EP1907372A1 - Substituierte cyclohexylderivate als nk-3-rezeptorantagonisten - Google Patents

Substituierte cyclohexylderivate als nk-3-rezeptorantagonisten

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Publication number
EP1907372A1
EP1907372A1 EP06744364A EP06744364A EP1907372A1 EP 1907372 A1 EP1907372 A1 EP 1907372A1 EP 06744364 A EP06744364 A EP 06744364A EP 06744364 A EP06744364 A EP 06744364A EP 1907372 A1 EP1907372 A1 EP 1907372A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
optionally substituted
optionally
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06744364A
Other languages
English (en)
French (fr)
Inventor
Andrew Pate Terlings Park OWENS
Duncan Edward Shaw
Francine Sternfeld
Brian John Williams
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dirat Olivier
Elliott Jason Matthew
Organon Pharma UK Ltd
Original Assignee
Dirat Olivier
Elliott Jason Matthew
Merck Sharp and Dohme Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dirat Olivier, Elliott Jason Matthew, Merck Sharp and Dohme Ltd filed Critical Dirat Olivier
Publication of EP1907372A1 publication Critical patent/EP1907372A1/de
Withdrawn legal-status Critical Current

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to substituted cyclohexyl derivatives, pharmaceutical compositions comprising them and their use in treating diseases mediated by neurokinin-3 (NK-3) receptors. These compounds can thus be used in methods of treatment to suppress and treat such disorders.
  • NK-3 neurokinin-3
  • NK-3 receptor antagonists can be found in literature reviews such as Giardina and Raveglia, Exp. Opin. Ther. Patents (1997) 7(4): 307-323 and Giardina et ah, Exp. Opin. Ther. Patents (2000) 10(6): 939-960. These references also contain pertinent information on preclinical validation of therapies that can be treated with NK-3 antagonists. Representative examples of compounds prepared in the art as NK-3 antagonists are to be found in WO-A-9719926 (SmithKline Beecham S.p.a.) and US-A-5741910 (Sanofi).
  • cyclohexyl derivatives are known in the art.
  • published International applications WO 2004/031137 and WO 2004/031139 both Merck Sharp & Dohme Limited disclose cyclohexyl sulfones as gamma-secretase inhibitors useful in the treatment of Alzheimer's disease.
  • substituted cyclohexyl derivatives are useful as NK-3 antagonists and are thus useful in the treatment of diseases such as schizophrenia.
  • the present invention thus provides a compound of Formula (I):
  • rings A and B are independently aryl or heteroaryl; n is 0, 1 or 2;
  • X and Y are independently selected from a bond, -CH 2 -, and -N(Ci -4 alkyl)-; Z is a bond, -CH 2 - or R 1 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxy, Ci -6 alkoxy, halogen,
  • R 2 is hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or halogen
  • R 3 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxy, Ci -6 alkoxy, halogen or CN, optionally substituted by 1 to 8 halogen atoms
  • R 4 is hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or halogen;
  • R 5 and R 6 are independently selected from hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- scycloalkyl, hydroxy, Ci -6 alkoxy or halogen;
  • R 7 is hydrogen, Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3-8 cycloalkyl, (CH 2 ) 0 - 2 aryl, (CH 2 ) 0- 2 heteroaryl or Het, optionally substituted by 1 to 8 halogen atoms, hydrox or heteroaryl, which heteroaryl is optionally substituted by 1 to 3 groups selected from
  • R 8 is hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl; or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 4— to 7- membered heterocycle, optionally containing 1, 2 or 3 further heteroatoms selected from N, O and S, which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from d_ 6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl or C 3-8 CyClOaIlCyI, hydroxy, oxo, (CH 2 ) 0-3 Ci -6 alkoxy, (CH 2 )o_ 3 Oaryl, (CH 2 )o_ 3 aryl, (CH 2 )o_ 3 heteroaryl, (CH 2 ) 0-3 Het, or (CH 2 ) 0-3 NR a R b , wherein said aryl
  • R a is hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl, C(O)OCi -6 alkyl, C(O)NH(Ci -6 alkyl), (CH 2 ) 0-3 aryl, (CH 2 )o -3 heteroaryl or SO 2 Ci -6 alkyl, optionally substituted by Ci -6 alkyl;
  • R b is hydrogen, Ci -6 alkyl or aryl; and pharmaceutically acceptable salts thereof.
  • ring A is phenyl, pyridyl or pyrimidyl.
  • ring A is phenyl or pyridyl.
  • ring B is aryl or pyridyl.
  • ring B is phenyl.
  • n is 1 or 2.
  • n is 2.
  • X is a bond, -CH 2 - or Preferably, X is a bond or -
  • X is a bond.
  • Y is a bond, -CH 2 - or Preferably, Y is a bond or - CH 2 -. More preferably, Y is a bond.
  • Z is a bond or -CH 2 -.
  • Z is a bond.
  • R 1 is hydrogen, Ci -6 alkyl ; hydroxy, Ci -6 alkoxy, halogen, CN, CO 2 (Ci-
  • R 1 is hydrogen, Ci- 4 alkyl, Ci -4 alkoxy, halogen, CN, CO 2 CH 3 or C(CH 3 ) 2 OH, optionally substituted by 1 to 3 halogen atoms. More preferably, R 1 is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, CN, CO 2 CH 3 or C(CH 3 ) 2 OH.
  • R 2 is hydrogen or Ci -6 alkyl.
  • R 2 is hydrogen or methyl. More preferably, R 2 is hydrogen.
  • R 3 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms.
  • R 3 is hydrogen, Ci -4 alkyl, Ci -4 alkoxy, halogen or CN, optionally substituted by 1 to 3 halogen atoms. More preferably, R 3 is hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN.
  • R 4 is hydrogen or halogen.
  • R 4 is hydrogen, fluorine or chlorine.
  • R 5 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy, or halogen.
  • R 5 is hydrogen, methyl, hydroxy, methoxy or fluorine. More preferably, R 5 is hydrogen, hydroxy or fluorine. Most preferably, R 5 is hydrogen.
  • R 6 is hydrogen or Ci -6 alkyl.
  • R 6 is hydrogen or methyl. More preferably, R 6 is hydrogen.
  • R 7 is hydrogen, Ci -6 alkyl, (CH 2 )o- 2 aryl, or Het, optionally substituted by or heteroaryl, which heteroaryl is optionally substituted by 1 or 2 methyl or ethyl groups.
  • R 7 is hydrogen, benzyl or piperidinyl, optionally substituted by methoxy or pyrazolyl, which pyrazolyl is optionally substituted by 1 or 2 methyl or ethyl groups. More preferably, R 7 is hydrogen, A- methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl.
  • R 8 is hydrogen or Ci -6 alkyl.
  • R 8 is hydrogen or methyl. More preferably, R 8 is hydrogen.
  • R 7 and R 8 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycle, optionally containing 1 or 2 further heteroatoms selected from N and O, which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from oxo, CH 2 -O-phenyl, phenyl, heteroaryl, CH 2 heteroaryl, Het, NH 2 , (CH 2 ) 0- iNHR a or CH 2 N(phenyl)SO 2 CH 3 , where said aryl, heteroaryl, and Het are optionally substituted by 1, 2 or 3 groups selected from oxo or halogen, which Ci -4 alkyl being optionally substituted by hydroxy or 1 to 3 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5-or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted by Ci -4
  • R 7 and R 8 together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, piperazinyl or morpholinyl ring, which ring is optionally substituted by one or two groups selected from oxo, methyl, phenyl, CHr-O-phenyl, NH 2 ,
  • ring A is phenyl or pyridyl.
  • n is 1 or 2. More preferably, n is 2.
  • X is a bond or -CH 2 -. More preferably, X is a bond.
  • Y is a bond or -CH 2 -. More preferably, Y is a bond.
  • R 1 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy, halogen, CN, or C(CH 3 ) 2 OH, optionally substituted by 1 to 5 halogen atoms. More preferably, R 1 is hydrogen, Ci -4 alkyl, halogen, CN, CO 2 CH 3 or C(CH 3 ) 2 OH, optionally substituted by 1 to 3 halogen atoms. Most preferably, R 1 is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, CN, CO 2 CH 3 or C(CH 3 ) 2 OH.
  • R 3 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. More preferably, R 3 is hydrogen, Ci -4 alkyl, halogen or CN, optionally substituted by 1 to 3 halogen atoms. Most preferably, R 3 is hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN. Preferably, R 4 is hydrogen or halogen. More preferably, R 4 is hydrogen, fluorine or chlorine.
  • R 7 is hydrogen, benzyl or piperidinyl, optionally substituted by methoxy or pyrazolyl, which pyrazolyl is optionally substituted by 1 or 2 methyl or ethyl groups. More preferably, R 7 is hydrogen, 4-methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl. Preferably, R 8 is hydrogen.
  • R 7 and R 8 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycle, optionally containing one further heteroatom selected from N and O, which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from oxo, CHr-O-phenyl, phenyl, heteroaryl, CH 2 heteroaryl, Het, NH 2 , (CH 2 ) 0 -iNHR a or CH 2 N(phenyl)SO 2 CH 3 , where said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups selected from Ci -4 alkyl, oxo, halogen, which Ci -4 alkyl being optionally substituted by hydroxy or 1 to 3 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted
  • R 7 and R 8 together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperazinyl or morpholinyl ring, or an oxo-substituted piperazinyl ring further substituted on the nitrogen atom by thiazolyl, l-ethyl-3-methyl-l,2-pyrazol-5-yl, fluorophenyl or pyridyl, or a piperidinyl or dihydropyridinyl ring optionally substituted with one or two groups selected from methyl, phenyl, CH 2 -O-phenyl, NH 2 ,
  • R 1 and R 3 are as defined in relation to formula (I)
  • R 9 is (CH 2 )o- 3 NR a R b , where R a and R b are as defined in relation to formula (I), or (CH 2 )o- 3 heteroaryl or (CH 2 )o- 3 Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from Ci -6 alkyl, hydroxy, oxo, Ci -6 alkoxy or halogen, which Ci -6 alkyl being optionally substituted by hydroxy or 1 to 5 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains 1 or 2 heteroatoms selected from N and O, and which ring is optionally substituted by Ci -4 alkyl, hydroxy or
  • R 1 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy, halogen, CN, or C(CH 3 ) 2 OH, optionally substituted by 1 to 5 halogen atoms. More preferably, R 1 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy, chlorine, CN, CO 2 CH 3 or C(CH 3 ) 2 OH.
  • R 3 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. More preferably, R 3 is methyl, trifluoromethyl, trifluoromethoxy, CN, fluorine, chlorine or bromine.
  • R 9 is (CH 2 ) 0- iNR a R b , where R a and R b are as hereinbefore defined, or heteroaryl or Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from Ci -4 alkyl or oxo, which being optionally substituted by hydroxy or 1 to 3 fluorine atoms, and where said heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted by methoxy.
  • suitable R 9 groups include:
  • R 3 is as defined in relation to formula (I) and R 9 is as defined in relation to formula (Iaa).
  • R 3 is hydrogen, Ci -6 alkyl, hydroxy, Ci -6 alkoxy or halogen. More preferably, R 3 is hydrogen or halogen. Most preferably, R 3 is fluorine, chlorine or bromine.
  • R 9 is heteroaryl, optionally substituted by 1 or 2 groups independently selected from and where said heteroaryl is optionally fused to a 5- or 6-membered ring which optionally contains a nitrogen atom.
  • suitable R 9 groups include:
  • the present invention includes within its scope solvates of the compounds of formula (I), for example hydrates, and salts thereof.
  • the present invention also includes within its scope any enantiomers, diasteromers, geometric isomers and tautomers of the compounds of formula (I). It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the invention.
  • the term "Ci -6 alkyl” means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t- butyl, n- and isopropyl, ethyl and methyl.
  • C ⁇ alkyl shall be understood in an analogous manner, as shall “Ci -6 alkoxy” and “d -4 alkoxy”.
  • C 2-6 alkenyl means linear or branched chain alkenyl groups having from 2 to 6 carbon atoms and includes all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3- butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).
  • C 2 - 6 alkynyl means linear or branched chain alkynyl groups having from 2 to 6 carbon atoms and includes all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3- butynyl, 1-propynyl, 2-propynyl, and ethynyl (or acetylenyl).
  • C 3-8 cycloalkyl means a cyclic alkane ring having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • aryl refers to phenyl and naphthyl.
  • heteroaryl as used herein is intended to include the following groups: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and pyrrolidinyl.
  • Het means a heteroaliphatic ring of 3 to 7 ring atoms, which ring contains 1, 2 or 3 heteroatoms selected from N, O or S or a group S(O), S(O) 2 , NH or Examples of Het include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, pyran, dioxanyl, morpholine, oxathiolanyl, dithianyl, oxathianyl, thiomorpholinyl, trioxanyl, trithianyl.
  • thiophenyl and "thienyl” have the same meaning herein and are used interchangeably. Similarly, the following pair of terms has the same meaning: “pyridinyl” and “pyridyl”. Exemplary compounds of the present invention include those listed in the Examples section hereinbelow and their pharmaceutically acceptable salts.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate
  • pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N 5 N 1 - dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N 5 N 1 - dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(
  • a free acid by reacting a free acid with a suitable organic or inorganic base.
  • a suitable organic or inorganic base such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions and methods of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of treatment of a subject suffering from a neurokinin-3 mediated disease which comprises administering to that patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Examples of diseases mediated by neurokinin-3 include CNS disorders such as depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g.
  • a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (including generalised anxiety disorder (GAD), social anxiety disorder (SAD), agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); phobias (including agoraphobia and social phobia); psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform- diseases, acute psychosis, alcohol psychosis, autism, delirium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases
  • cognitivo disorders including attention, orientation, memory (memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states)); convulsive disorders such as epilepsy (which includes simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures); psychosexual dysfunction (including inhibited sexual desire (low libido), inhibited sexual arousal or excitement, orgasm dysfunction, inhibited female orgasm and inhibited male orgasm, hypoactive sexual desire disorder (HSDD), female sexual desire disorder (FSDD), and sexual dysfunction side-effects induced by treatment with antidepressants of the SSRI-class); sleep disorders (
  • Parkinsonism and tardive dyskinesias neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities (such as abuse of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative, hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof); pain (which includes neuropathic pain (including diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; pain associated with fibromyalgia or cancer; AIDS-related and HlV-related neuropathy; chemotherapy- induced neuropathy; neuralgia, such as post-herpetic neuralg
  • musculoskeletal pain, post operative pain and surgical pain inflammatory pain and chronic pain, pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased, sensitivity, to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia), pain associated with migraine, and non-cardiac chest pain); certain CNS-mediated disorders such as emesis, irritable bowel syndrome, and non-ulcer dyspepsia; COPD, asthma, cough, gastro-oesophageal reflex induced cough, and exacerbated asthma; urinary incontinence; hypertension; and conditions associated with platelet hyperaggregability such as tissue ulceration, nephrotic syndrome, diabetes, migraine, coronary artery disease, pre-
  • the compounds of the invention are useful for the treatment of depression; anxiety disorders; phobias; psychosis and psychotic disorders; posttraumatic stress disorder; attention deficit hyperactive disorder (ADHD); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities; and irritable bowel syndrome. More preferably, the compounds of the invention are useful for the treatment of depression; anxiety disorders; phobias; and psychosis and psychotic disorders (especially schizophrenia, schizoaffective disorder, and schizophreniform diseases. Most preferably, the compounds of the invention are useful for the treatment of schizophrenia.
  • the compounds for use in the present invention are generally active in the following tests. They normally have an IC 50 of less than l ⁇ M and preferably less than 10OnM.
  • NK-3 receptor and its heterologous expression can be found in Huang et ah, BBRC, 1992, 184: 966-972 and Sadowski et ah, Neuropeptides, 1993, 24: 317-319.
  • a membrane preparation is prepared as follows.
  • a 10-layer cell factory is seeded with CHO cells stably expressing NK-3 receptors.
  • the CHO cells are prepared in a triple T 175 flask in 11 growth medium which contains Iscore's modified Dulbecco's medium containing lOml/120OmM L-Glutamine, lOml/1 penicillin-streptomycin, one vial of hypoxanthine-thymidine 500x/l, lmg/ml geneticin and 10% fetal bovine serum (inactivated).
  • the cells are grown for 3 days in an incubator.
  • the medium is washed off and the factory is rinsed twice with 400ml PBS (Ca, Mg-free). 400ml enzyme free dissoc.
  • EFDS EFDS solution
  • the supernatants are aspirated and the residual cell pellets are frozen at -80° for 30 min to improve cell lysis and then resuspended in 40ml Tris with inhibitors per cell factory.
  • the cells are homogenized in 40ml aliquots with 8 strokes of a glass-teflon grinder at setting 40.
  • the homogenate is transferred to 50ml centrifuge tubes and placed on a rocker for 15 min at r.t.
  • the homogenate is rehomogenised and held on ice if necessary before being centrifuged again as above.
  • the supernatant is transferred to Sorvall tubes for an SS-34 roter and held on ice.
  • a Storage Buffer consisting of 2.50ml IM Tris pH7.4, 50 ⁇ l 100Ox protease inhibitors (4mg/ml leupeptin (Sigmo), 40mg/ml Bacitracin (Sigma) and 1OmM phosphoranidon (Peninsula) all dissolved in water) plus 0.5ml 0.5M MnCl 2 made up to 50ml with H 2 O d ⁇ j.
  • a 10ml syringe is used with 20-, 23- and 25-gauge needles sequentially.
  • a Bradford protein assay in conducted on 2-10 ⁇ l aliquots with BSA as standard before 500- lOOO ⁇ l aliquots are snap-frozen in liquid nitrogen for storage at -8O 0 C.
  • the membrane binding assay is carried out as follows. The amount of membranes needed to specifically bind ⁇ 10% of 125 I-NeurokinB is predetermined. The frozen stocks are then diluted to allow addition in 50 ⁇ l.
  • test compounds are dissolved in DMSO.
  • An automated apparatus (Tecan) is programmed to add 5 ⁇ l of compound or DMSO, approximately 100,000 cpm of isotope in 20 ⁇ l buffer which is prepared from 50 ⁇ MTris, pH7.5, 150 ⁇ M NaCl, bovine serum albumin to 0.02%, and protease inhibitors as in the storage buffer, made up as 0.5M stock, and 175 ⁇ l assay buffer (as the storage buffer but containing 5 ⁇ M MnCl 2 and without NaCl) into deep well Marsh boxes (Marsh Biomedical Products) in a 96-well format. Excess unlabelled competing peptide is added by hand for non-specific binding as indicated below. The binding reaction is initiated by adding 50 ⁇ l of cell membranes.
  • Tomtec Mach III filtermats
  • Unifilter GF/C Unifilter GF/C
  • IX wash buffer O.lM.Tris, pH7.4 and
  • lO ⁇ g of membrane is used at 25,000 cpm which is filtered over a Unifilter GF/C presoaked in 0.5% BSA.
  • compounds of formula (I) where Z is a bond may be prepared by the reaction of a compound of formula (II) with a compound of formula (III):
  • a compound of formula (I) where R 4 is bromine may be transformed into a compound of formula (I) where R 4 is hydrogen by hydrogenation using, for example, a palladium on carbon catalyst and hydrogen gas, in a suitable solvent, such as ethyl acetate.
  • a compound of formula (I) where R 7 is methoxybenzyl may be transformed into a compound of formula (I) where R 7 is hydrogen by treatment with eerie ammonium nitrate in a suitable solvent system such as acetonitrile/water.
  • the resultant compound of formula (I) may be transformed into a different compound of formula (I) by reaction with, for example, a substituted piperidinone in the presence of a hydride source such as sodium triacetoxyborohydride, and acid, such as acetic acid, in a suitable solvent, such as 1,2-dichloroethane.
  • a compound of formula (Iaa) where R 9 is a BOC-protected amine may be transformed to a compound of formula (Iaa) where R 9 is an amine by treatment with acid, such as hydrochloric acid, in a suitable solvent, such as 1,4-dioxane.
  • acid such as hydrochloric acid
  • suitable solvent such as 1,4-dioxane.
  • the resultant compound of formula (Iaa) may be transformed into a compound of formula (Iaa) whereR 9 is a urea derivative by reaction with an alkyl isocyanate in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane.
  • Reagents i) Et 3 N, CH 2 Cl 2 ; ⁇ ) mCPBA, CH 2 Cl 2 ; iii) 2,2-bis(2-iodoethyl)-l,3-dioxolane, NaH, DMF; iv)pTsOH, AcOH, H 2 O, 50 °C; v) R 7 R 8 NH, NaBH(OAc) 3 , AcOH, 1,2-dichloroethane; vi) separate isomers
  • Reagents i) MeMgBr, THF, -78 ° C.
  • Reagents i) l,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate, CsF, DMF, 60 0 C; ii) mCPBA, CH 2 Cl 2 ; iii) nBuLi, THF; iv)/?TsOH, AcOH, H 2 O, 50 °C.
  • Reagents i) BF 3 OEt 2 , CH 2 Cl 2 ; U) ⁇ TsOH, AcOH, H 2 O, 50 °C; iii) NaIO 4 , MeOH, H 2 O.
  • Reagents i) MeSO 2 Cl, Et 3 N, CH 2 Cl 2 ; ii), Et 3 N, DMF, 80 0 C; iii) mCPBA, CH 2 Cl 2 ; ⁇ OpTsOH, AcOH, H 2 O, 50 °C.
  • e ring C aryl, heteroaryl Reagents: i) haloacetyl chloride, ii) ethanolamine, iii) di-tert-butyl azodicarboxylate, nBu 3 P, EtOAc.
  • Cesium fluoride (10.2 g, 67.7 mmol) was heated to 180 0 C under vacuum for 2 h, cooled to RT, placed under a N 2 atmosphere and 4-(trifluoromethyl)benzenethiol (5.2 g, 29.2 mmol), l,4-dioxa-spiro[4.5]dec- 8-yl methanesulfonate (J. Med. Chem. 1992, 55, 2243.) (5.3 g, 22.5 mmol) and DMF (44 mL) were added. The mixture was heated to 60 0 C for 3 h, cooled and water and EtOAc were added.
  • Trimethylsilyldiazomethane (2.0M in hexane, 147 mL, 0.29 mol) was added over 30 min. via an addition funnel to a stirred, cooled (0 C) solution of l-(l,l-dimethylethyl) 1,4-piperidinedicarboxylate (45.0 g, 0.20 mol) in CH 2 Cl 2 /Me0H (3:1. 1200 mL). The solvent was evaporated under reduced pressure to give the title compound (47 g) as a light yellow oil. This was used directly in the next step without further purification.
  • Trimethylsilyldiazomethane (2.0M in hexane, 53 mL, 0.11 mol) was added to a stirred, cooled (0 0 C) solution of l-[(l,l-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-piperidinebutanoic acid
  • Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexanes, 47 mL, 0.070 mol,) was added to a stirred, cooled (-78 0 C) solution of methyl l-[(l,l-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4- piperidinebutanoate (Description 50, 20.1 g, 0.058 mol) in THF (600 mL).
  • Pulverized lithium hydroxide (26 g, 1.10 mol) was added to a solution of (&S)-8-(l,l-dimethylethyl) 2- methyl l-oxo-8-azaspiro[4.5]decane-2,8-dicarboxylate (Description 51, 17.2 g, 0.055 mol) in ethanol/THF/water (2:2:1, 555 mL) and the mixture was stirred at 90 0 C for 60 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with CH 2 Cl 2 (3x). The combined organic fractions were washed with brine, dried (Na 2 SO 4 ), filtered, and the solvent was evaporated under reduced pressure.
  • 1,1-Dimethylethyl l-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 52, 4.5 g, 17.8 mmol) was dried by adding and evaporating toluene (3 x 10 mL) under reduced pressure, dissolved in THF (100 mL) and cooled to -78 0 C. Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 24 mL, 36 mmol,) was added and the mixture was stirred at -78 0 C for 30 min.
  • Acetyl chloride (1.17 mL, 16.4 mmol) was added to a stirred, cooled (0 0 C) solution of 1,1-dimethylethyl l,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(lH),4'-piperidine]-l '-carboxylate trifluoroacetate (Description 55, 0.547 g, 1.64 mmol) in MeOH (16 mL). The mixture was allowed to warm to RT and stirred for 60 h. The solvent was evaporated under reduced pressure to give the title compound.
  • Carbonyldiimidazole (39.4 g, 243 mmol) was added in portions to a stirred solution of 1 -(1,1- dimethylethyl) 4-piperidinedicarboxylate (42.5 g, 187 mmol) in CH 2 Cl 2 (550 mL) and the mixture was stirred at 4 0 C overnight.
  • the mixture was poured into Et 2 O (2 L) and ice water (2 L), the layers were separated and the organic layer was washed with cold aqueous NaHCO 3 (saturated, 500 mL) and brine (500 mL), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (52 g).
  • Description 63 4-(2-Ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine Prepared from 1,1 -dimethylethyl 4-[(2-oxocyclopentyl)carbonyl]-l-piperidinecarboxylate (Description 62) according to the methods of Descriptions 59 and 60, substituting ethyl hydrazine oxalate for t-butyl hydrazine hydrochloride.
  • Trifluoroacetic acid (2 mL) was added dropwise to a solution of 1,1-dimethylethyl l,2-dihydro-l-(l- methylethyl)-2-oxospiro[3H-indole-3,4'-piperidine]-r-carboxylate (Description 68) in CH 2 Cl 2 (20 mL) and the mixture was stirred at RT for 4 h. The solvent was evaporated under reduced pressure to give the title compound as a tan solid (2.35 g).
  • 1,1-Dimethylethyl 4-amino-l-piperidinecarboxylate (10.01 g, 50 mmol) and triethylamine (34.85 mL, 25.3 g, 250 mmol) were added to a solution of 2-chloro-6-methoxy-5-nitropyridine (9.43 g, 50 mmol) in DMSO (100 mL) and the mixture was stirred at 100 0 C for 12 h. The mixture was cooled and added dropwise to water (1200 mL). The mixture was stirred at RT for 12 h, then the solid was collected, washed with water and dried in vacuo to give the title compound as a yellow powder (16.70 g, 95%).
  • Acetic acid (20 mL) and hydrazine hydrate (136 mL (140 g, 2.8 mol) were added to a solution of (3RS)- ethyl l-(phenylmethyl)-3-piperidinecarboxylate (Description 72, 270 g, 1.092 mol) in ethanol (310 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled and the solvent was partly evaporated under reduced pressure until a precipitation occurred. The solid was collected, aqueous KOH (50 g in 100 mL) was added and the mixture was extracted with CHCl 3 (2 x 300 mL).
  • Example 122 rr ⁇ ns-l- ⁇ 4-Phenylmethyl-4-[4-(trifluoromethyl)benzenesulfonyl] cyclohexyl]-4-(2- ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
  • Ceric ammonium nitrate (232 mg, 0.423 mmol) was added to a stirred suspension of N-[trans-4-(4- bromophenyl)-4- ⁇ [4-(trifluoromethyl)phenyl] sulfonyl ⁇ cyclohexyl] -4-(methoxy)benzenemethanamine (Example 69, 99 mg, 0.17 mmol) in MeCN (1.0 ml) and water (0.35 ml) at RT. The mixture was stirred overnight and a further portion of ceric ammonium nitrate (29 mg, 0.053 mmol) was added. After stirring at RT for a further 1 h, the mixture was diluted with EtOAc and water.
  • Example 123 The following compound was prepared according to the method of Example 1 substituting trans A-(A- bromophenyl)-4- ⁇ [4-(trifluoromethyl)phenyl]sulfonyl ⁇ cyclohexanamine (Example 123) for 4-(4- bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone and l-(l-ethyl-3-methyl-lH-pyrazol-5-yl)-4- piperidinone (Description 93) for 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine.
  • Example 125 l-(7r ⁇ ns-4-(4-Chloropheiiyl)-4- ⁇ [4- (trifluoromcthyl)phcnyl]sulfonyl ⁇ cyclohcxyl)pipcridin-4-aminc Hydrochloride
  • Example 126 N-(l,l-Dimethylethyl)-N'-[l-(rrans-4-(4-chlorophenyl)-4- ⁇ [4- (trifluoromcthyl)phcnyl]sulfonyl ⁇ cyclohcxyl)pipcridin-4-yl]urca t-Butyl isocyanate (0.0255 mL, 0.224 mmol) was added to a stirred solution of l-(trans-4-(4- chlorophenyl)-4- ⁇ [4-(trifluoromethyl)phenyl] sulfonyl ⁇ cyclohexyl) piperidin-4-amine hydrochloride (Example 125, 0.1 g, 0.186 mmol) and triethylamine (0.077 mL, 0.558 mmol) in CH 2 Cl 2 (5 mL) and the mixture was stirred at RT for 2 h.

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US8394858B2 (en) 2009-12-03 2013-03-12 Novartis Ag Cyclohexane derivatives and uses thereof
WO2011143057A1 (en) 2010-05-11 2011-11-17 Merck Sharp & Dohme Corp. Novel prolylcarboxypeptidase inhibitors
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US9771320B2 (en) * 2014-01-06 2017-09-26 Bristol-Myers Squibb Company Carbocyclic sulfone RORγ modulators
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CN109608411A (zh) * 2018-12-17 2019-04-12 上海合全药物研发有限公司 一种叔丁基-1-氧亚基-6-氧杂-9-氮杂螺[4.5]癸烷-9-甲酸基酯的制法

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