombinant human IL-10 or IL-12.
Beta-agonists are, for example, formoterol, salmeterol or salbutamol.
Phosphodiesterase inhibitors are, for example, SB-207499 (ARIFLOO) or theophylline.
Antibodies are, for example, anti-IL-5 antibodies or anti-TNF-antibodies (such as infliximab).
CertaI : mpounds of formula (I) are capable of existing in isomeric forms (for example as tautomers, enantiomers, geometric isomers or diastereomers). The present invention encompasses all such isomers and mixtures thereof in all proportions.
Hydroxyalkyl is, for example, 2-hydroxyeth-l-yl. Haloalkyl is, for example, CF3.
Alkoxy is, for example, methoxy or ethoxy. Alkoxy (C1-6 alkyl) is, for example, methoxymethyl or ethoxyethyl. Cycloalkyl is, for example, cyclopropyl or cyclohexyl.
Cycloalkyl (C1-6 alkyl) is, for example, cyclopropylmethyl. Alkylthio is, for example, methylthio or ethylthio. Alkylthio (Cl 6 alkyl) is, for example, methylthiomethyl.
Alkylcarbonyloxy (C1-6 alkyl) is, for example, CH3C (O) OCH2. S (0) 2 (Cl 6 alkyl) is, for example, CH3S (0) 2. AlkylS (0) 2 (Cl 6 alkyl) is, for example, CH3S (0) 2CH2. AryI (Ci. 6 alkyl) is, for example, benzyl, 2-phenyleth-l-yl or 1-phenyleth-1-yl. Heterocyclyl (CI-6 alkyl) is, for example, heterocyclylmethyl. ArylS (0) 2 (C, 6 alkyl) is, for example, phenyl (0) 2CH2. HeterocyclyIS(O) 2 (Cl 6 alkyl) is, for example, heterocyclylS (0) 2CH2.
Aryl (CI-6 alkyl) S (0) 2 is, for example, benzylS (0) 2. Heterocyclyl (Cl 6 alkyl) S (0) 2 is, for example, heterocyclylCH2S (0) 2. Alkenyl is, for example, vinyl or allyl. Carboxysubstituted Cl 6 alkoxy is, for example, HOC (O) CH2CH20. Haloalkoxy is, for example, OCF3. Hydroxyalkoxy is, for example, HOCH2CH20. Alkylcarboxy-substituted CI-6 alkoxy is, for example, CH30C (O) CH2CH20. Aryloxy is, for example, phenoxy.
Heterocyclyloxy is, for example, pyridinyloxy or pyrimidinyloxy. C3-7 cycloalkyl (C3-6 alkylthio) is, for example, cyclopropylCH2S. Alkynylthio is, for example, propargylthio. Alkylcarbonylamino is, for example, acylamino. Haloalkylcarbonylamino is, for example, CICH2C (O) NH. Alkoxycarbonyl is, for example, CH30C (O).
Aryl is a carbocyclic aromatic ring optionally fused to one or more carbocyclic rings. Aryl is, for example, phenyl, naphthyl or indanyl.
Heterocyclyl is an aromatic or non-aromatic ring system preferably comprising up to 6 (preferably up to 4) heteroatoms selected from the group comprising nitrogen, oxygen and sulphur, and preferably comprising one, two or three 5-or 6-membered rings.
Heterocyclyl is, for example, furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3triazolyl, 1,2, 4-triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl (for example 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), pyrimidinyl (for example 2-pyrimidinyl or 4-pyrimidinyl), pyrazinyl, pyridazinyl, indolyl, 2,3-dihydroindolyl,
benzo [b] furyl, benz [b] thienyl, 2, 3-dihydrobenz thienyl (for example 1-dioxo-2, 3dihydrobenz [b] thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2, 3 dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl which is also known as 2-oxo-1, 3-benzothiazol-3 (2H)-yl), 1,2, 3-benzothiadiazolyl, 1,2, 3-benzoxadiazolyl, 2,1, 3benzothiadiazolyl, 2,1, 3-benzoxadiazolyl, quinoxalinyl, dihydro-I-benzopyryliumyl (for example a coumarinyl or a chromenonyl), 1,3-benzodioxolyl (also known as 1,2
methylenedioxyphenyl), 3, 4-dihydro-lH-2, 1-benzothiazinyl (for example 2-dioxo-3, 4dihydro-1H-2, I-benzothiazinyl), purine (for example IH-purine or 9H-purine), 1H pyrazolo [3, 4-d] pyrimidinyl, thieno [2, 3-d] pyrimidinyl, thieno [3, 2-d] pyrimidinyl, quinolinyl (for example 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), isoquinolinyl, quinazolinyl or dibenzothiophenyl; or a ring as shown below:
The group R 1 may represent an optionally substituted 3-to 14-membered (especially 5-to 10-membered) saturated or unsaturated ring system which optionally comprises one or two ring carbon atoms that form carbonyl groups and which optionally further comprises one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples off1 ring systems, which can be moncyclic or polycyclic, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, indanyl, furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1, 2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl,
tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl (for example 2pyridinyl, 3-pyridinyl or 4-pyridinyl), pyrimidinyl (for example 2-pyrimidinyl or 4 pyrimidinyl), pyrazinyl, pyridazinyl, indolyl, 2,3-dihydroindolyl, benzo [b] furyl, benz [b] thienyl, 2, 3-dihydrobenz thienyl (for example 1-dioxo-2, 3dihydrobenz [b] thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl which is also known as 2-oxo-1, 3-benzothiazol-3 (2H)-yl), 1, 2,3-benzothiadiazolyl, 1,2, 3-benzoxadiazolyl, 2,1, 3benzothiadiazolyl, 2,1, 3-benzoxadiazolyl, quinoxalinyl, dihydro-l-benzopyryliumyl (for example a coumarinyl or a chromenonyl), 1,3-benzodioxolyl (also known as 1,2
methylenedioxyphenyl), 3, 4-dihydro-lH-2, I-benzothiazinyl (for example 2-dioxo-3, 4dihydro-lH-2, l-benzothiazinyl), purine (for example IH-purine or 9H-purine), 1Hpyrazolo [3, 4-d] pyrimidinyl, thieno [2, 3-d] pyrimidinyl, thieno [3, 2-d] pyrimidinyl, quinolinyl (for example 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), isoquinolinyl, quinazolinyl or dibenzothiophenyl; or a ring as shown below:
Alkyl may be linear or branched. Examples of alkyl groups/moieties containing up to twelve carbon atoms include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tertbutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups. A CI-6 hydroxyalkyl group will comprise at least one hydroxyl group (for example one, two or three hydroxyl groups) which may be attached to an internal or terminal carbon
atom of the alkyl chain. Similarly, a carboxy-substituted CI-6 alkoxy group will comprise at least one carboxyl group (for example one, two or three carboxyl groups) which may be attached to an internal or terminal carbon atom of the alkyl chain. A CI-6 haloalkyl or CI-6 haloalkoxy group will comprise at least one halogen atom (for example one, two, three or four halogen atoms independently selected from fluorine, chlorine, bromine and iodine) which may be attached to an internal or terminal carbon atom of the alkyl chain. A halophenyl group will comprise from 1 to 5 halogen atoms independently selected from
fluorine, chlorine, bromine and iodine. A CI-6 alkylbenzyl group will comprise at least one C 1-6 alkyl group (for example one, two or three CI-6 alkyl groups) attached to the phenyl ring of the benzyl moiety. If there is more than one CI-6 alkyl group attached to the phenyl ring, the groups may be the same or different. In a Ci. 6 alkoxycarbonylpiperazinyl substituent group, the piperazinyl moiety is attached through a nitrogen atom to the carbonyl moiety. When T represents C (O) NR9, it should be understood that the nitrogen atom is attached directly to the six-membered heterocyclic ring in formula (I).
The group R1 may represent a CI-12, preferably CI-10, more preferably CI-6, alkyl group optionally substituted by one or more (for example one, two, three or four) substituents independently selected from cyano, hydroxyl, CI-6, preferably CI-4, alkoxy, Ci- 6, preferably CI-4, alkylthio and Ci-6 alkoxycarbonyl, preferably C alkoxycarbonyl.
The group R may alternatively represent an optionally substituted 3-to 10membered saturated or unsaturated ring system which optionally comprises one or two ring carbon atoms that form carbonyl groups and which optionally further comprises one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur.
Examples of ring systems that may be used which can be money die or polycyclic include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, furyl, thienyl, imidazolyl, quinolinyl (for example 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), pyridinyl (for example 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), 1,3-benzodioxolyl, thiazolyl, benzimidazolyl, oxadiazolyl (for example 1,2, 4-oxadiazolyl), triazolyl (such as 1,2, 3triazolyl or 1,2, 4-triazolyl), benzothiazolyl, pyrimidinyl (for example 2-pyrimidinyl or 4pyrimidinyl), benzothienyl,
The ring system ofR1 may be optionally substituted by one or more (for example one, two, three or four) substituents independently selected from halogen (for example fluorine, chlorine, bromine or iodine) ; cyano ; nitro ; hydroxyl ; carboxyl ; Cl-6, preferably Ci4, alkyl (especially methyl or ethyl) ; CI-6, preferably CI-4, hydroxyalkyl ; CI-6, preferably Ci4, haloalkyl (for example trifluoromethyl) ; CI-6, preferably CI-4, alkoxy (especially methoxy, ethoxy, n-propoxy or isopropoxy) ; carboxy-substituted CI-6, preferably CI-4, alkoxy ; CI-6, preferably Ci4, alkylthio (especially methylthio, ethylthio, n-propylthio and tert-butylthio) ; CI-6, preferably CI-4, alkylthiomethyl (particularly methylthiomethyl) ; CI-6, preferably CI-4, alkyl carbonyl amino (especially methylcarbonylamino) ;-NRR ; C (O) NR7R8 ; CI-6, preferably Ci-4, alkylcarbonyloxymethyl (particularly methylcarbonyloxymethyl) ; CI-6, preferably CI-4, alkoxycarbonyl (especially methoxycarbonyl or ethoxycarbonyl) ; CI-6, preferably CI-4, alkoxycarbonylpiperazinyl ; furyl ; phenyl ; pyridinyl ; pyrazinyl ; halophenyl (especially chlorophenyl) ; thienyl ; thienylmethyl ; CI-6, preferably CI-4, alkylbenzyl (particularly methylbenzyl) ; and
The group R 1 may be an aromatic 5-membered heterocyclyl having 2, 3 or 4 ring nitrogen atoms (for example 1, 2, 4-triazole, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole or tetrazole) substituted by one heteroaromatic ring (such as pyridine or pyrazole) which is itself optionally substituted by halogen or Cl-4 alkyl ; or RI is halophenyl (for example phenyl optionally substituted (such as in the 4-position) by fluoro or chloro ; such as 4chlorophenyl or 4-fluorophenyl).
The group Q is especially oxygen or m is 0. Alternatively, Q may be a sulphur atom or a group NH, C (O) or NHC (O).
The group n is, for example, 1 or 2.
The group T is, for example, NH, C (O) NH or NHC (O) NH ; for example T is a NH or C (O) NH group ; especially T is C (O) NH.
The groups X', X2, X3 and X4 are preferably all CH2 or CHR 12, wherein the R 12 groups of Xl and X3 or X4, or, X2 and X3 or X4 join to form CH2CH2 ; provided always that at least two of Xl, X2, X3 and X4 are CH2. The groups Xl, X2, X3 and X4 are especially all CH2.
It is preferred that each R2 and R3 independently represents a hydrogen atom or a methyl group, especially a hydrogen atom.
The groups R4 and R are especially, independently, hydrogen or CI-4 alkyl ; particularly both hydrogen.
The group R is, for example, a phenyl group optionally substituted by one or more (for example one, two, three or four) substituents independently selected from halogen (for example fluorine, chlorine, bromine or iodine), amino, nitro, cyano, sulphonyl, sulphonamido, CI-6, preferably CI-4, alkyl, CI-6, preferably CI-4, haloalkoxy, methylenedioxy or CI-6, preferably CI-4, alkylsulphonyl. The group R6 is especially phenyl optionally substituted by halogen or methylenedioxy, particularly R6 is a phenyl group substituted by halogen. Examples ofR6 include 3-chlorophenyl, 4-chlorophenyl or, especially, 3, 4-dichlorophenyl.
The groups R7 and R8 are, for example, hydrogen, Ci-C6, preferably Cl-C4, hydroxyalkyl, C3-6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or Ci-6, preferably Cl-4, alkyl optionally substituted by phenyl (for example one or two phenyl groups). More preferably, R7 and R8 each independently represent hydrogen, C2 hydroxyalkyl, cyclopropyl or C 1-2 alkyl optionally substituted by phenyl.
Compounds of formula (I) can be prepared by one of the following methods : (a) when n is at least 1, the CR2R3 group attached directly to T is CHR3 and T is Nu10, reacting a compound of formula
2 3 wherein n'is 0 or an integer from 1 to 3 and R\ R, R3, m and Q are as defined above, with a compound of formula
or a salt thereof, wherein Xl, X2, X3, X4, Z, R6 and R10 are as defined above, in the presence of a reducing agent ; (b) when n is at least 1, the CR2R3 group attached directly to T is C (CI-C4 alkyl) 2 and T is NR, reacting a compound of formula
wherein n'is 0 or an integer from 1 to 3, R' and R ' each independently represent a Cl-C4 alkyl group, and R1 R2, R3, R10 m and Q are as defined above, with a compound of formula
wherein X1, X2, X3, X4, Z and R6 are as defined above, in the presence of a reducing agent; (c) when T is C (O) NU10, reacting a compound of formula
wherein R\ R2, R3, Q, m and n are as defined above, with a compound of formula (III) or a salt thereof as defined in (a) above; (d) when m is 1 and Q is NR9, reacting a compound of formula (VII), R - L, wherein
Li represents a leaving group (for example a halogen atom) and RI is as defined above, with a compound of formula
or a salt thereof, wherein n, T, Xl, X2, X3, X4, Z, R2, R3, R6 and R9 are as defined above ; (e) when at least one of R4 and R5 represents a hydrogen atom, reacting a compound of formula
or a salt thereof, wherein Rl, R2, R3, Q, m, n, Xl, X2, X3, X4 and T are as defined above, with a compound of general formula (X), R-C (O)-R20, wherein R20 represents a hydrogen atom or a Cl-C4 alkyl group and R6 is as defined above, in the presence of a reducing agent; (f) reacting a compound of formula (IX) as defined in (e) above, with a compound of formula
wherein L2 represents a leaving group (for example a halogen atom) and Z and R6 are as defined above; (g) when T is NU10, reacting a compound of formula
3 2 3 wherein L3 represents a leaving group (for example a halogen atom) and RI, R2, R3, m, n and Q are as defined above, with a compound of formula (III) or a salt thereof as defined in (a) above;
(h) when T is NHC (O) NR"\ reacting a compound of formula
1 2 3 wherein R, R, R, Q, m and n are as defined above, with a compound of formula (III) or a salt thereof as defined in (a) above; (i) when T is C (O) NH, Z is CH2, n is 1, R2 and R3 are hydrogen or Ci-C4 alkyl and Q is oxygen or sulphur, reacting a compound of formula (XIV):
wherein Hal is a suitable halogen (such as bromo or chloro), R2, R3, Xl, X2, X3, X4, Z and R6 are as defined above, with R'OH or R'SH in the presence of a suitable base (such as potassium carbonate or sodium or potassium hydroxide); and optionally after (a), (b), (c), (d), (e), (f), (g), (h) or (i) forming a pharmaceutically acceptable salt or solvate of the compound of formula (I) obtained. Compounds of formulae (II) to (XIV) are either commercially available, or are known in the literature or may be prepared using known techniques. The compounds of formula (I) can be isolated from reaction mixtures and purified using standard techniques.
When functional groups such as hydroxyl or amino are present in starting reagents or intermediate compounds they may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (1) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups. The protection and deprotection of functional groups is described in'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973) and'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor activity, especially as modulators of the activity of the CCR3 chemokine receptor.
The pharmaceutical combination of the present invention can be used to in the treatment of conditions or diseases in which both antagonism of CCR3 chemokine receptor activity and histamine antagonism, leukotriene modulation, beta-agonism,
phosphodiesterase inhibition or the administration of a steroid, human cytokine or an antibody is beneficial. Examples of these conditions include : (1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and conjunctivitis (for example vernal conjunctivitis); (3) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, food-related allergies which have effects remote from the gut, for example, migraine, rhinitis and eczema; (4) (bone and joints) rheumatoid arthritis, osteoarthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis; (5) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; and, (6) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura.
Thus, the present invention provides a pnarmaceutical combination as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a pharmaceutical combination as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term"therapy"also includes "prophylaxis"unless there are specific indications to the contrary. The terms"therapeutic" and"therapeutically"should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
In another aspect the present invention provides the use of a pharmaceutical combination as hereinbefore defined in the manufacture of a medicament for the modulation of the CCR3 chemokine receptor and histamine antagonism, leukotriene modulation, beta-agonism, phosphodiesterase inhibition or the administration of a steroid, human cytokine or an antibody is beneficial. In a further aspect such medicament is for the treatment of asthma or rhinitis.
The invention also provides a method of treating asthma or rhinitis in a person suffering from, or at risk of, said disease, which comprises administering to the person a therapeutically effective amount of a pharmaceutical combination as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compound of formula (I) and the histamine antagonist, steroid, leukotriene modulator, human cytokine, beta-agonist, phosphodiesterase inhibitor or antibody may be comprised in the same or separate formulations. When in separate formulations, the compound of formula (I) may be administered before, at or about the same time as or after the histamine antagonist, steroid, leukotriene modulator, human cytokine, beta-agonist, phosphodiesterase inhibitor or antibody.
In one further aspect of the invention the compound of formula (I) is administered at or about the same time as the histamine antagonist, steroid, leukotriene modulator, human cytokine, beta-agonist, phosphodiesterase inhibitor or antibody. Especially, the compound of formula (I) and the histamine antagonist, steroid, leukotriene modulator, human cytokine, beta-agonist, phosphodiesterase inhibitor or antibody. Further, said formulation is designed for oral administration.
In a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a histamine antagonist, steroid, leukotriene modulator, human cytokine, beta-agonist, phosphodiesterase inhibitor or antibody and a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to
99% w (per cent by weight), more preferably from 0. 05 to 80% w, still more preferably from 0. 10 to 70% w, and even more preferably from 0. 10 to 50% w, of active ingredients, all percentages by weight being based on total composition.
The pharmaceutical composition may be administered topically (for example to the lung and/or airways or to the skin) in the form of a solution, suspension, heptafluoroalkane aerosol or dry powder formulation ; or systemically, for example by oral administration in the form of a tablet, capsule, syrup, powder, aerosol or granule, or by parenteral administration in the form of a solution or suspension, or by subcutaneous administration or by rectal administration in the form of a suppository or transdermally.
The combination may be formulated as a tablet which may include a diluent such as microcrystalline cellulose or lactose monohydrate, a binder such as polyvinylpyrrolidone or hydroxypropylmethylcellulose, a disintegrant such as crospovidone or starch, a glidant such as talc or fumed silica and a lubricant such as magnesium stearate or sodium stearyl fumarate. Optionally, an excipient to control the release rate of the active compounds, such as hydroxypropylmethylcellulose or polymethylmethacrylate derivatives, may be included.
Alternatively, the formulation may be presented as a capsule with either a gelatin, starch or hydroxypropylmethylcellulose shell and a fill formulation comprising the active ingredients and a diluent such as microcrystalline cellulose or lactose monohydrate, a binder such as polyvinylpyrrolidone or hydroxypropylmethylcellulose, a disintegrant such as crospovidone or starch, a glidant such as talc or fumed silica, and a lubricant such as
magnesium stearate or sodium stearyl fumarate. Optionally, an excipient to control the release rate of the active compounds, such as hydroxypropylmethylcellulose or polymethylmethacrylate derivatives, may be included.
Parenteral dosage forms may be prepared using an aqueous or organic vehicle, such as oils, alcohols, propylene glycol, polyethylene glycol or other pharmaceutically acceptable solvent, solubilisers such as polyethylene oxide-polypropylene oxide block copolymers or polysorbates, tonicity modifiers such as sodium chloride or dextrose, stabilisers such as antixoidants or chelating agents, and pH modifiers and buffers such as sodium hydroxide or sodium borate.
Oral dosage forms can be prepared by tabletting or encapsulation of blends produced by wet granulation, dry granulation, print deposition, direct powder blending or other pharmaceutically acceptable process.
Parenteral dosage forms may be prepared by processes such as preparation of a solution, colloid, suspension or emulsion which is then sterilised, by processes such as filtration, autoclaving or irradiation. The dosage form may also be presented as a lyophilised solid for reconstitution.
The following Examples illustrate processes by which compounds of formula (I) can be prepared.
EXAMPLE A
Preparation of 1- (3, 4-dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt Step i : tert-butyl 1- (3, 4-dichlorobenzyl)-4-piperidinylcarbamate
Sodium triacetoxyborohydride (6g) was added to a stirred solution of 3, 4dichlorobenzaldehyde (4.2g) and l, l-dimethylethyl-4-piperidinyl carbamate (4g) in dichloromethane (50mil). The mixture was stirred at room temperature for 4h then partitioned between ethyl acetate and aqueous sodium hydrogencarbonate. The organic layer was washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether to give a white solid (3.5g) which was used directly in step ii.
Step ii: 1- (3, 4-Dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt
The product from step (i) (3. 5g) was treated with trifluoroacetic acid (I Oml) in dichloromethane (40ml). After 72h, the solution was evaporated, the residue triturated with ether and the solid (4.3g) collected.
Examples 1-47 1- (3, 4-Dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt (2mg), the appropriate aldehyde (2 equivalents), sodium triacetoxyborohydride (3 equivalents) and
diisopropylethylamine (2 equivalents) in acetonitrile (0. 08ml) and 1-methyl-2 pyrrolidinone (0.12ml) were left at room temperature for 24h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsuphoxide (0. 4ml).
Example 1 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (4-methylbenzyl) amine
Example 2
N- [4- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl) phenyl] acetamide
Example 3 3- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl) phenol
Example 4 N- [ (4-Chloro-1-methyl-1 H-pyrazol-3-yl) methyl]-1- (3, 4-dichlorobenzyl)-4-piperidinamine
Example 5 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- [ (5-methyl-2-furyl) methyl] amine
Example 6 N-[ 1- (3, 4- Dichlorobenzyl) -4-piperidinyl]- N - (4-nitrobenzyl) amine
Example 7 N-Benzyl-1- (3, 4-dichlorobenzyl)-4-pipendmamine
Example 8 N- [1- (3, 4-Dichlorobenzy !)-4-pipendinyl]-N- (4-fluorobenzyl) amine
Example 9 N- (2, 6-Dichlorobenzyl)-1- (3, 4-dichlorobenzyl)-4-piperidinamine
Example 10 N, 1-Bis (3, 4-dichlorobenzyl)-4-piperidinamine
Example 11 N- [1- (3, 4-Dichloroben2yl)-4-pipendinyl]-N- (2-pyridmylmethyl) amme
Example 12 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- [ (3-methyl-2-thienyl) methyl] amine
Example 13 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- [ (5-methyl-2-thienyl) methyl] amine
Example 14 5- ( {[1- (3, 4-Dichlorobenzyl) -4-piperidinyl]amino} methyl) -2-methoxyphenol
Example 15 4- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-2-nitrophenol
Example 16 3- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-4H-chromen-4-one
Example 17 N- [(5-Chloro-l,3-dimethyl-lH-pyrazol-4-yl)methyl]-l-(3,4-dichlorobenzyl)-4piperidinamine
Example 18 N- [ (4-Chloro-1 H-pyrazol-3-yl) methyl]-1- (3, 4-dichlorobenzyl)-4-piperidinamme
Example 19
N- [1- (3, 4-Dichlorobenzyl)-4-pipendinyl]-N- { [1- (4-methylbenzyl)-1 H-pyrazol-5yl] methyl} amine
Example 20 N- [1- (3, 4-Dichlorobenzyl)-4-pipendmyl]-N- [ (2-phenyl-1 H-imidazol-4-yl) mcthyl] amine
Example 21 N- [ (2-Chloro-3-quinoIinyl) methyl]-l- (3, 4-dichlorobenzyl)-4-pipendinamine
Example 22 N- [l- (3, 4-Dichlorobenzyl)-4-pipendmyl]-N- [ (6-methyl-2-pyndinyl) methyl] amine
Example 23 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (3-quinolmylmethyl) amine
Example 24 [5- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-2-iuryl] methyl acetate
Example 25 4- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-1, 5-dimethyl-2-phenyl-1, 2dihydro-3H-pyrazol-3-one
Example 26 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (4-pyridinylmethyl) amine
Example 27 5- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-2-nitrophenol
Example 28 N- [2- (tert-Butylsulfanyl) benzyl]-l- (3, 4-dichloroben2yI)-4-piperidinamme
Example 29 N- [1- (3, 4-Dichlorobenzyl)-4-piperidmyl]-N- (4-ethylbenzyl) amme
Example 30 5- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-2-hydroxybenzoic acid
Example 31
N- (l, 3-Benzodioxol-4-ylmethyl)-l- (3, 4-dichlorobenzyl)-4-pipendmamine
Example 32 N-[1-(3, 4-Dichlorobenzyl)-4-piperidinyl]-N-(1, 3-thiazol-2-ylmethyl) amine
Example 33 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- [ (5-ethyl-2-furyl) methyl] amine
Example 34 N- [l- (3, 4-Dichlorobenzy !)-4-piperidmyl]-N- (2-qumolmyImethyl) amme
Example 35 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (4-quinolinylmethyl) amine
Example 36 5- (f [I- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino I methyl)-2-hydroxy-3-methoxybenzoic acid
Example 37 N- [ (4-Bromo-lH-pyrazol-3-yl) methyl]-1- (3, 4-dichlorobenzyl)-4-piperidinamine
Example 38 2- [2- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-6-methoxyphenoxy] acetic acid
Example 39 N- [ (4-Bromo-1-methyl-1 H-pyrazol-3-yl) methyl]-1- (3, 4-dichlorobenzyl)-4-piperidinamine
Example 40 N- 1- (3, 4-Dichlorobenzyl) -4-piperidinyl]- N - (4-iodobenzyl) amine
Example 41 3- ( { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} methyl)-6, 7-dimethyl-4H-chromen-4one
Example 42 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (4-isopropoxybenzyl) amine
Example 43 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(1-methyl-lH-benzimidazol-2yl) methyl] amine
Example 44 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (3-methylbenzyl) amine
Example 45
N- [l- (3, 4-DicMorobenzyl)-4-piperidinyl]-N- (3-pyridinylmethyl) aminc
Example 46 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (2, 4-dimethylbenzyl) amine
Example 47 Ethyl 5- ( { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino} methyl)-2-methyl-3-furoate
Examples 48-73 Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2 equiv) was added to a solution of 1- (3, 4-dichlorobenzyl)-4-piperidinamine, di-hydrochloride salt (1 mg), the appropriate acid (2 equivalents) and diisopropylethylamine (5 equivalents) in dimethylformamide (0.17ml) and was left at room temperature for 24h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsulphoxide (0. 3ml).
Example 48 N- [1- (3, 4-DichlorobenzyI)-4-piperidinyl]-3-mramide
Example 49
N- [1- (3, 4-Dichlorobenzy !)-4-piperidmyl]-4- [3- (4-pyridmyl)-1, 2, 4-oxadiazol-5yl] butanamide
Example 50 2- { [5- (I-Benzyl-2-oxo-l, 2-dihydro-3-pyridinyl)-4-methyl-4H-l, 2, 4-triazol-3-yl] sulfamyl} N -[ 1- (3, 4-dichlorobenzyl) -4-piperidinyl]propanamide
Example 51 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-6-methoxy-4-quinolinecarboxamide
Example 52 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- (2-furyl)-4-quinolinecarboxamide
Example 53 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-4- (2-methyl-l-oxo-1, 2-dihydro-3isoquinolinyl) butanamide
Example 54 3- (1, 3-Benzothiazol-2-ylsulfanyl)-N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl] propanamide
Example 55 N- [l- (3, 4-Dichlorobenzyl)-4-piperidmyl]-2- (3, 5-dimethoxyphenyl) acetamide
Example 56 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- (2-methoxyphenyl) acetamide
Example 57 2-[ 5-Chloro-2-oxo-l, 3-benzothiazol-3 (2H)-yl]-N- [l- (3, 4-dichlorobenzyl)-4piperidinyi] acetamide
Example 58 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- [ (4, 6-dimethyl-2pyrimidmyl) suliaiiyl] acetamide
Example 59 2- (l-Benzothiophen-3-yl)-N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl] acetamide
Example 60 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-4- (3, 4-dimethoxyphenyl) butanamide
Example 61 5-Cyclohexyl-N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl] pentanamide
Example 62 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3-fluoro-2-methylbenzamide
Example 63 N'- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (1-phenylethyl) phthalamide
Example 64 2-Cyclopentyl-N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl] acetamide
Example 65 4-Chloro-N-[1-(3, 4-dichlorobenzyl)-4-piperidinyl]-2-nitrobenzamide
Example 66 2, 2-Dichloro-N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-l-methylcyclopropanecarboxamide
Example 67 tert-Butyl 4-[5- ( { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino} carbonyl)-2methoxyphenyl]-1-piperazinecarboxylate
Example 68 N- [1- (3, 4-Dichlorobenzyl)-4-pipendmyl]-5-oxo-1- (2-thienylmethyl)-3pyrrolidinecarboxamide
Example 69 N- [l- (3, 4-Dichlorobenzyl)-4-piperidmyl]-3- [2-oxo-l, 3-benzoxazol-3 (2H)-yl] propanamide
Example 70 N- [1- (3, 4-DicMorobenzyl)-4-piperidinyl]-4-fluorobenzamide
Example 71 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2-methylbenzamide
Example 72 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3-methylbenzamide
Example 73 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-4- (hydroxymethyl) benzamide
Examples 74-93 Step i : 1- (3, 4-Dichlorobenzyl)-4-piperidinone A solution of3, 4-dichlorobenzyl chloride (2. 8ml), 4-ketopiperidine hydrochloride monohydrate and triethylamine (8ml) in dimethylformamide (30ml) was stirred at room temperature for 20h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate/isohexane. Yield 2. 1 g.
Step ii : tert-Butyl 2- { [l- (3, 4-dichlorobenzyl)-4-piperidinyl] amino} ethylcarbamate
A solution of the product from step (i) (1. 61g), N- (tert-butoxycarbonyl)ethylenediamine (lug) and sodium triacetoxyborohydride (2. 12g) in dichloromethane (20ml) was stirred at room temperature for 3h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Yield 1. 28g.
Step iii : N-l- [I- (3, 4-Dichlorobenzyl)-4-piperidinyl]-1, 2-ethanediamine, tritrifluoroacetate salt
The product from step (ii) (1. 28g) was treated with trifluoroacetic acid (5ml) in dichloromethane (10mol). After 20h, the solution was evaporated, the residue triturated with ether and the solid (1. 62g) collected.
Step iv : Examples 74-93 The product from step (iii) (0. 0026g), the appropriate activated halo-aromatic (1. 25 equivalents) and diisopropylethylamine (10 equivalents) in 1-methyl-2-pyrolidinone (0. 15ml) was heated at 100oC for 20h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsuphoxide (0. 4ml).
Example 74 N 1-[1- (3, 4-Dichlorobenzyl) -4-piperidinyl]-N2 - {2-[ (methylsulfanyl) methyl]-4pyrimidinyl}-1, 2-ethanediamine
Example 75 N'- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- [2- (methylsulfanyl)-6- (trifluoromethyl)-4pyrimidinyl]-1, 2-ethanediamine
Example 76 Nl- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- [5-methoxy-2- (methylsulfanyl)-4pyrimidinyl]-1, 2-ethanediamine
Example 77 2- ( {4- [ (2- { [1- (3, 4-Dichlorobenzyl)-4-pipendmyl] amino} ethyl) amino]-2 pyrimidinyl} amino)-1-ethanol
Example 78 N4- (2- { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino} ethyl)-6-methyl-2, 4pyrimidinediamine
Example 79 N4-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl] amino}ethyl)-N,6-dimethyl-2, 4pyrimidinediamine
Example 80
2-Chloro-N4-cyclopropyl-N- (2- { [l- (3, 4-dichlorobenzyl)-4-piperidinyl] amino} ethyl)-4, 6pyrimidinediamine
Example 81 N'- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (4-phenyl-2-pynmidinyl)-1, 2-ethanediamine
Example 82 N'- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- [4- (trifluoromethyl)-2-pyrimidinyl]-1, 2 ethanediamine
Example 83 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[4-(propylsulfanyl)-2-pynmidmyl]-1, 2ethanediamine
Example 84 N-(2-{[l-(3,4-Dichlorobenzyl)-4-piperidiny]amino)ethyl)-N4,6-dimethyl-2, 4 pyrimidinediamine
Example 85 N4-Cyclopropyl-N2- (2- { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino} ethyl)-2, 4 pyrimidinediamine
Example 86 N'- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- [4- (3-pyndinyl)-2-pyrimidinyl]-1, 2ethanediamine
Example 87 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[4-(3-thienyl)-2-pyrimidinyl]-1,2ethanediamine
Example 88
N'- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- [4- (2-thienyl)-2-pynmidinyl]-1, 2ethanediamine
Example 89 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (1-methyl-lH-pyrazolo [3, 4-d] pynmidin-4yl)-1, 2-ethanediamine
Example 90 N'- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (1 H-purin-6-yl)-l, 2-ethanediamine
Example 91 N'- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N- (5-methylthieno [2, 3-d] pyrimidin-4-yl)-1, 2ethanediamine
Example 92 N'- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- (7-methylthieno [3, 2-d] pyrimidin-4-yl)-1, 2ethanediamine
Example 93 Nl- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N2- (9-methyl-9H-purin-6-yl)-1, 2-ethanediamine
Example 94
N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- { [5- (trifluoromethyl)-2pyridinyljsulfanyl) acetatnide
Carbonyldiimidazole (0. 105g) was added to a stirred solution of { [5 (trifluoromethyl)-2-pyridinyl] sulfanyl} acetic acid (0. 166g) in dimethylformamide (2ml).
After Ih a solution of the product from 1- (3, 4-dichlorobenzyl)-4-piperidinamine, ditrifluoroacetate salt (0. 3g) in a solution of dimethylformamide and diisopropylethylamine (2 equivalents) (1. 5ml) was added and stirred at room temperature for 2h. The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether and collected. Yield 0. 084g as a solid ; MP : 98OC.
Example 95 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- (5-methyl-l-phenyl-1 H-pyrazol-4yl) acetamide
The title compound was prepared from the product of 1- (3, 4-dichlorobenzyl)-4piperidinamine, di-trifluoroacetate salt (0. 3g) and of2- (5-methyl-l-phenyl-lH-pyrazol-4yl) acetic acid (0. 151 g) using the method of Example 94. Yield 0. 18g as a solid MP : 165OC.
Example 96 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-5-oxo-5-phenylpentanamide
The title compound was prepared from the product ofl- (3, 4-dichlorobenzyl)-4piperidinamine, di-trifluoroacetate salt (0. 3g) and of 5-oxo-5-phenylpentanoic acid (0. 134g) using the method of Example 94. Yield 0. 149g as a solid MP : 130 C.
Example 97 2- [2- (4-Chlorophenyl)-5-methyl-1, 3-thiazol-4-yl]-N- [ 1- (3, 4-dichlorobenzyl)-4piperidinyl] acetamide
The title compound was prepared from the product ofl- (3, 4-dichlorobenzyl)-4piperidinamine, di-trifluoroacetate salt (0. 3g) and 2-[2- (4-chlorophenyl) -5-methyl-l, 3thiazol-4-yl] acetic acid (0. 1 87g) using the method of Example 94. Yield 0. 1 g as a solid MP : 170oC.
Example 98 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- (phenylsulfanyl) acetamide
The title compound was prepared from the product ofl- (3, 4-dichloroben. zyl)-4piperidinamine, di-trifluoroacetate salt (0. 3g) and 2- (phenylsulfanyl) acetic acid (0. 118g) using the method of Example 94. Yield 0. 056g as a solid MP : 97-99OC.
Example 99 N- [l- (3, 4-Dichlorobenzyl)-4-pipendinyl]-2- (4-fluorophenyI) acetamide
The title compound was prepared from the product ofl- (3, 4-dichlorobenzyl)-4piperidinamine, di-trifluoroacetate salt (0. 3g) and 2- (4-fluorophenyl) acetic acid (0. 108g) using the method of Example 94. Yield 0. 15g as a solid MP : 144-7C.
Example 100 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- [2- (2-pyrazinyl)-1, 3-thiazol-4-yl] acetamide
The title compound was prepared from the product of 1- (3, 4-dichlorobenzyl)-4piperidinamine, di-trifluoroacetate salt (0. 3g) and 2- [2- (2-pyrazinyl)-1, 3-thiazol-4yl] acetic acid (0. 155g) using the method of Example 94. Yield 0. 08g as a solid MP : 1869 C.
Example 101 N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- [ (5-phenyl-2-pyrimidinyl) sulfanyl] acetamide
The title compound was prepared from the product of 1- (3, 4-dichlorobenzyl)-4- piperidinamine, di-trifluoroacetate salt (0. 3g) and 2- [ (5-phenyl-2-pyrimidinyl) sulfanyl]- acetic acid (0. 172g) using the method of Example 94. Yield 0. 115g as a solid MP: 157OC.
Example 102
N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5yl] propanamide
The title compound was prepared from the product of 1- (3, 4-dichlorobenzyl)-4piperidinamine, di-trifluoroacetate salt (0. 9g) and 3- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5yl] propanoic acid (0. 3g) using the method of Example 94. Yield 0. 074g as a solid MP : 155 C.
Example 103 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-1 H-benzimidazol-2-amine
(i) Ethyl 4- (lH-benzimidazol-2-ylamino)-l-piperidinecarboxylate A solution of 2-chlorobenzimidazole (Ig) and ethyl 4-amino-1piperidinecarboxylate (2g) in 1-methyl-2-pyrrolidinone was heated at 130 C for 24h. The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 1% triethylamine/5% methanol in dichloromethane. Yield 0.630g as a solid.
(ii) N- (4-Piperidinyl)-lH-benzimidazol-2-amine, dihydrochloride salt The product from step (i) (0.58g) was heated under reflux with 5M hydrochloric acid (20ml) for 24h. The solvent was evaporated under reduced pressure, the residue azeotroped with toluene, washed with ether. Yield 0.58g as a solid.
(iii) N-[I- (3, 4-Dichlorobenzyl) -4-piperidinyl]-1 H-benzimidazol-2-amine Triethylamine (0.223ml) was added to a stirred suspension of the product from step (ii) (0. 2g) in dimethylformamide. After 5min 3,4-dichlorobenzaldehyde (0. 175g) then sodium triacetoxyborohydride (0.212g) was added and the mixture stirred at room temperature for 3h. The mixture was partitioned between 2M hydrochloric acid and ether, the aqueous layer was basified with aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/ether and the solid collected. Yield 0.045g MP: 125OC.
Example 104 2- { [1- (3, 4-Dichlorobenzyl)-4-piperidinyl] amino}-N- (3-methoxyphenyl) acetamide, dihydrochloride salt
2-Chloro-N- (3-methoxyphenyl)-acetamide (0. 241g) was added to a stirred solution of 1- (3, 4-dichlorobenzyl)-4-piperidinamine, dihydrochloride salt (0. 4g), triethylamine
(0. 608g) in 1-methyl-2-pyrrolidinone (5ml). The reaction mixture was heated at 800C for 6h then partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried and evaporated under reduced pressure. Purification was by chromatography eluting with chloroformlisohexane/triethylamine/methanol 30: 15 : 3: 0.5. The resulting product was converted to the hydrochloride salt using ethereal hydrogenchloride. Yield 0. 135g MP : 274-6OC.
Example 105 N- [I- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N'- (3, 4-dichlorophenyl) urea
3,4-Dichlorophenyl isocyanate (0. 081g) was added to a stirred solution of 1- (3, 4dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt (0.13g), diisopropylethylamine (0. 2g) in dichloromethane (4ml). The reaction mixture was stirred for 20h and the solvent removed under reduced pressure. Purification was by chromatography eluting with 5% methanol/dichloromethane. Yield 0.09g as a solid MP: 189-190oc.
Example 106
N- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-N'- (3-methoxyphenyl) urea
3-Methoxyphenyl isocyanate (0. 064g) was added to a stirred solution of 1- (3, 4dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt (0. 13g), diisopropylethylamine (0. 2g) in dichloromethane (4ml). The reaction mixture was stirred for 20h and the solvent removed under reduced pressure. Purification was by chromatography eluting with 5% methanol/dichloromethane. Yield 0. 09g as a solid MP: 178-9OC.
Example 107 N-[1- (3, 4-Dichlorobenzyl) -4-piperidinyl]-N- ( 4-methoxybenzyl) amine, dihydrochloride salt
The title compound was prepared from 1- (3, 4-dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt (0. 185g) and 4-methoxybenzaldehyde (0. 49ul) using the method of Example A step (i). Yield 0. 84g as a solid MP : > 250 C.
The following table lists Examples 108-348 which are of compounds of formula (I) all of which accord to formula (Ib).
Example R1 (Q)m n R6 108 phenyl m=O 2 3, 4-Cl2-C6H3 109 4-Br-C6H4 m=0 1 3,4-Cl2-C6H3 110 4-NH2-C6H4 m=0 1 3,4-Cl2-C6H3 111 2-Br-C6H4 m=0 1 3,4-Cl2-C6H3 112 4-F-C6H4 m=O 1 3, 4-Cl2-C6H3 113 3-CH3-C6H4 m=0 1 3,4-Cl2-C6H3 114 2-CH3-C6H4 m=O 1 3,4-Cl2-C6H3 115 3-Cl-4-OH-C6H3 m=0 1 3,4-Cl2-C6H3 116 2-NO2-C6H4 m=0 1 3,4-Cl2-C6H3 117 2-Cl-C6H4 m=0 1 3,4-Cl2-C6H3 118 4-C1-C6H4 m=0 1 3,4-Cl2-C6H3 119 3,4-(OH)2-C6H3 m=0 2 3,4-Cl2-C6H3 120 4-NO2-C6H4 m=O 1 3, 4-Cl2-C6H3 121 phenyl m=O 4 3, 4-Cl2-C6H3 122 3,4-(OCH3)2-C6H3 m=0 1 3,4-Cl2-C6H3 123 3-F-4-OH-C6H3 m=0 1 3,4-Cl2-C6H3 124 3, 4-methylenedioxyphenyl m=O 1 3, 4-Cl2-C6H3
125 4-OH-C6H4 m=0 2 3,4-Cl2-C6H3 126 4-OH-C6H4 m=0 1 3,4-Cl2-C6H3 127 4-phenyl-phenyl m=0 1 3,4-Cl2-C6H3 128 3,4-Cl2-C6H3 m=0 1 3,4-Cl2-C6H3 129 3-OH-C6H4 m=O 23, 4-Cl2-C6H3 130 4-CH3-C6H4 m=0 2 3,4-Cl2-C6H3 131 4-NO2-C6H4 m=0 3 3,4-Cl2-C6H3 132 3,4-(OCH3) 2-C6H3 m=0 2 3,4-Cl2-C6H3 133 C6F5 m=0 2 3,4-Cl2-C6H3 134 4-CH3-C6H4 m=O 13, 4-Cl2-C6H3 135 4-OCF3-C6H4 m=0 1 3,4-Cl2-C6H3 136 3,4-(OCH3)2-C6H3 m=0 3 3,4-Cl2-C6H3 137 4-OCH3-C6H4 m=O1 3, 4-Cl2-C6H3 138 4-N (CH3) 2-C6H4 m=O1 3, 4-Cl2-C6H3 1394-OCH3-C6H4 m=O 2 3, 4-Cl2-C6H3 140 3, 4, 5- (OCH3) 3-C6H2 m=O1 3, 4-Cl2-C6H3 141 3,4-methylenedioxyphenyl m=0 2 3,4-Cl2-C6H3 142 3-NH2-C6H4 m=0 1 3,4-Cl2-C6H3 143 naphth-1-yl m=O I 3, 4-Cl2-C6H3 144 3-OCH3-4-OH-C6H3 m=0 1 3,4-Cl2-C6H3 145 3-(6-Br-l-(prop-2-en-l- m=0 1 3,4-Cl2-C6H3 yl)-naphth-2yloxymethyl) phenyl 146 4-(4-N02-C6H4-CH20)- m=0 1 3,4-Cl2-C6H3 C6H4 147 3-F-4-CH3O-C6H3 m=0 1 3,4-Cl2-C6H3 148 3-CH3-C6H4 m=O 4 3, 4-Cl2-C6H3 149 3-OH-C6H4 m=O1 3, 4-Cl2-C6H3 150 4-(C6HrCH2O)-C6H4 m=0 1 3,4-Cl2-C6H3 151 4-(3-NO2-C6H4)-C6H4 m=0 1 3,4-Cl2-C6H3 152 2,5-(CH3)2-C6H3 m=0 1 3,4-Cl2-C6H3
153 4-I-C6H4 m=0 1 3, 4-Cl2-C6H3 154 3-Br-C6H4 m=0 1 3,4-Cl2-C6H3 155 2-CH3-3-NO2-C6H3 m=0 1 3,4-Cl2-C6H3 156 3-OH-4-OCH3-C6H3 m=O 1 3, 4-Cl2-C6H3 157 3-F-C6H4 m=O 1 3, 4-Cl2-C6H3 158 2-F-C6H4 m=0I3, 4-Cl2-C6H3 159 3,5-(OCH3)2-C6H3 m=0 1 3,4-Cl2-C6H3 160 3-Cl-C6H4 m=0 1 3,4-Cl2-C6H3 161 phenyl m=O 1 3, 4-Cl2-C6H3 162 3,5-(CH3)2-C6H3 m=0 1 3,4-Cl2-C6H3 163 3-OCH3-C6H4 m=0 2 3,4-Cl2-C6H3 164 2,4-F2-C6H3 m=0 1 3,4-Cl2-C6H3 165 2-OCH3-C6H4 m=0 1 3,4-Cl2-C6H3 166 3,4-F2-C6H3 m=0 1 3,4-Cl2-C6H3 167 3,5-F2-C6H3 m=0 1 3,4-Cl2-C6H3 168 Pyridin-3-yl m=0 1 3,4-Cl2-C6H3 169 Pyridin-2-yl m=0 1 3,4-Cl2-C6H3 170 5-Br-pyridin-3-yl m=0 1 3,4-Cl2-C6H3 171 2,4-(OCH3)2-C6H3 m=0 1 3,4-Cl2-C6H3 172 4-(benzyloxy)phenyl m=0 1 3,4-Cl2-C6H3 173 3-(benzyloxy)phenyl m=0 1 3,4-Cl2-C6H3 174 2-methyl-naphth-1-yl m=0 1 3,4-Cl2-C6H3 175 2-CH3CH20-C6H4 m=0 1 3,4-Cl2-C6H3 176 3,4-(OCH3)2-C6H3 m=0 1 3,4-Cl2-C6H3 177 4-CH3(CH2)3O-C6H4 m=0 1 3,4-Cl2-C6H3 178 Indol-l-yl m=0 1 3,4-Cl2-C6H3 179 2-NO2-C6H4 m=0 1 3,4-Cl2-C6H3 180 Thien-2-yl m=0 1 3,4-Cl2-C6H3 181 3-Cl-4-OH-C6H3 m=0 1 3,4-Cl2-C6H3 182 2,4-Cl2-C6H3 m=0 1 3,4-Cl2-C6H3 183 2,6-Cl2-C6H3 m=0 1 3,4-Cl2-C6H3
184 2-Br-C6H4 m=0 1 3,4-Cl2-C6H3 m=0 1 3,4-Cl2-C6H3 185 3,4-Cl2-C6H3 m=0 1 3,4-Cl2-C6H3 186 3-Br-C6H4 m=0 1 3,4-Cl2-C6H3 187 3,5-F2-C6H3 m=0 1 3,4-Cl2-C6H3 188 3-NH2-C6H4 m=0 1 3, 4-Cl2-C6H3 189 2-(ClCH2C(O)NH)- m=0 1 3,4-Cl2-C6H3 thiazolyl-4-yl 190 3-C1-C6H4 m=O 1 3, 4-CI2-C6H3 191 2,5-(OCH3)2-C6H3 m=0 1 3,4-Cl2-C6H3 192 4-OH-C6H4 m=0 1 3,4-Cl2-C6H3 193 Indol-3-yl m=O 1 3, 4-Cl2-C6H3 194 5-OCH3-indol-3-yl m=0 1 3,4-Cl2-C6H3 195 Naphth-2-yl m=0 1 3,4-Cl2-C6H3 196 4-CH3-C6H4 m=0 1 3,4-Cl2-C6H3 197 3,4,5-(OCH3)3-C6H2 m=01 3,4-Cl2-C6H3 198 4-CH3(CH2)3O-C6H4 m=0 1 3,4-Cl2-C6H3 199 4-S(O)2CH3-C6H4 m=0 1 3,4-Cl2-C6H3 200 2, 4, 6- (CH3) 3-C6H2 m=O1 3, 4-Cl2-C6H3 201 4-F-C6H4 m=0 1 3,4-Cl2-C6H3 202 2-(pyrazin-2-yl)-thiazol-4- m=0 1 3,4-Cl2-C6H3 yl 203 2-CH3-5-(CH3)2CH-indol- m=0 1 3,4-Cl2-C6H3 3-yl 204 5-(pyrrolidin-l-yl)-m=0 1 3,4-Cl2-C6H3 tetrazol-2-yl 205 5-(4-CH3-phenyl)-tetrazol- m=0 1 3,4-Cl2-C6H3 2-yi 206 3,5-F2-C6H3 m=0 1 3,4-Cl2-C6H3 207 3-OCH3-C6H4 m=O1 3, 4-Cl2-C6H3 208 5-Cl-benzo[b]thiophen-3- m=0 1 3,4-Cl2-C6H3 yl
209 3,4-Cl2-C6H3 m=0 1 3,4-Cl2-C6H3 210 2-phenyl-5-methyl-thiazol- m=0 1 3,4-Cl2-C6H3 4-yl 211 4-OCF3-C6H4 m=0 1 3,4-Cl2-C6H3 212 3-methyl-5-Cl- m=0 1 3,4-Cl2-C6H3 benzo [b] thiophen-2-yl 213 3-methyl- m=0 1 3,4-Cl2-C6H3 benzo [b] thiophen-2-yl 214 2-NO2-C6H4 m=0 1 3, 4-Cl2-C6H3 215 3-NO2-1, 2, 4-triazol-l-yl m=0 1 3, 4-Cl2-C6H3 216 3,4-(NO2)2-5-CH3- m=0 1 3,4-Cl2-C6H3 pyrazolyl 217 4-(CH3)2CH(CH2)2O-C6H4 m=0 1 3 4-Cl2-C6H3 218 2,3-(CH3)2-indol-5-yl m=0 1 3,4-Cl2-C6H3 219 3,5-(CH3)2-4-Cl-pyrazol- m=0 1 3,4-Cl2-C6H3 1-yl 220 3,5-(CH3 2-4-NO2- m=0 1 3,4-Cl2-C6H3 pyrazol-1-yl 221 2,4-(NO2)2-imidazol-l-yl m=0 1 3,4-Cl2-C6H3 222 4-NO2-imidazol-1-yl m=0 1 3,4-Cl2-C6H3 223 3,5-(CH3)2-pyrazol-1-yl m=0 1 3,4-Cl2-C6H3 224 4-CH3 (CH2) 5-C6H4 m=0 1 3,4-Cl2-C6H3 225 2-CN-C6H4 m=01 3, 4-Cl2-C6H3 226 4-C1-C6H4 O 1 4-Cl-C6H4 227 4-C1-C6H4 O 1 2-Br-C6H4 228 4-Cl-C6H4 O 1 3-(CO2CH3)-4-Br C6H4 229 4-Cl-C6H4 O 1 4-NO2-C6H4 230 4-Cl-C6H4 O 1 3-benzoyl-phenyl 231 4-Cl-C6H4 O 1 5-OCH3benzimidazol-2-yl
232 4-Cl-C6H4 0 1 4-Br-C6H4 233 4-Cl-C6H4 O 1 4-(1,2,3-thiadiazol4-yl)-phenyl 234 4-Cl-C6H4 O 1 4-CH3-C6H4 235 4-Cl-C6H4 O 1 4-(2,6-Cl2 C6H3) CH2S (0) 2 C6H4 236 4-Cl-C6H4 O 1 3,5-Br2-C6H3 237 4-Cl-C6H4 O 1 Indan-5-yl 238 4-Cl-C6H4 O 1 2-F-3-C1-C6H3 239 4-Cl-C6H4 O 1 benzofurazan-5-yl 240 4-Cl-C6H4 O 1 7-Cl-quinolin-2-yl 241 4-F-C6H4 m=0 1 2,5-Cl2-C6H3 242 4-F-C6H4 m=01 2, 3-Cl2-C6H3 243 4-F-C6H4 m=0 1 4-F-C6H4 244 4-F-C6H4 m=O I3-CO2CH3-4-Br C6H3 245 4-F-C6H4 m=0 1 4-NO2-C6H4 246 4-F-C6H4 m=0 1 3-benzoyl-phenyl 247 4-F-C6H4 m=0 1 4-CH3-naphth-l-yl 248 4-F-C6H4 m=0 1 3,4-methylenedioxyphenyl 249 4-F-C6H4 m=0 1 5-OCH3benzimidazol-2-yl 250 4-F-C6H4m=0 1 3-NO2-4-CH3 C6H3 251 4-F-C6H4 m=0 1 3,4-(CH3)2-C6H3 252 4-F-C6H4 m=0 1 3-CH3-4-OCH3 C6H3 253 4-F-C6H4 m=0 14- (2-C (O) NH2 C6H4)-C6H4
254 4-F-C6H4 m=0 1 4-Br-C6H4 255 4-F-C6H4 m=0 1 4-(2,6-Cl2 C6H4) CH2S (0) 2 C6H4 2563- (pyridin-2-yl)-1, 2, 4-m=0'24-C1-C6H4 oxadiazol-5-yl 257 3-(pyridin-2-yl)-1,2,4- m=0 3-Cl-4-OCH3-C6H3 oxadiazol-5-yl 258 3-(pyridin-2-yl)-1,2,4- m=0 2 2,3-Cl2-C6H3 oxadiazol-5-yl 259 3-(pyridin-2-yl)-1,2,4- m=0 2 4-F-C6H4 oxadiazol-5-yl 2603- (pyridin-2-yl)-1, 2, 4-m=0 2 3-CF3-C6H4 oxadiazol-5-yl 261 3-(pyridin-2-yl)-1,2,4- m=0 2 4-NO2-C6H4 oxadiazol-5-yl 2623- (pyridin-2-yl)-1, 2, 4-m=0 2 3-benzoyl-phenyl oxadiazol-5-yl 263 3-(pyridin-2-yl)-1,2,4- m=0 2 3,4-methyleneoxadiazol-5-yl dioxyphenyl 264 3-(pyridin-2-yl)-1,2,4- m=0 2 3,5-(CH3)2-C6H3 oxadiazol-5-yl 265 3-(pyridin-2-yl)-1,2,4- m=0 2 3-NO2-4-CH3oxadiazol-5-yl C6H3 266 3-(pyridin-2-yl)-1,2,4- m=0 2 3,4- (CH3) 2-C6H3 oxadiazol-5-yl 267 3-(pyridin-2-yl)-1,2,4- m=0 2 3-CH3-C6H4 oxadiazol-5-yl 2683- (pyridin-2-yl)-1, 2, 4-'mO'23-CH3-4-OCH3oxadiazol-5-yl C6H4
269 3-(pyridin-2-yl)-1,2,4- m=0 2 4-Br-C6H4 oxadiazol-5-yl 2703- (pyridin-2-yl)-1, 2, 4-m=0"2Indan-5-yl oxadiazol-5-yl 271 3-(pyridin-2-yl)-1,2,4- m=0 2 4-CF3-C6H4 oxadiazol-5-yl 272 3-(pyridin-2-yl)-1,2,4- m=0 2 Naphth-2-yl oxadiazol-5-yl 273 3-(pyridin-2-yl)-1,2,4- m=0 2 4-CH3-C6H4 oxadiazol-5-yl 2743- (pyridin-2-yl)-1, 2, 4-m=0 2 benzofurazan-5-yl oxadiazol-5-yl 275 3-(pyridin-2-yl)-1,2,4- m=0 2 3,4-F2-C6H3 oxadiazol-5-yl 2763- (pyridin-2-yl)-1, 2, 4-m=0 2 7-Cl-quinolin-2-yl oxadiazol-5-yl 277 3-(pyridin-2-yl)-1,2,4- m=0 2 3-Cl-C6H4 oxadiazol-5-yl 278 3-(pyridin-2-yl)-1,2,4- m=0 2 4-CF3-C6H4 oxadiazol-5-yl 279 3-(pyridin-2-yl)-1,2,4- m=0 2 4-CH3-C6H4 oxadiazol-5-yl 280 4-OCH3-C6H4 O 1 3,4-C12-C6H3 281 4-C1-C6H4 0 1 3, 4-C12-C6H3 282 4-NO2-C6H4 O 1 3,4-Cl2-C6H3 283 4-NHC(O)CH3-C6H4 O 1 3,4-Cl2-C6H3 284 4-O(CH2)2CH3-C6H4 O 1 3,4-Cl2-C6H3 285 3-CO2CH2CH3-C6H4 O 3,4-Cl2-C6H3 286 2-C (CH3) 3-C6H4 0 1 3, 4-C12-C6H3 287 2-NHC(O)H3-C6H4 O 1 3,4-Cl2-C6H3
288 3, 5- (OCH3) 2-C6H3 0 1 3, 4-Cl2-C6H3 289 2-OCH3-5-NO2-C6H3 0 13, 4-Cl2-C6H3 290 4-CN -C6H4 0 1 3, 4-Ch-C6H3 291 2-C1-5-CF3-C6H3 0 13, 4-Cl2-C6H3 292 2-N02-5-CH3-C6H3 0 1 3, 4-Cl2-C6H3 293 3-Cl-S-OCH3-C6H3 0 1 3, 4-Ch-C6H3 294 3-NO2-C6H4 0 1 3, 4-Cl2-C6H3 29S 3-Br-C6H4 0 1 3, 4-Ch-C6H3 '2964-I-C6H4'0' ! 3, 4-Cl2-C6H3 '2973, 5-F2-C6H3'O'I3, 4-Cl2-C6H3 298 4, 6- (NH2) 2-pyrimidin-2-yl S 1 3, 4-F2-C6H3 299 Benzimidazol-2-yl S 1 3, 4-F2-C6H3 300 Thiazol-2-yl S 1 3, 4-F2-C6H3 ! 010'S1 3, 4-F2-C6H3 HN'"Y A 302 5-N02-benzimidazol-2-yl S 1 3, 4-F2-C6H3 '303Pyridin-2-yl'S'I3, 4-F2-C6H3 304 N N S 1 3, 4-F2-C6H3 J ? N H 305lH-1, 2, 4-triazol-3-yl S 1 3, 4-F2-C6H3 306 Pyrimidin-2-yl S 1 3, 4-F2-C6H3 307 1-phenyl-tetrazol-5-yl S I3, 4-F2-C6H3 308 4, 6- (CH3) 2-pyrimidin-2-yl S 1 3, 4-F2-C6H3 094- (thiophen-2-yl)-'S' ! 3, 4-F2-C6H3 pyrimidin-2-yl 310 2- (cyclopropyl-CH2S)- ST3, 4-F2-C6H3 1, 3, 4-thiadiazol-5-yl
311 4-methyl-3- (thiophen-2- S 1 3, 4-F2-C6H3 yl)-1, 2, 4-triazol-5-yl 312 3-CN-6- (CH3C (O))- S1 3, 4-F2-C6H3 pyridin-2-yl 313lH-pyrazolo [3, 4- S' 3, 4-F2-C6H3 d] pyrimidin-4-yl 314 5-OCH3-benzimidazol-2-'S' 1 3, 4-F2-C6H3 yl 3155-F-6-Cl-benzimidazol-2-SS' 3, 4-F2-C6H3 yl 316 4, S-dihydrothiazol- 2- yl S 1 3, 4-F2-C6H3 317lH-5-phenyl-l, 2, 4-triazol-'S'13, 4-F2-C6H3 3-yl 3182- (thiophen-2-yl)-1, 3, 4-'S'13. 4-F2-C6H3 oxadiazol-5-yl 319 Quinoxalin-2-yl S 13, 4-F2-C6H3 '3202, 5-Cl2-C6H3"S' ! 3. 4-F2-C6H3 3212- (pyridin-2-yl)-1, 3, 4- S' 3, 4-F2-C6H3 oxadiazol-5-yl 322 7-CF3-quinolin-4-yl S 1 3, 4-F2-C6H3 3232- (pyridin-2-yl)-4-CH3- S 1 3, 4-F2-C6H3 pyrimidin-6-yl '324Naphth-1-yl'S' ! 3. 4-F2-C6H3 325 3, 4- (OCH3) 2-C6H3 S 1 3, 4-F2-C6H3 326 1, 3, 4-thiadiazol-2-yl'S'13. 4-F2-C6H3 327 3-CF 3-C6H4 S 1 3, 4-F2-C6H3 N. 0 S'13. 4-F2-C6H3 N 0 N a '3293, 4-Cl2-C6H3"S'13. 4-F2-C6H3 '3303-CN-5-CH3-pyridm-2-yl'S'13. 4-F2-C6H3
331 4-phenyl-thiazol-2-yl S 1 3, 4-F2-C6H3 332 S S 1 3, 4-F2-C6H3 ' N : '=0 333 2-CH3-1, 3, 4-thiadiazol-5- S 1 3, 4-F2-C6H3 yl NNCHg'SI3, 4-F2-C6H3 N--N H H CH, 335 H S13, 4-F2-C6H3 NX : N < 'A 336 2-phenoxy-phenyl S 1 3, 4-F2-C6H3 337 2-0CH3-C6 S 1 3, 4-F2-C6H3 338 2-CH3-4-Cl-C6H3 S 1 3, 4-F2-C6H3 '3392-CH3-6-C1-C6H3'S'I3, 4-F2-C6H3 3402- (HC=C-CH2S)-1, 3, 4- S' 3, 4-F2-C6H3 thiadiazol-5-yl 341 2-CO2CH3-C6H4'SI3, 4-F2-C6H3 424-CN-C6H43'13, 4-F2-C6H3 3434- ( (CH3) 2NCH2)-C6H4 0 13, 4-F2-C6H3 344H O 1 3, 4-F2-C6H3 0 y N HN 0 345 3-CH2OH-C6H4 0 1 3, 4-F2-C6H3 462-OCH2CH20H-C6H4'O'13, 4-F2-C6H3 474-CH3 (CH2) 20-C6H4'0'13, 4-F2-C6H3
348 3-C1-5-OCH3-C6H3 0 1 3, 4-F2-C6H3
General Preparation of Examples 108-225 PyBroP@ (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 2 equivalents) was added to a solution of 1- (3, 4-dichlorobenzyl)-4-piperidinamine, hydrochloride salt (lmg) the appropriate acid (2 equivalents) and triethylamine in 1methyl-2-pyrrolidone (0. 2ml) and was left for 24h. The reaction mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.3ml).
General Preparation of Examples 225-240 Step i : tert-Butyl 4- { [ (4-chlorophenoxy) acetyl] amino}-1-piperidinecarboxylate Prepared following the method of Example 94 using (4-chlorophenoxy) acetic acid (0.50g), 1,1-carbonyldiimidazole (0.50g) and tert-butyl 4-amino-1-piperidinecarboxylate (0.46g) to give the subtitle compound (0.54g).
Step ii : 2- (4-chlorophenoxy)-N- (4-piperidinyl) acetamide Prepared following the method of Example A step (ii) using r-butyl 4- { [ (4- chlorophenoxy) acetyl] amino}-l-piperidmecarboxylate (0.52g) to give the subtitle compound (0. 35g).
Step iii: Final product A mixture of the product from step (ii) (1.07mg), the appropriate alkyl halide (2 equivalents) and N, N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0. 18ml) was left at room temperature for 24h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0. 4ml).
General Preparation of Examples 241-255 A mixture of2- (4-fluorophenyl)-N- (4-piperidinyl) acetamide (WO97/36871 ; 0.94mg), the appropriate alkyl halide (2 equivalents) and N, N-diisopropylethylamine (3 equivalents) in I-methyl-2-pyrrolidinone (0. 18ml) was left at room temperature for 24h.
The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0. 4mil).
General Preparation of Examples 256-279 Step i : tert-Butyl 4- ( {3- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5-yl] propanoyl} amino)-1- piperidinecarboxylate
3-[3- (2-Pyridinyl) -1, 2, 4-oxadiazol-5-yl] propanoic acid (0. 60g) was dissolved in dichloromethane (1Oml). 1, 1-Carbonyldiimidazole (0. 33g) was added followed by tert butyl 4-amino-1-piperidinecarboxylate hydrochloride (0.5g) and triethylamine (0. 31mil).
After 2hours water, brine and dichloromethane were added and the phases separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate: methanol (33 : 1) to give the subtitle compound (0. 40g).
Step ii : 7V- (4-Piperidinyl)-3- [3- (2-pyridmyl)-1, 2, 4-oxadiazol-5-yl] propanamide
tert-Butyl 4- {3-[3-(2-pyridinyl)-1, 2, 4-oxadiazol-5-yl] propanoyl} amino)-1piperidinecarboxylate (0. 40g) was dissolved in dichloromethane (6ml) and trifluoroacetic acid (3ml) was added. After 2hours water, 2N sodium hydroxide and dichloromethane were added and the phases were separated. The organic phase was dried, filtered and evaporated to give the subtitle compound (0. 19g).
Step iii : Final product A mixture of the product from step (ii) (1. 21mg), the appropriate alkyl halide (2 equivalents) and N, N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0. 18ml) was left at room temperature for 24h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0. 4ml).
General Preparation of Examples 280-296 Step i: 2-Chloro-N-[ 1- (3, 4-dichlorobenzyl) -4-piperidinyl ] acetamide Prepared following the general preparation method of Examples 297-357 step (iii) using 1- (3, 4-dichlorobenzyl)-4-piperidinamine hydrochloride (2.0g), N, N- diisopropylethylamine (5.55 ml) and chloracetyl chloride (0.55ml) to give the subtitle compound (l. 0g).
Step ii: Final Product A mixture of the product from step (i) (1.34 mg), the appropriate phenol (1.5 equivalents) and potassium ter-butoxid (1. 4 equivalents) in 1-methyl-2-pyrrolidinone (0. 13ml) was left at room temperature for 24hours. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0. 4ml).
General Preparation of Examples 297-340 Step i: Carbamic acid, [1-[ (3, 4-difluorophenyl) methyl]-4-piperidinyl]-, 1, 1-dimethylethyl ester
Carbamic acid, 4-piperidinyl-, 1, 1-dimethylethyl ester (6. 95g) was dissolved in NV-dimethylformamide (70ml). 3, 4-Difluorobenzylbromide (4. 55ml) and potassium carbonate (16.0g) were added. The mixture was heated to reflux for 16hours, then allowed to cool to room temperature. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate. The organic phases were washed with water (twice) and brine, then dried, filtered and evaporated. The residue was triturated with ether: isohexane (1: 1) to give the subtitle compound (8. 13g) Step ii: 1-[ (3, 4-Difluorophenyl) methyl]-piperidin-4-ylamine dihydrochloride
Carbamic acid, [1-[ (3, 4-difluorophenyl) methyl]-4-piperidinyl]-, 1, 1-dimethylethyl ester was suspended in 6N hydrochloric acid (100mil). After 16hours excess hydrochloric acid was evaporated and the residue azeotroped with toluene, dried and evaporated to give the subtitle compound (8.10 g).
Step iii : 2-Chloro-N- [1- [ (3, 4-difluorophenyl) methyl]-piperidin-4-yl]-acetamide 1-[(3,4-Difluorophenyl) methyl]-piperidin-4-ylamine dihydrochloride (3.18g) was dissolved in tetrahydrofuran (40ml). Diisopropylethylamine (6.84g) and chloroacetyl chloride (1.33g) were added. After 3hours water, brine and ethyl acetate were added the phase were separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate to give the subtitle compound (0.728g).
Step iv : Final Product The product from step (iii) (1.21mg) was dissolved in dimethylsulfoxide (50p. l) and diisopropylethylamine (1.55mg, 3 equivalents) was added as a solution in dimethylsulfoxide (50 l). The appropriate thiol was added (1 equivalent) in dimethylsulfoxide (40u.1) and the reaction mixture was left at room temperature for 24hours. The reaction mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (400ut).
General Preparation of Examples 341-348 Prepared from the product of general preparation for Examples 297-340 step (iii) and the appropriate phenol following the method of Examples 280-296 step (ii).
Example 351
3- [3- (4-Bromo-l-methyl-1H-pyrazol-3-yl)-1, 2, 4-oxadiazol-5-yl]-N- [1- (3, 4dichlorobenzyl)-4-piperidinyl] propanamide
Step i : Methyl 4- { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino}-4-oxobutanoate To a solution of 1- (3, 4-dichlorobenzyl)-4-piperidinamine hydrochloride (3. 50g) in dichloromethane (loom) was added methyl 4-chloro-4-oxobutanoate (2.00g) dropwise.
Triethylamine (3.90g) was added and the reaction stirred under nitrogen for 2 hours.
Saturated sodium hydrogen carbonate solution was then added, with the solution being extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over anhydrous magnesium sulfate. After filtration the solvent was removed under reduced pressure to leave methyl 4- { [1- (3, 4 dichlorobenzyl)-4-piperidinyl] amino}-4-oxobutanoate (3. 00g).
Step ii : Lithium 4- { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino}-4-oxobutanoate To a solution of methyl 4- { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino}-4 oxobutanoate (3.72g) in methanol (30ml) was added lithium hydroxide (0.41g) in water (lOml) which was stirred under nitrogen for 48 hours. The solvent was removed under reduced pressure, the residue was triturated with ether and filtered to leave lithium 4- { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino}-4-oxobutanoate (3. 50g).
Step iii : 3- [3- (4-Bromo-1-methyl-lH-pyrazol-3-yl)-1, 2, 4-oxadiazol-5-yl]-N- [1- (3, 4dichlorobenzyl)-4-piperidinyl] propanamide To lithium 4- { [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino}-4-oxobutanoate (0. 292g) in dichloromethane (6ml) was added dimethylformamide (1. 5ml), 1- (3dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0. 183g), 1 hydroxybenzotriazole hydrate (0. 130g), 4-bromo-A-hydroxy-l-methyl-1H-pyrazole-3- carboximidamide (0. 175g) and triethylamine (0. 161g). Reaction was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure, followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was
azeotroped twice with toluene and was purified by reverse phase hplc (RPHPLC ; 75%-5%, 0. 1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the titled compound (0. 164g).
Example 352 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- [3- (2-pyrazinyl)-1, 2,4-oxadiazol-5yl] propanamide
To lithium 4- {[ 1- (3, 4-dichlorobenzyl) -4-piperidinyl]amino} -4-oxobutanoate (Example 351, step ii) (0. 292g) in dichloromethane (6ml) was added N, Ndimethylformamide (1. 5ml), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0. 183g), I-hydroxybenzotriazole hydrate (0. 130g), N-hydroxy-2pyrazinecarboximidamide (O. 1 lOg) and triethylamine (0. 161g). The reaction mixture was left to stir for 24 hours before removal of dichloromethane under reduced pressure.
Pyridine (5ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by RPHPLC (75%-5%, 0. 1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the title compound (0. 067g).
Example 353 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- {3- [ (2-thienylsulfonyl) methyl]-1, 2, 4oxadiazol-5-yl} propanamide hydrochloride
Step i : 3- {3-[ (2-Thienylsulfonyl) methyl]-1, 2, 4-oxadiazol-5-yl} propanoic acid (lZ)-N-hydroxy-2- (2-thienylsulfonyl) ethanimidamide (0. 250g) with dihydro-2, 5furandione (0. 114g) in dimethylformamide (0. 2ml) was heated at 120 C for 2 hours. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave 3- {3-[ (2thienylsulfonyl) methyl]-1, 2, 4-oxadiazol-5-yl} propanoic acid (0. 332g).
Step ii : 7V- [l- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- {3- [ (2-thienylsulfbnyl) methyl]-l, 2, 4oxadiazol-5-yl} propanamide hydrochloride 3- {3- [ (2-Thienylsulfonyl) methyl]-l, 2, 4-oxadiazol-5-yl} propanoic acid (0.332g) in dichloromethane was stirred under nitrogen. Oxalyl chloride (0.252g) was added dropwise followed by the addition of one drop of dimethylformamide. After 30 minutes the solvent and oxalyl chloride was removed under reduced pressure followed by the addition of dichloromethane (1Oml), 1- (3, 4-dichlorobenzyl)-4-piperidinamine hydrochloride (0. 347g), and triethylamine (0.202g) and allowed to stir for 2 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a brown oil. This oil was purified by RPHPLC (75%-5%, 0. 1 % ammonium acetate/acetonitrile) followed by chromatography using 3% ethanol/dichloromethane. The solvent was removed under reduced pressure, followed by the addition of hydrogen chloride in diethyl ether, filtered and dried to leave N-[1-(3, 4 dichlorobenzyl) -4-piperidinyl ]-3- {3- [ (2-thienylsulfonyl) methyl] -1, 2, 4-oxadiazol-5
yl} propanamide hydrochloride (0. 04g) as a pale yellow solid.
Example 354 7V- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- [3- (4-pyridinyl)-1, 2, 4-oxadiazol-5yl] propanamide Step i : 3- [3- (4-Pyridinyl)-l, 2, 4-oxadiazol-5-yl] propanoic acid
N-hydroxy-4-pyridinecarboximi. amide (0. 300g) with dihydro-2, 5-furandione (0. 217g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300W to leave a fused mass. The reaction was allowed to cool and triturated with ethanol and filtered to leave 3-[3- (4-pyridinyl) -1, 2, 4-oxadiazol-5 yljpropanoic acid (0. 241g).
Step ii: N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- [3- (4-pyridinyl)-1, 2,4-oxadiazol-5 yljpropanamide
For method refer to Example 353 step ii. Purification was performed via chromatography (2. 5% ethanol/dichloromethane). Solvent removed under reduced pressure to leave N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-3- [3- (4-pyridinyl)-1, 2, 4 oxadiazol-5-yl] propanamide (0. 154g) as a pale cream solid.
Example 355 Cis-N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5- yl] cyclopropanecarboxamide
Step i : Cis-2-[3- (2-pyridinyl) -1, 2, 4-oxadiazol-5-yl] cyclopropanecarboxylic acid N-hydroxy-2-pyridinecarboximidamide (0. 137g) with 3-oxabicyclo [3. 1. 0] hexane 2,4-dione (0. 112g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300W to leave a fused mass. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave cis-2- [3- (2-pyridinyl)- 1, 2, 4-oxadiazol-5-yl] cyclopropanecarboxylic acid (0.200g).
Step ii : Cis-N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5- yl] cyclopropanecarboxamide Cis-2- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5-yl] cyclopropanecarboxylic acid (0.139g) and N,N'-carbonyldiimidazole (0.11 g) in dichloromethane was stirred under nitrogen for 1 hour. 1- (3, 4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.198g), and triethylamine (0.121g) was then added and allowed to stir for 24 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This oil was purified by RPHPLC (75%-5%, 0. 1 % ammonium acetate/acetonitrile). The solvent was removed under reduced pressure to
leave Cis-N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5yl] cyclopropanecarboxamide (0. 054g) as a white solid.
Example 356 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- [3- (2-pyridinyl)-lH-l, 2, 4-triazol-5yl] propanamide Step i : 3- [3- (2-Pyridinyl)-lH-l, 2, 4-triazol-5-yl] propanoic acid 2-Pyridinecarbohydrazonamide (0. 136g) and dihydro-2, 5-furandione (0. long) in 1 ml ofdimethylacetamide was heated for 10 times 30 seconds in a CEM MARS 5 microwave at 100% of 300W under nitrogen to leave 3- [3- (2-pyridinyl)-lH-l, 2, 4-triazol5-yl] propanoic acid in lml of dimethylacetamide.
Step ii : N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-3- [3- (2-pyridinyl)-lH-l, 2, 4-triazol-5yl] propanamide 3- [3- (2-Pyridinyl)-lH-l, 2, 4-triazol-5-yl] propanoic acid (0. 218g in lml dimethylacetamide) and N, N'-carbonyldiimidazole (0. 250g) in dichloromethane was stirred under nitrogen for 30 minutes. 1- (3, 4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0. 316g), and triethylamine (0. 218g) was then added and allowed to stir for 2 hours under nitrogen. 1 M sodium hydroxide was added to the reaction with the resulting solution being washed three times with dichloromethane. The aqueous phase was acidified with glacial acetic acid, with the water/acetic acid being removed under reduced pressure.
Water was then added and extracted three times with dichloromethane. The pooled organic phases were extracted once with water and the water removed under reduced pressure to leave a white solid. This was then triturated with diethyl ether/ dichloromethane, filtered and was purified by RPHPLC (75%-5%, 0. 1 % ammonium acetate/acetonitrile), solvent removed to leave N-[1-(3, 4-dichlorobenzyl)-4-piperidinyl]-3 [3- (2-pyridinyl)-lH-1, 2, 4-triazol-5-yl] propanamide (0. 02g).
Example 357 N-[ 1- (3, 4- Dichlorobenzyl) -4-piperidinyl]-2- (3-phenyl-1H-l, 2, 4-triazol-5-yl) acetamide (3-Phenyl-1H-1, 2, 4-triazol-5-yl) acetic acid (0. 020g) and N, N'-carbonyl diimidazole (0. 016g) in dichloromethane was stirred under nitrogen for 30 minutes. 1 (3, 4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0. 03 zig) and triethylamine (0. 036g) was then added and allowed to stir for 1 hour under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times
with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a white solid. This was purified by RPHPLC (75%-5%, 0. 1% ammonium acetate/acetonitrile). Saturated sodium hydrogen carbonate was added to the pooled collected fractions with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced
pressure to leave N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- (3-phenyl-1H-l, 2, 4-triazol-5yl) acetamide (O. 031 g).
Example 358 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- (5-phenyl-1, 3, 4-oxadiazol-2-yl) acetamide acetate 3- (5-Phenyl-l, 3, 4-oxadiazol-2-yl) propanoic acid (0. 175g) and N, N'carbonyldiimidazole (0. 148g) in dichloromethane was stirred under nitrogen for 30 minutes. 1- (3, 4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0. 263g), and triethylamine (0.126g) was then added and allowed to stir for 2 hours under nitrogen.
Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was purified by chromatography using 2.5% ethanol/dichloromethane. The solvent was removed under reduced pressure and was purified by RPHPLC (75%-5%, 0. 1 % ammonium acetate/ acetonitrile), followed by 1 ml of glacial acetic acid being added and the solvent removed under reduced pressure to leave N- [I- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- (5-phenyl- 1, 3,4-oxadiazol-2-yl) acetamide acetate (0.024g).
Example 359 N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5yl] acetamide
Step i : Lithium [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5-yl] acetate 2- (5-Methyl-1, 2, 4-oxadiazol-3-yl) pyridine (0. 150g) was stirred at -78OC in dry tetrahydrofuran under nitrogen. (1. 6M) n-butyl lithium (0. 757ml) was added dropwise so as to maintain the temperature at - 78OC. After 30 minutes carbon dioxide was passed
through the solution and the reaction was allowed to return to room temperature. Once the reaction had reached room temperature, water (lml) was added and all solvents were removed under reduced pressure to leave a yellow solid. This solid was triturated with ethyl acetate and filtered to leave a pale yellow solid (0. 150g).
Step ii : N- [1- (3, 4-Dichlorobenzyl)-4-piperidinyl]-2- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5yl] acetamide Lithium [3- (2-pyridinyl) -1, 2, 4-oxadiazol-5-yl] acetate (0. 140g), 1- (3, 4dichlorobenzyl)-4-piperidinamine (0. 170g), PyBroP (0. 400g) were stirred under nitrogen in dimethylformamide (15ml). N, N-Diisopropylethylamine (0. 171g) was added and left to stir for 2 hours. 1M sodium hydroxide was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave product plus dimethylformamide.
Water was added which resulted in precipitation of the product. The product was filtered and was purified by RPHPLC (75%-5%, 0. 1% ammonium acetate/acetonitrile). After removal of the solvent under reduced pressure the resulting white solid was triturated with diethyl ether, filtered and dried to leave N- [I- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- [3- (2pyridinyl)-1, 2, 4-oxadiazol-5-yl] acetamide (0. 067g ; m. p. 145 C).
Example 360 N- [1- (4-Bromobenzyl)-4-piperidinyl]-2- (4-fluorophenyl) acetamide 2- (4-Fluorophenyl) -N- ( 4-piperidinyl) acetamide (W097/36871 ; 1. wog), 1-brom-4 (bromomethyl) benzene (1. 06g) and potassium carbonate (0. 877g) in dimethylformamide (15mil) were heated to 70oC, under nitrogen for 1 hour. Water was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid.
This solid was triturated with diethyl ether, filtered and recrystallised from ethanol/water to give white crystalline needles of N- [l- (4-bromobenzyl)-4-piperidinyl]-2- (4fluorophenyl) acetamide (m. p. 144OC).
Example 361 2- (4-Fluorophenyl)-N- [l- (2-quinolinylmethyl)-4-piperidinyl] acetamide
2- (4-Fluorophenyl) -N- ( 4-piperidinyl) acetamide (W097/36871 ; 0. 05g), 2quinolinecarbaldehyde (0. 033g) and sodium triacetoxyborohydride (0. 067g) in dichloroethane (3ml) were stirred under nitrogen for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with diethyl ether/ethyl acetate and filtered to leave 2- (4 fluorophenyl)-N- [1- (2-quinolinylmethyl)-4-piperidinyl] acetamide (0.020g).
Example 362
N- [l- (3-Chloro-4-fluorobenzyl)-4-piperidinyl]-3- [3- (2-pyridinyl)-l, 2, 4-oxadiazol-5yl] propanamide 3-[3- (2-Pyridinyl) -1, 2, 4-oxadiazol-5-yl] propanoic acid (0. 218g) and N, N'carbonyldiimidazole (0. 194g) were stirred in dichloromethane (1Oml) under nitrogen for 1 hour. 1- (3-Chloro-4-fluorobenzyl)-4-piperidinamine (JP 59101483 ; 0. 242g) was then added and left to stir for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with ethyl acetate/ethanol and filtered to leave N- [l- (3-chloro-4-fluorobenzyl)-4- piperidinyl]-3- [3- (2-pyridmyl)-l, 2, 4-oxadiazol-5-yl] propanamide (m. p. 150 C).
Example 363
N- [1- (4-Chloro-3-fluorobenzyl)-4-piperidinyl]-3- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5yl] propanamide Step i : tert-Butyl 1- (4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate 4-Chloro-3-fluorobenzaldehyde (0. 793g) and tert-butyl 4-piperidinylcarbamate (1. 00g) were stirred under nitrogen in dried tetrahydrofuran (25ml). Sodium triacetoxyborohydride (1.266g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed
under reduced pressure to leave tert-butyl l- (4-chloro-3-fluorobenzyl)-4piperidinylcarbamate (1. 80g) as a white solid.
Step ii : 1- (4-Chloro-3-fluorobenzyl)-4-piperidinamine tert-Butyl 1- (4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1. 80g) in dichloromethane (20ml) was stirred under nitrogen. Trifluoroacetic acid (5ml) was then added dropwise and the reaction was left to stir for 2 hours. 1 M sodium hydroxide was added to the reaction until basic, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced
pressure. Product purified by chromatography (5% ethanol/dichloromethane to 10% ethanol/dichloromethane) and solvent removed under reduced pressure to leave an oil which crystallised over the period of 48 hours. The resulting solid was triturated with diethyl ether and filtered to leave 1- (4-chloro-3-fluorobenzyl)-4-piperidinamine (0. 500g) as a white solid.
Step iii : N- [I- (4-Chloro-3-fluorobenzyl)-4-piperidinyl]-3- [3- (2-pyridinyl)-1, 2, 4 oxadiazol-5-yl] propanamide 3- [3- (2-Pyridinyl)-1, 2, 4-oxadiazol-5-yl] propanoic acid (0.136g) and N, N'carbonyldiimidazole (0. 114g) were stirred in dichloromethane (10mol) under nitrogen for 1 hour. 1- (4-Chloro-3-fluorobenzyl)-4-piperidinamine (0. 150g) was then added and left to stir for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This was triturated with diethyl ether which caused product the to crystallise. After filtration, the product was
washed with diethyl ether and dried to N-[1- (4-chloro-3-fluorobenzyl) -4-piperidinyl]-3-[3 (2-pyridinyl)-1, 2, 4-oxadiazol-5-yl] propanamide (m. p. 132OC).
Example 364 2- (4-Chlorophenoxy) - N -[ 1-[ (3, 4-dichlorophenyl) methyl]-piperidin-4-yl]-acetamide
The product from Example A step (ii) was dissolved in dichloromethane (10mil) containing triethylamine (0. 081g) and the solution was cooled to 0 C. 4 Chlorophenoxyacetyl chloride (88mg) in dichloromethane (3ml) was added dropwise, the cooling bath was removed and the resulting solution was stirred for 1hour. Ethyl acetate, water and brine were added and the phases were separated. The organic phase was dried, filtered and evaporated to give an oil which was purified by reverse phase HPLC (with a
gradient eluent system (25% MeCN/NH40Acaq (0. 1 %) to 95% MeCN/NH40Ac, q (0. 1 %)) to give the title compound (0. 049g).
Example 365 N- (I-benzyl-4-piperidinyl)-3- [3- (2-pyridinyl)-1, 2, 4-oxadiazol-5-yl] propanamide To a solution of3- (3-pyridin-2-yl- [1, 2, 4] oxadiazol-5-yl)-propionic acid (zig) in tetrahydrofuran (5ml), was added carbonyldiimidazole (0. 74g). The mixture was stirred for 10 minutes before addition of 1-benzyl-piperidin-4-ylamine (Iml) in tetrahydrofuran (5ml). The reaction mixture was stirred for 15 minutes then partitioned between ethyl acetate (20ml) and water (20ml). The organic layer was separated, dried (MgSO4) and solvent removed by evaporation. Purification by Biotageo 40S eluting 3% MeOH/0. 5% 880 ammonia/dichloromethane gave the title compound (0. 93g).
Example 366 N- (2- { [1- (3, 4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-2- (2-fluoro-phenyl)acetamide Step i : (2-Methylamino-ethyl)-carbamic acid tert-butyl ester To a solution of (2-amino-ethyl)-carbamic acid-tert-butyl ester (5g) and triethylamine (6. 5ml) in tetrahydrofuran (1000mil) at 0 C was added methyliodide (1. 94ml) dropwise over a period of I hour. The mixture was allowed to warm to ambient temperature and stirred for 72 hours before removal of solvents by evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgS04) and solvent removed by evaporation to give the title compound (3. 7g).
Step ii : (2- { [l- (3, 4-Dichloro-benzyl)-pipehdin-4-yl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester To a solution of dichlorobenzyl-piperidin-4-one (Example 74, step (i), 4. 8g) and acetic acid (lml) in dichloromethane (loom) was added (2-methylamino-ethyl)-carbamic acid tert-butyl ester (3. 26g) and the mixture was stirred for 5 minutes before addition of sodium triacetoxyborohydride (7. 9g). The reaction mixture was stirred for 12 hours before addition of sodium bicarbonate solution. The mixture was stirred for 1/2 hour and then partitioned between water and dichloromethane. The organic layer was separated, dried (MgS04) and solvent removed by evaporation. Purification by Biotage 40S eluting 10% MeOH/2% triethylamine/dichloromethane gave the title compound (1. 7g).
Step iii : NI-[1- (3, 4-Dichloro-benzyl) -piperidin-4-yl]-NI-methyl-ethane-1, 2-diamine
(2-f [1- (3, 4-Dichloro-benzyl)-piperidin-4-yl]-methyl-ainino I-ethyl)-carbamic acid ter-butyl ester (1. 7g) was dissolved in 6M HC1 (20ml) and stirred for 12 hours. The solvent was evaporated and the residue was azeotroped with toluene and then sodium bicarbonate solution was added. The mixture was stirred for 10 minutes and the product was extracted with dichloromethane. The solvent was removed by evaporation to give the title compound (0.75g).
Step iv: N- (2- { [1- (3, 4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-2- (2-fluoro- phenyl)-acetamide
Prepared by the method of Example 359 step (ii) using N- [I- (3, 4-Dichlorobenzyl)-piperidin-4-yl]-/V-methyl-ethane-1, 2-diamine and 2-fluorophenylacetic acid.
Example 367 7V- [l- (3, 4-dichIoroben2yI)-4-piperidinyl]-V-methyl-2- (4-fluorophenyl) acetamide Step i : [1- (3, 4-Dichlorobenzyl)-piperidin-4-yl]-methyl-amine To a solution of 1- (3, 4-Dichloro-benzyl)-piperidin-4-one (3. 1 g) in dichloromethane (50ml) and acetic acid (0.69ml) was added methylamine (6ml of a 1M solution in tetrahydrofuran). The mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3g) and the resulting mixture stirred for 72 hours. Sodium bicarbonate solution (100mil) added and the mixture stirred vigorously for 5 minutes before extraction of the product with dichloromethane (2X200ml). The organics were separated, bulked and dried, (MgSO4). Purification by Biotagee 40S eluting 10% MeOH/0. 5% 880 ammonia/dichloromethane gave the sub-title compound (1. 8g).
Step ii: N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- (4-fluorophenyl) acetamide To a solution of 4-fluorophenylacetic acid (loom) in tetrahydrofuran (3ml) was added carbonyldiimidazole (105mg). The mixture was stirred for 10 minutes before addition of [1- (3, 4-dichlorobenzyl)-piperidin-4-yl]-methyl-amine (177mg) in tetrahydrofuran (2ml). Stirring was continued for 1 hour then solvent removed by evaporation. Purification by Biotageo 40S eluting 2% MeOH/0. 5% 880 ammonia/dichloromethane gave the title compound (166mg).
Example 368 N- [l- [ (3, 4-dichlorophenyl) methyl]-4-piperidinyl]-2- (2-pyrimidinyloxy)-acetamide Step i: Ethyl 2-pyrimidinyloxyacetate
Ethyl glycolate (1. 04g) was dissolved in tetrahydrofuran (10mil) and the solution was cooled to 0 C. Sodium hydride (60% suspension in oil, 0.43g) was added and the suspension was stirred and then sonicated in an ultrasonic bath. 2-Chloropyrimidine (1.14g) was added and the mixture was sonicated for a further 11 Omin. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate, the organic phases were washed with brine and dried, filtered and evaporated. The residue was purified by chromatography eluting with iso-hexane : ethyl acetate (13: 7) to give the subtitle compound (1.40g) as an oil.
Step ii: 2-Pyrimidinyloxyacetic acid Ethyl 2-pyrimidinyloxyacetate (1.4g) was dissolved in ethanol (10ml). Sodium hydroxide (2M aq) was added and the mixture was stirred for 64h. The solvent was evaporated and the reside was dissolved in water, filtered and the acidified with concentrated hydrochloric acid. The resulting precipitate was collected and dried to give the subtitle compound (0.698g).
Step iii : N- [1- [ (3, 4-dichlorophenyl) methyl]-4-piperidinyl]-2- (2-pyrimidinyloxy)- acetamide The title compound was prepared from the product of Example A step (ii) (hydrochloride salt, 335mg) and 2-pyrimidinyloxyacetic acid (170mg) using the method of Example 94. Yield 140mg, m. p. 120-122Oc.
* Example 369
N- [2- [ [8- [ (3, 4-Dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl] amino] ethyl]-3 methoxy-benzamide, bis toluene sulfonic acid salt
Step i: 8-[ (3, 4-Dichlorophenyl) methyl]-8-azabicycIo[3. 2. 1 octan-3-one 2,5-Dimethoxytetrahydrofuran (4.92g) was stirred in hydrochloric acid (1M, 25 ml) for 1 hour. 3, 4-Dichlorobenzylamine (5ml) was added to hydrochloric acid (1M, 15ml) and the resulting suspension was added to the first solution. Phosphate buffer solution (pH 5.5, 250ml) was added followed by sodium hydroxide (1.6g). A solution of acetone
dicarboxylic acid (4. 77g) in phosphate buffer solution (pH 5. 5, 90ml) was added to the mixture and the solution was stirred. A yellow solid formed and the mixture was left to stand for 64h. The aqueous supernatant was decanted and hydrochloric acid (2. 5M) was added to the solid along with ethyl acetate. The layers were separated and the aqueous phase was extracted twice with dichloromethane containing a little methanol. The organic layers were combined and evaporated to give a crude oil (ca 7g). A portion of the product (ca 2.5g) was purified by chromatography eluting with dichloromethane: methanol (19: 1) to give the subtitle compound (1.62g) as a yellow oil.
Step ii: Carbamic acid, Endo- [2- [ [8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct- 3-yl] amino] ethyl]-l, 1-dimethylethyl ester 8-[ (3, 4-Dichlorophenyl) methyl]-8-azabicyclo[3. 2. 1] octan-3-one (751 mg) and
carbamic acid, (2-aminoethyl)-1, 1-dimethylethyl ester (520 mg) were dissolved in dichloroethane (23ml). Sodium triacetoxyborohydride (697 mg) was added and the suspension was stirred at room temperature for 20hours. Dichloromethan was added and the solution was washed with sodium bicarbonate solution, then with water and then with brine. Chromatography of the residue eluting with ethyl acetate: methanol: triethylamine (80: 19: 1) gave the subtitle compound (688mg) as an oil.
Step iii : N-[2-[[8-[ (3, 4-Dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl] amino] ethyl]
3-methoxy-benzamide, bis toluene sulfonic acid salt Carbamic acid, [2- [ [8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3yl] amino] ethyl]-, 1, 1-dimethylethyl ester (337mg) was dissolved in dichloromethane (3ml) and trifluoroacetic acid (3ml) was added. The resulting solution was stirred for 1 hour then the volatiles were evaporated. The residue was dissolved in dichloromethane (3ml) and triethylamine (lml) was added followed by 3-methoxybenzoyl chloride (120put1). The solution was stirred overnight. The solvent was evaporated and the residue was purified by RPHPLC (gradient ammonium acetate 1% aqueous: acetonitrile (25% acetonitrile to 95% acetonitrile) ). Excess tosic acid in ether was added to the residue and the resultant salt was recrystallised from a mixture of ethyl acetate-ethanol with a little cyclohexane to give the title compound (77mg; m. p. 180-182. 5OC).
Example 370
Endo-N-[8-[ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl]-3- (2-pyridinyl)1, 2, 4-oxadiazole-5-propanamide hydrochloride
Step i : Endo-8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] octan-3-amine 8- [ (3, 4-Dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] octan-3-one (350mg) was dissolved in dry methanol (12ml) and ammonium acetate (1 g) was added. The mixture was stirred to get partial solution and then sodium cyanoborohydride (106mg) was added.
The mixture was heated under reflux for 150 minutes, then allowed to cool to room temperature. The methanol was evaporated, the residue was partitioned between sodium hydroxide and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried, filtered and evaporated to
give the subtitle compound.
Step ii : Endo-N-[8-[ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl]-3- (2pyridinyl)-1, 2, 4-oxadiazole-5-propanamide hydrochloride 3-(2-Pyridinyl)-1, 2, 4-oxadiazole-5-propanoic acid (305mg) was suspended in dichloromethane (6ml) and oxalyl chloride (O. 5mil) was added. The mixture was stirred overnight. Toluene (Iml) was added to the solution, the volatiles were evaporated, then the residue was redissolved in dichloromethane (2ml). Endo-8- [ (3, 4 dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] octan-3-amine (all from step (i) ) was dissolved in dichloromethane (4ml) containing triethylamine (0. 5ml) and then cooled in an ice bath.
The acid chloride solution was added to the amine and the mixture was stirred for 1hour.
Water was added to the reaction mixture and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were dried, filtered and evaporated. The residue was purified by RPHPLC (gradient ammonium acetate 1 % aqueous: acetonitrile (25% acetonitrile to 95% acetonitrile) ). The product was suspended in ether and the ethereal hydrochloric acid was added, the suspension was stirred and then the diethyl ether was evaporated. The residue was dissolved in hot ethyl acetate containing ethanol and crystallisation was induced by adding iso-hexane to give the title compound (47mg).
Example 371 2- [4- (acetylamino) phenoxy]-N- [l- [ (3, 4-dichlorophenyl) methyl]-4-piperidinyl]-acetamide Step i: Methyl (4-acetaminophenoxy) acetate
4-Acetaminophenol (1. 51g), potassium carbonate (1. 38g) and methyl bromoacetate (I. Oml) were combined in acetone (40ml) and heated to reflux for 5hours. The mixture was allowed to cool to room temperature, filtered and evaporated. The residue was
dissolved in ethyl acetate, washed with water and then with brine then dried, filtered and evaporated to give the subtitle compound (2. 32g).
Step ii: (4-Acetaminophenoxy) acetic acid Methyl (4-acetaminophenoxy) acetate was hydrolysed following the method of Example 368 step (ii) to give the subtitle compound (1.85g).
Step iii: 2- [4- (acetylamino) phenoxy]-N- [l- [ (3, 4-dichlorophenyl) methyl]-4-piperidinyl]acetamide The title compound was prepared from the product of Example A step (ii) (free base, 281mg) and (4-acetaminophenoxy) acetic acid (229mg) using a method hereinbefore described (yield 40mg ; m. p. 177-178. 5OC).
Example 372
N- [1- [ (3, 4-dichlorophenyl) methyl]-4-piperidinyl]-4-hydroxy- benzeneacetamide The title compound was prepared from the product of Example A step (ii) (free base, 172mg) and 4-hydroxyphenylacetic acid (135mg) using a method hereinbefore described (yield 57mg; m. p. 72-97OC).
Example 373
Exo-N-[8-[ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl]-3- (2-pyridinyl)-1, 2, 4 oxadiazole-5-propanamide Step i: Endo-8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] octan-3-ol 8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (330mg) was
dissolved in tetrahydrofuran (5ml) and cooled to 0 C. Lithium tris (3-ethylpentyl-3oxy) aluminohydride solution (0. 5M, 2. 5ml) was added dropwise and the mixture was allowed to attain room temperature overnight. Sodium sulfate decahydrate (ca 2g) was added and the suspension was stirred for Ihour. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr and evaporated. The residue was purified by chromatography eluting with dichloromethane: methanol (9: 1) to give the subtitle
compound 161mg.
Step ii : Exo-2- [8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl]-lisoindole1, 3 (2H)-dione Endo-8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] octan-3-ol (556mg), phthalimide (321mg) and polymer bound triphenylphosphine (821mg) were combined in tetrahydrofuran (10ml). Diethylazodicaboxylate (330) 1) was added and the mixture was
stirred gently overnight. Additional phosphine (0. 5g) and diethylazodicaboxylate (200Au1) were added and the mixture was stirred for an additional 5 days. The reaction mixture was diluted with ethyl acetate and filtered ; the residue was washed with ethyl acetate and methanol. The filtrate was evaporated, and chromatographed eluting with 9 : 1 ethyl acetate : methanol. RPHPLC of the product (gradient ammonium acetate 1% aqueous : acetonitrile (25% acetonitrile to 100% acetonitrile)) gave the subtitle compound (90mg).
Step iii : Exo-8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] octan-3-amine Exo-2- [8- [ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl]-lJV-isoindole1, 3 (2H)-dione (90mg) was dissolved in ethanol (6ml) containing dichloromethane (3ml) ; hydrazine hydrate (0. 2ml) was added and the resulting solution was stirred at room temperature for 26hours. The suspension was filtered and the filtrate was evaporated to give the subtitle compound (55mg).
Step iv : Exo-N-[8-[ (3, 4-dichlorophenyl) methyl]-8-azabicyclo [3. 2. 1] oct-3-yl]-3- (2pyridinyl)-1, 2, 4-oxadiazole-5-propanamide Prepared following the method of Example 370 step (iii) but without salt formation to give the title compound (15mg ; m. p. 177. 5-178 C).
Example 374 (R) N- [1- [1- (4-bromophenyl) ethyl]-4-piperidinyl]-3- (2-pyridinyl)-1, 2, 4-oxadiazole-5propanamide Step i : (R)-I- [l- (4-Bromophenyl) ethyl]-4-piperidinone (R)- (4-Bromophenyl) ethylamine (l. Olg) and potassium carbonate (1. 45g) were dissolved in a mixture of ethanol (13ml) and water (6ml) and then heated to a vigorous reflux. A solution of 4-hydroxy-4-methoxy-1, 1-dimethyl-piperidinium iodide (J. Chem.
Soc. Perkin Trans. 2, (1984) 1647) (1. 47g) in warm water (6ml) was added dropwise over 40 minutes ; reflux was maintained for a further 12hours, then the reaction was allowed to cool to room temperature. The mixture was evaporated and ethyl acetate and water were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the organic layer was washed with brine, dried, filtered and evaporated.
Chromatography of the residue eluting with iso-hexane : ethyl acetate (3 : 2) gave the subtitle compound (804mg).
Step ii : (R)-l- [l- (4-Bromophenyl) ethyl]-4-piperidinamine
Prepared following the general method of Example 370 step (i) (R)-l- [l- (4bromophenyl) ethyl]-4-piperidinone (420mg) ammonium acetate (0. 80g) and sodium cyanoborohydride (120mg) to give the subtitle compound (449mg).
Step iii : (R) N-[1-[1-(4-bromophenyl)ethyl]-4-piperidinyl]3-(2-pyridinyl)-l,2,4 oxadiazole-5-propanamide
Prepared following a method as hereinbefore described using (R)-l- [l- (4bromophenyl) ethyl]-4-piperidinamine (449mg), 3-(2-pyridinyl)-1, 2, 4-oxadiazole-5propanoic acid (0. 31 g), 1-hydroxybenzotriazole (0. 20g), 4- (N, N-dimethylamino)-pyridine (0. 13g) and l-ethyl-3- [3- (dimethylamino)-propyl] carbodiimide hydrochloride (0. 30g) to give the title compound (40mg ; m. p. 153-155OC).
Example 375 (S) N- [1- [1- (4-bromophenyl) ethyl]-4-piperidinyl]-3- (2-pyridinyl)-1, 2, 4-oxadiazole-5 propanamide Prepared following an analogous series of steps to example 374 but using (S)- (4bromophenyl) ethylamine to give the title compound. m. p. 141. 5-143OC aD-29. 55 (c= 0. 13, methanol, 21OC) Example 385 1- [3, 4-Dichlorobenzyl]-N- [3- (3-pyridinyl) propyl]-4-piperidinamine
The title compound was prepared from 1- (3, 4-dichlorobenzyl) piperidine-4-amine (free base 187mg), 3- (3-pyridinyl) propanal (125mg), sodium triacetoxyborohydride (70mg), and 0.02ml acetic acid, stirred together for 2hrs in dichloromethane (1Oml). Water was added, the mixture neutralised with sodium bicarbonate and the organic phase separated, dried and chromatographed on silica with ethyl acetate/methanol (9: 1) as eluant, to give the title compound (70mg) as a colourless oil.
Example 386 2- [ (1, 1'-Biphenyl)-4-yloxy]-N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl] acetamide
Example 387 N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-4-phenyl-3-butenamide
Example 388 N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-3- (3-methoxyphenyl)-2-propenamide.
Example 389 N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-3- (4-iodophenoxy) propanamide.
Example 390 N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-N'- (4-methoxyphenyl) succinamide
Example 391 N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- [ (5-phenyl-2-pyrimidinyl) oxy] acetamide
Example 392 N- [l- (4-iodobenzyl)-4-pipendmyl]-2- (5-phenyl-2-pyrimidinyl) thio] acetamide
Example 393 N- [l- (3, 4-dichlorobenzy)-4-piperidinyl]-2- [ (2-pyrimidinyl) thio] acetamide
Example 394 2- [ (5-Bromo-2-pynmidmyl) thio]-N- [ l- (3, 4-dichloroben2y)-4-piperidinyl] acetamide
Example 395 N- [l- (3, 4-difluororobenzyl)-4-piperidinyl]-2- (4-pyridinylthio) acetamide
Example 396 N- [1- (3, 4-dichlorobenzy)-4-piperidinyl]-3- (5-phenyl-1 H-pyrrol-2-yl) propanamide
Example 397 N -[ 1- (3, 4-dichlorobenzy) -4-piperidinyl]- N'- (5-phenyl-2-pyrimidinyl) -1, 2-ethandiamine
The title compound (20mg) was prepared by heating at reflux N- [1- (3, 4dichlorobenzyl)-4-piperidinyl]-1, 2-ethanediamine (lOOmg) and 2-chloro-5 phenypyrimidine (100mg) and Hunigs'base (100mg) in toluene for 8hours. The mixture was purified by chromatography on silica, with ethyl acetate methanol (9: 1) as eluant to give the title compound as a yellow oil.
Example 398 N-[5-bromo-2-pyrimidinyl]-N'-[1-(3,4-dichlorobenzy)-4-piperidinyl-1,2-ethandiamine
Prepared by the method of Example 397 amine (200mg), 2-chloro-5bromopyrimidine (130mg), Hunigs'base (200mg) to give the title compound (20mg).
Example 399 2-[(2-Chloro-4-pyrimidinyl)amino]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl] acetamide
Example 401 2-[(5-Bromo-2-pyrimidinyl)oxy]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-acetamide
Example 402
N- [l- (3, 4-dichlorobenzy)-4-piperidinyl]-2- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2 yl) acetamide
Example 403 N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-N- [2- (2-pyhdinylthio) ethylamine, dihydrochloride
Example 404 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-(phenylthio) propanamide
Example 405 N'- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- [4- (trifluoromethoxy) phenoxy] acetohydrazide
The title compound was prepared from 3, 4-dichlorobenzyl-4-piperidone (J. Med.
Chem, 1999, 42, 3629 ; lOOmg), 2- [4 (trifluoromethoxy) phenoxy] acetohydrazide (lOOmg), sodium triacetoxyborohydride (100mg), and 0. 02ml acetic acid, stirred together for 2hours in dichloromethane by the method of Example 369 step ii.
Example 406 N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl]-N- [3- [3- (2-pyridinyl)-l, 2, 4-oxadiazo-5yl] propyl] amine
The title compound (29mg) was prepared from 3, 4-dichlorobenzylpiperidine-4amine (100mg free base), 2-[ 5- (3-bromopropyl) -1, 2, 4-oxadiazol-3-yl] pyridine (loom), potassium carbonate (loom) in dimethyl formamide (I ml) were heated together in the microwave for 30secs, water was added and the product extracted into dichloromethane and chromatographed on silica with ethyl acetate/methanol (9 : 1) as eluant.
Example 407 N- [2- [1- (3, 4-dichlorobenzyl)-4-piperidinyl] amino] ethyl]-3- (methylsulphonyl) benzamide
Prepared from N- (2-aminoethyl)-N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-2, 2, 2trifluoroacetamide (lOOmg), 3-methylsulphonylbenzoic acid (50mg) and carbonyldiimidazole (40mg). The product obtained was stirred together with sodium hydroxide (40mg) in 50: 50 methanol/water for 12hrs, extracted into dichloromethane and purified by chromatography on silica with ethyl acetate/methanol (9: 1) as eluant, to give the title compound (25mg).
Example 408 3- [5- (4-chlorophenyl)-4H-1, 2, 4-triazol-3-yl]-N- [l- (3, 4-dichlorobenzyl)-4-piperidinyl] propanamide
Example 409 N -[ 1- (3, 4-dichlorobenzyl) -4-piperidinyl]- 3- (2-pyridinyl) propanamide
Example 410
N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-4- (4- (methylsulphonyl) phenyl-4-oxobutanamide
Example 411 N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-N'- [4- (methylsulphonyl) benzylamine
Example 412 N- [1- (3, 4-dichlorobenzyl)-4-pipendmyl]-N'- [ (2-pyndinyl) succinamide
Example 413 N- [1- (3, 4-dichlorobenzyl)-4-piperidinyl]-2- (4-phenyl-1, 3-thiazol-2-yl)) acetamide
Example 414 N- -[ 1- (3, 4-dichlorobenzyl) -4-piperidinyl]- 2- (2-phenyl-l, 3-thiazol-4-yl)) acetamide
Example 415 N- [1- (3, 4-difluorobenzyl)-4-piperidinyl]-3- (3-2-pyridinyl-1, 2, 4-oxadiazol-5 yl] propanamide
Example 416 N-trifluoroacetyl-N- [2- [l- (3, 4-dichlorobenzyl)-4-piperidinyl] amino] ethyl]-3- methoxybenzamide
a) ter-butyl 2- { [I- (3, 4-dichlorobenzyl)-4-piperidinyl] amino} ethylcarbamate The sub-title compound (800mg) was prepared from 3, 4-dichlorobenzyl-4 piperidone (1.3g) tert-butyl 2-aminoethylcarbamate (0.8g), sodium triacetoxyborohydride (100mg), and 0.02ml acetic acid, stirred together for 2hrs in dichloromethane. The subtitled compound was isolated by standard procedures.
MS [M+Ht (ES+) 402 b) N-(2-aminoethyl)-N- [1-(3,4-dichlorobenzyl) -4-piperidinyl]-2,2,2-trifluoroacetamide A mixture of the above amine (800mg), and triethylamine (0.5ml) in dichloromethane (50ml), treated with trifluoroacetic anhydride (420mg) over 30 mins, evaporated to dryness and dichloromethane (20ml) and trifluoroacetic acid (2ml) added, stirred for 3hrs, then neutralised with aqueous sodium bicarbonate, the organic phase separated, dried and evaporated to give the title compound (250mg) as a yellow oil. c) N-trifluoroacetyl-N-[2-[1-(3, 4-dichlorobenzyl)-4-piperidinyl] amino] ethyl]-3- methoxybenzamide The title compound (30mg) was prepared from the product above (40mg) 3methoxybenzoyl chloride (20mg) and triethylamine (50mg) using one of the methods described above.
MS [M+H]- (ES+) 580 Further compounds of formula (I), all according to formula (Ic), are shown in the table below.
Example (Q) m (CRR) n TR* Z Ro 380 4-Cl-C6H4 O CH2 C(O) H CH2C 2-Cl-5 (O) NH CH3-C6H3 381 4-Cl-C6H4 O CH2 C(O) H (CH2)3 C6H5 3823- (pyridin-2-yl)-'0 CH2 C (O) H allyl C6H5 1, 2,4-oxadiazol-5-yl 383 2-(cyclopropyl-NH)- m=0 n=0 - CH3 CH2 3,4-Cl2pyrimidin-4-yl C6H3
384 2-(pyridin-3-yl)- m=0 n=0 - CH3 CH2 3, 4-Cl2pyrimidin-4-yl C6H3 400 pyrimidin-2-yl S CH2 C (O) H C (O) 3, 4-Cl2 C6H3 EXAMPLE 417 A pharmaceutical combination comprising a compound of formula (I) (such as the compound of one of Examples 1 to 416; especially the compound of Example 99,100, 102 or 415) and loratidine, desloratidine, fexofenadine, cetirizine, ebastine, astemizole, norastemizole, epinastine, efletirizine, budesonide, fluticasone, mometasone, rofleponide, montelukast, pranlukast, zafirlukast, Z4407, zafirlukast, recombinant human IL-10, recombinant human IL-12, formoterol, salmeterol, salbutamol, SB-207499, theophylline, an anti-IL-5 antibody or an anti-TNF-antibody.

Claims (9)

  1. CLAIMS 1. A pharmaceutical combination comprising a compound of formula (I) :
    wherein Z is CR4R5, C (O) or CR-Z ; Z'is CI-4 alkylene (such as CH2), 2-4 alkenylene (such as CH=CH) or C (O) NH ; R'represents a 1-12 alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C-6 alkoxy (such as methoxy or ethoxy), C-6 alkylthio (such as methylthio), C3-7 cycloalkyl (such as cyclopropyl), Ci. 6 alkoxycarbonyl (such as methoxycarbonyl) and phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, Cl 6 alkyl, Cl 6 haloalkyl (such as CF3), phenyl (CI 6 alkyl) (such as benzyl), Ci-6 alkoxy, Ci-6 haloalkoxy, S (0) 2 (Ci6 alkyl), C (O) NH2, carboxy or Cl 6 alkoxycarbonyl) ; or R1 represents C2-6 alkenyl optionally substituted by phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, CI-6 alkyl, CI-6 haloalkyl, phenyl (CI-6 alkyl), Ci-6 alkoxy, Cl 6 haloalkoxy, S (0) (CI-6 alkyl), C (O) NH2, carboxy or C 1-6 alkoxycarbonyl) ; or R 1 represents a 3-to 14-membered saturated or unsaturated ring system which optionally comprises up to two ring carbon atoms that form carbonyl groups and which optionally further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from : halogen, cyano, nitro, oxo, hydroxyl, CI-8 alkyl, CI-6 hydroxyalkyl, CI-6 haloalkyl, CI-6 alkoxy (CI-6 alkyl), C3-7 cycloalkyl (CI~6 alkyl), Cl-6 alkylthio (C1-C6 alkyl), CI-6 alkylcarbonyloxy (Cl 6 alkyl), Cl-6 alkylS (0) 2 (CI-6 alkyl), aryl (CI-6 alkyl), heterocyclyl (CI~6 alkyl), arylS (O) 2 (CI-6 alkyl), heterocyclylS (0) (Cl-6 alkyl), aryl (Ci. 6 alkyl) S (0) 2, heterocyclyl (Cl 6 alkyl) S (0) 2, C2-6 alkenyl, Ci. 6 alkoxy, carboxy-substituted CI-6 alkoxy, CI-6 haloalkoxy, Cl-6 hydroxyalkoxy, CI-6 alkylcarboxy-substituted Cl-6 alkoxy, aryloxy, heterocyclyloxy, C)-6 alkylthio, 3-7
    cycloalkyl (Cl 6 alkylthio), C3-6 alkynylthio, Ci. 6 alkylcarbonylamino, Ci-6 7 8 23 24 20 haloalkylcarbonylamino, SO3H, NR7R8, C (O) NR23R24, S (0) 2NRR, S (0) 2R R25C (O), carboxyl, CI-6 alkoxycarbonyl, aryl and heterocyclyl ; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, CI-6 alkyl, CI-6 haloalkyl, phenyl (CI-6 alkyl), CI-6 alkoxy, Ci-Ce haloalkoxy, S (0) (CI-6 alkyl), C (O) NH2, carboxy or CI-6 alkoxycarbonyl ; m is 0 or 1 ; Q represents an oxygen or sulphur atom or a group NR9, C (O), C (O) NR9, NR9C (O) or CH=CH ; n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is 0 ; each R2 and R3 independently represents a hydrogen atom or a Cl alkyl group, or (CR2R3) n represents C3-7 cycloalkyl optionally substituted by CI-4 alkyl ; T represents a group Ni10, C (O) Ni10, NRl1C (O) NR' or C (O) NR"NR' ; xI, X2, X3 and X4 are, independently, CH2, CHR {wherein each R, is, independently, CI-4 alkyl or C3-7 cycloalkyl (CI-4 alkyl) l or C=O ; or, when they are CHR, the R12 groups of Xl and X3 or X4, or, X2 and X3 or X4 join to form a two or three atom chain which is CH2CH2, CH2CH2CH2, CH20CH2 or CH2SCH2 ; provided always that at least two of Xl, X2, X3 and X4 are CH2 ; R4 and R5 each independently represent a hydrogen atom or a Ci-C4 alkyl group ; R6 is aryl or heterocyclyl, both optionally substituted by one or more of : halogen, cyano, nitro, oxo, hydroxyl, C 1-8 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy (Ci-6 alkyl), C3-7 cycloalkyl (CI-6 alkyl), Ci-C6 alkylthio (CI-6 alkyl), CI-6 alkylcarbonyloxy (CI-6 alkyl), CI-6 alkylS (0) (CI-6 alkyl), aryl (Cl-6 alkyl), heterocyclyl (C1~6 alkyl), arylS (O) 2 (CI-6 alkyl), heterocyclylS (0) 2 (CI-6 alkyl), aryl (CI-6 alkyl) S (0) 2, heterocyclyl (Ci-6 alkyl) S (0) 2, 2-6 alkenyl, CI-6 alkoxy, carboxy-substituted CI-6 alkoxy, CI-6 haloalkoxy, CI-6 hydroxyalkoxy, Cl-C6 alkylcarboxy-substituted CI-6 alkoxy, aryloxy, heterocyclyloxy, CI-6 alkylthio, C3-7 cycloalkyl (CI-6 alkylthio), C3-6 alkynylthio, CI-6 alkylcarbonylamino, C 16 17 2 22 13 14 haloalkylcarbonylamino, SO3H, NR R, C (O) NR21R22, S (0) 2NRR, S (0) 2ru5, R26C (O), carboxyl, Cl-6 alkoxycarbonyl, aryl and heterocyclyl ; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more
    of halogen, nitro, cyano, CI-6 alkyl, CI-6 haloalkyl, phenyl (CI-6 alkyl), CI-6 alkoxy, CI-6 haloalkoxy, S (0) (CI-6 alkyl), C (O) NH2, carboxy or CI-6 alkoxycarbonyl ; R', R', R', R", R", R'\ R", R, R", R", R R, R R"and R"are, independently hydrogen, CI-6 alkyl, CI-6 haloalkyl, CI-6 hydroxyalkyl, C3-7 cycloalkyl, C3 7 cycloalkyl (C alkyl) or phenyl (Cl 6 alkyl) ; and, R and R20 are, independently, C1-6 alkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, C3-7 cycloalkyl (CI-4 alkyl) or CI-6 alkyl optionally substituted by phenyl; R25 and R26 are, independently, C1-6 alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, phenyl (CI-6 alkyl), CI-6 alkoxy, CI-6 haloalkoxy, S (0) (C1-6 alkyl), C (O) NH2, carboxy or C1-6 alkoxycarbonyl) ; or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof; provided that when T is C (O) NR10 and RI is optionally substituted phenyl then n is not 0 ; and a histamine antagonist, a steroid, a leukotriene modulator, a human cytokine, a beta-agonist, a phosphodiesterase inhibitor or an antibody.
  2. 2. A pharmaceutical combination as claimed in claim 1, wherein Q is a sulphur atom or a group NH, C (O) or NHC (O).
  3. 3. A pharmaceutical combination as claimed in claim 1 or 2, wherein T represents a group NH, C (O) NH or NHC (O) NH.
  4. 4. A pharmaceutical combination as claimed in claim 1,2 or 3, wherein Xl, XI, X3 and X4 are all CH2.
  5. 5. A pharmaceutical combination as claimed in claim 1 wherein the compound of formula (I) is a compound of Example 1 to 416.
  6. 6. A pharmaceutical combination as claimed in any one of the preceding claims wherein:
    the histamine antagonist is loratidine, desloratidine, fexofenadine, cetirizine, ebastine, astemizole, norastemizole, epinastine or efletirizine ; the steroid is budesonide, fluticasone, mometasone or rofleponide; the leukotriene modulator is montelukast, pranlukast, zafirlukast, Z4407 or zafirlukast; the human cytokine is recombinant human IL-10 or IL-12; the beta-agonist is formoterol, salmeterol or salbutamol; the phosphodiesterase inhibitor is SB-207499 or theophylline; or, the antibody is an anti-IL-5 antibody or an anti-TNF-antibody.
  7. 7. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a histamine antagonist, a steroid, a leukotriene modulator, a human cytokine, a beta-agonist, a phosphodiesterase inhibitor or an antibody, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  8. 8. A pharmaceutical combination as claimed in any one of claims 1 to 6 for use in therapy.
  9. 9. A pharmaceutical combination as claimed in any one of claims 1 to 6 in the manufacture of a medicament for the treatment of asthma or rhinitis.
GB0104534A 2001-02-23 2001-02-23 Pharmaceutical combinations of a CCR3 antagonist and a compound which is usefulreatment of asthma, allergic disease or inflammation Withdrawn GB2373186A (en)

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